Structure determination and total synthesis of (+)-16-hydroxy-16,22- dihydroapparicine

Article abstract of DOI:10.1002/chem.201300292

Herein, we describe the first asymmetric total synthesis and determination of the relative and absolute stereochemistry of naturally occurring 16-hydroxy-16,22-dihydroapparicine. The key steps include 1) a novel phosphinimine-mediated cascade reaction to

Full text of DOI:10.1002/chem.201300292

FULL PAPER
Total Synthesis
T. Hirose, Y. Noguchi, Y. Furuya,
A. Ishiyama, M. Iwatsuki, K. Otoguro,
¯
S. Omura,* T. Sunazuka* ... &&&& — &&&&
Composed by cascade: A concise
method for the construction of an
azabicycloACHTUNGTRENNUNG[4.2.2]decone with an indole
ring by using a phosphinimine-medi-
ated cascade reaction enabled the
structure determination and efficient
synthesis of (+)-16-hydroxy-16,22-
dihydroapparicine. This synthesis also
features a stereospecific 1,2-addition
construction of the tetrasubstituted
carbon center and an intramolecular
chirality-transferring Michael reaction
as key steps (see picture).
Structure Determination and Total
Synthesis of (+)-16-Hydroxy-16,22-
dihydroapparicine
Chem. Eur. J. 2013, 00, 0 – 0
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DOI: 10.1002/chem.201300292
Structure Determination and Total Synthesis of
(+)-16-Hydroxy-16,22-dihydroapparicine
Tomoyasu Hirose, Yoshihiko Noguchi, Yujiro Furuya, Aki Ishiyama, Masato Iwatsuki,
[a]
¯
Kazuhiko Otoguro, Satoshi Omura,* and Toshiaki Sunazuka*
Abstract: Herein, we describe the first
a methylketone through a Felkin–Anh
transition state for the construction of
a tetrasubstituted carbon center; and
3) an intramolecular chirality-transfer-
ring Michael reaction of the ketoester,
with neighboring-group participation,
asymmetric total synthesis and deter-
mination of the relative and absolute
stereochemistry of naturally occurring
16-hydroxy-16,22-dihydroapparicine.
The key steps include 1) a novel phos-
phinimine-mediated cascade reaction
to construct the unique 1-azabicyclo-
ACHTUNGTRENNUNG[4.2.2]decane core, including a pseudo-
aminal-type moiety; 2) a highly stereo-
specific 1,2-addition of 2-acylindole or
to introduce a chiral center at C15 in
the target molecule. In addition, we
evaluated the antimalarial activity of
synthetic
(+)-(15S,16R)-16-hydroxy-
16,22-dihydroapparicine and its inter-
mediate against chloroquine-resistant
Plasmodium falciparum (K1 strain)
parasites.
Keywords: asymmetric synthesis ·
cascade reactions · dihydroappari-
cine · Michael reaction · natural
products · stereochemistry
Introduction
The Tabernaemontana species
have a widespread distribution
and are known to produce alka-
loids with intriguing chemical
structures and novel bioactivi-
ties. Plant-derived alkaloids are
important compounds in medic-
inal research. Apparicine (1;
Figure 1) was isolated from
Tabernaemontana cumminsii in
1970[1] and was originally dis-
covered from Aspidosperma da-
Figure 1. Structure of 5-nor stemmadenine-type indole alkaloids.
sycarpon in 1965[2] as a 5-nor
stemmadenine-type monoterpe-
noid indole alkaloid. After the discovery of 1, more than 20
types of 5-nor stemmadenine alkaloids have been reported,
and several key compounds in this family are shown in
Figure 1.[3] We have focused on the screening of antimalarial
agents from natural products, and a crude extraction, includ-
ing 16-hydroxy-16,22-dihydroapparicine (4), originally isolat-
ed from the plant Tabernaemontana dichotoma in 1984 by
Verpoorte and co-workers,[4] was found to possess potent an-
timalarial activity in our preliminary screening experiments
(data not shown). Therefore, we needed to prepare a suffi-
cient amount of 4 to allow proper evaluation of its antima-
larial activity.
The unique structure of 4 consists of a strained 1-
azabicycloACHTUGNTRNE[NGU 4.2.2]decane structure with a tetrasubstituted
[a] Dr. T. Hirose, Dr. Y. Noguchi, Y. Furuya, Dr. A. Ishiyama,
carbon center directly connected at the indole 2-position,
with a single carbon atom as a connection between the
indole 3-position and aliphatic nitrogen atom, which essen-
tially equals the pseudo-aminal-type moiety of gramine
compounds (Scheme 1). The pseudo-aminal-type skeleton
could convert into the corresponding 3-methylene-3-H-indo-
linium cations, which have proven synthetic utility. The ali-
¯
Dr. M. Iwatsuki, Dr. K. Otoguro, Prof. Dr. S. Omura,
Prof. Dr. T. Sunazuka
Kitasato Institute for Life Sciences and Graduate School
of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane
Minato-ku, Tokyo 108-8641 (Japan)
Fax : (+81)3-5791-6340
E-mail: omuras@insti.kitasato-u.ac.jp
sunazuka@lisci.kitasato-u.ac.jp
phatic nitrogen–carbon bond as
moiety could be easily cleaved by a retro-Mannich reaction
a pseudo-aminal-type
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300292.
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Total Synthesis of 16-Hydroxy-16,22-dihydroapparicine
FULL PAPER
phane-mediate cascade reaction, which is the key reaction
in our pathway to construct the strained 1-azabicyclo-
AHCTUNGTREG[NNUN 4.2.2]decane structure. We also confirmed the antimalarial
properties of the natural form of 16-hydroxy-16,22-dihy-
droapparicine and related synthetic intermediates, including
activity against chloroquine resistant Plasmodium falcipa-
rum (K1 strain).
Scheme 1. Gramines as versatile pseudo-aminal-type compounds.
under acidic,[5] basic,[6] or thermal conditions[7] or by using
various reagents (e.g., trialkylphosphanes,[8] Lewis acids,[9]
phthalimides,[10] thiols,[11] and activated esters)[12] to generate
the indolinium cation, which reacts with the various nucleo-
philes at the 3-methylene position. Therefore, such reactivity
and instability for the apparicines, including our target com-
pound, can be predicted. The combination of a remarkable
structure, a wide range of biological activity (e.g, antimicro-
bial,[13] antituberculosis,[3h] opioid,[14] and so forth), and the
limited availability from natural sources makes these alka-
loids attractive targets. Total synthesis routes toward appari-
cine (1) and (+)-conolidine (8) have been reported.[15,16] Al-
though the relative stereochemistry of apparicines is known,
at the onset of our investigations, the absolute stereochemis-
try of apparicines had not been fully established, except for
8, for which an asymmetric total synthesis was completed by
Micalizio and co-workers in 2011.[16]
Results and Discussion
Retrosynthetic analysis of (15S*,16S*)-4: Our approach
toward the synthesis of the 1-azabicycloACTHNUTRGNEUNG[4.2.2]decane skele-
ton was guided by the hypothesis that pseudo-aminal-type
alkaloids occur via a biogenetic intermediate. In the final
step to obtain (15S*,16S*)-4, we envisaged the preparation
of the iminium cation 12 in situ, which could be generated
along a cascade sequence from azide 15. Given the reactivi-
ty of the phosphinimine group, we designed a novel phos-
phinimine-mediated cascade reaction, with the following se-
quence: 1) Staudinger reaction of 15 with triphenylphos-
phine to generate phosphinimine intermediate 14; 2) intra-
molecular N-allylation to the aminophosphinium derivative
13; 3) aza-Wittig reaction of 13 with formaldehyde, and
4) an intramolecular Mannich reaction, with nucleophilic
attack from the indole 3-position to the iminium cation of
12 (Scheme 2).
