Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines

Article abstract of DOI:10.1021/jo061537j

(Chemical Equation Presented) The reaction of alkene-tethered α-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems 4 to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. α-Methoxy-α,β-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. α-Ketoesters, α-ketoamides, and α-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.

Full text of DOI:10.1021/jo061537j

Stereocontrolled Synthesis of Functionalized
cis-Cyclopentapyrazolidines by 1,3-Dipolar Cycloaddition Reactions
of Azomethine Imines
Joshua Gergely, Jeremy B. Morgan, and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences 2, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
ReceiVed July 24, 2006
The reaction of alkene-tethered R-ketocarboxylic acid derivatives with monosubstituted hydrazines allows
highly substituted cis-cyclopentapyrazolidine ring systems 4 to be constructed rapidly. Successful
cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids
accelerate these reactions. R-Methoxy-R,â-unsaturated esters are suitable alkene components, as are alkenes
having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon.
R-Ketoesters, R-ketoamides, and R-ketothioesters can be employed. Various hydrazines substituted with
N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The
rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration
of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers
interconvert under the reaction conditions.
Introduction
Various methods to generate azomethine imines are available.
A commonly employed approach generates this dipole in situ
from the condensation of 1,2-disubstituted hydrazines with
aldehydes, acetals, or hemiacetals.2 This strategy has been used
widely, for example, by Jacobi and co-workers in their incisive
total synthesis of (()-saxitoxin.4 Azomethine imines can also
be generated from hydrazones by thermal5 or acid-induced6 1,2-
prototropy from the terminal nitrogen atom to the central
nitrogen atom. In our studies to prepare potential precursors of
the complex diguanidine alkaloid palau’amine (1, Figure 1), we
employed this latter approach to assemble pentacyclic pen-
taamine 3 (Scheme 1).7,8
Transformations that rapidly introduce molecular complexity
are essential for the efficient chemical synthesis of complex
natural products and other fine chemicals. 1,3-Dipolar cycload-
ditions are one such class of reactions that provide rapid access
to structurally complex five-membered heterocycles.1 Since the
initial reports by Oppolzer and co-workers in the early 1970s,2
intramolecular 1,3-dipolar cycloadditions of azomethine imines
have been used to construct a variety of complex heterocyclic
structures containing pyrazolidine rings.3
(1) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Chemistry of Heterocyclic Compounds Series 59; Wiley: Chichester,
2002.
In the context of a program in our laboratories to synthesize
the diguanidine alkaloid massadine (2),9,10 we sought to expand
(2) (a) Oppolzer, W. Tetrahedron Lett. 1970, 11, 3091-3094. (b)
Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10-23.
(3) (a) Schantl, J. G. Azomethine Imines. Science of Synthesis; Georg
Thieme Verlag: Stuttgart, 2004; Vol. 27, pp 731-824. (b) Padwa, A.
Intermolecular 1,3-Dipolar Cycloadditions. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991; Vol.
4, pp 1069-1109. (c) Wade, P. A. Intramolecular 1,3-Dipolar Cycloaddi-
tions: Azomethine Imine Cyclizations. In ComprehensiVe Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991; Vol. 4,
pp 1144-49.
(4) (a) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc.
1984, 106, 5594-5598. (b) Jacobi, P. A.; Brownstein, A.; Martinelli, M.;
Grozinger, K. J. Am. Chem. Soc. 1981, 103, 239-241. (c) Martinelli, M.
J.; Brownstein, A. D.; Jacobi, P. A.; Polanc, S. Croat. Chem. Acta 1986,
59, 267-295.
(5) Grigg, R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978, 31,
2827-2830.
(6) Le Fevre, G.; Sinbandhit, S.; Hamelin, J. Tetrahedron 1979, 35,
1821-1824.
(7) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559-9568.
10.1021/jo061537j CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/27/2006
9144
J. Org. Chem. 2006, 71, 9144-9152

Synthesis of Functionalized cis-Cyclopentapyrazolidines
SCHEME 2
FIGURE 1. Palau’amine and massadine.
SCHEME 1
developed. The synthesis of acyclic substrates in which the
double bond is substituted with both an electron-withdrawing
and an electron-donating substituent began with Horner-
Wadsworth-Emmons olefination of 2-hydroxytetrahydrofuran
(5) with phosphonate 611 in the presence of LiCl and DBU to
provide a separable mixture of (Z)-alkene 7 and the correspond-
ing E stereoisomer in a ∼1:1 ratio (Scheme 2).12 Oxidation of
7 with Dess-Martin periodinane furnished aldehyde 8 in 98%
yield.13 Reaction of this intermediate with phosphonates 9-1214
provided R-siloxy R,â-unsaturated acid derivatives 13-16 as
inconsequential mixtures of stereoisomers in yields ranging from
68% to 82%. Desilylation of esters 13 and 14 was accomplished
by reaction with CsF and acetic acid at room temperature to
cleanly give R-ketodiesters 17 and 18. As these intermediates
partially decomposed during silica gel chromatography, they
were used directly without purification. Reaction of isopropyl
R-ketodiester 18 with monosubstituted hydrazines and catalytic
the scope of intramolecular cycloaddition reactions of azome-
thine imine dipoles generated from the condensation of R-ke-
toesters and monosubstituted hydrazines. As massadine (2) lacks
the pyrrolidine ring of palau’amine (1), we wanted to define
whether the C ring of massadine and the elements of the A and
B rings could be assembled by a cycloaddition sequence
analogous to the one depicted in Scheme 1, in which the
R-hetero-substituted R,â-unsaturated ester dipolarophile was
acyclic. In this Article, we report the results of such an
investigation of the transformation depicted in eq 1. We
demonstrate several useful strategies for forming cis-cyclopen-
tapyrazolidines 4 having a variety of substituents at the 2, 3,
and 6a positions. We also report the discovery of several new
reaction conditions that accelerate the cycloaddition reaction
and allow otherwise unreactive substrates to participate in this
useful transformation.
(9) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata,
K.; van Soest, R. W. M.; Fusetani, N. Org. Lett. 2003, 5, 2255-2257.
(10) For reviews of guanidine-containing natural products, see: (a)
Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22, 516-550.
