1,4-Addition of chiral 2-propenylphosphonamide anions to α-substituted cyclopentenones: Use in enantioselective syntheses of methyl dihydrojasmonates and methyl jasmonates

Article abstract of DOI:10.1016/S0040-4039(01)01437-X

The addition of chiral 2-propenylphosphonamide anions, generated from the reaction products of (1R,2S)-ephedrine and 2-propene-1-phosphonyl dichloride, to α-substituted cyclopentenones is described. Ozonolysis of the addition products led to the synthesis of both enantiomers of methyl dihydrojasmonate and methyl jasmonate.

Full text of DOI:10.1016/S0040-4039(01)01437-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7325–7328
1,4-Addition of chiral 2-propenylphosphonamide anions to
a-substituted cyclopentenones: use in enantioselective syntheses of
methyl dihydrojasmonates and methyl jasmonates
Helen C. Hailes,a,* Ben Isaacb and M. Hashim Javaida
aDepartment of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK
bBush Boake Allen Ltd., Blackhorse Lane, London E17 5QP, UK
Received 2 July 2001; revised 25 July 2001; accepted 3 August 2001
Abstract—The addition of chiral 2-propenylphosphonamide anions, generated from the reaction products of (1R,2S)-ephedrine
and 2-propene-1-phosphonyl dichloride, to a-substituted cyclopentenones is described. Ozonolysis of the addition products led to
the synthesis of both enantiomers of methyl dihydrojasmonate and methyl jasmonate. © 2001 Elsevier Science Ltd. All rights
reserved.
The methyl jasmonates1 are key natural products occur-
ring in Jasminium grandiflorum L. and the blossoms of
many flowers, and are used widely in the formulation of
many perfumes. In addition, key biological roles have
been noted2 including roles in gene expression,3 odour
production4 and growth inhibition.5 The unnatural ana-
logue, methyl dihydrojasmonate possesses important
olfactory properties, biological activities have been
reported4 and it is a constituent of famous fragrances.6
Enantioselective syntheses of the dihydrojasmonates
(−)-1 and (+)-2 have been reported, for example using
solid–liquid asymmetric phase transfer catalysis where a
range of e.e.s was obtained depending on the phase
transfer catalyst and reaction conditions utilised.7 Syn-
theses of (−)-3 and (+)-4 have also been published
using, for example, bis(8-phenylmenthyl) malonate as
an enantiopure precursor which was converted into
cyclopropane intermediates,8 or the optically pure pre-
cursor cyclopent-2-ene-1,3-diol monoacetate and Mont-
forts et al. enantiodivergent alkylation route;9 however,
these syntheses are multistep and therefore low yielding
overall.
With the intense interest in these compounds and their
analogues, there is a continuing desire to develop ver-
satile, short, selective syntheses. We have recently inves-
tigated the 1,4-addition of chiral 2-propenylphos-
phonamide anions to a-substituted cyclopentenones
which highlighted their use in the synthesis of a,b-di-
substituted cyclopentanones. Herein, we report the
results of this investigation and demonstrate the effec-
tiveness of such a transformation in affording a direct
and flexible route to the jasmonates.
The conjugate addition of chiral phosphonamide
anions to a,b-unsaturated carbonyl compounds has
been reported by for example Haynes,10 Denmark who
used 1,3,2-oxazaphosphorane 2-oxides,11 Hanessian
who used C2-symmetrical phosphonamides12 and
Hua.13 Hua et al. have described the conjugate addition
of extended lithium anions of chiral phosphonamides to
2-cyclopentenone, 2-cyclohexenone and 2-cyclohep-
tenone leading to b-substituted acids and aldehydes in
28–98% e.e. (depending on the phosphonamide and
N-alkyl group used and the enone).13 Notably, the use
O
O
O
O
CO2Me
(-)-1
CO2Me
(+)-2
CO2Me
(-)-3
CO2Me
(+)-4
Keywords: flavours and fragrances; chiral propenylphosphonamides; ozonolysis.
* Corresponding author. Fax: +44 (0)20 7679 7463; e-mail: h.c.hailes@ucl.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01437-X

