Total synthesis of (-)-norzoanthamine

Article abstract of DOI:10.1002/anie.200804546

No bones about it: (-)-Norzoanthamine, a promising candidate for an anti-osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H₂O gave the DEFG ring, while the cyclization precursor was pr

Full text of DOI:10.1002/anie.200804546

Communications
DOI: 10.1002/anie.200804546
Natural Products Synthesis (2)
Total Synthesis of (À)-Norzoanthamine**
Daisuke Yamashita, Yoshihisa Murata, Naotsuka Hikage, Ken-ichi Takao, Atsuo Nakazaki, and
Susumu Kobayashi*
The Zoanthus alkaloids, to which zoanthamines and (À)-
norzoanthamine (1) belong, have attracted a great deal of
attention in the synthetic community owing to their signifi-
cant biological activity[1] as well as their unique and complex
heptacyclic structure. Although sev-
Our synthetic strategy for the preparation of 1, starting
from 8, is shown in Scheme 2. (À)-Norzoanthamine could be
synthesized from a ketoacid 4 or its equivalent based on our
eral groups have attempted the syn-
thesis of these alkaloids,[2–4] only the
Miyashita research group has
accomplished
a
total synthesis.[4]
The most challenging steps towards
the total synthesis of (À)-norzoanth-
amine are the construction of the
bisaminal skeleton in the CDEFG
ring moiety and a stereocontrolled
construction of the densely function-
alized C ring, which contains four
quaternary chiral centers. During
the course of our studies, we have already developed an
excellent methodology for bisaminal formation (Scheme 1),[3]
and have reported a synthesis of the ABC ring moiety in the
preceding paper.[5] Herein, we report the total synthesis of
(À)-norzoanthamine from the key intermediate 8.
Scheme 2. Retrosynthetic analysis. MOM=methoxymethyl,
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
efficient method of bisaminal formation. The cyclization
precursor 4, in turn, could be derived from the aldehyde 5 by
the Horner–Emmons reaction with nitrogen-containing keto-
phosphonate 6, which can be prepared from lactone 9.[6] As
mentioned in the preceding paper, we envisioned that the
cyclopentanol moiety in tetracyclic 8 might serve as a handle
for introducing the remaining C1–C7 fragment. Thus, oxida-
tive cleavage of cyclopentanone 7 and subsequent functional
group transformation would provide the requisite aldehyde 5.
For these manipulations, the key intermediate 8 was first
converted into cyclopentanone 7, in which the a,b-unsatu-
rated cyclohexenone moiety in ring A is masked as cyclo-
hexanol after introducing the methyl group at C26.
Scheme 1. Model study of bisaminal formation. Boc=tert-butoxycar-
bonyl.
[*] D. Yamashita, Dr. Y. Murata, Dr. N. Hikage, Prof. Dr. K.-i. Takao,
Dr. A. Nakazaki, Prof. Dr. S. Kobayashi
Faculty of Pharmaceutical Sciences, Tokyo University of Science
2641 Yamazaki, Noda-shi, Chiba 278-8510 (Japan)
Fax: (+81)4-7121-3671
E-mail: kobayash@rs.noda.tus.ac.jp
Dr. N. Hikage
Daiichi-Sankyo Co., Ltd.
1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-8560 (Japan)
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research (B; KAKENHI No.18390010) from the Japan Society for
the Promotion of Science. We thank Prof. Dr. Keiji Tanino (The
Hokkaido University) for helpful suggestions.
Synthesis of aldehyde 5, a substrate for the Horner–
Emmons reaction, was commenced with 1,4-addition of
enone
8
for introducing the methyl group at C26
(Scheme 3). Treatment of enone 8 with Gilman reagent led
to the corresponding ketone in 91% yield, which was then
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804546.
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Chemie
It should be emphasized that the sterically congested
bicyclic skeleton, with contiguous quaternary methyl groups,
facilitated an unexpected but desirable selectivity during
these last few steps. The remaining steps for the completion of
the synthesis of (À)-norzoanthamine were: 1) coupling of
formyl ester 12 and ketophosphonate 6, and 2) formation of
the bisaminal framework at the very end of the synthesis
(Scheme 4).
