The first total synthesis and reassignment of the relative stereochemistry of 16-hydroxy-16,22-dihydroapparicine

Article abstract of DOI:10.1016/j.tetlet.2012.01.110

We report the first total synthesis and reassignment of the relative stereochemistry of naturally occurring 16-hydroxy-16,22-dihydroapparicine. Our novel route proceeds by a cascade reaction to efficiently construct a 1-azabicyclo[4.2.2]decane core, along

Full text of DOI:10.1016/j.tetlet.2012.01.110

Tetrahedron Letters 53 (2012) 1802–1807
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first total synthesis and reassignment of the relative stereochemistry
of 16-hydroxy-16,22-dihydroapparicine
Yoshihiko Noguchi, Tomoyasu Hirose, Yujiro Furuya, Aki Ishiyama, Kazuhiko Otoguro,
⇑
⇑
¯
Satoshi Omura , Toshiaki 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
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the first total synthesis and reassignment of the relative stereochemistry of naturally occurring
16-hydroxy-16,22-dihydroapparicine. Our novel route proceeds by a cascade reaction to efficiently con-
struct a 1-azabicyclo[4.2.2]decane core, along with two stereocenters (C-15 and C-16). The C-16 quater-
nary carbon was constructed through stereospecific 1,2-addition using an indole nucleophile to an
aldehyde or a methylketone. The stereospecific synthesis of two diastereomers of the target product
has revealed the true relative stereochemistry of the natural compound.
Received 11 January 2012
Revised 24 January 2012
Accepted 25 January 2012
Available online 3 February 2012
Keywords:
Apparicines
Ó 2012 Elsevier Ltd. All rights reserved.
Total synthesis
Cascade reaction
Stereospecific 1,2-addition
Relative stereochemistry
Plants of the genus Tabernaemontana have a widespread distri-
bution and are known to provide alkaloids of intriguing molecular
structure and novel biological activity. Apparicine (1) was the first
monoterpenoid indole alkaloid, initially isolated from Aspidosper-
ma dasycarpon more than 45 years ago.1 It is the main representa-
tive of a small group of 5-nor stemmadenine alkaloids of which
there are 16 known species (including apparicine (1),1 16-hydro-
xy-16,22-dihydroapparicine (2),2 ervaticine (3),3 conolidine (4),4
and isobrafouedine (5)5) (Fig. 1).
The main structural and defining feature of these alkaloids is
the strained 1-azabicyclo[4.2.2]decane skeleton, including a single
carbon connection between the indole 3-position and aliphatic
Me
N
Me
HN
N
15
R2
R116
HN
H
H
2
16-hydroxy-16,22-dihydroapparicine ( )
apparicine(1)
15S ,16S (proposed) R = OH, R2 = Me
*
*
1
N
15S*,16R* (this report) R1 = Me, R2 = OH
OH
Me
O
R
N
1-azabicyclo[4.2.2]decane
N
HN
O
H
Me
HN
H
Me
ervaticine (3) R3
conolidine (4) R3
=
isobrafouedine (5)
=
Me
Figure 1. Structure of some 5-nor stemmadenine alkaloids.
⇑
¯
Corresponding authors. Tel./fax: +81 3 5791 6340 (T.S.); tel.: +81 3 5791 6101; fax: +81 3 3444 8360 (S.O.).
¯
E-mail addresses: omuras@insti.kitasato-u.ac.jp (S. Omura), sunazuka@lisci.kitasato-u.ac.jp (T. Sunazuka).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.110