(b) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617-649. (c) Berlinck, R.
G. S. Nat. Prod. Rep. 1999, 16, 339-365. (d) Berlinck, R. G. S. Nat. Prod.
Rep. 1996, 13, 377-409.
Results
(11) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall,
B. M.; Fegley, G. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981-
6990.
Synthesis of Cycloaddition Substrates. Flexible synthetic
strategies to access a variety of cycloaddition precursors were
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(14) (a) Nakamura, E. Tetrahedron Lett. 1981, 22, 663-666. (b) Horne,
D.; Gaudino, J.; Thompson, W. J. Tetrahedron Lett. 1984, 25, 3529-3532.
(8) For our earlier studies in this area, see: (a) Be´langer, G.; Hong,
F.-T.; Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Org.
Chem. 2002, 67, 7880-7883. (b) Overman, L. E.; Rogers, B. N.; Tellew,
J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997, 119, 7159-7160.
J. Org. Chem, Vol. 71, No. 24, 2006 9145

Gergely et al.
SCHEME 3
slow this side reaction. A model study was performed in which
pyruvate esters of various sizes were heated with thiosemicar-
bazide in d6-ethanol with the formation of thioxotriazinone 37
being monitored by 1H NMR analysis (eq 3). As we suspected,
formation of 37 occurred at a higher temperature with isopropyl
pyruvate and ethyl pyruvate than with methyl pyruvate (at 115,
100, and 80 °C, respectively). The even bulkier tert-butyl
pyruvate rapidly decarboxylated in the presence of thiosemi-
carbazide to produce thiourea, acetamide, and isobutene.
HCl in ethanol at room temperature provided hydrazones 19-
22, which were formed as single stereoisomers in yields of 61-
92%. The observation of the N-H hydrogen of these products
With this knowledge in hand, isopropyl R-ketodiester 18 was
chosen for further study. Heating this substrate in ethanol with
1.1 equiv of thiosemicarbazide at 100 °C for 60 h provided cis-
cyclopentapyrazolidine 38 as a single stereoisomer in variable
yields with thioxotriazinone 36 being a major byproduct
(Scheme 4). Cycloadduct 38 was converted into tricyclic
thiohydantion 39 by further heating the reaction mixture at 135
°C for an additional 24 h. The relative configuration of
triazatricycle 39 was obtained by single-crystal X-ray analysis
and is consistent with the cycloaddition proceeding by a chairlike
transition structure (vide infra).15
We hypothesized that the irreproducibility observed during
the cycloaddition reaction to form cyclopentapyrazolidine 38
might be caused by basic impurities, as crude R-ketoester 18
was used without purification. Therefore, the effect of adding
various acids and bases was investigated (Table 1). Although
the rate of formation of cycloadduct 38 from the reaction of
R-ketoester 18 and thiosemicarbazide was not significantly
affected by the presence of triethylamine, ammonium acetate,
acetic acid, or citric acid, the rate of formation of thioxotriazi-
none 36 decreased markedly with increasing acidity of the
reaction medium. Additionally, in the presence of acids, the
initially formed cis-cyclopentapyrazolidine 38 cyclized at 100
°C to form tricyclic product 39. The optimal additive was found
to be citric acid. With ethanol as solvent, byproducts resulting
from Fischer esterification of citric acid hindered product
purification. Employing tert-butyl alcohol avoided this com-
plication (entry 5).
1
at δ 11-12 ppm in their H NMR spectra indicates that the Z
stereoisomer was formed (vide infra).
A similar flexible strategy was employed to prepare cycload-
dition substrates that contain double bonds having various
terminal substituents (Scheme 3). The synthesis began with
Horner-Wadsworth-Emmons reaction of lactol 5 with phos-
phonate 914 to afford siloxy R,â-unsaturated ester 23 as an 8:1
mixture of stereoisomers in 55% yield. Oxidation of this product
with Dess-Martin periodinane provided the unstable aldehyde
24, which was used immediately in Wittig reactions to furnish
alkenes 29-32 in yields ranging from 54% to 82% over two
steps. Cleavage of the enoxysilane substituent of product 29
with CsF and acetic acid quantitatively yielded R-ketoester 33,
which was used without further purification. Hydrazones 34 and
35 were also prepared directly from R-ketoester 29 by HCl-
catalyzed condensation with the appropriate hydrazine.
Intramolecular Cycloaddition: Preliminary Optimization
Studies. Initially, the reaction of R-ketoester 17 and thiosemi-
carbazide was studied under thermal conditions similar to those
previously employed in our laboratories for related intramo-
lecular azomethine imine cycloaddition reactions.7 To our
surprise, dipolar cycloaddition was not observed, and thioxot-
riazinone 36 was formed exclusively (eq 2). Varying the solvent
and the reaction temperature had little effect on the outcome of
this reaction. Because thioxotriazinone 36 could conceivably
undergo prototropy to generate an azomethine imine and
participate in a subsequent intramolecular cycloaddition, this
compound was heated at elevated temperatures (130-200 °C),
but no reaction was observed.
Scope of Thermal Intramolecular Cycloadditions. After
developing a reliable procedure for forming cycloadduct 39,
we turned to explore the scope of related thermal intramolecular
As thioxotriazinone 36 is likely formed from the intermediate
thiosemicarbazone by intramolecular acylation of the terminal
nitrogen, increasing the steric bulk of the ester substituent should
(15) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: CCDC 614479.
9146 J. Org. Chem., Vol. 71, No. 24, 2006

Synthesis of Functionalized cis-Cyclopentapyrazolidines
TABLE 2. Reaction of r-Ketoester 18 with Various
Monosubstituted Hydrazines
SCHEME 4
entrya
R
time, h
product
yield, %b
1
2
3
4
5
3-pyridylcarbonyl
Bz
Ac
Cbz
Troc
18
18
18
60
18
40
41
42
43
44
92
88
56
82
64
a Conditions: crude 18 (1.0 equiv) and hydrazine (1.1 equiv) in EtOH
(0.05 M) at 100 °C. b Mean yield of purified product from duplicate
experiments.
