Scientific paper
1,3-Dipolar Cycloadditions of (4Ä*,5Ä*)-1-Arylmethylide ne-4-benzamido-3-oxo-5-phenylpyrazolidin-1-ium-2-ides
to Di-(-)-menthyl Maleate
Lidija Pezdirc, David Bevk, Samo Pirc and Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia
* Corresponding author: E-mail: jurij.svete@fkkt.uni-lj.si
Received: 16-09-2008
Dedicated to Professor Branko Stanovnik on the occasion of his 70th birthday
Abstract
1,3-Dipolar cycloadditions of racemic (1Z,4R*,5R*)-arylmethylidene-4-benzamido-5-phenyl-3-pyrazolidinon-1-azo-methine imines 3 to enantiopure di-(-)-menthyl maleate (4) afforded mixtures of diastereomeric cycloadducts 5/5'-7/7'. Selectivity as well as stereochemistry of cycloadditions were dependent on the substituents at the 1 '-Ar residue of dipo-les 3. Thus, reactions of dipoles 3a-j with at least one free ortho-position gave either di-(-)-menthyl (1R*,2S*,3R*,5R*,6R*)-3-aryl-6-benzamido-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylates 5/5' (the endo-isomers) and/or di-(-)-menthyl (1S*,2R*,3R*,5R*,6R*)-3-aryl-6-benzamido-7-oxo-5-phenylhexahy-dropyrazolo[1,2-a]pyrazole-1,2-dicarboxylates 6/6' (the exo-isomers) with syn-oriented 3-H and 5-H, whilst reactions of 4 with ortho-disubstituted dipoles 3k,l gave (1S*,2R*,3S*,5R*,6R*)-diastereomers 7/7'k,l with anti-oriented 3-H and 5-H. Separation of diastereomeric cycloadducts 5/5'-7/7' by crystallization and/or MPLC furnished isomerically pure compounds 5a,b,d,g, 5'b,d,h, 6c,d,j, and 6'c,d,f and purified mixtures of diastereomers 5/5'e, 6/6'e,h, and 7/7'k,l in 1-42% yields. The relative configuration of the pyrazolo[1,2-a]pyrazolone structural element in the products 5/5'-7/7' was determined by NMR.
Keywords: 1,3-dipolar cycloadditions, (-)-menthol, pyrazolidin-3-ones, azomethine imines, pyrazolo[1,2-a]pyrazoles, stereochemistry
1. Introduction
1,3-Dipolar cycloadditions are powerful methods for the preparation of five-membered heterocycles, since they enable access to various polyfunctionalized chiral compounds with multiple asymmetric centres, usually with excellent stereocontrol.1 Within this context, several examples of asymmetric cycloadditions in cyclic chiral azomethine imine series have also been reported. Generally, these reactions were accompanied by high facial and endo/exo-selectivity and afforded the corresponding fused pyrazolines with a bridgehead N-N structural element.2-14 2-Aminopyrazolo[1,2-a]pyrazole-7-carboxylate moiety belongs to a family of heterocyclic conformatio-nally constrained peptide mimetics.15 It is a constituent of biologically active compounds, such as Eli-Lilly's Y-lac-
tam antibiotics LY 186826, LY 193239, and LY 255262 (Figure 1).4'15
In this context, we have previously reported preparation and synthetic utilization of (4R*,5R*)-4-benzamido-5-phenyl-3-pyrazolidinone (1) and azomethine imines 3 derived from 1 and aromatic aldehydes 2. These studies
Figure 1.
were particularly focused on regioselective and stereoselective 1,3-dipolar cycloadditions of (1Z,4Ä*,5Ä*)-1-aryl-methylidene-4-benzamido-5-phenyl-3-pyrazolidinon-1-azomethine imines 3 leading to polysubstituted pyrazo-lo[1,2-a]pyrazoles.61°-141617 Generally, these cycloaddi-tions were highly selective and stereochemistry was controlled by the stereodirecting group in the chiral dipole, by the ortho-substituents at the 1'-Ar group, and by the structure of the dipolarophile.6,10-14 In extension, stereoselecti-ve combinatorial cycloadditions of these azomethine imi-
nes to maleimides11 and ^-keto esters12 have also been reported. All these cycloadditions were carried out with ra-cemic dipoles 3 and gave the corresponding racemic cycloadducts. In continuation, we aimed also at preparation of enantiopure pyrazolo[1,2-a]pyrazoles. This could be done in two ways, either by cycloaddition of enantio-pure azomethine imines 3 to achiral dipolarophiles, or by cycloaddition of racemic dipoles 3 to enantiopure dipola-rophiles followed by separation of the so formed diaste-reomeric cycloadducts. Since there is, to the best of our
H
^ N o ArCH0 2a-j^ Ph^NHBz Refs-11.12
{M
Ar e, Ph ^ NHBz
(ReD
1
(4R*,5/?*)
3a-j
(1Z,4R*,5f?*) Ar: 0 or 1 orffto-substituents
bis(rR,2'S,5'R)
1.	anisole, reflux
2.	FC
Bz = benzoyl Mnt = (-)-menthyl
MntOOC, 2 1 ^.COOMnt MntOOC.
Ar«
^	and Ar
»Ph^MBz ® PK
w
.COOMnt
and/or Ar
[ÄbL, ,
NHBz	- Ph
MntOOC COOMnt MntOOQ ,COOMn
n
^N^^O and [Äbii „„_ [Äbi]
NHBz
PK
NHBz
enofo-isomers 5/5'a-h
bis(rR,2'S,5'R)-(1R*,2S*,3R*,5R*,6R*)
exo-isomers 6/6'c-f,h-j bis(1 'R,2'S,5'R)-(1 S*,2R*,3R*,5R*,6R*)
crystallisation and/or MPLC
f
pure isomers 5 and/or 5' and/or 6 and/or 6' (see Table 2)
ArCHO 2k,I
Refs. 11,12
Ar e
-
pH' NHBz 3k,I
(1Z,4R*,5R*) Ar: 2 orffto-substituents
anisole, reflux, then FC
MntOOC
w
- Ph^ NHBz
COOMnt MntOOQ QOOMnt
and Ar
V-f
[Äbsi
PK
O NHBz
exo-isomers 7/7'k,l
bis(1 'R,2'S,5'R)-(1 S*,2R*,3S*,5R*,6R*)
Scheme 1.
knowledge, no general method for the preparation of enantiopure 4-acylamino-3-pyrazolidinone derivatives, we decided to explore cycloadditions of racemic dipoles 3 to enantiopure dipolarophiles, followed by separation of diastereomeric cycloadducts. Because previous studies showed that cycloadditions to dimethyl maleate were highly stereoselective regardless the structure of dipole,10 di-(-)-menthyl maleate (4)18 has been chosen as its chiral enantiopure analogue. Accordingly, 4 should react stereo-selectively as well to furnish two diastereomeric cycload-ducts, which would be then separated by crystallization or by chromatography. Herein, we report the results of this study, i.e. preparation of some enantiopure cycloadducts by this synthetic approach.
2. Results and Discussion
Azomethine imines 3a-l were prepared by parallel acid-catalyzed treatment of (4Ä*,5Ä*)-4-benzamido-5-phenyl-3-pyrazolidinone (1)6 with benzaldehydes 2a-l according to the literature procedure.11,12 Racemic dipoles 3a-l were then treated with one equiv. of di-(-)-menthyl maleate (4)18 in refluxing anisole followed by thorough evaporation and subsequent purification of the crude reaction mixture by flash chromatography (FC) to afford partially purified mixtures of isomeric cycloadducts 5/5'-7/7'. On the basis of previous results10 we expected, that all 12 dipoles 3a-l would react stereoselectively to give two diastereomeric cycloadducts. To our surprise, however, this was the case only in reactions of seven dipoles (3a,b,g,i-l), while the other five dipoles (3c-f,h) gave mixtures of four diastereomers 5/5'/6/6'c-f,h as a consequence of diminished endo/exo-selectivity. Thus, among azomethine imines 3a-j with at least one free ortho-position at the 1'-Ar group, only dipoles 3a,b,g gave the expected 1:1 mixtures of the endo-diastereomers 5/5'a,b,g, while cycloadditions of dipoles 3c-f,h gave mixtures of
the major endo-isomers 5/5'c-f,h and the minor exo-iso-mers 6/6'c-f,h, and reactions of dipoles 3i and 3j afforded the exo-diastereomers 6/6'i,j. On the other hand, both ort-ho-disubstituted dipoles, 3k and 3l, reacted selectively to afford the expected (1S*,2Ä*,3S*,5Ä*,6Ä*)-diastereo-mers 7/7'k,l (Scheme 1, Table 1).
To obtain enantiopure cycloadducts, two methods were employed for preparative separation of these mixtures of diastereomeric cycloadducts, crystallization and medium pressure liquid chromatography (MPLC). First, each mixture of diastereomers was crystallized from methanol. It has to be mentioned here, that attempts to obtain pure isomers by crystallization from other solvents were not successful. Upon crystallization from methanol, however, isomerically pure compounds 5a,b, 5'b, 6c,j, and 6'f were obtained in 1-42% yields. This method of separation was the most effective in the case of a mixture of 3-(4-nitrophenyl) substituted cycloadducts 5/5'b, since it furnished both diastereomers, 5b and 5'b, in pure form. Next, the non-resolved isomeric mixtures, including filtrates obtained upon successful crystallizations, were purified by MPLC to furnish isomerically pure compounds 5d, 5'd,h, 6d, and 6'c,d, and purified mixtures of isomers 5/5'e,i, 6/6'e,h, and 7/7'k,l (Scheme 1, Table 2).
