Enamine catalysis in the synthesis of chiral structural analogues of gem-Bisphosphonates known to be biologically active

Article abstract of DOI:10.1002/ejoc.200800170

The synthesis of chiral γ-keto bisphosphonates is described. Michael addition of cyclic ketones to vinyl gem-bisphosphonate catalyzed by 0.1 molequiv. (S)-(+)-1-(2-pyrrolidinyl)-pyrrolidine and benzoic acid gave the products in yields of up to 86%, dr (cis/trans) > 1:99 and ee of up to 99%. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800170

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800170
Enamine Catalysis in the Synthesis of Chiral Structural Analogues of
gem-Bisphosphonates Known To Be Biologically Active
Maria Teresa Barros*[a] and Ana Maria Faísca Phillips*[a]
Keywords: gem-Bisphosphonates / Organocatalysis / Asymmetric synthesis / Michael addition / Ketones
The synthesis of chiral γ-keto bisphosphonates is described.
Michael addition of cyclic ketones to vinyl gem-bisphos-
phonate catalyzed by 0.1 molequiv. (S)-(+)-1-(2-pyrrolidinyl)-
pyrrolidine and benzoic acid gave the products in yields of
up to 86%, dr (cis/trans) Ͼ 1:99 and ee of up to 99%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Many gem-bisphosphonates, compounds with a P–C–P
linkage, are well known for their biological activity. The
most common ones are currently in clinical use for the pre-
vention and treatment of several bone disorders, such as
osteoporosis, Paget’s disease of the bone, bone metastasis
resulting from multiple myeloma or certain forms of cancer,
rheumatoid arthritis, periodontal disease and inflam-
mation.[1] Examples (A–C) are shown in Figure 1. In recent
years gem-bisphosphonates have become the subject of re-
newed attention, since it was discovered that some are po-
tent growth inhibitors of protozoa responsible for diseases
considered by the World Health Organization as major
tropical diseases.[2] These include Trypanosoma cruzi, the
pathogen that causes Chagas’ disease, T. brucei, which
causes sleeping sickness, and Plasmodium falciparum, re-
sponsible for malaria. A few attempts have been made to
discover molecular targets for drug design. Potential candi-
dates were found to be farnesyl diphosphate synthase[3] and
hexokinase.[4] The first is an enzyme that catalyzes the for-
mation of the precursor of farnesyl diphosphate, a molecule
involved in protein prenylation, and a precursor of sterols,
dolichols, ubiquinones and heme a. The second catalyzes
the first step in glycolysis. Both are strongly inhibited by
certain gem-bisphosphonates.
Figure 1. Examples of biologically active bisphosphonates.
new bisphosphonates is thus highly desirable. Asymmetric
methods could provide interesting candidates to interact
with chiral allosteric sites of proteins.
For some time we have been interested in novel methods
of synthesis mediated by organocatalysts.[6] This chemistry
has the advantage of being environmentally friendly, eco-
nomically attractive and mild conditions are generally re-
quired.[7] Recently we reported that simple piperazine and
some 2,5-disubstituted chiral derivatives catalyze the
Michael addition of unmodified aldehydes to nitroalkenes
in good yields of up to 88%.[6b] In asymmetric reactions
excellent dr values of up to 97:3 and high ee values of up
to 85% were obtained. Since the first reports on the enan-
tioselective Michael addition for C–C bond formation by
enamine catalysis in 2000,[8] many chiral organocatalysts
have been used. This subject was reviewed recently,[9] and
many acceptors may now be used (nitroalkenes, enones, vi-
nyl sulfones, alkylidene malonates, maleimides, α,β-unsatu-
rated aldehydes, imides, α-substituted vinyl cyanoacetates,
acetylenic esters), and there have even been very elegant
multicomponent domino (tandem, cascade) reactions in-
volving 1,4-conjugate additions.[10] The first reports on
In addition, it has been shown that some gem-bisphos-
phonates inhibit the growth of several cancer cell lines.[5]
