Approach to the core structure of the polycyclic alkaloid palhinine A

Article abstract of DOI:10.1055/s-0032-1316899

A synthesis of the tricyclic partly substituted core structure of palhinine A was achieved. To reach the bicyclo[2.2.2]octane motif a domino Michael reaction was employed as a key step. After Arndt-Eistert homologation and intramolecular aldol reaction the isotwistane core could be obtained after simple functional-group manipulations. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1316899

LETTER
▌955
lAettper proach to the Core Structure of the Polycyclic Alkaloid Palhinine A
Palhinine A Model Study
Dominik Gaugele, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295137; E-mail: martin.e.maier@uni-tuebingen.de
Received: 11.02.2013; Accepted after revision: 18.03.2013
H
Abstract: A synthesis of the tricyclic partly substituted core struc-
O
ture of palhinine A was achieved. To reach the bicyclo[2.2.2]octane
motif a domino Michael reaction was employed as a key step. After
Arndt–Eistert homologation and intramolecular aldol reaction the
isotwistane core could be obtained after simple functional-group
manipulations.
OH
OH
O
NMe
=
=
O
N
O
O
Me
O
N
OH
Me
Key words: palhinine A, domino Michael reaction, X-ray crystal
structure, Arndt–Eistert homologation, intramolecular aldol re-
action
1
H
O
OMe
OH
O
O
H
The C16N-type alkaloid palhinine A (1, Figure 1) was de-
scribed in 2010 as an isolate from the whole plant of
Palhinhaea cernua L.1 No significant biological activity
was reported for this natural product, but the core or sub-
structures thereof might serve as a scaffold for medicinal
chemistry. The two contiguous quaternary stereocenters
together with the polycyclic structure pose a great chal-
lenge for synthetic chemists. Recently, two synthetic stud-
ies were published by Chinese groups.2,3 Thus, Xie and
She et al. utilized an intramolecular Diels–Alder reaction
of an ortho-quinone acetal to form the bicyclo[2.2.2]-
octane core for the synthesis of tricyclic diketone 2. In this
case the five-membered ring originated from an intramo-
lecular radical addition to a double bond.2 In another study
Fan et al. employed an intramolecular Diels–Alder reac-
tion as well.3 Here the five-membered ring of the isotwist-
ane system was formed in the course of the cycloaddition
reaction, eventually leading to core structure 3. As a mod-
el study we targeted the partly substituted isotwistane core
structure 5 of palhinine A. This was achieved via a domi-
no Michael strategy followed by an Arndt–Eistert homo-
logation and an intramolecular aldol reaction. Some
selected examples of isotwistane formation are listed in
the references.3
O
O
O
TBDPSO
BnO
NTs
Me
2
3
isotwistane (4)
core 5
Figure 1 The structure of palhinine A (1) in three different views,
already synthesized core structures 2 and 3, isotwistane (4), and the
target structure 5 of this work
domino Michael and
Arndt–Eistert
O
O
MeO2C
O
OH
TBDPSO
TBDPSO
TBDPSO
6
7
5
intramolecular aldol
O
Oi-Bu
O
OTBDPS
8
9
Scheme 1 Retrosynthetic analysis for the palhinine A core 5
Our retrosynthetic analysis (Scheme 1) features an intra-
molecular aldol reaction to close the third ring to reach the
tricyclic structure 6. The required bicyclo[2.2.2]octane
motif 7 could be established via a domino Michael re-
action, a transformation which was broadly described in
the literature,4–6 followed by an Arndt–Eistert homologa-
tion.7,8 As a starting material for the desired domino
Michael reaction we needed cyclohexenone 8, which
would be obtained via addition of the Normant–Grignard9
to vinylogous ester10 9.
