4-Fluoro and 4-hydroxy pyrrolidine-thioxotetrahydropyrimidinones: Organocatalysts for green asymmetric transformations in brine

Article abstract of DOI:10.1021/acs.joc.5b00283

The synthesis of both trans- and cis-diastereomers of pyrrolidinine-thioxotetrahydropyrimidinone bearing either a fluorine or a hydroxyl group was accomplished. The new compounds were tested for their catalytic properties in a variety of asymmetric organic transformations and compared with the first generation catalyst. It was found that the new catalysts could efficiently catalyze the reactions in brine, without the use of organic solvent, and by employing an almost stoichiometric amount of reagents. Thus, the products were isolated by simple extractions, avoiding the use of chromatography in excellent yields, diastereoselectivities, and enantioselectivities.

Full text of DOI:10.1021/acs.joc.5b00283

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)
Article
4-Fluoro and 4-Hydroxy Pyrrolidine-thioxotetrahydropyrimidinones:
Organocatalysts for Green Asymmetric Transformations in Brine
Nikolaos Kaplaneris, Giorgos Koutoulogenis, Marianna Raftopoulou, and Christoforos George Kokotos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00283 • Publication Date (Web): 05 May 2015
Downloaded from http://pubs.acs.org on May 10, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4-Fluoro and 4-Hydroxy Pyrrolidine-
thioxotetrahydropyrimidinones:
Organocatalysts for Green Asymmetric
Transformations in Brine
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
Nikolaos Kaplaneris, Giorgos Koutoulogenis, Marianna Raftopoulou and
Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens,
Panepistimiopolis, Athens 15771, Greece
Email address: ckokotos@chem.uoa.gr
KEYWORDS : Organocatalysis; Green Chemistry; Michael addition; Brine; Fluorine
ABSTRACT : The synthesis of both transꢀ and cisꢀ diastereomers of pyrrolidinineꢀ
thioxotetrahydropyrimidinone bearing either a fluorine or a hydroxyl group was
accomplished. The new compounds were tested for their catalytic properties in a
variety of asymmetric organic transformations and compared with the first generation
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 38
1
2
3
4
5
6
7
8
9
catalyst. It was found that the new catalysts could efficiently catalyze the reactions in
brine, without the use of organic solvent, and by employing an almost stoichiometric
amount of reagents. Thus, the products were isolated by simple extractions, avoiding
the use of chromatography in excellent yields, diastereoselectivities and
enantioselectivities.
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
INTRODUCTION
After centuries of misꢀtreating the environment, researchers have turned their
attention to finding efficient procedures, where various elements can be wisely
employed in order to ensure their use in the distant future. This concept of
elemental sustainability can be approached in various ways, like efficient
protocols for recycling and recovering or the development of more efficient
catalytic protocols (lower catalyst loadings) or even the development of
protocols, where these elements can be left out and not used. Along these lines,
Organocatalysis1,2 has provided an excellent alternative on transitionꢀmetalꢀ
catalysed processes, indicating that elemental sustainability of transition metals
can be ensured, just by not using them. In the past few years, we have been
actively involved in the field of Organocatalysis, either in developing new
organocatalysts and reactions,3 or providing novel and green oxidation
protocols.4 In one of our endeavours, we designed and synthesized pyrrolidineꢀ
thioxotetrahydropyrimidinone
1 (Figure 1), which proved to be a really
efficient organocatalyst for the Michael reaction between ketones and
nitroolefins.5 Although numerous catalysts exist for this transformation, the
2
ACS Paragon Plus Environment

Page 3 of 38
The Journal of Organic Chemistry
1
2
3
4
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
Figure 1. Known and novel organocatalysts utilized in this study.
advantage of
1
was the really low catalyst loading that could be used (1ꢀ2.5
was successfully employed in other reactions,6
mol%). Then, organocatalyst
1
like the αꢀalkylation of ketones6a and the development of novel tandem
cyclisations.6c However, the main disadvantage of this catalyst resides on the
fact that it only works in organic solvents and requires a high reagent ratio
(10:1 ketone:nitroalkene).
Fluorine is a very interesting element, possessing unique properties.7 The
incorporation of fluorine into a molecule usually modifies its physical and
chemical properties through electronic and stereoelectronic effects. The deep
understanding of fluorine effects has led to widespread application of fluorineꢀ
containing compounds in a variety of areas. In proline residues, the introduction
of fluorine at the 4ꢀposition of the pyrrolidine ring influences the puckering of
the ring. This effect has been taken advantage in changing the conformation of
prolineꢀcontaining biomolecules in order to study and tune biological
processes.8 Recently, the fluorine effect has been studied in organocatalysis,
where benchmark organocatalysts have been modified to carry fluorine atoms
and their catalytic properties have been studied.9 Unfortunately, only a handful
of studies related to diaryl prolinols,9a imidazolidinones,9c proline9d,e and
aminalꢀpyrrolidines9f have been presented. In most of these examples, the
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 38
1
2
3
4
5
6
7
8
9
fluorineꢀcontaining molecule was found to improve the catalytic properties,
without any major alterations to the reaction conditions. Pyrrolidine ring and
fiveꢀmembered rings in general, are very flexible, so in solution they adopt
multiple conformations. In aminocatalysis, some problems arise because every
conformer may have different catalytic activity. Fluorine and its gauche effect10
provide a valuable tool in order to make the pyrrolidine ring more rigid, since
the fluorine prefers the axial position in order to maximize the orbital overlap
between σCꢀF* and σCꢀH. To achieve this requirement the pyrrolidine ring (4ꢀcis
substituted prolines) adopts the Cγꢀendo conformation (Figure 2).11 Thus, by
incorporating a fluorine atom in the 4ꢀposition of the pyrrolidine ring, we
postulated that the derived enamine would be more planar and thus more
reactive towards electrophiles.12
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
Figure 2. Fluorine effect on the pyrrolidine ring.
Herein, we present the synthesis of four novel organocatalysts (2ꢀ5), bearing
either a fluorine or a hydroxyl moiety at the 4ꢀposition of the pyrrolidine ring
(Figure 1). The comparison of the catalytic properties of the new compounds is
also demonstrated in 4 different reactions, highlighting the improved properties
and the green character of the novel organocatalysts.
4
ACS Paragon Plus Environment

Page 5 of 38
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
9
Starting from 4ꢀhydroxyꢀproline derivative
synthesized (Scheme 1). After reduction of the ester to the corresponding
alcohol , azide was obtained after activation of the alcohol via the
corresponding mesyl ester. Staudiger reaction followed by coupling with
isothiocyanate 10, provided cisꢀfluoro derivative 11. After deprotection, cisꢀ
derivative was obtained.
6, cisꢀfluoroproline 7 was
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
8
9
2
Scheme 1. Synthesis of compound 2.
Then, transꢀfluoro derivative
Hydroxyproline 12 was synthesized from
as before, transꢀfluoro derivative was obtained. For comparison purposes, the
corresponding 4ꢀhydroxy derivatives and were also synthesized (Schemes 3
and 4). It was envisaged that the comparison of the hydroxylꢀcontaining
3
was synthesized (Scheme 2). cis
ꢀ
6
. Following a similar synthetic route
3
4
5
catalysts with the fluoroꢀcontaning catalysts and
information on the effect of fluorine.
1
could provide more
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 38
1
2
3
4
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
Scheme 2. Synthesis of compound
3
.
Scheme 3. Synthesis of compound 4.
Scheme 4. Synthesis of compound 5.
6
ACS Paragon Plus Environment