Low endo/exo-electivity of cycloadditions of ortho-unsubstituted dipoles 3c-f,h and ortho-monosubstituted dipoles 3i,j to di-(-)-menthyl maleate (4) was not in agreement with high endo-selectivity observed previously in cycloadditions of 3a,b,d,e to dimethyl maleate.10 We do not have a firm explanation for this loss of endo/exo-selec-tivity in reactions of dipoles 3 with di-(-)-menthyl malea-te (4), however, a similar phenomenon has already been observed previously in cycloadditions of ortho-unsubsti-tuted dipoles 3a,b,e to maleimides, which were exo-selec-tive.11 Therefore, stereocontrol in cycloadditions of dipo-les 3a-j to di-(-)-menthyl maleate (4) could be explained in analogous way. The dipoles 3a-j with at least one free ortho-position can adopt a planar conformation 3' where
Table 1. Selectivity of Cycloadditions.a
Reactants^Isomers formed	Ar	5:5':6:6'
3a+4^5a, 5a	phenyl	56:44:0:0
3b+4^5b, 5'b	4-nitrophenyl	54:46:0:0
3c+4^5c, 5'c, 6c, 6'c	4-methylphenyl	39:37:13:11
3d+4^5d, 5'd, 6d, 6'd	4-methoxyphenyl	31:29:20:20
3e+4^5e, 5'e, 6e, 6'e	3,4,5-trimethoxyphenyl	39:26:18:17
3f+4^5f, 5'f, 6f, 6'f	4-dimethylaminophenyl	43:27:16:14
3g+4^5g, 5'g	2-furyl	50:50:0:0
3h+4^5h, 5'h, 6h, 6'h	2-methoxyphenyl	28:25:25:22
3i+4^6i, 6'i	3-fluorophenyl	0:0:51:49
3j+4^6j, 6'j	2,4-dichlorophenyl	0:0:50:50
Reactants^Isomers formed	Ar	7:7'
3k+4>7k, 7'k	2,6-dichlorophenyl	51:49
3l+4>7l, 7'l	2,4,6-trimethylphenyl	56:44
' Determined by 'H NMR from the spectra of the product mixtures upon FC.
Table 2. Selected Experimental Data for Compounds 5, 5', 6, 6', and 7/7'.
Reactants^Isolated	Ar	Separation		Yield (%)			
Isomersa		Methodb	5	5'	6	6'	7/7'
3a+4^5a	phenyl	A	29				
3b+4^5b+5'b	4-nitrophenyl	A	32	42			
3c+4^6c+6'c	4-methylphenyl	A, B			1	2	
3d+4^5d+5'd+6d+6'd	4-methoxyphenyl	B	7	3	5	8	
3e+4^5/5'+6/6'e	3,4,5-trimethoxyphenyl	B	22c		11c		
3f+4^6f	4-dimethylaminophenyl	A				5	
3g+4^5g	2-furyl	A	6				
3h+4^5'h+6h	2-methoxyphenyl	B		6	2c		
3i+4^6/6'i	3-fluorophenyl	B			22c		
3j+4^6j	2,4-dichlorophenyl	A			21		
3k+4^7/7'k	2,6-dichlorophenyl	B					31
3l+4^7/7'l	2,4,6-trimethylphenyl	B					9
a)	Isolated isomers upon crystallization and/or chromatographic separation.
b)	A: crystallization; B: MPLC.
c)	Yield of a mixture of diastereomers 5/5' and/or 6/6'.
Scheme 2.
the (1'Si)-face is hindered by the phenyl group at position 5. In terms of facial selectivity, preferential approach of the dipolarophile from the less hindered (1'Re)-face is favored. In terms of endo/exo-selectivity, the endo-approach of the dipolarophile is not preferred any more, due to ste-ric hindrance between two bulky (1'R,2'S,5'R)-2-iso-propyl-5-methylcyclohexyl groups in the dipolarophile 4 and the benzoylamino group in the dipole 3. Accordingly, formation of isomeric mixtures 5/5'/6/6' is explainable by the concerted 1,3-dipolar cycloaddition mechanism via
mixed endo/exo-approach of 4 from the less hindered (1'Re)-face of the (Z)-dipoles 3f-j (Scheme 2).
On the other hand, selective formation of cycload-ducts 7/7'k,l was in agreement with stereocontrol in cycloadditions of ortho-disubstituted dipoles 3k,l to dimethyl maleate10 and maleimides.11 Since ortho-disubsti-tuted dipoles 3k and 3l cannot adopt a planar conformation 3', stereocontrol and mechanism of these two cycloadditions could be explained in two ways. According to the concerted 1,3-dipolar cycloaddition mechanism, the
dipoles would adopt a preferable conformation 3k,l, where the (1'Äe*)-face is strongly shielded by the ortho-sub-stituent facing the dipole's terminal nitrogen atom. The reaction would then proceed via preferential endo-attack of the dipolarophile from the less hindered (1'Si*)-face of the (Z)-dipole (Path A, Scheme 3). Alternatively, formation of cycloadducts 7/7'k,l is also explainable by a two-step addition-cyclization mechanism.10,11 In the mesome-ric structures 3"k,l, rotation around the exocyclic C-N bond leads to the conformers 3"'k,l, where the bulky aryl groups are twisted away from each other. Michael-type anti-addition of the dipolarophile 4 to the conformer 3''' gives the zwitterion (or a biradical) 8/8',19 which then cyclizes into the final product 7/7' (Path B, Scheme 3).
while identities of 6j and 7/7'l were confirmed by EI-MS.
Unfortunately, we were not able to determine the absolute configuration of the isolated optically pure compounds. This should be done unambiguously by X-ray structural determination of the representative compounds 5 and/or 5' and 6 and/or 6', however, all attempts to prepare suitable monocrystals failed. Nevertheless, the discrimination between the diastereomers within each diaste-reomeric pair 5/5'-7/7' was possible by 1H NMR on the basis of chemical shifts. To differentiate between the corresponding isomers 5-7 and 5'-7', the isomers with lower chemical shift for 2-H were assigned as the 'first' isomers 5-7, while isomers with higher chemical shift for 2-H were assigned as the 'second' (adjacent) isomers 5'-7'. Next,
enc/o-(1'S/*)-approach
MntOOa
.COOMnt
MntOOQ COOMnt
concerted R ^©.N o cycloaddition
H	-^
)—Path A Ph NHBz
3k,I
two orf/?o-substituents	_
.	hindered (1'Re*)-face
MntO-<>^\COOMnt
Co )
R ©^ '^N^O ^ Ar"„ © 'N o Michael-type anf/-addition H ^ ^	-►
Ph NHBz	Ph NHBz
W
H
Ph NHBz 7/7'k,l
cyclisation
^ COOIVlnt
QV^COOMnt ( T"H
3"k,l
3'"k,l
AP.^^^N o
Ph NHBz 8/8'k,l
Scheme 3.
3. Structure Determination
Structures of compounds 5/5'a-h, 6/6'c-f,h-j, and 7/7'k,l were determined by spectroscopic methods (IR, 1H NMR, 13C NMR, NOESY spectroscopy, MS) and by elemental analyses for C, H, and N. Compounds 5a,b,d, 5'b,d, 6c,d, and 6'c,d,f were prepared in isomerically pure form. The isomers 5c,f,h, 5'a,c,f,g, 6f, and 6'j were not isolated and were characterized only by 1H NMR. Compounds 5/5'e, 6/6'e,h,i, and 7k,l were isolated and characterized as mixtures of isomers. Compounds 5b, 6d,j, and 7/7'l were not prepared in analytically pure form. The identity of 5b was confirmed by EI-MS and 13C NMR,
relative configuration at the newly formed chiral center at position 3 in compounds 5d, 5'd, 6d,j, and 6'd were determined by NOESY spectroscopy. A strong NOE between 3-H and 5-H was in agreement with the syn-orientation between these two nuclei (Figure 2).
The relative configuration at the other chiral centers were determined on the basis of chemical shifts for protons at positions 1-3, 5, and 6 and on the basis of vicinal coupling constants, 3/H1-H2, 3^H2-H3, and 3/H5-H6. In cycloadducts 5/5' and 7/7', the chemical shifts for protons at positions 1-3, 5, and 6, as well as coupling constants, 3^H1-H2, 3^H2-H3, and 3/H5-H6 were in agreement with the data for their close dimethyl analogues.10 Similarly, NMR
MntOOC (DOOMnt
'.2
MeO^	Q

v
5% NOE ^ ^ ph NHBz 5d, 5'd
MntOOC
COOMnt
MeO
8% NOE ^ ph NHBZ 6d, 6'd
MntOOC COOMnt
CI ( —' 80/0 NOE^ Ph 'NHBZ
6j
J ~ 11 Hz
(trans)
J ~ 8.5 Hz (eis)
NHBz
J ~ 7 Hz (eis)
J ~ 8.5 Hz
H
( R^/ ("R
'NHBz
Ar
Ph-
J = 9.5 Hz ids)
J-10 Hz
(trans) ^ |_| |_| ( R-'-y f-R
H H O-
J ~ 12 Hz (trans)
Compounds 5/5'a-h (R = COOMnt)
Figure 2. Structure Determination by NMR Methods.
J ~ 9 Hz (trans)
Compounds 6/6'c-f,h-j
(R = COOMnt)

Ar^ Ph

O
NHBz
H H
O"
J ~ 9 Hz (trans)
Compounds 7/7'k,l (R = COOMnt)
data for the exo-isomers 6/6' were in agreement with the literature data for structurally related exo-cycloadducts (Figure 2, Table 2).11
In conclusion, this study showed, that optically active di-(-)-menthyl 3-aryl-6-benzamido-7-oxo-5-phenyl-perhydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylates are available via cycloaddition of racemic (1Z,4R*,5R*)-1-arylmethylidene-4-benzamido-5-phenyl-3-pyrazolidinon-1-azomethine imines 3 to di-(-)-menthyl maleate (4) followed by separation of diastereomeric cycloadducts. From the practical point of view, this method was not very efficient, because (a) loss of endo/exo-selectivity often resulted in formation of four (instead of two) isomeric cycload-ducts; (b) separation of diastereomers was usually complicated, and (c) the yields of the isolated optically active cycloadducts were generally low. On the other hand, this study also indicated, that the selectivity and stereocontrol in cycloadditions to azomethine imines 3 may vary significantly with increasing steric demand of the dipolarophile.
