Asymmetric synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines through rearrangement of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines

Article abstract of DOI:10.1021/acs.joc.7b01241

Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, ¹H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF₃-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.

Full text of DOI:10.1021/acs.joc.7b01241

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Article
Asymmetric synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines
through rearrangement of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines
Jeroen Dolfen, Esma Birsen Boydas, Veronique Van Speybroeck,
Saron Catak, Kristof Van Hecke, and Matthias D'hooghe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01241 • Publication Date (Web): 30 Aug 2017
Downloaded from http://pubs.acs.org on August 30, 2017
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Asymmetric synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines
through rearrangement of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines
†
‡
§
‡,§
∥
Jeroen Dolfen, Esma Birsen Boydas, Veronique Van Speybroeck, Saron Catak, Kristof Van Hecke, and
,
†
Matthias D’hooghe*
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†
SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
‡
Bogazici University, Department of Chemistry, Bebek, Istanbul, 34342, Turkey
§
Center for Molecular Modeling, Ghent University, Tech Lane Ghent Science Park Campus A, Technologiepark
903, B-9052 Zwijnaarde, Belgium
∥XStruct, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281-S3, B-9000 Ghent,
Belgium
ABSTRACT
Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of
chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde
modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment
of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur and
fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to
1
excellent yields (45-99%) and high diastereoselectivities (dr > 99/1, H NMR) via interception of
bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated
in a selective way and used for further synthetic elaboration to produce e.g. a CF
4,7-diazabicyclo[3.3.0]octan-3-one system.
3
-substituted 2-oxa-
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INTRODUCTION
In recent years, the search for synthetic strategies enabling the incorporation of a trifluoromethyl
group in organic molecules has been expanded considerably, as the presence of this entity is known
to provoke a pronounced impact on the physical and chemical properties of the resulting
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compounds. In particular, hydrogen-by-fluorine replacement has been shown to induce an
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enhancement of the metabolic stability and a change in lipophilicity of the involved molecules.
Furthermore, the introduction of fluorine can have a significant effect on the acidity or basicity of
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proximal functional groups. As a consequence, fluorine chemistry plays a pivotal role in
pharmaceutical research nowadays, which is reflected in the fact that nearly 25% of new drugs
3-4
contains at least one fluorine atom in their structure.
Although many protocols toward fluorinated target compounds have been developed in the chemical
literature, the preparation of enantiopure representatives still remains an important challenge and,
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as a consequence, novel routes toward these products are highly desirable. Within the range of
methods to access enantioenriched fluorinated azaheterocycles, ring enlargements of smaller-ring
homologs cover very useful reactions because they can provide a straightforward and efficient access
to different nitrogen-containing target molecules in a stereoselective way. Among them, ring-
expansion reactions associated with strained bicyclic aziridinium intermediates have attracted
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considerable attention bearing in mind the extent and scope of the involved transformations. In that
respect, Cossy et al. have studied the ring enlargement of enantiopure trifluoromethylated prolinols
toward 3-substituted 2-(trifluoromethyl)piperidines IV via bicyclic aziridinium intermediates III
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(
Scheme 1). It was shown that enantiopure piperidines IV could be prepared via regioselective ring
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expansion of 2-(hydroxymethyl)pyrrolidines I bearing a CF group at the C1’ position. Analogously, we
proposed to pursue the synthesis of enantiopure 2-(trifluoromethyl)pyrrolidines VIII via ring
enlargement of azetidines V (this work). Activation of the hydroxyl motif in azetidines V and
subsequent heating might lead to the formation of bicyclic aziridinium intermediates VII, and
interception by an appropriate nucleophile at the bridgehead carbon atom is then expected to afford
pyrrolidine scaffolds VIII in a selective way. Generation and utilization of analogous 1-
azoniabicyclo[2.1.0]pentane intermediates VII (starting from azetidine substrates with a leaving
group attached to the α-carbon of the C2 side chain) toward the preparation of polysubstituted
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pyrrolidines, has been the topic of many research activities. The synthesis of pyrrolidines VIII might
also be of biological relevance, as a lot of bioactive compounds are accommodated with a
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(trifluoromethylated) pyrrolidine scaffold (Figure 1).
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Scheme 1. Synthesis of 3-substituted 2-(trifluoromethyl)piperidines and -pyrrolidines via ring expansion of
the corresponding pyrrolidines and azetidines, respectively.
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Figure 1. Bioactive compounds with a (trifluoromethylated) pyrrolidine scaffold.
From a retrosynthetic point of view, enantiopure pyrrolidines VIII will thus be prepared via ring
expansion of trifluoromethylated 2-(hydroxymethyl)azetidines V through the intermediacy of bicyclic
aziridinium ions VII. The synthesis of azetidines V will be performed starting from 4-formyl-β-lactams
IX (Scheme 2), relying on a trifluoromethylation of the aldehyde moiety by the Ruppert-Prakash
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reagent (TMSCF
3
)
and subsequent reduction of the β-lactam unit by in situ prepared
Cl). It is worth mentioning that the class of 4-formyl-β-lactams has already
monochloroalane (AlH
2
proven to include versatile synthetic intermediates toward a broad range of substances of biological
interest, which is reflected by the large amount of reactivity studies concerning the deployment of
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these synthons in the preparation of amino sugars, bi- and polycyclic β-lactams, γ-lactams and γ-
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lactons, amino acids and complex natural products.
Scheme 2. Retrosynthetic approach for the synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines.
2
OH
O
R O
Nu
H
H
N
H
H
N
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R O
CF3
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RESULTS AND DISCUSSION
The synthesis of 4-formyl-β-lactams 4 was performed according to a well-known four-step
1
1b,11d,12
protocol
with a variety of alkylamines in the presence of MgSO
were immediately and as such treated with phenoxy- or benzyloxyacetyl chloride in the presence of
triethylamine in CH Cl , affording cis-β-lactams 2 in an overall yield of 73-87% after column
and was initiated by the imination of (R)-glyceraldehyde acetonide 1 upon treatment
4
(Table 1). The corresponding chiral imines
2
2
chromatography or recrystallization. Furthermore, it should be mentioned that these azetidine-2-
ones 2 were obtained with high cis-diastereoselectivity (diastereomeric ratios of 91-99/1-9,
1
determined by NMR, CDCl ). This cis-diastereoselectivity could be determined by means of H NMR
3
spectroscopy, as typical coupling constants of 5.0-5.2 Hz (CDCl ) between the 3H and 4H protons on
3
1
2
the β-lactam ring indicate a cis configuration according to the literature. Subsequently, acetal
hydrolysis in the latter compounds 2 was performed in THF/H O (1/1) upon stirring with an
equimolar amount of p-toluenesulfonic acid during four hours under reflux and afforded 4-(1,2-
dihydroxyethyl)-β-lactams 3 in good to excellent yields (67-99%). A final NaIO -mediated Malaprade-
2
4
type oxidation of the 1,2-dihydroxy moiety in β-lactams 3 furnished the desired 4-formyl-β-lactams 4
in 57-97% yield.
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Table 1. Synthesis of 4-(2,2-dimethyl-1,3-dioxolanyl)-β-lactams 2, 4-(1,2-dihydroxyethyl)-β-lactams 3 and 4-
formyl-β-lactams 4.
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1
2
[b]
Entry
R
R
Compound 2
d.r. (2)
Compound 3
(yield [%])
3a (99)
Compound 4
(yield [%])
4a (94)
[a]
(yield [%])
1
2
3
4
5
6
7
iPr
Ph
Ph
2a (73)
2b (81)
2c (87)
2d (74)
2e (80)
2f (87)
2g (74)
93/7
95/5
99/1
91/9
93/7
94/6
91/9
nPr
3b (95)
4b (80)
cHex Ph
3c (99)
4c (78)
Bn
iPr
nPr
Bn
Ph
Bn
Bn
Bn
3d (99)
4d (81)
3e (67)
4e (86)
3f (76)
4f (97)
[
c]
3g (98)
4g (57)
[
a]
After column chromatography (SiO
2
) or recrystallization from EtOH.
Determined by H NMR spectroscopy (CDCl ) of the crude reaction mixture.
After recrystallization from EtOAc/hexane (15/1).
[b]
[c]
1
3
Due to the presence of the aldehyde moiety in 4-formyl-β-lactams 4, the introduction of the
trifluoromethyl group could take place upon reaction with a nucleophilic CF source. To that end, 4-
3
formyl-β-lactams 4a,b were converted into the corresponding 4-(2,2,2-trifluoro-1-
hydroxyethyl)azetidin-2-ones 5a,b and 6a,b in a diastereomeric ratio of 72-74/26-28 using slightly
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adapted reaction conditions as compared to those employed for the synthesis of prolinols I, i.e. a
reduced amount of TMSCF (1.1 instead of 1.5 equiv) and CsF (3 instead of 5.3 equiv) was used in this
3
study to obtain the adducts 5a,b and 6a,b in 88-95% yield after 2 hours at room temperature (Entry 1
and 3, Table 2). Importantly, lowering the reaction temperature at which the reagents are added,
from room temperature to -78 °C, resulted in an improvement of the diastereomeric ratio in favor of
β-lactams 5 (diastereomeric ratio of 90-93/7-10, Entry 2 and 4, Table 2). Having the optimal reaction
conditions for the diastereoselective introduction of the CF
hand, the other 4-formyl-β-lactams 4c-g were also deployed as substrates, affording diastereomers
c-g and 6c-g in a 64-77/23-36 ratio (Entry 5-9, Table 2) and in 63-93% yield after work-up. The
3
group across the aldehyde moiety in
5
isolation of pure diastereoisomers out of the diastereomeric mixtures 5/6 appeared to be highly
dependent on the substitution pattern of the obtained 4-(trifluoroethyl)azetidin-2-ones. In particular,
purification of derivatives a-c,e via either recrystallization or column chromatography furnished the
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major isomers 5a-c,e exclusively in variable yields of 16-74% (Entry 1-5, 7, Table 2). For compounds
5
d,f and 6f, only minor amounts (< 2%) could be obtained for spectroscopic analysis and, as a
consequence, the involved diastereomeric mixtures 5/6d,f were used as such in the next step.
Fortunately, column chromatographic purification of 5g and 6g afforded the pure enantiomers in a
yield of 35% and 23%, respectively. The absolute stereochemistry of the major 4-(2,2,2-trifluoro-1-
hydroxyethyl)azetidin-2-ones 5 was unequivocally established by means of a single-crystal X-ray
analysis of compounds 5a and 5e (see Supporting Information). Although 4-formyl-β-lactams 4 are
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1a,11c
known to provoke a diastereoselective control upon reaction with a nucleophile,
the number of
3
group across
literature procedures involving a catalyst-free enantioselective introduction of a CF
5b
carbonyl moieties is rather limited, and for that reason, the above-described trifluoromethylation
procedure should be considered as relevant.
Table 2. Synthesis of 4-(2,2,2-trifluoro-1-hydroxyethyl)azetidin-2-ones 5 and 6.
1
2
Entry
R
R
Reaction
temp.
rt
Compound 5 + 6 d.r.
Compound 5
(yield [%])
Compound 6
(yield [%])
[
a]
[b]
[c]
[c]
(yield [%])
95
(5/6)
1
2
3
4
5
6
7
8
9
iPr
Ph
Ph
Ph
Ph
74/26 5a (65)
93/7 5a (74)
6a (-)
6a (-)
6b (-)
6b (-)
6c (-)
6d (-)
6e (-)
iPr
-78 °C – rt 92
rt 88
nPr
nPr
72/28 5b (18)
90/10 5b (29)
77/23 5c (16)
-78 °C – rt 64
-78 °C – rt 63
-78 °C – rt 93
-78 °C – rt 93
-78 °C – rt 92
-78 °C – rt 91
cHex Ph
[
d]
Bn
iPr
nPr
Bn
Ph
Bn
Bn
Bn
70/30 5d (-)
67/33 5e (50)
[
d]
[d]
6f (-)
71/29 5f (-)
64/36 5g (35)
6g (23)
[
[
[
a]
b]
c]
After work-up.
1
Determined by H NMR spectroscopy (CDCl
After column chromatography (SiO ) or recrystallization from EtOAc/hexane (5-15/1).
Only minor amounts (< 2%) could be obtained for spectroscopic analysis.
3
) of the crude reaction mixture.
2
[d]
In the next step, the obtained 4-(2,2,2-trifluoro-1-hydroxyethyl)azetidin-2-ones 5 and 6 were reduced
toward the corresponding azetidines through selective carbonyl removal without affecting the
sensitive ring system. To that end, azetidin-2-ones (3R,4S,1’S)-5a-c,e,g were subjected to 1.5 equiv of
1
3
monochloroalane (in situ prepared from AlCl and LiAlH ) and stirred during 2 hours at 0 °C,
3
4
1
4
affording the corresponding azetidines 7 in good to excellent yields (71-94%) (Scheme 3a).
Azetidine 7e appeared to be unstable upon purification on silica gel and, as a consequence, was used
as such in the next step. The same reaction conditions were applied for the selective reduction of the
carbonyl moiety in diastereomeric β-lactam mixtures 5/6d,f, and, fortunately, subsequent column
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chromatographic purification enabled the separation of the major azetidines 7d,f from the minor
isomers 8a,b, although in the case of minor compound 8a, no pure azetidine could be obtained
(
Scheme 3b). Finally, treatment of (3R,4S,1’R)-azetidin-2-one 6g with 1.5 equiv of AlH Cl afforded the
2
corresponding azetidine 8c in 79% yield (Scheme 3c). The isolation of azetidines 8b,c as the 1’-
epimers of azetidines 7 is important in order to be able to assess the influence of this stereocenter
on their further ring-rearrangement aptitude. Also in this stage of the reaction sequence, the
absolute stereochemistry of azetidines 7 was confirmed by means of a single-crystal X-ray analysis of
compounds 7a,b (see Supporting Information).
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Scheme 3. Synthesis of 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines 7 and 8.
In accordance with the work performed on the ring expansion of prolinols I as the higher homologs
7
of azetidines 7 (Scheme 1), azetidine 7a was treated with N,N,N’,N’-tetramethylnaphthalene-1,8-
2 2 2
diamine (Proton sponge, 2 equiv) and triflic anhydride (Tf O, 1.1 equiv) at 0 °C in CH Cl . Surprisingly,
no ring-expansion product was detected after addition of benzylamine and, instead, triflate 9a was
isolated from the reaction mixture in 61% yield (Scheme 4).
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Scheme 4. Synthesis of triflate 9a.