Page 7 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The asymmetric Michael addition constitutes one of the most powerful methods for
the formation of new CꢀC and CꢀX bonds in organic synthesis. Especially after the
development of organocatalysis, the aforesaid transformation has experienced
exponential growth, with a large number of new catalysts exhibiting impressive
results in terms of efficiency and selectivity.13 The Michael reaction between
cyclohexanone and transꢀbetaꢀnitrostyrene is a typical reaction for testing novel
organocatalysts. Pyrrolidineꢀthioxotetrahydropyrimidinone 1 was shown to be an
excellent catalyst for the above reaction, where at 2.5 mol% catalyst loading in THF
and reagent ratio 10:1 provided the product in excellent yield (97%) and selectivities
(98:2 dr and 97% ee).5 As mentioned earlier, catalyst 1 did not work in aqueous media
and at lower reagent ratios led to incomplete reactions. Utilizing catalyst 2 in THF,
the product was formed in excellent diastereoselectivities and enantioselectivities, but
the yield was low (entry 1, Table 1) (for full reaction optimization, see ESI). Utilizing
brine as the solvent, the product was obtained in quantitative yield and excellent
selectivities in shorter reaction time (entry 2, Table 1). Using only 2.5 mol% catalyst
loading, a number of solvents were tested, proving that brine afforded the best results
(entries 3ꢀ10, Table 1). A variety of acid additives were then tested, none of which led
to better results (entries 11ꢀ15, Table 1). After identifying the optimum reaction
medium for catalyst 2, catalysts 1 and 3ꢀ5 were also tested (Table 2 and ESI). As
mentioned before, a clear difference with our first generation catalyst 1, was the
different reaction medium (organic solvents for 1, but brine for 2). Catalyst 1 worked
in THF, but in brine afforded only traces of the product. In sharp contrast, catalyst 2
afforded the product in excellent yield in brine (entries 1 and 2 vs entries 3ꢀ5).
Another key aspect was the reagent ratio, since 1 worked only at 10:1 ratio. Catalyst 2
worked equally well at lower reagent ratios (entries 3ꢀ5, Table 2).14 We were happy to
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
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 38
1
2
3
4
5
6
Table 1. Optimization of the conditions for the reaction between
cyclohexanone and betaꢀnitrostyrene[a]
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
Entry
Solvent
Additive
Yield
(%)[b]
41
dr
(syn:anti)[c]
97:3
ee
(%)[d]
98
1[e]
2[f, g]
3[g]
4
THF
Brine
Brine
Et2O
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
4ꢀNBA
AcOH
100
93
>99:1
>99:1
>99:1
>99:1
99:1
99
99
55
99
5
Benzene
CHCl3
CH2Cl2
Water
Brine
Brine
Brine
Brine
Brine
Brine
67
98
6
72
93
7
87
99:1
99
8
90
99:1
99
9[g]
10[g]
11[g]
12[g]
13[g]
14[g]
70
>99:1
97:3
99
62
99
pFꢀPhOH
PhCOOH
4ꢀTBA
4ꢀCBA
41
98:2
85
83
99:1
98
100
95
97:3
99
96:4
99
[a] Reactions were performed using nitroolefin (0.20 mmol), ketone (2.0
mmol), 4ꢀNBA (15% mol) and H2O (2 equiv.) for 48 h. [b] Yield determined
by NMR. [c] The diastereomeric ratio (dr) was determined by HꢀNMR
spectroscopy. [d] The enantiomeric excess (ee) was determined by chiral
HPLC. [e] 10 mol% catalyst loading. [f] 5 mol% catalyst loading. [g] The
1
reaction time was 20 h. 4ꢀNBA:
4ꢀTBA: ꢀtrifluoromethylbenzoic acid, 4ꢀCBA:
pꢀNO2ꢀPhCOOH,
pꢀFꢀPhOH: pꢀfluorophenol,
p
pꢀcyanobenzoic acid.
8
ACS Paragon Plus Environment

Page 9 of 38
The Journal of Organic Chemistry
1
2
3
4
find out even at almost stoichiometric ratios (1.1:1), catalyst
2 performed
5
6
7
8
equally well (entry 5, Table 2). Thus, we were able to establish a green
protocol, where a low catalyst loading of 5 mol% could catalyse efficiently the
Michael reaction between cyclohexanone and nitrostyrene (in a stoichiometric
ratio) in brine. After the completion of the reaction, the product is just extracted
from the reaction mixture and no further purification is required. Having
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
already proven that catalyst
powerful procedure, we tested the other catalysts in two different reaction
conditions. transꢀFluoro catalyst proved to be a misꢀmatched case, since both
2 is more powerful than 1 and provides a green
3
in brine and organic solvent led to inferior results (entries 6 and 7, Table 2, see
also ESI). When the fluorine was substituted by the hydroxy group, similar
results were observed (entries 8ꢀ11, Table 2). Again the cisꢀhydroxy catalyst
4
2
proved to be the matched case, leading to slightly worse results than catalyst
(entries 8 and 9, Table 2). Interestingly, although transꢀhydroxy catalyst
5 was
the misꢀmatched case, the product was obtained in both organic solvent and
brine in slightly better yields and selectivities than fluoroꢀcatalyst
and 11 vs 6 and 7, Table 2).
3 (entries 10
Once the optimum reaction conditions were identified, a variety of ketones and
nitrostyrenes were tested in order to study the substrate scope (Scheme 5). A
number of nitrostyrenes bearing electronꢀwithdrawing and electronꢀdonating
substituents were tested affording products 25a-g in high yields and excellent
selectivities. Then, a variety of cyclic ketones were tested, affording products
25h-l in similar excellent results. Finally, some difficult substrates (when we
utilised catalyst
1
) were tested, affording the products in lower yields and
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 38
1
2
3
4
5
6
Table 2. Comparison of the catalytic properties of catalysts 2-5 in the reaction
between cyclonexanone and betaꢀnitrostyrene.[a]
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
Entry
Catalyst
Ketone
Yield
(%)[b]
97
dr
(syn:anti)[c]
99:1
ee
(%)[d]
97
ꢀ
(equiv.)
5
1[e]
2
1
1
2
2
2
3
3
4
4
5
5
5
traces
100
100
100
56
ꢀ
3
5
>99:1
>99:1
>99:1
90:10
85:15
>99:1
>99:1
95:5
99
99
99
88
92
98
96
98
96
4
2
5
1.1
1.1
10
1.1
10
1.1
10
6[f]
7[f, g]
8[f]
9[f, g]
10[f]
11[f, g]
23
86
25
81
22
85:15
[a] Reactions were performed using nitroolefin (0.20 mmol), ketone, 4ꢀNBA (15
mol%) in brine for 20 h. [b] Yield determined by NMR. [c] The diastereomeric ratio
(dr) was determined by HꢀNMR spectroscopy. [d] The enantiomeric excess (ee) of
the major diastereomer was determined by chiral HPLC. [e] The reaction was
performed in THF. [f] The reaction time was 48 h. [g] The reaction was performed in
CH2Cl2. 4ꢀNBA: pꢀNO2ꢀPhCOOH.
1
selectivities (products 25m-n). Aliphatic nitroalkenes could be employed with
some success (products 25o-p). Unfortunately, nonꢀsymmetrical ketones, like
10
ACS Paragon Plus Environment

Page 11 of 38
The Journal of Organic Chemistry
1
2
3
4
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
Scheme 5. Michael reaction between ketones and nitrostyrenes utilising catalyst 2.
2ꢀmethylꢀcyclohexanone did not give the product of the reaction. It has to be
highlighted that in most cases, the product was obtained by simple extractions
and no additional purification was necessary.
Since we had earlier demonstrated the catalytic activity of
1
in the reaction
performs in
between cyclohexanone and nitrodienes,6b we tested how catalyst
this reaction (Scheme 6).
2
As before, the reaction was performed in brine, a reaction medium that catalyst
could not be employed in earlier. Catalyst can catalyse the reaction in
toluene (93% yield, 98:2 dr, 97% ee), but it was unable to catalyse the reaction
in brine. Similarly to before, catalyst catalysed efficiently this transformation,
1
1
2
leading to Michael product 26a in excellent yield and selectivity. A variety of
substituted nitrodienes bearing electronꢀwithdrawing or electronꢀdonating
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 38
1
2
3
4
5
6
7
Ar
R
NO2
O
O
2
cat (10 mol%).
4-NBA (15 mol%)
NO2
R
brine, 48 h
Cl
Ar
8
9
Ph
NO2
O
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
O
O
NO2
NO2
NO2
26a
98%, >99:1, 99% ee
26b
26c
98%, 97:3, 99% ee
95%,>99:1, 98 % ee
OMe
Ph
O
O
NO2
NO2
26d
97%, >99:1, 98% ee
26e
93%, >99:1, 99% ee
Scheme 6. Michael reaction between ketones and nitrodienes utilising catalyst 2.
substituents were used successfully, leading to products 26b-d. Finally, a
trisubstituted nitrodiene was employed leading to product 26e
.
Finally, in an effort to test the limits of the novel catalysts, two additional
transformations were carried out (Scheme 7). Enantioselective αꢀalkylation of
cyclic ketones is a very difficult reaction,15 where partial solution was given by
catalyst
1
(in CH2Cl2 98% yield, 80% ee).6a Catalyst
2 afforded similar results,
but in brine, where catalyst
1
could not catalyse the reaction. The product 28
was obtained in almost quantitative yield and 70% ee. Although the
enantioselectivity is not excellent, the highest ee reported for this
transformation is around 80% ee (always in organic solvent).6a Thus, this is the
first time that an αꢀalkylation of this type is reported in aqueous medium. In
addition, a tandem MichaelꢀHenry reaction that was previously catalysed
efficiently by catalyst
1
,6c was possible to be carried out in brine by employing
was found to be the only catalyst that
catalyst . Again as before, catalyst
2
1
could promote efficiently this transformation, but only in organic solvent.6c
12
ACS Paragon Plus Environment

