Total Synthesis of (-)-Isoschizogamine

Article abstract of DOI:10.1002/chem.201503606

The total synthesis of (-)-isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson-Claisen rearrangement in basic media and the facile assembly of the key tetracyclic quinolone intermediate through a cascade cyclization. The characteristic cyclic aminal was constructed by late-stage C-H functionalization at the position adjacent to the lactam nitrogen using a combination of CrO₃ and nBu₄NIO₄ and subsequent Bi(OTf)₃-mediated cyclization.

Full text of DOI:10.1002/chem.201503606

DOI: 10.1002/chem.201503606
Communication
&
Synthetic Methods
Total Synthesis of (À)-Isoschizogamine
Akihiro Takada, Hiroaki Fujiwara, Kenji Sugimoto, Hirofumi Ueda, and
Hidetoshi Tokuyama*[a]
inspired a great number of synthetic studies,[4] only one race-
mic[5] and two enantioselective[6] total syntheses of 1 have
been reported to date. Herein, we describe the asymmetric
total synthesis of isoschizogamine (1) through late-stage CÀH
functionalization and a cyclic aminal formation.
Abstract: The total synthesis of (À)-isoschizogamine was
accomplished, featuring the construction of the quaterna-
ry carbon center by the modified Johnson–Claisen rear-
rangement in basic media and the facile assembly of the
key tetracyclic quinolone intermediate through a cascade
cyclization. The characteristic cyclic aminal was construct-
ed by late-stage CÀH functionalization at the position ad-
jacent to the lactam nitrogen using a combination of CrO3
and nBu4NIO4 and subsequent Bi(OTf)3-mediated cycliza-
tion.
The construction of the densely fused polycyclic skeleton
bearing oxygen and/or nitrogen functionalities represents a for-
midable challenge to the current state of the art in organic
synthesis.[7] One of the directions to solving this problem
would be a rapid framework assembly, taking advantage of the
simultaneous multiple bond formation through one-pot cas-
cade reactions, and late-stage functionalization of the frame-
work.[8] The most challenging task in synthesizing 1 is consid-
ered to be the construction of the aminal at the hindered posi-
tion adjacent to the quaternary carbon center. In the present
study, we attempted to construct the aminal structure from
the corresponding lactam derivative by oxidizing the C(sp3)ÀH
bond adjacent to the lactam amine and subsequently forming
the cyclic aminal (Scheme 1). This late-stage CÀH functionaliza-
tion strategy[9] should enable the rapid assembly of the fully
elaborated aminal compound precursor by lowering the oxida-
tion state of each intermediate.
Isoschizogamine (1), isoschizogaline (2), and their congeners
(3-6) were isolated from Schizozygia caffaeoides (Boj.) Baill,
which grows in the tropical zone of East Africa (Figure 1).[1] The
plant extract exhibits antimicrobial activity and has been used
in Kenya as a transitional medicine.[2] The structure of 1 was in-
itially considered as an epimer of schizogamine (5) at the C-7
position.[1] In 1998, however, Hµjicek and co-workers proposed
a revised structure for 1, which possesses a densely fused hex-
acyclic skeleton including a tetrasubstituted aminal carbon and
quaternary carbon center.[3] Although the structures of 1 and 2
Scheme 1. CÀH oxidation and cyclic aminal formation strategy.
Scheme 2 presents an outline of the conducted retrosyn-
thetic analysis. The hexacyclic skeleton of 1 would be formed
by ring-closing olefin metathesis of diene 7.[10] As discussed
above, the cyclic aminal formation would be realized by estab-
lishing chemoselective oxidation of 9 at the C(sp3)ÀH bond ad-
jacent to the lactam amine and subsequent cyclization. As
a result, the tetracyclic skeleton could be constructed rapidly
from ketoaldehyde 11 with an aniline appendage through
a triple cyclization cascade[11] initiated by intramolecular aldol
condensation and aza-Michael addition. We expected that
steric bias of the asymmetric quaternary carbon center would
determine the stereochemical outcome of cascade cyclization.
The optically active 11 would be readily prepared by the che-
moselective addition of aryl Grignard reagent to aldehyde 12,
which should be accessed from allylic alcohol 14 by the John-
son–Claisen rearrangement and oxidative cleavage of the
double bond.
Figure 1. Schizozygane alkaloids.
[a] Dr. A. Takada, H. Fujiwara, Dr. K. Sugimoto, Dr. H. Ueda,
Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences
Tohoku University
Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6877
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503606.
