Total synthesis of (+)-haplophytine

Full text of DOI:10.1002/anie.200902192

Communications
DOI: 10.1002/anie.200902192
Natural Product Synthesis
Total Synthesis of (+)-Haplophytine**
Hirofumi Ueda, Hitoshi Satoh, Koji Matsumoto, Kenji Sugimoto, Tohru Fukuyama,* and
Hidetoshi Tokuyama*
Haplophytine (1) is the major indole alkaloid found in the
dried leaves of the Mexican plant Haplophyton cimicidum
and was first isolated by Snyder and co-workers in 1952.[1,2]
Two decades after its isolation, Yates, Cava, and co-workers
determined its structure by X-ray crystallography.[3] Haplo-
phytine (1) is composed of two segments that are connected
by the formation of a quaternary carbon center (Scheme 1).
The left-half segment has an exceptionally unique structure,
which possesses a bicyclo[3.3.1]skeleton that includes bridged
ketone and aminal functionalities. The right-half segment is a
hexacyclic aspidosperma class of alkaloid, named aspidophy-
tine, which is obtained by the acidic degradation of (+)-
haplophytine.[3] Although five total syntheses of (À)-aspido-
phytine[4–8] have been reported to date, a total synthesis of
haplophytine has so far not been achieved owing to its unique
structural complexity.[9] Herein, we report the first total
synthesis of (+)-haplophytine through a convergent route.
Our synthetic strategy is outlined in Scheme 2. We
planned to construct the dimeric structure 3, a possible
precursor of (+)-haplophytine, by Fischer indole synthe-
sis[10,11] between the fully elaborated left-hand segment 4
(having a phenylhydrazine moiety) and the tricyclic ketone 5.
We envisaged that the key left-hand segment would be
formed by taking advantage of the intrinsic skeletal rear-
rangement of (+)-haplophytine, which was observed by
Yates, Cava, and co-workers during the structural determi-
nation of 1.[3] Thus, treatment of 1 with HBr would afford the
À
iminium ion 2 through 1,2-migration of the C N bond. On the
other hand, the iminium ion 2 can be converted into the
natural compound under basic conditions (Scheme 1) by a
semipinacol-type rearrangement.[12] We have demonstrated
the utility of the rearrangement for construction of the left-
hand segment.[13] Nicolaou, Chen, and co-workers[14] inde-
pendently reported the synthesis of a model compound of
haplophytine by a similar rearrangement reaction. The
rearrangement precursor 6 would be accessible by Friedel–
Crafts alkylation at the 4a position of a tetrahydro-b-carbo-
Scheme 1. Structure of (+)-haplophytine (1) and its rearrangement.
[*] H. Ueda, H. Satoh, Dr. K. Sugimoto, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6877
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Dr. K. Matsumoto, Prof. Dr. T. Fukuyama, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[**] This work was financially supported by the KAKENHI, a Grant-in-Aid
for Scientific Research (B) (20390003), the Uehara Memorial
Foundation, the Kato Memorial Bioscience Foundation, and the
JSPS (predoctoral fellowship to H.U.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902192.
Scheme 2. Retrosynthetic analysis of (+)-haplophytine (1). PG=pro-
tecting group.
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Chemie
line derivative 7.[13] For a synthesis of optically active tricyclic
ketone 5,[11] we planned to develop a facile assembly through
a stereoselective intramolecular Mannich reaction.[15]
Preparation of tricyclic ketone 5 commenced with stereo-
selective construction of the quaternary carbon center by an
asymmetric Michael addition developed by d’Angelo et al.