Page 13 of 38
The Journal of Organic Chemistry
1
2
3
4
Novel organocatalyst
2 provided the product as a single diastereomer and in
5
6
excellent ee, but under unoptimised conditions the yield was moderate.
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
Scheme 7. Other reactions catalysed by 2 in brine.
CONCLUSIONS
In conclusion, four novel organocatalysts were synthesized combining the
thioxotetrahydropyrimidinone with a 4ꢀsubstituted pyrrolidine either by fluorine or a
hydroxy moiety. Both cis catalysts were a matched case, while trans catalysts proved
to be a misꢀmatched case. In comparison to the first generation catalyst (without
substituent on the pyrrolidine ring), cisꢀfluoro catalyst 2 proved to catalyse four
different transformations more efficiently leading to higher yields and selectivities in
low catalyst loadings (5ꢀ10 mol%). Striking differences were found between the
parent and the novel catalysts. In more detail, the advantage of catalyst 2 in
comparison to the parent molecule, was the use of brine as the reaction medium,
which leads to greener approaches in synthesis. The fact that all four catalysts
provided the product in aqueous environment could be explained by hydrogen
bonding interaction between the catalyst and molecules of water. Moreover, the
reagent ratio could be reduced to stoichiometric using novel organocatalyst 2 (which
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 38
1
2
3
4
5
6
7
8
9
could not be done with catalyst 1). Thus, this provided a robust, green and efficient
protocol to perform these reactions, where the product could be isolated just by simple
extractions from the reaction mixture. These results open new avenues on green
organocatalytic approaches in performing reactions in aqueous media and we are on
the way to taking advantage of these molecules in order to anchor them in a variety of
materials in order to recycle the catalyst.
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
EXPERIMENTAL SECTION
General Remarks
Chromatographic purification of products was accomplished using forcedꢀflow
chromatography. Thinꢀlayer chromatography (TLC) was performed on aluminum
backed silica plates (0.2 mm, 60 F254). Visualization of the developed chromatogram
was performed by fluorescence quenching using phosphomolybdic acid, anisaldehyde
1
or potassium permanganate stains. H, 19F and 13C NMR spectra were recorded on
200 MHz, 188 MHz and 50 MHz respectively, and are internally referenced to
1
residual solvent signals. Data for H NMR are reported as follows: chemical shift (δ
ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, bs = broad signal, bs m = broad signal multiplet), coupling constant and
assignment. Data for 19F NMR are internally referenced to trifluoroacetic acid. Data
for 13C NMR are reported in terms of chemical shift (δ ppm). Chiral High
Performance Liquid Chromatography (HPLC) analyses were performed using an ADꢀ
H, ODꢀH and ASꢀH columns. The configuration of the products has been assigned by
comparison to literature data or assigned by analogy.
14
ACS Paragon Plus Environment

Page 15 of 38
The Journal of Organic Chemistry
1
2
3
4
5
(2S,4S)-1-tert-Butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (7).16 To a
o
stirring solution of alcohol 6 (1.20 g, 4.89 mmol) in dry CH2Cl2 (5 mL) at ꢀ78 C
6
7
8
under argon atmosphere, diethylaminosulfur trifluoride (DAST) (1.20 mL, 1.83 g,
9
o
11.35 mmol) was added. The reaction was stirred for 30 min at ꢀ78 C, and then
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
warmed to room temperature and was allowed to stir for 20 h before being quenched
with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic
phases were dried over Na2SO4, and concentrated to yield the crude product. The
crude oil was purified by silica gel chromatography (CHCl3/EtOAc, 20:1) to yield the
20
1
desired product 7. Pale yellow oil; 0.93 g, 77%; [α]D = ꢀ48.9 (c 1.0, CHCl3); H
NMR (200 MHz, CDCl3) δ 5.07 (1H, dm, J = 53.6 Hz), 4.44ꢀ4.22 (1H, m), 3.86ꢀ3.30
(5H, m), 2.44ꢀ2.06 (2H, m), 1.28 (6H, s), 1.33 (3H, s); 13C NMR (50 MHz, CDCl3) δ
171.9 (171.6), 153.3 (153.7), 90.8 (d, J = 177.6 Hz) [91.9 (d, J = 177.4 Hz)], 79.9,
57.3 (56.9), 52.5 (d, J = 25.5 Hz) [52.9 (d, J = 24.0 Hz)], 51.8, 37.1 (d, J = 22.0 Hz)
[36.2 (d, J = 21.9 Hz)], 27.9 (28.0); 19F NMR (188 MHz, CDCl3) δ ꢀ118.1 (1F, m);
MS (ESI) m/z (%): 248 [M+H, (100)]+.
(2S,4S)-tert-Butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (8). To a
stirring solution of 7 (0.59 g, 2.39 mmol) in dry CH2Cl2 (10 mL) at ꢀ78 oC, DIBALꢀH
(1M in toluene, 6 mL) was added dropwise. The reaction was stirred for 1 h at ꢀ78 oC
and then warmed to room temperature for 16 h before being quenched with MeOH (7
mL) and aq. potassium sodium tartrate (2M, 10 mL). The mixture was stirred
vigorously for 30 min. The organic layer was separated and the aqueous layer was
further extracted with CH2Cl2 (2 x 25 mL). The combined organic phases were
washed with brine (40 mL), dried over Na2SO4, concentrated under reduced pressure
and purified by silica gel chromatography (PE/AcOEt, 8:2) to yield the desired
product 8
.
Colorless oil; 286 mg, 55% yield; [α]D20 = ꢀ26.1 (c 1.0, CH2Cl2); 1H NMR
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 38
1
2
3
4
5
6
7
8
9
(200 MHz, CDCl3) δ 5.16 (1H, dm, J = 53.2 Hz, CHF), 4.18ꢀ3.94 (1H, m), 3.86ꢀ3.32
(5H, m), 2.36ꢀ2.18 (1H, m), 2.16ꢀ1.92 (1H, m), 1.41 (9H, s); 13C NMR (50 MHz,
CDCl3) δ 156.0, 92.1 (d, J = 176.4 Hz), 80.7 (80.5), 67.3, 58.8, 53.8 (d, J = 21.2 Hz),
34.9 (d, J = 21.2 Hz), 28.2; 19F NMR (188 MHz, CDCl3) δ ꢀ116.2 (1F, m); MS (ESI)
m/z (%): 220 [M+H, (100)]+; HRMS exact mass calculated for [M+Na]+
(C10H18O3NFNa+) requires m/z 242.1163, found m/z 242.1163.
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
(2S,4S)-tert-Butyl 2-(azidomethyl)-4-fluoropyrrolidine-1-carboxylate (9). To a
stirring solution of 8 (0.28 g, 1.16 mmol) in dry CH2Cl2 (8 mL), Et3N (0.29 mL, 2.00
o
mmol) and MsCl (0.15 mL, 1.70 mmol) were added at 0 C. After 30 min, the
reaction was warmed at room temperature and left stirring at room temperature for 4
h. The reaction mixture was concentrated under reduced pressure and water (12 mL)
was added. The crude product was extracted with EtOAc (3 x 15 mL). The combined
organic layers were washed with aq. KHSO4 (10%, 2 x 20 mL). The organic layer was
dried over Na2SO4 and concentrated under reduced pressure to yield the crude mesyl
ester. The crude mesyl ester was dissolved in DMF (5 mL) and NaN3 (0.20 g, 2.00
o
mmol) was added. The reaction mixture was heated at 60 C for 24 h. The reaction
mixture was cooled down to room temperature and concentrated under reduced
pressure. Water (10 mL) was added and the mixture was extracted with EtOAc (3 x
10 mL). The combined organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The crude oil was purified by silica gel chromatography
(PE/AcOEt, 8:2) to yield the desired product 9. Colorless oil; 87 mg, 60 % yield;
20
1
[α]D = ꢀ33.2 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 5.19 (1H, dm, J = 53.4
Hz), 4.20ꢀ3.80 (2H, m), 3.80ꢀ3.40 (2H, m), 3.25ꢀ3.05 (1H, m), 2.40ꢀ1.81 (2H, m),
1.42 (9H, s); 13C NMR (50 MHz, CDCl3) δ 154.0 (153.9), 92.8 (d, J = 176.8 Hz)
[92.2 (d, J = 178.7 Hz)], 80.5 (80.8), 55.8, 55.0, 53.4 (d, J = 22.3 Hz) [52.9 (d, J =
16
ACS Paragon Plus Environment

