Total synthesis and bioactivity of an unnatural enantiomer of merrilactone A: Development of an enantioselective desymmetrization strategy

Article abstract of DOI:10.1021/jo0700474

(Chemical Equation Presented) (-)-Merrilactone A [(-)-1], isolated from Illicium merrillianum in 2000, possesses neurite outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. A part from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. Here, we report the total synthesis of the unnatural enantiomer of merrilactone A [(+)-1], based on a novel desymmetrization strategy. The chiral lithium amide 16g promoted an enantioselective transannular aldol reaction of eight-membered meso-diketone 3d, establishing the absolute stereochemistries of four chiral centers of the cis-bicyclo[3.3.0]octane framework of 1 in a single step. The obtained compound 4d served as a platform for the subsequent functional group manipulations necessary for the construction of (+)-1. Surprisingly, both the natural and unnatural enantiomers of synthetic merrilactone A equally promoted neurite outgrowth in primary neuronal cultures.

Full text of DOI:10.1021/jo0700474

Total Synthesis and Bioactivity of an Unnatural Enantiomer of
Merrilactone A: Development of an Enantioselective
Desymmetrization Strategy
Masayuki Inoue,*,†,‡.§ Nayoung Lee,† Satoshi Kasuya,† Takaaki Sato,† Masahiro Hirama,†
Miyako Moriyama, and Yoshiyasu Fukuyama
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Aramaki, Aoba-ku, Sendai
980-8578, Japan, Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku UniVersity, Aramaki, Aoba-ku, Sendai 980-8578, Japan, PRESTO, Japan Science and Technology
Agency, Sendai 980-8578, Japan, and Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences,
Tokushima Bunri UniVersity, Yamashiro-cho, Tokushima 770-8514, Japan
inoue@ykbsc.chem.tohoku.ac.jp
ReceiVed January 9, 2007
(-)-Merrilactone A [(-)-1], isolated from Illicium merrillianum in 2000, possesses neurite outgrowth
activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential
for the treatment of neurodegeneration associated with Alzheimer’s and Parkinson’s diseases. Apart from
its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. Here,
we report the total synthesis of the unnatural enantiomer of merrilactone A [(+)-1], based on a novel
desymmetrization strategy. The chiral lithium amide 16g promoted an enantioselective transannular aldol
reaction of eight-membered meso-diketone 3d, establishing the absolute stereochemistries of four chiral
centers of the cis-bicyclo[3.3.0]octane framework of 1 in a single step. The obtained compound 4d served
as a platform for the subsequent functional group manipulations necessary for the construction of (+)-1.
Surprisingly, both the natural and unnatural enantiomers of synthetic merrilactone A equally promoted
neurite outgrowth in primary neuronal cultures.
Introduction
diseases such as Alzheimer’s and Parkinson’s diseases. How-
ever, their clinical use has been limited because of their
relatively poor bioavailability and pharmacokinetics: NTF
proteins are easily metabolized and unable to cross the blood-
brain barrier. Stable, nonpeptidal small molecules have been
the subject of intense attention as NTF alternatives.2
In this context, Fukuyama and co-workers isolated and
determined the structure of a series of natural products with
NTF-like activities.3 One of the most potent compounds, (-)-
merrilactone A [(-)-1, Figure 1], promoted neurite outgrowth
and exerted a neuroprotective effect at low concentrations (0.1-
10 µM) in primary cultures of fetal rat cortical neurons.4
Interestingly, 1 is the only neurotrophic member of the structur-
Neurotrophic factors (NTF) are endogenous proteins that
regulate neuronal survival, neurite outgrowth, differentiation of
nerve cells and synaptic connectivity, and maintenance of
structural integrity.1 Over the past two decades, NTFs have
served as potent therapeutic agents for neurodegenerative
† Department of Chemistry, Graduate School of Science, Tohoku University.
‡ Research and Analytical Center for Giant Molecules, Graduate School of
Science, Tohoku University.
§ PRESTO.
Tokushima Bunri University.
(1) For a review on neurotrophic activity, see: (a) Hefti, F. J. Neurobiol.
1994, 25, 1418. (b) Hefti, F. Annu. ReV. Pharmacol. Toxicol. 1997, 37,
239. (c) Sofroniew, M. V.; Howe, C. L.; Mobley, W. C. Ann. ReV. Neurosci.
2001, 24, 1217.
(2) Xie, Y.; Longo, F. M. Prog. Brain Res. 2000, 128, 333.
10.1021/jo0700474 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/14/2007
J. Org. Chem. 2007, 72, 3065-3075
3065

Inoue et al.
SCHEME 1. Synthetic plan of both enantiomers of
merrilactone A
synthesis of 1 also has been accomplished by Danishefsky et
al.11 Recently, we reported the asymmetric total synthesis of
the natural enantiomer (-)-1 from a chiral starting material,
and confirmed the absolute configuration.12
As a consequence of the potent activity of the natural product
and the uncertainty surrounding its mechanism of action, we
were especially keen to evaluate both enantiomers of 1, because
examination of the unnatural enantiomer should provide seminal
structural information about factors contributing to the biological
effects of the natural product. Here, we report the concise total
synthesis of the unnatural enantiomer of merrilactone A [ent-
(+)-1] based on a novel enantioselective desymmetrization
strategy, and provide a preliminary biological comparison of
the synthetic enantiomers.
FIGURE 1. Structures of both enantiomers of merrilactone A.
ally related anislactone-type sesquiterpenoids.5 Despite its
promising activity, its mode of action in neuronal cells and the
structural features necessary for activity have not been eluci-
dated.
In addition to significant biological activity, 1 possesses
interesting architecture from a synthetic point of view. The
highly oxygenated caged structure is composed of a central cis-
bicyclo[3.3.0]octane carbon framework, two γ-lactones, a unique
oxetane ring, and seven contiguous stereogenic carbon centers,
three of which are quaternary carbons (C5, C6, C9). This
challenging structure has been the target of intense synthetic
investigations,6 which led to the total synthesis of (()-
merrilactone A independently by our group,7 and the laboratories
of Danishefsky,8 Mehta,9 and Frontier.10 The asymmetric
Synthetic Plan
Merrilactone A (1) possesses a densely oxygenated carbon
framework fused with two γ-lactones and an oxetane ring
(Scheme 1). To simplify an asymmetric synthetic route to both
enantiomers of 1, we exploited a hidden structural symmetry
of the framework in 1: the plan involved assembly of the pivotal
cis-bicyclo[3.3.0]octane skeleton 4 or ent-4 by an enantiose-
lective transannular aldol reaction of the common meso-eight-
membered diketone 3.13,14 Installation of the absolute stereo-
chemistry of four centers (C4, C5, C6, C9) from an achiral
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Kodama, M.; Hasegawa, T.; Okazak, H.; Nagasawa, M. Tetrahedron Lett.
1989, 30, 5907. Caryolanemagnolol: Fukuyama, Y.; Otoshi, Y.; Miyoshi,
K.; Nakamura, K.; Kodama, M.; Nagasawa, M.; Hasegawa, T.; Okazaki,
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1990, 31, 4477. Mastigophorene: Fukuyama, Y.; Asakawa, Y. J. Chem.
Soc., Perkin Trans. 1 1991, 2737. Isodunnianin: Fukuyama, Y.; Shida, N.;
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Y.; Shida, N.; Kodama, M.; Chaki, H.; Yugami, T. Chem. Pharm. Bull.
1995, 43, 2270. Bicycloillicinone asarone acetal: Fukuyama, Y.; Hata, Y.;
Kodama, M. Planta Med. 1997, 63, 275. Garsobellin A: Fukuyama, Y.;
Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997, 45, 947. Jiadifenin:
Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. J. Nat. Prod.
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(4) (a) Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y.
Tetrahedron Lett. 2000, 41, 6111. (b) Huang, J.-M.; Yang, C.-S.; Tanaka,
M.; Fukuyama, Y. Tetrahedron 2001, 57, 4691.
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Tetrahedron Lett. 1989, 30, 7451. (b) Kouno, I.; Mori, K.; Okamoto, S.;
Sato, S. Chem. Pharm. Bull. 1990, 38, 3060.
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J.-L.; Gupta, A. K.; Lin, K.-J. Org. Lett. 2002, 4, 2249. (b) Mehta, G.;
Singh, S. R. Tetrahedron Lett. 2005, 46, 2079. (c) Iriondo-Alberdi, J.; Perea-
Buceta, J. E.; Greaney, M. F. Org. Lett. 2005, 7, 3969. (d) Harada, K.;
Kato, H.; Fukuyama, Y. Tetrahedron Lett. 2005, 46, 7407.
(7) Part of the work was published as a preliminary account. Inoue, M.;
Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772.
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(12) Inoue, M.; Sato, T.; Hirama, M. Angew. Chem., Int. Ed. 2006, 45,
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(13) For reviews on the construction of eight-membered rings, see: (a)
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Singh, V. Chem. ReV. 1999, 99, 881. (c) Maier, M. E. Angew. Chem., Int.
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Doyon, J.; Wilson, P. D.; Hickey, E. R.; Paquette, L. A. J. Am. Chem. Soc.