(Scheme 3).[16] We used thioacrylate[17] as a Michael accepter,
and it allowed us to elongate the side chain by palladium-
catalyzed coupling with a functionalized zinc reagent.[18] The
optically active cyclopentanone 10 thus obtained was reduced
and converted into its mesylate derivative as a mixture of
diastereomers. Chemoselective coupling of the thioester with
an alkylzinc reagent bearing a phthalimide group[19] pro-
ceeded smoothly and gave ketoimide 11. Ketalization by
using the protocol developed by Noyori and co-workers[20]
and elimination of the mesylate group afforded cyclopentene
12. After conversion of phthalimide 12 into the Ns-amide 13,
the cyclopentene ring was cleaved by ozonolysis and reduc-
tive treatment with NaBH4 gave diol 14. Regioselective
sulfonylation of the sterically less-hindered alcohol, oxidation
Scheme 4. Synthesis of the left-segment 25. Reagents and conditions:
a) POCl3, DMF, 08C to RT; then 1m KOH, 08C to reflux; b) MeNO2,
NH4OAc, reflux, 88% (2 steps); c) LiAlH4, THF, 08C to reflux; d) suc-
cinic anhydride, CH2Cl2, RT; e) SOCl2, MeOH, 08C to RT, 71%
(3 steps); f) H2, Pd/C, CH2Cl2/MeOH (1:1), RT; g) MsCl, Et3N, CH2Cl2,
08C, 86% (2 steps); h) POCl3, CH2Cl2, reflux; i) (R,R)-TsDPEN-RuII
complex, HCO2H/Et3N (5:2), DMF, 08C; j) CbzCl, iPr2NEt, CH2Cl2,
08C, 67% (3 steps), 96.6% ee; k) NIS, CH2Cl2, RT; l) N,N-diallyl-2,3-
dimethoxyaniline, AgOTf, CH2Cl2, À108C, 61% (2 steps; trans/
cis 2.4:1–2:1); m) LiOH·H2O, MeOH/H2O (3:1), RT; n) SOCl2, DMF,
CH2Cl2, RT; then iPr2NEt, RT, 59% (2 steps); o) [Pd(PPh3)4], N,N-
dimethylbarbituric acid, CH2Cl2, reflux, 94%; p) FmocCl, NaHCO3, 1,4-
dioxane/H2O (10:1), RT, 97%; q) mCPBA, NaHCO3, CH2Cl2, RT, 84%;
r) piperidine, DMF, RT, 96%; s) iAmONO, 6m HCl/MeOH/MeCN
(3:2:2), 08C; then SnCl2, conc. HCl, À108C to 08C, 77%. Bn=benzyl,
Cbz=benzyloxycarbonyl, DMF=N,N-dimethylformamide, DPEN=1,2-
diphenylethylenediamine, Fmoc=9-fluorenylmethoxycarbonyl,
mCPBA=m-chloroperbenzoic acid, NIS=N-iodosuccinimide, Ts=4-
toluenesulfonyl.
Scheme 3. Synthesis of tricyclic ketone 5. Reagents and conditions:
a) (S)-1-phenylethylamine, benzene, reflux; b) ethyl thioacrylate, THF,
08C; then AcOH, EtOH/H2O (5:3), RT, 74% (2 steps), 97.8% ee;
c) NaBH4, CeCl3·7H2O, EtOH, À788C; d) MsCl, Et3N, Me3N·HCl,
toluene, 08C to RT, (2 cycles), 90% (2 steps); e) IZn(CH2)3NPhth,
[PdCl2(PPh3)2] (10 mol%), toluene/THF (5:6), RT to 438C, 83%;
f) TMSO(CH2)2OTMS, TMSOTf, CH2Cl2, À788C to RT; g) LiCl, Li2CO3,
M.S. (4 ꢀ), DMPU/HMPA (4:1), 708C, 67% (2 steps); h) MeNHNH2,
EtOH, reflux; i) NsCl, Et3N, CH2Cl2, 08C to RT, quant. (2 steps); j) O3,
CH2Cl2/EtOH (4:3), À788C; then NaBH4, pH 6.5 buffer, À788C to RT,
87%; k) MesSO2Cl, CH2Cl2/pyridine (1:1), 08C; l) PCC, Celite, CH2Cl2,
RT, 79% (2 steps); m) Cs2CO3, M.S. (3 ꢀ), MeCN, 708C, 87%;
n) 1m HCl, THF, 508C; o) PhSH, Cs2CO3, MeCN, RT to 508C; then
evaporation; then silica gel, CH2Cl2, reflux; then TMSCHN2, NH4Cl,
MeOH, RT, 83% (4 steps). DMPU=N,N’-dimethylpropyleneurea,
HMPA=hexamethylphosphorous triamide, Mes=2,4,6-trimethylphe-
nyl, Ms=methanesulfonyl, M.S.=molecular sieves, Ns=2-nitroben-
zenesulfonyl, PCC=pyridinium chlorochromate, Phth=phthaloyl,
Tf =trifluoromethanesulfonyl, THF=tetrahydrofuran, TMS=trimethyl-
silyl.
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of the remaining alcohol, and intramolecular N-alkylation of
rearrangement precursor 23 was obtained by replacing the
two N-allyl groups to an Fmoc group. As expected, the key
oxidative skeletal rearrangement,[13] which was initiated by
mCPBA oxidation of the 1,2-diaminoethene moiety from the
convex face, took place and furnished the desired product
the Ns-amide gave the 11-membered cyclic secondary amine
derivative 15.[21] At this stage, we extensively studied the
crucial intramolecular Mannich reaction. After acidic hydrol-
ysis of the ketal and ester groups, the Ns group was removed
under standard reaction conditions.[22] We found that the
expected Mannich-type cyclization took place quite smoothly
by treatment of the crude amine with silica gel. The desired
tricyclic ketone 5 was obtained as a single isomer in 83% yield
after esterification with trimethylsilyldiazomethane. Notably,
this three-step sequence was carried out in a one-pot
operation.
With the key tricyclic ketone 5 in hand, we then turned
our attention to the synthesis of the left-hand segment. After
formylation of 7-benzyloxyindole 16[23] under the Vilsmeier–
Haack conditions, the resultant aldehyde was condensed with
nitromethane and afforded nitroalkene 17 (Scheme 4).
