Absolute Configuration Determination of 2,3-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles Using Chiroptical Methods at Different Wavelengths

Article abstract of DOI:10.1021/acs.joc.6b02270

A correlation between the absolute configuration and chiroptical properties of nonracemic 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles was studied. A series of 16 novel representatives were prepared by Cu-catalyzed [3 + 2] cycloadditions of racemic (Z)-2-benzylidene-5-oxopyrazolidin-2-ium-1-ides to tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate, and their structures were determined by NMR, VCD, ECD, and X-ray diffraction. A clear correlation between the sign of specific rotation and configuration at position C(1) allows for easy determination of the absolute configuration of 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by ECD and NMR. While VCD, requiring milligram quantities, allowed the determination of the correct relative and absolute configuration without additional information from other methods, the stereochemical analysis by ECD required knowledge of the relative configuration derived from NMR at a comparable computational level.

Full text of DOI:10.1021/acs.joc.6b02270

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Article
Absolute Configuration Determination of 2,3-Dihydro-1H,5H-pyrazolo-
[1,2-a]pyrazoles using Chiroptical Methods at Different Wavelengths.
Eva Pušavec Kirar, Uroš Grošelj, Amalija Golobi#, Franc Požgan, Stefan Pusch,
Carina Weber, Lars Andernach, Bogdan Štefane, Till Opatz, and Jurij Svete
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02270 • Publication Date (Web): 01 Nov 2016
Downloaded from http://pubs.acs.org on November 4, 2016
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Absolute Configuration Determination of 2,3-Dihydro-1H,5H-pyrazolo-
[1,2-a]pyrazoles using Chiroptical Methods at Different Wavelengths.
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Eva Pušavec Kirar,a Uroš Grošelja, Amalija Golobiča, Franc Požgan,a Stefan Pusch,b Carina
Weber,b Lars Andernach,b Bogdan Štefane,a Till Opatzb*1, and Jurij Svetea*1
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a) University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113,
SIꢀ1000 Ljubljana, Slovenia
b) Johannes GutenbergꢀUniversität Mainz, Institut für Organische Chemie, Duesbergweg 10ꢀ
14, Dꢀ55128, Mainz, Germany
Eꢀmail: opatz@uniꢀmainz.de; jurij.svete@fkkt.uniꢀlj.si
Abstract.
— A correlation between the absolute configuration and chiroptical properties of
nonꢀracemic 1,6,7ꢀtrisubstituted 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazoles was studied. A
series of 16 novel representatives were prepared by Cuꢀcatalyzed [3+2]ꢀcycloadditions of
racemic (Z)ꢀ2ꢀbenzylideneꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀides to tertꢀbutyl (S)ꢀ(3ꢀoxopentꢀ4ꢀynꢀ
2ꢀyl)carbamate, and their structures were determined by NMR, VCD, ECD, and Xꢀray
diffraction. A clear correlation between the sign of specific rotation and configuration at
position C(1) allows for easy determination of the absolute configuration of 1,6,7ꢀ
trisubstituted 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazoles by ECD and NMR. While VCD,
1 Corresponding author. Tel: +49(0)6131ꢀ39ꢀ22272/ꢀ24443; Fax: +49(0)6131ꢀ39ꢀ22338; eꢀ
mail: opatz@uniꢀmainz.de (TO). Tel.: +386 1 4798 562; Fax: +386 1 2419 144; eꢀmail:
jurij.svete@fkkt.uniꢀlj.si (JS).
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requiring milligram quantities, allowed the determination of the correct relative and absolute
configuration without additional information from other methods, the stereochemical analysis
by ECD required knowledge on the relative configuration derived from NMR at a comparable
computational level.
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Keywords: dihydropyrazolo[1,2ꢀa]pyrazoles; absolute configuration; chiroptical properties,
VCD.
1. Introduction
The determination of the relative and absolute configuration of organic molecules is an
important task for synthetic chemists. The use of chiroptical methods represents a standard
approach for this purpose if Xꢀray crystallography is not applicable or inconclusive. While
electronic circular dichroism (ECD) and especially visible light polarimetry are frequently
employed, the use of vibrational circular dichroism (VCD) is still rare in the synthetic organic
community.1 Here, we present a case study on the stereochemical analysis of a series of 2,3ꢀ
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazoles using chiroptical methods at three different
wavelength ranges.
Hetero(bi)cyles represent frequently used building blocks for applications in medicinal
chemistry, catalysis, and materials science.2 For example, dipeptide motifs in a given native
(or natural) peptidic substrate can be replaced with Uꢀshaped conformationally constrained
heterocyclic analogues that simulate βꢀturn structures.3 An important group of such
conformationally constrained dipeptide analogues are azabicycloalkane amino acids, which
comprise various saturated fused heterocycles with a bridgehead nitrogen atom.4 In this
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context, pyrazolo[1,2ꢀa]pyrazoles are a notable subgroup of 5,5ꢀfused systems with Eli Lilly’s
γꢀlactam antibiotics (Figure 1) as prototypical representatives.5 These antibiotics are based on
2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazole scaffold 3, which in turn is easily available by
[3+2] cycloaddition of 3ꢀoxopyrazolidinꢀ1ꢀiumꢀ2ꢀides 1 to acetylenes 2.6 In this context,
copperꢀcatalyzed cycloadditions of azomethine imines to acetylenes (CuAIAC)6b,7 provide an
easy access towards 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazoles 3 in a regioꢀ and
stereoselective manner under mild conditions that are compliant with requirements of "click"
chemistry (Figure 1).8,9
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Figure 1. Examples of biologically active 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazoles 3 and
their synthetic availability.
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In the absence of a general access to the nonꢀracemic dipoles 1 (and their pyrazolidinone
precursors), [3+2] cycloadditions are usually performed with achiral or racemic dipoles 1.6,7
Since compounds 3 contain up to three stereogenic centers (cf. Figure 1), mixtures of up to 8
stereoisomers are conceivable. Although mixtures of this kind are routinely separated and
characterized by HPLCꢀMS, unambiguous structure determination of a given isomer may not
be straightforward, since larger (tens of miligrams) quantities of the sample are required.
However, if the absolute configuration could be determined on the basis of NMR data and
chiroptical properties, this would significantly simplify and speed up structure elucidation.
The same would apply for compound series, for which relations of stereochemistry with
easily accessible chiroptical properties have been established using more sophisticated
measurements.
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Our previous studies on CuAIAC reactions also included cycloadditions of the racemic
(1Z,4R*,5R*)ꢀ1ꢀarylmethylideneꢀ4ꢀbenzoylaminoꢀ3ꢀoxoꢀ5ꢀphenyltetrahydropyrazolꢀ1ꢀiumꢀ2ꢀ
ides 1a–d to chiral nonꢀracemic (S)ꢀNꢀBocꢀalanineꢀderived ynone 2,10 which afforded
separable mixtures of diastereomeric nonꢀracemic cycloadducts, (+)-3a–d and (–)-3a–d (cf.
Table 2). Unfortunately, the absolute configurations of these nonꢀracemic products could
initially not be determined.7e In extension, novel analogous nonꢀracemic cycloadducts (+)-3e–
l and (–)-3e–l were synthesized and their absolute configuration was determined by Xꢀray
diffraction, VCD, ECD, and correlation between their sign of specific rotation and absolute
configuration. This might be useful as a simple method for the determination of absolute
configuration of novel cycloadducts of this type, if the dominance of one of the stereogenic
centers for the chiroptical properties in compound series is clearly demonstrated.
2. Results and Discussion
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2.1. Synthesis of cycloadducts 3. First, a small library of nonꢀracemic cycloadducts 3 with
different substituents at positions 1, 6, and 7 was synthesized. Later on, this would allow us to
compare the influence of a given substituent on the specific rotation. Azomethine imines 1a–l
with variable substituents at positions 4 and 5 and bearing typical aryl residues at position 1'
were prepared in good yields by condensation of racemic 3ꢀpyrazolidinones 4a,11 4b,12 4c,13
4d,14 and 4e15 and achiral compound 4f,16 with 5a–f following general literature
procedures.11,12,17 The (Z)ꢀconfiguration around the C=N double bond in 3ꢀoxopyrazolidinꢀ1ꢀ
iumꢀ2ꢀdes 1 and the trans configuration of 4,5ꢀdisubstituted pyrazolidinones 4a–c and dipoles
1 derived thereof were established previously.6,18,19 Selected experimental data for dipoles 1a–
l prepared from chemsets 4a–f and 5a–f are presented in Table 1.
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Table 1. Experimental data for azomethine imines 1a–l and chemsets 4a–f and 5a–f. Chiral
compounds 1a–h and 4a–e are racemic mixtures.
Reaction
R1
R2
Ph
Ph
Ph
R3
H
H
H
Ar
Yield (%)a Ref.