The designed cascade reaction has two challenging issues:
The first was the N-allylation of the phosphinimine group,
related reactions of which have been reported by Zimmer
and Singh[18] and others.[19] Phosphinimine has a relatively
high nucleophilicity; however, N-alkylation of phosphini-
mine involves a sensitivity with respect to the electrophilic
leaving group, so the choice of the leaving group would be a
critical factor in the cascade reaction. The second key issue
was the aza-Wittig reaction between the aminophosphonium
salt and formaldehyde. Similar reactions have not been re-
ported so far, except for the reaction of aminophosponium
salt with excess of DMF to generate the formamidinium
salt.[20] Therefore, the reactivity and applicability of the ami-
nophosphonium salt was unknown.
The relative stereochemistry of 16-hydroxy-16,22-dihy-
droapparicine was proposed to be a 15S*,16S* configuration
1
based on detailed H NMR spectroscopic analysis. However,
the relative and absolute configuration of 16-hydroxy-16,22-
dihydroapparicine has remained undetermined during the
28 years since its isolation. In 2012, we reported the first
total synthesis of (Æ)-4 and (Æ)-5 by using a novel phosphi-
nimine-mediated cascade reaction, and the relative stereo-
chemistry of 16-hydroxy-16,22-dihydroapparicine was reas-
signed and determined to be 5 (Figure 1).[17] Herein, we
report the development of our first- and second-generation
total synthesis of 16-hydroxy-16,22-dihydroapparicine, which
caused the reassignment of the relative stereochemistry and
the determination of the absolute configuration of naturally
occurring 16-hydroxy-16,22-dihydroapparicine ((15S,16R)-5),
and a better understanding of the mechanism of the phos-
Scheme 2. Retrosynthetic analysis of (15S,16S)-16-hydroxy-16,22-dihydroapparicine (4). LG=leaving group, PG=protecting group.
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Synthesis of azidoaldehyde 17: Our synthesis commenced
with the preparation of azidoaldehyde 17. The synthesis
began from known carboximide (À)-18,[21] which was sub-
jected to the remote stereocontrolled Michael reaction, with
enolate 19 as a Michael donor, to construct the C15 stereo-
center of 4 (corresponding to the C3 position of 20). Howev-
er, the desired Michael adduct 20 was obtained as an insepa-
rable diastereomeric mixture in low yield, with no diastereo-
selectivity at the C3 position, along with the g-adduct
(Scheme 3). Despite extensive optimization by using various
in excellent yield. In the next two steps, the benzyl group
was removed under oxidative deprotection by using DDQ[25]
in 85% yield, followed by the Dess–Martin oxidation[26] of
the resultant primary alcohol to yield the azidoaldehyde
(Æ)-17 in 93% yield.
Total synthesis of (Æ)-(15S*,16S*)-4 and correction of the
stereochemistry of the natural product: With the racemic al-
dehyde unit (Æ)-17 in hand, we turned our attention to com-
pleting the synthesis of racemic (15S*,16S*)-4. A diastereo-
selective 1,2-addition of the N-phenylsulfylindole nucleo-
phile 25 to (Æ)-17 was carried out (Scheme 4). In 1993, Nat-
Scheme 3. Reagents and conditions: a) 19, THF, À788C, 1.5 h (44%; four
inseparable diastereomers); b) DBU, THF, RT, 20 h (91%; two insepara-
ble diastereomers; d.r.=1:1); c) NaBH4, CeCl3·7H2O, THF/MeOH,
À508C, 45 min (82%); d) TsCl, Me3N·HCl, Et3N, CH2Cl2, RT, 1 h
(97%); e) Lindlar cat., Et3SiH, 1-hexene, quinoline, acetone/CH2Cl2, RT,
3 h (75%); f) NaBH4, CeCl3·7H2O, MeOH, 08C, 5 min (97%); g) NaN3,
DMSO, RT, 10 h (83%); h) PivCl, pyridine, RT, 1 h (99%); i) DDQ,
CH2Cl2/pH 7.2 phosphate buffer, RT, 58 h (85%); j) Dess–Martin period-
Scheme 4. Reagents and conditions: a) 25, nBuLi, THF, À788C, 30 min
(85%; d.r.= >20:1); b) Dess–Martin periodinane, CH2Cl2, RT, 30 min
(quant.); c) K2CO3, MeOH, RT, 48 h (87%); d) MeLi, THF, À788C,
10 min (91%; d.r.= >20:1); e) 2-chloro-3-nitropyridine, tris[2-(2-methoxy-
ethoxy)ethyl]amine, KOH, K2CO3, PhMe, À108C, 8 h (93%).
inane, CH2Cl2, RT, 15 min (93%). DBU=1,8-diazabicycloACTHNUTRGNE[NUG 5.4.0]undec-7-
ene, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMSO=dimeth-
yl sulfoxide, Piv=pivaloyl, Ts=tosyl.
sume and co-workers reported the diastereoselective 1,2-ad-
dition of the Garner aldehyde with 25 and nBuLi in À758C,
and the diastereoselectivity obeyed the Felkin–Anh rule.[27]
In our case, the 1,2-addition between (Æ)-17 and 25 under
the conditions developed by Natsume and co-workers pro-
vided the 2-substituted indole (Æ)-26 in 85% yield as a
single diastereomer. The stereochemistry of the newly con-
structed secondary alcohol of (Æ)-26 was predicted to be the
R* configuration (Scheme 4) on the basis of the Felkin–Anh
rule. Subsequently, deprotection of the N-phenylsulfonyl
group of (Æ)-26 was performed under several conditions
(i.e., TBAF,[28] basic solvolysis,[29] and reductive condi-
tion);[30] however, only decomposition of the substrate was
observed. Therefore, (Æ)-26 was transformed to 2-acylindole
by using Dess–Martin oxidation[26] to reduce the electron
density of the indole ring, which would assist in the depro-
tection of N-phenylsulfonyl group from the indole moiety.
