Synthesis of alkylated iridolactone analogs

Article abstract of DOI:10.1016/S0040-4039(03)01320-0

Bicyclic δ-lactones, iridolactones analogs with an alkyl group at the bicyclic junction, are obtained from α-alkyl-α-hydroxymethylcyclopentanones via an intramolecular Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1016/S0040-4039(03)01320-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5727–5730
Synthesis of alkylated iridolactone analogs
Zineb Guerrab,a,b Boujemaaˆ Daou,a Souad Fkih-Tetouani,a Mohammed Ahmarb and
Bernard Cazesb,*
aUniversite´ Mohammed V-Agdal, Laboratoire de Chimie des Plantes et de Synthe`se Organique et Bioorganique, Av. Ibn
Battouta, BP 1014 Rabat, Morocco
bUniversite´ Claude Bernard-Lyon, Laboratoire de Chimie Organique I, associe´ au CNRS, Baˆt. CPE-Lyon, 43 Bd du 11
Novembre 1918, 69622 Villeurbanne, France
Received 22 May 2003; accepted 26 May 2003
Abstract—Bicyclic d-lactones, iridolactones analogs with an alkyl group at the bicyclic junction, are obtained from a-alkyl-a-
hydroxymethylcyclopentanones via an intramolecular Horner–Wadsworth–Emmons reaction.
© 2003 Elsevier Ltd. All rights reserved.
Iridoids are important monoterpene natural products
which are characterized by a functionalized cis-fused
cyclopenta[c]pyran skeleton I.1 A large part of these
compounds present a b-non reducing link to a sugar
unit at C1 and a double bond at C3ꢀC4 (Scheme 1). A
sub-class of non-glycosidic iridoids, referred to as iri-
doid lactones II, is composed of cyclopentanoid com-
pounds fused to a d-lactone unit.2 These bicyclic
lactones are further divided in two sub-groups IIa,b
according to the position of the lactone keto group.
Scheme 2.
Particularly, iridomyrmecin (+)-1—the first isolated and
identified iridoid compound isolated from Iridomyrmex
humilis ants—belongs to sub-group IIa.3
We recently undertook a project aimed at synthesizing
new unsaturated III and saturated analogs IV of iri-
dolactone IIa with an alkyl group at the bicyclic junc-
tion, and report herein our approach from
a-alkyl-a-hydroxymethylcyclopentanones 8 using an
intramolecular Horner–Wadsworth–Emmons reaction
(Scheme 3).7
Scheme 1.
Iridoids have significant biological activities ranging
from sedative to antimicrobial or antileukemic effects.4
To the best of our knowledge, naturally occuring com-
pounds with a substituent at the bicyclic junction of an
3-oxa-bicyclo[4.3.0]nonane core are scarce. Diterpenes
xestolide 2 and guyanin 3 present such bicyclic struc-
tures (Scheme 2).5,6
Scheme 3.
The precursor b-ketoalcohols 8a,b and 8c–e were,
respectively, prepared according to two sequences
depicted in Scheme 4. The first one made use of the
reduction of the ethyleneketals 6 of b-ketoesters 5.8
* Corresponding author. Fax: +33.4.72.43.12.14; e-mail: cazes@
univ-lyon1.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01320-0

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Z. Guerrab et al. / Tetrahedron Letters 44 (2003) 5727–5730
Scheme 4. Reagents and conditions: (a) K2CO3, R-Br, acetone, rt, 24 h (88–93%); (b) glycol, cat. p-TsOH, toluene/Dean–Stark
(90%); (c) AlLiH4, ether, 0°C, 1 h; (d) cat. 6N HCl, THF, rt, 6 h (88–93%); (e) H2O2/NaOH, EtOH, 0–20°C (79–85%); (f)
BF3–Et2O (0.75 equiv.), CH2Cl2, 0°C (50–77%); (g) LiAlH(O-tBu)3 (1 equiv.) [AlLiH4, 3 equiv. t-BuOH, Et2O, −40°C, 4 h], Et2O,
−78°C, 1–3 h (52–78%).
This standard procedure was preferred to the more
direct selective reduction of b-ketoesters 5 via enolate
protection,9 which in our hands also gave some diols
9.
The second sequence involved the well documented
Lewis acid-mediated rearrangement of epoxycyclo-
hexenones 11 to b-ketoaldehydes 12,10 followed by
the chemoselective reduction of the formyl group by
lithium tri-ter-butoxyaluminum hydride11 according to
Welzel et al.10c,12 This second route was realized from
commercially available substituted 3-methylcyclo-
Scheme 5.
hexenones such as isophorone 10e. It advantageously
allowed the synthesis of polysubstituted b-ketoalco-
easily realized by their DMAP-catalyzed esterification
hols 8. It is worth noting that b-ketoaldehyde 12d
in the presence of dicyclohexylcarbodiimide DCC.13
was obtained as
a
80:20 mixture of trans–cis
diastereomers as already described.10d Consequently,
its reduction gave the b-ketoalcohol 8d with the same
diastereomeric 80:20 ratio (Schemes 4–6 show only
the major trans diastereomer with the two methyl
groups in trans position).
The intramolecular Horner–Wadsworth–Emmons reac-
tion then occurred by treatment of phosphonoacetates
13a–e with LiBr–NEt3 according to a procedure used
for base sensitive materials.14 Unsaturated lactones
14a–e were obtained with satisfactory 70–80% yield.15
Finally, the hydrogenation of these lactones 14 to cis
d-lactones 15 was classically carried out in ethyl ace-
tate under palladium/charcoal-catalyzed conditions
(96–98% yield).
However this chemoselective reduction was critical,
and it turned out that its success was largely depen-
dent on the preparation step of the hindered
LiAlH(O-tBu)3 from t-butanol and a titrated ethereal
LiAlH4 solution. The best results were obtained with
a reducing agent generated in situ at −40°C during 4
h, which gave a 57–100% conversion and suppressed
the overreduction to diol 9. The reduction of b-
ketoaldehydes 12c–e at −78°C for 1–3 h then afforded
In conclusion, we have shown that iridoid-like bi-
cyclic d-lactones 14 and 15 with an alkyl group at the
bicyclic junction are easily obtained by the intra-
molecular Horner–Wadsworth–Emmons reaction of
the intermediate diethylphosphonoacetates of a-alkyl-
a-hydroxymethylcyclopentanones.
chemoselectively
8c–e in 52–78% yield (Scheme 5).
a-hydroxymethylcyclopentanones
The synthesis of d-lactones 14 and 15 from the b-
ketoalcohols 8 is summarized in Scheme 6 and Table
1 (entries 1–5). The transformation of these precursor
b-ketoalcohols 8 to diethylphosphonoacetates 13 was
Acknowledgements
One of us (Z.G.) thanks Re´gion Rhoˆne-Alpes for a
doctoral fellowship (MIRA program).