Reduction of the nitroalkene unit and subsequent acylation
with succinic anhydride gave the tryptamide derivative, which
was converted into amide 18. After replacing the phenolic
benzyl ether group with a mesylate group, Bischler–Napier-
alski cyclization was executed and provided dihydro-b-carbo-
line 19,[14,24] which was then subjected to the Noyori asym-
metric reduction[24,25] and subsequent protection of the
resultant secondary amine with CbzCl led to tetrahydro-b-
carboline 20 in 96.6% ee.
24—which has
a bicyclo[3.3.1]skeleton—in 84% yield.
Finally, removal of the Fmoc group and conversion of the
aniline into a hydrazine gave 25 as the key precursor of the
Fischer indole synthesis.
The pivotal construction of the right-hand segment by
Fischer indole synthesis and the end game sequence are
illustrated in Scheme 5. Condensation of hydrazine 25 and
ketone 5 with 50% sulfuric acid gave the corresponding
hydrazone. First, we examined the crucial Fischer indole
synthesis in acetic acid at reflux, according to the protocol
developed by Stork and Dolfini for the total synthesis of
aspidospermine.[11a] To our disappointment, only a small
amount of the expected indolenine 26 and indole byproduct
27 were obtained (ca. 20% combined yield). After extensive
optimization, we eventually found that careful control of the
reaction temperature and the appropriate choice of acid and
solvent were essential to preferentially obtain the desired
indolenine 26 over the indole 27 in reasonable yield.[25] Thus,
treatment with pTsOH in tBuOH at 808C gave indolenine 26
in 47% yield along with indole 27 in 29% yield. After
conversion of imine 26 into the conjugated imine 28 [5b,26] the
Cbz group was removed by BBr3 in the presence of
pentamethylbenzene, which acted as a cation scavenger.[27]
One-pot 1,2-reduction of the imine and reductive methylation
of two secondary amino groups led to 29. Finally, basic
hydrolysis of the ester and the phenolic mesylate groups and
subsequent formation of the lactone ring with potassium
ferricyanide[4] furnished (+)-haplophytine (1). The spectro-
scopic data of the synthetic material were identical to those of
natural (+)-haplophytine (1).[2,3]
Having synthesized the desired optically active b-carbo-
line derivative 20, we examined coupling of 20 with 2,3-
dimethoxy-N,N-diallylaniline (Scheme 4). Iodoindolenine 21,
which was generated by treatment of a solution of 20 in
CH2Cl2 with NIS, was activated with silver triflate in the
presence of 2,3-dimethoxy-N,N-diallylaniline. The Friedel–
Crafts alkylation reaction proceeded smoothly and furnished
the desired coupling product 22 as the major isomer in
approximately
a 2.4:1–2:1 diastereoselectivity. Judicious
choice of solvent was crucial for this coupling reaction.
Thus, polar solvents such as MeCN or DMF, resulted in only
recovery of the starting carboline 20. After separation of the
diastereomers, the lactam ring was formed by saponification
and cyclization via a ketene intermediate. The desired
In conclusion, we have accomplished the first total
synthesis of (+)-haplophytine (1) featuring the facile assem-
bly of tricyclic ketone 5 by the intramolecular Mannich
reaction, construction of the quaternary carbon by the
Friedel–Crafts alkylation, formation of the left-hand segment
Scheme 5. Completion of the total synthesis of (+)-haplophytine (1). Reagents and conditions: a) 50% aq H2SO4, 1,4-dioxane, 08C, 80%;
b) pTsOH, tBuOH, 808C, 47% of 26 and 29% of 27; c) benzeneseleninic anhydride, THF, reflux, 61%; d) BBr3, pentamethylbenzene, CH2Cl2,
À788C to À258C, 67%; e) HCHO (37%), NaBH3CN, AcOH, CH2Cl2/MeOH (1:1), À788C to RT, 55%; f) 1m NaOH, MeOH, 608C;
g) K3[Fe(CN)6], NaHCO3, tBuOH/H2O (1:2), 08C to RT, 70% (2 steps).
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Chemie
[12] For a review on the semipinacol rearrangement, see: D. L.
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Coveney in Comprehensive Organic Synthesis Vol. 3 (Eds.: B. M.
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[13] K. Matsumoto, H. Tokuyama, T. Fukuyama, Synlett 2007, 3137.
[14] K. C. Nicolaou, U. Majumder, S. P. Roche, D. Y.-K. Chen,
Angew. Chem. 2007, 119, 4799; Angew. Chem. Int. Ed. 2007,
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Received: April 23, 2009
Published online: July 3, 2009
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Keywords: alkaloids · Mannich reaction · natural products ·
rearrangement · total synthesis
.
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Angew. Chem. Int. Ed. 2009, 48, 7600 –7603
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