The development of novel synthetic methods for existing or
[a] Department of Chemistry, CQFB – REQUIMTE, Faculdade
de Ciências e Tecnologia, Universidade Nova de Lisboa,
2829-516 Caparica, Portugal
Fax: +351-212948550
E-mail: mtbarros@dq.fct.unl.pt
amfp@dq.fct.unl.pt
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 2525–2529
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M. T. Barros, A. M. Faísca Phillips
SHORT COMMUNICATION
asymmetric organocatalytic Michael addition reactions to Table 1. Effect of solvents on the asymmetric Michael addition of
cyclohexanone to tetraethyl vinylidene bisphosphonate.[a]
vinyl bisphosphonate appeared very recently with alde-
hydes[11]and β-keto esters[12] as donors. Non-asymmetric
versions of additions to vinyl bisphosphonates were known,
with Grignard reagents,[13] organolithium compounds[3]
and carbanions generated with sodium ethoxide,[14] tertiary
amine,[15] lithium amide base[16] or inorganic base.[14] In this
paper we present a method for the synthesis of enantioen-
riched γ-keto bisphosphonates, which are chiral analogues
[b]
Entry
Solvent
Time [h] Conversion [%] ee [%]
of compounds known to have potent anti-arthritic and anti-
inflammatory activity[15,16] (D and E, Figure 1) by using en-
amine chemistry mediated by chiral diamines.
1
2
3
4
5
6
7
CH2Cl2
CH2ClCH2Cl
CHCl3
EtOH
DMF
[bmin]PF6
Brine
17
17
17
17
17
17
89
100
100
100
100
100
100
100
32
34
30
32
32
46
36
Results and Discussion
[a] Conditions: room temperature, bisphosphonate (1 m)/ketone/
catalyst 1:10:0.1. [b] Determined by 13C NMR spectroscopy with
(S,S)-2,3-butanediol.[19] The absolute configuration of the major
product is S.[19]
The vinyl bisphosphonate needed as starting material
was prepared from paraformaldehyde and commercially
available tetraethyl methylenediphosphonate according to a
literature procedure.[17] A simple cyclic ketone, cyclohexa-
none, was chosen initially for the development of the
method, and conditions often successful in other organoca-
talytic addition reactions were selected: 10-fold excess of
ketone to vinyl bisphosphonate and 10 mol-% catalyst.[9]
A few amines were evaluated as potential catalysts (Fig-
ure 2). Piperazine, which we found useful in the Michael
addition of aldehydes to β-nitroalkenes,[6b] gave no reaction,
and when used neat or in the presence of acids (pTsOH,
tartaric acid), neither did its N-methyl derivative II. The
same occurred with pyrrolidine derivative V. A commercially
available proline derivative, (S)-(+)-1-(2-pyrrolidininyl-
methyl)pyrrolidine, which has been very successful as an or-
ganocatalyst in several reactions, was tried next and led to a
Table 2. Effect of additives, temperature and catalyst load on the
Michael addition reaction.[a]
Entry Solvent
Additive
Time [h] Conversion [%] ee[b] [%]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
none
PhCOOH
LiCl
17
17
17
24
100
100
50
100
100
100
50
100
63
100
100
100
100
32
40
48
24
20
36
6
30
26
30
26
30
32
LiCl
CH3COOH 17
CF3COOH 17
pTsOH·H2O 40
PhCOOH
PhCOOH
LiCl
PhCOOH
PhCOOH
PhCOOH
8[c]
9[d]
10
17
168
17
17
17
17
smooth addition reaction.[7,18] The reaction conditions were 11
12
Toluene
CH2Cl2
then optimized, and the results are presented in Tables 1
13[e]
and 2. Generally asymmetric induction did not vary much
with a change in solvent. Even brine, an environmentally
benign reaction medium, well suited to large-scale applica-
tions, could be used. However, the reaction was particularly
slow, requiring 89 h for complete substrate conversion. LiCl
as additive gave one of the best results at t1/2, but some
racemization took place with time (Table 2, Entries 3, 4).
By lowering the temperature to 0 °C, the reaction was con-
siderably retarded (Entry 9). After 168 h, a conversion of
only 63% was obtained and there was no improvement in
the ee result. Increasing of the catalyst load to 20 mol-%
did not provide any advantage either. The best results were
obtained in [bmin]PF6 (ee 46%, Table 1).