1993, 115, 12189. (b) Paquette, L. A.; Geng, F. J. Am. Chem. Soc. 2002,
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3066 J. Org. Chem., Vol. 72, No. 8, 2007

Synthesis of the Unnatural Enantiomer of Merrilactone A
SCHEME 2. Synthesis of meso-Eight-Membered Diketone
SCHEME 3. Two Distinct Steps in the Enantioselective
Transannular Aldol Reaction
afforded 8. Although Swern oxidation19 of the obtained diol 8
generated diketone 9, the aqueous workup of 9 readily resulted
in its hydrated form, which turned out to be unreactive toward
various nucleophilic reagents. Thus, allyl magnesium bromide
was added directly to the Swern oxidation mixture containing
9,20 leading to 10rr and 10ââ as major isomers in high yield.
The cis-arrangement of allyl groups effectively facilitated the
ring-closing metathesis reaction21 of 10 to produce the bicyclo-
[4.2.0]octyl system 11, which was treated with Pb(OAc)4 in
situ22 to yield the meso-eight-membered diketone 3d. Therefore,
3d was synthesized in only seven steps through pairwise
symmetrical functionalization. To evaluate the effect of the
protective group on the outcome of the next aldol reaction,
various other meso-eight-membered diketones 3a-c were
prepared in a similar manner.
Enantioselective Transannular Aldol Reaction. As shown
in Scheme 3, the crucial asymmetric aldol reaction of 3
contained two distinct steps: enantioselective deprotonation and
diastereoselective C-C bond formation, both of which need to
be highly selective for obtaining 4 or ent-4 out of the four
possible cis-fused isomers.23 First, we evaluated the outcome
of the C-C bond formation (the second step) by varying two
elements: the reaction conditions (Table 1) and the protective
group of the primary alcohols (Table 2). As shown in Table 1,
treatment of 3a with LiN(TMS)2 in THF at -100 °C led to the
cis-fused products (()-4a and (()-13a, favoring the desired
isomer (()-4a (entry 1). Higher temperatures (entries 2 and 3)
resulted in lower selectivity, suggesting the kinetic nature of
material was considered the most prominent, yet challenging,
feature of this reaction.15 By taking advantage of its symmetry,
an efficient synthesis of meso-3 could be attained by applying
pairwise functionalization to meso intermediates after starting
with 2.16 This strategy allows readily available 4 and ent-4 to
serve as a platform structure for subsequent functional group
transformations necessary for the chemical construction of (-)-1
and ent-(+)-1, respectively.
Synthesis of Eight-Membered meso-Diketone. As shown
in Scheme 2, the synthesis of 3 started with [2+2] photocy-
cloaddition between 2,3-dimethylmaleic anhydride 217 and trans-
dichloroethylene 5 to install the two contiguous quaternary
stereocenters (C5, C6).18 Reductive dechlorination of 6 with Zn/
AcOH, followed by LiAlH4 reduction of the anhydride, provided
meso-diol 7. After protection of the primary alcohols of 7 by
their dichlorobenzyl (DCB) ethers, dihydroxylation of the olefin
(19) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(20) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198.
(21) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100. For recent reviews of RCM, see: (c) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. (d) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(15) For reviews on enantioselective desymmetrization, see: (a) Willis,
M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765. (b) O’Brien, P. J. Chem.
Soc., Perkin Trans. 1, 2001, 95.
(16) For reviews on the related approaches including two-directional
synthesis, see: (a) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27,
9. (b) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (c) Hoffmann, R. W.
Angew. Chem., Int. Ed. 2003, 42, 1096.
(22) Balskus, E. P.; Me´ndez-Andino, J.; Arbit, R. M.; Paquette, L. A. J.
Org. Chem. 2001, 66, 6695.
(17) (a) Schenck, G. O.; Hartmann, W.; Steinmetz, R. Chem. Ber. 1963,
96, 498. (b) Gauvry, N.; Comoy, C.; Lescop, C.; Huet, F. Synthesis 1999,
574.
(18) For recent reviews on cyclobutane derivatives, see: (a) Lee-Ruff,
E.; Mladenova, G. Chem. ReV. 2003, 103, 1449. (b) Namyslo, J. C.;
Kaufmann, D. E. Chem. ReV. 2003, 103, 1485.
(23) A trans-fused 5-5 ring system was not obtained in the aldol reaction,
probably due to its highly strained nature. (a) Chang, S.; McNally, D.; Shary-
Tehrany, S.; Hickey, S. M. J.; Boyd, R. H. J. Am. Chem. Soc. 1970, 92,
3109. (b) Allinger, N. L.; Tribble, M. T.; Miller, M. A.; Wertz, D. H. J.
Am. Chem. Soc. 1971, 93, 1637. (c) Gordon, H. L.; Freeman, S.; Hudlicky,
T. Synlett 2005, 2911.
J. Org. Chem, Vol. 72, No. 8, 2007 3067

Inoue et al.
TABLE 1. Diastereoselective C-C Bond Formation: Base Effect
SCHEME 4. Mechanistic Consideration of the Aldol
Reaction
a The yields were based on recovered starting material [80% conversion
(entry 7), 92% conversion (entry 8)].
TABLE 2. Diastereoselective C-C Bond Formation: Protective
Group Effect
As shown in Table 2, the yield of (()-4 also was improved
by increasing the steric bulk of the protective group (R).
Whereas replacement of the benzyl group with a 2-naphthyl
group (NAP) (entry 2) gave a result comparable to that shown
in entry 1 under the same conditions [LiN(TMS)2, THF], 3c
bearing a 2-trifluoromethylbenzyl group showed higher selectiv-
ity for (()-4c (entry 3). The preference for (()-4 was improved
further when substrates with doubly ortho-substituted benzyl
groups, 2,6-dichlorobenzyl (DCB, entry 4), were subjected to
the same reaction conditions. In this way, we successfully
developed highly diastereoselective C-C bond formation by
controlling the reaction conditions and protective groups.
A possible mechanism of the present transannular reaction
is explained by the conformations of 3 and subsequent enolate
intermediates. As depicted in Figure 2, X-ray crystallographic
analysis of 3d revealed that the two ketones are perpendicular
to the eight-membered ring and are oriented in the opposite
1
direction. The H NMR signals of 3d at -100 °C separated
(()-4a under these conditions. This hypothesis was reinforced
by the absence of isomerization of 4a to 13a upon re-treatment
with LiN(TMS)2. Interestingly, both MgBrN(TMS)2 (entry 4)
and LiN(TMS)2/Et3N24 in toluene (entry 5) induced the opposite
selectivity, favoring the undesirable diastereomer (()-13a,
whereas DBU did not exhibit a preference for either product
(entry 6). Since the lithium amide in THF (entry 1) gave the
most promising result, a number of other lithium bases were
applied to 3a. Lithium anilides25 (entries 7-9) improved
selectivity with lithium 4-chloro-N-methylanilide providing the
best results [(()-4a:(()-13a 11.2:1].
into two sets of peaks, representing two alternating conformers
(1:1, see the Supporting Information). Thus, it is very likely
that the eight-membered ring 3 exists as an equimolar mixture
of the two enantiomeric conformers 3′ and ent-3′ (Scheme 4).
Since cis-enolate formation from the eight-membered ring is
energetically more favorable than trans-enolate formation, only
one of the two protons orthogonal to the CdO bonds (indicated
(24) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008.
(25) (a) Xie, L.; Isenberger, K. M.; Held, G.; Dahl, L. M. J. Org. Chem.
1997, 62, 7516. (b) Xie, L.; Vanlandeghem, K.; Isenberger, K. M.; Bernier,
C. J. Org. Chem. 2003, 68, 641.
3068 J. Org. Chem., Vol. 72, No. 8, 2007

Synthesis of the Unnatural Enantiomer of Merrilactone A
TABLE 3. Enantioselective Transannular Aldol Reaction
FIGURE 2. X-ray crystallographic analysis of compound 3d.
in bold face) is considered to be abstracted by the base (-NR2).
Consequently, conformers 3′ and ent-3′ would lead to 4/13 and
ent-4/ent-13 via 12 and ent-12, respectively; only the former
path is shown in Scheme 4. After enolate formation from 3′,
the strong 1,3-diaxial-like steric interaction between the bulky
protected oxymethylene and C7-O bond in 12 would enforce
a conformational flip of the olefin to form 14, from which the
enolate reacts with the ketone to generate the desired cis-fused
5-5 ring system 4. The proposed mechanism agrees well with
the observation that a bulkier protecting group is beneficial in
obtaining 4 (Table 2). However, metal chelation could fix the
orientation between C7-O and C14-O in intermediate 15 that
leads to the undesired diastereomer 13. In fact, 13 was obtained
selectively in entries 4 and 5 (Table 1), where Li+ in nonpolar
solvent and Mg2+, respectively, would stabilize the seven-
membered chelate in 15, unlike Li+ in ethereal solvent. Hence,
the diastereoselectivity of the C-C bond formation appears to
be controlled by a balance between steric interaction and
chelation of C7-OM and C14-oxymethylene.
