Stereoselective Coupling of N-tert-Butanesulfinyl Aldimines and β-Keto Acids: Access to β-Amino Ketones

Article abstract of DOI:10.1021/acs.joc.7b01178

The reaction of chiral N-tert-butanesulfinyl aldimines with β-keto acids under basic conditions at room temperature proceeds with high levels of diastereocontrol, leading to β-amino ketones in high yields. Based on DFT calculations, an eight-membered cyclic transition state involving coordination of the lithium atom to the oxygens of carboxylate and sulfinyl units was proposed, being in agreement with the observed experimental diastereomeric ratios. The synthesis of the piperidine alkaloid (-)-pelletierine was successfully undertaken in order to demonstrate the utility of this methodology.

Full text of DOI:10.1021/acs.joc.7b01178

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Article
Stereoselective Coupling of N-tert-Butanesulfinyl
Aldimines and #-Keto Acids: Access to #-Amino Ketones
Alejandro Lahosa, Tatiana Soler, Ana Arrieta, Fernando P. Cossio, Francisco Foubelo, and Miguel Yus
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01178 • Publication Date (Web): 29 Jun 2017
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Stereoselective Coupling of NꢀtertꢀButanesulfinyl Aldimines and βꢀ
Keto Acids: Access to βꢀAmino Ketones
Alejandro Lahosa,a,b Tatiana Soler,c Ana Arrieta,d Fernando P. Cossío,d* Francisco Foubeloa,b*
and Miguel Yusa*
a Departamento de Química Orgánica, Facultad de Ciencias, and Centro de Innovación en Química
Avanzada (ORFEOꢀCINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
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b Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
c Servicios Técnicos de Investigación, Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
d Departamento de Quımica Organica I and Centro de Innovación en Química Avanzada (ORFEO
CINQA), University of the Basque Country (UPV/EHU), Pº Manuel Lardizabal 3, 20018
Donostia/San Sebastian, Spain.
fp.cossio@ehu.es, foubelo@ua.es, yus@ua.es
ABSTRACT. The reaction of chiral Nꢀtertꢀbutanesulfinyl aldimines with βꢀketo acids under basic
conditions at room temperature proceeds with high levels of diastereocontrol, leading to βꢀamino
ketones in high yields. Based on DFT calculations, an eightꢀmembered cyclic transition state
involving coordination of the lithium atom to the oxygens of carboxylate and sulfinyl units was
proposed, being in agreement with the observed experimental diastereomeric ratios. The synthesis
of the piperidine alkaloid (–)ꢀpelletierine was successfully undertaken in order to demonstrate the
utility of this methodology.
KEYWORDS. Chiral sulfinyl imines, βꢀketo acids, βꢀamino ketones, diastereoselective Mannich
reaction, DFT calculations.
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INTRODUCTION
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Coupling of enolizable carbonyl compounds with imines, the soꢀcalled Mannich reaction, render βꢀ
amino carbonyl compounds.1 These are interesting molecular systems because they can be
converted into polyfunctionalized molecules and act as versatile buildingꢀblocks.2 Highly efficient
methodologies to perform the stereoselective version of these transformations have been developed
in recent years by means of chiral organic and organometallic catalytic systems.3 The
stereoselective Mannich reactions are also performed with stoichiometric amounts of chiral
reagents. In these reactions, the stereochemical information could be provided by a chiral imine,4 in
which most commonly a chiral auxiliary is a substituent of the iminic nitrogen, or by a chiral
nucleophile derived from aldehydes, ketones, esters or enol ethers.5 Among chiral imines, those
derived from tertꢀbutanesulfinamide have been extensively used as electrophiles over the past
decade in many synthetic transformations,6 due mainly to the ready availability of both enantiomers
of tertꢀbutanesulfinamide at reasonable prices, the easy deprotection of the resulting amine under
mild acidic conditions and the possibility of recycling the chiral auxiliary.7 Davis reported the
synthesis of βꢀamino carbonyl compounds in a twoꢀstep process by reaction of the corresponding
sulfinyl imine (both, pꢀtoluene and tertꢀbutane derivatives) with the potassium enolate of Nꢀ
methoxy Nꢀmethylacetamide at low temperature, and subsequent addition of an organometallic
reagent to the resulting βꢀamino Weinreb amide.8 The same reaction products were also obtained by
direct addition of the corresponding methyl ketone enolate to the sulfinyl imine at low temperature
(Scheme 1A).9 Enolates of methyl ketones should be prepared with stoichiometric amounts of
strong bases at low temperature in order to avoid autocondensation, that representing a limitation of
this methodology. On the other hand, βꢀketo acids have been used as surrogate enolates in different
processes,10 among then decarboxylative Mannichꢀreactions by reacting with different imines.
Considering these transformations, as far as we know, there are only two examples of nucleophilic
additions of βꢀketo acids to activated Nꢀtertꢀbutanesulfinyl imines: the La(OTf)3 catalyzed addition
to Nꢀtertꢀbutanesulfinyl αꢀimino esters (Scheme 1B)11 and the nickel catalyzed addition to a
trifluoroacetaldehyde derivative (Scheme 1C).12 Based on our experience on nucleophilic additions
to Nꢀtertꢀbutanesulfinyl imines of homochiral enolates resulting from the diastereoselective addition
of dialkylzinc reagents to cyclic α,βꢀunsaturated enones (Scheme 1D)13 and of diethyl malonate
under basis conditions,14 we herein report our approach to the stereoselective synthesis of βꢀamino
carbonyl compound derivatives from dicarbonyl compounds as pronucleophiles.
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Scheme 1. Examples of Nꢀtertꢀbutanosulfinyl imines in Mannichꢀtype reactions.
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RESULTS AND DISCUSSION
The coupling of the Nꢀtertꢀbutanesulfinyl imine derived from 3ꢀphenylpropanal 1a and different
acetoacetate esters 2 under basic conditions was first studied. The applied reaction conditions were
identical to those we found to work well in the case of this type of imines and dimethyl malonate.14
The expected compounds 3 were obtained in variable yields, the nucleophilic addition taking place
in an almost total diastereoselective fashion. With regard to the second stereogenic center, an
equimolecular amount of both possible epimers was obtained, due to the presence of an acidic
proton at that center, so epimerization occurs very fast under the basic reaction conditions (Scheme
2). Unfortunately, all the attempts to carry out the decarboxylation of compounds 3 in order to
produce a βꢀamino carbonyl compound lead to a complex mixture of reaction products. For
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instance, α,βꢀunsaturated compounds 4 and 5 were the major components of these mixtures when
the tertꢀbutyl ester derivative 3b was the starting material (Scheme 2).
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Scheme 2. Baseꢀpromoted coupling of sulfinyl imine 1a and different acetoacetate esters 2.
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S
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S
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t-Bu
Ph
NH
O
N
t-Bu
NaHCO3 (2 equiv)
72 h, 23 ºC
O
O
Me
R
+
R
Ph
H
Me
O
O
O
1a
2 (4 equiv)
3a (R = Et, 58%)
3b (R = t-Bu, 57%)
3c (R = Bn, 34%)
O
O
Ph
Me
t-Bu
Ph
Me
O
O
4
5
Considering the previously commented results and that βꢀketo acids have been successfully used as
surrogate enolates,10 we decided to study the decarboxylative Mannichꢀreaction using these
compounds. For that reason, we took the imine derived from (R)ꢀtertꢀbutanesulfinamide and 3ꢀ
phenylpropanal 1a, along with the most challenging acetyl acetic acid (6a) among βꢀketo acids, as
model compounds for the optimization of the reaction conditions. It is worth to mention that acetyl
acetic acid (6a) is especially unstable and undergoes decarboxylation very easily at room
temperature, and this could be the reason why it has not been used in the reactions with Nꢀtertꢀ
butanesulfinyl αꢀimino esters (Scheme 1B)11 and the trifluoroacetaldehyde derivative (Scheme
1C).12 Although many assays were undertaken, only the most significant ones are compiled in Table
1. Thus, the reaction of imine 1a with 3 equivalents of keto acid 6a at room temperature for 12
hours under solventꢀfree conditions led to an almost 1:5 mixture of both expected diastereoisomers
7a and 8a. Unfortunately, starting imine 1a was not consumed completely in spite of working with
an excess of keto acid 6a, and a significant amount of tertꢀbutanesulfinamide was also formed,
presumably through a βꢀelimination process from the expected Mannich adducts 7a and 8a (Table
1, entry 1). Decomposition by decarboxylation at room temperature of 6a could explain that the
reaction did not go to completion after 12 hours. Compounds 7a and 8a were not found working in
a THF solution with the same reaction mixture (Table 1, entry 2) and low conversion was also
observed in ethyl acetate in the presence of 1.5 equivalents of sodium bicarbonate (Table 1, entry
3). When the reaction was carried out in the presence of a stronger base such as potassium tertꢀ
butoxide, total conversion occurred and tertꢀbutanesulfinamide was found to be the only reaction
product that we could identified from the crude reaction mixture (Table 1, entry 4). The reaction did
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not proceed in methanol with 3 equivalents of triethylamine (Table 1, entry 5), but total conversion
occurred when 6 equivalents of sodium methoxide in methanol were used. Importantly, βꢀamino
ketone derivatives 7a (48%) and 8a (29%) were now the major reaction products, and by contrary
to what we found in the previous entries, the one resulting from the nucleophilic attack to the Siꢀ
face of imine 7a is now predominant (Table 1, entry 6). Deprotonation of keto acid 6a with strong
bases prevents its decomposition. The diastereoselectivity was highly improved when keto acid 6a
was deprotonated first with nꢀBuLi in dry THF at low temperature and after that, the resulting
system reacted with the imine 1a at room temperature (Table 1, entry 7). However, no reaction took
place when lithium hydroxide was used as a base in THF (Table 1, entry 8). The reaction working
with 6 equivalents of a 2M lithium hydroxide solution in methanol led to total conversion but also
to a lower diastereoselectivity (Table 1, entry 9). The diastereoselectivity was improved again when
imine 1a reacted for 12 h at room temperature with a solution of 1.5 equivalents of keto acid 6a in
THF and 1.5 equivalents of a 2M lithium hydroxide methanol solution. However, almost half of the
starting imine 1a remained unreactive (Table 1, entry 10). The best result was obtained working in
THF at room temperature with 1.5 equivalents of keto acid 6a and 2.0 equivalents of lithium
hydroxide from a 2M solution in methanol. After just 30 minutes, compound 7a was produced in a
highly diastereoselective fashion (97:3 dr) in quantitative yields (Table 1, entry 13). When the
deprotonation step was performed with a 1M THF solution of lithium ethoxide, the results were
rather similar but in a slightly lower diastereoselectivity (Table 1, entry 14). Finally, lithium
hydroxide in methanol seemed to be superior to sodium methoxide in methanol in the deprotonation
step of keto acid 6a (Table 1, compare entries 11 and 12), and prolonged reaction times are not
beneficial for this reaction, since yield and diastereoselectivity were higher after 30 minutes than
after 16 hours (Table 1, compare entries 12 and 13).