Page 17 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
23.0 Hz)], 35.3 (d, J = 19.7 Hz) [34.5 (d, J = 20.3 Hz)], 28.3 (28.2); 19F NMR (188
MHz, CDCl3) δ ꢀ116.1 (1F, m); MS (ESI) m/z (%): 245 [M+H, (100)]+; HRMS exact
mass calculated for [M+Na]+ (C10H17O2N4FNa+) requires m/z 267.1233, found m/z
267.1239.
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
(2S,4S)-tert-Butyl 4-fluoro-2-(((S)-6-oxo-4-phenyl-2-thioxotetrahydropyrimidin-
1(2H)-yl)methyl)pyrrolidine-1-carboxylate (11). To a stirring solution of azide 9
(85 mg, 0.35 mmol) in dry THF (4 mL) in a pressure vessel, PPh3 (0.20 g, 0.46 mmol)
o
was added and the reaction mixture was left stirring at 65 C for 8 h. Then, H2O (0.4
o
mL) was added and the reaction mixture was left stirring at 65 C for 16 h. Then, the
solvent was removed and the crude amine was used in the next step without
purification. A solution of isothiocyanate 10 (135 mg, 0.52 mmol) in dry CH2Cl2 (8
mL) was added to a stirring solution of amine (67 mg, 0.30 mmol) in dry CH2Cl2 (8
mL) over a period of 5 min at room temperature and the reaction was left stirring for 2
h. The solvent was evaporated and the crude product was purified by silica gel
chromatography (PE/EtOAc, 7:3) to yield the desired product 11. Pale yellow oil; 65
20
1
mg, 47% yield; [α]D = ꢀ13.8 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 7.36ꢀ
7.14 (6H, m), 5.19 (1H, dm, J = 54.1 Hz), 4.60ꢀ4.46 (1H, m), 4.38ꢀ4.16 (2H, m), 3.76ꢀ
3.52 (3H, m), 3.28 (1H, ddd, J = 13.8, 7.0 and 1.7 Hz), 3.08ꢀ2.78 (1H, m), 2.06ꢀ1.92
(2H, m), 1.43 (6H, s), 1.37 (3H, s); 13C NMR (50 MHz, CDCl3) δ 183.7 (183.8), 173.8
(173.5), 154.4, 134.0, 128.9 (129.0), 128.9 (129.2), 127.3, 93.1 (d, J = 175.6 Hz), 79.5
(80.4), 60.6 (60.3), 53.6, 53.2 (d, J = 24.9 Hz) [53.3 (d, J = 25.7 Hz)], 44.7 (43.5),
36.7 (37.0), 35.6 (d, J = 20.3 Hz) [35.5 (d, J = 20.1 Hz)], 28.6; 19F NMR (188 MHz,
CDCl3) δ ꢀ115.6 (1F, m); HRMS exact mass calculated for [MꢀH]ꢀ (C20H25F N3O3Sꢀ)
requires m/z 406.1606, found 406.1609.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 38
1
2
3
4
(S)-3-(((2S,4S)-4-Fluoropyrrolidin-2-yl)methyl)-6-phenyl-2-
5
6
7
8
thioxotetrahydropyrimidin-4(1H)-one (2). To a stirring solution of 11 (65 mg, 0.16
mmol) in ΗCl 6N/ΜeOH (3 mL) in a pressure vessel, glacial AcOH (5 mL) was
9
o
added. The reaction mixture was left stirring for 3 h at 100 C. After cooling at room
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
temperature, the reaction mixture was treated with aq. NaHCO3 (10%) until pH=8.
The crude product was extracted with CH2Cl2 (3 x 10 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced pressure to yield the
20
desired product 2. Pale yellow oil; 45 mg, 92% yield; [α]D = ꢀ13.8 (c 1.0, CHCl3);
1H NMR (200 MHz, CDCl3) δ 7.40ꢀ7.10 (6H, m), 5.05 (1H, dm, J = 54.6 Hz), 4.55ꢀ
4.20 (1H, m), 4.19ꢀ3.70 (2H, m), 3.69ꢀ2.88 (3H, m), 2.87ꢀ2.21 (2H, m), 2.20ꢀ1.55
(2H, m), 1.23 (1H, s); 13C NMR (50 MHz, CDCl3) δ 184.0 (183.7), 174.7 (174.0),
135.6 (135.3), 129.1 (129.0), 128.9 (128.8), 127.5 (127.4), 94.7 (d, J = 173.9 Hz)
[94.6 (d, J = 174.6 Hz)], 61.0 (60.5), 57.1 (56.9), 53.6 (d, J = 23.6 Hz) [53.5 (d, J =
23.3 Hz)], 44.9, 37.4 (36.9), 37.3 (d, J = 21.1 Hz); 19F NMR (188 MHz, CDCl3) δ ꢀ
115.6 (1F, m); HRMS exact mass calculated for [MꢀH]ꢀ (C15H17F N3OSꢀ) requires m/z
306.1082, found 306.1080.
(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (12). The
title compound was obtained following literature procedure and all data for the
compound obtained matched literature data.17
(2S,4R)-1-tert-Butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (13).18
Following the same procedure as for compound 7, utilizing compound 12 (1.43 g,
20
5.83 mmol), to yield the desired product 13. Pale yellow oil; 0.96 g, 67%; [α]D = ꢀ
70.4 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 5.03 (1H, dm, J = 52.4 Hz), 4.35ꢀ
4.12 (1H, m), 3.86ꢀ3.14 (5H, m), 2.53ꢀ1.67 (2H, m), 1.28 (9H, s); 13C NMR (50 MHz,
CDCl3) δ 172.7 (172.5), 153.7 (153.1), 90.7 (d, J = 178.6 Hz) [91.5 (d, J = 178.1 Hz),
18
ACS Paragon Plus Environment