With the establishment of an efficient procedure for the
synthesis of (()-4 using bulky protective groups and lithium
amide as controlling elements, efforts turned toward the
development of a procedure for the synthesis of either 4 or ent-4
via an enantioselective deprotonation26 (path a or path b in
Scheme 4). We envisaged that a chiral lithium amide would
differentiate path a and path b through selective recognition of
the two enantiomeric conformers 3′ and ent-3′, respectively. To
realize the enantioselective transformation, DCB-protected dike-
tone 3d was treated with a substituted lithium (R)-1-phenyl-
ethylamide 16a-g with lithium chloride27 in THF (Table 3).28
As expected, all entries showed a diastereoselectivity for 4d +
ent-4d over 13d + ent-13d. In contrast, the enantiomer ratio
between 4d and ent-4d was highly sensitive to the lithium amide
structures: while enantioselectivity was not observed upon
treatment of 3d with 16b29 and 16c30 (entries 2 and 3), 16d,31
16e,32 16f,31 and 16g,33 selectively generated 4d (entries 4-7),
and 16a34 induced the opposite selectivity (entry 1). The absolute
structure of 4d was unambiguously determined by X-ray
crystallographic analysis (Supporting Information). Most im-
portantly, the enantiomer ratio obtained in the case of 16g (4d:
ent-4d 4.7:1, entry 7) was practically sufficient for the asym-
metric total synthesis of enantiopure merrilactone, because of
the crystalline nature of 4d (vide supra). Overall, the selective
formation of 4d among the four isomers was achieved by using
the novel enantioselective desymmetrization strategy.
Total Synthesis of (+)-Merrilactone A. Having developed
a flexible new route to 4d and ent-4d, our effort focused on
(27) Simpkins and Majewski independently reported that the presence
of lithium chloride improved the enantioselectivity of asymmetric depro-
tonation. (a) Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533. (b)
Bunn, B. J.; Simpkins, N. S.; Spavold, Z.; Crimmin, M. J. J. Chem. Soc.,
Perkin Trans. 1 1993, 3113. (c) Majewski, M.; Lazny, R. Tetrahedron Lett.
1994, 35, 3653. (d) Majewski, M.; Gleave, D. M.; Nowak, P. Can. J. Chem.
1995, 73. 1616. (e) Majewski, M.; Lazny, R.; Nowak, P. Tetrahedron Lett.
1995, 36, 5465.
(28) When 16g was used without lithium chloride, the ratio of 4d/ent-
4d was changed into 1.7:1 [(4d + ent-4d):(13d + ent-13d) 8.0:1)].
(29) Yamamoto, K.; Takemae, M. Bull. Chem. Soc. Jpn. 1989, 62, 2111.
(30) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 15506.
(31) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S.
Tetrahedron 1990, 46, 523.
(32) Aoki, K.; Koga, K. Tetrahedron Lett. 1997, 38, 2505.
(33) Although 16g and ent-16g are commercially available, these bases
have not been applied to enantioselective deprotonation reaction to the best
of our knowledge. For their preparation, see: Kowalczyk, B. A.; Rohloff,
J. C.; Dvorak, C. A.; Gardner, J. O. Synth. Commun. 1996, 26, 2009.
(34) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(26) For reviews of enantioselective deprotonation, see: (a) Cox, P. J.;
Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1. (b) Koga, K. Pure
Appl. Chem. 1994, 66, 1487. (c) O’Brien, P. J. Chem. Soc., Perkin Trans.
1 1998, 1439. (d) Plaquevent, J.-C.; Perrard, T.; Cahard, D. Chem. Eur. J.
2002, 8, 3300.
J. Org. Chem, Vol. 72, No. 8, 2007 3069

Inoue et al.
SCHEME 6. Total Synthesis of (+)-Merrilactone A
SCHEME 5. Synthesis of the Carboskeleton of
Merrilactone A
introduced to the hindered tertiary alcohol 19 by using 1,2-
dibromoethyl ethyl ether and N,N-dimethylaniline to provide
20. Treatment of 20 with Bu3SnH and BEt3 under the air38 at
room temperature successfully led to 5-exo product 21r and
C11-epimer 21â in 87% combined yield. When subjected to
acidic conditions, 21â was selectively isomerized to 21r.
NOESY experiments indicated the three-dimensional structure
of 21r, with the ethoxy and C14-O-benzyl groups located in
spatial proximity with the C3 carbon center. This arrangement
of functional groups was beneficial for the next site-selective
installation of C15 at C1: a combination of TMSOTf and i-Pr2-
NEt enabled the regioselective enolization of ketone 21R at the
C1 position in the presence of the sterically shielded C3
methylene, leading to silyl enol ether 22 as a single isomer.
Then, exposure of 22 to Eschenmoser’s salt and subsequent
elimination of amine via N-oxide furnished the carboskeleton
23.39
synthesis and biological evaluation of the unnatural enantiomer
of merrilactone A [(+)-1]. Diketone 3d was first treated with
ent-16g (Scheme 5) to selectively produce ent-4d (57% ee, 79%
yield); one recrystallization afforded enantiopure ent-4d (99%
ee). The C1-C9 olefin and C2-oxygen functionality then were
introduced in two steps: R-selective epoxidation of ent-4d and
subsequent florisil-mediated epoxide opening of 17, to provide
allylic alcohol 18.
To synthesize the entire carboskeleton of 1, introduction of
the C9-quaternary center and a C15-carbon was necessary
(Scheme 5). The former was particularly problematic, owing
to the large steric hindrance of three proximal tetrasubstituted
carbon centers (C4, C5, C6). After attempting a number of
unsuccessful reactions, we conducted intramolecular radical
cyclization of R-bromoacetal 2035,36 because of its powerful yet
mild nature. Oxidation of allylic alcohol 18 was attained by
using IBX37 to yield enedione 19. R-Bromoacetal then was
Seven selective functional group transformations yielded the
targeted (+)-1 from 23 (Scheme 6). Ethyl acetal 23 was
converted to lactone 24 by the action of mCPBA in the presence
of BF3‚Et2O.40 Then, lithium enolate formation from enone 24,
(36) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J. Am. Chem. Soc. 1982, 104, 5564. (b) Stork, G.; Mook, R., Jr.; Biller, S.
A.; Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741.
(37) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(b) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem.
1995, 60, 7272.
(38) (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 2547. For a review, see: (b) Ollivier, C.; Renaud, P. Chem. ReV. 2001,
101, 3415.
(35) For recent reviews on radical reactions, see: (a) Zhang, W.
Tetrahedron 2001, 57, 7237. (b) Salom-Roig, X. J.; De´ne`s, F.; Renaud, P.
Synthesis 2004, 1903. (c) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005,
61, 10377.
(39) Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am.
Chem. Soc. 1976, 98, 6715.
(40) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron lett. 1978, 19,
419.
3070 J. Org. Chem., Vol. 72, No. 8, 2007

Synthesis of the Unnatural Enantiomer of Merrilactone A
FIGURE 3. Three-dimensional molecular model (MM2*, MacroModel
Version 6.0) of compound 28.
using LiBH(s-Bu)3 followed by in situ triflation,41,42 afforded
enol triflate 25, whose palladium-mediated hydrogenolysis
proceeded smoothly to give trisubstituted olefin 26.43,44 Exposure
45
of 26 to Na in NH3 effected stereoselective reduction of the
hindered C7-ketone to R-alcohol, presumably via six-membered
chelate 27. Then the removal of both DCB groups gave rise to
lactol 29 along with lactone 28. This mixture was subjected to
Fetizon oxidation46 to produce the desired bis-γ-lactone 30 as
the exclusive isomer via 28. It appears that the reactivity toward
oxidation of the C12 alcohol is greater than that toward the C7
and C14 alcohols because of its more exposed nature: molecular
modeling (Macro Model Version 6.0)47 of 28 suggested that
only the C12-hydroxy methyl group adopts the pseudoequatorial
conformation depicted in Figure 3.
Last, epoxidation of 30 with dimethyldioxirane48 selectively
furnished 31, which was subjected to acid-promoted oxetane
formation to produce (+)-1. Comparison of 1H NMR, 13C NMR,
IR, and HRMS data revealed that the synthetic product was
identical with an authentic sample from a natural source except
for the optical rotation [[R]27 +15.7 (c 0.19, CH3OH); nat.:
D
[R]18 -16.7 (c 1.10, CH3OH)]].4,49
D
Neurite Outgrowth Activity of (-)- and ent-(+)-Merrilac-
tone A. We evaluated the neuritogenic activity of both enan-
tiomers of synthetic merrilactone [(-)-112, (+)-1] using primary
cultures of fetal rat cortical neurons (Figure 4).50 Surprisingly,
both enantiomers of merrilactone A stimulated neurite outgrowth
to a similar extent, in a dose-dependent manner between 0.1
µM and 1 µM. This unexpected but informative comparable
potency of the two enantiomers of 1 promotes elucidation of
the mechanism of action; such studies are in progress.
Conclusion
Concise total synthesis of (+)-merrilactone A has been
achieved based on the novel enantioselective desymmetrization
FIGURE 4. Neurite outgrowth-promoting activity of (+)-merrilactone
A and (-)-merrilactone A in primary cultures of fetal rat cortical
neurons: (A) control, (B) (-)-merrilactone A 0.1 µM, and (C) percent
change from untreated neurons. Key for part C: ***, p < 0.001
compared with control; **, p < 0.01 compared with control; and *, p
< 0.05 compared with control.