7326
H. C. Hailes et al. / Tetrahedron Letters 42 (2001) 7325–7328
of phosphonamides derived from (1R,2S)-ephedrine
(with an N-methyl group) led to the formation of
products in approximately 70% d.e. (from analysis of
the aldehydes, the ozonolysed compounds). However,
those prepared from (1R,2R)-norpseudoephedrine and
an N-ipropyl group led to excellent diastereoselectivities
with one of the diastereomeric phosphonamides but
much lower reaction selectivities with the other. We
rationalised that the introduction of an alkyl group at
the a-position on the enone system could enhance facial
stereodifferentiation, since chelation of the lithium ion
with the cyclopentenone is likely to be on the OꢀPꢁO
face of the phosphonamide due to the N-alkyl group
present. This could result in the formation of adducts in
overall higher diastereoselectivities and would also
provide rapid access to a,b-cyclopentanones.
5R)-3,4-dimethyl-5-phenyl-2-(2-propenyl)-1,3,2-oxaza-
phospholidin-2-one 6, were selected since high reaction
selectivities were sought when using both diastereoiso-
meric phosphonamides. These were prepared from 2-
propene-1-phosphonyl
dichloride
and
(1R,2S)-
ephedrine, as previously reported14 in a 1:1 ratio and
were readily separated by flash column chromatogra-
phy. Whilst in our studies both diastereoisomers were
required, a stereospecific synthesis of phosphonamides
has also been described.15 Deprotonation of the phos-
phorous template 5 using n-butyllithium at −78°C to
generate the anion and addition of 1 equivalent of
2-pentyl-2-cyclopenten-1-one led to the formation of 7
as the major addition product, together with a minor
diastereoisomer in a combined yield of 80% (Scheme 1
and Table 1). The relative configuration of 7 was
determined by correlation to the final product.
Attempts to separate the isomeric products were not
successful. The use of template 6 led to the formation
of 8 and a minor diastereoisomer in 86% yield.
Our initial studies focused on the use of the enone,
2-pentyl-2-cyclopenten-1-one. The chiral phospho-
namides
(2R,4S,5R)-3,4-dimethyl-5-phenyl-2-(2-pro-
and (2S,4S,
penyl)-1,3,2-oxazaphospholidin-2-one
5
1. n-BuLi, THF, -78 oC
O
O
O
2.
Ph
Me
Ph
Me
Ph
Me
O
O
N
Me
O
O
O
N
Me
+
O
N
P
P
P
Me
minor diastereoisomer
80%
5
7
Scheme 1.
Table 1. Selectivities observed for addition of phosphonamide anions to a-substituted cyclopentenones

H. C. Hailes et al. / Tetrahedron Letters 42 (2001) 7325–7328
7327
favoured
Li
Ph
Me
O
O
O
O
N
Me
Ph
Me
O
O
N
Me
P
P
si face
9-major product
Li
Ph
Me
disfavoured
O
O
O
N
Me
O
Ph
Me
P
O
O
N
Me
P
minor product
Figure 1.
O
O
Ozone, -78 oC, CH2Cl2
Ph
Me
O
2.5.M NaOH in MeOH
O
N
Me
91% e.e.
P
CO2Me
60%
(-)-1
7
O
1. Ozone, -78 oC, CH2Cl2
O
90% e.e.
Ph
Me
2.5.M NaOH in MeOH, 40%
O
CO2Me
(-)-3
O
N
Me
P
2. H2, Lindlar catalyst, 92%
9
Scheme 2.
from 7 (Scheme 2) and 2 in 57% yield from 8. The
optical purity of the products 1 and 2 was shown to be
91 and 85% e.e., respectively, using chiral HPLC.19
2-(2-Pentynyl)-2-cyclopenten-1-one was prepared as
previously reported.16 Reaction of the extended eno-
lates generated by the addition of n-butyllithium to 5
and 6 and the subsequent addition of 2-(2-pentynyl)-2-
cyclopenten-1-one led to the formation of 9 and 10,
together with minor diastereoisomers, in 76 and 83%
yield, respectively. The high reaction selectivities
observed, compared to those reported by Hua of
approximately 70% d.e., were consistent with the higher
facial stereodifferentiation due to the presence of an
alkyl chain at the a-position, as outlined in Fig. 1.
Oxidative cleavage of the phosphonamides 9 and 10
was less straightforward due to potential oxidation of
the alkyne moiety. Use of the azo-dye Sudan Red III20
indicated phosphonamide cleavage under reductive
ozonolysis conditions to give the corresponding alde-
hyde in 39% yield. However, Sudan III was observed to
be unstable under the conditions used above to gener-
ate 1 and 2. Therefore, to avoid the formation of
several over-oxidised products, the reaction was carried
out as before (Scheme 2) but was closely followed by
TLC analysis and rapidly quenched. The corresponding
methyl esters were then isolated in 39–40% yield and
subsequent Lindlar reduction afforded 3 and 4 in 92%
yield. Again HPLC analysis was used to indicate the
optical purity of 3 and 4 as 90 and 84% e.e.,
respectively.
Cleavage of the phosphonamide template from 7 and 8
using ozonolysis under oxidative conditions with
hydrogen peroxide generated a mixture of products.
However, under reductive conditions (dimethyl sulfide)
the corresponding aldehyde, 3-oxo-2-pentanylcyclo-
pentyl ethanal, was produced in 62% yield. Whilst a
stepwise oxidation of the aldehyde with subsequent
methyl ester formation was explored, it resulted in the
formation of 2 in only 20% yield from 8. A more direct
procedure was investigated, performing the ozonolysis
in a 2.5 M solution of sodium hydroxide in methanol,
together with dichloromethane as solvent.17,18 This
afforded (−)-methyl dihydrojasmonate 1 in 60% yield
In summary, we have demonstrated that the 1,4-addi-
tion of chiral 2-propenylphosphonamide anions to a-
substituted cyclopentenones can be achieved with high
diastereoselectivities. In addition, the reaction products