Page 19 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
80.0 (79.9), 57.2 (56.9), 52.5 (d, J = 22.6 Hz) [52.9 (d, J = 22.6 Hz)], 52.1 (52.3),
37.1 (d, J = 22.4 Hz) [36.2 (d, J = 22.7 Hz)], 27.5 (27.9); 19F NMR (188 MHz,
CDCl3) δ ꢀ122.6 (1F, m).
9
(2S,4R)-tert-Butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (14).
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
Following the same procedure as for compound 8, utilizing compound 13 (0.59 g,
20
2.39 mmol), to yield the desired product 14. Colorless oil 286 mg, 55% yield; [α]D
=
ꢀ41.6 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 5.11 (1H, dm, J = 52.3 Hz), 4.93
(1H, br), 4.25ꢀ3.18 (5H, m), 2.44ꢀ2.01 (2H, m), 1.44 (9H, s); 13C NMR (50 MHz,
CDCl3) δ 156.1, 91.0 (d, J = 176.3 Hz), 80.5 (79.6), 65.4, 58.3, 53.3 (d, J = 22.8 Hz),
35.1 (d, J = 21.9 Hz), 28.1; 19F NMR (188 MHz, CDCl3) δ ꢀ121.9 (1F, m); HRMS
exact mass calculated for [M+Na]+ (C10H18O3NFNa+) requires m/z 242.1163, found
m/z 242.1167.
(2S,4R)-tert-Butyl
2-(azidomethyl)-4-fluoropyrrolidine-1-carboxylate
(15).
Following the same procedure as for compound 9, utilizing compound 14 (405 mg,
20
1.85 mmol), to yield the desired product 15. Colorless oil; 331 mg, 73% yield; [α]D
1
= ꢀ48.3 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 5.03 (1H, dm, J = 52.9 Hz),
4.08ꢀ3.82 (2H, m), 3.81ꢀ3.53 (1H, m), 3.45ꢀ2.98 (2H, m), 2.32ꢀ1.68 (2H, m), 1.33
(9H, s); 13C NMR (50 MHz, CDCl3) δ 154 (153.7), 91.1 (d, J = 176.8 Hz) [90.7 (d, J
= 177.3 Hz)], 79.7 (80.1), 55.0, 53.5 (d, J = 22.5 Hz) [53.1 (d, J = 19.5 Hz)], 51.6,
34.9 (d, J = 21.7 Hz) [36.1 (d, J = 21.7 Hz)], 28.0; 19F NMR (188 MHz, CDCl3) δ ꢀ
122.0 (1F, m); HRMS exact mass calculated for [M+Na]+ (C10H17O2N4FNa+) requires
m/z 267.1233, found m/z 267.1241.
(2S,4R)-tert-Butyl 4-fluoro-2-(((S)-6-oxo-4-phenyl-2-thioxotetrahydropyrimidin-
1(2H)-yl)methyl)pyrrolidine-1-carboxylate (16). Following the same procedure as
for compound 11, utilizing compound 15 (331 mg, 1.35 mmol), to yield the desired
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 38
1
2
3
4
product 16. Pale yellow oil; 318 mg, 46% yield; [α]D = ꢀ2.0 (c 1.0, CHCl3); 1H
20
5
6
7
8
NMR (200 MHz, CDCl3) δ 8.71(0.4 Η, brs), 8.31ꢀ8.06 (0.6H, brm), 7.36ꢀ7.00 (5H,
m), 5.22ꢀ4.78 (1H, m), 4.46ꢀ4.18 (1H, m), 4.15ꢀ3.33 (4H, m), 3.32ꢀ2.77 (3H, m),
2.00ꢀ1.57 (1H, m), 1.56ꢀ1.10 (10H, m); 13C NMR (50 MHz, CDCl3) δ 183.3 (183.7),
173.6 (173.5), 154.6 (154.3), 135.1 (134.5), 129.5 (129.1), 128.6, 127.4, 91.0 (d, J =
177.9 Hz) [91.0 (d, J = 177.3 Hz)], 80.4 (79.7), 60.3 (60.0), 55.1, 52.3 (d, J = 18.8
Hz) [52.5 (d, J = 23.8 Hz)], 43.7 (44.1), 36.4, 35.5 (d, J = 21.6 Hz) [20.9 (d, J = 20.9
Hz)], 28.1; 19F NMR (188 MHz, CDCl3) δ ꢀ122.3 (1F, m); HRMS exact mass
calculated for [MꢀH]ꢀ (C20H25F N3O3Sꢀ) requires m/z 406.1606, found 406.1611.
(S)-3-(((2S,4R)-4-Fluoropyrrolidin-2-yl)methyl)-6-phenyl-2-
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
thioxotetrahydropyrimidin-4(1H)-one (3). Following the same procedure as for
compound 2, utilizing compound 16 (318 mg, 0.82 mmol), to yield the desired
20
1
product 3. Pale yellow oil; 161 mg, 64% yield; [α]D = +10.9 (c 1.0, CHCl3); H
NMR (200 MHz, CDCl3) δ 7.38ꢀ7.08 (6H, m), 5.07 (1H, dm, J = 53.6 Hz), 4.48ꢀ4.22
(1H, m), 3.71ꢀ3.55 (3H, m), 3.30ꢀ2.77 (4H, m), 2.07ꢀ1.75 (1H, m), 1.57ꢀ1.12 (2H, m);
13C NMR (50 MHz, CDCl3) δ 183.8 (183.7), 174.0 (173.9), 134.6 (134.9), 129.3
(129.2), 128.7, 127.4, 94.8 (d, J = 174.5 Hz), 60.5 (60.3), 54.9 (55.0), 52.5 (d, J =
23.1 Hz) [52.4 (d, J = 23.1 Hz)], 44.5 (44.6), 37.8 (d, J = 21.3 Hz) [37.7 (d, J = 23.3
Hz), 37.5; 19F NMR (188 MHz, CDCl3) δ ꢀ118.2 (1F, m); HRMS exact mass
calculated for [MꢀH]ꢀ (C15H17F N3OSꢀ) requires m/z 306.1082, found 306.1077.
(2S,4S)-1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-
dicarboxylate (17). To a stirring solution of alcohol 12 (0.48 g, 1.96 mmol 1.00 g,
o
4.08 mmol) in dry CH2Cl2 (20 mL) at 0 C under argon atmosphere, imidazole (0.40
g, 5.88 mmol) and TBDMSCl (0.36 g, 2.36 mmol) were added. The reaction was
o
stirred for 30 min at 0 C, and then warmed to room temperature and was allowed to
20
ACS Paragon Plus Environment

Page 21 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
stir for 20 h. Dichloromethane (20 mL) was added and the organic layer was washed
with water (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, and
concentrated to yield the crude product. The crude oil was purified by silica gel
chromatography (PE/EtOAc, 8:2) to yield the desired product 17 as colorless oil (0.60
g, 1.72 mmol, 88% yield); [α]D20 = ꢀ30.9 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3)
δ 4.30ꢀ4.10 (2H, m), 3.55 (3H, s), 3.54ꢀ3.39 (1H, m), 3.27ꢀ3.10 (1H, m), 2.24ꢀ2.05
(1H, m), 2.00ꢀ1.89 (1H, m), 1.32 (3H, s), 1.27 (6H, s), 0.70 (9H, s), ꢀ0.11 (6H, s); 13C
NMR (50 MHz, CDCl3) δ 172.5 (172.0), 153.3 (154.0), 79.5 (79.8), 69.5 (70.4), 57.5
(57.4), 53.9 (54.5), 51.6, 39.3 (38.5), 28.0 (28.1), 25.3, 17.6, ꢀ5.2; HRMS exact mass
calculated for [M+H]+ (C17H34O5NSi+) requires m/z 360.2201, found 360.2203.
(2S,4S)-tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-
1-carboxylate (18). To a stirring solution of 17 (0.50 g, 1.39 mmol) in dry THF (10
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
o
mL) at 0 C, NaBH4 (0.50 g, 12.51 mmol) was added. Methanol (8 mL) was added
o
dropwise to the reaction mixture. The reaction was stirred for 1 h at 0 C and then
warmed to room temperature for 20 h. The reaction was quenched with dropwise
addition of aq. NH4Cl (15 mL). The crude reaction mixture was extracted with AcOEt
(3 x 15 mL). The combined organic layers were washed with aq. NaHCO3 (40 mL),
brine (40 mL) and dried over Na2SO4. The organic solvent were concentrated under
reduced pressure and purified by silica gel chromatography (PE/AcOEt, 8:2) to yield
the desired product 18 as colorless oil (234 mg, 0.71 mmol, 51% yield); [α]D20 = ꢀ14.5
(c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 4.37ꢀ4.19 (1H, m), 4.08ꢀ3.39 (4H, m),
3.38ꢀ3.15 (1H, m), 2.30ꢀ2.06 (1H, m), 1.99ꢀ1.69 (1H, m), 1.57 (1H, br s), 1.42 (9H,
s), 0.84 (9H, s), 0.03 (6H, s); 13C NMR (50 MHz, CDCl3) δ 156.7, 79.8 (79.5), 69.5
(70.1), 66.1 (66.8), 58.5 (59.1), 55.6 (55.5), 37.5, 28.1, 25.4, 17.6, ꢀ5.2, ꢀ5.3; HRMS
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 38
1
2
3
4
5
exact mass calculated for [M+Na]+ (C16H33NNaO4Si+) requires m/z 354.2071, found
354.2079.
6
7
8
9
(2S,4S)-tert-Butyl 2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-
carboxylate (19). Following the same procedure as for compound 9, utilizing
compound 18 (230 mg, 0.69 mmol), to yield the desired product 19 as colorless oil
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
20
(116 mg, 0.33 mmol, 47% yield); [α]D = ꢀ10.6 (c 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 4.39ꢀ4.25 (1H, m), 4.12ꢀ3.67 (2H, m), 3.58ꢀ3.06 (3H, m), 1.99ꢀ1.84 (2H,
m), 1.39 (9H, s), 0.79 (9H, s), ꢀ0.01 (6H, s); 13C NMR (50 MHz, CDCl3) δ 154.7
(154.3), 79.7 (79.5), 69.8 (69.3), 55.4 (56.1), 55.3 (55.1), 52.4 (53.8), 37.8 (38.8),
28.2, 25.4, 17.7, ꢀ5.1; HRMS exact mass calculated for [M+H]+ (C16H33O3N4Si)
requires m/z 357.2316, found 357.2318.
(2S,4S)-tert-Butyl
4-((tert-butyldimethylsilyl)oxy)-2-(((S)-6-oxo-4-phenyl-2-
(20).
thioxotetrahydropyrimidin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate
Following the same procedure as for compound 11, utilizing compound 19 (116 mg,
0.33 mmol), to yield the desired product 20 as yellow oil (91 mg, 0.17 mmol, 53%
20
1
yield); [α]D = ꢀ22.7 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 7.38ꢀ7.15 (6H,
m), 4.54ꢀ4.21 (2H, m), 4.20ꢀ3.81 (1H, m), 3.78ꢀ2.77 (6H, m), 1.90ꢀ1.57 (2H, m),
1.49ꢀ1.29 (9H, m), 0.85 (9H, s), 0.04 (6H, s); 13C NMR (50 MHz, CDCl3) δ 183.7
(184.3), 173.2 (173.4), 155.0 (155.2), 136.1 (135.7), 129.0 (129.2), 128.8 (128.7),
128.2 (127.3), 79.1 (79.8), 69.9 (69.6), 60.3 (60.0), 53.8 (54.8), 52.6 (52.7), 52.0
(52.1), 36.7 (36.5), 35.6 (35.4), 28.2, 25.5, 17.7, ꢀ4.9, ꢀ5.1; HRMS exact mass
calculated for [MꢀH]ꢀ (C26H40N3O4SSiꢀ) requires m/z 518.2514, found 518.2522.
(S)-3-(((2S,4S)-4-Hydroxypyrrolidin-2-yl)methyl)-6-phenyl-2-
thioxotetrahydropyrimidin-4(1H)-one (4). Following the same procedure as for
compound 2, utilizing compound 20 (90 mg, 0.17 mmol), to yield the desired product
22
ACS Paragon Plus Environment