(41) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335.
(42) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(43) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
(44) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630.
(45) Huffman, J. W.; Charles, J. T. J. Am. Chem. Soc. 1968, 90, 6486.
(46) (a) Fetizon, M.; Golfier, M. Compt. Rend. 1968, 267, 900. (b)
McKillop, A.; Young, D. W. Synthesis 1979, 401.
strategy (1.3% overall yield, 23 steps). Key transformations in
the total synthesis include the following: (i) seven-step pairwise
symmetrical functionalization to synthesize 3d by taking
advantage of its meso-symmetry; (ii) a new enantioselective
transannular aldol reaction of meso-3d to construct the bicyclo-
[3.3.0]octane core 4d; (iii) radical cyclization to establish the
sterically congested C9-quaternary carbon of 21r; (iv) highly
selective substrate-controlled reactions to introduce three func-
tional groups (the C15-methylene of 23, C7-R-alcohol of 29,
and C12-γ-lactone of 30). Furthermore, synthetic (-)- and ent-
(47) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440-467.
(48) (a) Murray, R. W. Chem. ReV. 1989, 89, 1187. (b) Adam, W.; Curci,
R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205.
(49) The reported optical rotation of merrilactone A [[R]21 +11.8 (c
D
1.20, CH3OH), ref 4] was found to be an error. The correct value of the
natural product is [R]18 -16.7 (c 1.10, CH3OH). For unambigrous
D
determination of the absolute structure of merrilactone A, see ref 12.
(50) Brewer, G. J. J. Neurosci. Res. 1995, 42, 674.
J. Org. Chem, Vol. 72, No. 8, 2007 3071

Inoue et al.
(91%, 1.2:1). Major isomer: colorless solid; mp 263-266 °C; Rf
(+)-merrilactone A equally promoted neurite outgrowth in
primary neuronal culture. The unanticipated biological behavior
of ent-(+)-1 provided a rewarding culmination to the present
synthesis of the unnatural enantiomer. The flexible asymmetric
route described here would provide practical access not only to
both enantiomers, but also to analogous structures for future
detailed biological and SAR studies.
0.35 (silica gel, 3:1 hexane/EtOAc); IR (film) 3420, 2931, 1582,
1
1564, 1437, 1199, 1097, 998, 768, 730 cm-1; H NMR (CDCl3,
500 MHz) δ 1.03 (s, 6H), 3.34 (d, J ) 8.5 Hz, 2H), 3.67 (d, J )
9.5 Hz, 2H), 3.72 (d, J ) 9.5 Hz, 2H), 3.90 (d, J ) 8.5 Hz, 2H),
4.69 (d, J ) 11 Hz, 2H), 4.72 (d, J ) 11 Hz, 2H), 7.19 (m, 2H),
7.32 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 13.6, 45.6, 67.2,
70.1, 75.1, 128.2, 129.7, 133.5, 136.8. Minor isomer: colorless
solid ; mp 263-266 °C; Rf 0.30 (silica gel, 3:1 hexane/EtOAc); 1H
NMR (CDCl3, 500 MHz) δ 0.96 (s, 6H), 2.75 (s, 2H), 3.44 (d, J )
9 Hz, 2H), 3.47 (d, J ) 9 Hz, 2H), 4.00 (d, J ) 3 Hz, 2H), 4.61(d,
J ) 11 Hz, 2H), 4.64 (d, J ) 11 Hz, 2H), 7.14 (m, 2H), 7.27 (m,
4H).
Experimental Section
Diol 7. Benzophenone (3.63 g, 19.8 mmol) and trans-1,2-
dichloroethene 5 (60.8 mL, 793 mmol) were dissolved in acetone
(2.6 L). 2,3-Dimethylmaleic anhydride 2 (25.0 g, 198 mmol) was
divided into three portions and the first portion was added into a
flask. The solution was irradiated at room temperature for 60 min.
The second portion of 2,3-dimethylmaleic anhydride 2 was added
into the reaction mixture, which was then irradiated for 60 min.
Then, the last portion was added into the reaction mixture, which
was then irradiated for 70 min. Concentration gave the crude 6,
which was directly used in the next reaction.
Zinc dust was successively washed with 2% HCl, H2O, EtOH,
and Et2O, and then dried under reduced pressure. The freshly
activated zinc (205 g, 3.13 mol) was added into a flask equipped
with a mechanical stirrer, and toluene (150 mL) and TMSCl (30.0
mL, 235 mmol) were then introduced. To a suspension was added
a solution of 6 in toluene (150 mL) and acetic anhydride (192 mL).
The mixture was stirred at 85 °C for 2 d, then concentrated to give
the crude olefin, which was used directly in the next reaction: 1H
NMR (200 MHz, CDCl3) δ 1.46 (s, 6H), 6.46 (s, 2H).
Diene 10. To a solution of DMSO (5.4 mL, 76 mmol) in CH2-
Cl2 (100 mL) at -78 °C was added oxalyl chloride (5 mL, 57
mmol). After 5 min, diol 8 (4.7 g, 9.5 mmol) in CH2Cl2 (90 mL)
was introduced, and the resultant mixture was stirred for 30 min at
-78 °C, before being treated with triethylamine (21.2 mL, 152
mmol). The resultant mixture was stirred vigorously for 1 h at
-78 °C. Allylmagnesium bromide (0.7 M in Et2O, 95 mL, 66.5
mmol) was then added to the solution. The reaction mixture was
stirred for 15 min at -78 °C, quenched with saturated aqueous
ammonium chloride, and extracted twice with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated.
The residue was purified with flash column chromatography
(hexane/Et2O 30:1 to 10:1) to give 4.3 g of diene 10 as a mixture
of two diastereomers (80% for 2 steps, 10rr:10ââ 9:1). 10rr:
colorless solid; mp 90-92 °C; Rf 0.61 (silica gel, 3:1 hexane/
EtOAc); IR (film) 3448, 2976, 1582, 1563, 1437, 1199, 1097, 777,
1
729 cm-1; H NMR (CDCl3, 500 MHz) δ 1.07 (s, 6H), 2.28 (m,
To a suspension of LiAlH4 (23.8 g, 626 mmol) in THF (300
mL) at 0 °C was added the above olefin in THF (100 mL). The
reaction mixture was stirred at room temperature for 5 h, then
quenched with 2 M HCl. The aqueous layer was extracted with
EtOAc twice. The organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was purified with open
column chromatography (hexane/EtOAc 5:1 to 3:1), and recrystal-
lized from EtOAc/hexane to give 16.0 g of diol 7 (57% for 3
steps): colorless crystals: mp 98-99 °C (hexane/EtOAc); Rf 0.31
(silica gel, 1:1 hexane/EtOAc); IR (film) 3226, 2915, 1469, 1291,
1029, 769 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.23 (s, 6H), 2.70
(s, 2H), 3.48 (d, J ) 11.6 Hz, 2H), 3.90 (d, J ) 11.6 Hz, 2H), 6.01
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 19.1, 52.9, 68.2, 140.9;
HRMS (ESI) calcd for C8H14O2Na+ 165.0886 (M + Na+), found
165.0886.
Diol 8. To a suspension of NaH (1.2 g, 50.6 mmol) in DMF
(116 mL) at 0 °C were added diol 7 (3.6 g, 25.3 mmol) in DMF
(200 mL), and then DCBBr (18.2 g, 75.9 mmol). The reaction
mixture was stirred at room temperature for 1 d, quenched with
H2O, and extracted twice with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated. The
residue was purified with open column chromatography (hexane/
Et2O 10:1) to give 11.6 g of the bis-DCB ether (100%): colorless
solid; mp 120-122 °C; Rf 0.48 (silica gel, 3:1 hexane/EtOAc); IR
(film) 2864, 1454, 1094, 1074, 736, 697 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.21 (s, 6H), 3.47 (d, J ) 9.0 Hz, 2H), 3.60 (d, J ) 9.0
Hz, 2H), 4.46 (d, 12.0 Hz, 2H), 4.50 (d, J ) 12.0 Hz, 2H), 6.15 (s,
2H), 7.29-7.36 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 19.3,
51.8, 73.2, 75.4, 127.3, 127.5, 128.2, 138.8, 141.1; HRMS (ESI)
calcd for C22H22Cl4O2Na 481.0272 (M + Na+), found 481.0266.
A solution of the above bis-DCB ether (2.43 g, 5.28 mmol) in
t-BuOMe (7 mL), t-BuOH (7 mL), and H2O (7 mL) was treated
with NMO (0.5 M in H2O, 1.3 mL, 15.8 mmol) and OsO4 (38 mM
in t-BuOH, 1.4 mL, 0.05 mmol), and the mixture was stirred at
room temperature for 1 d. Then, the solution was diluted with H2O
and extracted three times with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated. The
residue was purified with open column chromatography (hexane/
Et2O 6:1) to give 2.37 g of diol 8 as a mixture of diastereomers
2H), 2.41 (m, 2H), 3.72 (d, J ) 9.5 Hz, 2H), 3.75 (d, J ) 9.5 Hz,
2H), 4.67 (d, J ) 10.5 Hz, 2H), 4.71 (d, J ) 10.5 Hz, 2H), 4.99
(d, J ) 10.5 Hz, 2H), 5.05 (dd, J ) 10.5, 2 Hz, 2H), 5.84 (m, 2H),
7.19 (t, J ) 8 Hz, 2H), 7.32 (d, J ) 8 Hz, 4H); 13C NMR (CDCl3,
125 MHz) δ 17.1, 38.4, 47.1, 67.4, 74.0, 77.9, 117.4, 128.3, 129.9,
133.4, 134.6, 136.8; HRMS (ESI) calcd for C28H32Cl4O4Na
595.0952 (M + Na+), found 595.0947.