We first attempted the reaction of formyl ester 12 and
ketophosphonate 6. However, all attempts failed and only
starting materials were recovered. The low reactivity of the
formyl group can be attributed to the presence of the
neighboring acetate and tert-butyldimethylsilyloxy groups.
Fortunately, selective removal of the TBS group on the C ring
Scheme 3. Synthesis of formyl ester 12. Reagents and conditions:
a) Me2CuLi, Et2O, À78–08C, 91%; b) NaBH4, MeOH, 08C–RT, 79%;
c) TBSOTf, 2,6-lutidine, CH2Cl2, 08C–RT, 95%; d) B-bromocatecholbor-
ane, CH2Cl2, À788C, 87%; e) DMP, CH2Cl2, 08C–RT, quant.; f) nBuLi,
TMSCl, THF, À78–08C; g) O3, CH2Cl2, MeOH, À788C, 79% (over 2
steps); h) Pb(OAc)4, benzene, MeOH, 08C–RT, 77%. DMP=Dess–
Martin periodinane, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
reduced with NaBH4 in MeOH to afford alcohol 10 in good
yield. Both the conjugate addition and the reduction reactions
proceeded in a highly stereoselective manner to afford 10 as a
single isomer. The assignment of the configuration was based
on NMR experiments.[7] Protection of the hydroxy group in 10
as the TBS ether, removal of the MOM group,[8] and
successive oxidation of the resulting hydroxy group afforded
the cyclopentanone derivative 7 in 83% overall yield.
To cleave the cyclopentanone moiety, 7 was subjected to
an a oxidation by using conventional procedures. However
the enolization step proved to be very difficult, probably
owing to the sterically encumbered carbonyl group resulting
from the buttressing effect of the angular methyl groups. We
were delighted that deprotonation proceeded cleanly to
afford the desired trimethylsilyl enol ether after successive
silylation reactions by using nBuLi as a base.[9]
Interestingly, ozonolysis of the silyl enol ether provided a-
hydroxy ketone 11 as a single diastereomer in 79% overall
yield from ketone 7, rather than the expected dicarbonyl
compound.[10] The configuration of the hydroxy group was
determined by use of the modified Mosher method.[11] To
obtain formyl ester 13, we next examined the oxidative
cleavage of hydroxy ketone 11 with the process established by
Criegee using Pb(OAc)4 in benzene/MeOH.[12] Surprisingly,
rather than the anticipated 13, the formyl ester 12 was
obtained in 77% yield as the sole product. A plausible
mechanism for this unprecedented oxidation process is out-
lined in the Supporting Information. Nonetheless, 12 is a
desirable intermediate because it can be directly employed as
a substrate for the Horner–Emmons reaction with 6.
Scheme 4. Completion of the total synthesis of (À)-norzoanthamine
(1). Reagents and conditions: a) TBAF, THF, 08C–RT, quant.; b) aq.
HF (4n), CH3CN, RT, quant.; c) TESCl, imidazole, CH2Cl2, RT, 76%;
d) 6, LiCl, iPr2NEt, CH3CN, 608C, 67% (94% based on the recovered
starting material); e) H2, Pd/C, EtOH, RT, 96%; f) AcOH, H2O, 508C,
56%; g) AlH3·EtNMe2, toluene, 508C, 59%; h) BzCl, NEt3, CH2Cl2,
08C–RT, 88%; i) DMP, CH2Cl2, RT, quant.; j) aq. HF (0.5N), CH3CN,
08C–RT, 94%; k) DMP, CH2Cl2, RT, quant.; l) LHMDS, TMSCl, THF,
À788C; m) cat. Pd(OAc)2, O2, DMSO, 608C, 74% (over 2 steps);
n) K2CO3, MeOH, RT; o) DMP, CH2Cl2, RT; p) NaClO2, NaH2PO4, 2-
methyl-2-butene, tBuOH, H2O, RT, 66% (over 3 steps); q) AcOH, H2O,
1008C, 92%. Bz=benzoyl, DMSO=dimethyl sulfoxide,
LHMDS=lithium hexamethyldisilazanide, TBAF=tetra-n-butylammo-
nium fluoride, TES=triethylsilyl.
