Asymmetric total synthesis of pinnaic acid

Article abstract of DOI:10.1002/anie.200701581

Pinned together: Asymmetric total synthesis of pinnaic acid was accomplished through a stereospecific route that features as key steps a Pd-catalyzed trimethylenemethane (TMM) [3+2] cyclization, a four-step tandem hydrogenation-cyclization, and cross-olefin-metathesis reactions (see scheme). (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200701581

Communications
DOI: 10.1002/anie.200701581
Natural Product Synthesis
Asymmetric Total Synthesis of Pinnaic Acid**
Shu Xu, Hirokazu Arimoto,* and Daisuke Uemura
Phospholipase A2 (PLA2) is involved in the initial step of a
cascade of enzymatic reactions which lead to the generation
of inflammatory mediators.[1] A cytosolic 85kDa phospholi-
pase (cPLA2) exhibits specificity for the release of arach-
idonic acid from membrane phospholipids.[2] Therefore,
compounds that inhibit cPLA2 activity are thought to be
potential drugs for the treatment of inflammation and other
disease states.
specific review[7] and a large number[8] of reports describing
efforts to synthesize them. However, as significant problems
still exist, only one asymmetric total synthesis has been
accomplished by Danishefsky and co-workers.[9] Asymmetric
construction of the contiguous stereogenic centers at C9, C13,
and C14 of 1 is a challenge, and thus most reported examples
focus on the preparation of the spiro framework in racemic
form. Another significant problem is the addition of side
chains onto the spiro core. Regardless of extensive synthetic
efforts, there is essentially only one protocol using a Wittig-
type reaction available for the lower side-chain installation.
The strategy was first used in Danishefskyꢀs total synthesis[9b]
and later modified by Heathcockꢀs synthesis.[10] Installation of
the C15–C21 side chain by this approach gave only a
moderate yield.[9a–b]
In 1996, a new class of marine natural products was
isolated in our laboratory represented by pinnaic acid[3] (1)
Our efforts toward the total synthesis of pinnaic acid have
taken the racemic route.[11a] Here, we describe the asymmetric
total synthesis based on a new tactic employing a Pd-
catalyzed trimethylenemethane [3+2] cyclization (Pd-TMM
cyclization; Scheme 1).[12] We anticipated that Pd-TMM
and halichlorine[4] (2) from the bivalve Pinna muricata[5] and
the black marine sponge Halichondria okadai Kadota,
respectively. Pinnaic acid inhibits cPLA2 in vitro at IC50
=
0.2 mm, whereas halichlorine blocks the induced expression of
vascular cell adhesion molecule-1[6] (VCAM-1) in vitro at
IC50 = 7 mgmLÀ1. Thus, both compounds are considered to be
potential leads for anti-inflammatory drugs, despite their
inhibiting different target proteins.
Even more impressive than their bioactivities are the
architectural 6-aza-spiro[4.5]decane structures of these two
molecules. They have attracted considerable attention in the
synthetic chemistry community. They have been the topic of a
[*] Prof. Dr. H. Arimoto
Graduate School of Life Sciences
Tohoku University
Tsutsumidori-Amamiyamachi
Aoba, Sendai 981-8555 (Japan)
Fax: (+81)22-717-8803
E-mail: arimoto@biochem.tohoku.ac.jp
Homepage: http://www.agri.tohoku.ac.jp/bunseki/index-j.html
Scheme 1. Synthetic plan for pinnaic acid. TMM=trimethyleneme-
thane;Cb z=benzyloxycarbonyl;PG 1, PG2, PG3 =protecting groups.
S. Xu, Prof. Dr. D. Uemura
Department of Chemistry
cyclization with cyclopentenone 3 would occur from the
opposite face of the adjacent methyl group to build up the
three contiguous stereogenic centers diastereoselectively. Our
tandem hydrogenation-cyclization protocol[11] can readily
assemble the aza-spiro moiety, and cross-olefin-metathesis[13]
reactions enable efficient installation of both the upper and
lower chains.
Graduate School of Science, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8602 (Japan)
Fax: (+81)52-789-3654
[**] We are grateful for financial support from Grants-in-Aid for
Scientific Research (16GS0206 and 16310150) from the JSPS and
the “21st Century COE program (Establishment of COE on Material
Science)” from the MEXT, Japan.
Following the synthetic plan, the cyclopentane ring of
pinnaic acid was constructed as shown in Scheme 2. Chiral
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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oxidative removal of p-methoxyphenyl ether by CAN gave
alcohol 18. Oxidation (SO3·Py, DMSO) to the aldehyde and
Horner–Wadsworth–Emmons reaction with phosphonate 19
afforded the key precursor 20 of the tandem hydrogenation-
cyclization as a single E isomer.
Our tandem hydrogenation-cyclization[11] (Scheme 3) is a
powerful protocol for constructing the piperidine ring of 1
with the desired configuration at C5. It consists of four
consecutive one-pot transformations: 1) saturation of the
alkene, 2) removal of Cbz, 3) intramolecular cyclic imine and/
or enamine formation, and 4) stereoselective reduction of the
imine/enamine intermediate. Similar reductive cyclizations
have been conducted lately by others.[8f,10] In our previous