11
4a+5a→1a
4a+5b→1b
4a+5c→1c
NHBz
NHBz
NHBz
Ph
89
11
4ꢀO2NC6H4
4ꢀMeOC6H4
76
11
78
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b
4a+5d→1d
4b+5e→1e
4b+5b→1f
4c+5a→1g
4d+5b→1h
4e+5b→1i
4e+5f→1j
4e+5d→1k
4f+5b→1l
NHBz
NHCbz
NHCbz
NHCbz
H
Ph
H
3,4,5ꢀ(MeO)3C6H2
4ꢀClC6H4
92
56
67
81
88
49
51
62
93
iꢀPr
iꢀPr
Ph
H
b
H
4ꢀO2NC6H4
Ph
13
b
H
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Ph
H
4ꢀO2NC6H4
4ꢀO2NC6H4
2,4ꢀCl2C6H3
3,4,5ꢀ(MeO)3C6H2
4ꢀO2NC6H4
b
NHBz
NHBz
NHBz
H
Me
Me
Me
Me
Me
Me
Me
Me
b
b
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a) Isolated yields. b) This paper.
The novel cycloadducts (+)ꢀ3e–l and (–)ꢀ3e–l were synthesized according to the same
strategy employed for the synthesis of the nonꢀracemic cycloadducts (+)ꢀ3a–d and (–)-3a–d
reported previously.7e Briefly, cycloadditions of racemic dipoles 1e–l to the nonꢀracemic
ynone 2 were performed in the presence of 20 mol% of CuI and DIPEA in MeCN at room
temperature. Subsequent workup by flash column chromatography (FC) afforded mixtures of
diastereomeric nonꢀracemic cycloadducts, (+)ꢀ3e–l/(–)ꢀ3e–l in 79–100% yield. These
mixtures of isomers (+)ꢀ3e–l/(–)ꢀ3e–l were separated, either by column chromatography (CC)
or by medium pressure liquid chromatography (MPLC) to furnish diastereomerically pure
nonꢀracemic compounds (+)ꢀ3e–l and (–)ꢀ3e–l in 21–44% yield (Table 2).
Table 2. Synthesis and experimental data of cycloadducts (+)ꢀ3a–l and (–)ꢀ3a–l.
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Compd. R1
R2
R3
Ar
Yield of 3 (%)a
Ref.
(+/–)a,b (+)a
(–)a
5
7e
7e
7e
7e
c
NHBz
Ph
H
H
H
H
H
H
H
H
Ph
91
95
98
44
39
25
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44
42d
42
39e
28
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35
28
3a
3b
3c
3d
3e
3f
NHBz
NHBz
NHBz
NHCbz
NHCbz
NHCbz
H
Ph
4ꢀO2NC6H4
4ꢀMeOC6H4
17
14
14
36
32d,e
21
37e
23
31
30
23
Ph
Ph
3,4,5ꢀ(MeO)3C6H2 66
iꢀPr
iꢀPr
Ph
4ꢀClC6H4
4ꢀO2NC6H4
Ph
quant.
c
quant.
96
c
3g
3h
3i
c
Ph
4ꢀO2NC6H4
97
c
NHBz
NHBz
NHBz
H
Me
Me
Me
Me
Me 4ꢀO2NC6H4
Me 2,4ꢀCl2C6H3
95
c
79
3j
c
Me 3,4,5ꢀ(MeO)3C6H2 89
Me 4ꢀO2NC6H4 93
3k
3l
c
a) Isolated yield. ) Combined yield of diastereomers (+)ꢀ3 and (–)ꢀ3 after workup by FC and
b
c
d
before separation of diastereomers by MPLC. ) This paper. ) Absolute configuration was
determined by VCD. e) Absolute configuration was determined by Xꢀray diffraction.
2.2. Structure elucidation. The structures of novel compounds (+)ꢀ3e–l and (–)ꢀ3e–l were
determined by spectroscopic methods [IR, NMR spectroscopy (1Hꢀ and 13CꢀNMR, COSY,
HSQC, HMBC and NOESY experiments), and MSꢀHRMS] and by elemental analyses for C,
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H, and N.20 The relative configurations of novel diastereomeric cycloaducts (+)ꢀ3e–l and (–)ꢀ
3e–l were initially determined by NOESY experiments and by inspection of the vicinal coupling
3
7e,12,18,19
constant JH(6)–H(7)
.
In compounds 3h, a NOE between H–C(1) and H–C(7) supported
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the synꢀorientation of these two nuclei. In compound 3i, on the other hand, the antiꢀorientation
of H–C(1) and H–C(6) was established by NOE between H–C(1) and Mea–C(7) as well as
between Meb–C(7) and H–C(6). In compounds 3e–g, the magnitude of vicinal coupling
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3
constant, JH(6)–H(7) ~ 12 Hz, was in agreement with the trans configuration around the C(6)–
C(7) bond (Figure 2).18 The structure and relative configuration of compounds 3a–g was
additionally confirmed by correlation of characteristic chemical shifts δ and vicinal coupling
constants (3JH(6)–H(7) ~ 12 Hz).20 These values were in very good agreement with the literature
values for closely related compounds.7e,12,18,19 Correlation also revealed a significant
difference in chemical shifts,
ꢁδ > 0.3 ppm, for protons H–C(3) and H–C(6) in
diastereoisomeric pairs 3a–g,i–k with a 6ꢀacylamino substituent.20
Figure 2. Determination of relative configuration of compounds 3e–l by NMR.
The absolute configurations of nonꢀracemic diastereomers (+)ꢀ3f and (–)ꢀ3f were
investigated by VCD spectroscopy, i.e. comparison of the experimental data with DFT
calculated spectra at the B3LYP/6ꢀ311G(d,p) level with IEFPCM solvation (see section 4.4
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and the Supporting Information for details). The calculated IR spectra were fitted to the
experimental spectra based on the wavenumber range from 1100 cm–1 to 1650 cm–1, thus
excluding the problematic carbonyl region and avoiding artifacts due to solvent absorptions.
Based on the optimized fitting parameters, the calculated and experimental VCD spectra were
compared generating a similarity factor f, using the method developed by Bringmann and coꢀ
workers.21 For the hypothetical enantiomeric calculated VCD spectra, analogous similarity
factors f* were generated along with the differences ꢁ = f – f* (also termed enantiomeric
similarity index, ESI, for the absolute value). In an ideal case, the values would be f = 1, f* =
0, and ꢁ = 1 (or f = 0, f* = 1, and ꢁ = –1 for the enantiomer). The f, f*, and ꢁ values for all
eight possible diastereomers of compound 3f are shown in Table 3 with CCl4 as a solvent; the
extremal value of each column is marked in boldface.
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Table 3. Similarity factors for the VCD analysis of (+)ꢀ3f and (–)ꢀ3f in CCl4.
(+)ꢀ3f
(–)ꢀ3f
f
f*
ꢁ
f
f*
ꢁ
(2'S,1R,6R,7R)
(2'S,1R,6R,7S)
(2'S,1R,6S,7R)
(2'S,1R,6S,7S)
(2'S,1S,6R,7R)
(2'S,1S,6R,7S)
(2'S,1S,6S,7R)
(2'S,1S,6S,7S)
0.3747 0.2247 0.1500 0.3802 0.2643 0.1159
0.2603 0.2895 –0.0292 0.6272 0.1015 0.5257
0.3566 0.3246 0.0320 0.6868 0.0720 0.6148
0.2157 0.4206 –0.2049
0.0496
0.7671
0.7175
0.1529
0.0501
–0.6189
0.5833
0.4304
0.6690
0.2463 0.3409 –0.0946 0.1071 0.5892 –0.4821
0.3675 0.1528 0.2147 0.0783 0.5711 –0.4928
0.1577
–0.3006 0.4805 0.1823 0.2982
0.4583
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The two structures out of the sixteen theoretically possible stereoisomers (eight
diastereomers plus the corresponding enantiomers) with the highest f and ꢁ values for each of
the two samples, respectively, are shown in Figure 3.
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Figure 3. Assignment of absolute configurations for the diastereomers (+)ꢀ3f and (–)ꢀ3f.
Based on the known (S)ꢀconfiguration of amino ketone 2, the trans configuration of dipole
1, and the syn orientation between the substituents at positions 1 and 7 (cf. Figure 2) the inital
set of possible stereoisomers reduces to only two configurations, (2'S,1R,6S,7S) and
(2'S,1S,6R,7R); the corresponding f values are marked in grey in Table 3. This strongly
supports the assignment made in Figure 3. The predicted configuration of (+)ꢀ3f appears to be
logical from a synthetic point of view, although the ꢁ value is only 43%. The deviation may
be attributed to intermolecular hydrogen bonding and/or missing conformers due to the sparse
conformational search algorithm required to reduce the computing time to an acceptable level.