[a] Conditions: room temperature, bisphosphonate (1 m)/ketone/
catalyst/additive 1:10:0.1:0.1. [b] Determined by 13C NMR spec-
troscopy with (S,S)-2,3-butanediol.[19] The absolute configuration
was found to be S.[19] [c] Reaction with 20 mol-% catalyst and addi-
tive. [d] Reaction at 0 °C. [e] Catalyst IV used instead.
However, in a few experiments, the reactions in DCM
with PhCOOH as additive gave better yields and only
slightly lower ee values; hence these conditions were used
afterwards. Diamine IV was also tried (Table 2, Entry 13),
but it provided no advantage over III.
With a catalyst and optimized reaction conditions, we
proceeded to explore the synthetic potential of the reaction,
trying other ketones as substrates (Table 3). The reactions
were very clean, and no ketone condensation products were
formed. Large differences in reactivity were observed as the
nature of the substrate was varied. 4-Substituted cycloalk-
anones reacted smoothly to give 2,4-disubstituted adducts
in high yields, very high dr (cis/trans Ͼ 1:99) values and
high ee (up to 99%) values. 2-Phenylcyclohexanone did not
react in CH2Cl2 with PhCOOH. The reaction was possible
Figure 2. Catalysts screened during the optimization.
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Enamine Catalysis in the Synthesis of Analogues of gem-Bisphosphonates
Table 3. Asymmetric synthesis of carbonyl-containing gem-bisphosphonates by Michael addition catalyzed by III.[a]
[a] Conditions: room temperature, bisphosphonate (1 m)/ketone/catalyst/PhCOOH 1:10:0.1:0.1. [b] After isolation by column
chromatography. [c] Determined by 31P NMR spectroscopy. [d] Determined by 13C NMR spectroscopy (Entry 1),[19,20] or by chiral HPLC
neat or after conversion into 2,4-dinitrophenylhydrazones (Entries 2, 5).[21] [e] Reaction in [bmin]PF6, conversion shown. [f] Determined
by NMR spectroscopy. The HPLC traces of the 2,4-dinitrophenylhydrazones show the presence of a 9% meso cis-disubstituted product,
which is not observed by NMR spectroscopy; hence this is probably the result of isomerization during derivatization.
in [bmin]PF6, but with a conversion of only 80% after 7 d stituted. The cyclopentanone obtained is chiral and shows
(Entry 4) and 20% of an unknown additional product. a high optical rotation in CHCl3. It is therefore trans-disub-
Product 6 was racemic.
stituted, with C2-symmetry. A cis-disubstituted compound
Cyclopentanone was very reactive. A 10-fold excess of would be meso and optically inactive. Some problems were
ketone gave full substrate conversion within 1.5 h. However, encountered during the chromatographic purification of
a 6:94 mixture of 2-mono- and 2,5-disubstituted cyclo- this compound. It seemed to be sensitive to silica gel, but
pentanone was formed. With a 1:1 ratio of ketone to bis- could be isolated if chromatographed fast on a small col-
phosphonate, a conversion of 60% was obtained after 1 h, umn. Perhaps a retro Michael reaction causes decomposi-
and the mono- and disubstituted ketones were formed in a tion. We are continuing our work in this area. The result
similar ratio. Thus, either the 2-monosubstituted cyclo- obtained suggests, however, that this methodology could
pentanone is more reactive towards the catalyst than the provide a useful approach to chiral 2,5-disubstituted cyclo-
unsubstituted ketone or an enamine intermediate reacts pentanones, for which only a few methods are available at
with the vinyl phosphonate to produce an iminium salt that present.[22]
is so reactive that after protonation it is deprotonated again
A linear ketone was also tried as a Michael donor but
to form a new enamine, before hydrolysis takes place. Hence there was no reaction even after 6 d. With a β-keto ester,
there is a second addition, and the product is mostly disub- addition product 9, which is known to be biologically
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M. T. Barros, A. M. Faísca Phillips
SHORT COMMUNICATION
Figure 3. Proposed facial selectivity for the transition state.