Diketone 3d. To a solution of diene 10 (3.88 g, 6.76 mmol) in
CH2Cl2 (560 mL) was added (PCy3)2Cl2RudCHPh (0.6 g, 0.68
mmol), and the resultant mixture was heated to reflux for 5 h. After
being cooled to room temperature, the solution was treated with
Pb(OAc)4 (3.60 g, 8.2 mmol). Then, the mixture was filtrated
through a pad of silica gel to give 3.50 g of diketone 3d (95%).
The obtained 3d was recrystallized from EtOAc for the X-ray
crystallographic analysis (see Figure 2): colorless crystals; mp 168-
170 °C; Rf 0.48 (silica gel, 3:1 hexane/EtOAc); IR (film) 2937,
2360, 1693, 1563, 1437, 1097, 1066, 772 cm-1; 1H NMR (CDCl3,
500 MHz) δ 1.20 (s, 6H), 2.96 (m, 2H), 3.14 (m, 2H), 3.45 (d, J
) 8.5 Hz, 2H), 4.09 (d, J ) 8.5 Hz, 2H), 4.65 (d, J ) 10.5 Hz,
2H), 4.68 (d, J ) 10.5 Hz, 2H), 5.63 (m, 2H), 7.18 (m, 2H), 7.29
(m, 4H); 13C NMR (CDCl3, 125 MHz) δ 15.919, 40.9, 56.2, 67.5,
73.6, 125.0, 136.8, 210.9; HRMS (ESI) calcd for C26H26Cl4O4Na
565.0483 (M + Na)+, found 565.0477.
General Procedure for the Transannular Aldol Reaction.
[S-(R*,S*)]-(+)-N-(1-Phenylethyl)-1-azabicyclo[2.2.2]octan-3-
amine (16g, 145 mg, 630 µmol) and LiCl (26.7 mg, 630 µmol)
were dissolved in THF (4 mL). To this solution at -78 °C was
added n-butyllithium (1.57 M in hexane, 401 µL, 630 µmol), and
the mixture was allowed to warm to room temperature. After 20
min, the solution was recooled to -78 °C and stirred for 1 h. In a
separate flask, diketone 3d (34.3 mg, 63.0 µmol) was dissolved in
THF (4 mL) and cooled to -78 °C. The solution of lithium amide
was transferred to the solution of 3d. After being stirred for 10
min at -78 °C, the reaction mixture was quenched with saturated
aqueous ammonium chloride and extracted twice with EtOAc. The
organic layer was washed with brine, dried over MgSO4, and
concentrated. The residue was purified with flash column chroma-
tography (hexane/EtOAc 10:1 to 2:1) to give 26.9 mg of 4d (78%,
65%ee), along with 4.1 mg of the undesired isomer 13d (12%).
3072 J. Org. Chem., Vol. 72, No. 8, 2007

Synthesis of the Unnatural Enantiomer of Merrilactone A
Enantiomeric excess were determined with HPLC (DAICEL
CHIRALCEL, OD, 250 × 4.6 mm, UV 254 nm, hexane/i-PrOH
85:15, 1.0 mL/min, 4d: TR ) 15 min, ent-4d: TR ) 9 min).
Aldol Product ent-4d. [R-(R*,S*)]-(-)-N-(1-Phenylethyl)-1-
azabicyclo[2.2.2]octan-3-amine (ent-16g, 4.12 g, 17.9 mmol) and
LiCl (759 mg, 17.9 mmol) were dissolved in THF (70 mL). To
this solution at -78 °C was added n-butyllithium (1.57 M in hexane,
11.4 mL, 17.9 mmol), and the mixture was allowed to warm to
room temperature. After 20 min, the solution was recooled to
-78 °C and stirred for 1 h. In a separate flask, diketone 3d (2.73
g, 5.02 mmol) was dissolved in THF (100 mL) and cooled to
-78 °C. The solution of lithium amide was transferred to the
solution of 3d. After being stirred for 10 min at -78 °C, the reaction
mixture was quenched with saturated aqueous ammonium chloride
and extracted twice with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated. The residue was
purified with flash column chromatography (hexane/EtOAc 10:1
to 2:1) to give 2.16 g of ent-4d (79%, 57% ee), along with 473 mg
of the undesired isomer ent-13d (17%). The obtained ent-4d was
recrystallized from 1:1 hexane/EtOAc to give 1.15 g of enantiopure
ent-4d (53%, 99% ee). Enantiopure ent-4d: colorless crystals; mp
150-151 °C; Rf 0.40 (silica gel, 3:1 hexane/EtOAc); [R]26D +208.7
(c 1.00, CHCl3); IR (film) 2928, 2359, 1737, 1564, 1437, 1199,
2 h, the solution was filtrated and concentrated to give allylic alcohol
18, which was used in the next reaction without further purifica-
tion: colorless crystals; mp 191-192.5 °C; Rf 0.26 (silica gel, 1:1
hexane/EtOAc); IR (film) 3467, 2934, 2877, 1736, 1581, 1563,
1437, 1199, 1100, 837, 768, 732 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.02 (s, 3H), 1.45 (s, 3H), 1.66 (d, J ) 14.5 Hz, 1H), 2.31 (dd,
J ) 14.5, 5.5 Hz, 1H), 2.48 (s, br, 2H), 3.32 (d, J ) 9.5 Hz, 1H),
3.56 (d, J ) 9.5 Hz, 1H), 3.62 (d, J ) 9 Hz, 1H), 3.83 (d, J ) 9
Hz, 1H), 4.33 (d, J ) 10.5 Hz, 1H), 4.38 (d, J ) 10.5 Hz, 1H),
4.68 (d, J ) 10 Hz, 1H), 4.73 (d, J ) 10 Hz, 1H), 4.90 (dd, J )
5.5, 2.5 Hz, 1H), 6.37 (d, J ) 2.5 Hz, 1H), 7.18 (m, 2H), 7.32 (m,
4H); 13C NMR (CDCl3, 125 MHz) δ 14.4, 20.8, 43.4, 47.9, 59.5,
66.6, 67.5, 73.8, 74.3, 79.8, 88.5, 128.3, 128.3, 128.3, 129.8, 130.0,
132.5, 133.6, 136.5, 136.9, 153.6, 204.2; HRMS (ESI) calcd for
C26H26Cl4O5Na 581.0432 (M + Na+), found 581.0427.
Enedione 19. A solution of allylic alcohol 18 in DMSO (50
mL) was treated with IBX (0.7 M in DMSO, 30.0 mL, 23.2 mmol),
and the mixture was stirred for 1 h at room temperature. Then, the
solution was diluted with H2O and Et2O, and filtrated through Celite.
The aqueous layer was extracted twice with Et2O. The combined
organic layer was washed with sodium bicarbonate and brine, dried
over MgSO4, and concentrated. The residue was purified with flash
column chromatography (hexane/EtOAc 4:1) to give 4.90 g of
enedione 19 (76%, 3 steps): colorless crystals; mp 195-198 °C;
1
1100, 768 cm-1; H (CDCl3, 500 MHz) δ 1.09 (s, 1H), 1.14 (s,
3H), 2.44 (s, 1H, br), 2.45 (d, J ) 18.5 Hz, 1H), 2.95 (dd, J )
18.5, 2 Hz, 1H), 3.10 (d, J ) 9 Hz, 1H), 3.19 (d, J ) 2.5 Hz, 1H),
3.46 (d, J ) 10 Hz, 1H), 3.48 (d, J ) 10 Hz, 1H), 4.11 (d, J ) 9
Hz, 1H), 4.62 (d, J ) 11 Hz, 1H), 4.66 (d, J ) 11 Hz, 1H), 4.70
(s, 2H), 5.55 (dd, J ) 5.5, 2 Hz, 1H), 5.58 (dd, J ) 5.5, 2.5 Hz,
1H), 7.21 (m, 2H), 7.33 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ
17.4, 19.1, 47.8, 50.2, 59.7, 60.4, 65.9, 67.2, 67.4, 73.2, 75.0, 86.9,
126.6, 128.4, 128.4, 130.0, 131.4, 133.0, 133.2, 136.7, 137.0, 215.4;
HRMS (ESI) calcd for C26H26Cl4O4Na 565.0477 (M + Na)+, found
565.0477. ent-13d: colorless crystals; mp 150.5-152 °C; Rf 0.36
(silica gel, 3:1 hexane/EtOAc); IR (film) 3537, 2877, 1737, 1582,
Rf 0.65 (silica gel, 1:1 hexane/EtOAc); [R]26 -49.2 (c 1.00,
D
CHCl3); IR (film) 3462, 2877, 1718, 1582, 1564, 1437, 1199, 1098,
779, 732 cm-1; 1H (CDCl3, 500 MHz) δ 1.09 (s, 3H), 1.50 (s, 3H),
2.35 (d, J ) 17 Hz, 1H), 2.70 (d, J ) 17 Hz, 1H), 3.40 (d, J ) 9.5
Hz, 1H), 3.60 (d, J ) 9.5 Hz, 1H), 3.73 (d, J ) 9.5 Hz, 1H), 3.80
(d, J ) 9.5 Hz, 1H), 4.33 (d, J ) 10.5 Hz, 1H), 4.36 (d, J ) 10.5
Hz, 1H), 4.69 (d, J ) 10.5 Hz, 1H), 4.74 (d, J ) 10.5 Hz, 1H),
6.15 (s, 1H), 7.25 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 14.6,
21.0, 48.1, 49.2, 56.5, 66.8, 67.5, 73.6, 74.3, 83.1, 128.0, 128.3,
128.4, 129.9, 130.2, 132.0, 133.3, 136.5, 136.9, 171.3, 204.4, 208.4;
HRMS (ESI) calcd for C26H24Cl4O5Na 579.0275 (M + Na+), found
579.0270.