7328
H. C. Hailes et al. / Tetrahedron Letters 42 (2001) 7325–7328
can be readily converted using a one-step conversion to
(−)- and (+)-methyl dihydrojasmonate and a two-step
route to (−)- and (+)-methyl jasmonate.
10. Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P.
A.; Vonwiller, S. C. J. Am. Chem. Soc. 1988, 110, 5411–
5423.
11. Denmark, S. E.; Kim, J.-O. J. Org. Chem. 1995, 60,
7535–7547.
Acknowledgements
12. Hanessian, S.; Gomtsyan, A.; Malek, N. J. Org. Chem.
2000, 65, 5623–5631.
13. Hua, D. H.; Chan-Yu-King, R.; McKie, J. A.; Myer, L.
We thank Bush Boake Allen for a studentship (M.H.J.)
and John Janes for helpful discussions. The ULIRS
Mass Spectrometry Facility at the University of Lon-
don School of Pharmacy are acknowledged for high
resolution mass spectra.
J. Am. Chem. Soc. 1987, 109, 5026–5029.
14. Cooper, D. B.; Hall, C. R.; Harrison, J. M.; Inch, T. D.
J. Chem. Soc., Perkin Trans. 1 1977, 1969–1979.
15. Hua, D. H.; Chen, J. S.; Saha, S.; Wang, H.; Roche, D.;
Bharathi, S. N.; Chan-Yu-King, R.; Robinson, P. D.;
Iguchi, S. Synlett 1992, 817–820.
16. Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021–2023.
17. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58,
3675–3680.
References
1. Demole, E. P.; Lederer, E.; Mercier, D. Helv. Chim. Acta
1962, 45, 675–685.
18. Typical procedure: To a solution of the phosphonamide
(800 mg, 2.0 mmol) in CH2Cl2 was added a solution of
NaOH in MeOH (2.5 M NaOH, 4.1 ml). The reaction
temperature was decreased to −78°C and ozone bubbled
through the solution for ca. 40 min, after which nitrogen
was passed through the solution for 30 min. The product
was extracted with Et2O (4×50 ml), and the combined
organic extracts were dried and concentrated in vacuo to
afford a colourless oil which was purified by flash column
chromatography (eluent: hexane/EtOAc, 25:1) to yield 1
(0.27 g, 60%).
2. Beale, M. H.; Ward, J. L. Nat. Prod. Rep. 1998, 533–548.
3. Boland, W.; Hopke, J.; Donath, J.; Nu¨ske, J.; Bublitz, F.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1600–1602.
4. Miersch, O.; Kramell, R.; Parthier, B.; Wasternack, C.
Phytochemistry 1999, 50, 353–361.
5. Koda, Y.; Kikuta, Y.; Kitahara, T.; Nishi, T.; Mori, K.
Phytochemistry 1992, 31, 1111–1114.
6. Fra´ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998,
54, 7633–7703.
7. Perrard, T.; Plaquevent, J.-C.; Desmurs, J.-R.; He´brault,
D. Org. Lett. 2000, 2, 2959–2962.
8. Quinkert, G.; Adam, F.; Durner, G. Angew. Chem., Int.
19. Optical purities were monitored using HPLC (Chiralcel
OD, 250×4.6 mm, detection UV, u 226 nm) and con-
firmed using optical rotations, 1- [h]2D5 −48.2 (c 0.90
CHCl3), 2- [h]D25 +38.2 (c 0.48 CHCl3), 3- [h]2D5 −85.5 (c
1.5 MeOH), 4- [h]2D5 −80.5 (c 1.1 MeOH).
Ed. 1982, 21, 856–856.
9. Montforts, F.-P.; Gesling-Zibulak, I.; Grammenos, W.;
Schneider, M.; Laumen, K. Helv. Chim. Acta 1989, 72,
1852–1859.
20. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis
1980, 807–809.