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Communications
was possible by simple treatment with TBAF. The resulting
throughout the synthesis, even though the ring was not
hydroxy ester underwent a simultaneous cyclization to afford
lactone 14 quantitatively. Upon deprotection, the formyl
group in 14 was rendered more reactive. At this stage, two
TBS groups in the AB rings of 14 were replaced by TES
groups.[13] The Horner–Emmons reaction of 15 and 6 was best
carried out under the conditions developed by Masamune,
Roush, and co-worker[14] and afforded 16 in good yield. Thus,
16 contains the complete carbon skeleton in (À)-norzoanth-
amine.
After catalytic hydrogenation the resulting saturated
ketone was treated with aqueous AcOH at 508C to result in
the formation of the monoaminal and afford 17 in 56% yield,
along with desilylated and uncyclized by-products. The by-
products were again exposed to aqueous AcOH and treated
with TESCl/imidazole to afford 17 in 39% yield (95% total
yield). Although our original scenario involved the formation
of a bisaminal at the final stage of the synthesis, early
formation of a monoaminal proved useful for the further
transformations. Attempted alcoholysis and hydrolysis of the
lactone in 17 failed. The cleavage of the lactone moiety was
only achieved by treatment with AlH3 in toluene. Selective
incorporated into (À)-norzoanthamine in its original form.
Received: September 16, 2008
Published online: December 3, 2008
Keywords: alkaloids · cleavage reactions · Horner–
.
Emmons reaction · natural products · total synthesis
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[15]
oxidation using DMP
gave 18 in 88% yield (over 2
steps). TES groups in the AB rings of 18 were removed, and
the diol was subjected to oxidation with DMP to produce a
triketone (not shown). The triketone was then subjected to a
selective silyl enol etherification according to the protocol
developed by Miyashita and co-workers,[4] and subsequent
Saegusa oxidation[16] afforded the enone 19. The benzoyl
group was cleaved and the primary hydroxy group was
converted into the carboxylic acid 20 in 66% overall yield for
the three steps.[17] Finally, a solution of 20 in aqueous AcOH
was heated at 1008C to complete the total synthesis of (À)-
norzoanthamine (1). The spectroscopic data (1H,13C NMR
and IR spectra, HRMS, optical rotation) for the final product
were, in all respects, identical to those of natural (À)-
norzoanthamine.
In conclusion, we have achieve the total synthesis of (À)-
norzoanthamine in 47 steps starting from the (À)-Hajos–
Parrish ketone. Some of the key features of our synthesis
include: 1) stereocontrol of the C ring was realized by
utilizing a bicyclo[4.3.0]nonane system, 2) the AB rings were
constructed by a highly diastereoselective intramolecular
Diels–Alder reaction, 3) a cyclopentanone moiety served as a
handle for installing the remaining bisaminal segment after
oxidative cleavage, 4) the DEFG ring moiety was constructed
by stepwise bisaminal formation using AcOH/H2O. Finally,
we would like to emphasize that the cyclopentanone moiety
of the (À)-Hajos-Parrish ketone played an important role
[5] Y. Murata, D. Yamashita, K. Kitahara, Y. Minasako, A.
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ange.200804544.
[6] The synthetic route for ketophosphonate 6 from the known
lactone 9 can be found in the Supporting Information.
[7] See the Supporting Information.
[8] R. K. Boeckman, Jr., J. C. Potenza, Tetrahedron Lett. 1985, 26,
1411 – 1414.
[9] No addition product was formed.
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[13] Removal of the TBS groups in the corresponding silyl ether 17
required harsh reaction conditions, which caused the undesired
loss of the Boc group.
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[17] As the resulting primary alcohol was unstable during column
chromatography on silica gel, subsequent DMP oxidation of the
crude alcohol was carried out without purification.
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