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Table 1. Optimization of the reaction of imine 1a and βꢀketo acid 6a
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a
Entry
1
Reaction conditions
1a/7a/8a/tꢀBuSONH2
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1a (0.2 mmol), 6a (0.6 mmol), 23 ºC, 12 h
31/6/33/30
2
1a (0.2 mmol), 6a (0.6 mmol), THF (0.2 mL), 23 ºC, 12 h
77/ꢀꢀ/ꢀꢀ/23
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1a (0.2 mmol), 6a (0.6 mmol), NaHCO3 (0.3 mmol), AcOEt (1 mL), 23 ºC, 12 h
1a (0.2 mmol), 6a (0.6 mmol), KOtꢀBu (0.3 mmol), THF (0.4 mL), 23 ºC, 12 h
1a (0.2 mmol), 6a (0.6 mmol), Et3N (0.6 mmol), MeOH (0.2 mL), 23 ºC, 12 h
1a (0.2 mmol), 6a (0.6 mmol), NaOMe/MeOH (2M, 1.2 mmol), 0 to 23 ºC, 12 h
79/3/5/13
ꢀꢀ/ꢀꢀ/ꢀꢀ/100
100/ꢀꢀ/ꢀꢀ/ꢀꢀ
ꢀꢀ/48/29/23
1) 6a (0.4 mmol), nꢀBuLi (2M, 0.6 mmol), THF (2 mL), ꢀ78 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 12 h
7
11/84/5/ꢀꢀ
1) 6a (0.3 mmol), LiOH (0.3 mmol), THF (2 mL), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 12 h
8
9
100/ꢀꢀ/ꢀꢀ/ꢀꢀ
ꢀꢀ/44/34/22
45/53/2/ꢀꢀ
1a (0.2 mmol), 6a (0.6 mmol), LiOH/MeOH (2M, 1.2 mmol), 0 to 23 ºC, 16 h
1) 6a (0.3 mmol), LiOH/MeOH (2M, 0.3 mmol), THF (2 mL), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 12 h
10
1) 6a (0.3 mmol), NaOMe/MeOH (2M, 0.4 mmol), THF (2 mL), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 16 h
11
12
13
14
ꢀꢀ/45/10/45
10/58/9/23
ꢀꢀ/97/3/ꢀꢀ
1) 6a (0.3 mmol), LiOH/MeOH (2M, 0.45 mmol), THF (2 mL), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 16 h
1) 6a (0.3 mmol), LiOH/MeOH (2M, 0.4 mmol), THF (2 mL), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 0.5 h
1) 6a (0.3 mmol), LiOEt/THF (1M, 0.4 mmol), 0 to 23 ºC
2) 1a (0.2 mmol), 23 ºC, 0.5 h
ꢀꢀ/95/5/ꢀꢀ
a Reaction products ratio was determined by 1HꢀNMR analysis of the crude reaction mixtures.
We studied next the scope of the reaction of Nꢀtertꢀbutanesulfinyl imines 1 with different βꢀketo
acids 6, by applying the optimized conditions shown in Table 1, entry 13. Two different sets of
reaction times were applied, depending of the type of imine 1: the reaction time was 1 hour for
aliphatic imines (although most of the reactions were over after 30 minutes) and 5 hours in the case
of the sterically hindered imine derived from isobutyraldehyde and also for aromatic imines (Table
2). The expected βꢀamino ketone derivatives 7 were obtained in high yields (quantitative yields in
most of the cases) with excellent diastereoselectivities (trace amounts of minor diastereoisomers 8
were detected but not isolated). The reaction was also performed on a gramꢀscale for the imine
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derived from decanal 1c (4.0 mmol) and βꢀketo acid 6a, giving rise to amino ketone derivative 7c in
82% isolated yield (Table 2). The poorest yields were found working with the βꢀketo acid 6d (R2 =
tꢀBu), with values ranging from 80 to 94% (Table 2, compounds 7qꢀt). The configuration of the
newly created stereogenic centre in compounds 7 was primary assigned by comparing the specific
rotation and the NMR data of 7g with those provided in the literature for its enantiomer,8b and later
confirmed by crystal Xꢀray analysis (see the Supporting Information) of the solid compounds 7h15
and 7u.16 We assume that the nucleophilic attack took always place to the Siꢀface of the imines with
RS configuration in compounds 7 (Table 2).
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Table 2. Scope of the Mannichꢀtype coupling of imines 1 and keto acids 6a
O
S
O
O
1) LiOH/MeOH (2M, 0.5 mmol), THF, 0 to 23 ºC
t-Bu
NH
O
HO
R2
O
S
R1
R2
(0.4 mmol)
6a (R2 = Me)
6b (R2 = Et)
6c (R2 = i-Pr)
6d (R2 = t-Bu)
6e (R2 = Ph)
7
N
t-Bu
2)
, (0.2 mmol), 23 ºC, 1 h
R1
H
1a [R1 = Ph(CH2)2], 1b [R1 = CH3(CH2)7]
1c [R1 = CH3(CH2)8], 1d [R1 = i-Pr], 1e [R1 = i-PrCH2]
1f
[R1 = Br(CH ) ],
1g
[R1 = Ph],
1h
[R1 = 4-BrC H ]
2 4
6 4
a
Reactions were carried out starting from 0.2 mmol of the corresponding imine 1. Isolated yields after column
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chromatography purification are given in parenthesis. This reaction was carried out starting from 4.0 mmol of the
imine derived from decanal 1c. c Reaction time: 5 h.
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Unfortunately, the coupling reactions did not worked well with βꢀketo acids bearing substituents at
2ꢀposition. For instance, the reaction of imine 1a with 2ꢀmethylꢀ3ꢀoxobutanoic acid (6f) under the
optimized reaction conditions led after 5 hours to the expected compound 7y, which was isolated as
mixture of epimers in 22% yield (Scheme 3).
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Scheme 3. Reaction of sulfinyl imine 1a with 2ꢀmethylꢀ3ꢀoxobutanoic acid (6f).
Enantiomerically pure βꢀamino ketone derivatives are interesting building blocks in the synthesis of
alkaloids and other compounds with potential biological activity. The utility of the here presented
methodology is demonstrated in the straightforward synthesis of piperidine alkaloid (–)ꢀpelletierine,
using 3ꢀoxobutanoic acid (6a) and the Nꢀtertꢀbutanesulfinyl imine derived from 4ꢀbromopentanal
(1f)17 as starting materials. Thus, the baseꢀpromoted decarboxylativeꢀMannich coupling of these
reagents led to βꢀamino ketone derivative 7f, which was not isolated and treated with a 6M
hydrochloric acid solution at 0 ºC for 4.5 hours. The resulting acidic aqueous phase containing the
ammonium salt was basified to produce the free amine and further extracted with dichloromethane.
To the new organic phase was added a saturated aqueous sodium bicarbonate solution, and the
reaction mixture was vigorously stirred at room temperature overnight. Combined GC/MS showed
the formation of (–)ꢀpelletierine, which was finally isolated as its hydrochloride derivative (see
Supporting Information for NMR spectra of the crude material) upon addition of a solution of
hydrogen chloride in diethyl ether solution and further removal of volatile solvents, in 66% overall
yield. All these transformations were easily followed by TLC and no column chromatography
purification was necessary at any moment (Scheme 4).
Scheme 4. Synthesis of (ꢀ)ꢀpelletierine from sulfinyl imine 1e and 3ꢀoxobutanoic acid (6a).
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We performed densityꢀfunctional theory (DFT) calculations in order to understand the origins of the
stereocontrol of this reaction, as well as the features of each elementary step associated with the
Mannichꢀlike/decarboxylation sequence. We focused our calculations on a model reaction in the
presence of lithium hydroxide and tetrahydrofuran as solvent, and took imine 1i as the model (E)ꢀ
imine (Scheme 5). After reaction with 3ꢀoxobutanoic acid 6a, under the aboveꢀindicated conditions,
imine 1i can yield diastereomeric βꢀaminoketones 7z and 8b, in which the (R) configuration of the
sulfur atom is the source of chiral induction to the new CꢀC bond. This model reaction captures the
essential features that control the stereochemical outcome of the process studied experimentally in
detail, namely the 1a+6a
→7a+8a reaction (Table 1).
Scheme 5. Model reaction considered in the DFT studies.
As far as the stereochemistry of the new CꢀC bond is concerned, since the decarboxylation step
destroys the chiral information of the αꢀcarbon atom of 3ꢀoxobutiric acid, only the two prochiral
faces of (E)ꢀimines 1 determine the final stereochemical outcome (Figure 1). In principle, the Si
attack of the nucleophiles 6 (actually, their carboxylate lithium salts) should result in the formation
of 7, in which the new chiral carbon atom has (R) configuration, whereas the Re attack would lead
to (S)ꢀdiastereomers 8. In this latter case, coordination of the sulfoxamide moiety to the lithium
cation should generate a significant steric congestion between the R2 group (tertꢀbutyl in the
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experimental system, methyl in the computational model reaction) and the nucleophile. Therefore,
preferential formation of (R) diastereomers 7 should be expected according to this preliminary
analysis.
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Figure 1. Model trajectories for the nucleophilic attacks on the Si and Re prochiral faces of (E)ꢀ
imines 1.
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DFT calculations18 at the B3LYP/6ꢀ31+G(d) level19 including Grimme’s D3 correction for the
dispersion energy20 and polarization continuum model (PCM)21 for unspecific solvent effects (THF
was used in the continuum dielectric approach) yielded the reaction profiles gathered in Figure 2.
Two discrete molecules of THF were included in the calculations in order to saturate the tetrahedral
coordination ability of lithium (I). Interestingly, when the nitrogen atom of the imine was installed
close to the Li(I) center and one molecule of THF was pushed away, the nitrogen was not able to
coordinate to the cationic center during the optimization. Instead, the second molecule of THF
interacted more efficiently thus providing a tetrahedral allꢀoxygen environment around the metal.
This coordination pattern was kept along the reaction coordinates leading to CꢀC adducts INT2(R)
and INT2(S).
Figure 2. Computational profiles [B3LYPꢀD3(PCM=THF)/6ꢀ31+G(d) level of theory] associated
with the nucleophilic attack of lithium 2ꢀoxobutyrate on model (E)ꢀimine 1i. Two discrete
molecules of THF were considered along the reaction coordinates leading to diastereomeric
intermediates INT2. Numbers in parenthesis correspond to the relative Gibbs energies (in kcal/mol)
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with respect to starting complex INT1. Bond distances are given in Å. The steric clash associated
with the proximity between the acetyl and Sꢀmethyl groups in TS1(S) is highlighted in red.