active,[15] was formed smoothly in good yield, but unfortu- K, where both the pyrrolidine ring of the preformed en-
nately it was racemic. The addition reaction also proceeded amine and the 4-methyl substituent have the thermodynami-
with a β-ketophosphonate,[23] but the triphosphonate pro- cally more stable equatorial orientation to minimize 1,3-al-
duced was also racemic.
lylic strain and 1,3-diaxial interactions (Figure 4). This
The stereochemistry of the products was analyzed. The agrees with existing knowledge on reactions of pyrrolidine
absolute configuration at position 2 of cyclic ketone 3 was enamines of 1,4-disubstituted cyclohexanones.[26] These re-
determined from the 13C NMR spectrum of the dia- sults provide further evidence supporting the current wave
stereomeric acetals formed with (2S,3S)-2,3-butanediol.[19] of thought that in organocatalytic reactions mediated by
Hence, the set of more intense signals in the spectrum, i.e. chiral amines, enamines are involved as intermediates.
those of the major diastereomeric acetal, corresponds to
Racemic mixtures were prepared for HPLC or NMR
the model for the 2R diastereoisomer of a cyclohexanone spectroscopy by the known DBU-mediated Michael ad-
derivative substituted at position 2 after derivatization with dition.[14] In these reactions, which proceed via intermediate
(2R,3R)-2,3-butanediol. The model in our case, according enolates, thermodynamically more stable cis-2,4-cyclohexa-
to CIP mIes, is that used for 2-benzylcyclohexanone. There- nones were formed. Probably, as a result of strong coordi-
fore, the configuration of the major enantiomer of product nation between the charged groups, equatorial attack takes
3 is 2S, since a (2S,3S)-2,3-butanediol derivative was used place to give a product with the opposite configuration, or
for our study. This absolute configuration is consistent with there is some proton transfer (enolate equilibration) during
the preferential formation of an anti enamine (Figure 3) in the reaction. Chiral and racemic 2,5-cyclohexanones have
which the double bond is oriented away from the bulky sub- the same trans configuration, as determined by a NOESY
stituent at position 2 of the pyrrolidine ring. Enamine ap- experiment,[27] which agrees with the existing knowledge on
proach from the Re face gives a tight acyclic synclinal tran- enamine and enolate reactions.
sition state G, which is stabilized by electrostatic interac-
tions between the partially positive nitrogen atom of the
enamine, the negatively charged oxygen atom of the phos-
Conclusions
phonate group, and the protonated nitrogen atom on the
We have developed a highly diastereo- and enantioselec-
second ring. This is in agreement with that generally ob- tive method to synthesize cyclic γ-keto gem-bisphosphon-
served in Michael addition reactions of ketones catalyzed ates, which are chiral structural analogues of biologically
by pyrrolidines: the configuration of the transition state de- active compounds. The values obtained for ee and dr are
pends on the functionality at position 2 of the pyrrolidine up to 99% and (cis/trans) Ͼ 1:99, respectively. With cyclo-
ring.[7f,9c,24] With catalyst protonation, hydrogen bonding in hexanone and its derivatives, monoalkylated products were
the transition state favours the anti enamine. In aprotic me- obtained, whereas with cyclopentanone, an unexpected re-
dia, our products also have a 2S configuration. Presumably, action occurred and a C2-symmetric disubstituted product
under these conditions, the nitrogen atom on the second formed preferentially. Hence this method could be useful
ring stabilizes the positively charged phosphorus atom in for the synthesis of other chiral C2-symmetric 2,5-disubsti-
transition state I.
tuted cyclopentanones for which there are not many meth-
The relative configuration of 4 was determined to be ods of synthesis available at present. With propiophenone
trans on the basis of a NOESY experiment.[25] This implies no adduct was obtained. Our studies in this area are contin-
an axial approach of the electrophile to cyclohexenyl ring uing.
Figure 4. Conformational preference for product formation.
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Enamine Catalysis in the Synthesis of Analogues of gem-Bisphosphonates
[8]
S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975–2978.
