Enantioselective total synthesis of a natural iridoid

Article abstract of DOI:10.1021/ol201089f

The first total synthesis of 6-hydroxy-7-(hydroxymethyl)-4- methylenehexahydrocyclopenta[c]pyran-1(3H)-one has been accomplished. A key feature of the synthesis includes facile construction of the bicyclic lactone intermediate via intramolecular Pd(0)-catalyzed allylic alkylation and the efficient transformation of this intermediate into the iridoid skeleton employing silicon tethered radical cyclization.

Full text of DOI:10.1021/ol201089f

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3344–3347
Enantioselective Total Synthesis of a
Natural Iridoid
Sujin Lee,† Seung-Mann Paek,‡ Hwayoung Yun,† Nam-Jung Kim,†
and Young-Ger Suh*,†
College of Pharmacy, Seoul National University, Seoul 151-742, Korea,
and College of Pharmacy, the Institute of Health Sciences, Gyeongsang National
University, Jinju daero, Jinju, Gyeongnam, 660-751, Korea
ygsuh@snu.ac.kr
Received April 26, 2011
ABSTRACT
The first total synthesis of 6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1(3H)-one has been accomplished. A key
feature of the synthesis includes facile construction of the bicyclic lactone intermediate via intramolecular Pd(0)-catalyzed allylic alkylation and
the efficient transformation of this intermediate into the iridoid skeleton employing silicon tethered radical cyclization.
Iridoids are a large family of natural monoterpenoid
products that are highly oxygenated and structurally
characterized by a cis-fused cyclopenta[c]pyran ring
system.1 The various biological activities of iridoids have
continuously attracted interests from both biologists and
chemists.2 The unique cis-fused cyclopenta[c]pyran ring
system has presented a variety of challenges for chemical
synthesis and in analysis of biological activities.3 We have
been interested in a recently reported iridoid lactone that is
structurally related to loganin and consists of a C7-sub-
stituted C6-hydroxycyclopenta[c]lactone, as illustrated in
Figure 1. Iridoid lactone 1 was isolated from the roots and
rhizomes of Nardostachys chinensis Batalin (Valerianaceae).4
This plant has been used as a Chinese folk medicine, and its
roots and rhizomes exhibit a variety of biological activities,
such as sedative, antimalarial, antinociceptive, cytotoxic,
and enhancement of nerve growth factor activities.5 How-
ever, the paucity of its key component 1 has hampered the
systematic research of the iridoid, including structureꢀ
activity relationship (SAR) analysis and further pharmaco-
logical studies. Thus, we have worked on the development of
an efficient synthetic route to the new iridoid lactone 1.
Herein we describe a concise and highly enantioselective
synthesis of 1that can be modulated to afford related iridoids.
† Seoul National University.
‡ Gyeongsang National University.
(1) (a) El-Naggar, L. J.; Beal, J. L. J. Nat. Prod. 1980, 43, 649. (b)
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Rao, P. B. Tetrahedron 1997, 53, 14507. For recent selected highlights in
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2010, 12, 4836.
Figure 1. Structures of iridoids.
Our retrosynthetic approach for iridoid lactone 1 is
illustrated in Scheme 1. This process involves the efficient
(4) Zhang, Y.; Lu, Y.; Zhang, L.; Zheng, Q.-T.; Xu, L.-Z.; Yang,
S.-L. J. Nat. Prod. 2005, 68, 1131.
(5) Tanitsu, M.; Takaya, Y.; Akasaka, M.; Niwa, M.; Oshima, Y.
Phytochemistry 2002, 59, 845 and references cited therein.
r
10.1021/ol201089f
Published on Web 05/27/2011
2011 American Chemical Society