For (–)ꢀ3f, the ꢁ value is satisfactory with 72% and the configuration could subsequently be
confirmed by Xꢀray crystallography of a single crystal (see below). The measurements and
calculations were repeated using three different solvents of higher polarity (chloroform,
acetonitrile, and DMSO).20 The results are very consistent among all four solvents and the
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same absolute configurations as those shown in Figure 3 are predicted for compounds (+)ꢀ3f
and (–)ꢀ3f.
6
7
8
9
Finally, the structure and absolute configuration of compounds (–)-3f, (+)-3h, and (–)-3h
were determined by Xꢀray diffraction. The results unambiguously established (2'S,1R,6S,7S)ꢀ
configuration for compound (–)-3f, (2'S,1S,7S)ꢀconfiguration for compound (+)-3h, and
(2'S,1R,7R)ꢀconfiguration for compound (–)-3h.20
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2.3. Correlation between the absolute configuration and specific rotation in novel
compounds 3e–l and known analogues 3a–d,m–r (Table 4, Figure 5). For the relevance of
this correlation, it is important that all specific rotations of known compounds 3a–d7e and
3m–r7a,b and novel compounds 3e–l were measured in CH2Cl2. First, the specific rotations of
diastereomers (+)-3e–g,h and (–)-3e–g,h and enantiomers (+)-3m–r and (–)-3m–r7a,b were
correlated with their absolute configurations that had been unambiguously determined by Xꢀ
ray diffraction or by VCD (Table 4, entries 6, 8, 13 and 16).22 This correlation revealed that
all (1S)ꢀisomers were strongly dextrorotatory while all (1R)ꢀisomers were strongly
levorotatory. The typical specific rotation value was ~450 regardless the number of
stereogenic centers. For example, the (1R)ꢀ(–)ꢀisomers 3p, 3m, 3h, and 3f with one to four
stereogenic centers exhibited specific rotation values, –442, –392, –524, and –741,
respectively. Alltogether, 55 literature examples,7a–d,f including representatives (+)-3m–r and
(–)-3m–r, were in complete agreement with the above correlation.20 This strongly suggested
substantially different contributions of each stereogenic center to the overall sign and the
magnitude of specific rotation of isomers (+)-3m–r and (–)-3m–r. Accordingly, the
configuration at position 1 had the major impact on specific rotation of compounds 3a–r,
whereas the configurations at stereogenic centers at positions 6, 7, and 2' have less influence
in this respect. Consequently, the (–)ꢀsign of specific rotation could be "anchored" to the (1R)ꢀ
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configuration in all compounds (–)-3a–r. In this case, assignment of the absolute
configuration of compounds 3a–e,g,i–l with multiple stereogenic centers is feasible by NMR
(cf. Figure 2).
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Table 4. Correlation of configuration of compounds 3a–r.a
Entry Cpd.
(+)ꢀIsomer
[α]D
(–)ꢀIsomer
[α]D
Ref.
7e
1
2
3
4
5
6
7
+260
+686
+509
+117
+584
+814d
+331
–532
–769
–607
–194
–718
3a
3b
3c
3d
3e
3f
7e
7e
7e
b
2'S,1R,6S,7S (–)ꢀ3a–g –741c,d
b
2'S,1S,6R,7R (+)ꢀ3a–g
b
–291
3g
b
8
+464c
–524c
3h
2'S,1S,7S (+)ꢀ3h
2'S,1R,7R (–)ꢀ3h
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Table 4 (Continued). Correlation of configuration of compounds 3a–r.a
4
5
6
7
8
Entry Cpd.
(+)ꢀIsomer
[α]D
(–)ꢀIsomer
[α]D
Ref.
b
9
+751
+572
+591
–611
–592
–533
3i
9
b
b
10
11
3j
3k
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2'S,1S,6R (+)ꢀ3i–k
2'S,1R,6S (–)ꢀ3i–k
b
12
+758
–520
3l
2'S,1S (+)ꢀ3l
2'S,1R (–)ꢀ3l
7b
7b
7b
13
14
15
3me
3ne
3oe
+400f
+315f
+220f
–392c
–315
–220
1S,7S (+)ꢀ3m–o
1R,7R (–)ꢀ3m–o
7a
7a
7a
16
17
18
3pe
3qe
3re
+440f,g
+410f,g
+240f,g
–442c
–410
–242
1S (+)ꢀ3p–r
1R (–)ꢀ3p–r
a) Unless otherwise stated, specific rotations were measured in CH2Cl2. ) This work. )
b
c
d
e
Determined by Xꢀray diffraction. ) Determined by VCD. ) R = Ph (3m, 3p), 2ꢀfuryl (3n), cꢀ
C6H11 (3o), 4ꢀF3CC6H4 (3q), 4ꢀFC6H4 (3r). f) Estimated value, only [α] for the other enantiomer
is given. g) Measured in CHCl3.
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The above hypothesis on the key role of the configuration at position C(1) on the sign of
specific rotation is exemplified in Figure 4. Similar specific rotation values of compounds 3a,
3h, 3m, and 3p with the same C(1)ꢀsubstituent (Ph) are in agreement with the hypothesis that
strong specific rotation is most probably due to the sterogenic center C(1).
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Figure 4. Deconvolutive estimation of participation of the three stereogenic centers in 6ꢀacylꢀ
5ꢀphenylꢀ2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ1ꢀones 3a,h,m,p to overall specific
rotation.
To additionally confirm the proposed correlation between the specific rotation and
configuration at position C(1), ECD spectra of diastereomers (+)ꢀ3e–l and (–)ꢀ3e–l were
recorded. Spectra of all diastereomeric pairs behaved almost like mirror images with the
strongest absorption bands located around 350 nm. These results were in agreement with the
proposed correlation between the specific rotation and absolute configuration of bicyclic
pyrazolidinones 3. The ECD spectra of diastereomeric pairs (+)ꢀ3e–l and (–)ꢀ3e–l are given in
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the Supporting Information, while the representative spectra of the diastereomeric pairs (+)-
3e/(–)-3e and (+)-3f/(–)-3f are shown in Figure 5.
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Figure 5. ECD spectra of diastereomeric pairs (+)-3e,f (blue) and (–)-3e,f (red).
On the other hand, comparison of the experimental ECD spectra with computational data at
the TDꢀB3LYP/def2ꢀTZVPP level with COSMO solvation (see section 4.4 for details) did
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only allow for a unique assignment of the absolute configuration of (+)ꢀ3f and (–)ꢀ3f if
additional information on the absolute configuration of the amino acid derived stereogenic
center C(2') and on the relative configuration of H(1)/H(7) as well as H(6)/H(7) determined
by NMR was used as an input (see the Supporting Information for details). The same
phenomenon has already been observed by us in another compound series.23 However, if
these strongly restrictive assumptions are taken into account, the ECD data support our
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previously made VCD assignments with satisfying
ꢁ values of approximately 89% for (+)ꢀ3f
and 64% for (–)ꢀ3f.
3. Conclusions
A series of nonꢀracemic 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ1ꢀones (+)ꢀ3a–l and (–
)ꢀ3a–l were prepared from racemic azomethine imines 1 and nonꢀracemic ynone 2 followed
by chromatographic separation. The structure and absolute configuration of compounds (+)/(–
)-3f and (+)/(–)-3h were unambiguously determined by Xꢀray diffraction or by VCD and
ECD spectroscopy. The structures of the remaining compounds in the 6,7ꢀdisubstituted series,
(+)/(–)-3a–e,g,i–l, were determined by correlation of their specific rotations, taking also
known derivatives 3m–r with unambiguously determined absolute configurations into
account. Correlation between the absolute configuration of compounds 3e–h and 3m–r and
their sign of specific rotation revealed that all dextrorotatory isomers had (1
S) configuration
while all levorotatory isomers had (1 ) configuration. In contrast, the configuration at
R
positions 6 and 7 did not affect the overall sign of the specific rotation. If proven reliable, this
correlation could be a useful and simple analytical tool that would enable easy absolute
configuration determination of novel 2,3ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ1ꢀones. The
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method might be particularly useful in highꢀthroughput synthesis of libraries of title
compounds, since HPLCꢀMS coupled with the determination of the optical rotation at
wavelength(s)24 above 350 nm would provide configuration at position C(1) along with the
basic characterization data. This type of analysis can be used wherever the configuration of a
single stereogenic center is solely responsible for the shape of an ECD curve (or a
charcteristic band) or the sign of specific rotation. As shown in our case, the predominance of
one of the stereogenic centers for the chiroptical properties and clear correlations are also
required for the analysis of other compound classes.
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4. Experimental
4.1. General methods. Melting points were determined on a Kofler micro hot stage and on
an automated melting point system. The NMR spectra were recorded in CDCl3 and DMSOꢀd6
using TMS as the internal standard on a 300 MHz or 500 MHz instrument at 300 and 500
1
MHz for H and at 75.5 and 126 MHz for 13C nucleus, respectively. Mass spectra were
recorded on TOF LC/MS spectrometer and IR spectra on a FTIR ATR spectrophotometer.