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In these simulations the cyclic geometries of transition structures are determined by the preferential
coordination of two molecules of solvent, the oxygen of the sulfinamide moiety and the carboxylate
group to the lithium cation. In addition, the (E)ꢀconfiguration of the starting imine folds the cyclic
array thus yielding an extended boat structure, which is completely different to the sixꢀmembered
chair conformation associated with the ZimmermanꢀTraxler22 arrangement. In the case of TS1(R)
(Figure 2), the SꢀMe group (SꢀtꢀBu in the experiments) lies away of the cyclic structure and the
proton migration from the starting enol to the carboxy moiety has been completed. The critical
C···C bond distance is close to 2 Å, an expected value for aldolꢀlike reactions involving complex
lithium enolates.23 The chief geometric features of TS1(S) are similar to those of its (R)ꢀcongener,
with the exception of the steric clash generated by the SꢀMe group and the acetyl group coming
from the 2ꢀoxobutirate. As a consequence, TS1(S) lies 2.9 kcal/mol above TS1(R). This difference
in Gibbs energy corresponds to a INT2(R):INT(S) kinetic ratio of 99.3:0.7, a result in qualitative
agreement with the 7a:8a ratio of 97:3 obtained in the experimental studies (Table 1, entry 13).
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In summary, βꢀamino ketone derivatives were prepared from Nꢀtertꢀbutanesulfinyl aldimines and βꢀ
keto acids with high diastereoselectivity in excellent yields, working under basic conditions in THF
at room temperature. The robustness of this method was proved working in a gramꢀscale with the
same levels of stereoselectivity and chemical yield, and a straightforward synthesis of piperidine
alkaloid (ꢀ)ꢀpelletierine demonstrated also the potential utility in synthesis of this procedure. In
addition, and in order to explain the stereochemical outcome of these processes, an eightꢀmembered
cyclic transition state, which is in agreement with the experimental results, has been proposed based
on DFT calculations. Since these reactions are stereospecific, the configuration of newly created
stereogenic centre bearing the nitrogen atom is determined by the configuration of the sulphur atom
of the starting sulfinyl imine.
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EXPERIMENTAL SECTION
General Remarks: (RS)ꢀtertꢀButanesulfinamide was a gift of Medalchemy (> 99% ee by chiral
HPLC on a Chiracel AS column, 90:10 nꢀhexane/iꢀPrOH, 1.2 mL/min,
λ=222 nm). TLC was
performed on silica gel 60 F254, using aluminum plates and visualized with phosphomolybdic acid
(PMA) stain. Flash chromatography was carried out on handpacked columns of silica gel 60 (230ꢀ
400 mesh). Melting points are uncorrected. Optical rotations were measured using a polarimeter
with a thermally jacketted 5 cm cell at approximately 20 ºC and concentrations (c) are given in
g/100 mL. Infrared analyses were performed with a spectrophotometer equipped with an ATR
component; wavenumbers are given in cmꢀ1. Lowꢀresolution mass spectra (EI) were obtained at 70
eV; and fragment ions in m/z with relative intensities (%) in parentheses. Highꢀresolution mass
spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV using a quadrupole
mass analyzer or in the electrospray ionization mode (ESI) using a TOF analyzer.
1H NMR spectra
1
were recorded at 300 or 400 MHz for H NMR and 75 or 100 MHz for 13C NMR, using CDCl3 as
the solvent and TMS as internal standard (0.00 ppm). The data are being reported as: s = singlet, d =
doublet, t = triplet, q = quadruplet, h = septuplet, m = multiplet or unresolved, br s = broad signal,
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1
coupling constant(s) in Hz, integration. C NMR spectra were recorded with Hꢀdecoupling at 100
MHz and referenced to CDCl3 at 77.16 ppm. DEPTꢀ135 experiments were performed to assign CH,
CH2 and CH3.
Compounds 1a,24 1b,25 1c,26 1d,27 1e,28 1f,29 1g27 and 1h30 were prepared from the
corresponding aldehyde and (RS)ꢀtertꢀbutanesulfinamide in THF in the presence of two equivalents
of titanium tetraethoxide. Compounds 6aꢀe were prepared by hydrolysis of the corresponding βꢀ
ketoester 2.
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General Procedure for the Reaction of βꢀKeto Esters 2 with NꢀtertꢀButanesulfinyl Imine 1a.
Synthesis of Compounds 3: A heterogeneous mixture of the corresponding βꢀketo ester 2 (4.0
mmol), NaHCO3 (118 mg, 2.0 mmol), and sulfinyl imine 1a (237 mg, 1.0 mmol) was stirred at rt
for 72 h. The resulting mixture was hydrolyzed with H2O (10 mL), acidified with 2M HCl (2 mL),
and extracted with AcOEt (3 × 15 mL). The organic phase was dried with anhydrous MgSO4, and
the solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel,
hexane/EtOAc) to yield products 3. Yields, physical and spectroscopic data follow.
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(3R,RS)ꢀEthyl
2ꢀAcetylꢀ3ꢀaminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ5ꢀphenylpentanoate
(3a):
The
representative procedure was followed by using βꢀketo ester 2a (520 mg, 0.51 mL, 4.0 mmol).
Purification by column chromatography (hexane/AcOEt, 4:1) yielded 3a (213 mg, 0.58 mmol, 58%)
as a yellow oil (1:1 mixture of diastereoisomers); Rf 0.27 (hexane/EtOAc, 1:1); IR
ν (film) 2959,
2927, 1732, 1713, 1455, 1363, 1235, 1157, 1062, 732, 700 cm–1;
δH 7.33–7.10 (m, 10H), 4.45 (d, J
= 9.9 Hz, 1H), 4.38 (d, J = 9.9 Hz, 1H), 4.32–4.08 (m,4H), 4.08 (d, J = 4.3 Hz, 1H), 4.00 (d, J = 4.7
Hz, 1H), 3.87–3.67 (m, 2H), 2.93–2.75 (m, 2H), 2.72–2.53 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H),
2.33–2.04 (m, 2H), 1.98–1.69 (m, 2H) 1.34–1.18 (m, 6H), 1.26 (s, 9H), 1.25 (s, 9H); δC 203.5,
202.8, 169.0, 168.7, 141.2, 141.2 (C), 128.6, 128.55, 126.2 (CH), 63.4, 63.2 (CH), 61.9, 61.7 (CH2),
56.4 (C), 56.3, 55.9 (CH), 35.5, 35.4, 32.7, 32.7 (CH2), 30.7 (CH3), 30.6, 22.9, 14.2, 14.1 (CH3);
LRMS (EI) m/z 246 (M+–tꢀBuSONH2, 3%), 204 (10), 201 (14), 200 (29), 158 (17), 157 (13), 129
(25), 128 (12), 117 (10), 91 (100), 65 (10); HRMS (EI): Calculated for C13H13O2 [M+–(tꢀ
BuSONH2+EtO)] 201.0916; found 201.0918.
(3R,RS)ꢀtertꢀButyl 2ꢀAcetylꢀ3ꢀaminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ5ꢀphenylpentanoate (3b): The
representative procedure was followed by using βꢀketo ester 2b (632 mg, 0.672 mL, 4.0 mmol).
Purification by column chromatography (hexane/AcOEt, 4:1) yielded 3b (225 mg, 0.57 mmol,
57%) as a yellow oil (1:1 mixture of diastereoisomers); Rf 0.42 and 0.33 (hexane/EtOAc, 1:1); IR
ν
(film) 2976, 2931, 1712, 1454, 1367, 1252, 1144, 1026, 843, 748, 696 cm–1;
δH 7.34–7.10 (m, 10H),
4.43 (d, J = 9.9 Hz, 1H), 4.28 (d, J = 9.6 Hz, 1H), 4.03 (d, J = 4.5 Hz, 1H), 3.95 (d, J = 4.5 Hz, 1H),
3.83–3.62 (m, 2H), 2.91–2.74 (m, 2H), 2.74–2.54 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 2.20–1.86 (m,
2H), 1.88–1.69 (m, 2H), 1.48 (s, 9H), 1.42 (s, 9H), 1.26 (s, 9H), 1.25 (s, 9H); δC 204.1, 202.6,
168.1, 168.0, 141.4, 141.3 (C), 128.6, 128.55, 126.2, 126.1 (CH), 83.3, 82.8 (C), 64.65, 63.8 (CH),
56.35 (C), 56.3, 55.5 (CH), 35.1, 34.8, 32.75, 32.5 (CH2), 30.7, 30.35, 28.1, 28.0, 22.9 (CH3);
LRMS (EI) m/z 218 [M+–(C4H9+tꢀBuSONH), 25%], 201 (25), 200 (47), 174 (17), 129 (15), 117
(20), 104 (15), 91 (100), 57 (28), 56 (27); HRMS (EI): Calculated for C13H14O3 [M+–(C4H9+tꢀ
BuSONH)] 218.0943; found 218.0938.
(3R,RS)ꢀBenzyl 2ꢀAcetylꢀ3ꢀaminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ5ꢀphenylpentanoate (3c): The
representative procedure was followed by using βꢀketo ester 2c (769 mg, 0.692 mL, 4.0 mmol).
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Purification by column chromatography (hexane/AcOEt, 4:1) yielded 3c (146 mg, 0.34 mmol, 34%)
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as a yellow oil (1:1 mixture of diastereoisomers); Rf 0.44 and 0.33 (hexane/EtOAc, 1:1); IR
ν (film)
2962, 1718, 1622, 1454, 1363, 1213, 1161, 1076, 895, 746, 696 cm–1;
δH 7.42ꢀ7.03 (m, 20H), 5.28–
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5.14 (m, 4H), 4.42 (d, J = 9.9 Hz, 1H), 4.33 (d, J = 10.1 Hz, 1H), 4.11 (d, J = 4.1 Hz, 1H), 4.05 (d, J
= 4.7 Hz, 1H), 3.88–3.68 (m, 2H), 2.90–2.70 (m, 2H), 2.68–2.46 (m, 2H), 2.23 (s, 3H), 2.17 (s, 3H),
2.16–1.79 (m, 2H), 1.79–1.63 (m, 2H), 1.22 (s, 9H), 1.21 (s, 9H); δC 203.2, 202.6, 168.7, 168.4,
141.1, 141.0, 135.0, 134.9 (C), 128.8, 128.7, 128.5, 128.4, 126.1 (CH), 67.7, 67.5 (CH2), 63.3, 63.1
(CH), 56.4 (C), 56.4, 56.0 (CH), 35.5, 32.7, 32.6 (CH2), 30.7, 30.6, 22.8 (CH3); LRMS (EI) m/z 218
[M+–(C7H7+tꢀBuSONH), 3%], 217 (22), 200 (8), 199 (50), 157 (20), 92 (9), 91 (100), 77 (9), 65
(11); HRMS (EI): Calculated for C13H13O3 [M+–(C7H7+tꢀBuSONH2)] 217.0865; found 217.0865.
