Total synthesis of merrilactone A

Article abstract of DOI:10.1021/ja036587+

Merrilactone A (1) has been shown to possess neurotrophic activity and thus is expected to hold therapeutic potential in the treatment of neurodegeneration diseases. In this paper, we report the total synthesis of (±)-1, employing, as key steps, a novel desymmetrization protocol of meso-diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1 (3 → 2) and a radical cyclization to install the highly congested C9-quaternary carbon (16 → 17). Copyright

Full text of DOI:10.1021/ja036587+

Published on Web 08/13/2003
Total Synthesis of Merrilactone A
Masayuki Inoue,* Takaaki Sato, and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received June 10, 2003; E-mail: inoue@ykbsc.chem.tohoku.ac.jp; hirama@ykbsc.chem.tohoku.ac.jp
Merrilactone A (1, Figure 1), which was isolated from Illicium
merrillianum in 2000,1 has been shown to possess neurotrophic
activity in cultures of fetal rat cortical neurons and therefore is
expected to hold therapeutic potential in the treatment of neuro-
degeneration associated with Alzheimer’s and Parkinson’s diseases.2
Apart from the biological aspects, the caged pentacyclic skeleton
of 1 served to pose interesting synthetic challenges. To date, the
sole synthesis of (()-1 was reported by Danishefsky and Birman.3,4
Herein, we report the total synthesis of (()-1 employing an efficient
and flexible strategy.
Figure 1. Retrosynthesis of merrilactone A.
Scheme 1 a
The construction of the cis-bicyclo[3.3.0]octane framework
embedded within 1 was envisioned to involve the desymmetrization
of meso-diketone 3 through an intramolecular aldol reaction (3 f
2, Figure 1).5,6 This reaction would establish the relative stereo-
chemistry of three stereocenters (C4, C5, C6) of 1, and the
asymmetric version would afford the enantiomeric 2 through a
simple, single-step process. Moreover, it is practically important
that 3 is efficiently prepared through pairwise symmetrical func-
tionalizations.7
To begin the synthesis of 3, [2+2] photocycloaddition between
4 and 5 was carried out to install the consecutive C5-C6 quaternary
carbons to give 6 (Scheme 1).8 Reductive dechlorination of 6 and
LAH-reduction of the anhydride yielded meso-diol 7, which was
protected as the benzyl ethers, and then subjected to dihydroxylation
to afford 8. The Swern oxidation/allylation sequence (8 f 9 f
10) was performed as a one-pot reaction,9 because of the strong
tendency of diketone 9 toward hydration in the aqueous workup.
In this reaction, the cis-introduction of allyl groups from the R-face
was strongly favored to provide 10rr as the major isomer. cis-
Arrangement of the olefins effectively facilitated the ring-closing
metathesis reaction10 of 10 to produce bicyclo[4.2.0]octyl system
11, which was treated with Pb(OAc)4 in situ11 to yield the eight-
membered ring 3.
The next stage of the synthesis involved the crucial transannular
aldol reaction. Gratifyingly, treatment of 3 with LiN(TMS)2 in THF
at -100 °C led to the selective formation of desired product 2
(Scheme 1, entry 1). The influence on the selectivity by the reaction
temperature (entry 2) suggested the kinetic nature of product 2 under
these conditions. Interestingly, both MgBrN(TMS)2 (entry 3) and
LiN(TMS)2/Et3N12 (entry 4) induced the opposite selectivity,
favoring the undesired diastereomer 12, whereas DBU did not
exhibit a preference for either product (entry 5). Although the factors
controlling the selectivities are yet to be clarified, we have
demonstrated desymmetrization protocols that are capable of
generating either diastereomer 2 or 12 by simply changing the
reaction conditions.
We then turned our attention to the introduction of the C9-
quaternary center and C15-methylene group (Scheme 2). Epoxi-
dation of 2 produced R-epoxide 13, which was converted to 15 via
a two-step procedure that involved the epoxide ring opening with
DBU, and then IBX oxidation.13 An R-bromoacetal was then
appended to 15 to afford 16 as a 4:1 mixture of diastereomers.
a Reagents and conditions: (a) benzophenone, acetone, hν, rt;(b) Zn,