Y. Noguchi et al. / Tetrahedron Letters 53 (2012) 1802–1807
1803
NR2
NR2
R
R2N NR2
+
+
NR2
NR2
R
R
R
N
H
N
H
aminal
gramine (R = Me)
Scheme 1. Gramine as a versatile pseudo-aminal type compound.
nitrogen moiety. The characteristic moiety of the single carbon-ali-
phatic nitrogen of the 5-nor stemmadenine alkaloids are like
gramine (Scheme 1). In gramine, the single carbon-aliphatic nitro-
gen bond is easily cleaved by retro-Mannich reaction to generate
the imine under acidic,6 basic,7 or thermic8 conditions. Therefore,
we anticipated that the aminomethyl moiety on 3-position of in-
dole was an indicator of reactivity similar to the aminal.
Recently, the total synthesis of simple 5-nor stemmadenine
alkaloids were reported by the Bennasar group9 and the Micalizio
group.10 Herein, we report the total assignment of the configura-
tion of 16-hydroxy-16,22-dihydroapparicine (2) identified through
the first stereospecific total synthesis of two diastereomers of 2.
16-Hydroxy-16,22-dihydroapparicine (2) was isolated from
Tabernaemontana dichotoma in 1984.2 Based on spectral analysis,
the relative stereochemistry of 2 was proposed to be a 15S⁄,16S⁄-
configuration. The total synthesis of 2, has not previously been
accomplished to help accurately determine the relative and abso-
lute stereochemistry.
constructed by a cascade reaction (Scheme 2). Given the reactivity
of phosphineimine, we designed a novel phosphineimine-medi-
ated cascade reaction, the sequence of which was; (1) Staudinger
reaction11 with triphenylphosphine and an azido group to generate
phosphineimine (8); (2) compound 8 was converted to aminophos-
phinium (7) by intramolecular N-allylation with an appropriate
electrophile; (3) aza-Wittig reaction of 7 with formaldehyde; (4)
intramolecular Mannich reaction. Consequently, nucleophilic at-
tack might be performed from the indole 3-position to iminium
cation (6) (see Scheme 2).
Our synthesis commenced with preparation of the azidoalde-
hyde (10) (Scheme 5). cis-Butenediol (12) was elaborated to the
a
,b-unsaturated imide (À)-13 using the robust four-step proce-
dure described by Martinelli.12 Subsequently, remote asymmetric
Michael reaction of (À)-13 was attempted to convert the desired
b-substituted product (15). However, the desired Michael addi-
tion product (15) appeared in low yield, along with other diaste-
reomers and
c-addition regioisomers of 14 under any extensive
Our synthesis pathway to the 1-azabicyclo[4.2.2]decane skele-
ton was guided by the hypothesis that pseudo-aminal type
alkaloids occur via a biogenetic intermediate. We envisaged the
in situ preparation of the iminium cation (6), which could be
conditions. Subsequently, DBU mediated isomerization of 15
afforded the sole E-olefin product (16) as a 1:1 mixture (of dia-
stereomer at C-3), in a 91% yield. The E-olefin product (16) was
reduced to alcohol in an 82% yield, without further reduction.13
N
Me
N
Me
15
R1
R1
HN
16 H
HN
H
HCHO
Me
R2
R2
15S*,16S*-2, R1 = Me, R2 = OH
6
(proposed stereochemistry)
PPh3
N
R1
Cascade reaction
HN
H
R2
7
LG
LG
PPh3
PPh3
N3
N
Me
Me
R1
R1
HN
HN
H
H
R2
R2
9
8
1,2-addition
N3
+
R3
OPG
N
PG
O
Me
10 (R3 = H)
11 (R3 = Me)
Scheme 2. Retrosynthetic analysis of 15S⁄,16S⁄-2.