0
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In order to effect the premised azetidine-to-pyrrolidine ring transformation, the reaction
temperature was increased and finally, after 3 days stirring at reflux conditions, the desired 3,4-
disubstituted pyrrolidine 10a was produced in a good yield (67%) and with excellent
diastereoselectivity (dr > 99/1, determined by NMR, CDCl ) (Scheme 5). The requirement of applying
3
a higher temperature and a prolonged reaction time to realize the formation of the bicyclic
aziridinium intermediates VII can be explained by the fact that generation of 1-
azoniabicyclo[2.1.0]pentanes might energetically be more difficult as compared to the production of
6
a
less-constrained 1-azoniabicyclo[3.1.0]hexanes.
Extension of the scope of the observed
diastereoselective azetidine-to-pyrrolidine rearrangement was then accomplished through variation
of the azetidine substrate and/or the applied nitrogen nucleophile. In the case of azetidines 7a-c,
reaction with different alkylamines (benzylamine, allylamine, butylamine, benzyl(methyl)amine and
ethanolamine) afforded
(trifluoromethyl)pyrrolidines 10a-g in good yields (61-89%) and with an excellent diastereoselectivity
dr > 99/1, determined by NMR, CDCl ) (Scheme 5).
a
broad range of novel enantiopure 3,4-disubstituted 2-
(
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Scheme 5. Scope for the synthesis of 3-amino-substituted 2-(trifluoromethyl)pyrrolidines 10a-g starting from
4
-(1-hydroxyethyl)azetidines 7a-c.
10
11
12
13
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However, the deployment of 1-benzylazetidine 7d as a substrate did not yield the anticipated
pyrrolidine scaffold upon treatment with benzylamine, even after 7 days at reflux temperature and,
instead, the corresponding triflate 9b was isolated from the reaction mixture in 73% yield (Scheme
6). This discrepancy in reactivity might be attributable to the less electron-donating properties of a
benzyl group in contrast to an alkyl group, hampering the generation of the corresponding bicyclic
aziridinium intermediate.
Scheme 6. Synthesis of triflate 9b.
To overcome this problem, the above-described one-pot reaction was modified to a two-step
approach, involving sulfonylation of the hydroxyl moiety in azetidine 7d followed by ring expansion
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toward the corresponding 2-(trifluoromethyl)pyrrolidine skeleton in another solvent. To that end,
treatment of azetidine 7d with Tf O in the presence of proton sponge afforded azetidine 9b in an
2
excellent yield of 95% after 40 minutes at 0 °C (Scheme 7). Analogously, the other azetidines 7e-g
and 8b,c were converted into their triflate-activated derivatives 9c-e and 11a,b. Triflate 9c appeared
to be unstable upon silica gel purification and, as a consequence, was used as such in the next step.
Remarkably, triflates 9b-e were obtained in higher yields (90-95%) as compared to their
diastereomeric counterparts 11a,b (71-74%).
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0
Scheme 7. Synthesis of triflates 9b-e and 11a,b.
With the sulfonylated azetidines 9b-e in hand, the premised azetidine-to-pyrrolidine ring expansion
was performed using a higher boiling solvent then CH Cl . In that respect, azetidines 9b-e were
2
2
treated with benzylamine in CH CN, affording 3-benzylamino-2-(trifluoromethyl)pyrrolidines 10h-k in
3
almost quantitative yields (96-99%) and with a high diastereoselectivity (dr > 99/1, determined by
3
NMR, CDCl ) (Scheme 8). Importantly, the obtained yields in this two-step protocol were (in contrast
to the one-pot approach, Scheme 5) much higher and the required reaction time for the
rearrangement could be reduced significantly (from 3 days to 2-3 hours). The absolute
stereochemistry of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines 10 was unambiguously
established by means of a single-crystal X-ray analysis of compound 10h (see Supporting
N
Information), pointing the diastereoselective formation of all-cis-pyrrolidines 10 in a double S 2-
fashion.
In order to further broaden the scope of this diastereoselective azetidine-to-pyrrolidine
rearrangement, other nucleophiles instead of amines were evaluated as well. Reaction of triflate 9c
with
2.5
equiv
of
benzylalcohol
furnished
the
corresponding
3-benzyloxy-2-
(trifluoromethyl)pyrrolidine 10l in 69% yield after silica gel column chromatography. Attempts to
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introduce a methoxy substituent at C3 started with treatment of triflate 9b with 2.5 equiv of sodium
methoxide. After 17 hours stirring at reflux conditions in CH CN, a
mixture of 2-(1-
hydroxyethyl)azetidine 7d and the desired 3-methoxy-2-(trifluoromethyl)pyrrolidine 10m was
obtained in a 77/23 ratio. However, by using a 10/1 mixture of CH CN/MeOH, triflate 9b was fully
3
3
converted to pyrrolidine 10m, which was isolated in an excellent yield (91%). The employment of
sulfur nucleophiles was also evaluated upon reaction of 9b with thiophenol, and the corresponding
10
11
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3
-phenylthio-2-(trifluoromethyl)pyrrolidine 10n was isolated in a moderate yield (45%) after column
chromatography. Efforts were also made concerning the use of carbon nucleophiles to trigger this
ring transformation. Unfortunately, reactions with TBACN in CH CN resulted in complex reaction
CN resulted in full recovery of
3
mixtures, whereas treatment of triflates 9 with KCN in DMSO or CH
3
the initial azetidine substrates 7.
Scheme 8. Scope for the synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines 10h-n starting from
triflates 9b-e.
The introduction of a fluorine substituent was also shown to be possible upon treatment of azetidine
7
2 2
e with diethylaminosulfur trifluoride (DAST, 2 equiv) in CH Cl , and the corresponding 3-fluoro-2-
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(trifluoromethyl)pyrrolidine 10o was thus obtained in 88% yield with a high diastereoselectivity (dr >
8a,8b,15
9
9/1, determined by NMR, CDCl ) (Scheme 9).
3
Scheme 9. Synthesis of 3-fluoro-2-(trifluoromethyl)pyrrolidine 10o.
0
1
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0
Based on the developed strategy for the synthesis of novel enantiopure 3,4-disubstituted 2-
trifluoromethyl)pyrrolidines 10, triflates 11 (the diastereomeric counterparts of triflates 9, epimeric
at the 1’-position) were also treated with 2.5 equiv of benzylamine in CH CN and stirred during 3
(
3
days at reflux conditions. Surprisingly, no ring-expansion products 12 were observed and the starting
material was completely recovered (Scheme 10). Apparently, the stereochemistry of the exocyclic
CF
3
-substituted carbon atom has a profound influence on the ring-rearrangement proclivity of
azetidines 9 versus 11.
Scheme 10. Reaction of triflates 11 with benzylamine.
In order to rationalize this unexpected behavior of (2R,3S,1’S)-azetidines 9 versus (2R,3S,1’R)-
azetidines 11 with respect to their ring-transformation ability, a computational analysis was
performed to elucidate the underlying factors.
Density Functional Theory (DFT) calculations were carried out with the Gaussian 09 software
1
6
17
package. The M06-2X functional, well-known for its performance at predicting accurate transition
18
state geometries, was used in conjunction with a 6-31+G(d,p) basis set for conformational analysis
on all reactants, transition states and intermediates to identify most plausible conformers. Free
energies are reported in kJ/mol at 1 atm and 81 °C. Normal mode analysis has been performed, as
1
9
well as Intrinsic Reaction Coordinate (IRC) calculations to verify the transition state geometries. The
possible pathways under study were modeled using the Conductor-like Polarizable Continuum Model
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2
0
(C-PCM), where the solute is placed in a continuous medium characterized by a dielectric constant,
21
22
to mimic the solvation effects. Energy refinements were performed at the MPW1K, ωB97X-D, and
2
3
PBE0 levels of theory, combined with a triple- ζ basis set (6-311+G(3df,3pd)), proven to be
2
4
particularly accurate.
10
11
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The ring transformation of (2R,3S,1’S)-azetidines 9 to pyrrolidines 10 is proposed to go through a
bicyclic intermediate (9-INT) as shown in Scheme 11 The initial step, which leads to the bicyclic
.
intermediate, involves a concerted displacement of the triflate leaving group via the nucleophilic
attack of the nitrogen lone pair. Pre-reactive conformers (PRC’s) and transition states (TS’s) leading
to the corresponding bicyclic intermediates were analyzed and compared for both azetidines 9 and
1
1. It is important to note that only one of the N-invertomers for compounds 9 and 11 have the
nitrogen lone pair in the right position to lead to an S 2-type attack. To that end, a thorough
N
conformational search of the reactants was performed to take into account the relative positions of
the nitrogen and triflate groups. Incidentally, calculations have shown in both cases, the most stable
invertomers are the ones that could lead to the formation of the bicyclic intermediate.
Scheme 11. Proposed mechanism for the synthesis of pyrrolidines 10 from azetidines 9 through the
formation of bicyclic intermediates 9-INT.
A free-energy reaction profile has been constructed for both azetidines at the MPW1K/6-
311+G(3df,3pd)//M06-2X/6-31+G(d,p) level of theory, where critical distances and angles of PRC’s
and TS’s have also been depicted (Figure 2). When the structures of the pre-reactive conformers are
closely inspected, the close proximity of the CF
to lead to a large geometrical distortion, which is reflected in an unusually large bond angle (126° in
e-PRC versus 114° in 11b-PRC). This, in turn, causes a remarkable energy difference of around 35
3
moiety and the benzyloxy group in 9e-PRC is shown
9
kJ/mol (MPW1K/6-311+G(3df,3pd)) between the two starting compounds. As a consequence, 11b-
PRC appears to be significantly more stable than 9e-PRC, making the latter intrinsically more
reactive. This result is consistently verified with all four levels of theory employed in this study (Table
3).
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‡
Table 3. Relative Gibbs free energies (kJ/mol) of activation (ΔG ) and reaction (ΔGrxn) with respect to 11b-
PRC.
[
a]
[b]
(c]
[d]
0
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8
9
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9
0
M06-2X
0.0
MPW1K
0.0
ωB97X-D
PBE0
0.0
11b-PRC
e-PRC
1b-TS
0.0
9
30.9
111.9
128.0
9.3
35.1
32.2
34.5
104.0
117.4
10.1
1
111.8
127.5
9.9
106.4
119.2
5.2
9e-TS
1
1b-INT
9
e-INT
-6.2
-9.2
-18.2
-10.0
[
[
a]
Optimizations with C-PCM in acetonitrile (ε = 37.5)
b,c,d]
Energy refinements on M06-2X/6-31+G(d,p) optimized geometries using a 6-311+G(3df,3pd)
basis set with C-PCM in acetonitrile (ε = 37.5).
‡
The differences between the activation barriers (ΔΔG ) for the formation of the bicyclic
intermediates are around 19 kJ/mol in a consistent manner for all levels of theory (Table 4), clearly
indicating the ease of reaction for azetidines 9. Moreover, 9e-INT is also thermodynamically more
stable than its counterpart 11b-INT. DFT calculations, consistent with experimental work, suggest the
formation of a bicyclic intermediate to be unfavorable for azetidines 11.
‡
Table 4. Relative Gibbs free energies (kJ/mol) of activation (ΔG ) and reaction (ΔGrxn).
[
a]
[b]
[c]
[d]
M06-2X
97.1
MPW1K
92.4
ωB97X-D
PBE0
‡
ΔG
86.9
82.9
-44.5
101.7
10.1
9
e
ΔGrxn
-37.1
111.9
9.3
-44.3
111.8
9.9
-50.4
106.4
5.2
‡
ΔG
1
1b
ΔGrxn
[
a]
Optimizations with C-PCM in acetonitrile (ε =37.5)
[
b,c,d]
Energy refinements on M06-2X/6-31+G(d,p) optimized geometries using a 6-311+G(3df,3pd)
basis set with C-PCM in acetonitrile (ε =37.5).
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9
e-TS
9e-PRC
11b-TS
11b-PRC
Figure 2. Free-energy profile (MPW1K/6-311+G(3df,3pd)//M06-2X/6-31+G(d,p)) for the formation of the bicyclic intermediates 9e-INT and 11b-INT (354 K and 1 atm, C-
PCM
in
acetonitrile
(ε
=37.5)).
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As the 3-amino-4-hydroxypyrrolidine unit has been reported to be present in compounds associated
25
with diverse biological activities, additional synthetic efforts were performed to evaluate the
debenzylation aptitude of 3-benzylamino-substituted azaheterocycles 10. To that end, a selection of
3
-benzylamino-2-(trifluoromethyl)pyrrolidines 10g,i,k was treated with Pd(OH)
in MeOH, resulting in 3-amino-2-(trifluoromethyl)pyrrolidines 13 and 14 after 4 hours at room
temperature in excellent yields (89-91%) (Scheme 12). In the case of pyrrolidine 10k, a double
debenzylation took place to furnish free diamine 14
2
/C (20% w/w) at 4 bar
H
2
0
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9
0
N
-
.
Scheme 12. Synthesis of 3-amino-2-(trifluoromethyl)pyrrolidines 13 and 14.
In order to encourage the
addition to -debenzylation, pyrrolidine 10i was subjected to more harsh deprotection conditions
Pd(OH) /C (40% w/w), 5 bar H ) and, eventually, 3-amino-4-hydroxy-2-(trifluoromethyl)pyrrolidine
O-debenzylation of 4-benzyloxy-substituted azaheterocycles 10 as well, in
N
(
2
2
1
5 was obtained in 92% yield after 4 days in MeOH at room temperature (Scheme 13). So, depending
on the reaction conditions used for the hydrogenolysis of azaheterocycles 10 (containing a benzyl
group at either the 1-, 3-amino and/or 4-hydroxy position of the pyrrolidine unit), the deprotection
of these molecules can be performed in a selective way through initial
N- and, if desired, subsequent
O-debenzylation. Bearing in mind the large number of bioactive compounds accommodating a 3-
amino-4-hydroxypyrrolidine entity, this straightforward and high-yielding debenzylation protocol
undoubtedly offers perspectives for further elaboration in the framework of bioactive compound
development.
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Scheme 13. Synthesis of 3-amino-4-hydroxy-1-isopropyl-2-(trifluoromethyl)pyrrolidine 15.
10
11
12
13
14
15
16
17
18
19
20
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Furthermore, the free NH and OH moieties in pyrrolidines 13-15 render these scaffolds very
2
promising building blocks for incorporation in larger bioactive structures and for additional synthetic
manipulations. In that respect, evaluation of the obtained 3-aminopyrrolidines was performed by
treatment of 3-amino-2-(trifluoromethyl)pyrrolidine 13b with an equimolar amount of triphosgene,
affording the corresponding 3-isocyanato-2-(trifluoromethyl)pyrrolidine 16 in 67% yield (Scheme 14).
In addition, 3-amino-4-hydroxypyrrolidine 15 was treated with triphosgene as well, applying the
2 2
same reaction conditions as for the preparation of pyrrolidine 16 (1 equiv triphosgene, CH Cl , room
temperature). After 2 hours, 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one 17 was obtained in an isolated
yield of 81% after silica gel column chromatography (Scheme 14). From these selected examples, it is
2
clear that further synthetic elaboration of the free NH and OH moieties in chiral pyrrolidines 13-15
offers many new opportunities for follow-up studies.