TABLE 3. Reaction of Various r-Ketocarbonyls with Benzoic
Hydrazide
TABLE 1. Reaction of r-Ketoester 18 and Thiosemicarbazide in
the Presence of Additives
entrya
precursor
R
product
yield, %b
1
2
3
4
13
14
15
16
CO2Me
CO2i-Pr
C(=O)NHBn
C(=O)SEt
45
41
46
47
81
87
89
50
entrya
additive
solvent
39:38:36c
yield of 39, %d
1
2
3
Et3N
NH4OAc
AcOH
citric acid
citric acid
EtOH
EtOH
EtOH
EtOH
t-BuOH
0:0:100
2:2:3
3:0:2
>20:0:1
>20:0:1
54
89
93
a Conditions: Step 1, silyl enol ether (1.0 equiv), CsF (3.2 equiv), and
AcOH (6.0 equiv) in MeCN (0.07 M) at rt for 3 h. Step 2, crude R-ketoester
(1.0 equiv) and benzoic hyrazide (1.1 equiv) in EtOH (0.05 M) at 100 °C
for 18 h. b Mean yield of purified product from duplicate experiments.
4
5b
a Conditions: 18 (1.0 equiv), thiosemicarbazide (1.05 equiv), and additive
(10 equiv) in solvent (0.05 M) at 110 °C for 60 h. b Five equivalents of
citric acid was used. c Determined by 1H NMR. d Yield of purified product.
yield of cycloadduct 44 was reduced because of product
decomposition under the reaction conditions (entry 5). Several
other monoprotected hydrazines were also examined. Both tert-
butyl carbazate and trifluoroacetic hydrazide were unstable to
the reaction conditions, resulting in complex product mixtures.
Phenylhydrazine, benzylhydrazine, and para-toluenesulfonyl-
hydrazide produced only the corresponding hydrazones upon
reaction with R-ketodiester 18 under these conditions.
azomethine imine dipolar cycloaddition reactions. Initially, we
examined the effect of substituents on the dipole component.
Using different monoprotected hydrazines in the reaction with
R-ketoester 18 allowed the dipole N-terminus substituent to be
easily varied. The optimal conditions identified for these
reactions employ 1.0 equiv of R-ketoester 18 and 1.1 equiv of
the monoprotected hydrazine in an alcohol solvent (EtOH,
t-BuOH, or s-BuOH). The use of nonpolar solvents, polar aprotic
solvents, or acetic acid as solvent resulted in increased reaction
times and decreased product yields.16 Increasing the equivalents
of hydrazine led to the formation of polar byproducts and
ultimately to lower yields of cycloadducts.
Results obtained from the reaction of five N-acyl or N-
carboalkoxyhydrazines with R-ketoester 18 in ethanol at 100
°C in a sealed reaction vessel are summarized in Table 2.
Nicotinic hydrazide (entry 1) and benzoic hydrazide (entry 2)
gave the highest yields of cycloadducts (92% and 88%,
respectively), with reaction times of 18 h. Acetic hydrazide
(entry 3) also reacted under these conditions; however, cycload-
duct 42 was isolated in only 56% yield. Hydrazines having
N-carboalkoxy substituents also performed well, with benzyl
carbazate providing cycloadduct 43 in 82% yield after 60 h
(entry 4). The reaction of R-ketodiester 18 with 2,2,2-trichlo-
roethyl (Troc) carbazate proceeded more rapidly (18 h), but the
Next, we examined a series of substrates in which the dipole
C-terminus substituent was varied. To minimize differences in
product yield resulting from the instability of the R-ketoester
component, the reactions were performed as a two-step sequence
starting with enoxysilane derivatives 13-16. The precursors
were treated with CsF and acetic acid at room temperature for
3 h, and the resulting crude â-ketoesters were immediately
allowed to react with benzoic hydrazide in ethanol at 100 °C
for 18 h in a sealed reaction vessel (Table 3). In general, the
nature of the substituent at the dipole C-terminus was found to
have little effect on reaction rate or yield. The R-ketoester
intermediates (entries 1 and 2) and R-ketoamide intermediate
(entry 3) provided cycloadducts 45, 41, and 46 in >80% yield
for the two-step sequence. The R-ketothioester intermediate
(entry 4) reacted at a similar rate, but the yield of cycloadduct
47 was lower because of the instability of the thioester
functionality under the reaction conditions.
We also examined the reaction of the related aldehyde
(16) Other solvents examined: toluene, 1,2-dichloroethane, acetic acid,
acetonitrile, 2,2,2-trifluoroethanol, and N,N-dimethylformamide.
substrate 48, which was available from 8 by a standard one-
J. Org. Chem, Vol. 71, No. 24, 2006 9147

Gergely et al.
SCHEME 5
FIGURE 2. Observed NOESY correlations for cycloadduct 41.
carbon homologation sequence.17 In this case, cis-cyclopen-
tapyrazolidine 49 was formed in nearly quantitative yield (eq
4).
The relative configuration of the C3 and C3a stereocenters
of cycloadduct 41 was assigned using 1H-1Η COSY and
NOESY correlations (Figure 2). The trans relationship between
the methoxy substituent and the angular hydrogen at C3a
demonstrates, as expected, that the alkene participated in
suprafacial fashion. The ring fusion is assigned as cis, because
molecular mechanics calculations find this isomer to be ∼8.5
kcal/mol lower in energy than the isomer having a trans ring
fusion (i.e., the C3,C3a epimer of 41).18-20 This assignment of
relative configuration of 41 is supported by the similarity of
1H NMR spectra of cycloadducts 41 and 39, with the signal for
the C3a hydrogen being particularly diagnostic: δ 3.40 ppm
(dd, J ) 9, 3 Hz) for cycloadduct 39 and δ 3.53 ppm (dd, J )
9, 3 Hz) for cycloadduct 41. This diagnostic signal also is
observed at δ 3.45-3.65 ppm in the 1H NMR spectra of
cycloadducts 40, 42-44, 45-47, and 49, whose relative
configurations are assigned by analogy to cycloadduct 41.
Next, we turned our attention to the dipolarophile component.
Initially, R-ketodiester 33 was condensed with benzoic hydrazide
and benzyl carbazate at 100 °C in sec-butanol (eq 5). When
benzoic hydrazide was employed, cycloadduct 50 formed in
nearly quantitative yield after 24 h, whereas with benzyl
carbazate, cis-cyclopentapyrazolidine 51 was produced in only
53% yield after 24 h. In the latter case, the (Z)-hydrazone 35a
(vide infra) constituted the majority of the remaining material.