The synthesis commenced with the addition of the
Normant–Grignard,9 which refers to the Grignard reagent
prepared from 3-chloropropanol, to vinylogous ester 9 ac-
cording to the literature (Scheme 2).11,12 First, 1,2-addi-
tion to the carbonyl group occurred, followed by acidic
hydrolysis of the vinylogous hemiacetal to form the de-
sired hydroxyenone 10a. We observed that a solution of
10a in CDCl3 partly converts into the spiroketone 10b,
probably via an acid-catalyzed intramolecular oxo-
Michael addition.11a This intramolecular reaction also
takes place in the purified product, so we always got a
mixture of hydroxyenone 10a and spiroketone 10b for the
subsequent step. This turned out to be inconsequential, be-
cause it was possible to use the mixture for the protection
SYNLETT 2013, 24, 0955–0958
Advanced online publication: 09.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316899; Art ID: ST-2013-B0137-L
© Georg Thieme Verlag Stuttgart · New York

956
D. Gaugele, M. E. Maier
LETTER
step with tert-butyldiphenylsilylchloride (TBDPSCl) giv-
ing good yields of silyloxyenone 8. Thus, this intramolec-
ular oxo-Michael reaction is reversible under the
conditions of the protection reaction.
O
O
1. chloropropanol, MeMgCl
Mg, THF, –10 °C
9
O
2. HCl, H2O, r.t.
(72%, 2 steps)
OH
10a
10b
O
OTBDPS
TBDPSCl, imidazole
Figure 2 X-ray analysis of bicyclic ester 11. The structure refine-
ment was done using SHELXL-97.14
CH2Cl2, 0 °C to r.t.
(89%)
8
To perform the Arndt–Eistert homologation4,5 (Scheme 4)
we first prepared the acid chloride from 12 using oxalyl
chloride and catalytic amounts of DMF. Reaction of the
crude acid chloride with trimethylsilyldiazomethane pro-
duced the α-diazoketone 13. Wolff rearrangement8 of di-
azoketone 13 in methanol in the presence of silver
benzoate under ultrasound irradiation provided an excel-
lent yield of the homologated ester 7. In order to convert
keto ester 7 into keto aldehyde 14 we again relied on a re-
dox sequence as before. Thus, full reduction of ester 7 to
the corresponding diol with LiAlH4 was followed by
Dess–Martin oxidation15 back to the keto aldehyde 14. To
close the third ring we performed an intramolecular aldol
reaction with K2CO3 as base in methanol to furnish a mix-
ture of the aldol products 6a/6b with an exo/endo ratio of
1.35:1. Both epimers could be separated and character-
ized. In endo-aldol 6b one proton on position 1′ showed a
NOESY cross peak to the proton on position 4 and addi-
tionally the coupling constant between 3-H and 4-H was
3JHH = 7.6 Hz. In the exo-epimer 6a there was no such
NOESY cross peak, and the coupling constant between
3-H and 4-H was 3JHH = 0.9 Hz.
Scheme 2 Grignard addition to vinylogous ester 9 and conversion of
the mixture of 10a/10b into silyloxyenone 8
The bimolecular domino Michael reaction4 (Scheme 3) on
cyclohexenone 8 was carried out under basic conditions
with LiN(SiMe3)2 (LHMDS) as base and methyl acrylate
(5 equiv). Use of LDA as base instead of LHMDS only led
to poor yields. During the optimization of this reaction it
turned out to be essential to use a mixture of THF and n-
hexane as solvent. The reaction only led to one isomer 11
due to a chelating effect between the lithium ion and the
carbonyl oxygen at the ring and the carbonyl oxygen of
the ester group.7 Standard ester cleaving conditions such
as LiOH in THF–water or NaSEt in DMF or DMSO only
led to decomposition or only to traces of product. The first
successful attempt to cleave the ester in moderate yields
was with Me3SnOH.13 But due to the high cost, high tox-
icity, high loading of the reagent (5 equiv), and the early
stage in the synthesis we decided to look for another pos-
sibility to get the free acid. To save additional protection
and deprotection steps we reduced the ketone and the ester
function of bicyclic ester 11 to the corresponding diol us-
ing LiAlH4 in one step, followed by a complete oxidation
with PDC in DMF back to the keto acid 12 in 61% yield
over two steps.