Scheme 14. Reactions of 3-amino-2-(trifluoromethyl)pyrrolidines 13b and 15 with triphosgene.
In a final experiment, evidence for the chiral integrity of the prepared pyrrolidines was provided. In
that respect, amidation of 3-amino-2-(trifluoromethyl)pyrrolidine 13b with an equimolar amount of
(1
S
)-(—)-camphanic chloride in CH
2
Cl
2
at room temperature for 2 hours on an analytical scale
1
afforded the corresponding 3-(camphanoylamino)pyrrolidine as a single diastereomer (based on H
NMR and GC analysis), pointing to the fact that no isomerization took place throughout the complete
reaction sequence.
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CONCLUSION
In summary, a straightforward and reliable four-step protocol was developed for the synthesis of
chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines starting from enantiopure 4-formyl-β-lactams.
To that end, trifluoromethylation of these 4-formylazetidin-2-ones resulted in the diastereoselective
0
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0
formation of 4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-β-lactams as the major isomers. Reduction of the
β-lactam carbonyl group and subsequent sulfonylation of the hydroxyl motif afforded the
corresponding triflate-activated azetidines without loss of chirality. Owing to the presence of the
triflate leaving group, ring expansion of these azetidine scaffolds could be realized through the
intermediacy of bicyclic aziridinium ions, although the premised rearrangement appeared to be
dependent on the stereochemistry of the exocyclic CF
3
-substituted carbon atom. Whereas the major
(1’S)-azetidines were easily converted to 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines with high
diastereoselectivity upon reaction with a variety of nitrogen, oxygen, sulfur and fluorine
nucleophiles, their diastereomeric counterparts (epimeric at 1’ position) were not able to act as
substrates for this type of ring rearrangement. Theoretical calculations revealed that the major (1’
azetidines are less stable than the minor (1’ )-azetidines, which in combination with a lower
activation barrier of (1’ )-azetidines toward the corresponding bicyclic aziridinium ions can explain
the remarkable difference in reactivity. Finally, - versus -selective debenzylation of some of the
S)-
R
S
N
O
obtained pyrrolidine ring systems was successfully effectuated, enabling the eventual incorporation
of these chiral building blocks into larger frameworks and their further synthetic elaboration, as
shown by the synthesis of a 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one scaffold.
EXPERIMENTAL SECTION
1
H NMR spectra were recorded at 400 MHz on a Bruker Advance III-400 with solvents as indicated and
1
9
tetramethylsilane as internal standard. F NMR spectra were recorded at 376 MHz on a Bruker Advance III-400
1
3
with solvents as indicated. C NMR spectra were recorded at 100 MHz on a Bruker Advance III-400 with
solvents as indicated. IR spectra were measured with a IRAffinity-1S FT-IR spectrophotometer. Electron spray
(ES) mass spectra were obtained with an Agilent 1100 Series MS (ES, 4000V) mass spectrometer. High
resolution electron spray (ES-TOF) mass spectra were obtained with an Agilent Technologies 6210 Series time-
of-flight mass spectrometer. The Mass analyzer type used is a double focusing High Resolution Magnetic Sector
(
Merk: Thermo Fisher, Type: Mat95XP-Trap). Melting points were determined on a Kofler bench, type WME
Heizbank of Wagner & Munz and were corrected. All other solvents and reagents were used as received from
the supplier.
2
6
(
R)-Glyceraldehyde acetonide 1 was synthesized according to literature procedures.
Synthesis of 4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]azetidin-2-ones 2.
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As a representative example, the synthesis of (3R,4S)-1-isopropyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-
4
phenoxyazetidine-2-one 2a is described. MgSO (7.22 g, 60 mmol, 2 equiv) and isopropylamine (1.77 g, 2.58
mL, 30 mmol, 1 equiv) were added to a solution of (R)-glyceraldehyde acetonide 1 (3.9 g, 30 mmol, 1 equiv) in
anhydrous CH Cl (120 mL). After stirring for 2 hours at room temperature, MgSO was removed by filtration.
2
2
4
Evaporation of the solvent in vacuo afforded the corresponding (E)-N-[((4S)-2,2-dimethyl-1,3-dioxolan-4-
1
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
yl)methylidene]isopropylamine in high purity (> 95% based on H NMR spectroscopy), which was used as such
in the next reaction step due to its hydrolytic instability. To an ice-cooled solution of (E)-N-[((4S)-2,2-dimethyl-
1
,3-dioxolan-4-yl)methylidene]isopropylamine (5.13 g, 30 mmol, 1 equiv) and triethylamine (9.10 g, 12.53 mL,
0 mmol, 3 equiv) in anhydrous CH Cl (100 mL), a solution of phenoxyacetyl chloride (6.65 g, 5.39 mL, 39
9
2
2
mmol, 1.3 equiv) in CH Cl (10 mL) was added dropwise. After stirring for 15 hours at room temperature, the
2
2
reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). Drying (MgSO4),
filtration of the drying agent, and removal of the solvent in vacuo afforded (3R,4S)-1-isopropyl-4-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-3-phenoxyazetidin-2-one 2a, which was isolated by means of recrystallization from
EtOH in an overall yield of 73% (6.68 g, 21.9 mmol) as a white powder.
(3R,4S)-1-Isopropyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-phenoxyazetidin-2-one (2a).
Yield 73% (6.68 g). White powder. Mp 86 ± 2 °C. Recrystallization from EtOH. ꢀαꢁ2 = +185.3 (c = 0.18, CH Cl ).
H NMR (400 MHz, CDCl
5
D
2
2
1
3
): δ 1.33 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H), 1.39 (s, 3H), 1.47 (s, 3H), 3.67 (dd, J
= 8.8, 6.5 Hz, 1H), 3.87 (dd, J = 8.9, 5.2 Hz, 1H), 3.98 (septet, J = 6.6 Hz, 1H), 4.25 (dd, J = 8.8, 6.6 Hz, 1H), 4.39
1
3
(
ddd, J = 8.9, 6.6, 6.5 Hz, 1H), 5.13 (d, J = 5.2 Hz, 1H), 7.00-7.04 (m, 1H), 7.07-7.09 (m, 2H), 7.27-7.31 (m, 2H).
NMR (100 MHz, ref = CDCl ): δ 19.5 (CH ), 21.3 (CH ), 25.1 (CH ), 26.8 (CH ), 44.9 (CH), 59.9 (CH), 67.1 (CH
7.1 (CH), 79.3 (CH), 109.6 (C), 115.8 (2 CH), 122.5 (CH), 129.6 (2
744, 1499, 1489, 1458, 1398, 1352, 1259, 1236, 1213, 1155, 1059, 1022, 852, 843, 758, 692, 509. MS (70 eV):
C
3
3
3
3
3
2
),
-1
7
1
×
×CH), 157.5 (C), 165.3 (C). IR (cm ): 2976,
+
m/z (%): 306 (M +1, 100).
(3R,4S)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-phenoxy-1-propylazetidin-2-one (2b).
= 0.19 (Petroleumether/EtOAc 6/1). ꢀαꢁ25 = +160.9 (c = 0.17,
Yield 81% (5.90 g). White powder. Mp 62 ± 2 °C. R
D
f
1
CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 0.95 (t, J = 7.4 Hz, 3H), 1.38 (s, 3H), 1.46 (s, 3H), 1.58-1.78 (m, 2H), 3.27
(
ddd, J = 13.7, 7.8, 5.9 Hz, 1H), 3.45 (ddd, J = 13.7, 7.5, 7.5 Hz, 1H), 3.68 (dd, J = 8.8, 6.2 Hz, 1H), 3.83 (dd, J =
9
7
2
.0, 5.0 Hz, 1H), 4.18 (dd, J = 8.8, 6.5 Hz, 1H), 4.43 (ddd, J = 9.0, 6.5, 6.2 Hz, 1H), 5.20 (d, J = 5.0 Hz, 1H), 7.00-
1
3
.04 (m, 1H), 7.07-7.09 (m, 2H), 7.28-7.32 (m, 2H). C NMR (100 MHz, ref = CDCl
3 3 2
): δ 11.5 (CH ), 20.8 (CH ),
5.1 (CH ), 26.8 (CH ), 43.3 (CH ), 60.4 (CH), 66.9 (CH ), 77.2 (CH), 79.8 (CH), 109.7 (C), 115.7 (2×CH), 122.5
3
3
2
2
-1
(
CH), 129.6 (2×CH), 157.4 (C), 166.0 (C). IR (cm ): 2967, 2936, 1748, 1599, 1589, 1495, 1371, 1238, 1209, 1155,
+
1061, 1013, 854, 754, 691, 507. MS (70 eV): m/z (%): 306 (M +1, 100).
(3R,4S)-1-Cyclohexyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-phenoxyazetidin-2-one (2c).
2
5
Yield 87% (9.00 g). White powder. Mp 79 ± 2 °C. R
f
= 0.12 (Petroleumether/EtOAc 6/1). ꢀαꢁD = +166.9 (c = 0.17,
1
CH
Cl
2 2
). H NMR (400 MHz, CDCl
3
): δ 1.11-1.34 (m, 3H), 1.39 (s, 3H), 1.47 (s, 3H), 1.59-1.92 (m, 7H), 3.53-3.60
(m, 1H), 3.66 (dd, J = 8.8, 6.5 Hz, 1H), 3.88 (dd, J = 8.9, 5.2 Hz, 1H), 4.23 (dd, J = 8.8, 6.5 Hz, 1H), 4.38 (dt, J = 8.9,
1
3
6
.5 Hz, 1H), 5.13 (d, J = 5.2 Hz, 1H), 7.00-7.03 (m, 1H), 7.07-7.09 (m, 2H), 7.27-7.31 (m, 2H). C NMR (100 MHz,
ref = CDCl ): δ 25.1 (CH ), 25.2 (CH ), 25.36 (CH ), 25.38 (CH ), 26.8 (CH ), 29.8 (CH ), 31.1 (CH ), 52.9 (CH), 60.0
CH), 67.1 (CH ), 77.2 (CH), 79.2 (CH), 109.5 (C), 115.8 (2×CH), 122.4 (CH), 129.6 (2×CH), 157.5 (C), 165.3 (C). IR
cm ): 2941, 1734, 1599, 1587, 1489, 1283, 1267, 1163, 1121, 1094, 1038, 752, 727, 691. MS (70 eV): m/z (%):
3
3
2
2
2
3
2
2
(
(
2
-1
+
346 (M +1, 100).
(3R,4S)-1-Benzyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-phenoxyazetidin-2-one (2d).
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2
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3
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3
3
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3
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
= 0.24 (Petroleumether/EtOAc 6/1). ꢀαꢁ25 = +70.1 (c = 0.19,
Yield 74% (7.84 g). White powder. Mp 107 ± 2 °C. R
D
f
1
CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 1.36 (s, 3H), 1.38 (s, 3H), 3.61 (dd, J = 8.9, 6.3 Hz, 1H), 3.70 (dd, J = 9.0, 5.1
Hz, 1H), 4.13 (dd, J = 8.9, 6.3 Hz, 1H), 4.29 (d, J = 14.6 Hz, 1H), 4.48 (dt, J = 9.0, 6.3 Hz, 1H), 4.87 (d, J = 14.6 Hz,
1
3
1H), 5.16 (d, J = 5.1 Hz, 1H), 7.02-7.08 (m, 3H), 7.26-7.35 (m, 7H). C NMR (100 MHz, ref = CDCl
3 3
): δ 25.1 (CH ),
26.7 (CH ), 45.4 (CH ), 59.4 (CH), 66.9 (CH ), 77.1 (CH), 80.0 (CH), 109.8 (C), 115.7 (CH), 122.5 (CH), 127.8 (CH),
3
2
2
-
1
1
28.7 (CH), 128.9 (CH), 129.7 (CH), 135.6 (C), 157.3 (C), 165.7 (C). IR (cm ): 2988, 1748, 1597, 1589, 1497, 1487,
+
1
209, 1061, 1040, 856, 754, 739, 694, 669. MS (70 eV): m/z (%): 354 (M +1, 100).
0
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2
3
4
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6
7
8
9
0
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2
3
4
5
6
7
8
9
0
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9
0
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2
3
4
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7
8
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9
0
Spectral data of 4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]azetidin-2-ones 2e-g correspond with those reported in
1
2,27
the literature.
Synthesis of 4-[(1S)-1,2-dihydroxyethyl]azetidin-2-ones 3.
As
phenoxyazetidin-2-one 3a is described. To a solution of (3R,4S)-1-isopropyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-phenoxy-azetidin-2-one 2a (1.83 g, 6 mmol, 1 equiv) in THF/H O (1/1, 60 mL) was added pTsOH∙H O (1.14
g, 6 mmol, 1 equiv) in a single portion. After a reflux period of 4 hours, the resulting reaction mixture was
allowed to cool to room temperature and was then neutralized to pH 7 with solid NaHCO . The mixture was
extracted with EtOAc (3 × 30 mL), the combined organic layers were dried (MgSO ), and the solvent was
removed under reduced pressure to afford (3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-1-isopropyl-3-phenoxyazetidin-
-one 3a in 99% yield (1.57 g, 5.94 mmol) as a colorless oil.
a
representative example, the synthesis of (3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-1-isopropyl-3-
2
2
3
4
2
(3R,4S)-4-[(1S)-1,2-Dihydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one (3a).
Yield 99% (1.57 g). Colorless oil. ꢀαꢁ 2D 5 = +152.1 (c = 0.37, CH
1
2 2
Cl
). H NMR (400 MHz, CDCl
3
): δ 1.33 (d, J = 6.7
Hz), 1.41 (d, J = 6.7 Hz, 3H), 2.17-2.20 (m, 1H), 2.76 (d, J = 4.2 Hz, 1H), 3.70-3.75 (m, 1H), 3.79-3.88 (m, 1H),
.83 (septet, J = 6.7 Hz, 1H), 3.96 (dd, J = 5.5, 5.3 Hz, 1H), 4.06-4.12 (m, 1H), 5.15 (d, J = 5.3 Hz, 1H), 7.01-7.05
3
1
3
(
(
(
m, 1H), 7.08-7.11 (m, 2H), 7.28-7.32 (m, 2H). C NMR (100 MHz, ref = CDCl
3 3 3
): δ 20.0 (CH ), 21.2 (CH ), 46.4
CH), 58.1 (CH), 63.8 (CH ), 71.3 (CH), 79.5 (CH), 115.9 (2×CH), 122.7 (CH), 129.7 (2×CH), 157.4 (C), 165.7 (C). IR
2
-
1
cm ): 3389, 2980, 2951, 1740, 1597, 1495, 1339, 1234, 1132, 1092, 1022, 910, 841, 748, 729, 689. MS (70 eV):
+
m/z (%): 266 (M +1, 100).