Microanalyses were performed by combustion analysis on a CHN analyzer. Flash column
chromatography (FC) and column chromatography (CC) were performed on silica gel
(particle size: 0.035–0.070 mm). Mediumꢀpressure liquid chromatography (MPLC) was
performed on silica gel (particle size 15–25 µm, wetꢀfilled column dimensions 22×460 mm)
using automated chromatography system equipped with UVꢀVIS detector and fraction
collector (backpressure: 15 bar, detection wavelength: 254 nm). The VCD spectra were
recorded using an FTIR spectrometer equipped with one photoelastic modulator optimized for
1400 cm−1. An accumulation time of 360 min, a spectral range of 1800−800 cm−1, a resolution
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of 4 cm−1, and a 100 ꢂm path length BaF2 sample cell were used for all measurements. All
spectra were baseline corrected by subtraction of a solvent spectrum recorded with the same
parameters. The sample concentrations amounted to 76–79 mM. The CD spectra were
recorded using a CD spectropolarimeter equipped with a thermoelectric temperature
controller at 25 °C, spectral range 200–450 nm, averaging time of 3 s, 1 nm bandwidth,
acetonitrile as solvent, and sample concentration of 1 mg mL–1.
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Aromatic aldehehydes 5a–f, trifluoroacetic acid, CuI, and DIPEA are commercially
available. Azomethine imines 1a–c,11 1d,19 1g,13 and 1l,17 tertꢀbutyl (
S)ꢀ(3ꢀoxopentꢀ4ꢀynꢀ2ꢀ
yl)carbamate (2),7e,10 3ꢀpyrazolidinones 4a,11 4b,12 4c,13 4d,14 4e,15 and 4f,16 and the nonꢀ
racemicꢀcycloadducts (+)-3a–d and (–)-3a–d7e were prepared following the literature
procedures.
4.2. General procedure for the synthesis of novel azomethine imines 1e,f,h–k.
Compounds 1e,f,h–k were prepared following general procedure for the synthesis of closely
analogous compounds.11,13 A mixture of pyrazolidinone 4 (1 mmol), aromatic aldehyde 5 (1.2
mmol), anh. EtOH (4 mL) was stirred at r.t. for 5 min. Then, trifluoroacetic acid (2 drops) was
added and the mixture was stirred at r.t. for 12 h. The precipitate was collected by filtration
and washed with EtOH and Et2O to give 1.
4.2.1.(3R*,4R*)ꢀ4ꢀBenzyloxycarbonylaminoꢀ2ꢀ((Z)ꢀ4ꢀchlorobenzylidene)ꢀ3ꢀisopropylꢀ5ꢀ
oxopyrazolidinꢀ2ꢀiumꢀ1ꢀide (1e). Prepared from pyrazolidinone 4b (2.722 g, 9.2 mmol) and
1
aldehyde 5e (1.505 g, 10.7 mmol). Yield: 2.182 g (56%) of white solid; mp 206–210
NMR (300 MHz, DMSOꢀd6): 0.75 and 1.04 (6H, 2d, 1:1,
4.10 (1H, dd, = 4.2, 7.6 Hz); 4.49 (1H, t,
and 8.37 (4H, 2d,
DMSOꢀd6):
°C. H
δ
J = 6.7 Hz); 2.50–2.59 (1H, m);
J
J
= 4.4 Hz); 5.05 (2H, s); 7.25–7.40 (5H, m); 7.64
13
J
= 8.7, 8.4 Hz); 7.81 (1H, s); 7.88–7.92 (1H, m). C NMR (75.5 MHz,
δ
14.1, 17.9, 30.5, 51.0, 65.6, 78.2, 127.7, 127.9, 128.3, 128.5, 128.9, 131.7,
133.0, 136.1, 136.8, 155.7, 180.4. m/z (HRMS) Found: 400.1421 (MH+). C21H23ClN3O3
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requires: m/z = 400.1422. (Found: C, 62.78; H, 5.28; N, 10.46. C21H22ClN3O3 requires: C,
63.08; H, 5.55; N, 10.51.); νmax (ATR) 3030, 1713 (C=O), 1659 (C=O), 1587, 1250, 1089,
1042, 748, 671 cm–1.
9
4.2.2.(3R*,4R*)ꢀ4ꢀBenzyloxy)carbonylaminoꢀ3ꢀisopropylꢀ2ꢀ((Z)ꢀ4ꢀnitrobenzylidene)ꢀ5ꢀ
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oxopyrazolidinꢀ2ꢀiumꢀ1ꢀide (1f). Prepared from pyrazolidinone 4b (824 mg, 3.0 mmol) and
1
aldehyde 5b (458 mg, 3.1 mmol). Yield: 814 mg (67%) of yellow solid; mp 188–191
NMR (300 MHz, DMSOꢀd6): 0.76 and 1.06 (6H, 2d, 1:1,
= 6.8 Hz); 4.13 (1H, dd, = 4.2, 7.9 Hz); 4.59 (1H, t,
(5H, m); 7.94–7.97 (2H, m); 8.38 and 8.58 (4H, 2d, 1:1,
MHz, DMSOꢀd6):
°C. H
δ
J = 6.7 Hz); 2.59 (1H, br septulet,
J
J
J
= 4.1 Hz); 5.05 (2H, s); 7.29–7.40
= 8.6, 8.8 Hz). 13C NMR (75.5
J
δ
14.0, 17.9, 30.6, 50.7, 65.7, 78.9, 123.8, 127.7, 127.9, 128.3, 130.1,
132.1, 135.2, 136.8, 147.8, 155.7, 181.1. m/z (HRMS) Found: 411.1654 (MH+). C21H23N4O5
requires: m/z = 411.1663. (Found: C, 61.12; H, 5.19; N, 13.71. C21H22N4O5 requires: C,
61.46; H, 5.40; N, 13.65.); νmax (ATR) 3036, 1713 (C=O), 1667 (C=O), 1569, 1519, 1272,
1100, 731, 679 cm–1.
4.2.3. (Z)ꢀ2ꢀ(4ꢀNitrobenzylidene)ꢀ5ꢀoxoꢀ3ꢀphenylpyrazolidinꢀ2ꢀiumꢀ1ꢀide (1h). Prepared
from pyrazolidinone 4d (486 mg, 3 mmol) and aldehyde 5b (458 mg, 3.1 mmol). Yield: 0.778
g (88%) of yellowish solid; mp 181–185
°
C. 1H NMR (500 MHz, DMSOꢀd6):
δ
2.59 (1H, dd,
J
= 16.6, 4.3 Hz); 3.26 (1H, dd,
J
= 16.7, 9.7 Hz); 5.98 (1H, dd, J = 9.8, 4.2 Hz); 7.38–7.47
13
(5H, m); 7.56 (1H, s); 8.31–8.34 (2H, m); 8.51–8.54 (2H, m). C NMR (126 MHz, DMSOꢀ
d6):
δ 38.4, 73.8, 123.8, 126.7, 129.1, 129.5, 129.6, 131.8, 135.3, 139.1, 147.6, 183.4. m/z
(HRMS) Found: 296.103 (MH+). C16H14N3O3 requires: m/z = 296.103. νmax (ATR) 3107,
1688 (C=O), 1569, 1508, 1336, 1262, 1091, 681 cm–1.
4.2.4.(Z)ꢀ4ꢀBenzoylaminoꢀ3,3ꢀdimethylꢀ2ꢀ(4ꢀnitrobenzylidene)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀ
ide (1i). Prepared from pyrazolidinone 4f (699 mg, 3 mmol) and aldehyde 5b (756 mg, 5
1
mmol). Yield: 0.540 g (49%) of yellow solid; mp 246–248
°
C. H NMR (500 MHz, DMSOꢀ
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d6): δ 1.55 and 1.87 (6H, 2s, 1:1); 4.90 (1H, d, J = 5.1 Hz); 7.48–7.52 (2H, m); 7.56–7.59
5
6
(1H, m); 7.93–7.95 (2H, m); 8.10 (1H, s); 8.41–8.43 (2H, m); 8.63–8.66 (2H, m); 8.97 (1H, d,
7
8
13
J
= 8.4 Hz). C NMR (126 MHz, DMSOꢀd6):
δ
23.3, 27.6, 57.9, 76.7, 123.8, 127.5, 128.4,
9
128.9, 131.6, 132.2, 133.5, 135.6, 147.8, 167.2, 179.7. m/z (HRMS) Found: 367.1406 (MH+).
C19H19N4O4 requires: m/z = 367.1411. νmax (ATR) 3325, 1686 (C=O), 1672 (C=O), 1655
(C=O), 1600, 1517, 1308, 1082 cm–1.