O
a) (COCl)2, CH2Cl2
AgOBz, Et3N
MeOH (94%)
12
b) Me3SiCHN2
MeCN–THF (63%)
H
OTBDPS
The stereochemistry of the bicyclic keto ester 11 could be
O
proofed by a single-crystal X-ray analysis (Figure 2).
N2
13
O
O
a) LiAlH4, THF, 0 °C
O
LiHMDS,THF–hexane
a) LiAlH4, THF, 0 °C
b) DMP, NaHCO3
CH2Cl2, r.t. (87%)
8
H
O
methyl acrylate
–85 °C to r.t. (50%)
b) PDC, DMF, r.t.
(61%, 2 steps)
MeO2C
OTBDPS
MeO2C
TBDPSO
7
14
TBDPSO
11
O
O
K2CO3, MeOH
O
+
3
0 °C to r.t.
(96%)
1'
4
HO2C
TBDPSO
OH
OH
TBDPSO
TBDPSO
6a
6b
12
(6a/6b = 58:42)
Scheme 3 Domino Michael reaction between enone 8 and methyl
acrylate followed by ester cleavage via a reduction–oxidation se-
quence
Scheme 4 Arndt–Eistert homologation of acid 12 to ester 7 and in-
tramolecular aldol reaction of derived keto aldehyde 14 to tricyclic β-
hydroxyketones 6a/6b
Synlett 2013, 24, 955–958
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palhinine A Model Study
957
Ströbele (University of Tübingen) for obtaining X-ray single-
crystal structure analysis.
Before forming a tosylhydrazone out of the ketone we
needed to protect the alcohol function as acetate 15
(Scheme 5), because otherwise the conditions for tosylhy-
drazone formation led to decomposition. It was only pos-
sible to convert the exo-acetate 15 into the corresponding
tosylhydrazone 16. Subjecting the endo-acetate to the
same reaction conditions led to decomposition, and only
traces of the corresponding tosylhydrazone could be iso-
lated. The next step was to reduce and defunctionalize the
tosylhydrazone function in molecule 16 to a methylene
group. This could be realized with the use of NaCNBH3
and ZnCl2 in methanol, and the acetate16 17 could be ob-
tained in good yield.17 Finally, after cleavage of the ace-
tate of 17 with the use of K2CO3 in methanol, Dess–
Martin oxidation15 of alcohol 18 furnished the desired
core structure 5 in good yield.18
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI: 10.4125/pd0043th.PmriDyramPatrDiyra41a2t0.5p/d0mP4h3.itarrDyaZtaheln101Chemyrtsi
References and Notes
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O
N
p-TsNHNH2
Ac2O, Et3N
6a
CH2Cl2, r.t.
(95%)
MeOH, 66 °C
(64%)
(4) For representative bimolecular domino Michael reactions,
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OAc
OAc
TBDPSO
TBDPSO
15
16
NaCNBH3, ZnCl2
DMP, NaHCO3
CH2Cl2 (88%)
MeOH, reflux
(71%)
OR
17 R = Ac
O
TBDPSO
TBDPSO
5
K2CO3, MeOH
r.t. (93%)
18 R = H
Scheme 5 Conversion of the acetylated tricyclic aldol product 6a
into the palhinine A core 5. DMP = Dess–Martin periodinane.
In conclusion, we achieved a racemic synthesis of the
partly substituted isotwistane core structure 5 of palhinine
A in 16 linear steps. Starting from vinylogous ester 9 we
obtained the bicyclo[2.2.2]octane motif 11 by exploiting
a domino Michael reaction. By means of single-crystal X-
ray structural analysis the stereoselectivity of the domino
Michael reaction could be proofed. The best yields in
cleaving the ester 11 were achieved via reduction fol-
lowed by oxidation. After Arndt–Eistert homologation,
reduction, and oxidation to the aldehyde 14, an intramo-
lecular aldol reaction furnished the tricyclic isotwistane
structures 6a/6b. From there palhinine A core structure 5
could be obtained by deoxygenation and oxidation of the
secondary alcohol in the five-membered ring.