4. Experimental
4. 1. General Procedures
Melting points were determined on a Kofler micro hot stage. The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using DMSO-d6 and CDCl3 as solvents and TMS as the internal standard. Mass spectra were recorded
on an AutoSpecQ spectrometer and IR spectra on a Per-kin-Elmer Spectrum BX FTIR spectrophotometer. Mi-croanalyses were performed on a Perkin-Elmer CHN Analyzer 2400. Column chromatography (CC) was performed on silica gel (Fluka, silica gel 60, 40-60 pm). Medium pressure liquid chromatography (MPLC) was performed with a Büchi isocratic system with detection on silica gel (Merck, silica gel 60, 1535 pm); column dimensions (dry filled): 15 x 460 mm; backpressure: 10-15 bar; detection: UV 254 nm; sample amount: 100-150 mg of isomeric mixture per each run. Ratio of isomers and d.e. were determined by 1H NMR.
(4R*,5R*)-4-Benzamido-5-phenyl-3-pyrazolidino-ne (1),6 azomethine imines 3a-l11,12 and di-(-)-menthyl maleate (4)18 were prepared according to the literature procedures.
Source of chirality: (-)-Menthol (Fluka AG), product number 636600, puriss. p.a., terpene standard for GC, >99.0% (sum of enantiomers, GC), [a]D20 -54.5 ± 1 (c = 10%, EtOH), mp ~43 °C, e.e. >98.0%.
4. 2. General Procedure for the Preparation and Separation of Isomeric Cycloadducts 5/5'-7/7'
A mixture of azomethine imine 3 (1 mmol), di-(-)-menthyl maleate (4) (1 mmol), and anisole (10 mL) was heated under reflux for 4 h. Volatile components were evaporated in vacuo (80 °C, 2-5 mbar). The residue was puri-
Table 3. Correlation of NMR data for compounds 5/5', 6/6', and 7/7'.
{1R*,2S*,3R*,5R*,6R*)-Isomers 5/5'
Compound	1-H	2-H	5 [ppm] 3-H	5-H	6-H	1-2	'Jh-H [Hz] 2-3	5-6
5a	4.73	3.79	4.39	4.28	5.63	8.3	11.1	12.1
5'a	4.74	3.81	4.38	4.30	5.57	8.5	11.0	12.3
5b	4.77	3.73	4.55	4.31	5.68	8.2	11.0	12.2
5'b	4.78	3.77	4.54	4.35	5.61	8.3	11.1	12.2
5c	a	3.75	a	a	a	8.3	11.0	a
5'c	a	3.79	a	a	a	8.5	11.0	a
5d	4.71	3.74	4.34	4.26	5.61	8.3	11.1	12.0
5'd	4.72	3.76	4.33	4.27	5.56	8.5	11.1	12.0
5e	4.70	3.7a	4.33	4.26	5.68	8.2	11.1	12.1
5'e	4.72	3.75	4.34	4.29	5.68	8.2	11.1	12.2
5f	4.70	3.76	4.29	4.25	5.58	8.3	11.1	12.0
5'f	4.71	a	a	4.26	5.53	8.4	a	12.0
5g	4.75	4.14	4.51	4.31	5.48	8.4	11.1	12.1
5'g	a	4.17	4.54	4.39	5.36	8.5	11.1	12.0
5h	4.73	4.08	4.96	4.31	5.45	8.3	11.1	12.0
5'h	4.76	4.09	4.97	4.30	5.40	8.6	11.1	11.7
(1S*,2R*,3R*,5R*,6R*)-Isomers 6/6'
Compound	1-H	2-H	5 [ppm] 3-H	5-H	6-H	1-2	3JH-H [Hz] 2-3	5-6
6c	5.04	3.47	4.17	4.69	5.67	6.4	9.2	9.2
6'c	5.12	3.56	4.17	4.39	4.86	7.1	9.3	8.6
6d	5.04	3.46	4.15	4.69	5.66	6.5	9.2	9.4
6'd	5.12	3.54	4.15	4.38	4.86	7.3	9.5	9.0
6e	5.08	3.51	4.24	4.41	4.84	7.5	9.5	9.3
6'e	5.15	3.54	4.29	4.40	4.78	6.5	8.6	8.1
6f	5.10	3.59	4.17	4.40	4.80	5.9	8.7	6.9
6'f	5.11	3.54	4.08	4.38	4.86	7.2	9.4	8.3
6h	5.10	3.65	a	4.47	4.93	3.9	6.8	6.6
6'h	5.11	3.69	a	4.43	5.00	4.8	7.4	7.0
6i	5.12	3.55	4.25	4.41	~4.8a	7.1	9.3	9.4
6'i	5.16	3.61	4.32	4.41	~4.8a	5.9	8.7	7.6
6j	5.12	3.61	4.86	4.44	5.05	4.8	7.0	7.7
6'j	5.14	3.64	a	4.46	4.97	4.6	6.8	6.7
(1S*,2R*,3S*,5R*,6R*)-Isomers 7/7'
Compound	1-H	2-H	5 [ppm] 3-H	5-H	6-H	1-2	3JH-H [Hz] 2-3	5-6
7k	5.83	4.80	5.29	4.31	5.09	9.6	8.2	9.8
7'k	5.91	4.84	5.30	4.36	5.09	9.7	8.3	10.2
7l	c4.9a	4.19	5.07	4.38	~4.9a	9.4	10.7	4.7
7'l	5.03	4.24	~4.9a	4.35	~4.9a	8.6	10.5	6.2
a Overlapped by other signals.
fied by flash chromatography (FC, silica gel, EtOAc-he-xanes, 1:2). Fractions containing the isomeric products were combined and evaporated in vacuo to give mixtures of isomeric cycloadducts 5/5'a,b,g, 5/5'/6/6'c-f,h, 6/6'i,j, and 7/7'k,l. These isomeric mixtures were then separated by crystallization from methanol or/and MPLC (EtOA-c-hexanes) to give isomerically pure compounds 5a,b,d,g, 5'b,d,h, 6c,d,j, and 6'c,d,f and purified mixtures of isomers 5/5'e,i, 6/6'e,h and 7/7'k,l.
The following compounds were prepared in this manner:
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1R*, 2S*,3R*,5R*,6R*)-6-benzamido-3,5-diphenyl-7-oxo-hexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate 5/5'a. Prepared from 4 and dipole 3a (369 mg, 1 mmol), 5a:5'a = 56:44, crystallization of 5/5'a from methanol afforded isomerically pure compound 5a.
Data for compound 5a. Yield: 211 mg (29%) of a white solid; mp 220-224 °C (from MeOH); [a]D21 -61.6 (c = 0.1, CH2Cl2). 1H NMR (CDCl3): 5 0.34, 0.47, 0.81, 0.87, 0.91, 0.95 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.55-1.85 (16H, m, 16H of menthyl); 1.93-2.04
(1H, m, 1H of menthyl); 2.26-2.35 (1H, m, 1H of men-thyl); 3.79 (1H, dd, J = 8.3, 11.1 Hz, 2-H); 4.28 (1H, d, J = 12.1 Hz, 5-H); 4.39 (1H, d, J = 11.1 Hz, 3-H); 4.54 (1H, dt, J = 4.4, 10.8 Hz, 1'-H); 4.73 (1H, dd, J = 0.8, 8.3 Hz, 1-H); 4.81 (1H, dt, J = 4.3, 10.8 Hz, 1'-H); 5.63 (1H, dd, J = 8.5, 12.1 Hz, 6-H); 6.54 (1H, d, J = 8.5 Hz, NH); 6.93-7.03 (6H, m, 6H of Ph); 7.07-7.20 (4H, m, 4H of Ph); 7.34-7.41 (2H, m, 2H of Ph); 7.43-7.49 (1H, m, 1H of Ph); 7.68-7.74 (2H, m, 2H of Ph). (Found: C, 73.99; H, 7.93; N, 5.51. C47H59N3O6 requires: C, 74.08; H, 7.80; N, 5.51.); IR, vmax (KBBr): ^368 (NH), 2952, 2928, 2867, 1729 (C=O), m!(548 (C=O), 1521, 1457, 1385, 1184, 960, 764, 694 cm-1.
1H NMR data for compound 5'a. 1H NMR (CDC-lj): 5 0.61, 0.70, 0.78, 0.86, 0.89, 0.94 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 3.81 (1H, dd, J = 8.5, 11.0 Hz, 2-H); 4.30 (1H, d, J = 12.3 Hz, 5-H); 4.38 (1H, d, J = 11.0 Hz, 3-H); 4.74 (1H, dd, J = 0.7, 8.5 Hz, 1-H); 5.57 (1H, dd, J = 8.2, 12.3 Hz, 6-H); 6.55 (1H, d, J = 8.2 Hz, NH).
Bis[(1Ä,2S ,5R )-2-isopropyl-5-methylcyclohexyl] (1R*,2S*,3R*,5R*,6R*)-6-benzamido-3-(4-nitrop-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyra-
zole-1,2-dicarboxylate 5/5'b. Prepared from 4 and dipole 3b (414 mg, 1 mmol), 5b:5'b = 54:46, crystallization from methanol afforded isomerically pure compound 5b. Subsequent evaporation of the filtrate gave isomerically pure compound 5'b.