For recent reviews on organocatalytic asymmetric conjugate
addition reactions see: a) O. M. Berner, L. Tedeschi, D. Enders,
Eur. J. Org. Chem. 2002, 12, 1877–1894; b) S. B. Tsogoeva, Eur.
J. Org. Chem. 2007, 11, 1701–1716; c) D. Almasi, D. A. Alonso,
C. Nájera, Tetrahedron: Asymmetry 2007, 18, 299–365; d) S.
Sulzer-Mossé, A. Alexakis, Chem. Commun. 2007, 3123–3135;
e) J. L. Vicario, D. Badía, L. Carrillo, Synthesis 2007, 14, 2065–
2092.
C. J. Chapman, C. G. Frost, Synthesis 2007, 1, 1–21.
S. Sulzer-Mossé, M. Tissot, A. Alexakis, Org. Lett. 2007, 9,
3749–3752.
M. Capuzzi, D. Perdicchia, K. A. Jørgensen, Chem. Eur. J.
2008, 14, 128–135.
Experimental Section
[9]
General Procedure for the Asymmetric Catalytic Michael Addition
Reaction: To vinyl gem-bisphosphonate (1.0 mmol) in dry dichloro-
methane (0.1 mL) was added the ketone (10.0 mmol), (S)-(+)-1-(2-
pyrrolidinylmethyl)pyrrolidine (0.1 mmol) and benzoic acid
(0.1 mmol). The solution was stirred at room temperature, under
argon, for the times specified. The reaction was then quenched with
a concentrated solution of ammonium chloride, and the products
[10]
extracted with dichloromethane. The extracts were dried with anhy-
[11]
drous sodium sulfate, and the solvent was evaporated by a rotary
evaporator to give the product, which was purified by column
chromatography on silica gel.
[12]
[13]
M. L. Lolli, L. Lazzarato, A. DiStilo, R. Fruttero, A. Gasco,
J. Organomet. Chem. 2002, 650, 77–83.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data for the new
compounds, selected NMR spectra and HPLC traces, are provided.
[14]
[15]
G. Sturtz, J. Guervenou, Synthesis 1991, 661–662.
R. A. Nugent, S. T. Schlachter, M. Murphy, C. J. Dunn, N. D.
Staite, N. A. Galinet, S. K. Shields, H. Wu, D. G. Aspar, K. A.
Richard, J. Med. Chem. 1994, 37, 4449–4454.
S. T. Schlachter, L. A. Galinet, S. K. Shields, D. G. Aspar, C. J.
Dunn, N. D. Staite, R. A. Nugent, Bioorg. Med. Chem. Lett.
1998, 8, 1093–1096.
C. R. Degenhardt, D. C. Burdsall, J. Org. Chem. 1986, 51,
3488–3490.
For a first report on the use of this compound as an organocat-
alyst see S. Saito, M. Nakadai, H. Yamamoto, Synlett 2001,
1245–1248.
Acknowledgments
[16]
A. M. Faísca Phillips thanks the Fundação para a Ciência e Tecno-
logia, MCTES (SFRH/BCC/15809/2206) for financial support.
[17]
[18]
[1] a) G. A. Rodan, Annu. Rev. Pharmacol. Toxicol. 1998, 38, 375–
388; b) G. A. Rodan, T. J. Martin, Science 2000, 289, 1508–
1514.
[2] a) J. A. Urbina, B. Moreno, S. Vierkotter, E. Oldfield, G. Pay-
ares, C. Sanoja, B. N. Bailey, W. Yan, D. A. Scott, S. N. J. Mor-
eno, R. Docampo, J. Biol. Chem. 1999, 274, 33609–33615; b)
M. B. Martin, J. S. Grimley, J. C. Lewis, H. T. Heath III, B. N.
Bailey, H. Hendrick, V. Yardley, A. Caldera, R. Lira, J. A. Ur-
bina, S. N. J. Moreno, R. Docampo, S. L. Croft, E. Oldfield, J.