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tional Johnson–Claisen rearrangement[14] in the presence of
weak acids resulted in formation of a complex mixture. After
extensive investigation,[15] we determined that the Johnson–
Claisen rearrangement could proceed in the presence of
MS4 Š although the optical purity was decreased. Further in-
vestigation on solvent effects revealed that reaction in a basic
media suppressed the loss of optical purity. Thus, heating
a Hünig’s base solution of the reaction mixture in the presence
of MS4 Š under microwave irradiation promoted the Johnson–
Claisen rearrangement to produce the desired ester 17 in 55%
yield without the loss of optical purity. The cyclohexene ring
was then cleaved by ozonolysis to provide the dialdehyde 18,
which reacted at the less sterically hindered aldehyde with the
aryl Grignard reagent[16] to afford the benzyl alcohol 19. Finally,
the oxidation of benzylic alcohol to aryl ketone and reduction
of the nitro group provided the substrate 20 for cascade cycli-
zation.
The initial cascade cyclization trial (Table 1) under basic con-
ditions produced a complex mixture comprising intramolecular
aldol cyclization product 22 and other unidentified byproducts
(Table 1, entry 1). Camphorsulfonic acid effectively resulted in
Scheme 2. Retrosynthetic analysis.
Table 1. Optimization of the triple cyclization cascade.
Entry
Reagent
Solvent
Temp. [8C]
Time [h]
Yield[a] [%]
1
2
3
K2CO3
CSA
CSA
MeOH
CPME
DMSO[b]
80
80
80
24
13
12
–
36
51
[a] Isolated yield. [b] Degassed solvent was used: CSA=camphorsufonic
acid, CPME=cyclopentyl methyl ether, DMSO=dimethyl sulfoxide.
sequential triple cyclizations including the intramolecular aldol
condensation, aza-Michael addition, and acid-mediated lactam-
ization in one-pot to provide the desired tetracyclic compound
21 as a single isomer, although the yield was low (entry 2). The
yield was improved by conducting the reaction at 1508C in
DMSO, producing 21 in 51% yield (entry 3). The excellent ob-
served stereoselectivity should imply equilibrium between the
two quinolone derivatives 23 and 24 via 22, and only 23 un-
derwent lactamization to generate the less strained cis-fused
lactam 21 (Scheme 4).
Before examining the CÀH functionalization, we processed
the tetracyclic quinolone 21 to derive 28 to install the requisite
side chain for the formation of the cyclic aminal (Scheme 5).
First, two methyl ethers and benzyl ether were cleaved[17] and
the resultant alcohol was treated with TsCl and acetic anhy-
dride to produce 26. To reduce electron density of the ben-
zene ring and achieve chemoselective oxidation (see below), it
was essential to convert the methoxy groups to tosyloxy
groups. 1,2-Addition of allyl zinc reagent proceeded smoothly
Scheme 3. Preparation of the substrate 20 for the cascade cyclization
through the modified Johnson–Claisen rearrangement. Reagents and condi-
tions: a) Ag2CO3, BnBr, CH2Cl2, RT, 90% yield; b) Ru* catalyst (0.5 mol%),
HCO2H/Et3N, RT, 89% yield, 95% ee; c) MeC(OEt)3, MS4 Š, iPr2NEt, 1808C,
MWI, 55% yield; d) O3, CH2Cl2, À788C; PPh3, À788C to RT, 66% yield; e) 4,5-
dimethoxy-2-nitrobenzenemagnesium chloride, THF, À40 to À208C, 46%
yield; f) IBX, MeCN, reflux, 86% yield; g) Fe, NH4Cl, EtOH/H2O, 808C, 90%
yield; MS=molecular sieves, MWI=microwave irradiation, THF=tetrahydro-
furan, IBX=o-iodoxybenzoic acid.
Our total synthesis commenced with the enantioselective
construction of the quaternary carbon center by the Johnson–
Claisen rearrangement (Scheme 3). The protection of the alco-
hol 15[12] as benzyl ether and subsequent asymmetric 1,2-re-
duction following Ikariya’s protocol[13] produces allyl alcohol 16
in a high yield and enantiomeric excess. However, the conven-
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Table 2. Investigation of CÀH functionalization with model compound.
Entry Reagents
Solvents
Temp. [8C] Time [h] Yield[a] [%]
1
2
3
RuCl2(PPh3)3 toluene
tBuOOH
80
22
28
1
–
Cr(CO)6
tBuOOH
CrO3
MeCN
reflux
18
53
Scheme 4. Plausible reaction mechanisms for the diastereoselective triple
cyclization cascade.
MeCN/CH2Cl2 À208C
nBu4NIO4
[a] Isolated yield.