study,[11] this reaction was either carried out under neutral or
acidic conditions with a catalytic amount of acetic acid. One
remaining problem was the amount of Pd catalyst (50 mol%)
required to obtain reproducible results. Careful re-examina-
tion of the reaction conditions revealed that the amino group
of product 21 seemed to be deterring the Cbz hydrogenolysis
step.[19] When a larger amount of acetic acid was used, as
expected, only 20 mol% of Pd catalyst was sufficient to
cleanly and reproducibly afford the desired diastereomer 21.
Protection of the amino group by TFAA and selective
deprotection of the TBS group (PPTS)[20] followed by
Grieco elimination[21] led to terminal olefin 23, NOE corre-
lations of which confirmed the stereochemistry of C5to be
that expected.
The stage was now set for installation of the side chains by
cross-olefin-metathesis reactions (Scheme 4). Although olefin
metathesis has become an indispensable tool, there is still a
limited number of examples of the application of cross-
metathesis strategy to the total synthesis of natural pro-
ducts.[13b] We first examined the upper side-chain connection,
with the less reactive ethyl methacrylate 24 as solvent.
Compound 26 was obtained in 74% yield by mixing
compound 23 and 10 mol% Hoveyda–Grubbs second-gen-
eration catalyst 25[22] under reflux for 13 h. The trisubstituted
alkene of 26 was exclusively obtained in the desired E confi-
Scheme 2. Preparation of unsaturated ketone 20. Reagents and con-
ditions: a) 11, Pd(OAc)2, (iPrO)3P, THF, reflux, 80%;b) MSH ( 13), 4-Š
MS, alumina, CH2Cl2, RT, 43% (100% based on recovered starting
material);c) O , MeOH, À788C;then Me 2S, À788C, 82%;
3
d) TsNHNH2, MeOH, 508C;e) NaBH 3CN, TsOH, THF, reflux, 60%
over two steps;f) NaH, CbzCl, THF, reflux, 87%;g) NaBH 4, LiBr, THF,
508C, quant.;h) TBDPSCl, DMAP, Et 3N, CH2Cl2, RT;i) CAN, MeCN/
H2O (1:1), 08C, 76% over two steps;j) SO ·py, Et3N, DMSO, RT;
3
k) 19, Et3N, LiCl, THF, 308C, quant. in two steps. CAN=(NH4)2Ce-
(NO3)6, DMAP=4-dimethylaminopyridine, DMSO=dimethyl sulfoxide,
MS=molecular sieves, MSH=O-mesitylsulfonylhydroxylamine,
PMP=p-methoxylphenyl, py=pyridine, TBDPS=tert-butyldiphenylsilyl,
TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl, Ts=p-toluenesul-
fonyl.
cyclopentenone 10 is a new chiral building block devel-
oped in this study.[14] It could be prepared easily from (R)-
(+)-pulegone (9) in 41% yield over five steps on a 20-
gram scale. As anticipated, the key Pd-TMM [3+2] cyc-
lization proceeded with high stereoselectivity and only the
anti adduct 12 could be isolated (80% yield). The
configuration of the C9 and C13 asymmetric centers was
verified by NOE experiments of 12. Regioselective
Beckmann rearrangement using a bulky hydroxylamine
reagent 13 (MSH)[15] afforded the desired lactam 14 in
43% yield (quantitative yield based on the recovered
starting material). Ozonolysis of the exo olefin, hydrazone
formation of the resultant ketone, and deoxygenation with
NaBH3CN[16] provided 15. Cbz protection of an amide
nitrogen and LiBH4 reductive opening of the lactam ring
gave alcohol 17. The enantiomeric purity of 17 was
determined to be over 98% ee[17] by the modified
Mosherꢀs method.[18] It confirmed that no racemization
had occurred during the above transformations from 10.
Scheme 3. Stereoselective construction of the aza-spiro ring. Reagents and
conditions: a) H2, Pd(OH)2/C (20 mol%), HOAc (7 equiv), EtOH, 258C;
b) TFAA, iPr2NEt/ClCH2CH2Cl (1:5), 08C, 81% over two steps;c) PPTS,
EtOH, 258C;d) o-NO2PhSeCN, nBu3P, THF, RT;then mCPBA, RT, 88%
over two steps. mCPBA=m-chloroperbenzoic acid, PPTS=pyridium p-
Silylation of the primary alcohol of 17 followed by toluenesulfonate, TFAA=trifluroacetic anhydride.
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could be efficiently controlled from a single methyl
group of cyclopentone 10, which was originally obtained
from the inexpensive (R)-pulegone. Further studies are
underway in our laboratory toward the synthesis of
halichlorine.
Received: April 11, 2007
Published online: June 25, 2007
Keywords: alkaloids · asymmetric synthesis · metathesis ·
.
natural products · total synthesis
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Scheme 4. End game to pinnaic acid by cross-olefin-metathesis installation
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In the previous attempts toward pinnaic acid,[9–11] using
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alcohol was generated by a diastereoselective reduction of
the Wittig products (dienones). Here we offer a second
choice: In our cross-metathesis-based strategy, the C17 center
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1
acid sodium salt on comparison of the H NMR spectra.[10]
In conclusion, we have successfully completed the effi-
cient asymmetric total synthesis of pinnaic acid through a
strategy involving Pd-TMM [3+2] cyclization, four-step
tandem hydrogenation-cyclization, and cross-olefin-metathe-
sis reactions. Except for that of C17, all of the stereochemistry
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