Iron-catalyzed enediene carbocyclizations. The total synthesis of (-)-gibboside

Article abstract of DOI:10.1016/S0040-4039(02)01662-3

The first total synthesis of (-)-gibboside is reported. The route features a novel iron-catalyzed carbocyclization as the key step for the construction of the cis,trans,cis-tetrasubstituted cyclopentane core.

Full text of DOI:10.1016/S0040-4039(02)01662-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8417–8420
Iron-catalyzed enediene carbocyclizations. The total synthesis of
(−)-gibboside
James M. Takacs,* Suresh Vayalakkada, Steven J. Mehrman and Celia L. Kingsbury
Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE 68588-0304, USA
Received 1 August 2002; accepted 9 August 2002
Abstract—The first total synthesis of (−)-gibboside is reported. The route features a novel iron-catalyzed carbocyclization as the
key step for the construction of the cis,trans,cis-tetrasubstituted cyclopentane core. © 2002 Elsevier Science Ltd. All rights
reserved.
The iridoid glucoside, (−)-gibboside (1), was isolated
from the methanol extracts of Patrinia gibbosa roots, a
plant indigenous to Sado Island in Japan.1 The struc-
ture was assigned as depicted in 1 on the basis of
spectroscopic analysis and the crystal structure deter-
mined of its pentaacetate derivative. While no biologi-
cal data for this compound have been published, a
variety of interesting activity has been seen in other
iridoid glucosides.2 Gibboside is structurally differenti-
ated from other iridoid glucosides, some of which are
shown in Scheme 1, by the presence of a hydroxymethyl
group adjacent to the ring fusion, by the attachment of
The iron-catalyzed carbocyclization of enedienes pro-
vides a novel method for the diastereoselective synthesis
of substituted five- and six-membered ring systems5 and
has previously been applied to the enantioselective syn-
thesis of a simple alkaloid analogue6 as well as to the
syntheses of iridoid monoterpenes (+)-isoiridomyrmecin
and (−)-mitsugashiwalactone.7 Herein, we report the
total synthesis of (−)-gibboside (1) via the retrosynthetic
plan outlined in Scheme 2. The plan features a
diastereoselective iron-catalyzed carbocyclization to
construct the cis,trans,cis-tetrasubstituted cyclopentane
core of the molecule (i.e. the cyclization of C to B).
a b-D-glucose unit at the secondary alcohol, and by the
presence of a lactone rather than dihydropyran ring.
Biosynthetic studies defined a pathway for the forma-
tion of gibboside and the related natural product patri-
noside, an iridoid glucoside also found in P. gibbosa,3
and it is concluded from labeling studies that both the
cyclopentane ring and the ring methyl substituent are
oxidized after construction of the iridoid skeleton. The
iridoids continue to attract significant synthetic inter-
est,4 but a total synthesis of gibboside has not previ-
ously been reported.
The synthesis of the functional version of enediene C
(i.e. 7) and its cyclization are shown in Scheme 3. We
have previously described the deconjugative boron-
mediated aldol reactions of the sorbic acid derived
N-acyloxazolidine 2.8 This extension of Evans’
chemistry9 provides an efficient method to introduce
1,3-diene moieties with control of stereochemistry.
Thus, condensation of
oxy)propanal followed by reduction of the crude aldol
2 with 3-(triisopropylsilyl-
product affords diol 3 (66–75% yield, >95% isomeric
Scheme 1. The structures of (−)-gibboside and several related iridoid glucosides.
* Corresponding author. Tel.: +1-402-472-6232; fax: +1-402-472-9402; e-mail: jtakacs1@unl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01662-3

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J. M. Takacs et al. / Tetrahedron Letters 43 (2002) 8417–8420
Scheme 2. Retrosynthesis of (−)-gibboside (1).
Scheme 3. The enantioselective preparation of enediene 7 and its iron-catalyzed cyclization.
purity). Initially, it was hoped that the boron-mediated
aldol reaction could be used to couple 2 with a b,g-
unsaturated aldehyde, for example 5-benzyloxy-3-pen-
tenal.10 This approach would have significantly
shortened the synthetic sequence required, but under
the conditions employed for the reaction, the b,g-unsat-
urated aldehyde apparently isomerizes to the more sta-
ble a,b-unsaturated isomer, 5-benzyloxy-2-pentenal,
and only its condensation product is isolated. Nonethe-
less, the two chiral centers required for the enediene are
efficiently set in the aldol reaction and elaboration of 3
is straightforward.
our hands for the olefination of other labile alde-
hydes,12 and the expected trienoate 6 was obtained in
good yield (88–90%). The ester functionality in 6 can be
selectively reduced upon treatment with DIBAL-H (2
equiv., −78°C in toluene) to give the corresponding
allylic alcohol in good yield (90% yield). However,
benzylidene acetals can also be cleaved regioselectively
by DIBAL-H,13 and the combined reductions of the
ester and acetal are readily effected with good regiocon-
trol using excess DIBAL-H (4 equiv., DCM, −78°C to
rt). Greater than 10:1 regioselectivity is observed in the
acetal opening. The intermediate diol is benzylated to
afford the desired enediene 7 (65–72% from 6). The key
iron-catalyzed carbocyclization of enediene 7 proved to
be problematic. The iron catalyst is generated in situ
via the reduction of iron(III) acetoacetonate with tri-
ethylaluminum in the presence of a bisoxazoline ligand
(i.e. 2,2% - (1 - methylethylidene)bis[4,5 - dihydro - 4,4 - di-
methyloxazole], DMO).14 This cyclization provides a
mixture of enol ethers, which is converted to the ethyl-
ene acetal upon treatment of the crude reaction mixture
with ethylene glycol and catalytic PPTS. Compound 8
is obtained in high diastereomer purity (>95% one
isomer). While we have a good deal of experience with
this reaction, and have successfully used it for a variety
of cyclization substrates, the yield obtained in this case
Protection of the 1,3-diol with para-anisaldehyde
dimethyl acetal using catalytic camphor sulfonic acid in
refluxing 1,2-dichloroethane (DCE) gives acetal 4 (4–12
h, 80–85%). When the reaction was run in refluxing
dichloromethane (DCM), it was found to be quite
sluggish and required significantly longer reaction time
(2 days, 70%). Acetal 4 was formed as a 6:1 mixture of
diastereomers at the acetal center. The mixture of
epimers was treated with TBAF (1.0 M in THF) to
remove the TIPS protecting group followed by Swern
oxidation to the labile aldehyde 5 (85–87% for two
steps). The aldehyde was subjected to olefination condi-
tions using the Horner–Emmons procedure introduced
by Bonadies,11 conditions that have proven useful in