1804
Y. Noguchi et al. / Tetrahedron Letters 53 (2012) 1802–1807
O
SEt
14
Bn
–
ref. 12
LDA, THF, 78 ºC
N
O
O
HO
OH
Bn
BnO
33%
O
O
O
12
( )-13
–
Bn
1) NaBH4, CeCl3•7H2O
THF/MeOH, 50 ºC
–
DBU
3
82%
N
O
N
THF
BnO
BnO
Me
91%
2) TsCl, Me3N•HCl
Et3N, CH2Cl2
97%
O
SEt
O
O
SEt
O
15
O
16
1) Lindlar cat., Et3SiH, 1-Hexene
Quinoline, Acetone/CH2Cl2, 75%
OTs
OTs
SEt
BnO
Me
BnO
Me
2) NaBH4, CeCl3•7H2O, MeOH
0 ºC, 97%
OH
O
17
( )-
18
( )-
N3
1) NaN3
DMSO
83%
1) DDQ
N3
CH2Cl2/pH 7.2 phosphate
buffer, 85%
BnO
Me
3
H
OPiv
2) PivCl
Pyridine
99%
2) Dess-Martin Periodinane
CH2Cl2, 93%
O
OPiv
( )-19
Me
10
( )-
Scheme 3. Synthesis of azidoaldehyde ( )-10.
The alcohol was converted to tosylate ( )-17 via the process re-
ported by Tanabe and co-workers.14 Subsequently,
,b-unsatu-
finally opted for a 3-nitropyridyl group,19 and prepared ( )-9 in a
93% yield under Ballesteros’s condition20 (Scheme 4).
a
rated thioester was transformed to the allyl alcohol ( )-18. The
Fukuyama reduction caused high chemoselectivity, causing the
thioester group to be converted to the conjugated aldehyde15
which was then converted to the desired allyl alcohol ( )-18 un-
der Luche condition12 in a 97% yield. Furthermore, azidation of
( )-18, followed by protection of the hydroxy group, afforded
the allyl pivalate ( )-19 in excellent yield. In the next step, the
benzyl group was removed from ( )-19 under oxidative deprotec-
tion using DDQ, as reported by Ikemoto and Schreiber.16 The ob-
tained alcohol was oxidized to azidoaldehyde ( )-10 using
Dess–Martin periodinane17 in a 93% yield (Scheme 3).
With the azidoaldehyde ( )-10 in hand, 1,2-addition of the in-
dole nucleophile (20), protected by phenylsulfone,18 provided the
hydroxyindole ( )-21 (as a single diastereomer) in an 85% yield.
Dess–Martin oxidation17 of ( )-21 was performed to give the
ketoindole ( )-22, following removal of the phenylsulfone and
pivaloyl groups under basic solvolysis, which was converted to
the hydroxyketoindole ( )-23 in an 87% yield.
In the final stage, we attempted a cascade reaction for construc-
tion of the 1-azabicyclo[4.2.2]decane skeleton, including the
pseudo-aminal type moiety. Thus, ( )-9 was treated with PPh3 at
60 °C. Subsequently, the reaction mixture was acidified using AcOH
for activation of the 3-nitropyridyl group. Finally, formaldehyde
and PPTS were added to the reaction mixture, and synthesis of
( )-2 was completed in an 88% yield (Scheme 5).
However, the spectral data of synthetic ( )-2 did not agree with
that of natural 2.2 In particular, ROESY analysis of synthetic ( )-2,
showed a relationship between H-18 or H-19 and 16-Me. Thus
the relative stereochemistry of synthetic ( )-2 was determined to
be a 15S⁄,16S⁄-configuration, which was the configuration pro-
posed by Verpoorte’s group.2 As a result, the C-16 stereocenter out-
come reflected the Felkin–Anh transition state. Comparison of 1H
and 13C NMR indicated 16-Me and H-6a,b proton difference (as
shown in the Supplementary data). Furthermore, the 13C signals
of the piperidine ring were greatly shifted from those seen in nat-
urally occurring 2. Therefore, we expected that the 16-Me group in
natural 2 was on the opposite face of the trisubstituted exo-cycli-
colefin. Thus, the relative stereochemistry was anticipated to be
the 15S⁄,16R⁄-configuration. To confirm this, we turned our atten-
tion to completing the synthesis of 15S⁄,16R⁄-isomer 33 with
methylketone (27).
Subsequently, diastereoselective methylation of ( )-23 was
converted to dihydroxyindole ( )-24 as a single diastereomer in
excellent yield. The C-16 stereocenter of ( )-24 was not confirmed
at this point. Preparation of full carbon and nitrogen skeletons was
completed and introduction of a suitable leaving group on the pri-
mary alcohol to attempt the cascade reaction was all that was now
required. After many attempts to find a suitable leaving group, we
Construction of the stereocenter of 16R⁄ of C-16 position was
adapted to our 1,2-addition procedure through the Felkin–Anh