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4.2.5.(Z)ꢀ4ꢀBenzoylaminoꢀ2ꢀ(2,4ꢀdichlorobenzylidene)ꢀ3,3ꢀdimethylꢀ5ꢀoxopyrazolidinꢀ2ꢀ
iumꢀ1ꢀide (1j). Prepared from pyrazolidinone 4f (1.398 g, 6 mmol) and aldehyde 5f (1.750 g,
10 mmol). Yield: 1.190 g (51%) of white solid; mp 204–205
d6): 1.55 and 1.86 (6H, 2s, 1:1); 4.87 (1H, d, = 8.4 Hz); 7.46–7.60 (3H, m); 7.67 (1H, dd,
°
C. 1H NMR (500 MHz, DMSOꢀ
δ
J
J
= 8.8, 2.2 Hz); 7.70 (1H, s); 7.78 (1H, d,
J
= 2.2 Hz); 7.92–7.95 (2H, m); 8.93 (1H, d,
J
= 8.2
Hz); 9.00 (1H, d,
J
= 8.8 Hz). 13C NMR (126 MHz, DMSOꢀd6):
δ 23.3, 27.5, 58.0, 76.8,
125.3, 126.3, 127.5, 127.7, 128.4, 129.5, 131.7, 132.9, 133.5, 135.0, 136.2, 167.3, 179.4. m/z
(HRMS) Found: 390.077 (MH+). C19H18Cl2N3O2 requires: m/z = 390.0771. (Found: C, 58.55;
H, 4.52; N, 10.51. C19H17Cl2N3O2 requires: C, 58.47; H, 4.39; N, 10.77.); νmax (ATR) 3264,
1673 (C=O), 1650 (C=O), 1582, 1537 cm–1.
4.2.6.(Z)ꢀ4ꢀBenzoylaminoꢀ2ꢀ(3,4,5ꢀtrimethoxybenzylidene)ꢀ3,3ꢀdimethylꢀ5ꢀoxopyrazolidinꢀ
2ꢀiumꢀ1ꢀide (1k). Prepared from pyrazolidinone 4f (233 mg, 1 mmol) and aldehyde 5d (235
1
mg, 1.2 mmol). Yield: 255 mg (62%) of white solid; mp 215–219
DMSOꢀd6):
°
C. H NMR (500 MHz,
δ
1.49 and 1.81 (6H, 2s, 1:1); 3.78 and 3.84 (9H, 2s, 1:2); 4.80 (1H, d, J = 8.3
Hz); 7.47–7.51 (2H, m); 7.54–7.58 (1H, m); 7.86 (1H, s); 7.90 (2H, s); 7.92–7.95 (2H, m);
= 8.4 Hz). 13C NMR (126 MHz, DMSOꢀd6):
8.91 (1H, d,
J
δ 23.1, 27.8, 56.1, 58.3, 60.3, 75.1,
109.5, 125.3, 127.5, 128.4, 131.6, 132.1, 133.6, 140.6, 152.6, 167.3, 178.6. m/z (HRMS)
Found: 412.1869 (MH+). C22H26N3O5 requires: m/z = 412.1867. νmax (ATR) 3246, 1656
(C=O), 1638 (C=O), 1596, 1327, 1237, 1131, 999 cm–1.
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4.3. General procedure for the synthesis of of cycloadducts (+)-3e–l and (–)-3e–l.
These compounds were prepared following the literature procedure for the synthesis of
closely related compounds (+)ꢀ3a–d and (–)-3a–d.7e CuI (117 mg, 0.6 mmol) and DIPEA
9
(156 µL, 0.9 mmol) were added to a stirred suspension of 1a–l (3 mmol) and tertꢀbutyl (S)ꢀ(3ꢀ
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60
oxopentꢀ4ꢀynꢀ2ꢀyl)carbamate (2) (651 mg, 3.3 mmol) in anh. acetonitrile (20 mL) and stirring
at r.t. was continued until complete dissolution of the starting dipole 1 (1–72 h). Volatile
components were evaporated in vacuo (35 °C, 10 mbar) and the residue was purified by FC
(EtOAc–hexanes). Fractions containing the product were combined and evaporated in vacuo
(40 °C, 10 mbar) to give a mixture of diastereomers (+)ꢀ3a–l/(–)-3a–l, which were separated
by CC or MPLC. Fractions containing the products were evaporated in vacuo to give two
diastereomeric nonꢀracemic compounds (+)ꢀ3a–l and (–)-3a–l.
4.3.1. tertꢀButyl
((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ7ꢀ
isopropylꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
yl)carbamate ((+)-3e) and its (S)ꢀ(1R,6S,7S)ꢀdiastereomer (–)-3e. Prepared from 1e (798 mg,
2 mmol) and 2 (433 mg, 2.2 mmol), CuI (76 mg, 0.4 mmol), DIPEA (105 ꢀL, 0.60 mmol), FC
(EtOAc), MPLC (EtOAcꢀhexanes, 1:2).
4.3.1.1. tertꢀButyl
isopropylꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
yl)carbamate ((+)-3e). Yield: 524 mg (44%) of yellowish solid; mp 173–177 C; [
= 0.24, CH2Cl2). 1H NMR (500 MHz, CDCl3):
0.82 and 0.85 (6H, 2d, 1:1,
(3H, d, = 7.1 Hz); 1.35 (9H, s); 1.76 (1H, br septet of d, = 7.0, 2.5 Hz); 3.19 (1H, dd,
2.8, 11.7 Hz); 4.77 (1H, p, = 7.3 Hz); 4.97 (1H, dd, = 9.7, 11.7 Hz); 5.08 and 5.13 (2H, 2d,
1:1, = 12.3 Hz); 5.17 (1H, s); 5.24 (1H, d,
(7H, m); 7.41 (2H, d,
((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ7ꢀ
23
589
°
α]
+584
(c
δ
J = 7.0); 1.11
J
J
J =
J
J
J
J
= 8.6 Hz); 6.85 (1H, d,
J
= 9.8 Hz); 7.28–7.31
17.0, 18.1,
13
J
= 8.4 Hz); 8.38 (1H, s). C NMR (126 MHz, CDCl3):
δ
20.4, 27.4, 28.4, 52.0, 55.9, 67.2, 73.2, 78.3, 80.3, 124.2, 128.1, 128.2, 128.5, 128.6, 129.5,
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130.2, 133.8, 136.3, 138.9, 155.7, 156.5, 166.4, 194.8. m/z (HRMS) Found: 597.2467 (MH+).
C31H38ClN4O6 requires: m/z = 597.2474. νmax (ATR) 2965, 1711 (C=O), 1696 (C=O), 1659
(C=O), 1487, 1436, 1244, 1160, 1035 cm–1.
9
4.3.1.2. tertꢀButyl ((S)ꢀ1ꢀ((1R,6S,7S)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ7ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
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32
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47
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49
50
51
52
53
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55
56
57
58
59
60
isopropylꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
23
589
yl)carbamate ((–)-3e) Yield: 358 mg (30%) of yellowish solid; mp 107–110
= 0.23, CH2Cl2). 1H NMR (500 MHz, CDCl3):
0.80 and 0.84 (6H, 2d, 1:1,
(3H, d, = 7.0 Hz); 1.37 (9H, s); 1.78 (1H, br septet of d, = 7.0, 2.8 Hz); 3.31 (1H, dd,
2.7, 11.5 Hz); 4.61 (1H, p, = 7.5 Hz); 4.72 (1H, dd, = 8.8, 11.7 Hz); 4.99 (1H, d, = 8.6
= 12.5 Hz); 5.21 (1H, s); 5.43 (1H, d, = 9.1 Hz); 7.29–
17.3, 17.8, 19.1, 27.5, 28.4, 51.4,
°C; [
α
]
–718
(c
δ
J = 7.0); 1.23
J
J
J =
J
J
J
Hz); 5.11 and 5.14 (2H, 2d, 1:1,
J
J
13
7.40 (9H, m); 7.76 (1H, s). C NMR (126 MHz, CDCl3):
δ
56.2, 67.7, 73.1, 77.5, 80.2, 123.7, 128.25, 128.3, 128.49, 128.53, 128.7, 129.3, 129.7, 133.8,
135.9, 139.0, 155.0, 156.0, 165.4, 194.6. m/z (HRMS) Found: 597.2464 (MH+).
C31H38ClN4O6 requires: m/z = 597.2474. (Found: C, 62.06; H, 6.39; N, 9.13. C31H37ClN4O6
requires: C, 62.36; H, 6.25; N, 9.38.); νmax (ATR) 2978, 1741 (C=O), 1697 (C=O), 1675
(C=O), 1509, 1245, 1160, 1040, 698 cm–1.
4.3.2.tertꢀButyl
((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ7ꢀisopropylꢀ1ꢀ(4ꢀ
nitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
yl)carbamate ((+)-3f) and its (S)ꢀ(1R,6S,7S)ꢀdiastereomer (–)-3f. Prepared from 1f (646 mg,
1.57 mmol) and 2 (318 mg, 1.61 mmol), CuI (32 mg, 0.17 mmol), DIPEA (84
ꢀL, 0.48
mmol), FC (EtOAc), CC (EtOAcꢀhexanes, 1:2).