As expected, the N-phenylsulfonyl after oxidation of (Æ)-26,
could be easily removed under basic solvolysis by using
esters of crotonic acid, we could not improve the reaction
yield and stereo- or regioselectivities. Further improvements
in the diastereoselective Michael reaction were shelved, and
our efforts turned toward the preparation of the racemic al-
dehyde 17 to attempt a diastereoselective 1,2-addition with
an indole anion. Subsequently, DBU-mediated isomerization
of 20 afforded the sole E olefin product 21 as a 1:1 diaster-
eomeric mixture in 91% yield. Subsequently, imide selective
reduction of 21 with NaBH4 with CeCl3·7H2O in THF/
MeOH[22] furnished a primary alcohol in 82% yield, fol-
lowed by conversion into tosylate (Æ)-22 in 97% yield by
using the protocol developed by Tanabe and co-workers
(i.e., TsCl, Me3N·HCl, Et3N).[23] A stepwise reduction of
(Æ)-22 by using a combination of conditions developed by
Fukuyama et al.[24] and Luche et al.[22] were carried out to
yield the desired allyl alcohol (Æ)-23 in good yield. Subse-
quently, azidation of (Æ)-23, followed by protection of the
hydroxy group with PivCl afforded the allyl pivalate (Æ)-24
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Total Synthesis of 16-Hydroxy-16,22-dihydroapparicine
FULL PAPER
K2CO3 in MeOH. Simultaneously, the pivaloyl group was
cleaved to afford hydroxyketoindole (Æ)-27 in 87% yield,
which was converted into dihydroxyindole (Æ)-28 by a 1,2-
addition reaction of the methyl anion as a single diastereom-
er in excellent yield. The relative configuration of (Æ)-28
was not confirmed at this point, which was expected to be as
shown in Scheme 4. The stereoselectivity of this 1,2-addition
reaction was defined from the stereochemistry of the final
product (Æ)-4 after completion of the total synthesis. We
also examined a methylation reaction after the oxidation of
(Æ)-26, which afforded the N-phenylsulfonylated product in
73% yield as a single diastereomer with the same relative
configuration as (Æ)-28. These results strongly suggested
that the 1,2-addition reaction followed the Felkin–Anh rule,
rather than the chelating control model. Next, a leaving
group was introduced to the primary alcohol of (Æ)-28 to
prepare a key intermediate for the cascade reaction to con-
struct the full skeleton of 4. Firstly, we selected a tosyl
group as the leaving group by using the conditions devel-
oped by Tanabe and co-workers.[23] However, the product
was readily cyclized between the 3-position of the indole
skeleton and the allyl position of the tosylate group. After
screening suitable leaving groups for this allyl alcohol, we
found the 3-nitropyridyl group[31] to be a very suitable leav-
ing group, which was easily introduced into (Æ)-28 under
basic conditions with 2-chloro-3-nitropyridine[32] to give (Æ)-
29 in good yield.
the target compound (Æ)-4. After purification on a silica gel
column chromatography, the synthetic product (Æ)-4 was
isolated in 88% yield. However, spectral data of (Æ)-4 did
not agree with that of naturally occurring 16-hydroxy-16,22-
dihydroapparicine. Detailed NMR spectroscopic analyses
(i.e., ROESY) of synthetic (Æ)-4 showed a relationship be-
tween H18 or H19 and 16-Me. Thus, the relative stereo-
chemistry of synthetic (Æ)-4 was determined to be a
15S*,16S* configuration, the configuration proposed by Ver-
poorte and co-workers (Scheme 5).[4]
A comparison of synthetic (Æ)-(15S*,16S*)-4 with the nat-
urally occurring compound found variance in the 1H and
13C NMR spectra, thus indicating the difference in the chem-
ical shifts in critical positions (see the Supporting Informa-
tion). In the 1H NMR spectra, 16-Me and H-6a,b signals
were registered with a difference of more than Dd=
0.20 ppm; furthermore, in the 13C NMR spectra, the signals
of the piperidine ring were greatly shifted from those seen
in naturally occurring 16-hydroxy-16,22-dihydroapparicine.
Therefore, we expected that the 16-Me group in the natural
product was on the opposite face of the trisubstituted exo-
cyclic olefin. Thus, the relative stereochemistry of the natu-
ral product was anticipated to be the 15S*,16R* configura-
tion.
Total synthesis of (Æ)-(15S*,16R*)-5 and reassignment of
the relative stereochemistry: Our initial effort achieved the
total synthesis of (Æ)-(15S*,16S*)-4, which produced spec-
troscopic data that was not identical with the natural prod-
uct, thus causing us to believe that the relative stereochemis-
try of natural 16-hydroxy-16,22-dihydroapparicine was the
15S*,16R* configuration. We now turned our attention to
complete the synthesis of the 15S*,16R* isomer (Æ)-5 from
methylketone (Æ)-33, which was simply prepared from (Æ)-
17 by using methylation and Dess–Martin oxidation in good
yields (Scheme 6).
For the final key cascade reaction (Scheme 5), (Æ)-29 was
treated with PPh3 at 608C to generate the phosphinimine in-
termediate 30. Continuously, the reaction mixture was acidi-
fied with AcOH and PPTS, the addition of which at this
time was expected to activate the 3-nitropyridinyloxy func-
tion as a leaving group, to form cyclic aminophosphinium
31. Formaldehyde was added to the resulting solution to
promote the intramolecular Mannich reaction, thus forming
Various indole derivatives (i.e., 25 and 35–37) were pre-
pared from the indole skeleton by using a known proce-
dure[33] to examine the diastereoselective 1,2-addition reac-
tion to (Æ)-33 (the results are summarized in Table 1). Al-
though the addition of the N-phenylsulfonyl indole 25 anion
afforded a desired adduct (Æ)-38 as a single diastereomer,
Scheme 5. Conclusion to the synthesis of (Æ)-(15S*,16S*)-4.
Scheme 6. Synthetic strategy of (Æ)-5 from aldehyde (Æ)-17.
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Table 1. Optimization of the stereoselective 1,2-addition reaction of
methylketone (Æ)-33.
Entry
Compounds
R1
R2
Product[e]
Yield [%]
1[a]
2[b]
3[c]
4[d]
25
35
PhSO2
H
SEM
TBSOM
H
I
I
(Æ)-38
(Æ)-39
(Æ)-40
(Æ)-41
20
35
90
98
36
Scheme 7. Reagents and conditions: a) TBAF, ethylenediamine, THF,
37[36]
I
RT, 5 min (96%); b) DIBAL-H, CH2Cl2, À788C, 5 min (96%); c) 2-
chloro-3-nitropyridine,
tris[2-(2-methoxyethoxy)ethyl]amine,
KOH,
[a] Compound 25 (1.5 equiv), nBuLi (1.5 equiv), THF, À788C, 1 h.
[b] Compound 35 (2.5 equiv), nBuLi (5.3 equiv), Et2O, À788C, 1 h.
[c] Compound 36 (1.2 equiv), nBuLi (1.2 equiv), THF, À788C, 1 h.