Page 23 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4 as pale yellow oil; (23 mg, 0.07 mmol, 44% yield); [α]D20 = ꢀ19.2 (c 0.25, CH3OH);
1H NMR (200 MHz, CDCl3) δ 7.39ꢀ7.17 (5H, m), 4.44ꢀ4.27 (1H, m), 3.93ꢀ3.63 (2H,
m), 3.49ꢀ2.69 (6H, m), 2.09ꢀ1.96 (1H, m), 1.69ꢀ1.62 (1H, m); 13C NMR (50 MHz,
CDCl3:CD3OD) δ 180.8 (181.2), 175.2 (176.1), 131.9 (133.2), 129.1 (129.2), 128.2
(128.4), 127.0 (127.4), 70.7 (69.6), 55.7 (55.0), 53.4 (53.6), 42.8 (43.1), 38.3 (38.2),
36.2 (36.0), 29.2; HRMS exact mass calculated for [MꢀH]ꢀ (C15H18 N3O2Sꢀ) requires
m/z 304.1125, found 304.1134.
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
(2S,4R)-1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-
dicarboxylate (21). Following the same procedure as for compound 17, utilizing compound
6 (1.00 g, 4.08 mmol), to yield the desired product 21 as a colorless oil (1.20 g, 3.34
20
1
mmol, 82%); [α]D = ꢀ32.9 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 4.40ꢀ4.22
(2H, m), 3.66 (3H, s), 3.58ꢀ3.46 (1H, m), 3.39ꢀ3.20 (1H, m), 2.20ꢀ2.02 (1H, m), 2.02ꢀ
1.86 (1H, m), 1.39 (3H, s), 1.34 (6H, s), 0.80 (9H, s), ꢀ0.01 (6H, s); 13C NMR (50
MHz, CDCl3) δ 173.6 (173.4), 153.7 (154.5), 79.9, 69.6 (70.3), 57.9 (57.5), 54.4
(54.7), 51.8, 39.7 (38.8), 28.1 (28.2), 25.6, 17.8, ꢀ5.0; MS (ESI) m/z (%): 360 [M+H,
(100)]+; HRMS exact mass calculated for [M+H]+ (C17H34O5NSi+) requires m/z
360.2201, found 360.2208.
(2S,4R)-tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-
1-carboxylate (22). Following the same procedure as for compound 8, utilizing
compound 21 (2.90 g, 8.10 mmol), to yield the desired product 22 as colorless oil
20
1
(1.63 g, 5.0 mmol, 61% yield); [α]D = ꢀ30.9 (c 1.0, CHCl3); H NMR (200 MHz,
CDCl3) δ 4.27ꢀ4.07 (1H, m), 4.03ꢀ3.12 (5H, m), 1.94ꢀ1.65 (1H, m), 1.64ꢀ1.40 (1H,
m), 1.32 (9H, s), 0.72 (9H, s), ꢀ0.08 (6H, s); 13C NMR (50 MHz, CDCl3) δ 156.8,
79.8, 69.6, 66.2, 58.6, 55.7, 37.5, 28.1, 25.4, 17.6, ꢀ5.1, ꢀ5.2; HRMS exact mass
calculated for [M+Na]+ (C16H33O4NSiNa+) requires m/z 354.2071, found 354.2078.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 38
1
2
3
4
5
6
7
8
(2S,4R)-tert-Butyl 2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-
carboxylate (23). Following the same procedure as for compound 9, utilizing
compound 22 (697 mg, 2.11 mmol), to yield the desired product 23 as colorless oil
9
(408 mg, 1.15 mmol, 54% yield); [α]D = ꢀ42.5 (c 1.0, CHCl3); 1H NMR (200 MHz,
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
CDCl3) δ 4.33ꢀ4.22 (1H, m), 4.08ꢀ3.88 (1H, m), 3.83ꢀ3.07 (4H, m), 1.93ꢀ1.79 (2H,
m), 1.38 (9H, s), 0.78 (9H, s), ꢀ0.02 (6H, s); 13C NMR (50 MHz, CDCl3) δ 154.8
(154.4), 79.5 (79.8), 69.9 (69.4), 55.5 (55.4), 54.9, 52.5 (53.8), 37.8 (38.8), 28.2, 25.5,
17.7, ꢀ5.1; HRMS exact mass calculated for [M+Na]+ (C16H32N4O3SiNa+) requires
m/z 379.2136, found 379.2144.
(2S,4R)-tert-Butyl
4-((tert-butyldimethylsilyl)oxy)-2-(((S)-6-oxo-4-phenyl-2-
(24).
thioxotetrahydropyrimidin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate
Following the same procedure as for compound 11, utilizing compound 23 (408 mg,
1.14 mmol), to yield the desired product 24 as pale yellow oil (422 mg, 0.81 mmol,
20
1
71% yield); [α]D = +3.2 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 7.32ꢀ6.98
(6H, m), 4.46ꢀ4.11 (2H, m), 3.95ꢀ3.72 (1H, m), 3.69ꢀ2.84 (6H, m), 2.08ꢀ1.54 (2H, m),
13
1.43 (9H, s), 0.83 (9H, s), 0.02 (6H, s); C NMR (50 MHz, CDCl3) δ 183.7 (183.6),
173.6 (173.5), 154.9 (155.0), 135.5 (134.6), 129.1 (129.3), 128.3 (128.6), 126.7
(127.2), 80.4 (79.8), 69.6 (70.0), 60.4 (60.0), 55.0 (53.9), 52.9 (53.3), 52.1 (52.7),
37.6 (37.9), 36.6 (36.9), 28.2, 25.6, 17.7, ꢀ4.9, ꢀ5.0; HRMS exact mass calculated for
[MꢀH]ꢀ (C26H40N3O4SSiꢀ) requires m/z 518.2514, found 518.2520.
(S)-3-(((2S,4R)-4-Hydroxypyrrolidin-2-yl)methyl)-6-phenyl-2-
thioxotetrahydropyrimidin-4(1H)-one (5). Following the same procedure as for
compound 2, utilizing compound 24 (227 mg, 0.44 mmol), to yield the desired
20
product 5 as pale yellow oil (73 mg, 0.24 mmol, 55% yield); [α]D = ꢀ1.2 (c 1.0,
CHCl3); 1H NMR (200 MHz, CDCl3:CD3OD) δ 7.31ꢀ7.05 (5H, m), 4.40ꢀ4.16 (1H,
24
ACS Paragon Plus Environment