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Reaction of βꢀKeto Acid 6a with NꢀtertꢀButanesulfinyl Imine 1a in NaOMe/MeOH. Synthesis
of Compounds 7a and 8a: To a mixture of 3ꢀoxobutanoic acid (6a, 61.2 mg, 0.6 mmol), and
sulfinyl imine 1a (48 mg, 0.2 mmol) was added a 2M solution of NaOMe in MeOH (1.2 mL, 2.4
mmol) at 0 ºC. The resulting mixture was stirred at rt for 12 h. After that, it was hydrolyzed with a
mixture of H2O (5 mL) and brine (5 mL), and extracted with AcOEt (3 × 15 mL). The organic
phase was dried with anhydrous MgSO4, and the solvent evaporated (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/EtOAc, 5:1) to yield products 7a (28.3 mg,
0.096 mmol, 48%) and 8a (17.1 mg, 0.058 mmol, 29%). Physical and spectroscopic data follow.
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(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀphenylhexanꢀ2ꢀone (7a): Yellow oild; [α]D –30.7 (c
= 1.04, CH2Cl2); Rf 0.14 (hexane/EtOAc, 1:3); IR
1410, 1362, 1161, 1050, 746, 699 cm–1;
H 7.34–7.11 (m, 5H), 4.15 (d, J = 9.3 Hz, 1H), 3.62–3.44
(m, 1H), 2.95 (dd, J = 17.8, 5.5 Hz, 1H), 2.85–2.70 (m, 2H), 2.70–2.53 (m, 1H), 2.12 (s, 3H), 2.08–
1.89 (m, 1H), 1.86ꢀ1.71 (m, 1H), 1.23 (s, 9H); C 208.3, 141.5 (C), 128.5, 128.45, 126.1 (CH), 56.1
ν (film) 2954, 2867, 1710, 1603, 1497, 1454,
δ
δ
(C), 53.4 (CH), 49.0, 37.4, 32.5 (CH2), 31.1, 22.8 (CH3); LRMS (EI) m/z 239 (M+–C4H8, 27%), 181
(37), 118 (12), 117 (100), 91 (49), 57 (30), 43 (26), 41 (9); HRMS (ESI): Calculated for
C16H26NO2S (M++H) 296.1684, found 296.1681.
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(4S,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀphenylhexanꢀ2ꢀone (8a): Yellow oild; [α]D –75.8 (c
= 1.06, CH2Cl2); Rf 0.26 (hexane/EtOAc, 1:3); IR
ν (film) 2952, 2867, 1710, 1603, 1496, 1454,
1408, 1363, 1176, 1046, 749, 700 cm–1;
δH 7.32–7.16 (m, 5H), 3.96 (d, J = 5.5 Hz, 1H), 3.71–3.59
(m, 1H), 2.99 (dd, J = 17.7, 9.3 Hz, 1H), 2.84–2.62 (m, 2H), 2.56 (dd, J = 17.7, 4.0 Hz, 1H), 2.19–
2.06 (m, 1H), 2.13 (s, 3H), 1.91–1.76 (m, 1H), 1.20 (s, 9H); δC 207.9, 141.3 (C), 128.6, 128.5,
126.1 (CH), 55.9 (C), 52.0 (CH), 49.8, 36.1, 32.35 (CH2), 30.75, 22.7 (CH3); LRMS (EI) m/z 239
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(M+–C4H8, 27%), 181 (37), 118 (12), 117 (100), 91 (49), 57 (30), 43 (26), 41 (9); HRMS (ESI):
Calculated for C16H26NO2S (M++H) 296.1684, found 296.1676.
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General Procedure for the Reaction of βꢀKeto Acids 6 with NꢀtertꢀButanesulfinyl Imines 1.
Synthesis of Compounds 7: To a solution of the corresponding βꢀketo acid 6 (0.3 mmol) in THF (2
mL) was added a 2M solution of LiOH in MeOH (0.2 mL, 0.4 mmol) at 0 ºC. The reaction mixture
was allowed to reach rt and then the corresponding imine 1 (0.2 mmol) was added and stirring was
continued for 1 or 5 h (see Table 2). The resulting mixture was hydrolyzed with H2O (10 mL), and
extracted with AcOEt (3 × 15 mL). The organic phase was dried with anhydrous MgSO4, and the
solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel,
hexane/EtOAc) to yield products 7. Yields, physical and spectroscopic data follow.
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(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀphenylhexanꢀ2ꢀone
(7a):
The
representative
procedure was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1a (48 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7a (57.9 mg, 0.196
mmol, 98%) as a yellow oil; physical and spectroscopic data have been given above.
(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)dodecanꢀ2ꢀone (7b): The representative procedure was
followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1b (49 mg, 0.2 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7b (59.5 mg, 0.196 mmol,
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98%) as a yellow oil; [α]D –45.5 (c = 1.05, CH2Cl2); Rf 0.22 (hexane/EtOAc, 1:3); IR
ν
(film)
2922, 2855, 1712, 1458, 1411, 1362, 1165, 1048, 889 cm–1;
δH 3.98 (d, J = 8.9 Hz, 1H), 3.57–3.44
(m, 1H), 2.87 (dd, J = 17.4, 5.5 Hz, 1H), 2.76 (dd, J = 17.8, 4.9 Hz, 1H), 2.14 (s, 3H), 1.73–1.21
(m, 14H), 1.18 (s, 9H), 0.85 (t, J = 5.8 Hz, 3H); δC 208.3, 55.9 (C), 53.7 (CH), 49.1, 35.7, 31.9
(CH2), 31.1 (CH3), 29.55, 29.3, 26.2 (CH2), 22.7, 14.2 (CH3); LRMS (EI) m/z 247 (M+–C4H8, 13%),
190 (11), 189 (100), 84 (9), 70 (14), 57 (28), 43 (29), 41 (12); HRMS (ESI): Calculated for
C16H34NO2S (M++H) 304.2310, found 304.2305.
(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)tridecanꢀ2ꢀone (7c): The representative procedure was
followed by using βꢀketo acid 6a (612 mg, 6.0 mmol) and imine 1c (1.0378 g, 4.0 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7c (1.0415 g, 3.28 mmol,
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82%) as a yellow oil; [α]D –45.3 (c = 1.19, CH2Cl2); Rf 0.20 (hexane/EtOAc, 1:3); IR
ν
(film)
2924, 2854, 1711, 1462, 1412, 1363, 1169, 1049, 897 cm–1;
δH 3.99 (d, J = 9.0 Hz, 1H), 3.59–3.44
(m, 1H), 2.89 (dd, J = 17.7, 5.5 Hz, 1H), 2.78 (dd, J = 17.7, 4.9 Hz, 1H), 2.16 (s, 3H), 1.66ꢀ1.23 (m,
16H), 1.20 (s, 9H), 0.88 (t, J = 6.7 Hz, 3H); δC 208.25, 55.9 (C), 53.7 (CH), 49.2, 35.7, 31.95
(CH2), 31.1 (CH3), 29.6, 29.35, 29.3, 26.25 (CH2), 22.75, 14.2 (CH3); LRMS (EI) m/z 261 (M+–
C4H8, 13%), 204 (12), 203 (100), 84 (9), 70 (15), 57 (27), 43 (37), 41 (11); HRMS (EI): Calculated
for C13H27NO2S (M+–C4H8) 261.1762, found 261.1761.
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(4S,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ5ꢀmethylhexanꢀ2ꢀone
(7d):
The
representative
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procedure was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1d (35 mg, 0.2
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8
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7d (28.9 mg, 0.124
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mmol, 62%) as a yellow oil; [α]D –67.0 (c = 1.01, CH2Cl2); Rf 0.15 (hexane/EtOAc, 1:3); IR
ν
(film) 2960, 2873, 1716, 1625, 1521, 1468, 1411, 1363, 1166, 1029, 904, 690 cm–1;
δH 3.91 (d, J =
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8.9 Hz, 1H), 3.38–3.30 (m, 1H), 2.83 (d, J = 5.3 Hz, 2H), 2.18 (s, 3H), 1.98ꢀ1.88 (m, 1H), 1.21 (s,
9H), 0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); δC 208.4 (C), 59.1 (CH), 56.2 (C), 46.4
(CH2), 32.1 (CH), 31.1, 22.9, 19.4 (CH3), 18.82(CH3); LRMS (EI) m/z 177 (M+–C4H8, 21%), 119
(100), 113 (20), 86 (16), 71 (10), 70 (12), 57 (61), 56 (22), 55 (13), 44 (19), 43 (94), 41 (26);
HRMS (ESI): Calculated for C11H24NO2S (M++H) 234.1528, found 234.1520.
(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀmethylheptanꢀ2ꢀone (7e): The representative
procedure was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1e (37.8 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7e (48.5 mg, 0.196
20
mmol, 98%) as a yellow wax; [α]D –46.8 (c = 1.02, CH2Cl2); Rf 0.15 (hexane/EtOAc, 1:3); IR
ν
(film) 3222, 2958, 1710, 1458, 1417, 1390, 1364, 1168, 1142, 1039, 900 cm–1; δH 3.98 (d, J = 9.8
Hz, 1H), 3.66–3.51 (m, 1H), 2.92 (dd, J = 17.9, 5.6 Hz, 1H), 2.79 (dd, J = 17.8, 4.3 Hz, 1H), 2.15
(s, 3H), 1.81–1.65 (m, 1H), 1.69–1.54 (m, 1H), 1.28–1.14 (m, 1H), 1.20 (s, 9H), 0.90 (d, J = 6.6 Hz,
3H), 0.89 (d, J = 6.5 Hz, 3H); δC 208.4, 56.0 (C), 52.1 (CH), 49.5, 44.85 (CH2), 31.2 (CH3), 24.8
(CH), 23.2, 22.7, 21.5 (CH3); LRMS (EI) m/z 191 (M+–C4H8, 18%), 191 (18), 133 (100), 91 (10),
86 (13), 77 (11), 71 (14), 70 (10), 69 (13), 57 (51), 44 (11), 43 (81), 41 (21); HRMS (ESI):
Calculated for C12H26NO2S (M++H) 248.1684, found 248.1680.