(3R,4S)-4-[(1S)-1,2-Dihydroxyethyl]-3-phenoxy-1-propylazetidin-2-one (3b).
Yield 95% (1.51 g). Colorless oil. ꢀαꢁ 2D 5 = +116.5 (c = 0.30, CH
1
2
2 3
Cl ). H NMR (400 MHz, CDCl ): δ 0.93 (t, J = 7.4 Hz,
3
7
5
H), 1.54-1.77 (m, 2H), 2.18 (br s, 1H), 2.75 (br s, 1H), 3.21 (ddd, J = 13.8, 8.1, 5.6 Hz, 1H), 3.52 (ddd, J = 13.8,
.7, 7.7 Hz, 1H 3.69-3.73 (m, 1H), 3.79-3.83 (m, 1H), 3.97 (dd, J = 5.1, 5.0 Hz, 1H), 4.11-4.16 (m, 1H), 5.23 (d, J =
13
.0 Hz, 1H), 7.02-7.04 (m, 1H), 7.09-7.11 (m, 2H), 7.28-7.32 (m, 2H). C NMR (100 MHz, ref = CDCl ): δ 11.5
3
(
3 2 2 2
CH ), 20.8 (CH ), 43.8 (CH ), 58.2 (CH), 64.0 (CH ), 71.3 (CH), 80.1 (CH), 115.9 (2×CH), 122.7 (CH), 129.7 (2×CH),
-1
1
57.4 (C), 166.3 (C). IR (cm ): 3401, 1732, 1591, 1495, 1416, 1344, 1231, 1090, 1067, 1043, 1028, 908, 891,
+
7
52, 729, 691. MS (70 eV): m/z (%): 266 (M +1, 100).
(3R,4S)-1-Cyclohexyl-4-[(1S)-1,2-dihydroxyethyl]-3-phenoxyazetidin-2-one (3c).
Yield 99% (1.81 g). Colorless oil. ꢀαꢁ25 = +102.7 (c = 0.20, CH
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 1.17-1.32 (m, 3H),
D
1
1
2
.61-1.92 (m, 6H), 2.01-2.08 (m, 2H), 2.66 (d, J = 4.4 Hz, 1H), 3.37-3.44 (m, 1H), 3.71-3.77 (m, 1H), 3.79-3.85 (m,
H), 3.98 (dd, J = 5.2, 5.2 Hz, 1H), 4.08-4.13 (m, 1H), 5.16 (d, J = 5.2 Hz, 1H), 7.01-7.05 (m, 1H), 7.09-7.10 (m,
13
H), 7.27-7.32 (m, 2H). C NMR (100 MHz, ref = CDCl
3 2 2 2 2
): δ 25.2 (CH ), 25.3 (CH ), 25.4 (CH ), 30.4 (CH ), 31.2,
(
CH
2
) 54.4 (CH), 58.0 (CH), 63.9 (CH ), 71.4 (CH), 79.5 (CH), 115.9 (2×CH), 122.7 (CH), 129.7 (2×CH), 157.4 (C),
2
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1
65.6 (C). IR (cm ): 3412, 2932, 2855, 1728, 1597, 1495, 1364, 1231, 1076, 1043, 907, 893, 752, 729, 689. MS
+
(70 eV): m/z (%): 306 (M +1, 100).
(
3R,4S)-1-Benzyl-4-[(1S)-1,2-dihydroxyethyl]-3-phenoxyazetidin-2-one (3d).
25
1
Yield 99% (1.86 g). Colorless oil. ꢀαꢁD = +71.5 (c = 0.46, CH Cl ). H NMR (400 MHz, CDCl ): δ 1.91 (t, J = 5.8 Hz,
H), 2.46 (d, J = 4.3 Hz, 1H), 3.60-3.66 (m, 1H), 3.70-3.75 (m, 1H), 3.83 (dd, J = 5.2, 5.2 Hz, 1H), 4.09-4.14 (m,
H), 4.39 (d, J = 14.9 Hz, 1H), 4.82 (d, J = 14.9 Hz, 1H), 5.23 (d, J = 5.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.10-7.12 (m,
2
2
3
1
1
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
13
H), 7.28-7.39 (m, 7H). C NMR (100 MHz, ref = CDCl
3 2 2
): δ 45.8 (CH ), 58.1 (CH), 63.8 (CH ), 71.3 (CH), 80.4 (CH),
-
1
15.9 (2×CH), 122.8 (CH), 128.0 (CH), 128.4 (CH), 129.0 (CH), 129.7 (CH), 135.6 (C), 157.3 (C), 166.4 (C). IR (cm
1
)
: 3406, 1736, 1589, 1408, 1350, 1229, 1134, 1076, 1028, 908, 839, 754, 729, 691, 646, 608. MS (70 eV): m/z
+
(
%): 314 (M +1, 100).
(
3R,4S)-3-Benzyloxy-4-[(1S)-1,2-dihydroxyethyl]-1-isopropylazetidin-2-one (3e).
Yield 67% (1.12 g). Colorless oil. ꢀαꢁ 2D 5 = +74.1 (c = 0.26, CH
H), 1.36 (d, J = 6.8 Hz, 3H), 2.41 (t, J = 5.6 Hz, 1H), 2.93 (d, J = 4.1 Hz, 1H), 3.65-3.78 (m, 4H), 3.93-3.98 (m, 1H),
1
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 1.27 (d, J = 6.7 Hz,
3
4
13
.58 (d, J = 5.1 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H), 4.94 (d, J = 11.7 Hz, 1H), 7.31-7.36 (m, 2H). C NMR (100 MHz,
): δ 20.0 (CH ), 21.2 (CH ), 46.0 (CH), 58.1 (CH), 63.8 (CH ), 71.3 (CH), 73.2 (CH ), 79.8 (CH), 128.1
2×CH), 128.2 (CH), 128.6 (2×CH), 136.7 (C), 167.3 (C). IR (cm ): 3397, 2974, 2936, 2878, 1717, 1454, 1404,
ref = CDCl
3
3
3
2
2
-1
(
+
1
339, 1229, 1215, 1148, 1067, 1022, 910, 779, 733, 696. MS (70 eV): m/z (%): 280 (M +1, 100).
(
3R,4S)-3-Benzyloxy-4-[(1S)-1,2-dihydroxyethyl]-1-propylazetidin-2-one (3f).
Yield 76% (1.27 g). Colorless oil. ꢀαꢁ25 = +69.5 (c = 0.36, CH
H), 1.48-1.70 (m, 2H), 2.50 (br s, 1H), 3.01 (br s, 1H), 3.11 (ddd, J = 13.8, 8.1, 5.5 Hz, 1H), 3.46 (ddd, J = 13.8,
.8, 7.8 Hz, 1H), 3.64-3.77 (m, 3H), 3.97-4.01 (m, 1H), 4.66 (d, J = 5.0 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.95 (d, J
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 0.89 (t, J = 7.4 Hz,
D
3
7
=
13
11.6 Hz, 1H), 7.29-7.38 (m, 5H). C NMR (100 MHz, ref = CDCl
3 3 2 2
): δ 11.4 (CH ), 20.7 (CH ), 43.5 (CH ), 58.1
(
(
(
CH), 64.0 (CH
2
), 71.3 (CH), 73.3 (CH ), 80.5 (CH), 128.1 (2×CH), 128.3 (CH), 128.6 (2×CH), 136.6 (C), 167.9 (C). IR
2
-1
cm ): 3393, 2965, 2934, 2876, 1724, 1454, 1416, 1383, 1342, 1215, 1155, 1070, 1020, 907, 822, 733, 696. MS
+
70 eV): m/z (%): 280 (M +1, 100).
(
3R,4S)-1-Benzyl-3-benzyloxy-4-[(1S)-1,2-dihydroxyethyl]azetidin-2-one (3g).
2
5
1
Yield 98% (1.92 g). Colorless oil. ꢀαꢁ = +22.2 (c = 0.38, CHCl ). H NMR (400 MHz, CDCl ): δ 2.01 (br s, 1H), 2.66
br s, 1H), 3.55-3.62 (m, 3H), 3.95-3.96 (m, 1H), 4.26 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 5.1 Hz, 1H), 4.26 (d, J = 11.7
D
3
3
(
13
Hz, 1H), 4.79 (d, J = 15.0 Hz, 1H), 4.97 (d, J = 11.7 Hz, 1H), 7.25-7.39 (m, 10H). C NMR (100 MHz, ref = CDCl ): δ
3
4
1
1
2 2 2
5.5 (CH ), 58.0 (CH), 63.9 (CH ), 71.0 (CH), 73.4 (CH ), 80.4 (CH), 127.9 (CH), 128.1 (2×CH), 128.30 (2×CH),
-1
28.35 (CH), 128.6 (2×CH), 128.9 (2×CH), 135.6 (C), 136.5 (C), 167.7 (C). IR (cm ): 3397, 2926, 2876, 1728, 1497,
+
454, 1406, 1341, 1217, 1155, 1074, 910, 822, 731, 696, 604. MS (70 eV): m/z (%): 328 (M +1, 100).
Synthesis of 4-formylazetidin-2-ones 4.
As a representative example, the synthesis of (2R,3R)-1-isopropyl-4-oxo-3-phenoxyazetidine-2-carbaldehyde 4a
is described. To a solution of (3R,4S)-4-[(1S)-1,2-dihydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one 3a (1.59
2 2 3 2 4
g, 6 mmol, 1 equiv) in CH Cl /NaHCO (sat. in H O) (15/1, 80 mL), NaIO (2.57 g, 12 mmol, 2 equiv) was added
portionwise during a period of 10 minutes. The resulting solution was stirred for 2 hours at room temperature.
Afterward, the crude mixture was filtered and the resulting filtrate was washed with H O (2 × 20 mL). Drying
2
(
4
MgSO ), filtration of the drying agent and evaporation of the solvent in vacuo afforded (2R,3R)-1-isopropyl-4-
oxo-3-phenoxyazetidine-2-carbaldehyde 4a in 94% yield (1.31 g, 5.64 mmol) as a yellow oil, which was purified
by means of column chromatography on silica gel (Petroleumether/EtOAc 4/1) to provide an analytically pure
sample.
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(2R,3R)-1-Isopropyl-4-oxo-3-phenoxyazetidine-2-carbaldehyde (4a).
2
D
5
1
Yield 94% (1.31 g). Yellow oil. R = 0.10 (Petroleumether/EtOAc 4/1). ꢀαꢁ = +86.3 (c = 0.28, CH Cl ). H NMR
f
2
2
(
400 MHz, CDCl
.8 Hz, 1H), 5.37 (d, J = 5.1 Hz, 1H), 7.00-7.06 (m, 3H), 7.26-7.32 (m, 2H), 9.74 (d, J = 3.8 Hz, 1H). C NMR (100
MHz, ref = CDCl ): δ 20.2 (CH ), 21.6 (CH ), 45.0 (CH), 62.4 (CH), 81.2 (CH), 115.6 (2×CH), 122.9 (CH), 129.7
3
): δ 1.27 (d, J = 6.7 Hz, 3H), 1.28 (d, J = 6.7 Hz, 3H), 4.06 (septet, J = 6.7 Hz, 1H), 4.37 (dd, J = 5.1,
1
3
3
3
3
3
-
1
(2×CH), 156.9 (C), 164.3 (C), 198.4 (C). IR (cm ): 2976, 1732, 1597, 1589, 1495, 1387, 1344, 1227, 1026, 845,
+
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
752, 689. MS (70 eV): m/z (%): 234 (M +1, 100). HRMS (ESI): m/z calcd for C13
H
16NO
3
: 234.1125 [M+H] , found:
234.1132.
(2R,3R)-4-Oxo-3-phenoxy-1-propylazetidine-2-carbaldehyde (4b).
= 0.05 (Petroleumether/EtOAc 4/1). ꢀαꢁ25 = +72.4 (c = 0.36, CH
1
Yield 80% (1.12 g). Yellow oil. R
f
2
Cl
2
). H NMR
D
(
400 MHz, CDCl ): δ 0.97 (t, J = 7.4 Hz, 3H), 1.52-1.70 (m, 2H), 3.29-3.36 (m, 1H), 3.39-3.46 (m, 1H), 4.38 (dd, J =
3
1
3
5
.0, 2.9 Hz, 1H), 5.46 (d, J = 5.0 Hz, 1H), 7.01-7.07 (m, 3H), 7.28-7.32 (m, 2H), 9.74 (d, J = 2.9 Hz, 1H). C NMR
): δ 11.5 (CH ), 21.2 (CH ), 43.9 (CH ), 63.8 (CH), 82.2 (CH), 115.5 (2×CH), 123.0 (CH), 129.8
2×CH), 156.9 (C), 165.0 (C), 197.7 (C). IR (cm ): 2965, 2934, 1732, 1597, 1589, 1495, 1412, 1344, 1231, 1130,
(
(
100 MHz, ref = CDCl
3
3
2
-
2
1
+
3
1067, 1022, 752, 729, 689. MS (70 eV): m/z (%): 234 (M +1, 100). HRMS (ESI): m/z calcd for C13H16NO :
+
234.1125 [M+H] , found: 234.1124.
(2R,3R)-1-Cyclohexyl-4-oxo-3-phenoxyazetidine-2-carbaldehyde (4c).
2
5
1
Yield 78% (1.16 g). Colorless oil. R
400 MHz, CDCl ): δ 1.11-2.01 (m, 10H), 3.66-3.73 (m, 1H), 4.35 (dd, J = 5.0, 4.1 Hz, 1H), 5.36 (d, J = 5.0 Hz, 1H),
.99-7.06 (m, 3H), 7.26-7.32 (m, 2H), 9.73 (d, J = 4.1 Hz, 1H). C NMR (100 MHz, ref = CDCl ): δ 24.8 (CH ), 24.9
f
= 0.29 (Petroleumether/EtOAc 7/3). ꢀαꢁD = +69.6 (c = 0.17, CH
2 2
Cl ). H NMR
(
3
1
3
6
3
2
(
CH
2
), 25.1 (CH
2 2 2
), 30.6 (CH ), 31.9 (CH ), 52.4 (CH), 62.6 (CH), 81.3 (CH), 115.6 (2×CH), 122.9 (CH), 129.7 (2×CH),
-1
1
56.9 (C), 164.4 (C), 198.6 (C). IR (cm ): 2932, 2855, 1732, 1597, 1589, 1495, 1229, 1076, 1047, 1026, 752, 691.
+
+
3
MS (70 eV): m/z (%): 274 (M +1, 100). HRMS (ESI): m/z calcd for C16H20NO : 274.1438 [M+H] , found: 274.1436.
(2R,3R)-3-Benzyloxy-1-isopropyl-4-oxoazetidine-2-carbaldehyde (4e).