Page 25 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
m), 3.75ꢀ3.43 (3H, m), 3.39ꢀ2.59 (5H, m), 1.71ꢀ1.54 (1H, m), 1.46ꢀ1.25 (1H, m); 13C
NMR (50 MHz, CDCl3:CD3OD) δ 183.2 (183.5), 174.5 (174.2), 134.2 (134.1), 129.2
(129.1), 128.3, 127.1, 71.1 (71.0), 55.4 (55.5), 53.8 (53.6), 43.6 (43.5), 38.1 (38.4),
36.2 (36.3), 29.3; HRMS exact mass calculated for [MꢀH]ꢀ (C15H18 N3O2Sꢀ) requires
m/z 304.1125, found 304.1131.
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
General procedure for the Michael reaction between ketones and nitrostyrenes
in brine.
To a stirring solution of catalyst 2 (5 mg, 0.016 mmol) and nitroolefin (0.32 mmol), 4ꢀ
NBA (8.1 mg, 0.049 mmol), brine (1.5 mL) and ketone (0.35 mmol) were added and
the reaction mixture was stirred vigorously for 20ꢀ48 h. The reaction mixture was
extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried over
Na2SO4 and the solvent was evaporated. In most cases, the product was of sufficient
purity (>95%). If the reaction did not reach completion, the product was purified by
column chromatography (PE/EtOAc).
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (25a).5 White solid, 78 mg, 99%;
mp 133ꢀ134 oC; [α]D20 = ꢀ27.0 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ 7.45ꢀ7.05
(5H, m), 4.93 (1H, dd, J = 12.5 Hz and 4.4 Hz), 4.60 (1H, dd, J = 12.3 and 10.3 Hz),
3.83ꢀ3.65 (1H, m), 2.78ꢀ2.57 (1H, m), 2.54ꢀ2.22 (2H, m), 2.17ꢀ1.92 (1H, m), 1.90ꢀ
1.40 (4H, m), 1.38ꢀ1.07 (1H, m); 13C NMR (50 MHz, CDCl3): δ 212.2, 138.0, 129.1,
128.4, 127.9, 79.1, 52.7, 44.2, 42.9, 33.4, 28.8, 25.2; HPLC analysis: 99% ee; Diacel
Chiralpak® ADꢀH column, hexane/2ꢀpropanol: 95/5, flow rate 1 mL/min, tR= 17.95
min (minor) and 23.34 min (major).
(S)-2-((R)-2-Nitro-1-(4-nitrophenyl)ethyl)cyclohexanone (25b).5 Pale yellow oil,
93 mg, 99%; [α]D20 = ꢀ30.3 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ 8.18 (2H, d,
J =8.8 Hz), 7.38 (2H, d, J = 8.8 Hz), 4.98 (1H, dd, J = 13.0 and 4.5 Hz), 4.67 (1H,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 38
1
2
3
4
5
6
7
8
9
dd, J = 13.0 and 10.2 Hz), 3.91 (1H, td, J = 9.8 and 4.5 Hz), 2.80ꢀ2.58 (1H, m), 2.52ꢀ
2.25 (2H, m), 2.18ꢀ2.09 (1H, m), 1.88ꢀ1.43 (4H, m), 1.37ꢀ1.28 (1H, m); 13C NMR (50
MHz, CDCl3): δ 210.9, 147.4, 145.5, 129.3, 124.1, 77.9, 52.1, 43.7, 42.7, 33.2, 28.3,
25.1; HPLC analysis: 93% ee; Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol:
80/20, flow rate 0.5 mL/min, tR= 39.66 min (minor) and 69.34 min (major).
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
(S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)cyclohexanone (25c).5 White solid, 79
o
1
mg, 93%; mp 72ꢀ74 C; [α]D20 = ꢀ19.9 (c 1, CHCl3); H NMR (200 MHz, CDCl3): δ
7.18ꢀ6.91 (4H, m), 4.91 (1H, dd, J = 12.5 and 4.6 Hz), 4.56 (1H, dd, J = 12.4 and 10.2
Hz), 3.74 (1H, td, J = 10.2 and 4.6 Hz), 2.72ꢀ2.54 (1H, m), 2.51ꢀ2.23 (2H, m),
2.02ꢀ1.90 (1H, m), 1.84ꢀ1.43 (4H, m), 1.23ꢀ1.17 (1H, m); 13C NMR (50 MHz,
CDCl3): δ 211.7, 162.1 (d, J = 240 Hz), 133.4, 129.8 (d, J = 10 Hz), 115.8 (d, J = 20
Hz), 78.7, 52.4, 43.2, 42.7, 33.2, 28.4, 25.0; 19F NMR (188 MHz, CDCl3): δ ꢀ59.4 (1F,
m); HPLC analysis 99% ee; Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol:
75/25, flow rate 0.7 mL/min, tR= 13.34 min (minor) and 15.51 min (major).
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone (25d).19 White solid, 89
mg, 99%; mp 122ꢀ124 C; [α]D20 = ꢀ23.7 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3):
o
δ 7.29 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 HzH) 4.93 (1H, dd, J = 12.6 and 4.6
Hz), 4.58 (1H, dd, J = 12.6 and 10.0 Hz), 3.74 (1H, td, J = 10.0 and 4.6), 2.73ꢀ2.54
(1H, m), 2.52ꢀ2.31 (2H, m), 2.21ꢀ1.96 (1H, m), 1.85ꢀ1.47 (4H, m), 1.22ꢀ1.06 (1H, m);
13C NMR (50 MHz, CDCl3): δ 211.5, 136.2, 133.5, 129.5, 129.1, 78.5, 52.3, 43.3,
42.7, 33.1, 28.1, 25.0; HPLC analysis: 99% ee; Diacel Chiralpak® ADꢀH column,
hexane/2ꢀpropanol: 90/10, flow rate 0.5 mL/min, tR= 32.50 min (minor) and 48.88
min (major).
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone (25e).5 White solid, 78
o
mg, 88%; mp 78ꢀ80 C; [α]D20 = ꢀ25.1 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ
26
ACS Paragon Plus Environment