[d] Compound 37 (1.2 equiv), nBuLi (1.2 equiv), THF, À788C, 1 h. [e] Di-
astereomeric ratios in all cases was >20:1, as determined by 1H NMR
spectroscopic analysis. SEM=2-(trimethylsilyl)ethoxymethyl, TBSOM=
tert-butyldimethylsiloxymethyl.
K2CO3, PhMe, À108C, 48 h (83%); d) PPh3, THF/H2O (50:1 v/v), 608C,
17 h; AcOH, RT, 3.5 h; PPTS, formaldehyde (aq.), RT, 10 h (83%).
PPTS=pyridinium para-toluenesulfonate, TBAF=tetrabutylammonium
fluoride.
separated on a octadecylsilane reverse-phase chromatogra-
phy system, and the synthetic product (Æ)-5 coeluted with
the natural product. Thus, the relative stereochemistry of
natural 16-hydroxy-16,22-dihydroapparicine was reassigned
and defined as a 15S*,16R* configuration.
the yield was not satisfactory (Table 1, entry 1). Moreover,
deprotection of the N-phenylsulfonyl group from (Æ)-38 was
not successful and led to degradation of the substrate. To
improve the efficiency of the conversion from (Æ)-33 and N-
deprotection of the corresponding adducts, nonprotected
indole 35 or protected indoles 36 and 37 with acetal groups
on the nitrogen atom, which could be deprotected by using
a fluoride anion under neutral conditions, were examined.
The addition of 35 provided the desired (Æ)-39 in 35% yield
as a single diastereomer and the starting material was recov-
ered in 14% yield (Table 1, entry 2). The acetal protection
group (i.e., SEM and TBSOM)[34] on the indole nitrogen
atom were expected to act as a chelator to stabilize the lithi-
um anion at the 2-position of the indole skeleton (Table 1,
entries 3 and 4).[35] As a result, the addition of both nucleo-
philes, derived from 36 and 37,[36] generated the correspond-
ing desired products (Æ)-40 and 41 with satisfactory yields
of 90 and 98%, respectively, while maintaining high diaster-
eoselectivity.
Analysis of the cascade reaction: After achieving the total
synthesis of (Æ)-(15S*,16R*)-5 by using a successful cascade
reaction to construct the unique 1-azabicycloACTHNURTGNEU[GN 4.2.2]decane
core, we tried to clarify the cascade-reaction mechanism. At
first, (Æ)-43 was treated with PPh3 with heating to reflux to
isolate the corresponding primary amine, which could be
converted from the imine 44. However, a desired primary
amine could not be detected by mass spectrometric analysis
during the reaction. Unexpectedly, piperidineindole (Æ)-46
was rapidly and directly formed from imine 44, without
acidic activation of the 3-nitropyridinyl group (Scheme 8).
Therefore, a desired primary amine from 44 could not be
isolated at all. In a time-dependent change from (Æ)-43 to
45, with monitoring by ESI mass-spectrometric analysis, 44
Subsequently, the TBSOM group of (Æ)-41 was removed
by using TBAF and ethylenediamine in 96% yield, followed
by reductive deprotection of the pivaloyl group[37] to give al-
cohol (Æ)-42 in 96% yield (Scheme 7). Following the same
reaction sequence as in the synthesis of (15S*,16S*)-4, 3-ni-
tropyridinylation of (Æ)-42 was performed to form (Æ)-43 in
83% yield. Finally, the cascade reaction of (Æ)-43 furnished
the desired product (Æ)-(15S*,16R*)-5 in 83% yield. The
NOE interactions in (Æ)-5 were observed between H14a
and H22 to support this relative configuration. All data for
the synthetic product (Æ)-5 were fully consistent with the
data for the naturally occurring 16-hydroxy-16,22-dihydroap-
paricine reported by Verpoorte and co-workers.[4] Further-
more, we also analyzed the synthetic diastereomers (Æ)-4
and (Æ)-5 and an authentic sample of the natural product by
means of HPLC analysis. Both synthetic diastereomers were
Scheme 8. Stepwise synthesis of (Æ)-5 from (Æ)-43.
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Total Synthesis of 16-Hydroxy-16,22-dihydroapparicine
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Figure 2. ESI mass spectroscopic analysis of the cascade reaction mechanism.
was smoothly and directly converted into the cyclic amino-
phosphonium cation 45, without observation of the primary-
amine intermediate (Figure 2). Although the electrophilicity
of the 3-nitropyridinyl group is relatively weak under neu-
tral conditions, it was unnecessary for acidic activation, thus
showing that the phosphinimine group acts as a very strong
nucleophile. We also inferred that the effect of the 1,3-allylic
strain in 44[38] induces the allylic carbon atom at the 3-nitro-
pyridinyl group to get very close to the nitrogen atom of the
phosphinimine group. Because of the high reactivity of
phosphinimine and the steric effect, autocyclization would
occur to form the cyclic aminophosphonium cation. The pi-
peridineindole (Æ)-46 could be converted into (Æ)-5 by an
intramolecular Mannich reaction with formaldehyde under
acidic conditions in low yield, which may suggest that the
aminophosphonium is a key intermediate in forming an imi-
nium cation through an aza-Wittig reaction in a cascade se-
quence. However, an iminium intermediate could not be de-
tected by ESI mass-spectrometric analysis.
Scheme 9. Retrosynthetic analysis of optically active (15S,16R)-5.
pared from chiral acyclic ketoester 48 through 5-exo-cycliza-
tion between the acetylacetate and a,b-unsaturated ester
moieties. Synthetic pathways for related compounds of bu-
tyrolactone 47 are already available,[39] but the enantioselec-
tive preparation is limited and has only been reported by
Smith et al.[39a,b] We expected that the chiral derivative 47,
including a corresponding C15 stereocenter of 5, would be
formed by the intramolecular chirality-transferring Michael
reaction, which should be stereospecifically controlled by
the Baldwin rule[40] and Thorpe–Ingold effect.[41]
Asymmetric total synthesis and determination of the abso-
lute stereochemistry of naturally occurring (+)-5: Our syn-
thesis commenced with the preparation of the optically pure
methylketone unit 33 to achieve the asymmetric total syn-
thesis of 5 (Scheme 9). The synthesis of chiral methylketone
33 was envisaged from chiral butyrolactone 47, which pos-
sesses the appropriate functional groups and could be pre-
The synthesis of optically pure 33 began with protection
of commercially available (R)-methyl lactate (+)-49 by
using para-methoxybenzyl (PMB)[42] followed by reduction
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with DIBAL-H and a Horner–Wadsworth–Emmons reaction
with ethyl diethylphosphono acetate in the presence of
LiCl[43] to provide the (E)-a,b-unsaturated ethyl ester (+)-50
as
a sole isomer in good yield over all the steps
(Scheme 10). Subsequently, deprotection of the PMB group
with DDQ provided the g-hydroxy-a,b-unsaturated ethyl
Scheme 11. Reagents and conditions: a) NaBH4, MeOH, 08C, 10 min
(88%; d.r.=3:1); b) TsCl, Et3N, N-methylimidazole, PhCl, RT, 15 h
(96%); c) DBU, PhH, 808C, 2 h (79 and 19% for (À)-52 and (À)-53, re-
spectively); d) LiOH, THF/MeOH/H2O (3:1:1), RT, 2.5 h; e) EtOCOCl,
Et3N, THF, 08C, 45 min; NaBH4 in EtOH, 08C, 15 min (82% over
2 steps); f) DPPA, DEAD, PPh3, THF, RT, 2 h (85%); g) DIBAL-H,
THF, À788C, 2 h (51%); h) PivCl, pyridine, CH2Cl2, 08C, 3 h (79%);
i) Dess–Martin periodinane, CH2Cl2, RT, 30 min (98%; 97% ee).