J. M. Takacs et al. / Tetrahedron Letters 43 (2002) 8417–8420
8419
Scheme 4. The final stages of the synthesis of (−)-gibboside (1).
varied over a wide range (40–80%). We know from
previous studies that the catalyst is quite sensitive to trace
impurities in the reagents or starting material, and our
attempts to fully understand and optimize the cyclization
of 7 were hampered by its relatively limited availability.
References
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The conversion of 8 to (−)-gibboside is straightforward
(Scheme 4). Cleavage of the double bond by ozonolysis
followed by reduction with NaBH4 gives the hydroxyac-
etal 9 (68–70%). Hydrolysis by treatment with aqueous
acetic acid (75°C) gives an intermediate lactol which upon
PCC oxidation gives lactone 10 (70%). Diastereoselective
alkylation of its derived enolate at low temperature
(−78°C) by treatment with methyl iodide gives a 3:1
mixture of diastereomers (77%). Unfortunately, the
diastereomer ratio could not be improved by further
lowering the temperature to −100°C. The major isomer
was treated with DDQ in DCM/H2O to cleave the PMB
group (85%).15 BF3·OEt2-catalyzed glycosidation with
2,3,4,6-tetra-O-benzyl-a-
D
-glucopyranosyl
trichloro-
acetimidate16 (10% BF3·OEt2, DCM, −20°C, 4 A molec-
ular sieves) gives a 4:1 mixture of diastereomers (60%),
the major isomer being the expected b-glucoside 12.
Global benzyl group deprotection was effected by cata-
lytic hydrogenation in the presence of Pd/C (85%). The
analytical data for our synthetic (−)-gibboside17 agree
with that reported for the natural product.1
,
In summary, the first total synthesis of the unusual
iridoid glycoside (−)-gibboside is reported. The route
features a novel iron-catalyzed carbocyclization as the
key step for the construction of the tetrasubstituted
cyclopentane core.
10. Crimmins, M. T.; Tabet, E. A. J. Org. Chem. 2001, 66,
4012–4018.
11. Bonadies, F.; Cardilli, A.; Lattanzi, A.; Orelli, L. R.;
Scettri, A. Tetrahedron Lett. 1994, 35, 3383–3386.
12. Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J.
Org. Chem. 1998, 63, 6757–6760.
Acknowledgements
13. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K.
Chem. Lett. 1983, 1593–1596.
Support from the NIH under grant GM34927 is gratefully
acknowledged.

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J. M. Takacs et al. / Tetrahedron Letters 43 (2002) 8417–8420
14. CAS registry number: 239103–32–3.
15. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yone-
mitsu, O. Tetrahedron 1986, 42, 3021–3028.
16. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980,
19, 731–732.
17. Synthetic (−)-gibboside (1): 4.9 mg obtained as a white
amorphous solid: [h]D −17.5° (c 0.1, MeOH) (lit. [h]D
−22.1° (c 1, MeOH). Note: Unfortunately, we were
unable to measure the optical rotation under conditions
identical to those reported in the literature); 1H NMR
(CD3OD, 300 MHz) l 4.42–4.31 (m, 3H), 4.10 (t, J=11.2
Hz, 1H), 3.88–3.81 (m, 2H), 3.70–3.60 (m, 2H), 3.36–3.22
(m, 3H), 3.14 (t, J=8.4 Hz, 1H), 2.55–2.43 (m, 2H),
2.41–2.20 (m, 2H), 1.93 (m, 1H), 1.54 (m, 1H), 1.14 (d,
J=6.5, 3H); 13C (CD3OD 75 MHz) l 179.2, 105.1, 84.7,
78.2, 77.9, 75.4, 71.1, 71.0, 62.7, 61.6, 51.4, 42.3, 41.2,
40.5, 39.9, 14.4; IR (NaCl plate) 3400, 2928, 1738, 1344,
1241, 1170, 1080, 1028 cm−1
;
HRMS calcd for
C16H26NaO9 (M+ plus Na) 385.1467, found 385.1471
m/z.