(4R,RS)ꢀ4ꢀAminoꢀ8ꢀbromoꢀNꢀ(tertꢀbutanesulfinyl)octanꢀ2ꢀone (7f): The representative procedure
was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1f (53.6 mg, 0.2 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7f (64.0 mg, 0.196 mmol,
20
98%) as a yellow oil; [α]D –38.0 (c = 1.01, CH2Cl2); Rf 0.12 (hexane/EtOAc, 1:3); IR
ν (film)
2946, 1710, 1459, 1362, 1254, 1168, 1051, 907, 731 cm–1; δH 4.02 (d, J = 9.1 Hz, 1H), 3.58–3.45
(m, 1H), 3.41 (t, J = 6.6 Hz, 2H), 2.92 (dd, J = 17.9, 5.6 Hz, 1H), 2.81 (dd, J = 17.9, 4.6 Hz, 1H),
2.16 (s, 3H), 1.93–1.79 (m, 2H), 1.70–1.42 (m, 4H), 1.21 (s, 9H); δC 208.2, 56.01 (C), 53.5 (CH),
49.1, 34.65, 33.7, 32.2 (CH2), 31.1 (CH3), 24.8 (CH2), 22.7 (CH3); LRMS (EI) m/z 271 (M+–C4H9,
13%), 269 (13%), 213 (100), 211 (99), 172 (13), 84 (14), 57 (62), 43 (54), 41 (20); HRMS (EI):
Calculated for C8H1679BrNO2S (M+–C4H8) 269.0085, found 269.0083.
(4S,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ4ꢀphenylbutanꢀ2ꢀone
(7g):
The
representative
procedure was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1g (41.8 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7g (46.0 mg, 0.172
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mmol, 86%) as a yellow solid; mp 73–74 ºC (hexane/CH2Cl2); [α]D –96.3 (c = 1.06, CH2Cl2); Rf
3
4
0.17 (hexane/EtOAc, 1:3); IR (film) 3205, 2957, 1704, 1455, 1421, 1362, 1277, 1159, 1046, 890,
ν
774, 704 cm–1; δH 7.33 (m, 5H), 4.83–4.74 (m, 1H), 4.66 (d, J = 4.6 Hz, 1H), 3.08–2.96 (m, 2H),
2.13 (s, 3H), 1.20 (s, 9H); δC 207.5, 140.9 (C), 128.7, 127.95, 127.4 (CH), 55.7 (C), 55.3 (CH),
50.65 (CH2), 30.9, 22.7 (CH3); LRMS (EI) m/z 211 (M+–C4H8, 15%), 153 (47), 148 (11), 147 (87),
105 (13), 104 (21), 77 (11), 59 (12), 57 (42), 43 (100), 41 (14); HRMS (ESI): Calculated for
C14H22NO2S (M++H) 268.1371, found 268.1362.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4S,RS)ꢀ4ꢀAminoꢀ4ꢀ(4ꢀbromophenyl)ꢀNꢀ(tertꢀbutanesulfinyl)butanꢀ2ꢀone
(7h):
The
representative procedure was followed by using βꢀketo acid 6a (30.6 mg, 0.3 mmol) and imine 1h
(57.6 mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7h
20
(67.8 mg, 0.196 mmol, 98%) as a yellow solid; mp 89–90 ºC (hexane/CH2Cl2); [α]D –73.4 (c =
1.03, CH2Cl2); Rf 0.17 (hexane/EtOAc, 1:3); IR
ν (film) 3203, 2954, 1715, 1592, 1485, 1412, 1362,
1288, 1161, 1045, 1011, 902, 815 cm–1; δH 7.51–7.42 (m, 2H), 7.25–7.17 (m, 2H), 4.79–4.70 (m,
1H), 4.68 (d, J = 4.5 Hz, 1H), 3.07–2.93 (m, 2H), 2.14 (s, 3H), 1.20 (s, 9H); δC 207.2, 140.0 (C),
131.9, 129.2 (CH), 121.85, 55.8 (C), 54.7 (CH), 50.4 (CH2), 30.9, 22.7 (CH3); LRMS (EI) m/z 291
(M+
(100), 41 (15); HRMS (ESI): Calculated for C14H2179BrNO2S (M++H) 346.0476, found 346.0472.
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ7ꢀphenylheptanꢀ3ꢀone (7i): The representative
−C4H9, 7%), 289 (6%), 233 (16), 231 (15), 227 (44), 225 (45), 184 (14), 182 (11), 57 (60), 43
procedure was followed by using βꢀketo acid 6b (34.8 mg, 0.3 mmol) and imine 1a (48 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7i (59.3 mg, 0.192
20
mmol, 96%) as a yellow solid; mp 52–53 ºC (hexane/CH2Cl2); [α]D
0.34 (hexane/EtOAc, 1:3); IR
cm–1;
H 7.33–7.11 (m, 5H), 4.25 (d, J = 9.2 Hz, 1H), 3.63–3.45 (m, 1H), 2.92 (dd, J = 17.6, 5.5 Hz,
1H), 2.86–2.69 (m, 2H), 2.68–2.54 (m, 1H), 2.48–2.33 (m, 2H), 2.07–1.90 (m, 1H), 1.87–1.71 (m,
1H), 1.24 (s, 9H), 1.02 (t, J = 7.3 Hz, 3H); C 211.2, 141.5 (C), 128.5, 128.5, 126.1 (CH), 56.1 (C),
53.6 (CH), 47.75, 37.5, 37.05, 32.6 (CH2), 22.8, 7.5 (CH3); LRMS (EI) m/z 253 (M+
C4H8, 28%),
–31.8 (c = 1.02, CH2Cl2); Rf
ν
(film) 3265, 2937, 1699, 1454, 1361, 1116, 1064, 942, 748, 703
δ
δ
−
181 (33), 118 (12), 117 (100), 91 (47), 57 (63), 41 (9); HRMS (ESI): Calculated for C17H28NO2S
(M++H) 310.1841, found 310.1831.
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)tridecanꢀ3ꢀone (7j): The representative procedure was
followed by using βꢀketo acid 6b (34.8 mg, 0.3 mmol) and imine 1b (49 mg, 0.2 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7j (56.5 mg, 0.178 mmol,
20
89%) as a yellow oil; [α]D –41.0 (c = 1.05, CH2Cl2); Rf 0.46 (hexane/EtOAc, 1:3); IR
ν
(film)
2925, 2855, 1710, 1458, 1411, 1363, 1051, 897, 671 cm–1;
δH 4.06 (d, J = 8.9 Hz, 1H), 3.57–3.43
(m, 1H), 2.84 (dd, J = 17.4, 5.4 Hz, 1H), 2.73 (dd, J = 17.4, 4.9 Hz, 1H), 2.41 (q, J = 7.3 Hz, 2H),
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1.65–1.20 (m, 14H), 1.18 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 6.9 Hz, 3H); δC 211.1, 55.9
3
4
5
6
(C), 53.85 (CH), 47.8, 37.1, 35.7, 31.9, 29.55, 29.3, 26.2 (CH2), 22.75 (CH3), 22.7 (CH2), 14.2, 7.55
(CH3); LRMS (EI) m/z 247 (M+–C4H8, 13%), 190 (11), 189 (100), 84 (9), 70 (14), 57 (28), 43 (29),
41 (12); HRMS (ESI): Calculated for C16H34NO2S (M++H) 304.2310, found 304.2305.
7
8
9
(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀmethylheptanꢀ3ꢀone (7k): The representative
procedure was followed by using βꢀketo acid 6b (34.8 mg, 0.3 mmol) and imine 1d (35 mg, 0.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7k (28.9 mg, 0.194
20
mmol, 97%) as a yellow oil; [α]D –67.0 (c = 1.01, CH2Cl2); Rf 0.15 (hexane/EtOAc, 1:3); IR
ν
(film) 2960, 2873, 1716, 1625, 1521, 1468, 1411, 1363, 1166, 1029, 904, 690 cm–1;
δH 3.91 (d, J =
8.9 Hz, 1H), 3.38–3.30 (m, 1H), 2.83 (d, J = 5.3 Hz, 2H), 2.18 (s, 3H), 1.98ꢀ1.88 (m, 1H), 1.21 (s,
9H), 0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); δC 208.4 (C), 59.1 (CH), 56.2 (C), 46.4
(CH2), 32.1 (CH), 31.1, 22.9, 19.4 (CH3), 18.82(CH3); LRMS (EI) m/z 261 (M+
−C4H8, 13%), 197
(9), 190 (12), 189 (100), 142 (10), 84 (9), 70 (14), 57 (63), 41 (11); HRMS (ESI): Calculated for
C17H36NO2S (M++H) 318.2467, found 318.2467.
(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ5ꢀphenylpentanꢀ3ꢀone
(7l):
The
representative
procedure was followed by using βꢀketo acid 6b (34.8 mg, 0.3 mmol) and imine 1g (41.8 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7l (46.0 mg, 0.196
20
mmol, 98%) as a yellow solid; mp 57–58 ºC (hexane/CH2Cl2); [α]D –92.2 (c = 1.03, CH2Cl2); Rf
0.36 (hexane/EtOAc, 1:3); IR
ν (film) 3218, 2979, 1707, 1455, 1354, 1278, 1048, 888, 762, 702
cm–1;
δH 7.40–7.24 (m, 5H), 4.83–4.74 (m, 2H), 3.06–2.89 (m, 2H), 2.41 (dd, J = 7.3, 1.8 Hz, 1H),
2.38 (dd, J = 7.3, 1.7 Hz, 1H), 1.21 (s, 9H), 1.00 (t, J = 7.3 Hz, 3H); δC 210.4, 141.1 (C), 128.7,
127.9, 127.4 (CH), 55.7 (C), 55.4 (CH), 49.4, 37.0 (CH2), 22.7, 7.5 (CH3); LRMS (EI) m/z 225
(M+
−C4H8, 8%), 161 (37), 153 (27), 121 (7), 105 (7), 104 (13), 57 (100), 41 (7); HRMS (ESI):
Calculated for C15H24NO2S (M++H) 282.1528, found 282.1515.
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2ꢀmethylꢀ7ꢀphenylheptanꢀ3ꢀone
(7m):
The
representative procedure was followed by using βꢀketo acid 6c (39 mg, 0.3 mmol) and imine 1a (48
mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7m (63.4 mg,
0.196 mmol, 98%) as a yellow oil; [α]D20 –33.0 (c = 1.07, CH2Cl2); Rf 0.50 (hexane/EtOAc, 1:3); IR
ν
(film) 2966, 1705, 1496, 1455, 1363, 1173, 1054, 736, 697 cm–1;
δH 7.33–7.13 (m, 5H), 4.32 (d, J
= 9.2 Hz, 1H), 3.62–3.47 (m, 1H), 2.97 (dd, J = 17.8, 5.6 Hz, 1H), 2.89–2.71 (m, 2H), 2.70–2.46
(m, 2H), 2.03 – 1.86 (m, 1H), 1.85–1.68 (m, 1H), 1.24 (s, 9H), 1.07 (d, J = 6.9 Hz, 3H), 1.07 (d, J =
6.8 Hz, 3H); δC 214.5, 141.5 (C), 128.5, 128.5, 126.0 (CH), 56.0 (C), 53.6 (CH), 45.8 (CH2), 41.6
(CH), 37.4, 32.6 (CH2), 22.8, 18.0 (CH3); LRMS (EI) m/z 267 (M+
−C4H8, 23%), 249 (12), 203 (9),
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181 (27), 134 (11), 118 (11), 117 (100), 91 (51), 71 (31), 57 (27), 43 (29), 41 (11); HRMS (ESI):
Calculated for C18H30NO2S (M++H) 324.1997, found 324.1993.