Y. Noguchi et al. / Tetrahedron Letters 53 (2012) 1802–1807
1805
N
20 SO2Ph
OPiv
Dess-Martin Periodinane
n-BuLi, THF
–78 ºC
CH2Cl2
N3
Me
10
( )-
quant.
85%
dr = >20 : 1
N
PhO2S
HO
Single diastereomer
( )-21
OPiv
OH
N3
MeLi, THF
K2CO3, MeOH
87%
N3
–78 ºC
Me
O
Me
91%
dr = >20 : 1
N
HN
PhO2S
O
23
( )-
22
( )-
O2N
Cl
N
NO2
Tris[2-(2-methoxyethoxy)ethyl]amine
KOH, K2CO3, Toluene
–20 to –10 ºC
OH
N3
N
O
Me
*
15
N3
Me
Me
93%
*
Me *
HO16
HN
H
HN
*
H
HO
( )-9
( )-24
Single diastereomer
Scheme 4. Synthesis of the cascade reaction precursor ( )-9.
NO2
without decomposition of the substrate. Characterization data pro-
vided for synthetic ( )-(15S⁄,16R⁄)-33 were fully consistent with
the data for the natural compound reported by Verpoorte’s group.2
In addition, NOE relationship was observed between H-14a and H-
22 (i.e., 16-Me). As the result, the relative stereochemistry of C15
and C16 was determined to be the 15S⁄,16R⁄-configuration. Fur-
thermore, we also analyzed ( )-(15S⁄,16S⁄)-1, ( )-(15S⁄,16R⁄)-33
and natural product via HPLC. Both diastereomer 1 and 33 were
separated, and the natural product was identical to synthetic 33.
In conclusion, we have achieved the first total synthesis of
16-hydroxy-16,22-dihydroapparicine and determined the true rel-
ative stereochemistry of the naturally occurring compound ( )-
(15S⁄,16R⁄)-16-hydroxy-16,22-dihydroapparicine (33). Synthesis
involved a novel cascade reaction allowing efficient construction
of the 1-azabicyclo[4.2.2]decane, including a pseudo-aminal type
moiety, plus a Staudinger reaction, N-allylation, aza-Wittig reac-
tion and Mannich reaction. In addition, we developed a novel
method employing diastereoselective 1,2-addition of aldehyde or
methylketone using N-protected indole-nucleophiles. Further de-
tailed study of the cascade reaction mechanism and development
of asymmetric total synthesis is in progress, and the results of
these and related investigations will be reported in due course.
a. PPh3
THF
b. AcOH
PPTS
N
O
PPh3
( )-9
N
Me
60 ºC
*
Me
HN
*
H
HO
25
18
19
Me
6
N
Me
c. HCHO aq.
88%
HN
15
Me
*
Me
HO16
H
HN
HN
*
H
HO
26
( )-(15S ,16S )-2
*
*
ROESY;
Scheme 5. Total synthesis of ( )-(15S⁄,16S⁄)-16-hydroxy-16,22-dihydroapparicine
(2).
transition state (Scheme 6). The methylketone was prepared from
the aldehyde ( )-10 by the addition of methyl anion, plus subse-
quent oxidation using Dess–Martin periodinane, in good yields. Ac-
cess to the isomer, 16R⁄-33 was obtained by applying an identical
reaction sequence with an improvement for 1,2-addition by the
use of SEM protected indole nucleophile,21 similar to that used
for the preparation of 16S⁄-2 from methylketone ( )-27. Actually,
1,2-addition of PhSO2-protected indole (20) to ( )-27 not only pro-
duced the 1,2-adduct product in a 20% yield, but also the deprotec-
tion of PhSO2 group could not proceed under any conditions
Acknowledgments
This work was supported by a Grant for the 21st Century COE
Program, Ministry of Education Culture, Sports, Science and Tech-
nology (MEXT) (Grant No. 18790022), a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Cul-
ture, Japan (JSPS) and a Kitasato University Research Grant for
Young Researchers. We also thank Dr. K. Nagai and N. Sato (School

1806
Y. Noguchi et al. / Tetrahedron Letters 53 (2012) 1802–1807
I
N3
N
1) MeMgBr, THF
SEM
–78 ºC, 87%
n-BuLi
3
10
( )-
Me
OPiv
2) Dess-Martin Periodinane
CH2Cl2, 97%
THF, –78 ºC
90%
O
Me
27
( )-
OPiv
OH
N3
1) DIBAL, CH2Cl2, –78 ºC
N3
Me
94%
Me
Me
*
OH
OH
*
2) TASF, ethylenediamine
THF/DMF, 50 ºC, 46%
N
*
H
SEM
Me
HN
*
H
28
( )- (Single diastereomer)
29
( )-
O2N
Cl
N
NO2
NO2
Tris[2-(2-methoxyethoxy)-
ethyl]amine
KOH, K2CO3, Toluene
–20 to –10 ºC
N
N
O
O
PPh3
PPh3
N3
N
Me
Me
THF/H2O
reflux
83%
OH *
OH
HN
*
HN
H
H
Me
Me
( )-30
31
PPh3
HCHO aq.
PPTS
N
AcOH
Me
Me
Me
N
15
OH
OH
83%
HN
14Hb
H
16
HN
H
Me
Ha
22
NOE ;
32
( )-(15S ,16R )-33
*
*
Scheme 6. Total synthesis of ( )-(15S⁄,16R⁄)-isomer (33).
8. Diker, K.; Döé de Maindreville, M.; Royer, D.; Provost, F. L.; Lévy, J. Tetrahedron
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Supplementary data
Supplementary data (representative experimental procedure
and characterization data of compound (( )-15S⁄,16S⁄-1 and ( )-
15S⁄,16R⁄-33) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2012.01.110.
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