As a carbamate-protecting group is more synthetically useful
than an amide-protecting group, we further explored the
difference in reactivity between the intermediate hydrazone
derivatives 34 and 35 (Scheme 5). First, the hydrazone
intermediates were isolated, and their configurations were
determined by single-crystal X-ray analysis. Hydrazone 34, the
sole product of the reaction of benzoic hydrazide with R-keto-
diester 33, has the Z configuration.21 An intramolecular hydrogen
bond between the hydrazone and the carbonyl group of the
methyl ester of 34 is apparent both in the solid state and in
1
solution where this hydrogen is observed at a diagnostic H
NMR chemical shift of δ 13.38. The Cbz-protected hydrazone,
on the other hand, was generated as a separable 2:1 mixture of
geometric isomers from the reaction of R-ketodiester 33 with
benzyl carbazate. The major hydrazone stereoisomer 35a has
the Z configuration with an intramolecular hydrogen bond
between the hydrazone N-H and the carbonyl group being
suggested by the single-crystal X-ray model.22 Hydrazone
1
stereoisomers 35a and 35b show diagnostic H NMR signals
for the N-H hydrogen at δ 11.85 and 8.20 (CDCl3), respec-
tively. As summarized in Scheme 5, a dramatic and surprising
difference in reactivity was observed between hydrazone ste-
reoisomers: (Z)-hydrazone 34 and (E)-hydrazone 35b were
converted completely (by NMR analysis) to their respective
cycloadducts when heated in sec-butanol at 100 °C for 24 h,
whereas (Z)-hydrazone 35a was recovered unchanged under
these conditions.
The development of new reaction conditions was necessary
to circumvent the reactivity difference between the benzyl
carbazate-derived hydrazone stereoisomers. We hypothesized
that establishing rapid equilibrium between hydrazone isomers
35a and 35b would allow reaction of the stereoisomeric mixture
through the reactive E stereoisomer. Toward this end, (Z)-
hydrazone 35a was exposed to various Bronsted or Lewis acids
at temperatures ranging from 25 to 115 °C, or to nucleophiles
such as chloride ion, acetate ion, or excess hydrazine. This
survey identified catalytic pyridinium p-toluenesulfonate (PPTS,
5%) in refluxing toluene as a useful reaction condition. Under
(17) Wittig reaction of aldehyde 8 with methoxymethyltriphenylphos-
phonium chloride and potassium hexamethyldisilazane (KHMDS) in THF,
followed by hydrolysis of the resulting enol ether with aqueous hydrochloric
acid in THF, gave aldehyde 48 in 85% yield over two steps.
(18) A Monte Carlo conformational search was performed using the
MMFF force field as implemented in Spartan 2005.
(19) The cis cycloadduct 41 was calculated to have a conformational
energy of 163.4 kcal/mol, whereas the cycloadduct (epimeric at C3 and
C3a) had a conformational energy of 171.9 kcal/mol.
(20) cis-Diquinanes are known to be lower in energy than the corre-
sponding trans stereoisomers; see: Paquette, L. A.; Doherty, A. M.
Polyquinane Chemistry-Synthesis and Reactions; Springer-Verlag: New
York, 1987.
(21) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: CCDC 614481.
(22) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: CCDC 614480.
9148 J. Org. Chem., Vol. 71, No. 24, 2006

Synthesis of Functionalized cis-Cyclopentapyrazolidines
TABLE 4. Cycloaddition Reactions with an r,â-Unsaturated Ester
Dipolarophile
TABLE 5. Cycloaddition Reactions Varying the Dipolarophile
Component
entrya
R
temp, °C
product
yield, %b
1
2
3
4
5
6
Cbz
CO2Me
Troc
Teoc
C(=S)NHBn
(4-Ph)-C6H4
115
115
110
110
115
100
51
52
53
54
55
56
85
85
63
71
66
94
a Conditions: crude 33 (1.0 equiv), benzyl carbazide (1.2 equiv), and
PPTS (0.05 equiv) in toluene (0.25 M) at a specified temperature for 24 h.
b Mean yield of purified product from duplicate experiments.
a Conditions: (1) Silyl enol ether (1.0 equiv), CsF (3.2 equiv), and AcOH
(6.0 equiv) in MeCN (0.07 M) at rt for 3 h. (2) Crude R-ketoester (1.0
equiv), benzyl carbazate (1.2 equiv), and PPTS (0.05 equiv) in toluene (0.25
M) at 115 °C for 24 h. b Mean yield of purified product from duplicate
experiments. c Mixture of four alkene isomers.
these conditions, (Z)-hydrazone 35a was transformed completely
to cycloadduct 51 within 24 h at 115 °C (eq 6).23
cycloadducts as single stereoisomers in good yields (entries
1-3). The electron-rich enol ether 32 was also a suitable
substrate. In this case, intramolecular cycloaddition was followed
by elimination of methanol to deliver hexahydrocyclopentapy-
razole 59 in 59% yield (entry 4). In contrast, reaction of the
analogous substrate having an unfunctionalized alkene unit (R
) H, not shown) yielded largely the hydrazone intermediate
with only trace amounts (<10%) of a cycloadduct after 24 h.
The relative configuration of a representative cyclopentapy-
razolidine formed by intramolecular dipolar cycloaddition in
the presence of PPTS was confirmed by single-crystal X-ray
analysis. Although diester 51 was not crystalline, reaction with
benzoylisothiocyanate provided the corresponding thiourea 60,
which gave single crystals suitable for X-ray analysis (eq 7).
The cis ring junction and cis relationship of the ester substituents
are apparent in the X-ray model (see Supporting Information).24
This relative configuration is the same as that observed in
cycloadducts formed in the absence of PPTS. Diagnostic angular
hydrogen signals appear between δ 2.96-3.20 ppm for cyclo-
pentapyrazolidines 51-58, allowing their relative configuration
to be assigned by analogy to thiourea 60.
After identifying improved reaction conditions for forming
cycloadduct 51, we explored further the scope of the thermal
intramolecular azomethine imine dipolar cycloaddition reaction.