Z. Guerrab et al. / Tetrahedron Letters 44 (2003) 5727–5730
5729
Scheme 6. Reagents and conditions: (a) (EtO)2PO-CH2-CO2H (1 equiv.), DCC (1 equiv.), 6 mol% DMAP, CH2Cl2, rt, 3 h; (b)
LiBr (3.2 equiv.), NEt3 (10 equiv.), THF, rt, 3–4 h; (c) H2, cat Pd/C, AcOEt, rt, 20 h.
Table 1. Synthesis of bicyclic d-lactones 14–15
Entry
b-Ketoalcohols 8a–e
R1, R2
R
Yields (%)a
13a–e
14a–e
15a,c–e
1
2
3
4
8a
8b
8c
R1=R2=H
R1=R2=H
R1=R2=H
R1=H
R=CH2-Ph
R=CH2-CHꢁCH2
R=CH3
91
80
82
90c
80
85
70
71c
96
– (94)d
97
8db
R=CH3
98c
R2=CH3
5
8e
R1=R2=CH3
R=CH3
90
70
98
a Refers to yield of isolated product by flash-chromatography.
b b-Ketoalcohol 8d was a trans–cis 80:20 mixture of diastereomers (major trans-diastereomer shown in Scheme 6).
c Lactones 14d and 15d obtained as 80:20 mixtures of diastereomers.
d Hydrogenation gave the fully saturated lactone with 94% yield.
References
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15. Typical procedure (Table 1, entry 3): synthesis of 7a-
methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-3(1H)-one
14c. To a stirred solution at 0°C of diethylphospho-
noacetic acid (1.6 g, 8.19 mmol) in anhydrous CH2Cl2 (10
mL) was added DMAP (61 mg, 0.5 mmol) and 2-hydrox-
ymethyl-2-methylcyclopentanone 8c (0.7 g, 8.19 mmol).
DCC (1.7 g, 8.19 mmol) was added at 0°C, and the
reaction mixture was stirred at 20°C for 3 h. The precipi-
tated urea was filtered off and the filtrate was evaporated
in vacuo. The residue was taken up in CH2Cl2, the
solution washed twice with 0.5N HCl, and with saturated

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Z. Guerrab et al. / Tetrahedron Letters 44 (2003) 5727–5730
NaHCO3 solution, and then dried over MgSO4. The
870, 840 cm−1; 1H NMR (300 MHz, CDCl3) l 1.18 (s, 3H),
2
3
3
1.42 (ddd, J=12.5, J=8.5, J=2.2 Hz, 1H), 1.65 (ddd,
solvent was removed by evaporation and the ester 13c
isolated by flash-chromatography (silica, ether, Rf=0.1)
(1.3 g, 82%). To a solution of ester 13c (930 mg, 3.04 mmol)
and LiBr (846 mg, 9.73 mmol) in dry THF (10 mL) at 0°C
under nitrogen was added NEt3 (4.23 mL, 30.3 mmol). The
reaction mixture was then stirred at room temperature for
3 h. The mixture was filtered through a plug of silica gel,
washing with ethyl acetate. The filtrate was concentrated,
and the residue purified by flash-chromatography (silica
gel, PE/ether 6:4) to give lactone 14c (320 mg, 70%). TLC
(SiO2, Rf=0.2); IR (CHCl3) 2940, 1740, 1460, 1220, 1140,
3
3
2J=12.5, J=6.6, J=2.6), 1.80–2.05 (m, 2H), 2.52 (dtd,
3
4
2
2J=19.1, J=8.5, J=1.5 Hz, 1H), 2.63 (dddd, J=19.1,
3J=9.2, J=4.8, J=1.8 Hz, 1H), 4.04 (d, J=10.7 Hz,
3
4
2
2
4
4
1H), 4.24 (d, J=10.7 Hz, 1H), 5.66 (dd, J=1.5, J=1.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) l 21.4 (C-8), 22.4
(C-6), 26.7 (C-7), 35.7 (C-5), 42.1 (C-7a), 77.2 (C-1), 110.8
(C-4), 164.6 (C-4a), 174.1 (C-3); MS (70 eV): m/z (%): 152
(4, M ), 122 (33), 108 (20, M −CO2), 93 (23), 79 (100),
65 (20), 51 (36), 39 (79). Anal. calcd for C9H12O2: C, 71.02;
H, 7.95. Found: C, 70.77; H, 8.12.
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