TMSCl, Ac2O, toluene, 85 °C; (c) LiAlH4, THF, rt, 47% (three steps); (d)
BnBr, NaH, THF/DMF (10:1), rt, 99%; (e) OsO4, NMO, t-BuOMe/t-BuOH/
H2O (1:1:1), rt, 94%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, then
allylmagnesium bromide, -78 °C, 78% (10rr:10ââ:10râ )15:2.6:1); (g)
(PCy3)2Cl2RudCHPh, CH2Cl2, reflux, then Pb(OAc)4, rt, 95%.
Despite the steric congestion around C9 of 16, radical cyclization
using Bu3SnH and BEt314 delivered 5-exo cyclized product 17 (â:R
) 3.5:1) in a high yield.15 Using acidic ethanol, we transformed
17r into the major C11-isomer 17â. The regioselective silyl enol
formation from 17â, followed by reactions with Eschenmoser
reagent and subsequently with mCPBA,16 produced 18, which has
all of the carbons of 1 in place.
In regard to the successful total synthesis from 18, the proper
arrangement of the functional group manipulations was the most
critical issue. Although the stereoselective reduction of the hindered
C7-ketone was particularly troublesome, we found that the
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J. AM. CHEM. SOC. 2003, 125, 10772-10773
10.1021/ja036587+ CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
The synthesis of 1 described here should provide access to an-
alogous structures for future biological and SAR studies. Inves-
tigations of the asymmetric desymmetrization (3 f 2) to prepare
enantiomerically pure 1 and biological studies of the synthetic inter-
mediates are currently underway and will be reported in due course.
Acknowledgment. This study was partly supported by the
MEXT (13780464) and the Chugai Pharmaceutical Award for
Synthetic Organic Chemistry to M.I.
Supporting Information Available: Experimental procedures and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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a Reagents and conditions: (a) mCPBA, CH2Cl2, rt, 81%; (b) DBU,
CH2Cl2, -40 °C, 81%; (c) IBX, DMSO, rt, 94%; (d) BrCH2Br(OEt),
PhNMe2, CH2Cl2, -78 °C to rt, 62% (dr ) 4:1, 100% based on recovered
16); (e) Bu3SnH, BEt3/O2, toluene, rt, 57% (17â), 16% (17r); (f) CSA,
EtOH, rt, 86%; (g) TMSOTf, EtN(i-Pr)2, CH2Cl2, -20 °C; (h) Me2NCH2+I-,
CH2Cl2, rt; (i) mCPBA, CH2Cl2, rt, 70% (three steps); (j) TFA/H2O (9:1),
rt, 94%; (k) MsCl, Et3N, THF, 50 °C, 77%; (l) LiBH(s-Bu)3 (L-Selectride),
THF, MS4A, -78 °C then 2-Tf2N-5-chloropyridine, -78 °C, 99%; (m)
Pd(OAc)2, Ph3P, Bu3N, HCOOH, DMF, 40 °C, 89%; (n) DIBAL, CH2Cl2,
-78 °C, 88% (dr ) 6:1); (o) Na, NH3, THF/EtOH (5:1), -78 °C, 100%;
(p) DOWEX 50WX2, THF/H2O (2:1), rt; (q) Ag2CO3 on Celite, toluene,
130 °C, 64% (two steps), C14-oxidized regioisomer of 25, 4% (two steps);
(r) dimethyldioxirane, CH2Cl2, rt, 96%; (s) p-TsOH, CH2Cl2, rt, 81%.
stereoselectivity can be dramatically improved with the use of enol
ether 21 that was synthesized as follows.17 First, acetal 18 was
transformed to enol ether 19 by a two-step sequence: (i) treatment
with TFA/H2O and (ii) mesylation and base-induced elimination.
The subsequent 1,4-reduction of enone 19 using L-Selectride,
followed by an in situ triflation of the resultant enolate,18,19
generated 20, which was then converted to olefin 21 through
palladium-mediated reduction.20 Reduction of ketone 21 using
DIBAL at -78 °C in CH2Cl2 provided the desired isomer 22 (â-
OH:R-OH ) 6:1); presumably the enol ether contributed in reducing
the steric hindrance of the hydride-accepting R-face.
Birch reduction of the benzyl ethers of 22 generated triol 23, of
which the enol ether was hydrated to give 24. Simultaneous Fetizon
oxidation21 of the C11- and C12-alcohols in tetraol 24 proceeded
with remarkable regio- and chemoselectivities to produce the desired
bis-lactone 25. Lastly, epoxidation of 25 using dimethyldioxirane22
generated 26 as the sole product, which was subjected to acidic
conditions to afford the synthetic (()-merrilactone A (1) through
the epoxide-opening oxetane formation.1,3,23
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(23) Professor Y. Fukuyama (Tokushima Bunri University) is gratefully
acknowledged for providing NMR spectra of merrilactone A.
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