5
6
7
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2ꢀmethyltridecanꢀ3ꢀone (7n): The representative
procedure was followed by using βꢀketo acid 6c (39 mg, 0.3 mmol) and imine 1b (49 mg, 0.2
8
9
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7n (64.3 mg, 0.194
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mmol, 97%) as a yellow oil; [α]D –37.8 (c = 1.04, CH2Cl2); Rf 0.57 (hexane/EtOAc, 1:3); IR
ν
(film) 2925, 2855, 1707, 1466, 1363, 1176, 1051, 912, 731 cm–1;
3.48 (m, 1H), 2.91 (dd, J = 17.6, 5.6 Hz, 1H), 2.81 (dd, J = 17.6, 4.6 Hz, 1H), 2.57 (h, J = 6.9 Hz,
1H), 1.65–1.23 (m, 14H), 1.21 (s, 9H), 1.10 (s, 3H), 1.08 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H); C 214.5,
55.9 (C), 53.9 (CH), 45.9 (CH2), 41.7 (CH), 35.6, 31.9, 29.6, 29.3, 26.3 (CH2), 22.8 (CH3), 22.7
(CH2), 18.0, 14.2 (CH3); LRMS (EI) m/z 275 (M+
C4H8, 15%), 211 (14), 190 (12), 189 (100), 142
δH 4.14 (d, J = 8.9 Hz, 1H), 3.58–
δ
−
(18), 84 (10), 71 (39), 70 (16), 57 (29), 43 (36), 41 (14); HRMS (ESI): Calculated for C18H38NO2S
(M++H) 332.2623, found 332.2620.
(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2,6ꢀdimethylheptanꢀ3ꢀone (7o): The representative
procedure was followed by using βꢀketo acid 6c (39 mg, 0.3 mmol) and imine 1d (35 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7o (50.3 mg, 0.190
20
mmol, 95%) as a yellow oil; [α]D –62.8 (c = 1.04, CH2Cl2); Rf 0.48 (hexane/EtOAc, 1:3); IR
ν
(film) 2961, 2873, 1705, 1467, 1385, 1364, 1175, 1056, 904, 733 cm–1;
δH 4.10 (d, J = 8.8 Hz, 1H),
3.42–3.27 (m, 1H), 2.98–2.76 (m, 2H), 2.60 (h, J = 7.0 Hz, 1H), 2.00–1.86 (m, 1H), 1.22 (s, 9H),
1.12 (s, 3H), 1.09 (s, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); δC 214.5 (C), 59.2
(CH), 56.1 (C), 43.0 (CH2), 41.6, 31.8 (CH), 22.8, 19.4, 18.8, 18.15, 18.1 (CH3); LRMS (EI) m/z
205 (M+
−C4H8, 24%), 144 (29), 141 (23), 119 (100), 114 (10), 72 (19), 71 (63), 70 (15), 69 (11), 57
(48), 56 (22), 55 (16), 43 (98), 41 (30); HRMS (ESI): Calculated for C13H28NO2S (M++H)
262.1841, found 262.1836.
(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2ꢀmethylꢀ5ꢀphenylpentanꢀ3ꢀone
(7p):
The
representative procedure was followed by using βꢀketo acid 6c (39 mg, 0.3 mmol) and imine 1g
(41.8 mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7p
20
(63.4 mg, 0.196 mmol, 98%) as a yellow solid; mp 50–51 ºC (hexane/CH2Cl2); [α]D –93.4 (c =
1.02, CH2Cl2); Rf 0.50 (hexane/EtOAc, 1:3); IR
ν (film) 3210, 2970, 1708, 1456, 1352, 1278, 1046,
896, 758, 698 cm–1;
δH 7.41–7.22 (m, 5H), 4.86 (d, J = 4.4 Hz, 1H), 4.84–4.72 (m, 1H), 3.07 (dd, J
= 17.1, 4.7 Hz, 1H), 2.96 (dd, J = 17.1, 7.5 Hz, 1H), 2.52 (h, J = 6.9 Hz, 1H), 1.21 (s, 9H), 1.04 (s,
3H), 1.02 (s, 3H); δC 213.6, 141.15 (C), 128.6, 127.8 (CH), 127.35 (CH), 55.6 (C), 55.45 (CH),
47.45 (CH2), 41.7 (CH), 22.7, 17.8 (CH3); LRMS (EI) m/z 239 (M+
−C4H8, 9%), 175 (30), 153 (28),
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135 (10), 105 (9), 104 (15), 71 (100), 57 (24), 43 (36), 41 (12); HRMS (ESI): Calculated for
C16H26NO2S (M++H) 296.1684, found 296.1682.
5
6
7
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2,2ꢀdimethylꢀ7ꢀphenylheptanꢀ3ꢀone
(7q):
The
representative procedure was followed by using βꢀketo acid 6d (43.2 mg, 0.3 mmol) and imine 1a
8
9
(48 mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7q (63.4
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mg, 0.188 mmol, 94%) as a yellow wax; [α]D –30.4 (c = 1.00, CH2Cl2); Rf 0.55 (hexane/EtOAc,
1:3); IR
ν
(film) 2954, 2865, 1703, 1477, 1455, 1364, 1054, 946, 747, 699 cm–1; δH 7.33–7.12 (m,
5H), 4.42 (d, J = 9.3 Hz, 1H), 3.64–3.47 (m, 1H), 2.99 (dd, J = 18.0, 5.6 Hz, 1H), 2.87 (dd, J =
17.9, 4.1 Hz, 1H), 2.85–2.71 (m, 1H), 2.69–2.53 (m, 1H), 2.05–1.84 (m, 1H), 1.82–1.64 (m, 1H),
1.25 (s, 9H), 1.11 (s, 9H);
δC 216.1, 141.6 (C), 128.5, 128.5, 126.0 (CH), 56.0 (C), 53.9 (CH), 44.5
(C), 42.3, 37.3, 32.7 (CH2), 26.3, 22.9 (CH3); LRMS (EI) m/z 281 (M+
−
C4H8, 33%), 217 (12), 206
(11), 181 (30), 134 (14), 118 (11), 117 (100), 91 (52), 85 (14), 57 (88), 41 (15); HRMS (ESI):
Calculated for C19H32NO2S (M++H) 338.2154, found 338.2155.
(5R,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2,2ꢀdimethyltridecanꢀ3ꢀone (7r): The representative
procedure was followed by using βꢀketo acid 6d (43.2 mg, 0.3 mmol) and imine 1b (49 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7r (56.0 mg, 0.162
20
mmol, 81%) as a yellow oil; [α]D –36.2 (c = 1.08, CH2Cl2); Rf 0.66 (hexane/EtOAc, 1:3); IR
ν
(film) 2925, 2855, 1702, 1465, 1364, 1176, 1052, 905 cm–1;
(m, 1H), 2.94 (dd, J = 17.8, 5.5 Hz, 1H), 2.85 (dd, J = 17.8, 4.5 Hz, 1H), 1.63–1.22 (m, 14H), 1.21
(s, 9H), 1.13 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H); C 216.0, 55.9 (C), 54.2 (CH), 44.5 (C), 42.4, 35.5,
31.9, 29.6, 29.3 (CH2), 26.3, 22.8 (CH3), 22.75 (CH2), 14.2 (CH3); LRMS (EI) m/z 289 (M+
C4H8,
δH 4.23 (d, J = 9.0 Hz, 1H), 3.62–3.43
δ
−
17%), 225 (19), 214 (10), 190 (12), 189 (100), 142 (22), 85 (19), 70 (16), 57 (96), 43 (19), 41 (19);
HRMS (ESI): Calculated for C19H40NO2S (M++H) 346.2780, found 346.2780.
(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2,2,6ꢀtrimethylheptanꢀ3ꢀone (7s): The representative
procedure was followed by using βꢀketo acid 6d (43.2 mg, 0.3 mmol) and imine 1d (35 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7s (48 mg, 0.174
20
mmol, 87%) as a yellow oil; [α]D –61.7 (c = 1.05, CH2Cl2); Rf 0.55 (hexane/EtOAc, 1:3); IR
ν
(film) 3172, 2963, 1703, 1478, 1465, 1364, 1006, 916, 715 cm–1;
δH 4.11 (d, J = 8.8 Hz, 1H), 3.40–
3.29 (m, 1H), 2.96 (dd, J = 17.9, 5.4 Hz, 1H), 2.85 (dd, J = 17.9, 5.0 Hz, 1H), 2.01–1.88 (m, 1H),
1.22 (s, 9H), 1.15 (s, 9H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); δC 215.8 (C), 59.3
(CH), 56.1 (C), 44.6 (C), 39.4 (CH2), 31.5 (CH), 26.45, 22.9, 19.4, 18.8 (CH3); LRMS (EI) m/z 219
(M+
−C4H8, 15%), 155 (13), 144 (17), 128 (13), 119 (56), 85 (21), 72 (14), 71 (11), 70 (12), 69 (13),
57 (100), 56 (13), 55 (13), 43 (45), 41 (25); HRMS (ESI): Calculated for C14H30NO2S (M++H)
276.1997, found 276.1990.
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(5S,RS)ꢀ5ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ2,2ꢀdimethylꢀ5ꢀphenylpentanꢀ3ꢀone
(7t):
The
3
4
5
6
representative procedure was followed by using βꢀketo acid 6d (43.2 mg, 0.3 mmol) and imine 1g
(41.8 mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7t (49.5
20
mg, 0.160 mmol, 80%) as a yellow solid; mp 75–76 ºC (hexane/CH2Cl2); [α]D –88.9 (c = 1.06,
7
8
9
CH2Cl2); Rf 0.55 (hexane/EtOAc, 1:3); IR
916, 764, 701 cm–1;
H 7.41–7.24 (m, 5H), 4.91 (d, J = 4.3 Hz, 1H), 4.82–4.70 (m, 1H), 3.12 (dd, J
= 17.2, 4.4 Hz, 1H), 2.94 (dd, J = 17.2, 7.8 Hz, 1H), 1.22 (s, 9H), 1.06 (s, 9H); C 215.1, 141.3 (C),
128.65, 127.9, 127.5 (CH), 55.7 (C), 55.6 (CH), 44.6 (C), 44.1 (CH2), 26.0, 22.8 (CH3); LRMS (EI)
m/z 253 (M+
C4H8, 7%), 189 (18), 153 (18), 104 (13), 85 (46), 57 (100), 41 (12); HRMS (ESI):
ν (film) 3089, 2979, 1700, 1476, 1459, 1363, 1177, 1043,
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δ
δ
−
Calculated for C17H28NO2S (M++H) 310.1841, found 310.1833.