= 0.09 (Petroleumether/EtOAc 7/3). ꢀαꢁ 2D 5 = +64.7 (c = 0.19, CHCl
1
Yield 86% (1.27 g). Yellow oil. R
f
3
). H NMR
(
400 MHz, CDCl
3
): δ 1.19 (d, J = 6.7 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 4.00 (septet, J = 6.7 Hz, 1H), 4.11 (dd, J = 5.1,
4
7
.0 Hz, 1H), 4.63 (d, J = 11.7 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H), 4.82 (d, J = 5.1 Hz, 1H), 7.00-7.06 (m, 3H), 7.29-
13
3 3 3
.37 (m, 2H), 9.65 (d, J = 4.0 Hz, 1H). C NMR (100 MHz, ref = CDCl ): δ 20.2 (CH ), 21.6 (CH ), 44.6 (CH), 62.5
-
1
(
CH), 73.3 (CH ), 82.4 (CH), 128.2 (CH), 128.4 (CH), 128.6 (CH), 136.0 (C), 165.9 (C), 199.9 (C). IR (cm ): 2976,
2
+
2
936, 2878, 1728, 1454, 1387, 1339, 1210, 1155, 1130, 1009, 912, 733, 698. MS (70 eV): m/z (%): 248 (M +1,
+
3
100). HRMS (ESI): m/z calcd for C14H18NO : 248.1281 [M+H] , found: 248.1281.
(2R,3R)-3-Benzyloxy-4-oxo-1-propylazetidine-2-carbaldehyde (4f).
Yield 97% (1.44 g). Colorless oil. ꢀαꢁ 2D 5 = +71.8 (c = 0.20, CH
1
2
2 3
Cl ). H NMR (400 MHz, CDCl ): δ 0.92 (t, J = 7.4 Hz,
3
3
H), 1.45-1.64 (m, 2H), 3.25 (ddd, J = 14.1, 8.0, 6.2 Hz, 1H), 3.35 (ddd, J = 14.1, 8.0, 6.8 Hz, 1H), 4.12 (dd, J = 5.0,
.2 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H), 4.92 (d, J = 5.0 Hz, 1H), 7.31-7.38 (m, 5H), 9.62 (d,
13
J = 3.2 Hz, 1H). C NMR (100 MHz, ref = CDCl ): δ 11.4 (CH ), 21.2 (CH ), 43.6 (CH ), 64.0 (CH), 73.4 (CH ), 83.4
3
3
2
2
2
-1
(
CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 136.0 (C), 166.5 (C), 199.2 (C). IR (cm ): 2965, 2934, 2876, 1728, 1454,
+
1
408, 1342, 1217, 1155, 1069, 1009, 735, 696. MS (70 eV): m/z (%): 248 (M +1, 100). HRMS (ESI): m/z calcd for
+
14 3
C H18NO : 248.1281 [M+H] , found: 248.1289.
27-28
Spectral data of 4-formylazetidin-2-ones 4d,g correspond with those reported in the literature.
Synthesis of 4-(2,2,2-trifluoro-1-hydroxyethyl)azetidin-2-ones 5 and 6.
As a representative example, the synthesis of (3R,4S)-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-
phenoxyazetidin-2-one 5a and (3R,4S)-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-
one 6a is described. A solution of (2R,3R)-1-isopropyl-4-oxo-3-phenoxyazetidine-2-carbaldehyde 4a (2.10 g, 9
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mmol, 1 equiv) in dry THF (20 mL) was cooled to -78 °C. Then, CsF (4.10 g, 27 mmol, 3 equiv) and TMSCF (1.41
g, 1.14 mL, 9.9 mmol, 1.1 equiv) were added and the resulting solution was heated up slowly to room
temperature during a period of 2 hours. Next, EtOH (10 mL) was added and the solution was stirred for an
additional 1 hour at room temperature. Afterward, H O was added and the aqueous phases were extracted
2
with EtOAc (3 × 20 mL). Drying (MgSO
afforded (3R,4S)-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one 5a and (3R,4S)-4-
(1R)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one 6a in a diastereomeric ratio of 93/7.
Purification of the crude reaction mixture by means of recrystallization from EtOAc/hexane (5/1) afforded
3R,4S)-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one 5a as a white powder in a
4
), filtration of the drying agent and evaporation of the solvent in vacuo
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
[
(
yield of 74% (2.02 g, 6.66 mmol). This purification method also accounts for the isolation of 4-(2,2,2-trifluoro-1-
hydroxyethyl)azetidin-2-ones 5b,c,e. 4-(2,2,2-Trifluoro-1-hydroxyethyl)azetidin-2-ones 5d,f,g and 6g were
purified by means of column chromatography on silica gel.
(3R,4S)-4-[(1S)-2,2,2-Trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one (5a).
2
5
Yield 74% (2.02 g). White powder. Mp 161 ± 2 °C. Recrystallization from EtOAc/Hexane (5/1). ꢀαꢁ = +124.5 (c =
D
1
0.10, CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 1.33 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H), 2.73 (d, J = 5.2 Hz,
1H), 3.63 (septet, J = 6.8 Hz, 1H), 4.24 (dd, J = 5.1, 2.2 Hz, 1H), 4.34-4.42 (m, 1H), 5.22 (d, J = 5.1 Hz, 1H), 7.05-
1
9
13
7
.12 (m, 3H), 7.30-7.34 (m, 2H). F NMR (376 MHz, ref = CDCl
ref = CDCl ): δ 20.0 (CH ), 20.6 (CH ), 47.5 (CH), 55.5 (CH), 67.9 (q, J = 31.3 Hz, CH), 79.5 (CH), 116.0 (2×CH),
23.1 (CH), 124.3 (q, J = 281.3 Hz, C), 129.8 (2×CH), 157.1 (C), 165.3 (C). IR (cm ): 3256, 2984, 1732, 1597, 1589,
3
): -76.27 (d, J = 8.1 Hz, 3F). C NMR (100 MHz,
3
3
3
-1
1
1
1
+
413, 1362, 1262, 1229, 1175, 1163, 1130, 1115, 1026, 812, 754, 689, 669. MS (70 eV): m/z (%): 304 (M +1,
+
17 3 3
00). HRMS (ESI): m/z calcd for C14H F NO : 304.1155 [M+H] , found: 304.1155.
(3R,4S)-4-[(1S)-2,2,2-Trifluoro-1-hydroxyethyl]-3-phenoxy-1-propylazetidin-2-one (5b).
2
5
Yield 29% (791 mg). White powder. Mp 101 ± 2 °C. Recrystallization from EtOAc/Hexane (5/1). ꢀαꢁ = +113.5 (c
D
1
= 0.15, CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 0.93 (t, J = 7.4 Hz, 3H), 1.52-1.74 (m, 2H), 2.88 (d, J = 5.2 Hz, 1H),
3.10 (ddd, J = 13.8, 8.2, 5.5 Hz, 1H), 3.52-3.59 (m, 1H), 4.25 (dd, J = 5.0, 1.8 Hz, 1H), 4.35-4.43 (m, 1H), 5.30 (d, J
1
9
13
=
5.0 Hz, 1H), 7.05-7.12 (m, 3H), 7.30-7.34 (m, 2H). F NMR (376 MHz, ref = CDCl
NMR (100 MHz, ref = CDCl ): δ 11.4 (CH ), 20.5 (CH ), 43.6 (CH ), 55.4 (CH), 67.9 (q, J = 31.5 Hz, CH), 80.3 (CH),
16.0 (2×CH), 123.2 (CH), 124.3 (q, J = 276.7 Hz, C), 129.9 (2×CH), 157.0 (C), 165.9 (C). IR (cm ): 3377, 2978,
753, 1495, 1418, 1285, 1236, 1173, 1155, 1150, 1125, 1113, 1028, 750, 689, 665. MS (70 eV): m/z (%): 304
3
): -76.72 (d, J = 8.1 Hz, 3F). C
3
3
2
3
-1
1
1
+
+
(
M +1, 100). HRMS (ESI): m/z calcd for C H F NO : 304.1155 [M+H] , found: 304.1163.
14 17 3 3
(3R,4S)-1-Cyclohexyl-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3-phenoxyazetidin-2-one (5c).
2
5
Yield 16% (494 mg). White powder. Mp 136 ± 2 °C. Recrystallization from EtOAc/Hexane (15/1)ꢂꢀαꢁ = +118.0
D
1
(c = 0.27, CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 1.17-1.29 (m, 3H), 1.61-1.95 (m, H), 2.11-2.14 (m, 1H), 2.86 (d, J
= 5.4 Hz, 1H), 3.18-3.26 (m, 1H), 4.25 (dd, J = 5.1, 2.4 Hz, 1H), 4.37 (qdd, J = 7.9, 5.4, 2.4, 1H), 5.21 (d, J = 5.1 Hz,
1
9
13
1H), 7.04-7.10 (m, 3H), 7.28-7.34 (m, 2H). F NMR (376 MHz, ref = CDCl
3
): δ -76.29 (d, J = 7.9 Hz, 3F). C NMR
), 30.6 (CH ), 55.3 (CH), 55.4 (CH), 67.8
q, J = 31.3 Hz, CH), 79.4 (CH), 116.0 (2×CH), 123.1 (CH), 124.3 (q, J = 281.8 Hz, C), 129.8 (2×CH), 157.1 (C), 165.3
(
(
(
100 MHz, ref = CDCl
3
): δ 25.16 (CH
2
), 25.19 (CH
2
), 25.5 (CH
2
), 30.2 (CH
2
2
-1
+
C). IR (cm ): 3252, 2943, 1724, 1265, 1229, 1169, 1126, 1098, 808, 746, 689. MS (70 eV): m/z (%): 344 (M +1,
+
1
00). HRMS (ESI): m/z calcd for C H F NO : 344.1468 [M+H] , found: 344.1482.
17 21 3 3
(3R,4S)-1-Benzyl-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3-phenoxyazetidin-2-one (5d).
White powder. Mp 88 ± 2 °C. R
f
= 0.23 (Petroleumether/EtOAc 4/1, 4 CV 0% EtOAc, 24 CV 0-9% EtOAc, 1 CV 9-
100% EtOAc, UV = 222 nm).ꢀαꢁ25 = +11.3 (c = 0.16, CH
1
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 3.06 (d, J = 5.5 Hz, 1H),
D
4.08 (dd, J = 5.1, 2.4 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 4.39 (qdd, J = 7.7, 5.5, 2.4, 1H), 4.97 (d, J = 15.0 Hz, 1H),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
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5
5
5
5
6
1
9
5
.26 (d, J = 5.1 Hz, 1H), 7.04-7.10 (m, 3H), 7.25-7.39 (m, 7H). F NMR (376 MHz, ref = CDCl
3
): δ -76.51 (d, J = 7.7
1
3
Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 45.7 (CH ), 55.0 (CH), 67.9 (q, J = 31.5 Hz, CH), 80.5 (CH), 116.0
3
2
(2×CH), 123.2 (CH), 124.2 (q, J = 282.4 Hz, C), 128.1 (CH), 128.5 (CH), 129.0 (CH), 129.8 (CH), 135.0 (C), 157.0
-1
(C), 166.1 (C). IR (cm ): 3422, 1755, 1489, 1418, 1229, 1179, 1169, 1125, 1078, 764, 733, 696. MS (70 eV): m/z
+
+
(%): 352 (M +1, 100). HRMS (ESI): m/z calcd for C H F NO : 352.1155 [M+H] , found: 352.1163.
1
8
17
3
3
(
3R,4S)-3-Benzyloxy-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropylazetidin-2-one (5e).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yield 50% (1.43 g). White powder. Mp 101 ± 2 °C. Recrystallization from EtOAc/Hexane (5/1). ꢀαꢁ2 = +79.9 (c =
5
D
1
0
3
1
3
.35, CHCl
3
). H NMR (400 MHz, CDCl
3
): δ 1.27 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.06 (d, J = 4.7 Hz, 1H),
.54 (septet, J = 6.8 H, 1H z), 3.99 (dd, J = 5.1, 2.2 Hz, 1H), 4.13-4.20 (m, 1H), 4.65 (d, J = 5.1 Hz, 1H), 4.70 (d, J =
19
1.6 Hz, 1H), 4.94 (d, J = 11.6 Hz, 1H), 7.31-7.40 (m, 2H). F NMR (376 MHz, ref = CDCl
3
): δ -76.10 (d, J = 8.1 Hz,
13
F). C NMR (100 MHz, ref = CDCl
), 79.8 (CH), 124.3 (q, J = 282.2 Hz, C), 128.3 (CH), 128.6 (CH), 128.8 (CH), 136.2 (C), 166.9 (C). IR (cm ):
3302, 2978, 2936, 2886, 1717, 1418, 1344, 1263, 1169, 1123, 1024, 986, 818, 702, 756, 685. MS (70 eV): m/z
3 3 3
): δ 20.1 (CH ), 20.6 (CH ), 47.3 (CH), 55.4 (CH), 67.9 (q, J = 31.3 Hz, CH), 73.7
-
1
(CH
2
+
+
(%): 318 (M +1, 100). HRMS (ESI): m/z calcd for C H F NO : 318.1312 [M+H] , found: 318.1314.
1
5
19
3
3
(
3R,4S)-3-Benzyloxy-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-propylazetidin-2-one (5f).
White powder. Mp 101 ± 2 °C. Reversed phase column chromatography (CH
3
CN/H
2
O) (40 CV 33% CH
3
CN, 5 CV
CN). ꢀαꢁ25 = +62.9 (c = 0.18, CHCl
1
3
7
7
4
3-50% CH
3
CN, 5 CV 50-100% CH
3
3
). H NMR (400 MHz, CDCl
3
): δ 0.88 (t, J =
D
.4 Hz, 3H), 1.45-1.65 (m, 2H), 3.01 (ddd, J = 14.0, 8.3, 5.4 Hz, 1H), 3.13 (d, J = 4.4 Hz, 1H), 3.49 (ddd, J = 14.0,
.7, 7.7 Hz, 1H), 4.01 (dd, J = 5.0, 1.7 Hz, 1H), 4.13-4.20 (m, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.75 (d, J = 5.0 Hz, 1H),
1
9
13
.95 (d, J = 11.6 Hz, 1H), 7.32-7.40 (m, 5H). F NMR (376 MHz, ref = CDCl
): δ 11.3 (CH ), 20.4 (CH ), 43.2 (CH ), 55.2 (CH), 68.1 (q, J = 31.4 Hz, CH), 73.8 (CH
2
3
): δ -76.55 (d, J = 8.2 Hz, 3F). C NMR
(100 MHz, ref = CDCl
3
3
2
2
), 80.6
-
1
(CH), 124.3 (q, J = 280.8 Hz, C), 128.3 (CH), 128.6 (CH), 128.8 (CH), 136.1 (C), 167.4 (C). IR (cm ): 3227, 2967,
+
1717, 1429, 1344, 1261, 1173, 1011, 691, 687. MS (70 eV): m/z (%): 318 (M +1, 100). HRMS (ESI): m/z calcd for
+
C
15
H
19
F
3
NO
3
: 318.1312 [M+H] , found: 318.1326.