Data for compound 5b. Yield: 224 mg (32%) of a yellowish solid; mp 207-209 °C (from MeOH); [a]D23 -24.7 (c = 0.012, CH2Cl2). EI-MS: m/z = 807 (M+). 1H NMR (CDCl3): 5 0.41, 0.49, 0.81, 0.87, 0.92, 0.96 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.71-1.83 (16H, m, 16H of menthyl); 1.91-2.04 (1H, m, 1H of menthyl); 2.23-2.32 (1H, m, 1H of menthyl); 3.73 (1H, dd, J = 8.2, 11.0 Hz, 2-H); 4.31 (1H, d, J = 12.2 Hz, 5-H); 4.55 (1H, d, J = 11.0 Hz, 3-H); 4.56 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 4.77 (1H, dd, J = 0.7, 8.2 Hz, 1-H); 4.81 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 5.68 (1H, dd, J = 8.4, 12.2 Hz, 6-H); 6.52 (1H, d, J = 8.4 Hz, NH); 6.96-7.03 (3H, m, 3H of Ar); 7.16-7.23 (2H, m, 2H of Ar); 7.30-7.42 (4H, m, 4H of Ar); 7.45-7.50 (1H, m, 1H of Ar); 7.66-7.73 (2H, m, 2H of Ar); 7.84-7.91 (2H, m, 2H of Ar). 13C NMR (CDCl3): 5 16.08, 16.14, 20.85, 21.44, 22.27, 22.42, 23.13, 25.61, 25.77, 31.91, 32.00, 34.26, 34.53, 40.89, 41.15, 47.22, 58.08, 58.26, 60.60, 70.07, 76.31, 78.59, 79.58, 123.37, 127.67, 128.51, 128.54, 128.84, 129.24, 129.48, 132.23, 133.78, 134.20, 142.74, 148.03, 164.69, 166.45, 167.62, 167.96. (Found: C, 68.85; H, 7.83; N, 7.08. C47H58N4O8 requires: C, 69.95; H, 7.24; N, 6.94.); IR, vmax (IK:BI-): 3433 (NH), 2957, 2929, 2868, 1724 (C=O), 1652 (C=O), 1524, 1456, 1349, 1206, 1177, 1110, 980, 954, 851, 697 cm-1.
Data for compound 5'b. Yield: 297 mg (42%) of a yellowish solid; mp 120-123 °C (from MeOH); [a]D23
-67.6 (c = 0.13, CH2Cl2). 1H NMR (CDCl3): 5 0.60, 0.67, 0.81, 0.86, 0.95, 0.96 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.71-1.79 (16H, m, 16H of menthyl); 2.10-2.22 (2H, m, 2H of menthyl); 3.77 (1H, dd, J = 8.3, 11.1 Hz, 2-H); 4.35 (1H, d, J = 12.2 Hz, 5-H); 4.54 (1H, d, J = 11.1 Hz, 3-H); 4.56 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 4.78 (1H, dd, J = 0.7, 8.3 Hz, 1-H); 4.81 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 5.61 (1H, dd, J = 8.5, 12.2 Hz, 6-H); 6.52 (1H, d, J = 8.5 Hz, NH); 6.96-7.03 (3H, m, 3H of Ar); 7.16-7.23 (2H, m, 2H of Ar); 7.30-7.42 (4H, m, 4H of Ar); 7.43-7.50 (1H, m, 1H of Ar); 7.66-7.73 (2H, m, 2H of Ar); 7.84-7.91 (2H, m, 2H of Ph). (Found: C, 69.93; H, 7.56; N, 6.83. C47H58N4O8 requires: C, 69.95; H, 7.24; N, 6.94.); IR, vmax (KBBr): 3429 (NH), 2955, 2929, 2868, 1735 (C=O), 16571 (C=O), 1525, 1457, 1348, 1208, 980, 953, 851, 697 cm1.
Bis[(1R ,2S ,5R )-2-isopropyl-5-methylcyclohexyl] (1R*,2S*,3R*,5R*,6R*)-6-benzamido-3-(4-methylp-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyra-zole-1,2-dicarboxylate 5/5'c and (1S*,2R*,3R*,5R*, 6R*)-isomer 6/6'c. Prepared from 4 and dipole 3c (383 mg, 1 mmol), 5c:5'c:6c:6'c = 39:37:13:11, crystallization from methanol afforded isomerically pure compound 6c. Evaporation of the filtrate followed by separation by MPLC afforded isomerically pure compound 6'c.
1H NMR data for compound 5c. 1H NMR (CDC-l3): 5 3.75 (1H, dd, J = 8.3, 11.0 Hz, 2-H).
1H NMR data for compound 5'c. 1H NMR (CDC-l3): 5 3.79 (1H, dd, J = 8.5, 11.0 Hz, 2-H).
Data for compound 6c. Yield: 10 mg (1%) of a white solid; mp 200-206 °C (from MeOH); [a]D13 -130.9 (c = 0.008, CH1Cl1). 1H NMR (CDCl3): 5 0.65, 0.74, 0.82 (9H, 3d, 1:1:1, J = 6.9 Hz, 3 x MeCH); 0.78-0.97 (13H, m, 3 x MeCH and 4H of menthyl); 0.97-1.60 (8H, m, 8H of menthyl); 1.61-1.78 (3H, m, 3H of menthyl); 1.94-2.12 (3H, m, 3H of menthyl); 2.19 (3H, s, MeAr); 3.47 (1H, dd, J = 6.4, 9.2 Hz, 2-H); 4.17 (1H, d, J = 9.2 Hz, 3-H); 4.69 (1H, d, J = 9.2 Hz, 5-H); 4.71 and 4.89 (2H, 2dt, 1:1, J = 4.3, 10.7 Hz, 2 x 1'-H); 5.04 (1H, d, J = 6.4 Hz, 1-H); 5.67 (1H, dd, J = 7.9, 9.2 Hz, 6-H); 5.84 (1H, d, J = 7.9 Hz, NH); 7.09 (2H, d, J = 7.9 Hz, 2H of CgH4); 7.19-7.28 (5H, m, 2H of CgH4 and 3H of Ph); 7.30-7.38 (6H, m, 6H of Ph); 7.39-7.4t7 (1H, m, 1H of Ph). (Found: C, 74.49; H, 8.22; N, 5.67. C48Hg1N3Og requires: C, 74.29; H, 7.92; N, 5.41.); IR, vma5 (KBr): 3423 (NH), 2954, 2928, 2866, 1732 (C=O), 1656^ (C=O), 1521, 1456, 1372, 1231, 1182, 1099, 1150, 983, 819, 704 cm1.
Data for compound 6'c. Yield: 18 mg (2%) of a white solid; mp 240-242 °C; [a]D13 -28.6 (c = 0.005, CH1Cl1). 1H NMR (CDCl3): 5 0.56, 0.65, 0.83, 0.90, 0.92, 0.93 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.75-1.60 (12H, m, 12H of menthyl); 1.60-1.70 (3H, m, 3H of menthyl); 1.95-2.09 (3H, m, 3H of menthyl); 2.20 (3H, s, MeAr); 3.56 (1H, dd, J = 7.1, 9.3 Hz, 2-H); 4.17 (1H, d, J = 9.3 Hz, 3-H); 4.39 (1H, d, J = 8.6 Hz, 5-H);
4.68 and 4.84 (2H, 2dt, 1:1, J = 4.3, 10.7 Hz, 2 x 1'-H); 4.86 (1H, dd, J = 7.0, 8.6 Hz, 6-H); 5.12 (1H, d, J = 7.1 Hz, 1-H); 6.71 (1H, d, J = 7.0 Hz, NH); 6.89 (2H, d, J = 7.9 Hz, 2H of CgH4); 7.06 (2H, d, J = 7.9 Hz, 2H of CgH4); 7.11-7.19 (3H, m, 3H of Ph); 7.31-7.37 (2H, m, 2H of Ph); 7.38-7.46 (2H, m, 2H of Ph); 7.47-7.54 (1H, m, 1H of Ph); 7.75-7.81 (2H, m, 2H of Ph). (Found: C, 74.43; H, 8.17; N, 5.41. C48Hg1N3Og requires: C, 74.29; H, 7.92; N, 5.41.); IR, vmax (KBBr): ^443 (NH), 2955, 2920, 2866, 1732 (C=O), 1(^79 (C=O), 1524, 1454, 1389, 1233, 1182, 1113, 1150, 953, 700 cm-1.
Bis[(1Ä,2S ,5R )-2-isopropyl-5-methylcyclohexyl] (1R*,2S*,3R*,5R*,6R*)-6-benzamido-3-(4-methoxyp-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyra-zole-1,2-dicarboxylate 5/5'd and (1S*,2R*,3R*,5R*, 6R*)-isomer 6/6'd. Prepared from 4 and dipole 3d (399 mg, 1 mmol), 5c:5'c:6c:6'c = 31:29:20:20, separation by MPLC afforded isomerically pure compounds 5d, 5'd, 6d, and 6'd.
Data for compound 5d. Yield: 56 mg (7%) of a white solid; mp 196-200 °C; [a]D26 -50.1 (c = 0.06, CH2Cl2). 1H NMR (CDCl3): 5 0.34, 0.48, 0.81, 0.88, 0.90, 0.95 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.75-1.64 (13H, m, 13H of menthyl); 1.65-1.85 (3H, m, 3H of menthyl); 1.90-2.06 (1H, m, 1H of menthyl); 2.25-2.36 (1H, m, 1H of menthyl); 3.65 (3H, s, OMe); 3.74 (1H, dd, J = 8.3, 11.1 Hz, 2-H); 4.26 (1H, d, J = 12.0 Hz, 5-H); 4.34 (1H, d, J = 11.1 Hz, 3-H); 4.53 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 4.71 (1H, dd, J = 0.7, 8.3 Hz, 1-H); 4.79 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 5.61 (1H, dd, J = 8.5, 12.0 Hz, 6-H); 6.53 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.57 (1H, d, J = 8.5 Hz, NH); 6.96-7.06 (5H, m, 2H of CgH4 and 3H of Ph); 7.13-7.21 (2H, m, 2H of Ph); 7.33-7.41 (2H, m, 2H of Ph); 7.42-7.50 (1H, m, 1H of Ph); 7.67-7.75 (2H, m, 2H of Ph). (Found: C, 72.90; H, 8.00; N, 5.27. C48H61N3O7 requires: C, 72.79; H, 7.76; N, 5.31.); IR, vmax (ICBr): 3429 (NH), 2955, 2931, 2868, 1727 (C=O), 16^7 (C=O), 1518, 1456, 1381, 1249, 1189, 1119, 1134, 957, 694 cm-1.