4.3.2.1. tertꢀButyl
((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ7ꢀisopropylꢀ1ꢀ(4ꢀ
nitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
23
589
yl)carbamate ((+)-3f). Yield: 401 mg (42%) of yellow solid; mp 183–185
°C; [
α]
+814 (
c
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= 0.25, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ
0.82 and 0.86 (6H, 2d, 1:1,
J
= 6.8, 7.1 Hz);
5
6
7
8
1.09 (3H, d,
4.77 (1H, p,
J
J
= 7.1 Hz); 1.35 (9H, s); 1.70–1.77 (1H, m); 3.23 (1H, dd,
J
= 2.6, 11.5 Hz);
= 7.5 Hz); 4.99–5.03 (1H, m); 5.06–5.15 (2H, m); 5.22 (1H, d,
J
= 8.7 Hz);
9
5.32 (1H, s); 6.89–6.94 (1H, m); 7.29–7.34 (5H, m); 7.70 and 8.21 (4H, 2d, 1:1,
J = 8.6 Hz);
10
11
12
13
14
15
16
17
18
19
20
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22
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24
25
26
27
28
29
30
31
32
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37
38
39
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
8.48 (1H, s). C NMR (126 MHz, CDCl3):
δ 17.1, 18.1, 20.4, 27.5, 28.4, 51.9, 55.8, 67.3,
73.1, 78.2, 80.4, 123.5, 123.7, 128.1, 128.3, 128.5, 129.2, 130.8, 136.2, 147.5, 147.7, 155.7,
156.5, 166.6, 194.8. m/z (HRMS) Found: 608.2712 (MH+). C31H38N5O8 requires: m/z
=
608.2715. (Found: C, 61.13; H, 6.18; N, 11.45. C31H37N5O8 requires: C, 61.27; H, 6.14; N,
11.53.); νmax (ATR) 3438, 2970, 1710 (C=O), 1700 (C=O), 1655 (C=O), 1346, 1244, 1158,
1030, 752 cm–1.
4.3.2.2. tertꢀButyl
((S)ꢀ1ꢀ((1R,6S,7S)ꢀ6ꢀbenzyloxycarbonylaminoꢀ7ꢀisopropylꢀ1ꢀ(4ꢀ
nitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
23
589
yl)carbamate ((–)-3f). Yield: 308 mg (32%) of yellow solid; mp 128–130
°C; [
α]
–741 (
c
=
1
0.23, CH2Cl2). H NMR (500 MHz, CDCl3):
δ
0.79 and 0.84 (6H, 2d, 1:1,
J
= 6.9, 7.1 Hz);
= 2.7, 11.5 Hz);
= 8.3 Hz); 5.11–5.16 (2H, m);
= 8.3 Hz); 7.80 (1H, s).
1.25 (3H, d,
4.61 (1H, p,
J
J
= 7.0 Hz); 1.35 (9H, s); 1.71–1.79 (1H, m); 3.38 (1H, dd,
= 7.3 Hz); 4.69–4.73 (1H, m); 4.91 (1H, d,
J
J
5.34ꢀ5.40 (2H, m); 7.31–7.38 (5H, m); 7.66 and 8.19 (4H, 2d, 1:1,
13C NMR (126 MHz, CDCl3):
J
δ
17.4, 17.9, 18.8, 27.6, 28.4, 51.4, 56.1, 67.7, 73.1, 77.3, 80.3,
123.0, 123.6, 128.3, 128.6, 128.8, 129.4, 129.7, 135.9, 147.7, 155.0, 155.9, 165.6, 194.6. m/z
(HRMS) Found: 608.2713 (MH+). C31H38N5O8 requires: m/z = 608.2715. νmax (ATR) 3377,
2975, 1747 (C=O), 1697 (C=O), 1674 (C=O), 1518, 1246, 1040, 754, 698 cm–1.
4.3.3. tertꢀButyl
((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1,7ꢀdiphenylꢀ5ꢀoxoꢀ6,7ꢀ
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3g) and its
(S)ꢀ(1R,6S,7S)ꢀdiastereomer (–)-3g. Prepared from 1g (798 mg, 1.57 mmol) and 2 (433 mg, 2
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mmol), CuI (76 mg, 0.4 mmol), DIPEA (105
hexanes, 1:1).
ꢀL, 0.60 mmol), FC (EtOAc), MPLC (EtOAcꢀ
7
8
4.3.3.1. tertꢀButyl ((S)ꢀ1ꢀ((1S,6R,7R)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1,7ꢀdiphenylꢀ5ꢀoxoꢀ6,7ꢀ
9
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3g). Yield:
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
23
589
500 mg (42%) of yellow solid; mp 167–170
(500 MHz, CDCl3): 1.23 (3H, br d,
(1H, br p, = 7.3 Hz); 4.89 (1H, br t,
°
C; [
α]
+331 (
c
= 0.28, CH2Cl2). H NMR
= 11.5 Hz); 4.81
= 10.4 Hz); 4.99 and 5.03 (2H, 2d, 1:1, = 12.4 Hz);
= 8.2 Hz); 6.63 (1H, br d, = 8.3 Hz); 6.99–7.36 (15H, m); 8.37
20.4, 28.5, 52.2, 62.7, 67.2, 73.4, 76.8, 80.2, 123.7,
δ
J = 7.0 Hz); 1.40 (9H, s); 4.26 (1H, d, J
J
J
J
5.24 (1H, s); 5.30 (1H, d,
J
J
13
(1H, s). C NMR (126 MHz, CDCl3):
δ
127.7, 127.9, 128.0, 128.1, 128.17, 128.22, 128.51, 128.54, 129.0, 130.8, 133.7, 136.2, 140.0,
155.7, 156.3, 165.8, 194.7. m/z (HRMS) Found: 597.2703 (MH+). C34H37N4O6 requires: m/z
=
597.2708. (Found: C, 68.61; H, 5.83; N, 9.36. C34H36N4O6 requires: C, 68.44; H, 6.08; N,
9.39.); max (ATR) 2979, 1722 (C=O), 1711 (C=O), 1661 (C=O), 1490, 1245, 1044, 696, 660,
ν
639, 617 cm–1.
4.3.3.2. tertꢀButyl ((S)ꢀ1ꢀ((1R,6S,7S)ꢀ6ꢀbenzyloxycarbonylaminoꢀ1,7ꢀdiphenylꢀ5ꢀoxoꢀ6,7ꢀ
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((–)-3g). Yield:
1
23
250 mg (21%) of yellow solid; mp 94–98
MHz, CDCl3): 1.23 (3H, br d,
°C; [
α]
–259 (
c
= 0.23, CH2Cl2). H NMR (500
589
δ
J
= 6.6 Hz); 1.40 (9H, s); 4.49 (1H, br s); 4.67 (1H, br p,
J
=
7.4 Hz); 5.00–5.12 (3H, m); 5.24 (1H, br s); 5.44 (1H, br s); 6.95–7.40 (16H, m); 7.88 (1H, s).
13C NMR (126 MHz, CDCl3):
δ
19.1, 28.4, 51.4, 63.2, 67.6, 73.2, 75.1, 80.1, 123.1, 127.88,
127.90, 128.0, 128.16, 128.19, 128.4, 128.6, 128.7, 129.0, 130.5, 134.0, 135.9, 140.1, 155.1,
155.7, 164.6, 194.6. m/z (HRMS) Found: 597.2705 (MH+). C34H37N4O6 requires: m/z
max (ATR) 3032, 1705 (C=O), 1656 (C=O), 1496, 1232, 1162, 695 cm–1.
=
597.2708.
ν
4.3.4.tertꢀButyl
((S)ꢀ1ꢀ((1S,7S)ꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ7ꢀphenylꢀ6,7ꢀdihydroꢀ1H,5Hꢀ
pyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3h) and its ((S)ꢀ(1R,7R)ꢀ
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diastereomer (–)-3h. Prepared from 1h (414 mg, 1.40 mmol) and 2 (287 mg, 1.45 mmol), CuI
4
5
6
(29 mg, 0.15 mmol), DIPEA (49 ꢀL, 0.28 mmol), CC (EtOAcꢀhexanes, 2:3).
