Synthesis and stereochemical confirmation of the secoiridoid glucosides nudiflosides D and A

Article abstract of DOI:10.1021/ol0615230

We describe herein an efficient access to the highly substituted cyclopentane unit present in the Nudifloside secoiridoid family via crotyl phosphonamide anion mediated conjugate addition to cyclopentenone.

Full text of DOI:10.1021/ol0615230

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4047-4049
Synthesis and Stereochemical
Confirmation of the Secoiridoid
Glucosides Nudiflosides D and A
Stephen Hanessian,* Emily Mainetti, and Fabien Lecomte
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec H3C 3J7 Canada
stephen.hanessian@umontreal.ca
Received June 21, 2006
ABSTRACT
We describe herein an efficient access to the highly substituted cyclopentane unit present in the Nudifloside secoiridoid family via crotyl
phosphonamide anion mediated conjugate addition to cyclopentenone.
The leaves and stems of Jasminium nudiflorum LINDL
belonging to the Oleaceae genus are a rich source of oleoside-
type secoiridoid glucosides containing tetrasubstituted cy-
clopentanoid monoterpene units. Leaf extracts from this plant
have been used as remedies for inflammation and traumatic
bleeding in China for years.
Extensive studies by Tanahashi and co-workers1 have
resulted in the isolation of several isomeric new iridoid
glucosides containing essentially the same branched cyclo-
pentane triols. Two representative examples named Nudi-
flosides D and A (1 and 2, respectively, Figure 1), were
recently reported and their structures proposed, based on
chemical correlation and NMR spectroscopic methods.
In this Letter, we describe the first stereocontrolled total
synthesis of the common tetrasubstituted cyclopentane ag-
lycon, and its conversion to the natural nudiflosides D and
A (1 and 2), thereby confirming their structural identities
and stereochemical assignment.
The main challenge in the elaboration of the substituted
cyclopentane unit was the stereochemical control of four
contiguous core stereogenic centers and an additional one
Figure 1. Proposed structures for Nudiflosides D and A1.
in the branched hydroxyethyl side chain. Extensive studies
of conjugate addition with C2-symmetrical chiral nonracemic
alkylphosphonamides in our laboratory have shown that allyl
and crotyl reagents add to cyclic enones, lactones, and
lactams, as well as to acyclic enoates with high diastereo-
selectivity.2 Sequential alkylation of the resulting enolates
in situ leads to the respective carbonyl compounds harboring
two or three contiguous stereogenic carbons with excellent
diastereoselectivities. The strategic sequence of three bond-
(1) (a) Tanahashi, T.; Takenaka, Y.; Nagakura, N.; Nishi, T. J. Nat. Prod.
1998, 62, 1311. (b) Tanahashi, T.; Takenaka, Y.; Nagakura, N.; Nishi, T.
Chem. Pharm. Bull. 2000, 48 (8), 1200. (c) Takenaka, Y.; Tanahashi, H.;
Taguchi, H.; Nagakura, N.; Nishi, T. Chem. Pharm. Bull. 2002, 50 (3),
384.
(2) (a) Hanessian, S.; Gomtsyan, A.; Malek, N. J. Org. Chem. 2000, 65,
5623. (b) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161.
10.1021/ol0615230 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/01/2006