DEAD=diethyl azodicarboxylate, DPPA=diphenyl phosphorazidate.
Scheme 10. Reagents and conditions: a) PMBOACTHNUTRGEN(UNG =NH)CCl3, cat. TfOH,
CH2Cl2/hexane (1:1 v/v), RT, 30 min (75%); b) DIBAL-H, CH2Cl2,
À788C, 1 h; c) ethyl diethylphosphonoacetate, iPr2NEt, LiCl, MeCN, RT,
1.5 h (63% over 2 steps); d) DDQ, CH2Cl2/pH 7.0 phosphate buffer (3:2
v/v), RT, 2.5 h (96%); e) diketene, DMAP, THF, RT, 2 h (quant.);
f) K2CO3, EtOH, RT, 5 h (91%). DMAP=4-dimethylaminopyridine,
DIBAL-H=diisobutylaluminium hydride, PMB=4-methoxybenzyl, Tf=
trifluoromethanesulfonyl.
tion of separable isomers (À)-52 and (À)-53 (E/Z=4.1:1) in
98% yield. The trisubstituted exo-cyclic olefin moieties of
each product were determined by means of NOE interac-
tions. The S configuration of the C3 center of (À)-52 was de-
termined by means of NOE and ROESY interactions for
the hydrogenated product of (À)-52[50] because it could not
be determined from NOE interactions for (À)-52. In the fol-
lowing steps, (À)-52 was transformed into the targeted
methylketone (+)-33. Selective hydrolysis of the ethyl ester
group under basic conditions afforded a carboxylic acid
functionality, followed by formation of the corresponding
carboxylic anhydride, which was immediately reduced with
NaBH4 to the desired primary alcohol in 82% yield over
the two steps.[51] Alternatively, the carboxylic acid group was
directly transformed into the primary alcohol by using
boron-mediated reduction,[52] although in an unsatisfactory
yield. Subsequently, the azidation of the hydroxy group
under Mitsunobu conditions[53] produced the azidolactone
(À)-54 in good yield. The lactone moiety was reduced to the
diol in 51% yield by using DIBAL-H in THF, followed by
the selective protection of the primary alcohol with a Piv
group to provide (+)-55. Next, oxidation of (+)-55 by using
the Dess–Martin periodinane provided the desired chiral
methylketone (+)-33 in excellent yield without racemiza-
tion. The optical purity of (+)-33 (S isomer; 97% ee) was
confirmed by means of chiral HPLC analysis with the com-
parable R isomer of (À)-33 (see the Supporting Informa-
tion), which was prepared in the same manner from (À)-(S)-
methyl lactate.
ester, the optical rotation of which was compared with that
of a reported enantiomer[44] to confirm the R configuration
of this secondary alcohol. Esterification of this alcohol with
diketene in the presence of DMAP[45] afforded the acetoace-
tyl ester (+)-48 in quantitative yield. We next attempted the
intramolecular chirality-transferring Michael reaction.
Through extensive optimization of comparative reaction
conditions,[46] we obtained acetylbutyrolactone (+)-47 under
simple basic conditions with K2CO3 in 91% yield as a single
diastereomer, the relative stereochemistry of which was as-
signed by comparison with related compounds for the cou-
pling constants[47] and NOE interactions between the a and
g protons of (+)-47. The effect of the alcoholic solvent,
which would stabilize the anticipated transition state,[41b] was
one of the key factors in the intramolecular chirality-trans-
ferring Michael reaction. In addition, the substrate benefit-
ted from the Thorpe–Ingold effect[41] by suitable methyl sub-
stitution at the g-position of the a,b-unsaturated ester to
promote kinetically favorable cyclization. This reaction can
be performed on a large scale (>9 g) without any side reac-
tions or decrease in the diastereoselectivity.
To construct the E-ethylidene function, the ketone of the
acetyl group of (+)-47 was reduced with NaBH4 to afford
the b-hydroxylactone as an inseparable diastereomixture
(d.r.=3:1), which was subjected to tosylation with TsCl in
the presence of Et3N and N-methylimidazole, as reported by
Tanabe and co-workers,[48] to provide 51 in excellent yield
(Scheme 11). Subsequently, heating of 51 in the presence of
DBU[49] facilitated b-elimination of the tosyl group and iso-
merization of the ethylidene group, thus resulting in produc-
In the final stage, chiral methylketone (+)-33 was convert-
ed into (+)-(15S,16R)-5 by using the same reaction sequen-
ces as in the synthesis of racemic 5 (Scheme 12). The optical
purity of the substrates after the 1,2-addition reaction was
checked for intermediate (À)-56 by means of chiral HPLC
analysis and confirmed as 97% ee (see the Supporting Infor-
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Total Synthesis of 16-Hydroxy-16,22-dihydroapparicine
FULL PAPER
an intramolecular chirality-transferring Michael reaction
with neighboring-group participation. In particular, the
latter proved a useful method for the synthesis of the chiral
trisubstituted butyrolactone. Some synthetic compounds in-
cluding (Æ)-(15S,16R)-5 were evaluated for bioactivity
against the chloroquine-resistant Plasmodium falciparum
(K1 strain) malaria parasites; however, none of the com-
pounds showed sufficient antimalarial activity. In fact, a
crude extraction, including 5, had been found to possess
potent antimalarial activity in our preliminary screening. It
is expected that a minor component in the crude extract
from plant Tabernaemontana dichotoma may be a desirable
candidate as a antimalarial agent.
Scheme 12. Conclusion to the total synthesis of (+)-(15S, 16R)-5.
mation). The characterization data indicated that synthetic
(+)-(15S,16R)-5 was fully consistent with the data for the
natural compound reported by Verpoorte and co-workers.[4]
The optical rotation of synthetic (+)-(15S,16R)-5 compared
well with the values reported for the natural sample ([a]D24
=
+119.2 (c=0.1 in EtOH) vs [a]2D0 = +129 (c=0.1 in EtOH),
respectively). Otherwise, the optical rotation of synthetic
(À)-(15R, 16S)-5, prepared by using the same synthetic
pathway, was [a]2D6 =À104.2 (c=0.1 in EtOH).