Initially, we reexamined the effect of the dipole N-terminus
substituent by using different monoprotected hydrazines in the
reaction with R-ketodiester 33 in the presence of 5% PPTS
(Table 4). Under these conditions, benzyl carbazate (entry 1)
and methyl carbazate (entry 2) provided cycloadducts in 85%
yield. Cycloadditions with carbazates bearing 2,2,2-trichloro-
ethyl (Troc) or 2-(trimethylsilyl)ethyl (Teoc) substituents were
complicated by competitive formation of decomposition prod-
ucts (entries 3 and 4). Optimal yields of cycloadducts derived
from these latter substrates (63% and 71%, respectively) were
obtained at a slightly lower temperature (110 °C). N-(Carbam-
othioyl)hydrazines and N-acylhydrazines also reacted under
these mildly acidic conditions. N-Benzylthiosemicarbazide
provided cycloadduct 55 in moderate yield (entry 5), whereas
p-phenylbenzoic hydrazide gave the highest yield of cycloadduct
(94%, entry 6). In all cases, the cycloadducts were isolated as
single stereoisomers. Monosubstituted hydrazines such as tert-
butyl carbazate and trifluoroacetic hydrazide were found to be
unstable to these reaction conditions, giving low yields of
cycloadducts.
Next, we investigated the role of substituents on the dipo-
larophile (Table 5). As in our earlier study, crude R-ketoester
intermediates were generated from enoxysilane precursors 29-
32 by reaction with CsF and acetic acid and were combined
immediately with benzyl carbazate and PPTS in toluene and
heated at 115 °C for 24 h. Precursors containing dipolarophile
fragments bearing various electron-withdrawing groups reacted
well under these conditions: R,â-unsaturated ester 29, R,â-
unsaturated thioester 30, and R,â-unsaturated amide 31 provided
Alternative Cycloaddition Conditions. Lewis acids have
been shown to promote the cycloaddition reaction between
hydrazones and alkenes.25,26 Hydrazone 19 was chosen as a
suitable substrate to screen in the presence of a broad selection
(24) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: CCDC 614482.
(25) (a) Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
11279-11282. (b) Chung, F.; Chauveau, A.; Seltki, M.; Bonin, M.; Micouin,
L. Tetrahedron Lett. 2004, 45, 3127-3130. (c) Kobayashi, S.; Hirabayashi,
R.; Shimizu, H.; Ishitani, H.; Yamashita, Y. Tetrahedron Lett. 2003, 44,
3351-3354. (d) Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.;
(23) The toluene/PPTS conditions were also examined with substrates
that contained R-methoxy, R,â-unsaturated esters dipolarophile fragments.
In these cases, the cycloaddition substrates decomposed to give intractable
mixtures.
J. Org. Chem, Vol. 71, No. 24, 2006 9149

Gergely et al.
TABLE 6. FeCl3-Promoted Cycloadditions of Hydrazones 19-22
after 45 min at room temperature. Reactions with acetyl
hydrazone 21 (entry 3) and 4-pentenoyl hydrazone 22 (entry 4)
required 6 h. In these cases, some polar side products were
observed, thereby diminishing the yields of cycloadducts. A
variety of other hydrazones (trifluoroacetyl, Cbz, 3-pyridylcar-
bonyl, formyl) were either unreactive or unstable to the reaction
conditions.
Finally, we briefly examined the use of microwave irradiation
to shorten the reaction times of a representative thermal
entrya hydrazone
R
product time, h yield, %b
intramolecular azomethine imine cycloaddition reaction.29,30
A
1
2
3
4
19
20
21
22
Ph
41
61
42
62
0.75
0.75
6
88
86
64
56
sec-butanol solution of hydrazone 19 was converted to cycload-
duct 41 in 82% yield when heated at 200 °C for 2 h in a 255
W microwave reactor (eq 10). However, directly treating
R-ketoester 18 with a variety of monosubstituted hydrazines
under identical conditions led to intractable mixtures.
(4-Ph)-C6H4
Me
CH2dCH(CH2)2
6
a Conditions: hydrazone (1.0 equiv) and FeCl3 (1.0 equiv) in CH2Cl2
(0.05 M) at rt. b Mean yield of purified product from duplicate experiments.
of Lewis acids.27,28 Two Lewis acids were found to promote
cycloaddition. Hydrazone 19 was converted into cycloadduct
41 in 88% yield after 45 min at room temperature in the presence
of 1 equiv of FeCl3 and in 79% yield after 6 h in the presence
of 1 equiv of AlCl3 (eq 8). Hydrazone 19 was recovered
unchanged when treated with either aqueous or anhydrous
hydrochloric acid under identical conditions. The cycloaddition
promoted by FeCl3 was found to be quite tolerant of water.
Employing FeCl3‚6H2O instead of anhydrous FeCl3 gave nearly
identical results; 1 equiv of FeCl3‚6H2O provided 41 in 89%
yield after 45 min. Cycloadduct 41 was also produced in 76%
yield by the direct reaction of R-ketoester 18 with benzoic
hydrazide in the presence of 1 equiv of FeCl3 at room
temperature (eq 9).
Discussion
The results described herein demonstrate the broad utility of
intramolecular azomethine imine dipolar cycloaddition reactions
in forming highly substituted cis-cyclopentapyrazolidines from
simple starting materials. This systematic investigation of a
range of substrates and reaction conditions revealed reactivity
trends that will allow more general application of this powerful
transformation.
Several trends concerning the hydrazine component of the
cycloaddition reaction are evident. For instance, only N-acyl,
N-carboalkoxy, and N-carbamothioylhydrazines give high-
yielding reactions. Moreover, this hydrazine substituent must
be compatible with the temperatures and additives required for
the cycloaddition to take place at a practical rate. For example,
tert-butoxycarbonyl, trifluoroacetyl, and formyl protecting
groups performed poorly in the cycloaddition reactions surveyed
in this study. Reactivity generally increases as the electron-
withdrawing ability of the hydrazine protecting group increases;
thus, acylhydrazines perform better than carbazates. This trend
may reflect the stability of the azomethine imine tautomer of
the hydrazone. As the dipole’s negative charge is more localized
on the N-terminus than on the C-terminus, a better electron-
withdrawing group (acyl rather than carboalkoxy) attached to
the N-terminus should better stabilize the reactive dipole,
increasing the equilibrium concentration of this reactive tau-
tomer.