(3R,RS)ꢀ3ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ1,5ꢀdiphenylpentanꢀ1ꢀone (7u): The representative
procedure was followed by using βꢀketo acid 6e (49.2 mg, 0.3 mmol) and imine 1a (48 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7u (61.5 mg, 0.172
mmol, 86%) as a yellow solid; mp 40–41 ºC (hexane/CH2Cl2); [α]D20 –39.1 (c = 1.01, CH2Cl2); Rf
0.40 (hexane/EtOAc, 1:2); IR
ν (film) 3191, 2962, 1680, 1449, 1355, 1211, 1057, 1005, 959, 895,
753, 727, 687 cm–1; δH 7.96–7.86 (m, 2H), 7.61–7.49 (m, 1H), 7.50–7.37 (m, 2H), 7.33–7.21 (m,
2H), 7.23–7.12 (m, 3H), 4.35 (d, J = 9.0 Hz, 1H), 3.86–3.68 (m, 1H), 3.41 (d, J = 5.5 Hz, 2H),
2.91–2.75 (m, 1H), 2.75–2.59 (m, 1H), 2.15–1.96 (m, 1H), 1.99–1.81 (m, 1H), 1.25 (s, 9H); δC
199.5, 141.55, 137.05 (C), 133.5, 128.7, 128.55, 128.5, 128.2, 126.1 (CH), 56.2 (C), 53.9 (CH),
44.4, 37.5, 32.6 (CH2), 22.9 (CH3); LRMS (EI) m/z 301 (M+
−C4H8, 15%), 181 (43), 134 (12), 133
(12), 121 (12), 118 (12), 117 (100), 116 (11), 105 (99), 91 (86), 78 (11), 77 (40), 57 (41), 43 (16),
41 (14); HRMS (ESI): Calculated for C21H28NO2S (M++H) 358.1841, found 358.1834.
(3R,RS)ꢀ3ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ1ꢀphenylundecanꢀ1ꢀone (7v): The representative
procedure was followed by using βꢀketo acid 6e (49.2 mg, 0.3 mmol) and imine 1b (49 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7v (71.6 mg, 0.196
20
mmol, 98%) as a yellow oil; [α]D –46.0 (c = 1.08, CH2Cl2); Rf 0.51 (hexane/EtOAc, 1:2); IR
ν
(film) 2924, 1685, 1448, 1363, 1212, 1050, 900, 752, 688 cm–1;
δH 7.98–7.91 (m, 2H), 7.61–7.51
(m, 1H), 7.50–7.41 (m, 2H), 4.16 (d, J = 8.8 Hz, 1H), 3.81–3.67 (m, 1H), 3.41 (dd, J = 17.3, 4.8 Hz,
1H), 3.34 (dd, J = 17.3, 5.9 Hz, 1H), 1.75–1.53 (m, 2H), 1.49–1.23 (m, 12H), 1.22 (s, 9H), 0.86 (t, J
= 7.0 Hz, 3H);
δC 199.5, 137.1 (C), 133.4, 128.7, 128.2 (CH), 56.0 (C), 54.2 (CH), 44.5, 35.7, 31.9,
29.6, 29.4, 29.3, 26.3 (CH2), 22.8 (CH3), 22.8 (CH2), 14.21 (CH3); LRMS (EI) m/z 309 (M+
−
C4H8,
8%), 190 (12), 189 (100), 142 (18), 121 (27), 120 (10), 105 (99), 84 (10), 77 (32), 70 (17), 57 (37),
43 (9), 41 (14); HRMS (ESI): Calculated for C21H36NO2S (M++H) 366.2467, found 366.2465.
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(3S,RS)ꢀ3ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ4ꢀmethylꢀ1ꢀphenylpentanꢀ1ꢀone
(7w):
The
3
4
5
6
representative procedure was followed by using βꢀketo acid 6e (49.2 mg, 0.3 mmol) and imine 1d
(35 mg, 0.2 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7w (31.9
20
mg, 0.108 mmol, 54%) as a yellow wax; [α]D –67.8 (c = 0.99, CH2Cl2); Rf 0.40 (hexane/EtOAc,
7
8
9
1:2); IR
ν δH 8.00–7.90 (m,
(film) 2959, 1681, 1597, 1448, 1364, 1211, 1053, 896, 749, 689 cm–1;
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59
60
2H), 7.61–7.52 (m, 1H), 7.50–7.42 (m, 2H), 4.12 (d, J = 8.7 Hz, 1H), 3.62–3.47 (m, 1H), 3.43 (dd, J
= 17.2, 5.0 Hz, 1H), 3.34 (dd, J = 17.2, 5.8 Hz, 1H), 2.14–1.96 (m, 1H), 1.23 (s, 9H), 0.97 (d, J =
6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); δC 199.6 (C), 137.1 (C), 133.45 (CH), 128.8 (CH), 128.2
(CH), 59.6 (CH), 56.3 (C), 41.5 (CH2), 31.8 (CH), 22.9 (CH3), 19.5 (CH3), 18.7 (CH3); LRMS (EI)
m/z 239 (M+
−C4H8, 10%), 221 (11), 188 (18), 175 (11), 121 (28), 119 (100), 105 (99), 77 (33), 72
(13), 57 (28), 56 (18), 43 (10), 41 (12); HRMS (EI): Calculated for C12H17NO2S (M+–C4H8)
239.0980, found 239.0970.
(3S,RS)ꢀ3ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ1,3ꢀdiphenylpropanꢀ1ꢀone (7x): The representative
procedure was followed by using βꢀketo acid 6e (49.2 mg, 0.3 mmol) and imine 1g (41.8 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7x (45.5 mg, 0.138
20
mmol, 69%) as a yellow wax; [α]D –69.1 (c = 1.03, CH2Cl2); Rf 0.42 (hexane/EtOAc, 1:2); IR
ν
(film) 2958, 1681, 1597, 1449, 1363, 1258, 1205, 1026, 919, 749 cm–1;
δH 7.97–7.86 (m, 2H), 7.62–
7.51 (m, 1H), 7.50–7.23 (m, 7H), 4.97 (dt, J = 8.1, 4.2 Hz, 1H), 4.86 (d, J = 4.1 Hz, 1H), 3.60 (dd, J
= 17.4, 4.4 Hz, 1H), 3.49 (dd, J = 17.4, 7.9 Hz, 1H), 1.22 (s, 9H); δC 198.65, 141.1, 136.6 (C),
133.7, 128.8, 128.2, 128.0, 127.6 (CH), 55.7 (C) 55.45 (CH), 46.0 (CH2), 22.75 (CH3); LRMS (EI)
m/z 273 (M+
(ESI): Calculated for C19H24NO2S (M++H) 330.1528, found 330.1522.
(4R,RS)ꢀ4ꢀAminoꢀNꢀ(tertꢀbutanesulfinyl)ꢀ6ꢀphenylhexanꢀ2ꢀone (7y):
−C4H8, 3%), 209 (11), 153 (49), 106 (15), 105 (100), 104 (9), 77 (24), 57 (14); HRMS
The
representative
procedure was followed by using βꢀketo acid 6f (34.8 mg, 0.3 mmol) and imine 1a (48 mg, 0.2
mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded 7y (13.6 mg, 0.044
mmol, 22%) as a yellow wax; Rf 0.27 (hexane/EtOAc, 1:3); IR
ν (film) 2925, 1705, 1495, 1454,
1362, 1174, 1047, 951, 733, 698 cm–1; Major isomer δH 7.34–7.10 (m, 5H), 4.26 (d, J = 8.8 Hz,
1H), 3.46–3.26 (m, 1H), 3.14–2.72 (m, 2H), 2.66–2.51 (m, 1H), 2.11 (s, 3H), 2.08–1.89 (m, 1H),
1.82–1.69 (m, 1H), 1.28 (s, 9H), 1.23 (d, J = 7.3 Hz, 3H); δC 212.3, 141.5 (C), 128.6, 128.5, 126.2,
58.8 (CH), 56.5 (C), 51.0 (CH), 36.5, 32.6 (CH2), 29.85, 23.0, 13.5 (CH3); Minor isomer δH 7.32–
7.10 (m, 5H), 4.12 (d, J = 8.1 Hz, 1H), 3.46–3.26 (m, 1H), 3.11–2.73 (m, 1H), 2.67–2.50 (m, 2H),
2.15 (s, 3H), 2.07–1.92 (m, 1H), 1.84–1.65 (m, 1H), 1.25 (s, 9H), 1.17 (d, J = 7.4 Hz, 3H); δC
212.4, 141.6 (C), 128.6, 128.5, 126.1, 58.5 (CH), 56.25 (C), 50.8 (CH), 33.4, 32.9 (CH2), 29.5,
22.9, 13.4 (CH3); LRMS (EI) m/z 253 (M+
−C4H8, 14%), 181 (45), 134 (12), 133 (8), 118 (11), 117
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(100), 91 (50), 57 (27), 43 (25), 41 (8); HRMS (EI): Calculated for C13H19NO2S (M+
253.1136, found 253.1133.
−C4H8)
5
6
Synthesis of (−)ꢀPelletierine Hydrochloride from βꢀKeto Acid 6a and Imine 1f: To a solution of
7
8
βꢀketo acid 6a (82.0 mg, 0.8 mmol) in THF (4 mL) was added a 2M solution of LiOH in MeOH
(0.5 mL, 1.0 mmol) at 0 ºC. The reaction mixture was allowed to reach rt and then the imine 1f
(107.2 g, 0.4 mmol) was added and stirring was continued for 1 h. Complete formation of the βꢀketo
amine derivative 7f was followed by TLC. After that, 6M HCl (0.5 mL, 3.0 mmol) was added to the
resulting mixture at 0 ºC and it was stirred for 4.5 h at the same temperature. Removal of the tertꢀ
butanesulfinyl group with concomitant formation of the free amine hydrochloride was also followed
by TLC. Then, a mixture of H2O (5 mL) and AcOEt (5 mL) was added. The resulting aqueous
phase was basified with a 2M NaOH aqueous solution (12 mL) and extracted with CH2Cl2 (4 × 3
mL). To this new organic phase containing exclusively the free amine was added a saturated
aqueous solution of NaHCO3 (8 mL) and this heterogeneous mixture was stirred 12 h at room
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temperature. The organic phase containing (
14%)] was treated with a 2M HCl solution in Et2O (0.5 mL, 1.0 mmol) for 15 min and after that the
−
)ꢀpelletierine [GCꢀMS.ꢀ single peak, m/z 141 (M+,
solvents were evaporated (15 Torr) to yield (
−
)ꢀpelletierine hydrochloride as a white solid (46.9
20
mg, 0.26 mmol, 66%); [α]D20 –16.1 (c = 0.61, EtOH) [lit.31 for (–)ꢀpelletierine hydrochloride [α]D
–18.0 (c = 0.5, EtOH)], ca. 92% ee (from the dr of the intermediate 7f); δH 9.44 (s, 1H), 9.17 (s,
1H), 3.58–3.44 (m, 2H), 3.32 (dd, J = 18.2, 4.1 Hz, 1H), 2.99 (dd, J = 18.2, 8.0 Hz, 1H), 2.95–2.86
(m, 1H), 2.22 (s, 3H), 2.03–1.82 (m, 4H), 1.79–1.67 (m, 1H), 1.62–1.47 (m, 1H);
(CH), 46.0 (CH2), 45.1 (CH2), 30.6 (CH3), 28.4, 22.3, 22.15 (CH2).