Acknowledgements
This work was supported by a Grant for the 21st Century COE Program;
a Grants-in-Aid for Young Scientists (22790017) to T.H. from the Minis-
try of Education, Culture, Sports, Science and Technology (MEXT); and
a Kitasato University Research Grant for Young Researchers to T.H. We
also thank Dr. Nagai and Ms Sato (School of Pharmacy, Kitasato Univer-
sity) for their contributions. We are grateful to Dr. Kam for providing an
authentic natural sample of 16-hydroxy-16,22-hihydroapparicine.
Evaluation of antimalarial activity: In 2010, Rottmann and
co-workers reported that spiroindolones showed potent anti-
malarial activity against chloroquine-resistant Plasmodium
falciparum (K1 strain).[54] Based on this information and
with our preliminary results from antimalarial tests, a crude
extraction including (+)-5, synthetic (Æ)-(15S*,16S*)-4,
(+)-(15S,16R)-5, (À)-(15R,16S)-5, and some key intermedi-
ates in the total synthesis pathway were evaluated against
Plasmodium falciparum (K1 strain) and for cytotoxicity[55] in
vitro in comparison with the clinically used antimalarial
drug chloroquine.[56] Belying our expectations, all of the syn-
thetic compounds, including an equivalent of natural 16-hy-
droxy-16,22-dihydroapparicine did not show sufficient anti-
malarial activity (see the Supporting Information). Some
compounds may have a slight possibility for use as antima-
larial agents (IC50 =8.98~10.87 mgmLÀ1), but our results in-
dicated that all the compounds have a weaker activity than
that of chloroquine. The selectivity index (cytotoxicity (IC50
for the MRC-5 cell)/antimalarial activity (IC50 for the K1
strain)), used to compare the antimalarial activity and cyto-
toxicity, also indicated that the values of all the compounds
are very low, thus showing no selectivity between antimalar-
ial activity and cytotoxicity.
[1] P. A. Crooks, B. Robinson, J. Pharm. Pharmacol. 1970, 22, 799–800.
[2] a) B. Gilbert, A. P. Duarte, Y. Nakagawa, J. A. Joule, S. E. Flores,
J. A. Brissolese, J. Campello, E. P. Carrzzoni, R. J. Owellen, E. C.
Blossey, K. S. Brown Jr, C. Djerassi, Tetrahedron 1965, 21, 1141–
1166; b) J. A. Joule, H. Monteiro, L. J. Durham, B. Gilbert, C. Djer-
assi, J. Chem. Soc. 1965, 4773–4780.
[3] a) A. Walser, C. Djerassi, Helv. Chim. Acta 1964, 47, 2072–2086;
b) L. Akhter, R. T. Brown, D. Moorcroft, Tetrahedron Lett. 1978, 19,
4137–4140; c) A. Rahman, A. Muzaffar, Heterocycles 1985, 23,
2975–2978; d) S. Michel, F. Tillequin, M. Koch, J. Nat. Prod. 1986,
49, 452–455; e) K.-H. Pawelka, J. Stockigt, B. Danieli, Plant Cell
Rep. 1986, 5, 147–149; f) M. Zeches, T. Ravao, B. Richard, G. Mas-
siot, L. Le Men-Olivier, J. Nat. Prod. 1987, 50, 714–720; g) T. Ya-
mauchi, A. Fumiko, W. G. Padolina, F. M. Dayrit, Phytochemistry
1990, 29, 3321–3325; h) A. P. G. Macabeo, K. Krohn, D. Gehle,
R. W. Read, J. J. Brophy, G. A. Cordell, S. G. Franzblau, A. M. Agui-
naldo, Phytochemistry 2005, 66, 1158–1162; i) S.-J. Tan, Y.-Y. Low,
K. Komiyama, T.-S. Kam, Phytochemistry 2011, 72, 2212–2218.
[4] P. Perera, T. A. van Beek, R. Verpoorte, J. Nat. Prod. 1984, 47, 835–
838.
[5] C. L. Martin, S. Nakamura, R. Otte, L. E. Overman, Org. Lett. 2011,
13, 138–141.
[6] a) C. R. Hurt, R. Lin, H. Rapoport, J. Org. Chem. 1999, 64, 225–
233; b) D. J. Hart, N. A. Magomedov, J. Org. Chem. 1999, 64, 2990–
2991; c) Y. Wada, H. Nagasaki, M. Tokuda, K. Orito, J. Org. Chem.
2007, 72, 2008–2014.
[7] K. Diker, M. D. de Maindreville, D. Royer, F. L. Provost, J. Lꢁvy,
Tetrahedron Lett. 1999, 40, 7463–7467.
[8] a) M. Somei, Y. Karasawa, C. Kaneko, Heterocycles 1981, 16, 941–
949; b) J. D. Freed, D. J. Hart, N. A. Magomedov, J. Org. Chem.
2001, 66, 839–852; c) K. H. Low, N. A. Magomedov, Org. Lett. 2005,
7, 2003–2005; d) A. W. Grubbs, G. D. Artman, III, S. Tsukamoto,
R. M. Williams, Angew. Chem. 2007, 119, 2307–2311; Angew. Chem.
Int. Ed. 2007, 46, 2257–2261; e) G. D. Artman, III, A. W. Grubbs,
R. M. Williams, J. Am. Chem. Soc. 2007, 129, 6336–6342; f) R.
Dubey, B. Olenyuk, Tetrahedron Lett. 2010, 51, 609–612.
Conclusion
We have achieved the first total synthesis and determined
the absolute stereochemistry of naturally occurring
(+)-(15S,16R)-16-hydroxy-16,22-dihydroapparicine (5) with
the (À)-enantiomer 5 and its diastereomer (Æ)-4. The syn-
thesis involved a novel cascade reaction for the efficient
construction of the 1-azabicycloACTHNUGRTNEUNG[4.2.2]decane core, including
a pseudo-aminal-type moiety, by using a Staudinger reac-
tion, N-allylation, aza-Wittig reaction, and Mannich reac-
tion. In addition, we developed a new method that em-
ployed a diastereoselective 1,2-addition of a methylketone
by using N-TBSOM to protect the indole nucleophile and
[9] a) A. B. Smith, III, N. Kanoh, H. Ishiyama, R. A. Hartz, J. Am.
Chem. Soc. 2000, 122, 11254–11255; b) G. de la Herrꢂn, A. Segura,
A. G. Csꢂkꢃ, Org. Lett. 2007, 9, 961–964.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

¯
S. Omura, T. Sunazuka et al.
[10] B. Chauder, A. Larkin, V. Snieckus, Org. Lett. 2002, 4, 815–817.