Interpretation of reactivity trends arising from the hydrazine
component is complicated by the different reactivity of hydra-
zone stereoisomers derived from R-ketoesters. In the case of
the N-benzyloxycarbonyl hydrazone stereoisomers 35a and 35b,
only E isomer 35b underwent cycloaddition at 100 °C; Z
stereoisomer 35a was recovered unchanged under these condi-
tions (Scheme 5). The (Z)-hydrazone stereoisomer is stabilized
by an intramolecular hydrogen bond between the hydrazone
To examine the scope of the FeCl3-promoted cycloaddition,
monoprotected hydrazones 19-22 were exposed to 1 equiv of
this Lewis acid in dichloromethane at room temperature (Table
6). Both benzoyl hydrazone 19 (entry 1) and p-phenylbenzoyl
hydrazone 20 (entry 2) underwent cycloaddition in >80% yield
Kobayashi, J. J. Am. Chem. Soc. 2002, 124, 13678-13679. (e) Norman,
M. H.; Heathcock, C. H. J. Org. Chem. 1987, 52, 226-235. (f) Padwa, A.;
Ku, H. J. Am. Chem. Soc. 1980, 45, 3756-3766. (g) Wilson, R. M.; Rekers,
J. W. J. Am. Chem. Soc. 1979, 101, 4005-4007.
(26) Lewis acids have also been used to promote related azomethine
ylide cycloadditions: (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem.
Soc. 2003, 125, 10174-10175. (b) Nyerges, M.; Rudas, M.; Toth, G.;
Herenyi, B.; Kadas, I.; Bitter, I.; Toke, L. Tetrahedron 1995, 48, 13321-
13330.
(27) Carlson, R.; Lundstedt, A. N.; Prochazka, M. Acta Chem. Scand.
1986, 40B, 522-533.
(28) Additional Lewis acids examined: BF3‚Et2O, SnCl4, TiCl4, TM-
SOTf, Sc(OTf)3, Zr(Oi-Pr)4, TiCl3, CrBr3, AgOAc, LiBr, MgBr‚Et2O, ZnI2,
SnCl2, AlBr3, and Cu(OTf)2.
(29) For a general review of microwave chemistry, see: Galema, S. A.
Chem. Soc. ReV. 1997, 26, 233-238.
(30) Microwave irradiation has previously been reported to promote
intermolecular azomethine imine cycloaddition reactions, see: Arrieta, A.;
Carrillo, J. R.; Coss´ıo, F. P.; D´ıaz-Ortiz, A.; Go´mez-Escalonilla, M. J.; de
la Hoz, A.; Langa, F.; Moreno, A. Tetrahedron 1998, 54, 13167-13180.
9150 J. Org. Chem., Vol. 71, No. 24, 2006

Synthesis of Functionalized cis-Cyclopentapyrazolidines
N-H and the carbonyl oxygen of the ester, whereas the
corresponding azomethine imine tautomer 63 should be desta-
bilized by charge repulsion (eq 11). As a result, prototropy to
form the reactive azomethine imine tautomer should be much
less favorable with the (Z)-hydrazone stereoisomer. We suggest
that this factor is responsible for the lack of reactivity of the
(Z)-N-carboalkoxy hydrazone stereoisomer. As this trend should
be seen also with hydrazones having N-acyl substituents, we
attribute the successful cycloaddition of the (Z)-N-benzoyl
hydrazone isomer 34 (Scheme 5) to rapid equilibration of these
hydrazone steroisomers. One indication that equilibration might
be rapid for hydrazone 34 is seen in our isolation of only the
(Z)-hydrazone stereoisomer in the N-benzoyl series (and in acyl
hydrazones 19-22). Thus, the rate of intramolecular cycload-
dition appears to reflect not only the reactivity and equilibrium
concentration of the azomethine imine intermediate, but in some
cases also the rate at which hydrazone stereoisomers interconvert
under the reaction conditions.
cyclopentapyrazolidines having an ester, thioester, or amide
substituent at C6a. R-Methoxy-R,â-unsaturated esters are suit-
able alkene components, as are alkenes having either electron-
withdrawing or electron-donating substituents at the terminal
alkene carbon. Depending upon the specific case, these cyclo-
condensations are achieved optimally either under thermal
conditions or in the presence of protic acids or Lewis acids.
Experimental Section34
General Method A for Formation of Cycloadducts. 3-Meth-
oxy-2-(pyridine-3-carbonyl) Hexahydrocyclopentapyrazole-3,-
6a-dicarboxylic Acid 6a-Isopropyl Ester 3-Methyl Ester (40).
A solution of R-ketoester 18 (54 mg, 0.20 mmol) and 3-pyridyl-
carbonyl hydrazide (30 mg, 0.22 mmol) in EtOH (3.9 mL) was
maintained at 100 °C for 18 h. EtOH was removed in vacuo, and
the resulting yellow oil was purified via flash chromatography (40%
EtOAc/hexanes) to yield 72 mg (93%) of cycloadduct 40 as a clear
glaze: 1H NMR (500 MHz, CDCl3) δ 9.35 (br s, 1H), 8.68 (br s,
1H), 8.60 (dt, J ) 8.0, 1.9 Hz, 1H), 7.38 (dd, J ) 7.9, 4.9 Hz, 1H),
5.05 (sept, J ) 6.3 Hz, 1H), 4.35 (s, 3H), 3.77 (s, 3H), 3.58 (s,
3H), 3.50 (dd, J ) 9.2, 3.1 Hz, 1H), 2.26-2.21 (m, 1H), 2.12-
2.04 (m, 1H), 1.95-1.78 (m, 3H), 1.76-1.68 (m, 1H), 1.18 (d, J
) 6.3 Hz, 3H), 1.15 (d, J ) 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 173.3, 168.3, 165.7, 151.2, 150.8, 138.2, 130.2, 122.8,
93.7, 79.8, 69.4, 63.0, 54.4, 52.9, 35.4, 27.7, 27.4, 21.8, 21.7; IR
(film) 3250, 1756, 1745, 1723, 1640, 1596 cm-1; HRMS (ESI)
m/z calcd for C19H25NaN3O6 (M + Na) 414.1641, found 414.1653.