Satyanarayana, G. Tetrahedron Lett. 2007, 48, 73.
(o) Fukushima, M.; Morii, A.; Hoshi, T.; Suzuki, T.;
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Synthesis 2011, 1984.
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see: (a) Ihara, M.; Toyota, M.; Fukumoto, K.; Kametani, T.
Tetrahedron Lett. 1984, 25, 2167. (b) Ihara, M.; Ishida, Y.;
Abe, M.; Toyota, M.; Fukumoto, K.; Kametani, T. J. Chem.
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Sakanishi, K.; Iimori, E.; Nishimura, K. i.; Iwabuchi, Y.
Org. Lett. 2011, 13, 2864.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged. This
work was done in the framework of COST Action CM0804 – Che-
mical Biology with Natural Products. We thank D. B. Ushakov
(University of Tübingen) and A. Reiss (University of Tübingen) for
helpful discussions. We also thank Dr. D. Wistuba (University of
Tübingen) for obtaining high-resolution mass spectra and Dr. M.
(6) For a review, see: Ihara, M.; Fukumoto, K. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1010; Angew. Chem. 1993, 105,
1059.
(7) Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 955–958

958
D. Gaugele, M. E. Maier
LETTER
(8) For some reviews, see: (a) Kirmse, W. Eur. J. Org. Chem.
2002, 2193. (b) Zhang, Z.; Wang, J. Tetrahedron 2008, 64,
6577.
(9) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett.
1978, 19, 3013.
(10) (a) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.;
Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1999, 121,
3072. (b) Yamada, S.; Suemune, H. Chem. Pharm. Bull.
2000, 48, 1171. (c) Gulías, M.; Rodríguez, J. R.; Castedo, L.;
Mascareñas, J. L. Org. Lett. 2003, 5, 1975.
(11) Addition reactions with Grignard reagents derived from ω-
halohydrins: (a) Conia, J.-M.; Rouessac, F. Tetrahedron
1961, 16, 45. (b) Tietze, L. F.; Schirok, H.; Wöhrmann, M.
Chem. Eur. J. 2000, 6, 510. (c) Findley, T. J. K.; Sucunza,
D.; Miller, L. C.; Davies, D. T.; Procter, D. J. Chem. Eur. J.
2008, 14, 6862.
Rf = 0.63 (cyclohexane–EtOAc = 2:1). 1H NMR (400 MHz,
CDCl3): δ = 1.05 (s, 9 H, Ht-Bu), 1.16–1.31 (m, 2 H, 2′-H, 10-
H), 1.35–1.64 (m, 9 H, 1-H, 1′-H, 2′-H, 5-H, 8-H, 9-H),
1.73–1.95 (m, 9 H, 2-H, 3-H, 5-H, 6-H, 10-H, CH3CO2),
3.56–3.69 (m, 2 H, 3′-H), 4.89–4.96 (m, 1 H, 4-H), 7.34–
7.45 (m, 6 H, HAr), 7.65–7.70 (m, 4 H, HAr). 13C NMR (100
MHz, CDCl3): δ = 19.2 [C(CH3)3], 21.3 (CH3CO2), 24.0 (C-
8), 24.0 (C-1), 26.9 [C(CH3)3], 27.3 (C-1′),28.6 (C-9), 33.2
(C-2′), 34.4 (C-5), 37.1 (C-10), 38.5 (C-6), 40.7 (C-7), 41.1
(C-2), 44.9 (C-3), 64.8 (C-3′), 85.3 (C-4), 127.6 (CAr), 129.5
(CAr), 134.1 (CAr), 134.1 (CAr), 135.5 (CAr), 170.9 (CH3CO2).
HRMS: calcd for C31H42O3Si [M + Na]+: 513.279543;
found: 513.279442.
(17) Taber, D. F.; Wang, Y.; Stachel, S. J. Tetrahedron Lett.