(
3R,4S)-1-Benzyl-3-benzyloxy-4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]azetidin-2-one (5g).
= 0.04 (Petroleumether/EtOAc 6/1). ꢀαꢁ25 = -9.2 (c = 0.19,
Yield 35% (1.15 g). White powder. Mp 70 ± 2 °C. R
D
CHCl ). H NMR (400 MHz, CDCl ): δ 3.02 (d, J = 4.7 Hz, 1H), 3.85 (dd, J = 5.1, 2.0 Hz, 1H), 4.02 (d, J = 15.0 Hz,
f
1
3
3
1
H), 4.12-4.19 (m, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.73 (d, J = 5.1 Hz, 1H), 4.93 (d, J = 15.0 Hz, 1H), 4.96 (d, J = 11.6
19
13
Hz, 1H), 7.21-7.38 (m, 10H). F NMR (376 MHz, ref = CDCl
3
): δ -76.21 (d, J = 8.1 Hz, 3F). C NMR (100 MHz, ref
), 81.0 (CH), 124.1 (q, J = 278.9 Hz, C), 127.9
=
CDCl ): δ 45.2 (CH ), 54.8 (CH), 68.1 (q, J = 31.5 Hz, CH), 73.8 (CH
3
2
2
-
1
(CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 135.1 (C), 136.0 (C), 167.3 (C). IR (cm ): 3261,
+
3034, 2943, 1724, 1420, 1346, 1263, 1163, 1134, 1101, 1026, 825, 669. MS (70 eV): m/z (%): 366 (M +1, 100).
+
HRMS (ESI): m/z calcd for C19
H
19
F
3
NO
3
: 366.1312 [M+H] , found: 366.1328.
(
3R,4S)-3-Benzyloxy-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-1-propylazetidin-2-one (6f).
Colorless oil. Reversed phase column chromatography (CH
3
CN/H
2
O) (40 CV 33% CH
3 3
CN, 5 CV 33-50% CH CN, 5
CN). ꢀαꢁ25 = +67.6 (c = 0.11, CHCl
1
CV 50-100% CH
3
3
). H NMR (400 MHz, CDCl
3
): δ 0.93 (t, J = 7.4 Hz, 3H), 1.50-
D
1
1
.68 (m, 2H), 3.03 (ddd, J = 14.1, 8.1, 5.8 Hz, 1H), 3.40 (ddd, J = 14.1, 7.6, 7.6 Hz, 1H), 3.95 (dd, J = 4.7, 4.6 Hz,
H), 4.09 (d, J = 8.8 Hz, 1H), 4.23-4.32 (m, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.86 (d, J = 4.7 Hz, 1H), 4.98 (d, J = 11.4
1
9
13
Hz, 1H), 7.32-7.40 (m, 5H). F NMR (376 MHz, ref = CDCl ): δ -76.27 (d, J = 8.0 Hz, 3F). C NMR (100 MHz, ref =
3
3 3 2 2 2
CDCl ): δ 11.4 (CH ), 20.8 (CH ), 42.3 (CH ), 55.0 (CH), 70.0 (q, J = 31.3 Hz, CH), 73.8 (CH ), 82.2 (CH), 124.3 (q, J
-
1
= 283.1 Hz, C), 128.2 (CH), 128.6 (CH), 128.7 (CH), 135.7 (C), 166.6 (C). IR (cm ): 3354, 2967, 2938, 2880, 1740,
+
1342, 1271, 1215, 1173, 1148, 1123, 1090, 1067, 1009, 737, 698. MS (70 eV): m/z (%): 318 (M +1, 100). HRMS
+
(ESI): m/z calcd for C15
H
19
F
3
NO
3
: 318.1312 [M+H] , found: 318.1325.
(
3R,4S)-1-Benzyl-3-benzyloxy-4-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]azetidin-2-one (6g).
= 0.07 (Petroleumether/EtOAc 6/1). ꢀαꢁ25 = +33.2 (c = 0.16, CHCl
): δ 3.78 (dd, J = 4.8, 4.6 Hz, 1H), 4.04 (d, J = 8.9 Hz, 1H), 4.08 (d, J = 15.2 Hz, 1H), 4.12-4.22 (m,
1
Yield 23% (756 mg). Colorless oil. R
f
3
). H NMR
D
(
400 MHz, CDCl
3
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H), 4.78 (d, J = 15.2 Hz, 1H), 4.79 (d, J = 11.5 Hz, 1H), 4.83 (d, J = 4.8 Hz, 1H), 4.97 (d, J = 11.5 Hz, 1H), 7.22-7.38
1
9
13
(m, 10H). F NMR (376 MHz, ref = CDCl ): δ -76.08 (d, J = 7.6 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 44.6
3
3
(CH
2
), 54.5 (CH), 69.7 (q, J = 31.4 Hz, CH), 73.9 (CH
2
), 82.5 (CH), 124.2 (q, J = 282.9 Hz, C), 128.2 (CH), 128.3 (CH),
-
1
128.6 (CH), 128.7 (CH), 129.1 (CH), 134.3 (C), 135.6 (C), 166.7 (C). IR (cm ): 3397, 3032, 2938, 1744, 1342, 1271,
+
1163, 1126, 1094, 1028, 739, 696. MS (70 eV): m/z (%): 366 (M +1, 100). HRMS (ESI): m/z calcd for C H F NO :
1
9
19
3
3
+
366.1312 [M+H] , found: 366.1313.
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Synthesis of 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines 7 and 8.
As a representative example, the synthesis of (2S,3S)-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-
phenoxyazetidine 7a is described. To an ice-cooled solution of AlCl (0.6 g, 4.5 mmol, 1.5 equiv) in dry Et O (20
mL), a solution of LiAlH (4.5 mL, 4.5 mmol, 1.5 equiv, 1.0 M in Et O) was added via a syringe. Then, the
resulting solution was stirred at room temperature for 30 minutes, after which a solution of (3R,4S)-4-[(1S)-
,2,2-trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidin-2-one 5a (909 mg, 3 mmol, 1 equiv) in dry Et O
3
2
4
2
2
2
(10 mL) was added at 0 °C, followed by stirring for 2 hours at 0 °C. Afterward, the reaction mixture was
quenched with brine (10 mL) to neutralize the excess of LiAlH . Then, an excess of MgSO (5 g) was added and
the reaction mixture was filtered. Subsequently, the remaining solids on the filter were washed intensively with
EtOAc ( × 20 mL). Evaporation of the combined organic phases in vacuo afforded (2S,3S)-2-[(1S)-2,2,2-
4
4
5
trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidine 7a in a yield of 94% (815 mg, 2.82 mmol) as a white
powder, which was purified by means of column chromatography on silica gel (Petroleumether/EtOAc 9/1) to
provide an analytically pure sample. Azetidine 7e appeared to be unstable upon purification on silica gel.
(2S,3S)-2-[(1S)-2,2,2-Trifluoro-1-hydroxyethyl]-1-isopropyl-3-phenoxyazetidine (7a).
= 0.13 (Petroleumether/EtOAc 9/1). ꢀαꢁ25 = +39.3 (c = 0.15,
Yield 94% (815 mg). White powder. Mp 87 ± 2 °C. R
D
f
1
CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): δ 1.02 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H), 2.89 (septet, J = 6.5 Hz, 1H),
3
.45-3.49 (m, 1H), 3.68 (dd, J = 9.7, 7.3 Hz, 1H), 4.0.3-4.06 (m, 1H), 4.22-4.29 (m, 1H), 4.93 (ddd, J = 7.3, 7.3, 3.7
1
9
Hz, 1H), 5.63 (br s, 1H), 6.75-6.77 (m, 2H), 6.96-7.00 (m, 1H), 7.25-7.29 (m, 2H). F NMR (376 MHz, ref = CDCl
3
):
), 60.7,
64.0 (q, J = 30.9 Hz, CH), 66.7 (CH), 114.8 (2×CH), 121.7 (CH), 125.3 (q, J = 281.9 Hz, C), 129.7 (2×CH), 156.8 (C).
13
3 3 3 2
-78.33 (d, J = 8.1 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 16.4 (CH ), 20.0 (CH ), 51.4 (CH), 53.0 (CH
-
1
+
IR (cm ): 3030, 1599, 1587, 1489, 1227, 1165, 1121, 1094, 908, 752, 727, 692. MS (70 eV): m/z (%): 290 (M +1,
+
19 3 2
100). HRMS (ESI): m/z calcd for C14H F NO : 290.1362 [M+H] , found: 290.1364.
(2S,3S)-2-[(1S)-2,2,2-Trifluoro-1-hydroxyethyl]-3-phenoxy-1-propylazetidine (7b).
2
5
Yield 86% (746 mg). White powder. Mp 95 ± 2 °C. R
f
= 0.14 (Petroleumether/EtOAc 9/1). ꢀαꢁD = +96.1 (c = 0.25,
): δ 0.90 (t, J = 7.4 Hz, 3H), 1.36-1.46 (m, 2H), 2.49 (ddd, J = 11.7, 7.3, 6.2 Hz,
H), 2.71-2.78 (m, 1H), 3.40 (dd, J = 9.6, 6.5 Hz, 1H), 3.63-3.66 (m, 1H), 3.82-3.85 (m, 1H), 4.37-4.43 (m, 1H),
1
2 2 3
CH Cl ). H NMR (400 MHz, CDCl
1
1
9
4
.96 (ddd, J = 6.6, 6.5, 2.5 Hz, 1H), 6.05 (br s, 1H), 6.76-6.78 (m, 2H), 6.96-7.00 (m, 1H), 7.25-7.29 (m, 2H). F
1
3
3 3 3 2
NMR (376 MHz, ref = CDCl ): -78.87 (d, J = 8.1 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 11.5 (CH ), 20.6 (CH ),
58.5 (CH
2 2
), 59.2 (CH ), 64.7 (q, J = 30.8 Hz, CH), 65.2 (CH), 67.8 (CH), 114.8 (2×CH), 121.6 (CH), 125.2 (q, J =
-
1
282.0 Hz, C), 129.7 (2×CH), 156.7 (C). IR (cm ): 2963, 1591, 1497, 1489, 1265, 1225, 1165, 1121, 1092, 750, 691.
+
+
MS (70 eV): m/z (%): 290 (M +1, 100). HRMS (ESI): m/z calcd for C H F NO : 290.1362 [M+H] , found:
1
4
19
3
2
290.1359.
(2S,3S)-1-Cyclohexyl-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3-phenoxyazetidine (7c).
= 0.11 (Petroleumether/EtOAc 19/1). ꢀαꢁ25 = +38.9 (c =
Yield 71% (701 mg). White powder. Mp 99 ± 2 °C. R
D
f
1
0
.11, CH Cl ). H NMR (400 MHz, CDCl ): δ 1.01-1.28 (m, 5H), 1.63-1.66 (m, 1H), 1.77-1.84 (4H, m, 4H), 2.43-
2
2
3
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5
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6
2
.49 (m, 1H), 3.50 (dd, J = 9.7, 3.9 Hz, 1H), 3.73 (dd, J = 9.7, 7.4 Hz, 1H), 4.13-4.15 (m, 1H), 4.19-4.25 (m, 1H),
1
9
4.94 (ddd, J = 7.4, 7.4, 3.9 Hz, 1H), 5.59 (br s, 1H), 6.74-6.76 (m, 2H), 6.96-7.00 (m, 1H), 7.25-7.30 (m, 2H).
F
1
3
NMR (376 MHz, ref = CDCl
(CH ), 25.7 (CH ), 27.2 (CH
114.8 (2×CH), 121.7 (CH), 125.3 (q, J = 281.8 Hz, C), 129.7 (2×CH), 156.8 (C). IR (cm ): 2934, 2857, 1589, 1489,
3
): δ -78.17 (d, J = 8.1 Hz, 3F). C NMR (100 MHz, ref = CDCl
3 2
): δ 24.8 (CH ), 25.1
2
2
2
), 30.6 (CH ), 54.1 (CH ), 59.9 (CH), 60.1 (CH), 63.9 (q, J = 30.8 Hz, CH), 67.0 (CH),
2
2
-
1
+
1234, 1215, 1167, 1123, 1090, 1016, 750, 691, 669. MS (70 eV): m/z (%): 330 (M +1, 100). HRMS (ESI): m/z
+
calcd for C H F NO : 330.1675 [M+H] , found: 330.1673.
1
7
23
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2S,3S)-1-Benzyl-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3-phenoxyazetidine (7d).
Yield 43% (435 mg). White powder. Mp 110 ± 2 °C. Reversed phase column chromatography (CH
3
CN/H
2
O) (2 CV
):
CN). ꢀαꢁ25 = +67.6 (c = 0.16, CH
1
40% CH
3
CN, 20 CV 40-60% CH
3
CN, 5 CV 60% CH
3
2
Cl
2
). H NMR (400 MHz, CDCl
3
D
δ 3.46-3.53 (m, 2H), 3.62 (d, J = 13.1 Hz, 1H), 4.01 (d, J = 13.1 Hz, 1H), 4.06-4.08 (m, 1H), 4.26 (~q, J = 8.0 Hz,
1H), 4.95 (ddd, J = 6.5, 6.5, 3.4 Hz, 1H), 5.34 (br s, 1H), 6.71-6.73 (m, 2H), 6.94-6.98 (m, 1H), 7.23-7.7.36 (m, 7H).
1
9
13
F NMR (376 MHz, ref = CDCl
3 3 2
): δ -78.68 (d, J = 8.0 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 57.9 (CH ), 59.8
(CH ), 64.2 (CH), 64.9 (q, J = 30.9 Hz, CH), 67.4 (CH), 114.7 (2×CH), 121.6 (CH), 125.1 (q, J = 281.3 Hz, C), 127.8
2
-
1
(CH), 128.6 (CH), 128.7 (CH), 129.7 (CH), 136.3 (C), 156.7 (C). IR (cm ): 3030, 2698, 1599, 1489, 1362, 1227,
+
1165, 1121, 1094, 1040, 752, 727, 691. MS (70 eV): m/z (%): 338 (M +1, 100). HRMS (ESI): m/z calcd for
+
18 19 3 2
C H F NO : 338.1362 [M+H] , found: 338.1359.
(2S,3S)-3-Benzyloxy-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-1-propylazetidine (7f).