δC 205.1 (C), 53.1
ASSOCIATED CONTENT
1
Supporting Information. Copies of H, 13C NMR and DEPT spectra for all the reported
compounds, Xꢀray structures of compounds 7h (Figure S1) and 7u (Figure S2), as well as
Cartesian coordinates, number of imaginary frequencies (NIMAG), and energy data of stationary
points gathered in Figure 2 (Tables S1ꢀS6).
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: yus@ua.es
ACKNOWLEDGMENT
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We thank the continued financial support from our Ministerio de Ciencia e Innovación (MCINN;
projects CTQ2010ꢀ20387, CONSOLIDER INGENIO 2010ꢀCDS2007ꢀ00006, CTQ2011ꢀ24165),
the Ministerio de Economía y Competitividad (MINECO; projects CTQ2014ꢀ53695ꢀP, CTQ2016ꢀ
80375ꢀP, CTQ2014ꢀ51912ꢀREDC, CTQ2016ꢀ81797ꢀREDC), FEDER, the Generalitat Valenciana
(PROMETEO 2009/039, PROMETEOII/2014/017), Gobierno Vasco/Eusko Jaurlaritza (Grant ITꢀ
324ꢀ07), and the University of Alicante.
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References
1. For reviews of Mannich reaction, see: (a)Davis, F. A. Phosphorus, Sulfur Silicon Relat. Elem.
2016, 191, 297. (b) Ishitani, H.; Suzuki, H.; Saito, Y.; Yamashita, Y.; Kobayashi, S. Eur. J. Org.
Chem. 2015, 5485. (c) Decostanzi, M.; Campagne, J.ꢀM.; Leclerc, E. Org. Biomol.
Chem. 2015, 13, 7351. (d) Alvim, H. G. O.; da Silva Jr, E. N.; Neto, B. A. D. RSC
Adv. 2014, 4, 54282. (e) Sreevalli, W.; Ramachandran, G.; Madhuri, W.; Sathiyanarayanan, K. I.
Mini Rev. Org. Chem. 2014, 11, 97. (f) Akiyama, T. The bimolecular and Intramolecular Mannich
and related reaction. In Comprehensive Organic Synthesis (2nd ed.); Knochel, P.; Molander, G. A.,
Eds.; Elsevier: Oxford, 2014, Vol 2, pp 629ꢀ681. (g) Akiyama, T. CꢀC bond formation. Mannich
reaction. In Comprehensive Chirality; Carreira, E. M.; Yamamoto, H., Eds.; Elsevier: Amsterdam,
2012, pp. 69ꢀ96.
2. For recent reviews on synthetic applications of βꢀamino carbonyl compounds, see: (a) Ferreira,
A. J.; Beaudry, C. M. Tetrahedron 2017, 73, 965. (b) VargasꢀCaporali, J.; Juaristi, E.
Synthesis 2016, 48, 3890. (c) Prashad, M.; Shieh, W.ꢀC.; Liu, Y. Tetrahedron 2016, 72, 17.
3. For recent reviews of catalytic enantioselective Mannich reactions, see: (a) Pellissier, H. Chem.
Rev. 2016, 116, 14868. (b) Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Chem. Rev. 2016, 116,
4006. (c) Reid, J. P.; Simon, L.; Goodman, J. M. Acc. Chem. Res. 2016, 49, 1029. 4. For selected
examples, see: (a) Chan, J. Z.; Yao, W.; Hastings, B. T.; Lok, C. K.; Wasa, M. Angew. Chem. Int.
Ed. 2016, 55, 13877. (b) Zhang, H.; Yang, B.; Yang, Z.; Lu, H.; Li, G. J. Org.
Chem. 2016, 81, 7654. (c) Parise, L.; Pellacani, L.; Sciubba, F.; Trulli, L.; Fioravanti, S. J. Org.
Chem. 2015, 80, 8300. (d) Xie, C.; Dai, Y.; Mei, H.; Han, J.; Soloshonok, V. A.; Pan, Y. Chem.
Commun. 2015, 51, 9149. (e) Iwanejko, J.; Wojaczynska, E.; Wojaczynski, J.; Bakowicz, J.
Tetrahedron Lett. 2014, 55, 6619. (f) Liu, Y.; Huang, Y.; Qing, F.ꢀL. Tetrahedron 2012, 68, 4955.
(g) Gu, C.ꢀL.; Liu, L.; Wang, D.; Chen, Y.ꢀJ. J. Org. Chem. 2009, 74, 5754. (h) Cao, H. T.;
Roisnel, T.; Valleix, A.; Grée, R. Eur. J. Org. Chem. 2011, 3430.
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5. For selected examples, see: (a) Zhu, L.; Lu, C.; Chen, Z.; Yang, G.; Li, Y.; Nie, J. Tetrahedron:
Asymmetry 2015, 26, 6. (b) Li, X.ꢀR.; Lu, C.ꢀF.; Chen, Z.ꢀX.; Li, Y.; Yang, G.ꢀC. Tetrahedron:
Asymmetry 2012, 23, 1380. (c) Galestoková, Z.; Sebesta, R. Eur. J. Org. Chem. 2011, 7092.
6. For reviews, see: (a) Lin, G.ꢀQ.; Xu, M.ꢀH.; Zhong, Y.ꢀW.; Sun, X.ꢀW. Acc. Chem. Res. 2008,
41, 831. (b) Ferreira, F.; Botuha, C.; Chemla, F.; PérezꢀLuna, A. Chem. Soc. Rev. 2009, 38, 1162.
(c) Robak, M. A. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
7. (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646. (b) Aggarwal, V. K.; Barbero,
N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suárez, J. R.; Unthank, M. G.; Yar, M. Tetrahedron
Lett. 2009, 50, 3482.
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8. (a) Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73, 9619. (b) Davis, F.
A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J.
Org. Chem. 2005, 70, 2184. (c) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398.
9. (a) Li, Y.; Li, X.; Shang, H.; Chen, X.; Ren, X. J. Org. Chem. 2016, 81, 9858. (b) Xie, C.; Mei,
H.; Wu, L.; Soloshonok, V. A.; Han, J.; Pan, Y. RSC Adv. 2014, 4, 4763. (c) Wu, L.; Xie, C.; Mei,
H.; Soloshonok, V. A.; Han, J.; Pan, Y. Org. Biomol. Chem. 2014, 12, 4620. (d) Babij, N. R.;
Wolfe, J. P. Angew. Chem. Int. Ed. 2012, 51, 4128. (e) Liu, Y.; Huang, Y.; Qing, F.ꢀL. Tetrahedron
2012, 68, 4955. (f) Mei, H.; Xiong, Y.; Han, J.; Pan, Y. Org. Biomol. Chem. 2011, 9, 1402. (g)
Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
10. For recent selected examples, see: (a) Han, F.ꢀZ.; Su, B.ꢀB.; Jia, L.ꢀN.; Wang, P.ꢀW.; Hu, X.ꢀP.
Adv. Synth. Catal. 2017, 359, 146. (b) Kaur, J.; Kumari, A.; Chimni, S. S. Tetrahedron 2017, 73,
802. (c) Li, C.; Grugel, C. P.; Breit, B. Chem. Commun. 2016, 52, 5840.
11. Yang, C.ꢀF.; Shen, C.; Wang, J.ꢀY.; Tian, S.ꢀK. Org. Lett. 2012, 14, 3092.
12. Qian, P.; Dai, Y.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y. RSC Adv. 2015, 5, 26811.
13. (a) GonzalezꢀGomez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74, 2547. (b) Gonzalezꢀ
Gomez, J. C.; Foubelo, F.; Yus, M. Synthesis 2009, 2083. (c) GonzalezꢀGomez, J. C.; Foubelo, F.;
Yus, M. Tetrahedron Lett. 2008, 49, 2343.
14. Dema, H. K.; Foubelo, F.; Yus, M. Helv. Chim. Acta 2012, 95, 1790.
15. Crystal data (excluding structure factors) deposited at the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 1548560.
16. Crystal data (excluding structure factors) deposited at the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 1548559.
17. For selected examples of Nꢀtertꢀbutanesulfinyl haloimines in the synthesis of heterocycles, see:
(a) Leemans, E.; Mangelinckx, S.; De Kimpe, N. Chem. Commun. 2010, 46, 3122. (b) Denolf, B.;
Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211. (c) Denolf, B.; Mangelinckx, S.;
Törnroos, K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129.
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6
7
8
18. Gaussian 16, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.;
Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian,
H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; WilliamsꢀYoung, D.; Ding, F.; Lipparini, F.;
Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.;
Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.;
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.;
Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.;
Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J.
B.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2016.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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34
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47
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49
50
51
52
53
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55
56
57
58
59
60
19. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev.
B: Condens. Matter Mater. Phys. 1988, 37, 785. (c) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J.
Phys. 1980, 58, 1200.
20. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104.
21. Cammi, R.; Mennucci, B.; Tomasi. J. J. Phys. Chem. A 2000, 104, 5631.
22. Zimmerman, H.; Traxler, M. J. Am. Chem. Soc. 1957, 79, 1920.
23. Larrañaga, O.; de Cózar, A.; Bickelhaupt, M. F.; Zangi, R.; Cossío, F. P. Chem. Eur. J. 2013,
19, 13761.
24. Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621.
25. Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 2484.
26. Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2006, 8, 2353.
27. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
28. Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem. 2007, 72,
10035.
29. Ye, L.; He, W.; Zhang, L. Angew. Chem. Int. Ed. 2011, 50, 3236.
30. Zhong, Y.ꢀW.; Xu, M.ꢀH.; Lin, G.ꢀQ. Org. Lett. 2004, 6, 3953.
31. Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter, R. G. J. Org. Chem. 2008, 73,
5155.
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