Anal. Calcd for C19H25N3O6: C, 58.30; H, 6.44; N, 10.74. Found:
C, 58.17; H, 6.52; N, 10.61.
General Method B for Formation of Cycloadducts. 2-Benzoyl-
3-methoxy Hexahydrocyclopentapyrazole-3,6a-dicarboxylic Acid
6a-Isopropyl Ester 3-Methyl Ester (41). A solution of hydrazone
19 (11 mg, 0.03 mmol) in CH2Cl2 (1.0 mL) was added in one
portion to a flask containing solid iron(III) chloride (4.6 mg, 0.03
mmol), and the resulting yellow-green solution was maintained at
room temperature for 45 min. The solution was directly loaded onto
silica gel and purified by flash chromatography (20% EtOAc/
hexanes) to give 9.8 mg (88%) of cycloadduct 41 as a clear glaze:
1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J ) 6.1, 1.5 Hz, 2H),
7.47-7.27 (m, 3H), 5.08 (sept, J ) 6.3 Hz, 1H), 4.26 (s, 3H), 3.78
(s, 3H), 3.54 (dd, J ) 9.2, 3.0 Hz, 3H), 2.26-2.21 (m, 1H), 2.08-
2.01 (m, 1H), 1.92-1.66 (m, 4H), 1.21 (d, J ) 6.3 Hz, 3H), 1.17
(d, J ) 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 168.6,
168.0, 134.0, 131.2, 129.9, 127.7, 93.5, 79.7, 69.2, 62.7, 54.2, 52.9,
35.6, 27.7, 27.4, 21.8, 21.7; IR (film) 3256, 1756, 1745, 1719, 1637,
1448, 1384 cm-1; HRMS (ESI) m/z calcd for C20H26NaN2O6 (M
+ Na) 413.1689, found 413.1671. Anal. Calcd for C20H26N2O6:
C, 61.53; H, 6.71; N, 7.18. Found: C, 61.44; H, 6.67; N, 7.05.
General Method C for Formation of Cycloadducts. 2-Ben-
zoyl-3-methoxy Hexahydrocyclopentapyrazole-3,6a-dicarboxylic
Acid Dimethyl Ester (45). Following the previously described
procedure to prepare R-ketoester 17, enoxysilane 13 (52 mg, 0.15
mmol) gave 40 mg (99%) of R-ketoester 17 as a clear glaze. Next,
a solution of R-ketoester 17 (40 mg, 0.15 mmol) and benzoic
Considerable variation in the dipolarophile fragment of the
intramolecular cycloaddition precursors examined in this study
was tolerated. Substrates containing electron-donating or electron-
withdrawing groups at the alkene terminus underwent intramo-
lecular dipolar cycloaddition efficiently. However, analogous
substrates containing a terminal vinyl substituent were converted
only slowly to cyclopentapyrazolidines. As HOMO and LUMO
energies of azomethine imines and alkenes are fairly similar,31
either raising the alkene HOMO or lowering the alkene LUMO
could increase reaction rate by decreasing the HOMO-LUMO
gap between the reacting partners. Such a trend would be
consistent with perturbation theory calculations reported previ-
ously by Houk and co-workers.32
The synthetic value of 1,3-dipolar cycloaddition reactions is
directly linked to the ability to predict the reactivity and the
regiochemical and stereochemical outcome of these transforma-
tions. The regiochemistry of the intramolecular azomethine
imine cycloaddition reactions studied here is dictated by the
three-carbon tether, which favors the formation of only
diazabicyclo[3.3.0]octane products.33 The high stereoselectivity
seen in these cycloadditions is consistent with cycloadditions
proceeding by chairlike transition structure 64, which allows
favorable overlap between the π orbitals of the dipole and
dipolarophile (eq 12).
(31) Sustmann, R. Pure Appl. Chem. 1974, 40, 569-593.
(32) (a) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George,
J. K. J. Am. Chem. Soc. 1973, 95, 7287-7301. (b) Houk, K. N.; Sims, J.;
Watts, C. R.; Kuskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301-7315.
(33) Although bicyclo[3.3.0]octane ring systems are generally observed
in intermolecular dipolar cycloadditions in which a dipole is connected to
an alkene through a three-carbon tether, bicyclo[3.2.1]octane ring systems
have been observed, see: Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem.
2003, 7, 585-628.
(34) All cycloaddition reactions were performed in thick-walled sealed
tubes for reaction volumes greater than 2 mL and in screw-cap vials with
Teflon caps for reaction volumes of 2 mL or less. Other general experimental
details have been described: MacMillan, D. W. C.; Overman, L. E.;
Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033-9044.
Conclusions
Intramolecular dipolar cycloaddition reactions of azomethine
imines derived from the condensation of hydrazines bearing an
electron-withdrawing substituent and R-ketoesters, R-ketoam-
ides, and R-ketothioesters provide access to a wide variety of
J. Org. Chem, Vol. 71, No. 24, 2006 9151

Gergely et al.
hydrazide (22 mg, 0.16 mmol) in EtOH (2.9 mL) was maintained
at 100 °C for 18 h. The reaction was cooled and concentrated in
vacuo, and the resulting light yellow oil was further purified by
silica gel chromatography (20% EtOAc/hexanes) to give 43 mg
(82%) of cycloadduct 45 as a clear glaze: 1H NMR (500 MHz,
CDCl3) δ 7.95 (dt, J ) 7.0, 1.6 Hz, 2H), 7.47 (tt, J ) 7.2, 1.4 Hz,
1H), 7.41 (app t, J ) 7.0 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.59
(s, 3H), 3.56 (dd, J ) 9.1, 3.5 Hz, 1H), 2.26-2.20 (m, 1H), 2.09-
2.02 (m, 1H), 1.94-1.70 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
174.5, 168.8, 168.6, 134.5, 131.0, 129.2, 127.8, 93.6, 79.6, 62.9,
54.3, 53.0, 52.7, 35.6, 29.9, 27.6, 27.3; IR (film) 3252, 1750, 1735,
1642, 1448 cm-1; HRMS (ESI) m/z calcd for C18H22NaN2O6 (M
+ Na) 385.1375, found 385.1372. Anal. Calcd for C18H22N2O6:
C, 59.66; H, 6.12; N, 7.73. Found: C, 59.66; H, 6.03; N, 7.68.