Page 27 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.06 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.8 Hz), 4.90 (1H, dd, J = 12.3 and 4.6 Hz),
4.56 (1H, dd, J = 12.3 and 10.1 Hz), 3.79ꢀ3.62 (4H, m), 2.72ꢀ2.54 (1H, m), 2.47ꢀ2.25
(2H, m), 2.17ꢀ1.97 (1H, m), 1.83ꢀ1.43 (4H, m), 1.32ꢀ1.15 (1H, m); 13C NMR (50
MHz, CDCl3): δ 212.0, 158.9, 129.5, 129.1, 114.2, 79.0, 55.1, 52.6, 43.1, 42.6, 33.1,
28.5, 24.9; HPLC analysis: 99% ee; Diacel Chiralpak® ADꢀH column, hexane/2ꢀ
propanol: 95/5, flow rate 1 mL/min, tR= 24.68 min (minor) and 31.42 min (major).
(S)-2-((R)-1-(Naphthalen-2-yl)-2-nitroethyl)cyclohexanone (25f).5 White solid, 83
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
o
mg, 87%; mp 91ꢀ93 C; [α]D20 = ꢀ36.2 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ
7.87ꢀ7.71 (3H, m), 7.66ꢀ7.57 (1H, s), 7.53ꢀ7.39 (2H, m), 7.28 (1H, dd, J = 8.5 and 1.8
Hz), 5.02 (1H, dd, J = 12.5 Hz and 4.5 Hz), 4.72 (1H, dd, J = 12.5 and 10.0 Hz), 3.94
(1H, td, J = 10.0 and 4.5 Hz), 2.85ꢀ2.68 (1H, m), 2.58ꢀ2.28 (2H, m), 2.18ꢀ1.97 (1H,
m), 1.80ꢀ1.53 (4H, m), 1.37ꢀ1.19 (1H, m); 13C NMR (50 MHz, CDCl3): δ 211.8,
135.1, 133.3, 132.8, 128.8, 127.7, 127.6, 126.4, 126.1, 125.2, 78.8, 52.4, 44.0, 42.7,
33.2, 28.4, 24.9; HPLC analysis: 99% ee; Diacel Chiralpak® ADꢀH column, hexane/2ꢀ
propanol: 95/5, flow rate 1 mL/min, tR= 33.85 min (minor) and 39.89 min (major).
(S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone (25g).5 White solid, 75 mg,
99%; mp 76ꢀ78 oC; [α]D20 = ꢀ15,4 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ 7.41ꢀ
7.20 (1H, m), 6.34ꢀ6.07 (2H, m), 4.86ꢀ4.53 (2H, m), 4.04ꢀ3.83 (1H, m), 2.83ꢀ2.60
(1H, m), 2.54ꢀ2.23 (2H, m), 2.18ꢀ2.08 (1H, m), 1.93ꢀ1.49 (4H, m), 1.42ꢀ1.10 (1H, m);
13C NMR (50 MHz, CDCl3): δ 210.9, 151.1, 142.3, 110.4, 109.0, 75.2, 51.2, 42.5,
37.6, 32.5, 28.2, 25.1; HPLC analysis: 99% ee; Diacel Chiralpak® ADꢀH column,
hexane/2ꢀpropanol: 95/5, flow rate 0.5 mL/min, tR= 37.39 min (major) and 45.46 min
(minor).
(R)-3-((R)-2-Nitro-1-phenylethyl)dihydro-2H-pyran-4(3H)-one (25h).5 White
o
1
solid, 53 mg, 66%; mp 97ꢀ99 C; [α]D20 = ꢀ27.5 (c 1, CHCl3); H NMR (200 MHz,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 38
1
2
3
4
5
6
CDCl3): δ 7.38ꢀ7.10 (5H, m) 4.93 (1H, dd, J = 12.7 and 4.6 Hz), 4.63 (1H, dd, J =
12.7 and 10.1 Hz), 4.22ꢀ4.03 (1H, m), 3ꢀ90ꢀ3.60 (3H, m), 3.25 (1H, dd, J = 11.4 and
7
8
13
8.9 Hz), 3.00ꢀ2.77 (1H, m), 2.76ꢀ2.38 (2H, m); C NMR (50 MHz, CDCl3): δ 207.3,
9
136.2, 129.1, 128.3, 127.8, 78.6, 71.5, 68.9, 53.2, 42.9, 41.2; HPLC analysis: 99% ee;
Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol: 85/15, flow rate 1 mL/min, tR=
29.22 min (minor) and 41.48 min (major).
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
(S)-3-((R)-2-Nitro-1-phenylethyl)dihydro-2H-thiopyran-4(3H)-one (25i).5 White
o
solid, 82 mg, 97%; mp 132ꢀ134 C; [α]D20 = ꢀ26.9 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3): δ 7.37ꢀ7.17 (5H, m), 4.75 (1H, dd, J = 12.4 and 4.4 Hz), 4.62 (1H, dd, J =
12.4 and 9.6 Hz), 3.86 (1H, dt, J = 9.6 και 4.4 Hz), 3.07ꢀ2.92 (3H, m), 2.88ꢀ2.75 (2H,
m), 2.63ꢀ2.56 (1H, m), 2.48ꢀ2.41 (1H, m); 13C NMR (50 MHz, CDCl3): δ 209.5,
136.5, 129.3, 128.3, 128.1, 78.6, 54.9, 44.5, 42.9, 35.1, 31.6; HPLC analysis: 99% ee;
Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol : 85/15, flow rate 1 mL/min, tR=
23.48 min (minor) and 41.94 min (major).
(S)-4,4-Dimethyl-2-((R)-2-nitro-1-phenylethyl)cyclohexanone (25j).5 White solid,
o
20
1
87 mg, 99%; mp 79ꢀ81 C; [α]D = ꢀ105.8 (c 1, CH2Cl2); H NMR (200 MHz,
CDCl3): δ 7.38ꢀ7.08 (5H, m), 4.99 (1H, dd, J = 12.3 and 4.6 Hz), 4.61 (1H, dd, J =
12.3 and 9.7 Hz), 3.69 (1H, td, J = 9.7 and 4.6 Hz), 2.86 (1H, ddd, J = 13.3, 9.6 and
5.4 Hz), 2.55 (1H, ddd, 13.5, 13.4 6.5 Hz), 2.29 (1H, ddd, J = 13.5, 4.6 and 2.9 Hz),
1.83ꢀ1.55 (2H, m), 1.44ꢀ1.16 (2H, m), 1.12 (3H, s), 0.87 (3H, s);13C NMR (50 MHz,
CDCl3): δ 212.6, 137.7, 128.9, 128.1, 127.7, 79.0, 47.6, 45.8, 43.8, 40.6, 39.1, 31.0,
24.2; HPLC analysis: 99% ee; Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol:
95/5, flow rate 0.5 mL/min, tR= 32.02 min (minor) and 35.16 min (major).
(S)-7-((R)-2-nitro-1-phenylethyl)-1,4-dioxaspiro[4.5]decan-8-one (25k).5 White
o
solid, 74 mg, 76%; mp 117ꢀ119 C; [α]D20 = ꢀ13.9 (c 1, CHCl3); 1H NMR (200 MHz,
28
ACS Paragon Plus Environment

Page 29 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CDCl3): δ 7.36ꢀ7.26 (3H, m), 7.19ꢀ7.17 (2H, m), 4.96 (1H, dd, J = 12.5 and 4.7 Hz),
4.63 (1H, dd, J = 12.5 and 9.8 Hz), 4.01ꢀ3.82 (5H, m), 3.08 (1H, ddd, J = 13.0, 10.1
and 5.5 Hz), 2.78ꢀ2.68 (1H, m), 2.48 (1H, dd, J = 13.8, 5.1 and 3.5 Hz), 2.06 (1H, ddt,
J = 13.0, 6.6 and 3.5 Hz), 1.97 (1H, td, J = 13.0 and 5.1 Hz), 1.70 (1H, ddd, J = 13.0,
5.5 and 3.5 Hz), 1.57 (1H, t, J = 13.4 Hz);13C NMR (50 MHz, CDCl3): δ 201.3, 137.2,
128.9, 128.2, 127.8, 107.0, 78.9, 64.7, 64.5, 48.1, 43.4, 39.2, 38.5, 35.0; HPLC
analysis: 99% ee,; Diacel Chiralpak® ADꢀH column, hexane/2ꢀpropanol : 80/20, flow
rate 1 mL/min, tR= 15.82 min (minor) and 20.92 min (major).
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
(2S,4S)-4-Methyl-2-((R)-2-nitro-1-phenylethyl)cyclohexanone (25l).20 Pale yellow
1
oil, 83 mg, 99%; [α]D20 = ꢀ49.6 (c 1, CHCl3); H NMR (200 MHz, CDCl3): δ 7.36ꢀ
7.26 (3H, m), 7.18ꢀ7.16 (2H, m), 4.73ꢀ4.56 (2H, m), 3.84ꢀ3.76 (1H, m), 2.77ꢀ2.69
(1H, m), 2.50 (2H, t, J = 6.6 Hz), 2.12ꢀ1.94 (2H, m), 1.68ꢀ1.56 (1H, m), 1.50ꢀ1.35
(2H, m), 0.97 (3H, d, J = 6.6 Hz); 13C NMR (50 MHz, CDCl3): δ 213.0, 137.3, 129.1,
128.0, 79.1, 50.0, 44.1, 38.6, 37.9, 34.4, 26.5, 19.4; HPLC analysis: 95% ee,; Diacel
Chiralpak® ODꢀH column, hexane/2ꢀpropanol : 90/10, flow rate 0.5 mL/min, tR=
42.46 min (minor) and 48.27 min (major).
(S)-2-((R)-2-Nitro-1-phenylethyl)cycloheptanone (25m).21 Colorless oil, 28 mg,
34%; [α]D20 = ꢀ4.0 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): δ 7.35ꢀ7.27 (3H, m),
7.18ꢀ7.17 (2H, m), 4.67ꢀ4.53 (2H, m), 3.68 (1H, ddd, J = 10.3, 8.5 and 5.2 Hz), 3.01
(1H, td, J =10.3 and 3.3 Hz), 2.59ꢀ2.49 (2H, m), 1.94ꢀ1.86 (2H, m), 1.79ꢀ1.42 (3H,
m), 1.27ꢀ1.14 (3H, m) 13C NMR (50 MHz, CDCl3): δ 214.7, 137.7, 129.0, 128.1,
127.9, 78.7, 53.7, 45.5, 43.4, 29.9, 28.6, 28.5, 23.9 ; HPLC analysis: 85% ee; Diacel
Chiralpak® ADꢀH column, hexane/2ꢀpropanol : 98/2, flow rate 1 mL/min, tR= 25.03
min (minor) and 35.10 min (major).
29
ACS Paragon Plus Environment