Yield 41% (373 mg). Yellow oil. Reversed phase column chromatography (CH
3
CN/H
2
O) (3 CV 30-35% CH
3
CN, 30
CN). ꢀαꢁ25 = +50.1 (c = 0.24, CHCl
1
CV 35-70% CH
3
CN, 5 CV 70% CH
3
3
). H NMR (400 MHz, CDCl
3
): δ 0.87 (t, J = 7.4
D
Hz, 3H), 1.31-1.43 (m, 2H), 2.38 (ddd, J = 11.6, 7.7, 5.9 Hz, 1H), 2.64-2.71 (m, 1H), 3.11 (dd, J = 9.3, 6.5 Hz, 1H),
3.52-3.55 (m, 1H), 3.60-3.63 (m, 1H), 4.26 (ddd, J = 6.6, 6.5, 2.5 Hz, 1H), 4.30 (qd, JHF = 8.0, J = 3.4 Hz, 1H), 4.41
1
9
(d, J = 12.2 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 6.05 (br s, 1H), 7.26-7.35 (m, 5H). F NMR (376 MHz, ref = CDCl3):
1
3
δ -78.67 (d, J = 8.0 Hz, 3F). C NMR (100 MHz, ref = CDCl
3
): δ 11.5 (CH
), 125.3 (q, J = 281.8 Hz, C), 127.6 (2×CH), 127.8 (CH), 128.5
2×CH), 137.4 (C). IR (cm ): 3076, 2961, 2878, 1456, 1281, 1265, 1165, 1121, 1040, 908, 729, 692. MS (70 eV):
3 2 2 2
), 20.6 (CH ), 58.5 (CH ), 59.2 (CH ), 64.7
(
(
q, J = 30.7 Hz, CH), 65.8 (CH), 69.2 (CH), 71.1 (CH
2
-
1
+
+
21 3 2
m/z (%): 304 (M +1, 100). HRMS (ESI): m/z calcd for C15H F NO : 304.1519 [M+H] , found: 304.1528.
(2S,3S)-1-Benzyl-3-benzyloxy-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]azetidine (7g).
= 0.16 (Petroleumether/EtOAc 6/1). ꢀαꢁ25 = +48.8 (c = 0.2, CHCl
1
Yield 80% (842 mg). Colorless oil. R
400 MHz, CDCl ): δ 3.22 (dd, J = 9.5, 6.7 Hz, 1H), 3.46-3.53 (m, 1H), 3.52 (d, J = 13.1 Hz, 1H), 3.86-3.88 (m, 1H),
3.94 (d, J = 13.1 Hz, 1H), 4.26 (qd, JHF = 8.2, J = 1.3 Hz, 1H), 4.30 (ddd, J = 6.9, 6.7, 2.7 Hz, 1H), 4.40 (d, J = 12.1
f
3
). H NMR
D
(
3
1
9
Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 5.31 (br s, 1H), 7.20-7.38 (m, 10H). F NMR (376 MHz, ref = CDCl ): δ -78.58
3
1
3
(d, J = 8.2 Hz, 3F). C NMR (100 MHz, ref = CDCl
3 2 2
): δ 58.1 (CH ), 60.0 (CH ), 64.8 (CH), 65.0 (q, J = 30.8 Hz, CH),
69.0 (CH), 71.2 (CH ), 125.4 (q, J = 276.7 Hz, C), 127.52 (2×CH), 127.54 (CH), 127.9 (CH), 128.51 (2×CH), 128.54
2
-
1
(
2×CH), 128.8 (2×CH), 137.0 (C), 137.3 (C). IR (cm ): 3030, 2930, 2862, 1454, 1265, 1217, 1163, 1115, 1028,
+
849, 752, 731, 694, 627, 604. MS (70 eV): m/z (%): 352 (M +1, 100). HRMS (ESI): m/z calcd for C19
H
21
F
3
NO
2
:
+
352.1519 [M+H] , found: 352.1520.
(2S,3S)-3-Benzyloxy-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-1-propylazetidine (8b).
Yield 15% (136 mg). Purity = 80%. Yellow oil. Reversed phase column chromatography (CH
3
CN/H
2
O) (3 CV 30-
): δ
CN). ꢀαꢁ25 = +70.0 (c = 0.13, CHCl
1
35% CH
3
CN, 30 CV 35-70% CH
3
CN, 5 CV 70% CH
3
3
). H NMR (400 MHz, CDCl
3
D
0.89 (t, J = 7.4 Hz, 3H), 1.36-1.52 (m, 2H), 2.29 (ddd, J = 11.3, 8.4, 6.5 Hz, 1H), 2.60 (ddd, J = 11.3, 8.8, 7.0 Hz,
1H), 2.93 (dd, J = 9.0, 5.6 Hz, 1H), 3.39-3.41 (m, 1H), 3.60-3.62 (m, 1H), 4.15 (qd, JHF = 8.0, J = 4.1 Hz, 1H), 4.40-
19
4.44 (m, 1H), 4.41 (d, J = 11.6 Hz, 1H), 4.56-4.68 (m, 1H), 4.60 (d, J = 11.6 Hz, 1H), 7.27-7.39 (m, 5H). F NMR
1
3
(
(
(
376 MHz, ref = CDCl
3
): δ -76.91 (d, J = 8.0 Hz, 3F). C NMR (100 MHz, ref = CDCl
3 3 2
): δ 11.8 (CH ), 21.0 (CH ), 58.2
CH ), 60.0 (CH ), 65.9 (CH), 71.4 (q, J = 30.1 Hz, CH), 71.5 (CH
2
2
2
), 73.5 (CH), 124.9 (q, J = 283.2 Hz, C), 127.9
-
1
2×CH), 128.2 (CH), 128.6 (2×CH), 136.6 (C). IR (cm ): 3435, 2961, 2936, 2876, 1456, 1269, 1153, 1117, 1101,
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+
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045, 1028, 853, 737, 692. MS (70 eV): m/z (%): 304 (M +1, 100). HRMS (ESI): m/z calcd for C15
H
21
F
3
NO
2
:
+
304.1519 [M+H] , found: 304.1527.
(
2S,3S)-1-Benzyl-3-benzyloxy-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]azetidine (8c).
25
D
1
Yield 79% (832 mg). Colorless oil. R = 0.16 (Petroleumether/EtOAc 6/1). ꢀαꢁ = +78.8 (c = 0.21, CHCl ). H NMR
f
3
(
400 MHz, CDCl
3
): δ 3.05 (dd, J = 9.3, 5.6 Hz, 1H), 3.54-3.57 (m, 2H), 3.63 (d, J = 12.7 Hz, 1H), 3.74 (d, J = 12.7 Hz,
1
1
H), 3.85 (dqd, J = 8.2, JHF = 8.1, J = 3.8 Hz, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.43-4.45 (m, 1H), 4.60 (d, J = 12.1 Hz,
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
1
9
13
H), 4.58 (d, J = 8.2 Hz, 1H), 7.24-7.36 (m, 10H). F NMR (376 MHz, ref = CDCl
): δ 57.7 (CH ), 61.5 (CH ), 65.2 (CH), 71.3 (q, J = 29.9 Hz, CH), 71.5 (CH
24.8 (q, J = 283.2 Hz, C), 127.5 (CH), 127.9 (2×CH), 128.2 (CH), 128.5 (2×CH), 128.6 (2×CH), 128.9 (2×CH), 136.5
3
): δ -76.91 (d, J = 8.1 Hz).
C
NMR (100 MHz, ref = CDCl
3
2
2
2
), 73.5 (CH),
1
-
1
(
C), 137.0 (C). IR (cm ): 3447, 3030, 2934, 2866, 1454, 1269, 1171, 1117, 1105, 1057, 1028, 854, 713, 692, 604.
+
+
21 3 2
MS (70 eV): m/z (%): 352 (M +1, 100). HRMS (ESI): m/z calcd for C19H F NO : 352.1519 [M+H] , found:
352.1532.
Synthesis of trifluoromethanesulfonates 9 and 11.
As
trifluoroethyl trifluoromethanesulfonate 9b is described. To an ice-cooled solution of (2S,3S)-1-benzyl-2-[(1S)-
,2,2-trifluoro-1-hydroxyethyl]-3-phenoxyazetidine 7d (1.01 g, 3 mmol, 1 equiv) in dry CH Cl (20 mL),
N,N,N’,N’-tetramethylnaphthalene-1,8-diamine (1.28 g, 6 mmol, 2 equiv) and triflic anhydride (0.93 g, 0.55 mL,
.3 mmol, 1.1 equiv) were added via a syringe. Then, the resulting solution was stirred at 0 °C for 40 minutes.
Afterward, the solvent was evaporated and the resulting crude solid reaction mixture was washed with Et (3
10 mL) and filtered. The filtrate was evaporated and the crude reaction mixture was purified by means of
a representative example, the synthesis of 1-[(2R,3S)-1-benzyl-3-phenoxyazetidin-2-yl]-(1S)-2,2,2-
2
2
2
3
2
O
×
column chromatography on silica gel to afford 1-[(2R,3S)-1-benzyl-3-phenoxyazetidin-2-yl]-(1S)-2,2,2-
trifluoroethyl trifluoromethanesulfonate 9b in 95% yield (1.34 g, 2.85 mmol) as a colorless oil. Triflate 9c
appeared to be unstable upon purification on silica gel.
(1S)-2,2,2-Trifluoro-1-[(2R,3S)-1-isopropyl-3-phenoxyazetidin-2-yl]ethyl
trifluoromethanesulfonate
(9a).
= 0.29 (Petroleumether/EtOAc 96/4). ꢀαꢁ25 = +27.9 (c = 0.54, CH
1
Yield 61% (770 mg). Colorless oil. R
NMR (400 MHz, CDCl
1H), 4.91 (ddd, J = 7.2, 6.4, 3.7 Hz, 1H), 5.83 (dq, J = 8.7 Hz, J = 5.9 Hz, 1H), 6.76-6.78 (m, 2H), 6.98-7.02 (m,
f
2
Cl
2
). H
D
3
): δ 0.99 (d, J = 6.4 Hz, 6H), 2.83 (septet, J = 6.4 Hz, 1H), 3.48-3.55 (m, 2H), 3.96-4.00 (m,
HF
19
13
1H), 7.26-7.30 (m, 2H). F NMR (376 MHz, ref = CDCl
3
): δ -78.37 (s, 3F), -63.75 (br s, 3F). C NMR (100 MHz, ref
= CDCl ): δ 16.6 (CH ), 20.1 (CH ), 53.8 (CH ), 53.9 (CH), 59.0 (CH), 65.9 (CH), 77.9 (q, J = 32.7 Hz, CH), 115.1
3
3
3
2
-1
(
2×CH), 118.5 (q, J = 319.5 Hz, C), 121.9 (CH), 122.1 (q, J = 281.0 Hz, C), 129.7 (2×CH), 156.2 (C). IR (cm ): 2990,
+
+
1
591, 1495, 1389, 1223, 1152, 1028, 756, 691, 637. MS (70 eV): m/z (%): 331 (M +1, 100), 422 (M +1, 35).
1-[(2R,3S)-1-Benzyl-3-phenoxyazetidin-2-yl]-(1S)-2,2,2-trifluoroethyl trifluoromethanesulfonate (9b).
= 0.25 (Petroleumether/EtOAc 19/1). ꢀαꢁ25 = +88.0 (c = 0.17, CH
1
Yield 95% (1.34 g). Colorless oil. R
400 MHz, CDCl
.6 Hz, 1H), 4.20 (d, J = 12.6 Hz, 1H), 4.86 (ddd, J = 6.6, 5.8, 1.9 Hz, 1H), 5.94 (dq, J = 9.4 Hz, JHF = 5.6 Hz, 1H),
f
2
Cl
2
). H NMR
D
(
3
): δ 2.94 (dd, J = 9.5, 5.8 Hz, 1H), 3.41-3.43 (m, 1H), 3.46 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 9.4,
6
19
6.71-6.74 (m, 2H), 6.95-6.99 (m, 1H), 7.23-7.34 (m, 7H). F NMR (376 MHz, ref = CDCl ): δ -75.66 till -75.61 (m,
3
1
3
3F), -74.26 till -74.23 (m, 3F). C NMR (100 MHz, ref = CDCl
3 2 2
): δ 57.1 (CH ), 62.0 (CH ), 62.6 (CH), 67.3 (CH), 79.1
(q, J = 33.5 Hz, CH), 115.0 (2×CH), 118.4 (q, J = 319.5 Hz, C), 121.7 (q, J = 281.4 Hz, C), 121.7 (CH), 127.5 (CH),
-1
128.4 (2×CH), 128.8 (2×CH), 129.7 (2×CH), 136.3 (C), 156.1 (C). IR (cm ): 3032, 1497, 1422, 1366, 1285, 1267,
+
+
1
213, 1190, 1136, 1101, 991, 858, 752, 725, 691, 611. MS (70 eV): m/z (%): 431 (M +1, 100), 470 (M +1, 95).
+
18 6 4
HRMS (ESI): m/z calcd for C19H F NO S: 470.0855 [M+H] , found: 470.0872.
1-[(2R,3S)-3-Benzyloxy-1-propylazetidin-2-yl]-(1S)-2,2,2-trifluoroethyl trifluoromethanesulfonate (9d).
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2
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1
1
1
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1
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2
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2
2
2
2
2
3
3
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3
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4
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5
5
5
5
5
5
5
6
= 0.35 (Petroleumether/EtOAc 5/1). ꢀαꢁ25 = +32.6 (c = 0.1, CHCl
1
Yield 93% (1.21 g). Colorless oil. R
(400 MHz, CDCl ): δ 0.87 (t, J = 7.4 Hz, 3H), 1.27-1.47 (m, 2H), 2.23 (ddd, J = 10.9, 9.0, 4.9 Hz, 1H), 2.74 (ddd, J =
f
3
). H NMR
D
3
10.9, 9.8, 6.8 Hz, 1H), 2.92 (dd, J = 9.0, 6.0 Hz, 1H), 3.54 (dd, J = 9.6, 6.5 H, 1H z), 3.57-3.59 (m, 1H), 4.21 (ddd, J
= 6.5, 6.0, 1.7 Hz, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 5.69 (dq, J = 9.6 Hz, JHF = 5.9 Hz, 1H),
19
13
7.28-7.37 (m, 5H). F NMR (376 MHz, ref = CDCl ): δ -75.69 till -75.64 (m, 3F), -74.53 till -74.50 (m, 3F). C NMR
3
(
100 MHz, ref = CDCl
3
): δ 11.5 (CH
3 2 2 2 2
), 20.5 (CH ), 57.8 (CH ), 60.9 (CH ), 63.7 (CH), 68.4 (CH), 71.0 (CH ), 79.2 (q, J
=
1
33.1 Hz, CH), 118.4 (q, J = 319.5 Hz, C), 121.9 (q, J = 276.4 Hz, C), 127.7 (2×CH), 127.9 (CH), 128.5 (2×CH),
-
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37.1 (C). IR (cm ): 2968, 2878, 1423, 1279, 1215, 1134, 1028, 988, 934, 860, 752, 696, 638, 611. MS (70 eV):
+
+
m/z (%): 303 (M +1, 35), 436 (M +1, 55).