forming reactions in the case of the cyclopentane subunit of
1 and 2 is shown in Figure 2.
Scheme 1
Figure 2. Strategic bond-forming sequence.
Starting with the O-protected 2-(hydroxymethyl)cyclo-
pentenone, conjugate addition would be done with the crotyl
phosphonamide reagent A, to introduce the side chain and
concomitant stereocenters, followed by a stereocontrolled
introduction of an epoxide, regiocontrolled reductive opening,
and an olefination-reduction of the corresponding exo-
methylene product. The success of this strategy would depend
in large measure on the stereochemical outcome on the initial
conjugate addition whereby three contiguous stereogenic
centers could be secured in one step.
The ketal 3 readily available from cyclopentenone in two
steps3 was metalated with n-BuLi and the resulting lithio
intermediate was treated with benzyloxymethyl chloride
(BOMCl) in THF containing 2 equiv of HMPA at -78 °C
to give the benzyl ether 4 in 94% yield. Addition of 4 to the
lithium anion of the crotyl phosphonamide reagent A easily
prepared from N,N′-dimethyl-1,2-diaminocyclohexane at -78
°C in THF2 gave a single adduct 5 in 72% yield on a 1 g
scale. Yields were slightly lower on a 5 g scale. Ozonolysis
of the double bond, reduction of the resulting aldehyde with
NaBH4, and protection of the alcohol as the TBDPS ether
gave 6 in high overall yield. Since it was not possible to
chemoselectively reduce the aldehyde in the presence of the
ketone, the mixture of alcohols was oxidized with PCC and
the regenerated ketone 7 was converted to the enone 8 by
using two methods.Thus, treatment of 7 with LDA/TMSCl
followed by addition of Pd(OAc)2 as described elsewhere4
gave 8 in 51% yield with recovery of starting ketone 7 (24%).
Alternatively, formation of R-phenylseleno ketone and
oxidative elimination in the presence of hydrogen peroxide
furnished 8 in 57% yield with recovery of starting ketone 7
(14%). Epoxidation of 8 in the presence of basic hydrogen
peroxide afforded the desired epoxide 9 as the major isomer
in addition to the diastereoisomeric epoxide (9:1) in a
combined 80% yield. Evidently the spatial disposition of the
vicinal substituents favored the desired 9, albeit not with
complete selectivity. Treatment of 9 with Na[PhSeB(OEt)3]5
in ethanol led to a regioselective reductive opening to afford
10 in 74% yield with recovery of 8 (14%). Treatment with
samarium iodide was much less effective, affording a poor
yield of 10 and recovery of 9. The next step involved
transformation of the hydroxy ketone 10 to the corresponding
exo-methylene analogue, which was performed with Nysted’s
reagent6 affording 11 in 74% yield. The last stereochemical
hurdle en route to the intended cyclopentane subunit was to
secure a stereocontrolled reduction of the exo-methylene
group. Preliminary studies with a variety of catalysts (Pd/C
or Pd(OH)2/C in the presence of hydrogen, nickel chloride
in the presence of NaBH4, p-tosylhydrazine in xylene)
afforded mixtures of isomers. We anticipated that a free
hydroxymethyl group would provide a beneficial directing
effect by prior coordination to a catalyst. Treatment of 11
(3) (a) Dunn, G. L.; DiPasquo, V. J.; Hoover, J. R. E. J. Org. Chem.
1968, 33, 1454. (b) Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro,
M. A. J. Org. Chem. 1982, 47, 1855.
(4) (a) House, H. O.; Czuba, L. T.; Gall, M.; Olmstead, H. D. J. Org.
Chem. 1969, 34, 2324. (b) Ito, Y.; Hirao, J.; Saegusa, J. J. Org. Chem.
1978, 43, 1011.
(5) Miyashita, M.; Suzuki, T.; Hoshiro, M.; Yohokoshi, A. Tetrahedron
1997, 53, 37, 12469.
(6) (a) Matsubara, S.; Sugishara, M.; Utimoto, K. Synlett 1998, 313. (b)
Nysted, L. N. U.S. Patent 3865848, 1975; Chem. Abstr. 1975, 83, 10406q.
4048
Org. Lett., Vol. 8, No. 18, 2006

with BCl3 in CH2Cl2 at -40 °C effected smooth debenzy-
lation without affecting the robust TBDPS ether. Reduction
in the presence of p-tosylhydrazine or hydrazine in the
presence of hydrogen peroxide and copper sulfate gave a
1:1 mixture of epimeric C-methyl products. However, in the
presence of the Crabtree catalyst3 reduction took place to
afford 12 as a single isomer in 74% yield. Removal of the
TBDPS group with BuN4F in THF proceeded uneventfully
Scheme 3
to give the cyclopentane triol 13. Comparison of 1H and 13
C
NMR data indicated the structural identity of synthetic
material and a sample obtained by hydrolysis of Nudifloside
A.1b Stereochemical confirmation was also secured from
optical rotation data, [R]28 +16 (c 0.28, MeOH), reported
D
[R]20 +11 (c 0.3, MeOH).1b
D
Oleuropein 14, readily available from commercial extracts
of olive oil, proved to be an excellent source of the oleoside
subunit8 (Scheme 2). Treatment of 14 with 1 equiv of NaOH,
Scheme 2
In conclusion, we have developed a practical and stereo-
controlled synthesis of the highly substituted cyclopentane
ring present in the iridoids nudiflosides D and A, and
confirmed their absolute stereochemical identities. A note-
worthy feature of the synthesis is the utilization of a crotyl
phosphonamide anion mediated conjugate addition to a
cyclopentenone, thus creating three contiguous stereogenic
centers in one step of which one resides on the side chain.
followed by acetylation afforded the oleoside monomethyl
ester peracetate 15 in good overall yield. Depending on the
number of equivalents used, 15 was activated as the mixed
anhydride according to Yamaguchi,9 followed by treatment
with 12, to give the protected precursors to the intended
targets. Sequential removal of the TBDPS group with Bu4-
NF and the acetates with Et2NH gave Nudiflosides D and
A, respectively (Scheme 3).
Acknowledgment. We thank NSERC (Canada) for
generous financial assistance and the Ministe`re des Affaires
e´trange`res (France) for a fellowship to E.M.
Supporting Information Available: Full experimental
procedures, compound characterizations, and selected 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(7) Crabtree, R. H.; Davis, M., W. J. Org. Chem. 1986, 51, 2655.
(8) Capozzi, F.; Piperno, A.; Uccella, N. J. Agric. Food Chem. 2000,
48, 1623.
(9) Inanaga, J.; Hiroka, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
OL0615230
Org. Lett., Vol. 8, No. 18, 2006
4049