regio- and stereoselective elaboration of the C7-hydroxy-
methyl substituent through the silicon-tethered intra-
molecular radical cyclization6 of cyclopentenol ether 2,
followed by TamaoꢀFleming oxidation.7 Its precursor
cyclopentanol 3 is generated by functional group transfor-
mation from bicyclic lactone 4, which can be efficiently
constructed by the palladium-catalyzed cyclization of
allylic carbonate 5 using the protocol developed by our
group.8 The allylic carbonate 5 was expected to be con-
veniently derived from the known hydroxy tosylate 6.9
precursor. However, the intermolecular cross-metathesis
led to γ-lactone 5 with only 43% yield.10 Thus, we turned
our attention to silicon-tethered ring-closing metathesis
(RCM),11 which is considered superior in terms of entropic
benefit and concomitant alcohol protection. Alkoxysilane
8 was prepared from the known hydroxy tosylate 6 with a
78% yield. Alkylation of tosylate 8 with the anion of
benzenesulfonyl acetate 9 and subsequent RCM provided
the cyclic bis-alkoxysilane 10. Removal of the tethered
silicon of bis-alkoxysilane 10 with TBAF and the sponta-
neous isomerization of the resulting hydroxy ester pro-
vided the γ-lactone intermediate, which was protected with
TBSCl to afford allylic carbonate 5.
Scheme 1. Retrosynthetic Approach
Scheme 2. Synthesis of γ-Lactone 5
The synthesis commenced with the preparation of the
requisite γ-lactone 5 for Pd(0)-catalyzed allylic alkylation,
as illustrated in Scheme 2. To address the trisubstituted
alkene unit, we initially attempted olefin cross-metathesis
of the allyl γ-lactone with the hydroxymethyl-substituted
allyl carbonate to produce the Pd(0)-catalyzed cyclization
We next conducted a survey of stereoselective Pd(0)-
catalyzed cyclization of 5 under a variety of reaction
conditions including ligands and solvents as summarized
in Table1. Stereoselective cyclization of 5 inthe presenceof
Pd(dppe)2 in THF afforded the desired product of 4 with a
91% yield along with a minor product 11 (entry 1).
Cyclization of 5 in the presence of Pd(PPh3)4 resulted in
low stereoselectivity regardless of the solvent (entries 3ꢀ5).
Cyclization in the presence ofPd(OAc)2 withdppp or dppb
(entries 6 and 7) also showed good stereoselectivities,
although the yield was slightly lower.
The excellent stereoselectivity is likely due to the presence
of the silyloxymethyl substituent, given the lower stereo-
selectivity (10:1) for the disubstituted alkene 12 under the
same conditions as shown in Scheme 3. This type of facial
preference is well supported by our previous report.12
With the requisite building block 4 in hand, we focused
our attention to the facile introduction of the hydroxymethyl
(6) For
a review of silicon-tethered-radical cyclization, see:
(a) Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthisis 1997, 8,
813. (b) Bols, M.; Skrydstrup, T. Chem. Rev. 1995, 95, 1253.
(7) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120.
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Tetrahedron Lett. 1997, 38, 3911. (b) Suh, Y.-G.; Jung, J.-K.; Suh, B.-C.;
Lee, Y.-C.; Kim, S.-A. Tetrahedron Lett. 1998, 39, 5377. (c) Suh, Y.-G.;
Jung, J.-K.; Seo, S.-Y.; Min, K.-H.; Shin, D.-Y.; Lee, Y.-S.; Kim, S.-H.;
Park, H.-J. J. Org. Chem. 2002, 67, 4127. (d) Seo, S.-Y.; Jung, J.-K.;
Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Lee, K.-O.; Suh, Y.-G. Org. Lett.
2004, 6, 429. (e) Paek, S.-M.; Seo, S.-Y.; Min, K.-H.; Shin, D.-M.;
Chung, Y.-K.; Suh, Y.-G. Heterocycles 2007, 71, 1059.
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(10) When cross-metathesis was attempted using various solvents
(CH2Cl2, toluene), catalysts (Grubbs’ first- and second-generation
catalysts, GrubbsꢀHoveyda catalyst), and a microwave, disappoint-
ingly, the yield was no higher than 43% at any conditions.
(11) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang,
H.-R. J. Am. Chem. Soc. 2003, 125, 14702.
(12) Han, Y.-T.; Paek, S.-M.; Lee, S.; Jung, J.-W.; Jung, J.-K.; Seo,
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Org. Lett., Vol. 13, No. 13, 2011
3345