7
8
4.3.4.1. tertꢀButyl ((S)ꢀ1ꢀ((1S,7S)ꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ7ꢀphenylꢀ6,7ꢀdihydroꢀ1H,5Hꢀ
9
pyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3h). Yield: 272 mg (39%) of
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
= 0.35, CH2Cl2). 1H NMR (500 MHz, CDCl3):
= 6.8, 16.6 Hz); 3.03 (1H, dd, = 12.1,
= 6.9, 12.0 Hz); 4.69 (1H, p, = 7.3 Hz); 5.09 (1H, d, = 7.9 Hz);
δ
23
589
yellow solid; mp 196–199
1.18 (3H, d,
16.5 Hz); 4.44 (1H, dd,
°
C; [
α
]
+464 (
c
J
= 7.2 Hz); 1.42 (9H, s); 2.94 (1H, dd,
J
J
J
J
J
5.41 (1H, d,
J = 1.0 Hz); 7.16–7.23 (5H, m); 7.33–7.35 (2H, m); 7.83 (1H, s); 8.01–8.03 (2H,
m). 13C NMR (126 MHz, CDCl3):
δ
19.2, 28.4, 44.2, 51.9, 71.6, 72.3, 80.1, 122.1, 123.4,
127.5, 128.6, 128.9, 129.2, 130.3, 135.1, 147.4, 147.5, 155.3, 166.6, 194.9. m/z (HRMS)
Found: 493.2082 (MH+). C26H29N4O6 requires m/z = 493.2082
.
(Found: C, 63.11; H, 5.69; N,
11.15. C26H28N4O6 requires: C, 63.40; H, 5.73; N, 11.38.); νmax (ATR) 3087, 1736 (C=O),
1718 (C=O), 1653 (C=O), 1597, 1342, 1152, 1013, 834 cm–1.
4.3.4.2. tertꢀButyl ((S)ꢀ1ꢀ((1R,7R)ꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ7ꢀphenylꢀ6,7ꢀdihydroꢀ1H,5Hꢀ
pyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((–)-3h). Yield: 258 mg (37%) of
= 0.35, CH2Cl2). 1H NMR (500 MHz, CDCl3):
= 6.7, 16.6 Hz); 3.03 (1H, dd, = 12.2,
= 6.7, 12.2 Hz); 4.68 (1H, p, = 7.2 Hz); 5.01 (1H, d, = 8.3 Hz);
= 9.2 Hz); 7.86 (1H, s); 7.99 (2H, d, = 8.6
δ
23
589
yellow solid; mp 177–180
1.29 (3H, d,
16.5 Hz); 4.44 (1H, dd,
°
C; [
α
]
–524 (
c
J
= 7.0 Hz); 1.39 (9H, s); 2.97 (1H, dd,
J
J
J
J
J
5.36 (1H, s); 7.18–7.24 (5H, m); 7.28 (2H, d,
Hz). 13C NMR (126 MHz, CDCl3):
J
J
δ
19.0, 28.4, 44.2, 51.4, 71.7, 72.1, 80.2, 121.8, 123.4,
127.6, 128.8, 128.9, 129.2, 130.7, 135.1, 147.3, 147.6, 155.1, 166.7, 194.8. m/z (HRMS)
Found: 493.2079 (MH+). C26H29N4O6 requires m/z = 493.2082. (Found: C, 63.17; H, 5.77; N,
11.16. C26H28N4O6 requires: C, 63.40; H, 5.73; N, 11.38.); νmax (ATR) 3081, 1735 (C=O),
1709 (C=O), 1659 (C=O), 1595, 1342, 1225, 1146, 1015, 836 cm–1.
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4.3.5.tertꢀbutyl
((S)ꢀ1ꢀ((1S,6R)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀ
4
5
6
7
8
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate (+)-3i and its (S)ꢀ
1ꢀ((1R,6S)ꢀdiastereomer (–)-3i. Prepared from 1i (275 mg, 0.75 mmol), 2 (148 mg, 0.75
9
mmol), CuI (29 mg, 0.15 mmol), DIPEA (39 ꢀL, 0.22 mmol), CC (EtOAcꢀhexanes, 1:1).
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
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26
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28
29
30
31
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47
48
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53
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55
56
57
58
59
60
4.3.5.1. tertꢀbutyl ((S)ꢀ1ꢀ((1S,6R)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀ
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3i). Yield:
1
23
589
148 mg (35%) of yellow solid; mp 132–135
(500 MHz, CDCl3): 1.15 (3H, d,
(1H, p, = 7.3 Hz); 5.34 (1H, d,
°C; [
α]
+751 (
c
= 0.23, CH2Cl2). H NMR
δ
J
= 7.0 Hz); 1.17 (3H, s); 1.25 (3H, s); 1.31 (9H, s); 4.90
J
J
= 8.2 Hz); 5.48 (1H, d, = 8.3 Hz); 5.72 (1H, s); 7.42 (2H,
J
t,
J
= 7.6 Hz); 7.50–7.54 (1H, m); 7.50–7.55 (1H, m); 7.73 (2H, d,
J
= 8.6 Hz); 7.85 (2H, d,
J
13
= 8.1 Hz); 8.23 (2H, d,
J
= 8.7 Hz); 8.36 (1H, s). C NMR (126 MHz, CDCl3):
δ
13.9, 20.3,
24.0, 28.4, 51.8, 62.8, 64.5, 70.7, 80.3, 123.4, 123.9, 127.6, 128.7, 128.9, 130.6, 132.3, 133.3,
147.8, 148.3, 155.6, 166.0, 168.4, 195.0. m/z (HRMS) Found: 564.2443 (MH+). C29H34N5O7
requires m/z = 564.2453. (Found: C, 61.07; H, 5.59; N, 12.03. C29H33N5O7·⅓H2O requires: C,
61.15; H, 5.96; N, 12.30.); νmax (ATR) 2977, 1720 (C=O), 1656 (C=O), 1521, 1346, 1153,
831, 694 cm–1.
4.3.5.2. tertꢀbutyl ((S)ꢀ1ꢀ((1R,6S)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀ
dihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((–)-3i). Yield:
1
23
589
126 mg (30%) of yellow solid; mp 127–130
(500 MHz, CDCl3): 1.10 (3H, s); 1.27 (3H, d,
(1H, p, = 7.2 Hz); 4.93 (1H, d, = 7.9 Hz); 5.31 (1H, d,
°
C; [
α]
–611 (
c
= 0.23, CH2Cl2). H NMR
δ
J
= 7.0 Hz); 1.29 (3H, s); 1.38 (9H, s); 4.66
= 7.5 Hz); 5.64 (1H, s); 6.64–6.67
= 8.3 Hz); 7.81–7.83 (2H,
13.4, 18.7, 23.9, 28.4,
J
J
J
(1H, m); 7.47 (2H, t,
J = 7.7 Hz); 7.54–7.58 (1H, m); 7.67 (2H, d, J
m); 7.88 (1H, s); 8.20–8.22 (2H, m). 13C NMR (126 MHz, CDCl3):
δ
51.4, 62.7, 64.4, 71.3, 80.5, 123.1, 123.8, 127.4, 128.9, 129.0, 130.4, 132.5, 133.1, 147.8,
148.5, 155.1, 166.5, 168.0, 194.7. m/z (HRMS) Found: 564.2447 (MH+). C29H34N5O7 requires
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5
6
7
8
m/z = 564.2453. (Found: C, 60.75; H, 5.87; N, 12.02. C29H33N5O7·½H2O requires: C, 60.83;
H, 5.99; N, 12.23.); νmax (ATR) 2978, 1708 (C=O), 1656 (C=O), 1580, 1520, 1346, 1237,
1154, 711 cm–1.
9
4.3.6.tertꢀButyl ((S)ꢀ1ꢀ((1R,6R)ꢀ6ꢀbenzamidoꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ
6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3j) and
its (S)ꢀ((1S,6S)ꢀdiastereomer (–)-3j. Prepared from 1j (387 mg, 0.99 mmol) and 2 (195 mg,
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
0.99 mmol), CuI (38 mg, 0.2 mmol), DIPEA (52
ꢀL, 0.30 mmol), CC (EtOAcꢀhexanes, 1:1).
4.3.6.1. tertꢀButyl ((S)ꢀ1ꢀ((1R,6R)ꢀ6ꢀbenzamidoꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀ7,7ꢀdimethylꢀ5ꢀ
oxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3j).
23
589
Yield: 163 mg (27%) of yellow solid; mp 132–135
1.26 (9H, m); 1.28 (9H, s); 4.97 (1H, p,
(1H, dd, = 8.4, 2.1 Hz); 7.40 (1H, d,
m); 7.68 (1H, d, = 8.5 Hz); 7.85 (2H, d,
CDCl3):
°C; [
α]
+572 (
c
= 0.32, CH2Cl2). 1.23–
J
= 7.0 Hz); 5.42–5.44 (2H, m); 6.13 (1H, s); 7.29
J
J
= 2.0 Hz); 7.42 (2H, d,
J = 7.6 Hz); 7.48–7.52 (2H,
J
J
= 7.4 Hz); 8.53 (1H, s). 13C NMR (126 MHz,
δ
14.3, 20.8, 23.9, 28.4, 51.6, 61.3, 63.0, 70.3, 80.1, 124.1, 127.7, 128.0, 128.6,
129.4, 130.7, 130.9, 132.1, 133.4, 134.0, 134.5, 137.4, 155.7, 165.3, 168.5, 194.7. m/z
(HRMS) Found: 587.182 (MH+). C29H33Cl2N4O5 requires m/z = 587.1823. (Found: C, 58.88;
H, 5.68; N, 9.15. C29H32Cl2N4O5·⅓H2O requires: C, 58.69; H, 5.55; N, 9.44.); νmax (ATR)
2977, 1721 (C=O), 1657 (C=O), 1583, 1435, 1372, 1244, 1153, 852 cm–1.