1-[(2R,3S)-1-Benzyl-3-benzyloxyazetidin-2-yl]-(1S)-2,2,2-trifluoroethyl trifluoromethanesulfonate (9e).
= 0.21 (Petroleumether/EtOAc 14/1). ꢀαꢁ25 = +72.8 (c = 0.17, CHCl
1
Yield 90% (1.30 g). Colorless oil. R
(400 MHz, CDCl
12.6 Hz, 1H), 4.21 (ddd, J = 6.5, 6.0, 1.7 Hz, 1H), 4.37 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 12.1 Hz, 1H), 5.81 (dq, J =
f
3
). H NMR
D
3
): δ 2.94 (dd, J = 9.3, 6.0 Hz, 1H), 3.35-3.38 (m, 2H), 3.73 (dd, J = 9.8, 6.5 Hz, 1H), 4.14 (d, J =
1
9
9.8 Hz, JHF = 5.5 Hz, 1H), 7.23-7.35 (m, 5H). F NMR (376 MHz, ref = CDCl ): δ -75.63 till -75.58 (m, 3F), -74.40 till
3
1
3
-74.36 (m, 3F). C NMR (100 MHz, ref = CDCl
3
): δ 56.8 (CH
2
), 62.2 (CH
2
), 63.1 (CH), 68.2 (CH), 70.9 (CH
2
), 79.2
(
q, J = 33.3 Hz, CH), 118.4 (q, J = 319.6 Hz, C), 121.8 (q, J = 281.3 Hz, C), 127.4 (CH), 127.7 (2×CH), 128.0 (CH),
-1
1
28.3 (2×CH), 128.5 (2×CH), 128.9 (2×CH), 136.6 (C), 137.0 (C). IR (cm ): 3032, 2934, 2868, 1420, 1366, 1267,
+
1
211, 1192, 1136, 1061, 1028, 986, 856, 727, 696, 611. MS (70 eV): m/z (%): 484 (M +1, 100). HRMS (ESI): m/z
+
calcd for C H F NO S: 484.1012 [M+H] , found: 484.1030.
2
0
20
6
4
1
-[(2R,3S)-3-Benzyloxy-1-propylazetidin-2-yl]-(1R)-2,2,2-trifluoroethyl
trifluoromethanesulfonate
(11a).
= 0.33 (Petroleumether/EtOAc 9/1). ꢀαꢁ25 = -48.6 (c = 0.11, CHCl
1
Yield 74% (966 mg). Colorless oil. R
f
3
). H NMR
D
(
400 MHz, CDCl
3
): δ 0.85 (t, J = 7.4 Hz, 3H), 1.57-1.67 (m, 2H), 3.28-3.42 (m, ~4H), 3.45-3.49 (m, 1H), 3.60-3.64
1
9
(
m, ~1H), 3.78-3.82 (m, 1H), 4.52 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.3 Hz, 1H), 7.29-7.40 (5H, m, 5H). F NMR
13
(
376 MHz, ref = CDCl ): δ -75.26 (s, 3F), -73.79 (d, J = 4.4 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 10.7 (CH ),
3
3
3
2
1.0 (CH
2
), 49.5 (CH
2
2 2
), 51.3 (q, J = 41.3 Hz, CH), 52.0 (CH ), 54.4 (CH), 73.8 (CH ), 74.4 (CH), 120.0 (q, J = 324.7
-1
Hz, C), 122.3 (q, J = 276.2 Hz, C), 128.1 (2×CH), 128.4 (CH), 128.7 (2×CH), 136.7 (C). IR (cm ): 2972, 2884, 1391,
+
1
288, 1125, 1161, 1130, 1047, 908, 741, 698. MS (70 eV): m/z (%): 436 (M +1, 100). HRMS (ESI): m/z calcd for
+
C
16 23 6 2 4 4
H F N O S: 453.1277 [M+NH ] , found: 453.1297.
1
-[(2R,3S)-1-Benzyl-3-benzyloxyazetidin-2-yl]-(1R)-2,2,2-trifluoroethyl
trifluoromethanesulfonate
(11b).
= 0.23 (Petroleumether/EtOAc 14/1). ꢀαꢁ 2D 5 = -35.9 (c = 0.16, CHCl
1
Yield 71% (1.03 g). Colorless oil. R
f
3
). H NMR
(
400 MHz, CDCl ): δ 3.14-3.15 (m, 1H), 3.32-3.38 (m, 2H), 3.49-3.59 (m, 2H), 4.38 (d, J = 11.3 Hz, 1H), 4.56 (br s,
3
19
2
4
H), 4.60 (d, J = 11.3 Hz, 1H), 7.22-7.41 (m, 10H). F NMR (376 MHz, ref = CDCl
3
): δ -75.13 (s, 3F), -73.82 (d, J =
), 51.4 (q, J = 41.4 Hz, CH), 53.7 (CH ), 54.3 (CH), 73.5
2
), 73.9 (CH), 120.0 (q, J = 322.9 Hz, C), 122.2 (q, J = 275.4 Hz, C), 128.2 (CH), 128.4 (CH), 128.7 (CH), 128.8
13
.4 Hz, 3F). C NMR (100 MHz, ref = CDCl
3
): δ 48.8 (CH
2
2
(
CH
CH), 129.1 (CH), 133.7 (C), 136.7 (C). IR (cm ): 3034, 2934, 2878, 1387, 1285, 1225, 1148, 1117, 1016, 927,
-1
(
+
+
9
05, 789, 735, 696, 685, 608. MS (70 eV): m/z (%): 442 (M +1, 100), 484 (M +1, 18). HRMS (ESI): m/z calcd for
+
20 20 6 4
C H F NO S: 484.1012 [M+H] , found: 484.1013.
Synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines 10a-g.
As
trifluoromethyl)pyrrolidine 10a is described. To an ice-cooled solution of (2S,3S)-2-[(1S)-2,2,2-trifluoro-1-
hydroxyethyl]-1-isopropyl-3-phenoxyazetidine 7a (0.29 g, 1 mmol, 1 equiv) in dry CH Cl (20 mL) was added
a
representative example, the synthesis of (2R,3R,4S)-3-benzylamino-1-isopropyl-4-phenoxy-2-
(
2
2
N,N,N’,N’-tetramethylnaphthalene-1,8-diamine (0.43 g, 3 mmol, 2 equiv) and triflic anhydride (0.31 g, 0.18 mL,
1.1 mmol, 1.1 equiv). Then, the resulting solution was stirred at 0 °C for 40 minutes. Subsequently, benzylamine
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(
0.27 g, 0.27 mL, 2.5 mmol, 2.5 equiv) was added and the reaction mixture was stirred for another 3 days at
reflux temperature. Afterward, H
2 2 2
O was added and the aqueous phases were extracted with CH Cl (3 × 20 mL).
Drying (MgSO ), filtration of the drying agent and evaporation of the solvent in vacuo afforded a crude reaction
4
mixture, which was purified by means of column chromatography on silica gel to afford (2R,3R,4S)-3-
benzylamino-1-isopropyl-4-phenoxy-2-(trifluoromethyl)pyrrolidine 10a in 67% yield (0.25 g, 0.67 mmol) as a
colorless oil.
10
11
12
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60
(
2R,3R,4S)-3-Benzylamino-1-isopropyl-4-phenoxy-2-(trifluoromethyl)pyrrolidine (10a).
2
5
1
Yield 67% (250 mg). Colorless oil. R
f
= 0.15 (Petroleumether/EtOAc 4/1). ꢀαꢁD = +71.2 (c = 0.12, CH
Cl ). H NMR
2 2
(
400 MHz, CDCl
3
): δ 0.93 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 2.20 (br s, 1H), 2.93 (dd, J = 11.0, 4.6 Hz, 1H),
3
7
.12-3.22 (m, 2H), 3.48-3.60 (m, 2H), 3.84 (s, 2H), 4.70-4.73 (m, 1H), 6.87-6.90 (m, 2H), 6.94-6.98 (m, 1H), 7.22-
19
13
.34 (m, 7H). F NMR (376 MHz, ref = CDCl
), 21.1 (CH ), 48.4 (CH ), 50.9 (CH), 52.3 (CH
21.1 (CH), 126.3 (q, J = 283.8 Hz, C), 127.0 (CH), 128.0 (2×CH), 128.4 (2×CH), 129.5 (2×CH), 140.1 (C), 157.8 (C).
3
): -68.66 (d, J = 8.5 Hz, 3F). C NMR (100 MHz, ref = CDCl
3
): δ 14.9
(
CH
3
3
2
2
), 61.5 (CH), 62.1 (q, J = 27.9 Hz, CH), 74.7 (CH), 115.8 (2×CH),
1
-1
IR (cm ): 2968, 1597, 1587, 1495, 1454, 1391, 1366, 1267, 1240, 1179, 1121, 1026, 918, 883, 750, 691, 669,
+
6
35, 590, 573, 509. MS (70 eV): m/z (%): 379 (M +1, 100). HRMS (ESI): m/z calcd for C H F N O: 379.1992
21 26 3 2
+
[
M+H] , found: 379.1985.
(2R,3R,4S)-3-Allylamino-1-isopropyl-4-phenoxy-2-(trifluoromethyl)pyrrolidine (10b).
= 0.25 (Petroleumether/EtOAc 9/1). ꢀαꢁ 2D 5 = +67.7 (c = 0.11, CH
1
Yield 61% (200 mg). Yellow oil. R
f
2 2
Cl ). H NMR
(
400 MHz, CDCl ): δ 0.96 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.93 (br s, 1H), 2.98 (dd, J = 11.0, 4.6 Hz, 1H),
3
3
5
.12-3.22 (m, 2H), 3.28-3.30 (m, 2H), 3.49-3.59 (m, 2H), 4.77-4.79 (m, 1H), 5.06-5.10 (m, 1H), 5.15-5.21 (m, 1H),
19
.86 (dddd, J = 17.1, 10.2, 5.9, 5.9 Hz, 1H), 6.89-6.91 (m, 2H), 6.94-6.98 (m, 1H), 7.26-7.30 (m, 2H). F NMR
13
(
(
376 MHz, ref = CDCl ), 21.0 (CH
3
): -68.78 (d, J = 8.6 Hz, 3F). C NMR (100 MHz, ref = CDCl
3
): δ 14.9 (CH
3
3
), 48.5
CH ), 50.9 (CH), 51.1 (CH ), 61.4 (CH), 62.1 (q, J = 28.0 Hz, CH), 74.7 (CH), 115.8 (2×CH), 116.3 (CH ), 121.2 (CH),
2
2
2
-
1
1
26.2 (q, J = 283.8 Hz, C), 129.5 (2×CH), 136.7 (CH), 157.7 (C). IR (cm ): 2970, 1599, 1495, 1366, 1271, 1240,
+
1
179, 1119, 1076, 1028, 995, 918, 883, 872, 752, 691, 629, 509. MS (70 eV): m/z (%): 329 (M +1, 100). HRMS
+
(
ESI): m/z calcd for C17
H
24
F
3
N
2
O: 329.1835 [M+H] , found: 329.1842.
(2R,3R,4S)-3-Butylamino-1-isopropyl-4-phenoxy-2-(trifluoromethyl)pyrrolidine (10c).
25
1
Yield 78% (268 mg). Colorless oil. R = 0.26 (Petroleumether/EtOAc 4/1). ꢀαꢁD = +62.6 (c = 0.18, CH Cl ). H NMR
f
2
2
(
400 MHz, CDCl
3
): δ 0.86 (t, J = 7.3 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H), 1.25-1.35 (m, 2H),
1
.40-1.48 (m, 2H), 1.71 (br s, 1H), 2.57-2.66 (m, 2H), 2.98 (dd, J = 11.0, 4.6 Hz, 1H), 3.12-3.22 (m, 2H), 3.46-3.50
19
(
m, 1H), 3.56 (~pentet, J = 8.7 Hz, 1H), 4.79-4.82 (m, 1H), 6.89-6.97 (m, 2H), 7.25-7.29 (m, 2H). F NMR (376
13
MHz, ref = CDCl
3 3 3 3 2
): -68.78 (d, J = 8.7 Hz, 3F). C NMR (100 MHz, ref = CDCl ): δ 13.9 (CH ), 14.9 (CH ), 20.3 (CH ),
2
1.0 (CH ), 32.5 (CH ), 48.5 (CH ), 48.6 (CH ), 50.9 (CH), 62.1 (q, J = 28.0 Hz, CH), 62.7 (CH), 74.6 (CH), 115.8
3
2
2
2
-1
(
2×CH), 121.1 (CH), 126.2 (q, J = 283.9 Hz, C), 129.4 (2×CH), 157.8 (C). IR (cm ): 2961, 2930, 1599, 1587, 1494,
366, 1271, 1240, 1180, 1140, 1115, 1076, 1059, 1028, 881, 750, 691, 631, 507. MS (70 eV): m/z (%): 345
1
+
+
(
28 3 2
M +1, 100). HRMS (ESI): m/z calcd for C18H F N O: 345.2148 [M+H] , found: 345.2152.
(2R,3R,4S)-3-(N-Benzyl-N-methylamino)-1-isopropyl-4-phenoxy-2-(trifluoromethyl)pyrrolidine (10d).
= 0.20 (Petroleumether/EtOAc 9/1). ꢀαꢁ 2D 5 = +20.3 (c = 0.16, CH
1
Yield 65% (255 mg). Colorless oil. R
f
2 2
Cl ). H NMR
(
400 MHz, CDCl
3
): δ 0.97 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 2.29 (br s, 1H), 3.07-3.12 (m, 2H), 3.19-3.23
(
m, 2H), 3.61 (d, J = 13.0 Hz, 1H), 3.66 (~pentet, J = 8.0 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 4.84-4.86 (m, 1H), 6.89-
19
13
6
3
.96 (m, 3H), 7.22-7.36 (m, 7H). F NMR (376 MHz, ref = CDCl ): -68.87 (d, J = 8.0 Hz). C NMR (100 MHz, ref =
CDCl ): δ 14.4 (CH ), 21.2 (CH ), 40.6 (CH ), 48.7 (CH ), 50.9 (CH), 61.3 (CH ), 62.7 (q, J = 28.3 Hz, CH), 68.7 (CH),
3
3
3
3
2
2
7
5.8 (CH), 115.7 (2×CH), 121.0 (CH), 126.0 (q, J = 283.6 Hz, C), 126.9 (CH), 128.1 (2×CH), 128.9 (2×CH), 129.5
-
1
(
2×CH), 138.9 (C), 157.5 (C). IR (cm ): 2968, 1599, 1587, 1495, 1454, 1391, 1366, 1277, 1240, 1202, 1179, 1119,
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