[11] a) A. R. Kennedy, M. H. Taday, J. D. Rainier, Org. Lett. 2001, 3,
2407–2409; b) T. Nishimura, K. Yamada, T. Takebe, S. Yokoshima,
T. Fukuyama, Org. Lett. 2008, 10, 2601–2604.
[12] a) H. Shinohara, T. Fukuda, M. Iwao, Tetrahedron 1999, 55, 10989–
11000; b) D. T. Jones, G. D. Artman, III, R. M. Williams, Tetrahe-
dron Lett. 2007, 48, 1291–1294.
[13] a) T. A. van Beek, A. M. Deelder, R. Verpoorte, A. B. Svendsen,
Planta Med. 1984, 50, 180–185; b) T. A. van Beek, R. Verpoorte,
A. B. Svendsen, R. Fokkens, J. Nat. Prod. 1985, 48, 400–423; c) R.
van der Heijden, R. L. Brouwer, R. Verpoorte, T. A. van Beek,
P. A. A. Harkes, A. B. Svendsen, Planta Med. 1986, 52, 144–147.
[14] K. Ingkaninan, A. P. Ijzerman, T. Taesotikul, R. Verpoorte, J.
Pharm. Pharmacol. 1999, 51, 1441–1446.
[15] a) M.-L. Bennasar, E. Zulaica, D. Solꢁ, S. Alonso, Chem. Commun.
2009, 3372–3374; b) M.-L. Bennasar, E. Zulaica, D. Solꢁ, T. Roca,
D. Garcꢄa-Dꢄaz, S. Alonso, J. Org. Chem. 2009, 74, 8359–8368.
[16] M. A. Tarselli, K. M. Raehal, A. K. Brasher, J. M. Streicher, C. E.
Groer, M. D. Cameron, L. M. Bohn, G. C. Micalizio, Nat. Chem.
2011, 3, 449–453.
[32] a) P. Ballesteros, R. M. Claramunt, Tetrahedron 1987, 43, 2557–
2564; b) M. Nakano, W. Kikuchi, J. Matsuo, T. Mukaiyama, Chem.
Lett. 2001, 30, 424–425.
[33] a) T. Kline, J. Heterocycl. Chem. 1985, 22, 505–509; b) J. Bergman,
L. Venemalm, J. Org. Chem. 1992, 57, 2495–2497; c) J. Jiang, G. W.
Gribble, Tetrahedron Lett. 2002, 43, 4115–4117.
[34] a) T. Benneche, L. L. Gundersen, K. Undheim, Acta Chem. Scand.
Acta Chem. Scand. B 1988, 42, 384–389; b) L.-L. Gundersen, T.
Benneche, K. Undheim, Acta Chem. Scand. 1989, 43, 706–709; c) S.
Pitsch, P. A. Weiss, X. Wu, D. Ackermann, T. Honegger, Helv.
Chim. Acta 1999, 82, 1753–1761; d) S. Pitsch, P. A. Weiss, L. Jenny,
A. Stutz, X. Wu, Helv. Chim. Acta 2001, 84, 3773–3795; e) M. A.
Zajac, E. Vedejs, Org. Lett. 2004, 6, 237–240; f) S. Attaluri, R. R.
Bonala, I.-Y. Yang, M. A. Lukin, Y. Wen, A. P. Grollman, M.
Moriya, C. R. Iden, F. Johnson, Prog. Nucleic Acid Res. Mol. Biol.
2010, 50, 339–352.
[35] a) R. J. Sundberg, H. F. Russell, J. Org. Chem. 1973, 38, 3324–3330;
b) H. W. Gschwend, H. R. Rodriguez, Organomet. React. 1979, 26,
1–360.
[36] N-TBSOM-2-iodoindole 37 was prepared from commercially availa-
ble 2-iodoindole.
[17] Part of this investigation was published as a preliminary account;
see: Y. Noguchi, T. Hirose, Y. Furuya, A. Ishiyama, K. Otoguro, S.
¯
Omura, T. Sunazuka, Tetrahedron Lett. 2012, 53, 1802–1807.
[18] H. Zimmer, G. Singh, J. Org. Chem. 1963, 28, 483–486.
[19] a) H. Zimmer, M. Jayawant, P. Gutsch, J. Org. Chem. 1970, 35,
2826–2828; b) E. M. Briggs, G. W. Brown, J. Jiricny, M. F. Meidine,
Synthesis 1980, 295–296; c) J. Barluenga, F. Palacios, Org. Prep.
Proced. Int. 1995, 27, 1–65; d) F. Palacios, A. M. Ochoa, J. Pagalday,
Eur. J. Org. Chem. 2003, 913–919.
[20] P. Frøyen, J. Skramstad, Tetrahedron Lett. 1998, 39, 6387–6390.
[21] M. J. Martinelli, J. Org. Chem. 1990, 55, 5065–5073.
[22] a) J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227; b) J.-L.
Luche, L. Rodiriguez-Hahn, P. Crabbe, J. Chem. Soc. Chem.
Commun. 1978, 601–602.
[37] E. M. Carreira, J. Du Bois, J. Am. Chem. Soc. 1995, 117, 8106–8125.
[38] E. W. Hoffmann, Chem. Rev. 1989, 89, 1841–1860.
[39] a) A. B. Smith, III, J. P. Sestelo, P. Dormer, J. Am. Chem. Soc.
1995, 117, 10755–10756; b) A. B. Smith,
III, J. P. Sestelo, P.
Dormer, Heterocycles 2000, 52, 1315–1328; c) B. W. Greatrex, M. C.
Kimber, D. K. Taylor, G. Fallon, E. R. Tiekink, J. Org. Chem. 2002,
67, 5307–5314; d) M. PeÇa-Lꢅpez, M. M. Martꢄnez, L. A. Sarande-
ses, J. P. Sestelo, Chem. Eur. J. 2009, 15, 910–916.
[23] Y. Yoshida, Y. Sakakura, N. Aso, S. Okada, Y. Tanabe, Tetrahedron
1999, 55, 2183–2192.
[24] a) T. Fukuyama, S.-C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050–
7051; b) D. A. Evans, J. S. Johnson, J. Org. Chem. 1997, 62, 786–787;
c) T. Fukuyama, H. Tokuyama, Aldrichimica Acta 2004, 37, 87–96;
d) G. E. Keck, M. B. Kraft, A. P. Troung, W. Li, C. C. Sanchez, N.
Kedei, N. E. Lewin, P. M. Blumberg, J. Am. Chem. Soc. 2008, 130,
6660–6661.
[25] a) N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc. 1992, 114, 2524–
2536; b) R. Araoz, D. Servent, J. Molgꢅ, B. I. Iorga, C. Fruchart-
Gaillard, E. Benoit, Z. Gu, C. Stivala, A. Zakarian, J. Am. Chem.
Soc. 2011, 133, 10499–10511.