1
1564, 1437, 1199, 1100, 1065, 767, 732 cm-1; H (CDCl3, 500
MHz) δ 1.00 (s, 3H), 1.04 (s, 3H), 2.47 (d, J ) 19.5 Hz, 1H), 2.92
(dd, J ) 19.5, 2.5 Hz, 1H), 2.99 (s, br, 1H), 3.06 (d, J ) 2.5 Hz,
1H), 3.56 (d, J ) 9.5 Hz, 1H), 3.58 (d, J ) 9.5 Hz, 1H), 3.66 (d,
J ) 9.5 Hz, 1H), 3.70 (d, J ) 9.5 Hz, 1H), 4.51 (d, J ) 10.5 Hz,
1H), 4.54 (d, J ) 10.5 Hz, 1H), 4.70 (d, J ) 11 Hz, 1H), 4.74 (d,
J ) 11 Hz, 1H), 5.66 (dd, J ) 5.5, 2.5 Hz, 1H), 5.68 (dd, J ) 5.5,
2.5 Hz, 1H), 7.20 (m, 2H), 7.32 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 15.7, 19.5, 45.6, 50.2, 55.8, 67.0, 67.5, 69.4, 73.5, 74.2,
86.7, 128.2, 128.5, 130.0, 130.3, 130.8, 132.4, 133.1, 136.5, 136.9,
216.6; HRMS (ESI) calcd for C26H26Cl4O4Na 565.0477 (M + Na)+,
found 565.0477.
r-Bromoacetal 20. To a solution of bromine (11.0 mL, 214
mmol) in CH2Cl2 (60 mL) at -78 °C was added ethyl vinyl ether
(22.4 mL, 229 mmol). The resultant mixture was stirred at -78 °C
for 15 min, warmed to room temperature over 5 min, and then
recooled to -78 °C. This mixture was added to a solution of
enedione 19 (6.0 g, 10.7 mmol) and N,N-dimethylaniline (68.2 mL,
537 mmol) in CH2Cl2 (540 mL). The mixture was allowed to warm
to room temperature, and stirred for 4 d. Then, the solution was
diluted with 1 M HCl and CH2Cl2. The organic layer was washed
with 1 M HCl (3×), saturated aqueous sodium bicarbonate, and
brine, dried over MgSO4, and concentrated. The residue was purified
with flash column chromatography (hexane/EtOAc 17:1 to 5:1) to
give 4.36 g of an inseparable diastereomeric mixture of R-bro-
moacetal 20 (62%, 4:1), along with recovered enedione 19 (2.06 g,
38%).
Epoxide 17. A solution of ent-4d (6.30 g, 11.6 mmol) in CH2Cl2
(580 mL) was cooled to 0 °C and treated with mCPBA (3.6 g,
34.7 mmol). The reaction mixture was stirred at room temperature
for 4 h, and then quenched with saturated aqueous sodium
thiosulfate. The aqueous layer was extracted three times with
EtOAc. The organic layer was washed with saturated aqueous
sodium bicarbonate and brine, dried over MgSO4, and concentrated
to give epoxide 17, which was used in the next reaction without
further purification: Rf 0.35 (silica gel, 3:1 hexane/EtOAc); IR
(film) 3401, 2932, 1714, 1563, 1437, 1247, 1199, 1098, 1079, 767,
Cyclized Product 21. To a solution of bromide 20 (1.0 g, 1.41
mmol) and Bu3SnH (1.15 mL, 8.5 mmol) in toluene (140 mL) was
added BEt3 (1.0 M in hexane, 4.25 mL, 8.5 mmol) at room
temperature under air. After being stirred for 30 min, the mixture
was concentrated to 1/3 of total volume, and purified with flash
column chromatography (hexane/Et2O 3:1) to give 648 mg of
cyclized product 21r (73%) and 131 mg of 21â (14%). 21r:
colorless solid; mp 160-162.5 °C; Rf 0.40 (silica gel, 3:1 hexane/
EtOAc); [R]27D -22.2 (c 1.00, CHCl3); IR (film) 2976, 2928, 2878,
1
668 cm-1; H NMR (CDCl3, 500 MHz) δ 1.09 (s, 3H), 1.10 (s,
3H), 1.69 (d, J ) 15 Hz, 1H), 2.85 (dd, J ) 15, 2 Hz, 1H), 2.87
(s, 1H), 3.00 (dd, J ) 2, 2 Hz, 1H), 3.50 (d, J ) 2 Hz, 1H), 3.52
(d, J ) 9.5 Hz, 1H), 3.60 (d, J ) 9.5 Hz, 1H), 3.61 (d, J ) 9.5 Hz,
1H), 3.72 (d, J ) 9.5 Hz, 1H), 4.54 (d, J ) 10 Hz, 1H), 4.57 (d,
J ) 10.5 Hz, 1H), 4.59 (d, J ) 10 Hz, 1H), 4.60 (d, J ) 10.5 Hz,
1H), 7.20 (m, 2H), 7.31 (m, 2H), 7.32 (m, 2H); 13C NMR (CDCl3,
125 MHz) δ 18.1, 19.7, 39.2, 50.1, 57.2, 59.1, 59.1, 60.4, 62.1,
67.2, 73.7, 74.8, 86.4, 128.3, 128.4, 128.4, 130.0, 130.1, 132.8,
133.1, 136.7, 136.8.
1
1739, 1582, 1564, 1438, 1199, 1099, 769, 732 cm-1; H (CDCl3,
500 MHz) δ 1.0 (s, 3H), 1.13 (t, J ) 6.5, 3H), 1.28 (s, 3H), 2.20
(d, J ) 14 Hz, 1H), 2.49 (dd, J ) 14, 5 Hz, 1H), 2.51 (d, J ) 19
Hz, 1H), 2.63 (d, J ) 19 Hz, 1H), 2.80 (d, J ) 19 Hz, 1H), 2.96
(d, J ) 19 Hz, 1H), 3.26 (d, J ) 10 Hz, 1H), 3.37 (d, J ) 10 Hz,
1H), 3.40 (dq, J ) 9, 6.5 Hz, 1H), 3.42 (d, J ) 10 Hz, 1H), 3.56
(d, J ) 10 Hz, 1H), 3.72 (dq, J ) 9, 6.5 Hz, 1H), 4.10 (d, J ) 11
Hz, 1H), 4.36 (d, J ) 11 Hz, 2H), 4.47 (d, J ) 11 Hz, 1H), 5.24
(d, J ) 5 Hz, 1H), 7.26 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ
Allylic Alcohol 18. To a solution of the above epoxide 17 in
CH2Cl2 (580 mL) was added florisil (63 g). After being stirred for
J. Org. Chem, Vol. 72, No. 8, 2007 3073

Inoue et al.