introduction of a hydroxymethyl equivalent via R-methy-
lenation with Eschenmoser’s salt16 as well as formylation
with HCO2CH2CF317 to the cyclopentanone did not pro-
vide satisfactory results. Stereoselective reduction of enone
13 with (S)-CBS18 afforded cyclopentenol 14 with the
correct stereochemistry.
Table 1. Pd(0)-Catalyzed Cyclization of 5a
entry
catalyst
solvent
yieldb (%)
ratioc (4:11)
Scheme 4. Completion of Synthesis of Iridoid 1
1
2
3
4
5
6
7
Pd(dppe)2
Pd(dppe)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
THF
91
90
91
90
78
78
89
30:1
3.5:1
1:1
CH2Cl2
THF
CH2Cl2
DMSO
THF
2.5:1
1:1
d
Pd(dppp)2
Pd(dppb)2
10:1
25:1
d
THF
a All reactions were conducted under reflux conditions. b Isolated
yields. c Determined by 300-MHz 1H NMR spectra of the crude diaster-
eomeric mixtures. d Premixed Pd(OAc)2 and dppp/dppb in THF was
added to a solution of 5. dppe: bis(diphenylphosphino) ethane. dppp:
bis(diphenylphosphino)propane. dppb: bis(diphenylphosphino)butane.
Scheme 3. Plausible Mechanism for High Stereoselectivity
Silylation of cyclopentenol 14 with (bromomethyl)
chlorodimethyl silane 15 yielded the bromosilyl ether,
which was directly subjected to the radical cyclization.19
Intramolecular radical cyclization of the labile silyl ether
intermediate with Et3B20 and Bu3SnH afforded the desired
cis-fused oxasilole 16 in good yield. The newly generated
C8 stereogenic center could be established by an intramo-
lecular hydrogen atom transfer from the proximal silyl-
methyl group to C8.21 Subsequent TamaoꢀFleming oxida-
tion of oxasilole 16 gave diol 17. Finally, lactone iridoid 1
was obtained in good yield by TBS deprotection with
TsOH,22 followed by a concomintant lactonization. The
structure of 1 was confirmed by comparison of its spectral
data with those of the authentic sample (optical rotation,
1H NMR, 13C NMR, IR, HRMS).
substituent at C7. Convenient methanolysis13 of bicyclic
lactone 4 afforded cyclopentanol 3, which was subjected to
DessꢀMartin oxidation to produce enone 13 after con-
comitant β-elimination of sulfonate14 (Scheme 4). At this
stage, a direct R-hydroxymethylation with HCHO15 or the
(16) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A.
Angew. Chem., Int. Ed. 1971, 10, 330.
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(13) Initially, deprotection of TBS with TBAF resulted in isomeriza-
tion of the bicyclic lactone, and oxidation of cyclopentanol yielded
elimination of cyclopentenone with an excellent yield. Disappointingly,
stereoselective reduction of bicyclic cyclopentenone was unsuccessful as
shown below.
(18) (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.
(b) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.; Hoarau, C.
Org. Lett. 2004, 6, 3861. (c) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama,
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Soc. 1978, 100, 346. (b) Cheng, W.-C.; Kurth, M. K. J. Org. Chem. 2002,
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3346
Org. Lett., Vol. 13, No. 13, 2011

In summary, the first total synthesis of (þ)-6-hydroxy-
7-(hydroxymethyl)-4-methylenehexahydrocyclopenta-
[c]pyran-1(3H)-one 1 was accomplished in 13 steps. The
key features of the synthesis involve the stereoselective and
efficient preparation of the cyclopentanol intermediate via
Pd(0)-catalyzed cyclization and then the silicon-tethered
radical cyclization followed by TamaoꢀFleming oxidation
for the stereoselective introduction of the C7-hydroxymethyl
substituent. This versatile synthetic approach is expected to be
widely utilized for the syntheses of iridoids and iridoalkaloids.
Acknowledgment. This research was supported by a
grant (2009 K001255) from the Brain Research Center of
the 21stCenturyFrontierResearchProgramfunded bythe
Ministry of Education, Science and Technology (MEST)
of the Republic of Korea and the Research Institute of
Pharmaceutical Science, Seoul National University.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
3347