Data for compound 5'd. Yield: 25 mg (3%) of a white solid; mp 175-178 °C; [a]D26 -43.7 (c = 0.012, CH2Cl2). 1H NMR (CDCl3): 5 0.62, 0.72, 0.79, 0.86, 0.94, 0.95 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.69-1.64 (14H, m, 14H of menthyl); 1.65-1.77 (2H, m, 2H of menthyl); 2.10-2.22 (2H, m, 2H of menthyl); 3.65 (3H, s, OMe); 3.76 (1H, dd, J = 8.5, 11.1 Hz, 2-H); 4.27 (1H, d, J = 12.0 Hz, 5-H); 4.33 (1H, d, J = 11.1 Hz, 3-H); 4.50 (1H, dt, J = 4.4, 10.9 Hz, 1'-H); 4.72 (1H, dd, J = 0.7, 8.5 Hz, 1-H); 4.82 (1H, dt, J = 4.4, 11.1 Hz, 1'-H); 5.56 (1H, dd, J = 8.5, 12.0 Hz, 6-H); 6.54 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.60 (1H, d, J = 8.4 Hz, NH); 6.96-7.06 (5H, m, 2H of CgH4 and 3H of Ph); 7.15-7.22 (2H, m, 2H of Ph); 7.33-741 (2H, m, 2H of Ph); 7.42-7.50 (1H, m, 1H of Ph); 7.67-7.74 (2H, m, 2H of Ph). (Found: C, 72.89; H, 7.95; N, 5.30 C48Hg1N3O7 requires: C, 72.79; H, 7.76; N,
5.31.); IR, vmax (KBr): 3397 (NH), 2951, 2930, 2866, 1732 (C=O), "1642 (C=O), 1516, 1457, 1370, 1254, 1206, 1175, 1030, 959, 826, 706 cm-1.
Data for compound 6d. Yield: 37 mg (5%) of a white solid; mp 91-94 °C; [a]D2g -18.7 (c = 0.062, CH2Cl2). 1H NMR (CDCl3): 5 0.65, 0.74, 0.82, (9H, 3d, 1:1:1, /= 6.9 Hz, 3 x MeCH); 0.90, 0.91, 0.94, (9H, 3d, 1:1:1, J = 6.6 Hz, 3 x MeCH); 0.79-1.52 (12H, m, 12H of menthyl); 1.62-1.79 (3H, m, 3H of menthyl); 1.93-2.13 (3H, m, 3H of menthyl); 3.46 (1H, dd, J = 6.5, 9.2 Hz, 2-H); 3.76 (3H, s, OMe); 4.15 (1H, d, J = 9.2 Hz, 3-H); 4.69 (1H, d, J = 9.4 Hz, 5-H); 4.71 and 4.89 (2H, 2dt, 1:1, J = 4.4, 10.9 Hz, 2 x 1'-H); 5.04 (1H, d, J = 6.5 Hz, 1-H); 5.66 (1H, dd, J = 7.9, 9.4 Hz, 6-H); 5.84 (1H, d, J = 7.9 Hz, NH); 6.81 (2H, d, J = 8.8 Hz, 2H of CgH4); 7.19-7.38 (11H, m, 2H of CgH4 and 9H of Ph); 7.39-7.47 (1H, m, 1H of Ph). (Found: C, 72.29; H, 8.04; N, 5.31. C48H61N3O7 requires: C, 72.79; H, 7.76; N, 5.31.); IR, vm4ax (^Br): 3441 (NH), 2955, 2928, 2868, 1734 (C=O), 16ai5 (C=O), 1516, 1457, 1370, 1251, 1179, 704 cm1.
Data for compound 6'd. Yield: 60 mg (8%) of a white solid; mp 215-218 °C; [a]D2g -18.7 (c = 0.008, CH2Cl2). 1H NMR (CDCl3): 5 0.56, 0.66, 0.84, (9H, 3d, 1:1:1, /= 6.8 Hz, 3 x MeCH); 0.90, 0.92, 0.94, (9H, 3d, 1:1:1, J = 6.5 Hz, 3 x MeCH); 0.72-1.28 (9H, m, 9H of menthyl); 1.37-1.54 (3H, m, 3H of menthyl); 1.60-1.78 (3H, m, 3H of menthyl); 1.95-2.09 (3H, m, 3H of menthyl); 3.54 (1H, dd, J = 7.3, 9.5 Hz, 2-H); 3.68 (3H, s, OMe); 4.15 (1H, d, J = 9.5 Hz, 3-H); 4.38 (1H, d, J = 9.0 Hz, 5-H); 4.68 and 4.84 (2H, 2dt, 1:1, J = 4.4, 10.8 Hz, 2 x 1'-H); 4.86 (1H, dd, J = 6.8, 9.0 Hz, 6-H); 5.12 (1H, dd, J = 0.5, 7.3 Hz, 1-H); 6.62 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.72 (1H, d, J = 6.8 Hz, NH); 7.09 (2H, d, J = 8.8 Hz, 2H of CgH4); 7.10-7.18 (3H, m, 3H of Ph); 7.28-7.35 (2H, m, 2H of Ph); 7.37-7.46 (2H, m, 2H of Ph); 7.47-7.54 (1H, m, 1H of Ph); 7.74-7.81 (2H, m, 2H of Ph). (Found: C, 72.97; H, 7.92; N, 5.33. C48Hg1N3O7 requires: C, 72.79; H, 7.76; N, 5.31.); IR, v6ax (KgBr): 3447 (NH), 2957, 2928, 2868, 1731 (C=O), 1678 (C=O), 1517, 1456, 1387, 1250, 1176, 1031, 953, 829, 702 cm-1.
Bis[(1R,2S ,5R )-2-isopropyl-5-methylcyclohexyl] (1R*,2S*,3R*,5R*,6R*)-6-benzamido-7-oxo-5-phenyl-3-(3,4,5-trimethoxyphenyl)hexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate 5/5'e and (1S*,2R*,3R*, 5R*,6R*)-isomer 6/6'e. Prepared from 4 and dipole 3e (459 mg, 1 mmol), 5e:5'e:6e:6'e = 39:26:18:17, separation by MPLC afforded purified mixtures of isomers 5/5'e and
6/6'e.
Data for a mixture of compounds 5/5'e. Yield: 189 mg (22%) of a white solid, 5e:5'e = 50:50; mp 91-94 °C; [a]D26 -49.6 (c = 0.082, CH2Cl2). (Found: C, 70.69; H, 8.02; N, 4.77 C50Hg5N3O9 requires: C, 70.48; H, 7.69; N, 4.93.); IR, v6ax (K:Br): 3374 (NH), 2955, 2930, 2870, 1732 (C=O), 16569 (C=O), 1593, 1535, 1508, 1459, 1371, 1234, 1184, 1126, 1009, 912, 845, 698 cm1.
ìH NMR data for compound 5e. 1H NMR (CDC-l3): 5 0.37-0.96 (18H, m, 6 x MeCH); 0.72-1.64 (10H, m, 10H of menthyl); 1.65-1.77 (4H, m, 4H of menthyl); 1.91-2.02 (1H, m, 1H of menthyl); 2.07-2.23 (2H, m, 2H of menthyl); 2.25-2.34 (1H, m, 1H of menthyl); 3.66, 3.69, 3.70 (9H, 3s, 1:1:1, 3 x OMe); 3.7 (1H, overlapped by OMe signals, 2-H); 4.26 (1H, d, J = 12.1 Hz, 5-H); 4.33 (1H, d, J = 11.1 Hz, 3-H); 4.55 (1H, dt, J = 4.4, 10.6 Hz, 1'-H); 4.70 (1H, dd, J = 0.5, 8.2 Hz, 1-H); 4.82 (1H, dt, J = 4.4, 10.6 Hz, 1'c-H); 5.68 (1H, dd, J = 8.5, 12.1 Hz, 6-H); 6.33 (2H, s, CgH2); 6.60 (1H, d, J = 8.5 Hz, NH); 6.99-7.06 (3H, m, 3H of Ar); 7.16-7.24 (2H, m, 2H of Ph); 7.32-7.42 (2H, m, 2H of Ph); 7.43-7.50 (1H, m, 1H of Ph); 7.68-7.75 (2H, m, 2H of Ph).
^H NMR data for compound 5'e. 1H NMR (CDC-l3): 5 0.37-0.96 (18H, m, 6 x MeCH); 0.72-1.64 (10H, m, 10H of menthyl); 1.65-1.77 (4H, m, 4H of menthyl);
I.91-2.02	(1H, m, 1H of menthyl); 2.07-2.23 (2H, m, 2H of menthyl); 2.25-2.34 (1H, m, 1H of menthyl); 3.66, 3.69, 3.70 (9H, 3s, 1:1:1, 3 x OMe); 3.75 (1H, dd, J = 8.2,
II.1	Hz, 2-H); 4.29 (1H, d, J = 12.3 Hz, 5-H); 4.34 (1H, d, J = 11.1 Hz, 3-H); 4.55 (1H, dt, J = 4.4, 10.6 Hz, 1'-H); 4.72 (1H, dd, J = 0.5, 8.2 Hz, 1-H); 4.82 (1H, dt, J = 4.4, 10.6 Hz, 1'-H); 5.68 (1H, dd, J = 8.5, 12.2 Hz, 6-H); 6.35 (2H, s, CgH2); 6.63 (1H, d, J = 8.5 Hz, NH); 6.99-7.06 (3H, m, 3H of Ph); 7.16-7.24 (2H, m, 2H of Ph); 7.32-7.42 (2H, m, 2H of Ph); 7.43-7.50 (1H, m, 1H of Ph); 7.68-7.75 (2H, m, 2H of Ph).