Scheme 5. Introduction of amino side chain. Reagents and conditions:
a) BBr3, pentamethylbenzene, CH2Cl2, À208C; b) TsCl, Et3N, CH2Cl2, À208C;
Ac2O, DMAP, RT, 70% yield (two steps); c) allylzinc bromide, THF, 08C, 93%
yield; d) TMSOTf, 2,6-lutidine, CH2Cl2, À208C, 95% yield; e) O3, CH2Cl2/MeOH,
À788C; NaBH4, RT, 67% yield; f) NsNHBoc, DIAD, PPh3, THF/toluene, RT to
608C, 96% yield; Ts=p-toluenesulfonyl, DMAP=4-(dimethylamino)pyridine,
TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, Ns=2-nitrobenzenesul-
fonyl, Boc=t-butoxycarbonyl, DIAD=diisopropyl azodicarboxylate.
Scheme 6. CÀH oxidation and aminal formation. Reagents and conditions:
neat, 1758C; Bi(OTf)3, MS4 Š, CH2Cl2, RT, 77% yield.
was constructed by thermally removing the Boc group and
subsequently treating with Bi(OTf)3 in the presence of
MS4 Š.[21]
to give the homoallyl alcohol 27 as a sole isomer, which was
converted to the protected primary amine 28 through a se-
quence, including alcohol silylation, ozonolysis, and reductive
treatments with NaBH4 to afford the corresponding primary al-
cohol, and the Mitsunobu reaction to install the doubly-pro-
tected amino group.
The endgame of the total synthesis of (À)-isoschizogamine
(1) is depicted in Scheme 7. First, the acetate 34 was converted
to the diene 35 by removing the acetyl group with Bu2SnO,[22]
dehydrating the resultant primary alcohol using the Grieco–
Nishizawa protocol,[23] and installing the N-allyl group under N-
allylation conditions after the removal of the nosyl group.[24]
The dehydropiperidine ring was formed by ring-closing meta-
thesis using the Hoveyda–Grubbs second-generation catalyst[10]
in the presence of benzoquinone and following desilyation
was conducted with TBAF.[25] We effectively removed the hy-
droxy group by desilyation and subsequent Barton–McCombie
deoxygenation protocol[26] to provide 37. Finally, the two tosyl
groups were reductively cleaved and subsequently methylated
using diazomethane furnished (À)-isoschizogamine (1), which
was in agreement with all the previously reported data.[3]
In conclusion, we accomplished the asymmetric total synthe-
sis of (À)-isoschizogamine. The most significant synthesis steps
include the facile construction of the tetracyclic quinolone in-
termediate by diastereoselective triple cyclization cascade and
construction of the cyclic aminal structure through the late-
stage CÀH functionalization.
Thereafter, we investigated the key CÀH oxidation. Initially,
we examined various oxidants using a simple model com-
pound 29 to explore the possible oxidation conditions
(Table 2). The oxidation conditions with Ru,[18] which were pre-
viously reported as effective for the oxidation of amines, result-
ed in a complex mixture (Table 2, entry 1). In contrast, a combi-
nation of Cr(CO)6 and tBuOOH[19] did give the expected elimi-
nation product 31 via hemiaminal 30 in low yield (entry 2).
Screening several other conditions, we eventually found that
the Fuchs’ conditions using a combination of CrO3 and
[20]
nBu4NIO4 were effective. As a result, we succeeded in the
chemoselective CÀH oxidation at the position adjacent to the
nitrogen atom and obtained the corresponding elimination
product 31 (entry 3). Furthermore, the Fuchs’ conditions also
successfully facilitated the oxidation of 28 to furnish the hemi-
aminal 32 in high yield (Scheme 6). Finally, the cyclic aminal
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Scheme 7. Total synthesis of (À)-isoschizogamine. a) Bu2SnO, toluene, reflux,
90% yield; b) 2-nitrobenzeneselenyl cyanide, PBu3, CH2Cl2, 08C to RT;
mCPBA, RT, 73% yield; c) PhSH, Cs2CO3, MeCN, 508C; allyl iodide, 408C, 63%
yield; d) the second-generation Hoveyda–Grubbs catalyst (10 mol%), 1,4-
benzoquinone, CH2Cl2, RT to 408C; TBAF, RT, 71% yield; e) NaH, THF, 08C;
CS2, RT; MeI, 64% yield; f) AIBN, nBu3SnH, toluene, 808C, 87% yield; g) Na
naphthalenide, THF, 08C; h) CH2N2, Et2O/CH2Cl2/MeOH, 08C to RT, 94% yield
(two steps); mCPBA=m-chloroperbenzoic acid, TBAF=tetra-n-butylammoni-
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Acknowledgements
This work was financially supported by the Cabinet Office, Gov-
ernment of Japan through its “Funding Program for Next Gen-
eration World-Leading Researchers” (LS008), a Grant-in-aid for
Scientific Research (A) (26253001), and Young Scientists (B)
(26860004).
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Keywords: alkaloids
functionalization · total synthesis
·
aminal
·
cascade reaction
·
CÀH
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Received: September 8, 2015
Published online on October 1, 2015
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