1993, 34, 6209.
(18) Ketone 5
(12) Addition reactions with other Grignard reagents: (a) Becker,
D.; Harel, Z.; Nagler, M.; Gillon, A. J. Org. Chem. 1982, 47,
3297. (b) Schinzer, D. Angew. Chem., Int. Ed. Engl. 1984,
23, 308; Angew. Chem. 1984, 96, 292.
(13) Mascaretti, O. A.; Furlán, R. L. E. Aldrichimica Acta 1997,
30, 55.
To a solution of alcohol 18 (58 mg, 129 μmol) in abs. CH2Cl2
(1.3 mL) were added NaHCO3 (43 mg, 517 μmol, 4 equiv)
and DMP (71 mg, 168 μmol, 1.3 equiv) at r.t. After 1 h at r.t.
DMP (71 mg, 168 μmol, 1.3 equiv) was added. After
additional 30 min at r.t. sat. aq NaHCO3 solution (2 mL) and
sat. aq Na2S2O3 solution (2 mL) were added, and the mixture
was stirred for 30 min. H2O (5 mL) was added, and the
mixture was extracted with Et2O (3 × 15 mL). The combined
organic layers were washed with sat. NaCl solution (10 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (1.5 × 15 cm,
PE–EtOAc = 8:1) to give 51 mg (114 μmol, 88%) of tricyclic
ketone 5 as a colorless oil; Rf = 0.45 (cyclohexane–EtOAc,
5:1). 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9 H, Ht-Bu),
1.08–1.28 (m, 2 H, 1′-H), 1.36–1.72 (m, 9 H, 1-H, 2-H, 2′-H,
8-H, 9-H, 10-H), 1.79–2.05 (m, 4 H, 2-H, 3-H, 5-H, 10-H),
2.13–2.21 (m, 1 H, 6-H), 2.42 (dd, J = 7.2, 18.8 Hz, 1 H, 5-
H), 3.53–3.66 (m, 2 H, 3′-H), 7.33–7.46 (m, 6 H, HAr), 7.60–
7.68 (m, 4 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 19.1
[C(CH3)3], 24.0 (C-8), 24.3 (C-1), 26.8 [C(CH3)3], 27.1 (C-
2′), 28.0 (C-9), 30.5 (C-2), 33.7 (C-1′), 35.0 (C-6), 36.5 (C-
10), 38.6 (C-7), 45.4 (C-5), 51.5 (C-3), 64.1 (C-3′), 127.6
(CAr), 129.5 (CAr), 133.9 (CAr), 135.5 (CAr), 222.4 (C-4).
HRMS: m/z calcd for C29H38O2Si [M + Na]+: 469.253328;
found: 469.253565.
(14) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, 64, 112.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59,
7549. (c) Boeckman, R. K. Jr.; Shao, P.; Mullins, J. J. Org.
Synth. 2000, 77, 141; Org. Synth., Coll. Vol. X; 2004, 696.
(16) Acetate 17
To a solution of tosylhydrazone 16 (182 mg, 270 μmol) in
abs. MeOH (3 mL) were added anhyd ZnCl2 (44 mg, 703
μmol, 2.6 equiv) and NaCNBH3 (59 mg, 433 μmol, 1.6
equiv) at r.t. The reaction was then stirred at reflux
temperature for 3.5 h. Then additional NaCNBH3 (59 mg,
433 μmol, 1.6 equiv) was added and reflux was continued for
2 h. Thereafter, the mixture was cooled to r.t. and treated
with aq NaOH (10 mL, 1 M) and sat. NaCl solution (10 mL).
The milky mixture was extracted with EtOAc (3 × 40 mL).
The combined organic layers were dried over Na2SO4,
filtered, concentrated in vacuo, and purified by flash
chromatography (1.5 × 15 cm, PE–EtOAc, 10:1 to 0:1) to
give 94 mg (192 μmol, 71%) of acetate 17 as a colorless oil;
Synlett 2013, 24, 955–958
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