14.2, 14.7, 21.0, 46.3, 49.6, 50.3, 60.4, 62.7, 65.2, 65.7, 67.1, 72.9,
73.6, 95.5, 105.2, 116.8, 128.2, 129.8, 130.1, 131.8, 133.2, 136.8,
137.2, 148.1, 171.2, 202.6, 216.0; HRMS (ESI) calcd for C30H32-
Cl4O6Na 651.0851 (M + Na+), found 651.0845. 21r: colorless
solid; mp 201-203 °C; Rf 0.25 (silica gel, 3:1 hexane/EtOAc);
aqueous layer was extracted twice with Et2O. The organic layer
was washed with aqueous sodium bicarbonate three times and brine,
dried over MgSO4, and concentrated. The residue was purified with
flash column chromatography (hexane/EtOAc 10:1 to 5:1) to give
140 mg of γ-lactone 24 (78%): colorless solid; Rf 0.31 (silica gel,
3:1 hexane/EtOAc); [R]25D -12.0 (c 1.00, CHCl3); IR (film) 2929,
[R]27 -80.5 (c 1.00, CHCl3); IR (film) 2676, 2878, 1741, 1581,
D
1
1
1564, 1437, 1198, 1099, 769, 731 cm-1; H (CDCl3, 500 MHz) δ
1785, 1734 cm-1; H NMR (500 MHz, CDCl3) δ 1.08 (s, 3H),
1.02 (s, 3H), 1.19 (t, J ) 7 Hz, 3H), 1.46 (s, 3H), 2.34 (m, 4H),
2.85 (d, J ) 19.5 Hz, 1H), 2.99 (d, J ) 19.5 Hz, 1H), 3.25 (d, J )
9.5 Hz, 1H), 3.32 (d, J ) 9.5 Hz, 1H), 3.42 (d, J ) 9.5 Hz, 1H),
3.55 (dq, J ) 9.5, 6 Hz, 1H), 3.61 (d, J ) 9.5 Hz, 1H), 3.80 (dq,
J ) 9.5, 6 Hz, 1H), 4.07 (d, J ) 10 Hz, 1H), 4.34 (d, J ) 10 Hz,
1H), 4.45 (d, J ) 12 Hz, 1H), 5.24 (dd, J ) 6, 6 Hz, 1H), 7.23 (m,
6H); 13C NMR (CDCl3, 125 MHz) δ 14.4, 15.3, 20.8, 46.5, 48.1,
49.2, 49.8, 54.1, 60.1, 65.7, 66.0, 67.1, 73.4, 73.7, 94.9, 104.4,
128.2, 128.5, 129.8, 130.3, 131.7, 133.3, 136.7, 137.2, 212.9, 219.6;
HRMS (ESI) calcd for C28H32Cl4O4Na 651.0851 (M + Na+), found
651.0844.
Isomerization of 21â to 21r. A solution of acetal 21â (15.0
mg, 23.8 µmol) in EtOH (1.2 mL) was treated with camphorsulfonic
acid (17.0 mg, 71.4 µmol), and the mixture was heated to 40 °C
for 1 d. The reaction mixture was quenched with saturated aqueous
sodium bicarbonate, and extracted twice with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated.
The residue was purified with flash column chromatography
(hexane/Et2O 3:1) to give 15.0 mg of 21r (100%).
1.22 (s, 3H), 2.55 (d, J ) 19.5 Hz, 1H), 2.78 (d, J ) 19.5 Hz, 1H),
3.11 (d, J ) 19.5 Hz, 1H), 3.28 (d, J ) 9.5 Hz, 1H), 3.31 (d, J )
19.5 Hz, 1H), 3.41 (d, J ) 10.0 Hz, 1H), 3.46 (d, J ) 9.5 Hz, 1H),
3.61 (d, J ) 10.0 Hz, 1H), 4.09 (d, J ) 10.5 Hz, 1H), 4.25 (d, J )
12.0 Hz, 1H), 4.37 (d, J ) 12.0 Hz, 1H), 4.38 (d, J ) 10.5 Hz,
1H), 5.62 (s, 1H), 5.78 (s, 1H), 7.19 (m, 2H), 7.29 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 14.7, 19.7, 43.0, 45.8, 50.8, 60.1, 65.8,
67.3, 72.8, 73.3, 95.4, 118.4, 128.4, 128.5, 130.1, 130.5, 131.3,
133.0, 136.8, 137.4, 146.5, 174.1, 198.6, 214.2; HRMS (ESI) calcd
for C29H26Cl4O6Na (M + Na)+ 633.0376, found 633.0375.
Enol Triflate 25. A solution of γ-lactone 24 (139 mg, 227 µmol),
Commins reagent (267 mg, 681 µmol), and 4 Å molecular sieves
in THF (7.5 mL) was cooled to -78 °C and treated with L-selectride
(1.06 M in THF, 642 µL, 681 µmol). The resultant solution was
stirred at the same temperature for 15 min. Then, the reaction
mixture was quenched with H2O, and extracted twice with Et2O.
The organic layer was washed with brine, dried over MgSO4, and
concentrated. The residue was purified with flash column chroma-
tography (hexane/EtOAc 20:1 to 10:1) to give 124 mg of enol
triflate 25 (73%): yellow oil; Rf 0.26 (silica gel, 3:1 hexane/EtOAc);
Enone 23. A solution of ketone 21r (500 mg, 793 µmol) in
CH2Cl2 (8 mL) was cooled to -20 °C and treated with EtN(i-Pr)2
(2.2 mL, 12.7 mmol) and TMSOTf (1.44 mL. 7.93 mmol). The
reaction mixture was stirred for 4 h at the same temperature,
quenched with saturated aqueous sodium bicarbonate, and extracted
twice with EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated to give silyl enol ether 22, which
was used in the next reaction without further purification.
A solution of the above silyl enol ether in CH2Cl2 (8.0 mL) was
treated with Me2NCH2+I- (900 mg, 4.76 mmol), and the mixture
was stirred for 3 h at 35 °C, then the reaction mixture was cooled
to 0 °C and quenched with 1 M HCl. Potassium carbonate was
introduced to neutralize the mixture. The aqueous layer was
extracted three times with EtOAc. The organic layer was washed
with brine and concentrated to give a mixture of the â-amino ketone
and enone 23, which was used directly in the next reaction.
A solution of the above mixture in CH2Cl2 (8.0 mL) was treated
with mCPBA (65%, 400 mg, 2.4 mmol), and the mixture was stirred
for 1 h at room temperature. Then, the reaction was quenched with
saturated aqueous thiosulfate. The aqueous layer was extracted twice
with EtOAc. The organic layer was washed with aqueous sodium
bicarbonate and brine, dried over MgSO4, and concentrated. The
residue was purified with flash column chromatography (hexane/
Et2O 3:1 to hexane/EtOAc 3:1) to give 356 mg of enone 23 (69%
for 3 steps): colorless crystals; mp 108-111 °C; Rf 0.48 (silica
[R]26 +71.7 (c 1.00, CHCl3); IR (film) 2930, 1787, 1743 cm-1
;
D
1H NMR (500 MHz, CDCl3) δ 1.08 (s, 3H), 1.14 (s, 3H), 1.52 (m,
3H), 2.62 (d, J ) 19.0 Hz, 1H), 2.66 (d, J ) 19.0 Hz, 1H), 2.74
(dq, J ) 17.5, 2.5 Hz, 1H), 3.30 (dq, J ) 17.5, 2.5 Hz, 1H), 3.49
(d, J ) 9.5 Hz, 1H), 3.54 (d, J ) 9.5 Hz, 1H), 3.66 (d, J ) 10.0
Hz, 1H), 3.72 (d, J ) 10.0 Hz, 1H), 4.52 (d, J ) 10.0 Hz, 1H),
4.53 (d, J ) 10.0 Hz, 1H), 4.59 (d, J ) 10.0 Hz, 1H), 4.60 (d, J )
10.0 Hz, 1H), 7.22 (m, 2H), 7.33 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 8.9, 17.6, 18.9, 37.4, 40.0, 50.2, 57.6, 64.6, 67.2, 67.6,
73.6, 74.3, 95.0, 118.4 (q, J ) 319 Hz, 1C), 127.4, 128.5, 128.6,
130.3, 130.6, 132.4, 132.7, 136.8, 136.9, 141.1, 173.9, 214.7; HRMS
(ESI) calcd for C30H27Cl4F3O8SNa (M + Na)+ 767.0025, found
767.0023.
Olefin 26. A solution of enol triflate 25 (124 mg, 166 µmol)
and tributylamine (236 µL, 996 µmol) in DMF (5.0 mL) was
degassed by using the freeze-pump-thaw technique (3×). To this
mixture were added PPh3 (43.5 mg, 166 µmol) and Pd(OAc)2 (19.8
mg, 88.0 µmol) and then formic acid (31.3 µL, 830 µmol) in DMF
(1.0 mL), which was separately degassed by using the freeze-
pump-thaw technique (3×) beforehand. The mixture was stirred
at 40 °C for 2 h, and then diluted with H2O. The aqueous solution
was extracted twice with EtOAc. The organic layer was washed
with H2O two times and brine, dried over MgSO4, and concentrated.
The residue was purified with flash column chromatography
(hexane/EtOAc 20:1 to 10:1) to give 90.9 mg of olefin 26 (92%):
gel, 3:1 hexane/EtOAc); [R]26 -3.6 (c 1.00, CHCl3); IR (film)
D
colorless solid; Rf 0.40 (silica gel, 3:1 hexane/EtOAc); [R]25
2878, 1731, 1640, 1582, 1564, 1438, 1201, 1080, 1060, 767, 733
cm-1; 1H (CDCl3, 500 MHz) δ 1.0 (s, 3H), 1.10 (t, J ) 7 Hz, 3H),
1.29 (s, 3H), 2.26 (d, J ) 13.5 Hz, 1H), 2.63 (dd, J ) 13.5, 5.5
Hz, 1H), 2.64 (d, J ) 19.5 Hz, 1H), 3.04 (d, J ) 19.5 Hz, 1H),
3.25 (d, J ) 9.5 Hz, 1H), 3.35 (d, J ) 10.5 Hz, 1H), 3.59 (d, J )
9.5, 7 Hz, 1H), 3.41 (d, J ) 9.5 Hz, 1H), 3.52 (d, J ) 10.5 Hz,
1H), 3.69 (dq, J ) 9.5, 7 Hz, 1H), 4.10 (d, J ) 10.5 Hz, 1H), 4.24
(d, J ) 12 Hz, 1H), 4.35 (d, J ) 12 Hz, 1H), 5.23 (d, J ) 5.5 Hz,
1H), 5.54 (s, 1H), 5.70 (s, 1H), 7.22 (m, 6H); 13C NMR (CDCl3,
125 MHz) δ 14.7, 21.0, 46.3, 49.6, 50.3, 60.4, 62.7, 65.1, 65.7,
67.1, 72.9, 73.6, 95.5, 105.2, 116.8, 128.2, 128.3, 129.8, 130.1,
131.8, 133.2, 136.8, 137.2, 148.1, 202.6, 216.0; HRMS (ESI) calcd
for C31H32Cl4O6Na 663.0851 (M + Na+), found 663.0845.