Data for a mixture of compounds 6/6'e. Yield: 96 mg (11%) of a white solid, 6e:6'e = 40:60; mp 206-212 °C; [a]D26 -31.8 (c = 0.06, CH2Cl2). (Found: C, 70.68; H, 7.99; N, 4.90 C5oHg5N3O9 requires: C, 70.48; H, 7.69; N, 4.93.); IR, vmax (K:Br): 3438 (NH), 3359 (NH), 2956, 2929, 2868, 1734 (C=O), 1712 (C=O), 1667 (C=O), 1597, 1537, 1509, 1462, 1427, 1371, 1327, 1236, 1204, 1128, 957, 700 cm-1.
iH NMR data for compound 6e. 1H NMR (CDCl3): 5 0.56-0.96 (18H, m, 6 x MeCH); 0.68-1.64 (11H, m, 11H of menthyl); 1.63-1.76 (4H, m, 4H of menthyl); 1.81-2.13 (3H, m, 3H of menthyl); 3.51 (1H, dd, J = 7.5, 9.5 Hz, 2-H); 3.62 and 3.69 (9H, 2s, 2:1, 3 x OMe); 4.24 (1H, d, J = 9.5 Hz, 3-H); 4.41 (1H, d, J = 9.3 Hz, 5-H); 4.72 and 4.84 (2H, 2dt, 1:1, J = 4.4, 10.9 Hz, 2 x 1'-H); 4.84 (1H, dd, J = 7.0, 9.3 Hz, 6-H); 5.08 (1H, d, J = 7.5 Hz, 1-H); 6.40 (2H, s, CgH2); 6.75 (1H, d, J = 7.0 Hz, NH); 7.11-7.23 (3H, m, 3H of Ph); 7.28-7.46 (4H, m, 4H of Ph); 7.47-7.55 (1H, m, 1H of Ar); 7.74-7.82 (2H, m, 2H of Ph).
iH NMR data for compound 6'e. 1H NMR (CDC-l3): 5 3.54 (1H, dd, J = 6.5, 8.6 Hz, 2-H); 3.61 and 3.71 (9H, 2s, 2:1, 3 x OMe); 4.29 (1H, d, J = 8.6 Hz, 3-H); 4.40 (1H, d, J = 8.1 Hz, 5-H); 5.15 (1H, d, J = 6.5 Hz, 1-H); 4.78 (1H, dd, J = 7.2, 8.1 Hz, 6-H); 6.43 (2H, s, CgH2); 6.82 (1H, d, J = 7.2 Hz, NH).
Bis[(1Ä,2S ,5R )-2-isopropyl-5-methylcyclohexyl] (1S*,2R*,3R*,5R*,6R*)-6-benzamido-3-(4-dimethyla-
minophenyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate 6/6'f and (1R*,2S*,3R*, 5R*,6R*)-isomer 5/5'f. Prepared from 4 and dipole 3f (412 mg, 1 mmol), 5f:5'f:6f:6'f = 43:27:14:16, crystallization from methanol afforded a pure isomer 6'f.
iH NMR data for compound 5f. 1H NMR (CDCl3): 2.79 (6H, s, NMe2); 3.76 (1H, dd, J = 8.3, 11.1 Hz, 2-H); 4.25 (1H, d, J = 12.0 Hz, 5-H); 4.29 (1H, d, J = 11.1 Hz, 3-H); 4.53 (1H, dt, J = 4.2, 10.9 Hz, 1'-H); 4.70 (1H, dd, J = 0.5, 8.3 Hz, 1-H); 4.79 (1H, dt, J = 4.2, 10.9 Hz, 1'-H); 5.58 (1H, dd, J = 9.0, 12.0 Hz, 6-H); 6.35 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.60 (1H, d, J = 9.0 Hz, NH).
iH NMR data for compound 5'f. 1H NMR (CDC-l3): 5 2.78 (6H, s, NMe2); 4.26 (1H, d, J = 12.0 Hz, 5-H); 4.71 (1H, dd, J = 0.5, 8.4 Hz, 1-H); 5.53 (1H, dd, J = 8.4, 12.0 Hz, 6-H); 6.36 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.59 (1H, d, J = 8.4 Hz, NH).
iH NMR data for compound 6f. 1H NMR (CDCl3): 5 2.84 (6H, s, NMe2); 3.59 (1H, dd, J = 5.9, 8.7 Hz, 2-H); 4.17 (1H, d, J = 8.7 Hz, 3-H); 4.40 (1H, d, J = 6.9 Hz, 5-H); 4.73 (1H, dt, J = 4.4, 10.67 Hz, 1'-H); 4.80 (1H, br t, J = 6.5 Hz, 6-H); 4.86 (1H, dt, J = 4.4, 10.6 Hz, 1'-H); 5.10 (1H, d, J = 5.8 Hz, 1-H); 6.47 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.76 (1H, d, J = 6.3 Hz, NH).
Data for compound 6'f. Yield: 41 mg (5%) of a white solid; mp 231-234 °C (from MeOH; [a]D23 -12.9 (c = 0.06, CH2Cl2). 1H NMR (CDCl3): 5 0.56, 0.65, 0.84, 0.90, 0.92, 0.93 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.78-1.64 (6H, m, 6H of menthyl); 1.37-1.78 (9H, m, 9H of menthyl); 1.96-2.09 (3H, m, 3H of menthyl); 2.82 (6H, s, NMe2); 3.54 (1H, dd, J = 7.2, 9.4 Hz, 2-H); 4.08 (1H, d, J = 9.4 Hz, 3-H); 4.38 (1H, d, J = 8.3 Hz, 5-H); 4.67 (1H, dt, J = 4.3, 10.6 Hz, 1'-H); 4.84 (1H, dt, J = 4.3, 10.6 Hz, 1'-H); 4.86 (1H, dd, J = 6.8, 8.3 Hz, 6-H); 5.11 (1H, d, J = 7.2 Hz, 1-H); 6.43 (2H, d, J = 8.8 Hz, 2H of CgH4); 6.71 (1H, d, J = 6.8 Hz, NH); 7.01 (2H, d, J = 8.8 Hz, 2H of CgH4); 7.08-7.21 (3H, m, 3H of Ph); 7.33-7.47 (4H, m, 4H of Ph); 7.47-7.55 (1H, m, 1H of Ph); 7.74-7.84 (2H, m, 2H of Ph). (Found: C, 73.17; H, 8.14; N, 6.91 C45Hg4N4Og requires: C, 73.10; H, 8.01; N, 6.96.); IR, vmax (KBr): 3427 (NH), 2957, 2931, 2868, 1732 (C=O), 16)80 (C=O), 1616, 1526, 1452, 1362, 1274, 1231, 1186, 1099, 953, 812, 704 cm1.
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1R*, 2S*,3R*,5R*,6R*)-6-benzamido-3-(2-furyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-1,2-dicar-boxylate 5/5'g. Prepared from 4 and dipole 3g (359 mg, 1 mmol), 5g:5'g = 50:50, crystallization from methanol afforded isomerically pure compound 5g.
Data for compound 5g. Yield: 45 mg (6%) of a white solid; mp 204-207 °C (from MeOH); [a]DS3 -41.8 (c = 0.08, CH2Cl2). 1H NMR (CDCl3): 5 0.47, 0.D68, 0.80, 0.89, 0.92, 0.94 (18H, 6d, 1:1:1:1:1:1, J = 6.7 Hz, 6 x MeCH); 0.73-1.76 (15H, m, 15H of menthyl); 1.79-1.89 (1H, m, 1H of menthyl); 1.94-2.07 (1H, m, 1H of men-
thyl); 2.22-2.31 (1H, m, 1H of menthyl); 4.14 (1H, dd, J = 8.4, 11.1 Hz, 2-H); 4.31 (1H, d, J = 12.1 Hz, 5-H); 4.51 (1H, d, J = 11.1 Hz, 3-H); 4.59 (1H, dt, J = 4.3, 10.9 Hz, 1'-H); 4.75 (1H, dd, J = 0.5, 8.4 Hz, 1-H); 4.78 (1H, dt, J = 4.3, 10.9 Hz, 1'-H); 5.48 (1H, dd, J = 8.4, 12.0 Hz, 6-H); 5.86 (1H, dd, J = 0.6, 3.3 Hz, 1H of furan); 5.94 (1H, dd, J = 1.8, 3.3 Hz, 1H of furan); 6.51 (1H, d, J = 8.4 Hz, NH); 7.07-7.17 (4H, m, 3H of Ph, 1H of furan); 7.19-7.27 (2H, m, 2H of Ph); 7.35-7.43 (2H, m, 2H of Ph); 7.44-7.52 (1H, m, 1H of Ph); 7.68-7.76 (2H, m, 2H of Ph). (Found: C, 71.92; H, 7.81; N, 5.45. C45H57N3O7 requires: C, 71.88; H, 7.64; N, 5.59.); IR, vmax (KBr): 3462 (NH), 2951, 2926, 2868, 1728 (C=O), 1645 (C=O), 1523, 1389, 1188, 1129, 694 cm-1.
^H NMR data for compound 5'g. 1H NMR (CDCsl3): 5 4.17 (1H, dd, J = 8.5, 11.1 Hz, 2-H); 4.39 (1H, d, J = 12.0 Hz, 5-H); 4.54 (1H, d, J = 8.5 Hz, 3-H); 5.36 (1H, dd, J = 8.4, 12.0 Hz, 6-H).
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1R*, 2S*,3R*,5R*,6R*)-6-benzamido-3-(2-methoxyop-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyra-zole-1,2-dicarboxylate 5/5'h and (1S*,2R*,3R*,5R*, 6R*)-isomer 6/6'h. Prepared from 4 and dipole 3h (399 mg, 1 mmol), 5h:5'h:6h:6'h = 28:25:25:22, separation by MPLC afforded a pure isomer 5'h and a purified mixture of isomers 6/6'h.