[26] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156;
b) A. B. Smith, III, V. A. Doughty, C. Sfouggatakis, C. S. Bennett,
J. Koyanagi, M. Takeuchi, Org. Lett. 2002, 4, 783–786; c) M. Ball,
M. J. Gaunt, D. F. Hook, A. S. Jessiman, S. Kawahara, P. Orsini, A.
Scolaro, A. C. Talbot, H. R. Tanner, S. Yamanoi, S. V. Ley, Angew.
Chem. 2005, 117, 5569–5574; Angew. Chem. Int. Ed. 2005, 44, 5433–
5438.
[27] I. Utsunomiya, M. Fuji, T. Sato, M. Natsume, Chem. Pharm. Bull.
1993, 41, 854–860.
[28] A. Yasuhara, T. Sakamoto, Tetrahedron Lett. 1998, 39, 595–596.
[29] a) A. P. Kozikowski, Y.-Y. Chen, J. Org. Chem. 1981, 46, 5250–5252;
b) M. G. Saulnier, G. W. Gribble, J. Org. Chem. 1982, 47, 2812–
2814.
[30] a) G. W. Gribble, T. C. Barden, J. Org. Chem. 1985, 50, 5902–5905;
b) M. Sato, M. Kahn, Z. Lin, M. E. Johnson, T. K. Hayes, Bioorg.
Med. Chem. Lett. 1993, 3, 1277–1282; c) T. Yamakawa, E. Ideue, Y.
Iwaki, A. Sato, H. Tokuyama, J. Shimokawa, T. Fukuyama, Tetrahe-
dron 2011, 67, 6547–6560.
[31] a) T. Yasukochi, C. Inaba, K. Fukase, S. Kusumoto, Tetrahedron
Lett. 1999, 40, 6585–6589; b) T. Yasukochi, K. Fukase, S. Kusumoto,
Tetrahedron Lett. 1999, 40, 6591–6593.
[40] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736.
[41] a) M. E. Jung, J. Gervay, J. Am. Chem. Soc. 1989, 111, 5469–5470;
b) H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, K.
Omoto, H. Fujimoto, J. Am. Chem. Soc. 2000, 122, 11041–11047.
[42] a) W. R. Roush, C. E. Bennett, S. E. Roberts, J. Org. Chem. 2001,
66, 6389–6393; b) S. Imuta, H. Tanimoto, K. M. Momose, N. Chida,
Tetrahedron 2006, 62, 6926–6944.
[43] a) L. Horner, H. Hoffmann, H. G. Wippel, Chem. Ber. 1958, 91, 61–
63; b) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Ma-
samune, W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183–
2186.
[44] a) S. Tsuboi, J. Sakamoto, T. Kawano, M. Utaka, A. Takeda, J. Org.
Chem. 1991, 56, 7177–7179; b) B. M. Trost, J.-P. Surivet, F. D. Toste,
J. Am. Chem. Soc. 2004, 126, 15592–15602.
[45] T. Hudlicky, T. Tsunoda, K. G. Gadamasetti, J. A. Murry, G. E.
Keck, J. Org. Chem. 1991, 56, 3619–3623.
[46] a) T.-T. Li, Y.-L. Wu, Tetrahedron Lett. 1988, 29, 4039–4040; b) C.
Somoza, J. Darias, E. A. Rfflveda, J. Org. Chem. 1989, 54, 1539–
1543; c) J. A. Bacigaluppo, M. I. Colombo, M. D. Preite, J. Zinczuk,
E. A. Rfflveda, Synth. Commun. 1996, 26, 2737–2749; d) K. Uchida,
K. Ishigami, H. Watanabe, T. Kitahara, Tetrahedron 2007, 63, 1281–
1287.
[47] C. Jaime, R. M. OrtuÇo, J. Font, J. Org. Chem. 1986, 51, 3946–3951;
see also ref. [39a].
[48] H. Nakatsuji, K. Ueno, T. Misaki, Y. Tanabe, Org. Lett. 2008, 10,
2131–2134.
[49] a) L. E. Overman, S. R. Angle, J. Org. Chem. 1985, 50, 4021–4028;
b) M. S. Betson, I. Fleming, Org. Biomol. Chem. 2003, 1, 4005–
4016; c) J. D. Winkler, A. T. Londregan, J. R. Ragains, M. T.
Hamann, Org. Lett. 2006, 8, 3407–3409.
[50] The S configuration of the C3 center of (À)-52 was determined after
hydrogenation.
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Total Synthesis of 16-Hydroxy-16,22-dihydroapparicine
FULL PAPER
[54] M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zou,
B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen,
K. R. Spencer, G. E. Gonzꢂlez-Pꢂez, S. B. Lakshminarayana, A.
Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Burn, F.
Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winz-
eler, T. T. Diagana, Science 2010, 329, 1175–1180.
[55] a) K. Otoguro, A. Kohana, C. Manabe, A. Ishiyama, H. Ui, K.
¯
Shiomi, H. Yamada, S. Omura, J. Antibiot. 2001, 54, 658–663; b) K.
Otoguro, A. Ishiyama, H. Ui, M. Kobayashi, C. Manabe, G. Yan, Y.
Takahashi, H. Tanaka, H. Yamada, S. Omura, J. Antibiot. 2002, 55,
[51] a) J. R. Crow, R. J. Thomson, L. N. Mander, Org. Biomol. Chem.
2006, 4, 2532–2544; b) M. D. Lainchbury, M. I. Medley, P. M. Taylor,
P. Hirst, W. Dohle, K. I. Booker-Milburn, J. Org. Chem. 2008, 73,
6497–6505.
[52] a) C. F. Lane, Chem. Rev. 1976, 76, 773–799; b) B. W. Gung, H.
Dickson, Org. Lett. 2002, 4, 2517–2519.
[53] a) A. G. Schultz, M. A. Holoboski, M. S. Smyth, J. Am. Chem. Soc.
1996, 118, 6210–6219; b) M. H. Becker, P. Chua, R. Downham, C. J.
Douglas, N. K. Garg, S. Hiebert, S. Jaroch, R. T. Matsuoka, J. A.
Middleton, F. W. Ng, L. E. Overman, J. Am. Chem. Soc. 2007, 129,
11987–12002; c) K. Miyashita, T. Tsunemi, T. Hosokawa, M. Ikejiri,
T. Imanishi, J. Org. Chem. 2008, 73, 5360–5370; d) S. Hanessian, E.
Stoffman, X. Mi, P. Renton, Org. Lett. 2011, 13, 840–843.
¯
832–834; c) M. Iwatsuki, S. Takada, M. Mori, A. Ishiyama, M. Na-
matame, A. Nishihara-Tsukashima, K. Nonaka, R. Masuma, K. Oto-
¯
guro, K. Shiomi, S. Omura, J. Antibiot. 2011, 64, 183–188.
[56] S. R. Meshnick, M. J. Dobson, “The history of antimalarial drugs” in
Antimalarial chemotherapy: mechanisms of action resistance and
new directions in drug discovery (Ed: P. J. Rosenthal), Humana
Press, Totowa, 15–25, 2001.
Received: January 25, 2013
Revised: April 22, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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