γ-Lactone 24. To a solution of enone 23 (189 mg, 294 µmol)
and mCPBA (329 mg, 1.47 mmol) in CH2Cl2 was added BF3‚Et2O
(150 µL, 1.18 mmol). The mixture was stirred at room temperature
for 10 min and quenched with saturated aqueous thiosulfate. The
D
+148.4 (c 1.00, CHCl3); IR (film) 2938, 1775, 1738 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.02 (s, 3H), 1.13 (s, 3H), 1.55 (m, 3H), 2.48
(m, 1H), 2.55 (d, J ) 19.0 Hz, 1H), 2.61 (d, J ) 19.0 Hz, 1H),
3.00 (m, 1H), 3.46 (d, J ) 9.0 Hz, 1H), 3.47 (d, J ) 9.0 Hz, 1H),
3.63 (d, J ) 9.5 Hz, 1H), 3.69 (d, J ) 9.5 Hz, 1H), 4.57 (d, J )
10.5 Hz, 1H), 4.59 (d, J ) 10.5 Hz, 1H), 4.60 (d, J ) 10.5 Hz,
1H), 4.63 (d, J ) 10.5 Hz, 1H), 4.82 (m, 1H), 7.20 (m, 2H), 7.32
(m, 4H); 13C NMR (125 MHz, CDCl3) δ12.7, 14.2, 17.9, 20.9, 29.2,
37.0, 41.7, 49.8, 54.0, 59.1, 67.2, 67.3, 69.2, 73.0, 73.9, 100.0,
125.21, 125.24, 128.38, 128.40, 130.0, 130.1, 132.9, 133.1, 136.9,
137.0, 137.8, 175.4, 214.8; HRMS (ESI) calcd for C29H28Cl4O5Na
(M + Na)+ 619.0583, found 619.0583.
Bis-γ-lactone 30. To a solution of olefin 26 (9.8 mg, 16.4 µmol)
in THF (680 µL) and EtOH (140 µL) at -78 °C was introduced
liquid ammonia (1.6 mL). Then, sodium (37.0 mg, 1.64 mmol) was
added to this solution, and the mixture was stirred at -78 °C for
3074 J. Org. Chem., Vol. 72, No. 8, 2007

Synthesis of the Unnatural Enantiomer of Merrilactone A
30 min. The reaction mixture was quenched with ammonium
chloride, stirred at -78 °C for 40 min, and allowed to warmed to
room temperature. After liquid ammonia was removed, the resultant
solution was filtrated through a pad of florisil to give 3.4 mg of
lactone 28 and lactol 29 (28:29 1.0:3.9).
CD3OD) δ 16.1, 16.6, 17.9, 37.3, 38.5, 57.3, 64.8, 67.4, 69.4, 71.7,
75.8, 83.9, 108.3, 177.4, 180.2; HRMS (ESI) calcd for C15H18O6-
Na (M + Na)+ 317.1001, found 317.0996.
(+)-Merrilactone A (1). A solution of epoxide 31 (10.4 mg,
35.3 µmol) in CH2Cl2 (3.5 mL) was treated with p-TsOH‚H2O (33.6
mg, 177 µmol), and the mixture was stirred for 1 d at room
temperature. After filtration and concentration, the residue was
purified with flash column chromatography (EtOAc) to give 10
mg of (+)-merrilactone A (1) (96%): colorless crystals; mp 269-
A solution of the above mixture in toluene (3.2 mL) was treated
with 50% Ag2CO3 on Celite (181 mg, 328 µmol) and heated to
130 °C. The mixture was stirred at the same temperature for 4 h.
The suspension was filtrated through Celite and concentrated. The
residue was purified with flash column chromatography (hexane/
EtOAc 2:1) to give 1.9 mg of bis-γ-lactone 30 (41% for 2 steps):
colorless crystals; mp 166-169 °C; Rf 0.43 (silica gel, 1:1 hexane/
272 °C; Rf 0.34 (silica gel, 1:3 hexane/EtOAc); [R]28 +15.9 (c
D
0.22, MeOH); IR (film) 3482, 2976, 2930, 1766, 1259, 1076, 1017,
1
986 cm-1; H NMR (500 MHz, CD3OD) δ 1.08 (s, 3H), 1.25 (s,
EtOAc); [R]27 +141.3 (c 0.27, CH3OH); IR (film) 3467, 2925,
3H), 1.49 (s, 3H), 2.28 (dd, J ) 15.5, 1.5 Hz, 1H), 2.68 (d, J )
19.5 Hz, 1H), 2.72 (dd, J ) 15.5, 5.0 Hz, 1H), 2.91 (d, J ) 19.5
Hz, 1H), 3.95 (dd, J ) 5.0, 1.5 Hz, 1H), 4.02 (d, J ) 10.0 Hz,
1H), 4.61 (d, J ) 10.0 Hz, 1H), 4.74 (s, 1H); 13C NMR (125 MHz,
CD3OD) δ 16.0, 17.3, 17.5, 32.3, 44.1, 58.5, 61.2, 66.1, 75.5, 80.0,
90.4, 96.2, 107.3, 177.6, 179.3; HRMS (ESI) calcd for C15H18O6-
Na (M + Na)+ 317.1001, found 317.0996.
D
1770 cm-1; 1H NMR (500 MHz, CD3OD) δ 1.16 (s, 3H), 1.20 (d,
J ) 1.0 Hz, 3H), 1.80 (ddd, J ) 2.5, 2.0, 1.5 Hz, 3H), 2.37 (ddq,
J ) 18.5, 2.5, 2.5 Hz, 1H), 2.58 (ddq, J ) 18.5, 2.0, 2.0 Hz, 1H),
2.78 (d, J ) 19.0 Hz, 1H), 2.88 (d, J ) 19.0 Hz, 1H), 3.98 (d, J )
8.5 Hz, 1H), 4.09 (s, 1H), 4.17 (dd, J ) 8.5, 1.0 Hz, 1H), 5.34
(ddq, J ) 2.5, 2.0, 1.5 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ
15.1, 16.1, 16.9, 40.6, 41.9, 57.0, 64.0, 71.6, 74.4, 87.0, 106.5,
125.1, 143.8, 177.9, 180.2; HRMS (ESI) calcd for C15H18O5Na (M
+ Na)+ 301.1052, found 301.1045.
Acknowledgment. This work was supported by a Grant-
in-Aid for Young Scientists (A) (JSPS), and Scientific Research
on Priority Area “Creation of Biologically Functional Mol-
ecules” (MEXT) to M.I., and the Open Research Center Fund
from Promotion and Mutual Aid Corporation for Private School
of Japan to Y.F. A fellowship to T.S. from the Japan Society
for the Promotion of Science (JSPS) is gratefully acknowledged.
We thank Dr. Chizuko Kabuto for crystallographic analyses.
Epoxide 31. A solution of 30 (13.0 mg, 46.7 µmol) in CH2Cl2
(4.0 mL) was treated with dimethyldioxirane (0.078 M in acetone,
2.5 mL, 234 µmol), and the resultant mixture was stirred at room
temperature for 5 h. After concentration, the residue was purified
with flash column chromatography (hexane/EtOAc 1:1) to give 12.1
mg of 31 (88%) along with 1 mg of the undesired isomer (7%):
colorless crystals; mp 229-232 °C; [R]31D +22.6 (c 0.32, MeOH);
Rf 0.21 (silica gel, 1:1 hexane/EtOAc); IR (film) 3435, 2981, 1768,
1258, 1190, 1020, 752 cm-1; 1H NMR (500 MHz, CD3OD) δ 1.11
(s, 3H), 1.17 (s, 3H), 1.55 (s, 3H), 2.08 (d, J ) 16.5 Hz, 1H), 2.26
(dd, J ) 16.5, 2.0 Hz, 1H), 2.59 (d, J ) 19.0 Hz, 1H), 3.02 (d, J
) 19.0 Hz, 1H), 3.95 (d, J ) 9.0 Hz, 1H), 4.13 (s, 1H), 3.66 (d, J
) 2.0 Hz, 1H), 4.48 (d, J ) 9.0 Hz, 1H); 13C NMR (125 MHz,
Supporting Information Available: General methods and
spectroscopic and analytical data for selected compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO0700474
J. Org. Chem, Vol. 72, No. 8, 2007 3075