Med. Chem. 2001, 44, 909–916; c) M. B. Martin, J. M. Sanders,
H. Kendrick, K. de Luca-Fradley, J. C. Lewis, J. S. Grimley,
E. M. van Bussel, J. R. Olsen, G. A. Meints, A. Burzynska, P.
Kafarski, S. L. Croft, E. Oldfield, J. Med. Chem. 2002, 45,
2904–2916.
[3] S. H. Szajnman, A. Montalvetti, Y. Wong, R. Docampo, J. B.
Rodriguez, Bioorg. Med. Chem. Lett. 2003, 13, 3231–3235.
[4] M. P. Hudock, C. E. Sanz-Rodríguez, Y. Song, J. M. W. Chan,
Y. Zhang, S. Odeh, T. Kosztowski, A. Leon-Rossell, J. L. Con-
cepción, V. Yardley, S. L. Croft, J. A. Urbina, E. Oldfield, J.
Med. Chem. 2006, 49, 215–223.
[5] Y. Zhang, A. Leon, Y. Song, D. Studer, C. Haase, L. A. Kosci-
elski, E. J. Oldfield, J. Med. Chem. 2006, 49, 5804–5814.
[6] a) M. T. Barros, A. M. Faísca Phillips, Molecules 2006, 11,
177–196; b) M. T. Barros, A. M. Faísca Phillips, Eur. J. Org.
Chem. 2007, 178–185.
[7] For recent reviews on organocatalysis see, for example a) W.
Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37,
580–591; b) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed.
2004, 43, 5138–5175; c) C. Bolm, I. Schiffers, L. Zani, Angew.
Chem. Int. Ed. 2005, 44, 1758–1763; d) J. Seayad, B. List, Org.
Biomol. Chem. 2005, 3, 719–724; e) G. Guillena, D. J. Ramón,
Tetrahedron: Asymmetry 2006, 17, 1465–1492; f) B. List, Chem.
Commun. 2006, 819–829; g) S. Mukherjee, J. W. Yang, S.
Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569.
[19]
a) H. Hiemstra, H. Wynberg, Tetrahedron Lett. 1977, 18, 2183–
2186; b) G. L. Lemière, R. A. Dommisse, J. A. Lepoivre, F. C.
Alderweireldt, H. Hiemstra, H. Wynberg, J. B. Jones, E. J.
Toone, J. Am. Chem. Soc. 1987, 109, 1363–1370.
The 2-configuration of 4–7 was assumed to be the same as that
of 3, since a similar reaction mechanism is involved.
a) Y. Kawai, M. Hayashi, N. Tokitoh, Tetrahedron Lett. 2002,
43, 465–467; b) A. Hall, L. D. Harris, C. L. Jones, Tetrahedron
Lett. 2003, 44, 111–114; c) Y. Kawai, M. Hayashi, N. Tokitoh,
Tetrahedron 2005, 61, 5049–5055.
N. T. Reynolds, T. Rovis, Tetrahedron 2005, 61, 6368–6378.
a) I. J. Borowitz, M. Anschel, S. J. Firstenberg, Org. Chem.
1967, 5, 1723–1729; b) F. Mathey, P. H. Savignac, Tetrahedron
1978, 34, 649–654.
a) D. Seebach, J. Golinski, Helv. Chim. Acta 1981, 64, 1413–
1423; b) S. J. Blarer, W. B. Schweizer, D. Seebach, Helv. Chim.
Acta 1982, 65, 1637–1654.
A 2D-NOESY experiment of 4 showed a cross peak between
a multiplet at 2.89–3.01 ppm (H-1Ј) and a doublet at δ =
1.26 ppm (C5Ј–CH3), which indicates that these protons have
a syn relationship, which establishes the configuration of the
major product as trans.
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
For cis–trans equilibration in 2,x-disubstituted cyclohexanones
see, for instance, F. Johnson, L. G. Duquette, A. Whitehead,
L. C. Dorman, Tetrahedron 1974, 30, 3241–3251.
The absence of a cross peak between the multiplets at 2.78–
2.91 ppm (H-1Ј) and 3.36–3.50 ppm (H-3Ј) shows a trans rela-
tionship.
Received: February 12, 2008
Published Online: April 15, 2008
Eur. J. Org. Chem. 2008, 2525–2529
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