4.3.6.2. tertꢀButyl
((S)ꢀ1ꢀ((1S,6S)ꢀ6ꢀbenzamidoꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀ7,7ꢀdimethylꢀ5ꢀ
oxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((–)-3j).
1
23
589
Yield: 191 mg (23%) of yellow solid; mp 123–127
NMR (500 MHz, CDCl3):
Hz); 4.96 (1H, d, = 8.5 Hz); 5.23 (1H, d,
7.25–7.27 (1H, m); 7.37–7.42 (2H, m); 7.46 (2H, t,
°
C; [
α]
–592 (
c
= 0.30, CH2Cl2). H
= 7.2
= 7.6 Hz);
= 7.7 Hz); 7.53–7.58 (1H, m); 7.80–7.83
13.7, 18.9, 23.8, 28.4, 51.3, 61.2, 62.8,
δ
1.14 (3H, s); 1.26–1.29 (6H, m); 1.41 (9H, s); 4.68 (1H, p,
= 7.6 Hz); 6.06 (1H, s); 6.52 (1H, d,
J
J
J
J
J
(2H, m); 7.85 (1H, s). 13C NMR (126 MHz, CDCl3):
δ
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7
8
70.9, 80.3, 123.8, 127.4, 128.0, 128.9, 129.3, 130.0, 131.0, 132.5, 133.2, 133.7, 134.4, 137.7,
155.1, 165.6, 167.9, 194.2. m/z (HRMS) Found: 587.1816 (MH+). C29H33Cl2N4O5 requires
m/z = 587.1823. (Found: C, 58.98; H, 5.51; N, 9.29. C29H32Cl2N4O5 requires: C, 59.29; H,
9
5.49; N, 9.54.); ν
max (ATR) 2977, 1711 (C=O), 1656 (C=O), 1583, 1438, 1239, 1154, 850 cm–
10
11
12
13
14
15
16
17
18
19
20
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46
47
48
49
50
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58
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60
1
.
4.3.7.tertꢀbutyl
((S)ꢀ1ꢀ((1S,6R)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ1ꢀ(3,4,5ꢀ
trimethoxyphenyl)ꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
yl)carbamate ((+)-3k) and its (S)ꢀ1ꢀ((1R,6S)ꢀdiastereomer (–)-3k. Prepared from 1k (304 mg,
0.74 mmol), 2 (150 mg, 0.76 mmol), CuI (29 mg, 0.15 mmol), DIPEA (39 ꢀL, 0.22 mmol),
MPLC (EtOAcꢀhexanes, 1:2).
4.3.7.1. tertꢀbutyl
((S)ꢀ1ꢀ((1S,6R)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ1ꢀ(3,4,5ꢀ
trimethoxyphenyl)ꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
23
589
yl)carbamate ((+)-3k). Yield: 130 mg (29%) of yellow solid; mp 128–131
°C; [
α]
+591 (
c
1
= 0.24, CH2Cl2). H NMR (500 MHz, CDCl3):
δ
1.17 (3H, s); 1.23 (3H, d,
J = 7.0 Hz); 1.31
(9H, s); 1.34 (3H, s); 3.86 (3H, s); 3.88 (6H, s); 4.94 (1H, p,
J
= 6.8 Hz); 5.43–5.45 (1H, m);
5.49 (1H, d,
J
= 8.4 Hz); 5.57 (1H, s); 6.70 (2H, s); 7.42 (2H, t,
J = 7.6 Hz); 7.52 (1H, t, J =
7.5 Hz); 7.55–7.59 (1H, m); 7.87 (2H, d,
J
= 7.4 Hz); 8.36–8.39 (1H, m). 13C NMR (126
MHz, CDCl3):
δ 13.9, 20.7, 24.1, 28.4, 52.0, 56.3, 61.0, 62.9, 65.3, 70.7, 80.0, 104.7, 124.3,
127.7, 128.6, 130.3, 132.2, 133.4, 136.8, 137.6, 153.3, 155.6, 166.1, 168.4, 195.2. m/z
(HRMS) Found: 609.2911 (MH+). C32H41N4O8 requires m/z = 609.2919. (Found: C, 63.03; H,
6.85; N, 9.00. C32H40N4O8 requires: C, 63.14; H, 6.62; N, 9.20.); νmax (ATR) 2975, 1712
(C=O), 1655 (C=O), 1582, 1423, 1235, 1125, 1011 cm–1.
4.3.7.2. tertꢀbutyl
((S)ꢀ1ꢀ((1R,6S)ꢀ6ꢀbenzamidoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ1ꢀ(3,4,5ꢀ
trimethoxyphenyl)ꢀ6,7ꢀdihydroꢀ1H,5Hꢀpyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀ
23
589
yl)carbamate ((–)-3k). Yield: 139 mg (31%) of yellow solid; mp 113–116
°C; [
α]
–533 (
c
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2
3
4
1
= 0.26, CH2Cl2). H NMR (500 MHz, CDCl3):
δ
1.08 (3H, s); 1.26 (3H, d,
J
= 6.9 Hz); 1.37
= 8.6
5
6
(3H, s); 1.40 (9H, s); 3.85 (3H, s); 3.89 (6H, s); 4.68 (1H, p,
J
= 7.2 Hz); 5.02 (1H, d,
J
7
8
Hz); 5.32 (1H, d,
J = 7.6 Hz); 5.49 (1H, s); 6.65 (2H, s); 6.69 (1H, d, J = 7.7 Hz); 7.46 (2H, t,
9
J
= 7.7 Hz); 7.54–7.57 (1H, m); 7.81–7.83 (3H, m). 13C NMR (126 MHz, CDCl3):
δ 13.3,
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
18.8, 23.9, 28.4, 51.4, 56.2, 60.9, 62.7, 65.1, 71.4, 80.2, 104.7, 123.7, 127.4, 128.9, 130.1,
132.4, 133.2, 137.0, 137.6, 153.3, 155.1, 166.8, 167.9, 194.8. m/z (HRMS) Found: 609.2914
(MH+). C32H41N4O8 requires m/z = 609.2919. (Found: C, 62.43; H, 6.81; N, 8.94.
C32H40N4O8·⅓H2O requires: C, 62.53; H, 6.67; N, 9.11.); νmax (ATR) 2932, 1706 (C=O),
1658 (C=O), 1581, 1422, 1233, 1152, 1125, 1009 cm–1.
4.3.8.tertꢀbutyl
((S)ꢀ1ꢀ((1S)ꢀ7,7ꢀdimethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀ
pyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3l) and its (S)ꢀ(1R)ꢀ
diastereomer (–)-3l. Prepared from 1l (182 mg, 0.74 mmol), 2 (145 mg, 0.74 mmol), CuI (28
mg, 0.15 mmol), DIPEA (39 ꢀL, 0.22 mmol), CC (EtOAcꢀhexanes, 1:1).
4.3.8.1. tertꢀbutyl ((S)ꢀ1ꢀ((1S)ꢀ7,7ꢀdimethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ1H,5Hꢀ
pyrazolo[1,2ꢀa]pyrazolꢀ2ꢀyl)ꢀ1ꢀoxopropanꢀ2ꢀyl)carbamate ((+)-3l). Yield: 115 mg (35%) of
yellow solid; mp 193–195
1.14 (6H, s and d (overlapping),
Hz); 2.90 (1H, d,
s); 7.68 (2H, d,
CDCl3):
°
C; [
α
]
+758 (
c
= 0.25, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ
23
589
J
= 6.7 Hz); 1.24 (3H, s); 1.42 (9H, s); 2.49 (1H, d,
J
= 15.9
J
= 15.9 Hz); 4.65 (1H, p,
J
= 7.4 Hz); 5.14 (1H, d,
J = 7.5 Hz); 5.68 (1H,
J
= 8.3 Hz); 7.73 (1H, s); 8.20 (2H, d, J
= 8.2 Hz). 13C NMR (126 MHz,
δ
19.1, 19.5, 25.1, 28.4, 49.2, 51.8, 64.1, 64.6, 80.0, 122.1, 123.8, 128.8, 129.9,
147.6, 149.1, 155.2, 167.0, 194.9. m/z (HRMS) Found: 445.2077 (MH+). C22H29N4O6 requires
m/z = 445.2082. (Found: C, 58.72; H, 6.21; N, 12.32. C22H28N4O6·⅓H2O requires: C, 58.66;
H, 6.41; N, 12.44.); νmax (ATR) 2971, 1725 (C=O), 1700 (C=O), 1652 (C=O), 1589, 1522,
1344, 1239, 1016, 829 cm–1.
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