^H NMR data for compound 5h. 1H NMR (CDC-l3): 5 0.32, 0.52, 0.81, 0.86, 0.92, 0.95 (18H, 6d, 1:1:1:1:1:1, J = 6.9 Hz, 6 x MeCH); 3.59 (3H, s, OMe);
4.08	(1H, br dd, J = 8.3, 11.1 Hz, 2-H); 4.31 (1H, d, J = 12.0 Hz, 5-H); 4.51 (1H, dt, J = 4.3, 10.9 Hz, 1'-H); 4.73 (1H, dd, J = 0.5, 8.3 Hz, 1-H); 4.78 (1H, dt, J = 4.3, 10.9 Hz, 1'-H); 4.96 (1H, br d, J = 11.1 Hz, 3-H); 5.45 (1H, dd, J = 8.5, 12.0 Hz, 6-H); 6.55 (1H, d, J = 8.5 Hz, NH).
Data for compound 5'h. Yield: 41 mg (6%) of a white solid; mp 95-97 °C; [a]D28 -40.4 (c = 0.06, CH2Cl2). EI-MS: m/z = 792 (M+). 1H NMR (CDCl3): 5 0.5^, 0.62, 0.80, 0.87, 0.94, 0.96 (18H, 6d, 1:1:1:1:1:1, J =
6.9	Hz, 6 x MeCH); 0.67-1.60 (13H, m, 13H of menthyl); 1.62-1.79 (3H, m, 3H of menthyl); 2.14-2.28 (2H, m, 2H of menthyl); 3.61 (3H, s, OMe); 4.09 (1H, br t, J = 9.5 Hz, 2-H); 4.30 (1H, d, J = 11.7 Hz, 5-H); 4.47 (1H, dt, J = 4.5, 10.9 Hz, 1'-H); 4.76 (1H, dd, J = 0.7, 8.6 Hz, 1-H); 4.84 (1H, dt, J = 4.5, 10.9 Hz, 1'-H); 4.97 (1H, br d, J = 11.1 Hz, 3-H); 5.40 (1H, dd, J = 8.3, 11.7 Hz, 6-H); 6.43 (1H, d, J = 8.1 Hz, 1H of CgH4); 6.53 (1H, d, J = 8.3 Hz, NH); 6.69 (1H, t, J = 7.5 Hz, 1H of CgH4); 6.90-7.00 (4H, m, 4H of Ph); 7.10-7.18 (2H, m, 2H ofPh); 7.21 (1H, br d, J = 7.3 Hz, 1H of Ar); 7.34-7.42 (2H, m, 2H of Ar); 7.43-7.50 (1H, m, 1H of Ar); 7.67-7.75 (2H, m, 2H of Ar). (Found: C, 73.10; H, 8.13; N, 5.06 C48Hg1N3O7 requires: C, 72.79; H, 7.76; N, 5.31.); IR, vmax (KBr): 3423 (NH), 1735 (C=O), 1672 (C=O) cm1.
Data for a mixture of compounds 6/6'h. Yield: 14 mg (2%) of a white solid, 6h:6'h = 50:50; mp 81-84 °C.
(Found: C, 72.50; H, 8.11; N, 5.22 C48Hg1N3O7 requires:
C, 72.79; H, 7.76; N, 5.31.).	48 61 3 7
NMR Data for compound 6h. 1H NMR (CDCl3): 5 0.60-0.95 (18H, m, 6 x MeCH); 0.73-1.60 (13H, m, 13H of menthyl); 1.63-1.76 (3H, m, 3H of menthyl); 1.98-2.09 (2H, m, 2H of menthyl); 3.62 (3H, s, OMe); 3.65 (1H, dd, J = 3.9, 6.8 Hz, 2-H); 4.47 (1H, d, J = 6.6 Hz, 5-H); 4.69-4.87 (3H, m, 2 x 1'-H, 3-H); 4.93 (1H, dd, J = 5.7, 6.6 Hz, 6-H); 5.10 (1H, d, J = 3.9 Hz, 1-H); 6.65 (1H, dd, J = 0.6, 8.2 Hz, 1H of CgH4); 6.74-6.82 (1H, m, 1H of CgH4); 7.04-7.30 (5H, m, 4H of Ar and NH); 7.37-7.5(5 (5H, m, 5H of Ar); 7.60-7.67 (1H, m, 1H of Ar); 7.82-7.90 (2H, m, 2H of Ph).
NMR Data for compound 6'h. 0.60-0.95 (18H, m, 6 x MeCH); 0.73-1.60 (13H, m, 13H of menthyl); 1.63-1.76 (3H, m, 3H of menthyl); 1.98-2.09 (2H, m, 2H of menthyl); 3.64 (3H, s, OMe); 3.69 (1H, dd, J = 4.8, 7.4 Hz, 2-H); 4.43 (1H, d, J = 7.0 Hz, 5-H); 4.69-4.87 (3H, m, 2 x 1'-H, 3-H); 5.00 (1H, t, J = 7.0 Hz, 6-H); 5.11 (1H, d, J = 4.8 Hz, 1-H); 6.69 (1H, dd, J = 0.5, 7.6 Hz, 1H of C5H4); 6.74-6.82 (1H, m, 1H of C5H4); 7.04-7.30 (5H, m,4H of Ar and NH); 7.37-7.56 (5H, m, 5H of Ar); 7.60-7.67 (1H, m, 1H of Ar); 7.82-7.90 (2H, m, 2H of Ph).
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S*, 2R*,3R*,5R*,6R*)-6-benzamido-3-(3-fluorophenyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate 6/6'i. Prepared from 4 and dipole 3i (387 mg, 1 mmol), 6i:6'i = 51:49, purification by MPLC afforded a purified mixture of isomers 6/6'i.
Data for a mixture of compounds 6/6'i. Yield: 170 mg (22%) of a white solid, 6i:6'i = 55:45, mp 95-99 °C; [a]D23 -38.4 (c = 0.047, CH2Cl2). (Found: C, 72.49; H, 7.79; N, 5.34. C47H58FN3O5 requires: C, 72.37; H, 7.50; N, 5.39.); IR, vmax (KBr): 3361 (NH), 2957, 2929, 2871, 1734 (C=O), 165(5 (C=O), 1536, 1489, 1454, 1371, 1267, 1228, 1186, 1150, 982, 956, 785, 696 cm-1.
1H NMR Data for compound 6i. 1H NMR (CDC-l3): 5 0.56-0.98 (22H, m, 6 x MeCH and 4H of menthyl); 0.99-1.56 (8H, m, 8H of menthyl); 1.61-1.78 (4H, m, 4H of menthyl); 1.93-2.13 (2H, m, 2H of menthyl); 3.55 (1H, dd, J = 7.1, 9.3 Hz, 2-H); 4.25 (1H, d, J = 9.3 Hz, 3-H); 4.41 (1H, d, J = 9.4 Hz, 5-H); 4.66-4.90 (3H, m, 2 x 1'-H, 6-H); 5.12 (1H, dd, J = 0.5, 7.1 Hz, 1-H); 6.74-6.87 (2H, m, 1H of Ar, NH); 6.87-7.10 (3H, m, 3H of Ar); 7.12-7.23 (3H, m, 3H of Ar); 7.27-7.34 (1H, m, 1H of Ar); 7.35-7.45 (3H, m, 3H of Ar); 7.46-7.55 (1H, m, 1H of Ar); 7.74-7.11 (2H, m, 2H of Ar).
^H NMR data for compound 6'i. 1H NMR (CDC-l3): 5 0.56-0.98 (22H, m, 6 x MeCH and 4H of menthyl); 0.99-1.56 (8H, m, 8H of menthyl); 1.61-1.78 (4H, m, 4H of menthyl); 1.93-2.13 (2H, m, 2H of menthyl); 3.61 (1H, dd, J = 5.9, 8.7 Hz, 2-H); 4.32 (1H, d, J = 8.7 Hz, 3-H); 4.41 (1H, d, J = 7.6 Hz, 5-H); 4.66-4.90 (3H, m, 2 x 1'-H, 6-H); 5.16 (1H, d, J = 5.9 Hz, 1-H); 6.74-6.87 (2H, m, 1H
of Ar, NH); 6.87-7.10 (3H, m, 3H of Ar); 7.12-7.23 (3H, m, 3H of Ar); 7.27-7.34 (1H, m, 1H of Ar); 7.35-7.45 (3H, m, 3H of Ar); 7.46-7.55 (1H, m, 1H of Ar); 7.74-7.11 (2H, m, 2H of Ar).
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1R*, 2S*,3R*,5R*,6R*)-6-benzamido-3-(2,4-dichlorop-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyra-zole-1,2-dicarboxylate 6/6'j. Prepared from 4 and dipole 3j (438 mg, 1 mmol), 6j:6'j = 50:50, crystallization from methanol afforded isomerically pure compound 6j.
Data for compound 6j. Yield: 174 mg (21%) of a white solid; mp 210-213 °C (from MeOH); [a]D21 -32.3 (c = 0.08, CH2Cl2). EI-MS: m/z = 792 (M+). DH NMR (CDCl3): 5 0.70 (3H, d, J = 6.9 Hz, MeCH); 0.75-1.15 (17H, i6, 17H of menthyl); 1.22-1.60 (9H, m, 9H of men-thyl); 1.61-1.76 (5H, m, 5H of menthyl); 1.83-2.17 (2H, m, 2H of menthyl); 3.61 (1H, dd, J = 4.8, 7.0 Hz, 2-H); 4.44 (1H, d, J = 7.7 Hz, 5-H); 4.70-4.84 (2H, m, 2 x 1'-H); 4.86 (1H, d, J = 7.0 Hz, 3-H); 5.05 (1H, t, J = 7.5 Hz, 6-H); 5.12 (1H, d, J = 4.8 Hz, 1-H); 7.01 (1H, d, J = 7.4 Hz, NH); 7.07 (1H, dd, J = 2.0, 8.5 Hz, 1H of Ar); 7.18-7.23 (3H, m, 3H of Ar); 7.36-7.57 (7H, m, 7H of Ar); 7.79-7.87 (2H, m, 2H of Ar). (Found: C, 67.46; H, 6.86; N, 5.17. C47H57Cl2N3Og requires: C, 67.94; H, 6.91; N, 5.06.); IR, v"4^^ (^Br): 3445 (NH), 2955, 2927, 2868, 1734 (C=O), 1676 (C=O), 1526, 1478, 1456, 1372, 1273, 1232, 1194, 1151, 1100, 982, 955, 793, 702 cm-1.