General Method D for Formation of Cycloadducts. 3-Ethyl-
6a-methyl-2-benzoyloctahydrocyclopenta[c]pyrazole-3,6a-dicar-
boxylate (50). A solution of hydrazone 34 (6.9 mg, 0.02 mmol) in
sec-butanol (0.2 mL) was heated at 100 °C for 24 h under an inert
173.8, 170.7, 156.3 (br), 136.3, 128.5, 128.4, 128.2, 77.3, 67.9,
67.0, 61.7, 57.1, 52.9, 38.1, 33.4, 26.6, 14.1; IR (film) 2958, 1733,
1698, 1456, 1395, 1288, 1199 cm-1; HRMS (ESI) m/z calcd for
C19H24NaN2O6 (M + Na)+ 399.1532, found 399.1540.
General Method F for Formation of Cycloadducts. 2-Benzyl-
6a-methyl-3-(ethylthiocarbonyl)hexahydrocyclopenta[c]pyrazole-
2,6a(1H)-dicarboxylate (57). Following the procedure to prepare
33, enoxysilane 30 (0.2 mmol) was converted to the corresponding
R-ketoester. A suspension of crude R-keto ester, benzyl carbazate
(40 mg, 0.24 mmol), and pyridinium p-toluenesulfonic acid (2.5
mg, 0.01 mmol) in toluene (0.8 mL) was then heated at 115 °C for
24 h under an inert atmosphere. Solvent was then removed in vacuo,
and the residue was purified by silica gel chromatography (3:1
hexanes/ethyl acetate) to give 58 mg (74%) of 57 as a clear oil:
1H NMR (500 MHz, CDCl3 @ 328 K) δ 7.42-7.27 (m, 5H), 5.37
(s, 1H), 5.25 (d, J ) 24.0 Hz, 1H), 5.23 (d, J ) 24.0 Hz, 1H), 4.67
(br s, 1H), 3.74 (s, 3H), 3.20 (ddd, J ) 8.1, 5.0, 1.9 Hz, 1H), 2.90-
2.81 (m, 2H), 2.32-2.24 (m, 1H), 2.15-2.05 (m, 1H), 1.79-1.55
(m, 4H), 1.24 (t, J ) 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
199.6, 173.8, 157.0 (br), 136.1, 128.5, 128.3, 128.2, 74.4, 68.2,
56.8, 52.9, 38.1, 33.2, 29.7, 26.5, 23.4, 14.4; IR (film) 2960, 1734,
1685, 1466, 1388, 1298, 1113 cm-1; HRMS (ESI) m/z calcd for
C19H24NaN2O5S (M + Na)+ 415.1304, found 415.1313.
1
atmosphere. The solvent was then removed in vacuo. H NMR of
the residue indicated complete conversion to cyclopentapyrazolidine
50: 1H NMR (500 MHz, CDCl3) δ 7.87-7.74 (m, 2H), 7.47-
7.36 (m, 3H), 5.64 (br s, 1H), 5.12 (br s, 1H), 4.29-4.18 (m, 2H),
3.75 (s, 3H), 3.08 (br s, 1H), 2.30-2.12 (m, 2H), 1.82-1.72 (m,
3H), 1.63-1.53 (m, 1H), 1.30 (t, J ) 7.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 173.7, 170.6, 170.2, 134.2, 130.7, 129.2, 127.6,
65.0, 61.6, 56.5, 52.8, 37.2, 33.4, 29.6, 26.5, 14.1; IR (film) 3272,
2960, 1734, 1647, 1447, 1388, 1283, 1198 cm-1; HRMS (ESI) m/z
calcd for C18H22NaN2O5 (M + Na)+ 369.1426, found 369.1424.
General Method E for Formation of Cycloadducts. 2-Benzyl-
3-ethyl-6a-methylhexahydrocyclopenta[c]pyrazole-2,3,6a(1H)-
tricarboxylate (51). A suspension of R-keto ester 33 (39 mg, 0.17
mmol), benzyl carbazate (34 mg, 0.20 mmol), and pyridinium
p-toluenesulfonic acid (2.1 mg, 0.0085 mmol) in toluene (0.68 mL)
was heated at 115 °C for 24 h under an inert atmosphere. After
this time, the solvent was removed by rotary evaporation. The
residue was purified by silica gel chromatography (2:1 hexanes/
ethyl acetate) to give 55 mg (85%) of 51 as a clear oil: 1H NMR
(500 MHz, CDCl3 @ 348 K) δ 7.40-7.27 (m, 5H), 5.41 (br s,
1H), 5.23 (d, J ) 20.0 Hz, 1H), 5.20 (d, J ) 20.0 Hz, 1H), 4.58
(d, J ) 1.5 Hz, 1H), 4.23-4.13 (m, 2H), 3.76 (s, 3H), 3.09 (ddd,
J ) 8.0, 4.5, 2.0 Hz, 1H), 2.30 (dt, J ) 13.0, 6.5 Hz, 1H), 2.18-
2.09 (m, 1H), 1.86-1.78 (m, 1H), 1.78-1.70 (m, 2H), 1.70-1.60
(m, 1H), 1.25 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
Acknowledgment. Financial support from the NIH Heart,
Lung, and Blood Institute (HL-25854), postdoctoral fellowship
support for J.B.M. (GM073312) from NIGMS, and support from
Amgen, Merck, Pfizer, and Roche Palo Alto are gratefully
acknowledged. We thank Joseph Ziller for single-crystal X-ray
analyses, and John Greaves for mass spectrometric analyses.
NMR, mass spectra, and X-ray analyses were determined at UC
Irvine with instruments purchased with the assistance of NSF
and NIH.
Supporting Information Available: Experimental procedures
and tabulated characterization data for new compounds not reported
in the Experimental Section, X-ray models of compounds 34, 35a,
and 60, copies of 1H and 13C NMR spectra for all new compounds,
and X-ray crystallographic files (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061537J
9152 J. Org. Chem., Vol. 71, No. 24, 2006