1H NMR data for compound 6'j. 1H NMR (CDC-l3): 5 3.64 (1H, dd, J = 4.6, 6.8 Hz, 2-H); 4.46 (1H, d, J = 6.7 Hz, 5-H); 4.97 (1H, t, J = 7.0 Hz, 6-H); 5.14 (1H, d, J = 4.6 Hz, 1-H).
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S*, 2R*,3S*,5R*,6R*)-6-benzamido-3-(2,6-dichlorop-henyl)-7-oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate 7/7'k. Prepared from 4 and dipole 3k (438 mg, 1 mmol), 7k:7'k = 51:49, purification by MPLC afforded a purified mixture of compounds 7/7'k.
Data for a mixture of compounds 7/7'k. Yield: 258 mg (31%) of a white solid, 7k:7'k = 51:49, mp 109-113 °C; [a]D2g -43.8 (c = 0.1, CH2Cl2). (Found: C, 67.64; H, 7.16; N, 5.08. C47H57Cl2N3Og requires: C, 67.94; H, 6.91; N, 5.06.); IR, v"4^^ (^Br): 3441 (NH), 2957, 2930, 2870, 1733 (C=O), 1662 (C=O), 1536, 1450, 1370, 1290, 1204, 1098, 954, 773, 697 cm-1.
1H NMR data for compound 7k. 1H NMR (CDC-l3): 5 0.57-0.96 (18H, m, 6 x MeCH); 0.70-1.65 (13H, m, 13H of menthyl); 1.66-1.77 (2H, m, 2H of menthyl); 1.92-2.19 (3H, m, 3H of menthyl); 4.31 (1H, d, J = 9.8 Hz, 5-H); 4.52-4.68 (1H, m, 1'-H); 4.75-4.86 (1H, m, 1'-H); 4.80 (1H, dd, J = 8.2, 9.6 Hz, 2-H); 5.09 (1H, dd, J = 7.90, 9.8 Hz, 6-H); 5.29 (1H, d, J = 8.2 Hz, 3-H); 5.83 (1H, d, J = 9.6 Hz, 1-H); 6.45 (1H, d, J = 7.9 Hz, NH); 7.01-7.20 (6H, m, 6H of Ar); 7.23-7.31 (2H, m, 2H of
Ar); 7.34-7.42 (2H, m, 2H of Ar); 7.43-7.52 (1H, m, 1H of Ar); 7.66-7.74 (2H, m, 2H of Ar).
1H NMR data for compound 7'k. 1H NMR (CDC-l3): 5 0.57-0.96 (18H, m, 6 x MeCH); 0.70-1.65 (13H, m, 13H of menthyl); 1.66-1.77 (2H, m, 2H of menthyl); 1.92-2.19 (3H, m, 3H of menthyl); 4.36 (1H, d, J = 10.2 Hz, 5-H); 4.52-4.68 (1H, m, 1'-H); 4.75-4.86 (1H, m, 1'-H); 4.84 (1H, dd, J = 8.3, 9.7 Hz, 2-H); 5.09 (1H, dd, J = 7.9, 10.2 Hz, 6-H); 5.30 (1H, d, J = 8.3 Hz, 3-H); 5.91 (1H, d, J = 9.7 Hz, 1-H); 6.50 (1H, d, J = 7.9 Hz, NH);
7.01-7.20	(6H, m, 6H of Ar); 7.23-7.31 (2H, m, 2H of Ar); 7.34-7.42 (2H, m, 2H of Ar); 7.43-7.52 (1H, m, 1H of Ar); 7.66-7.74 (2H, m, 2H of Ar).
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1R*, 2S*,3R*,5S*,6S*)-6-benzamido-7-oxo-5-phenyl-3-(2,4, 6-trimethylphenyl)hexahydropyrazolo[1,2-a]pyrazole-
1.2-dicarboxylate	7/7'l. Prepared from 4 and dipole 3l (412 mg, 1 mmol), 7k:7'k = 56:44, purification by MPLC afforded a purified mixture of compounds 7/7'l.
Data for a mixture of compounds 7/7'l. Yield: 69 mg (9%) of a white solid, 7k:7'k = 47:53, mp 105-109 °C; [a]D28 -42.2 (c = 0.07, CH2Cl2). EI-MS: m/z = 803 (M+). (Found: C, 74.13; H, 8.40; N, 5.13. C50Hg5N3Og requires: C, 74.69; H, 8.15; N, 5.23.); IR, v6ax (K:^r): 3429 (NH), 2956, 2929, 2870, 1734 (C=O), 1665 (C=O), 1533, 1456, 1371, 1288, 1180, 1096, 955, 698 cm1.
1H NMR data for compound 7l. 1H NMR (CDCl3): 5 0.36-0.99 (18H, m, 6 x MeCH); 0.63-2.30 (18H, m, 18H of menthyl); 1.38, 2.15, 2.16 (9H, 3s, 1:1:1, 3 x MeAr); 4.19 (1H, dd, J = 9.4, 10.7 Hz, 2-H); 4.38 (1H, d, J = 4.7 Hz, 5-H); 4.43-4.57 (1H, m, 1'-H); 4.80-4.97 (3H, m, 1'-H, 1-H, and 6-H); 5.07 (1H, d, J = 10.7 Hz, 3-H); 6.66 (1H, d, J = 6.8 Hz, NH); 6.46 and 6.74 (2H, 2br s, 1:1, CgH2); 7.07-7.14 (1H, m, 1H of Ph); 7.15-7.29 (3H, m, 3H of Ph); 7.35-7.45 (3H, m, 3H of Ph); 7.45-7.55 (1H, m, 1H of Ph); 7.68-7.78 (2H, m, 2H of Ph).
1H NMR data for compound 7'l. 1H NMR (CDC-l3): 5 0.36-0.99 (18H, m, 6 x MeCH); 0.63-2.30 (18H, m, 18H of menthyl); 1.50, 2.56, 2.57 (9H, 3s, 1:1:1, 3 x MeAr); 4.24 (1H, dd, J = 8.6, 10.5 Hz, 2-H); 4.35 (1H, d, J = 6.2 Hz, 5-H); 4.43-4.57 (1H, m, 1'-H); 4.80-4.97 (3H, m, 1'-H, 3-H, and 6-H); 5.03 (1H, d, J = 8.6 Hz, 1-H); 6.60 (1H, d, J = 6.9 Hz, NH); 6.46 and 6.74 (2H, 2br s, 1:1, CgHf); 7.07-7.14 (1H, m, 1H of Ph); 7.15-7.29 (3H, m, 3H of Ph); 7.35-7.45 (3H, m, 3H of Ph); 7.45-7.55 (1H, m, 1H of Ph); 7.68-7.78 (2H, m, 2H of Ph).
5. Acknowledgements
The financial support from the Ministry of Science and Technology, Slovenia through grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully acknowledged. We acknowledge with thanks the financial support from pharmaceutical companies Krka d.d. (Novo mesto,
Slovenia) and Lek d.d., a new Sandoz company (Ljubljana, Slovenia).
The authors wish to express their gratitude to the Alexander von Humboldt Foundation, Germany, for the donation of a Büchi medium pressure liquid chromatograph.
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Povzetek
1.1-Dipolarne cikloadicije racemnih (1Z,4R*,5R*)-1-arilmetiliden-4-benzamido-5-fenil-1-pirazolidinon-1-azometin iminov 3 na optično aktivni dipolarofil, di-(-)-mentil maleat (4), so vodile do zmesi diastereomernih cikloaduktov 5/5'-7/7'. Selektivnost in stereokemija cikloadicij sta bili odvisni od substituentov na arilni skupini na položaju 1' dipo-lov 3. Tako so reakcije dipolov 3a-j z vsaj eno prosto orto-pozicijo vodile do zmesi dveh ali štirih izomernih cikloaduktov, bis[(1'R,1'S,5'R)-1-izopropil-5-metilcikloheksil] (1R*,1S*,1R*,5R*,6R*)-1-aril-6-benzamido-5-fenil-7-oksohek-sahidropirazolo[1,2-a]pirazol-1,2-dikarboksilatov 5/5' (endo-izomerov) in/ali bis[(1'R,2'S,5'R)-2-izopropil-5-metilci-kloheksil] (1S*,1R*,1R*,5R*,6R*)-1-aril-6-benzamido-5-fenil-7-oksoheksahidropirazolo[1,1-a]pirazol-1,1-dikarbok-silatov 6/6' (e^so-isomerov) s sin-orientacijo med protonoma na položajih 3 in 5. Pri reakcijah dipolarofila 4 z orto-di-substituiranima dipoloma 3k,l pa so nastale zmesi (1S*,1R*,1S*,5R*,6R*)-diastereomerov 7/7'k,l z anti-orientiranima protonoma 3 in 5. Ločbe diastereomernih cikloaduktov 5/5'-7/7' smo izvajali s kristalizacijo in/ali s preparativno tekočinsko kromatografijo (MPLC), pri čemer smo izolirali izomerno čiste spojine 5a,b,d,g, 5'b,d,h, 6c,d,j in 6'c,d,f ter očiščene zmesi diastereomerov 5/5'e, 6/6'e,h in 7/7'k,l z nizkimi do zmernimi izkoristki. Relativno konfiguracijo na pi-razolo[1,1-a]pirazolonskem strukturnem elementu produktov 5/5'-7/7' smo določili z NMR spektroskopijo.