Enantioselective total synthesis of (S)-(-)-quinolactacin B

Article abstract of DOI:10.1016/j.tetlet.2008.04.130

The enantioselective total synthesis of (-)-quinolactacin B (-)-1 was performed in seven steps and 33% overall yield from tryptamine. The synthesis features the use of ruthenium catalytic asymmetric hydrogen reaction to introduce the chirality in dihydro-

Full text of DOI:10.1016/j.tetlet.2008.04.130

Tetrahedron Letters 49 (2008) 4289–4291
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Enantioselective total synthesis of (S)-(À)-quinolactacin B
Nagula Shankaraiah a, Wender A. da Silva a,b, Carlos Kleber Z. Andrade b, Leonardo Silva Santos a,
*
a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Universidad de Talca, Talca, PO Box 747, Talca, Region 7, Chile
b Institute of Chemistry, Universidade de Brasília, UnB, Brasília, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective total synthesis of (À)-quinolactacin B (À)-1 was performed in seven steps and 33%
overall yield from tryptamine. The synthesis features the use of ruthenium catalytic asymmetric hydro-
gen reaction to introduce the chirality in dihydro-b-carboline 2. Based on Noyori’s work, the hydrogena-
tion using the (R,R)-TsDPEN-Ru complex produces dihydro-b-carbolines possessing the (S) absolute
configuration, the corrected asymmetric center of the natural product. The synthetic quinolactacin B dis-
played optical rotations that was in accordance with that of the natural product, thereby supporting the
(S) configuration for natural quinolactacin B. The final product’s stereochemical assignment is in agree-
ment with that proposed by Nakagawa and co-workers.
Received 4 March 2008
Revised 22 April 2008
Accepted 23 April 2008
Available online 27 April 2008
Keywords:
Quinolactacin B
Noyori asymmetric hydrogenation
Enantioselective
Ó 2008 Elsevier Ltd. All rights reserved.
Anodic oxidation
Quinolactacin B (1) shows an interesting pyrrolo-quinolone
moiety conjugated with a c-lactam ring, as depicted in Scheme
1.1 The unusual structure present in these compounds exhibited
activity against tumor necrosis factor production, and biomimetic
synthesis of 1 by Tatsuta et al. was suggested to undergo biologi-
cally through anthranilic acid, valine, and acetic acid.2 In 2003,
Zhang et al. reported a chiral auxiliary-based approach to this class
of compounds,3 and in 2004, Lee and coworkers achieved the syn-
thesis of (+)-quinolactacin A2 from isatoic anhydride and N-Boc-
(2S,3S)-isoleucine utilizing Friedlander-type annulation.4
Inspired by its unusual structure, we undertook the stereoselec-
tive synthesis of 1 by taking advantage of the Noyori asymmetric
hydrogen-transfer reaction of appropriately functionalized b-carb-
oline derivative 2.5,6 Our strategy to quinolactacin B can be seen
through the retrosynthetic analysis depicted in Scheme 1. In prin-
ciple, the chirality in the molecule can be inserted through Noyori
asymmetric hydrogenation of imine 2. Then, protected b-carboline
system can be converted to the pyrrolo–quinolone moiety by oxi-
dative rearrangement of an appropriately functionalized precursor
(4) through the unexplored Winterfeldt oxidation.7
We envisioned assembling the quinolactacin core of 1 by either
a transition metal-catalyzed or an anodic oxidation to introduce
the pyrrolo moiety. Then, an anodic oxidation reaction followed
by further oxidation of resulting alcohol was appealing for its sim-
plicity. The N-Boc carbamate C-ring of compound similar 6 was ex-
pected to give readily an alcohol intermediary on the pyrrolo ring.
We first set out to the introduction of the chirality in the b-carb-
oline system through the imine 2. Following the sequence depicted
in Scheme 2, triptamine was converted in the imine 2 by exposure
to isobutyric acid and DCC with catalytic amount of DMAP afford-
ing the corresponding amide. The crude amide in CH2Cl2 was acid-
ified with diluted HCl, washed with H2O, dried, evaporated, and
used with no further purification. Treatment of the amide with
POCl3 promoted the Bischler–Napieralsky cyclization to give imine
2 in 89% yield (two steps). Having prepared imine 2, the next step
was set to introduce the required asymmetry in the molecule
through the Noyori asymmetric hydrogenation (NAH) reaction.
The NAH reaction uses an azeotropic mixture (HCO2H–Et3N) as
O
O
O
NH
N
R
N
N
H
N
N
H
O
Me
1)
(
R,R)-TsDPENRu(II)
HCO2H:Et3N
HO
tryptamine
5
2
1
N
NR
DCC/DMAP
N
H
2
N
H
(S
)-(−
)-Quinolactacin B
DMF, 0 o
C
CH2Cl2, 12 h, rt
2) POCl3/C6H6
(two steps 89%)
(Boc)2O
CH2Cl2
(99%)
Scheme 1. Retrosynthetic analysis of (À)-quinolactacin B (1).
(− )- 3, R = H, 89%
(−)-4a, R = Boc
(> 90% ee
)
* Corresponding author. Tel.: +56 71 201575; fax: +56 71 200448.
E-mail address: lssantos@utalca.cl (L. S. Santos).
Scheme 2. Noyori asymmetric hydrogenation of imine 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.130

4290
N. Shankaraiah et al. / Tetrahedron Letters 49 (2008) 4289–4291
the source of hydrogen and allows a convenient, general route to
natural and unnatural b-carboline alkaloids depending on the con-
figuration of chiral ligand employed.
ated by addition of HCHO in CH2Cl2 at 0 °C for 15 min affording
the iminium ion, which was reduced in an one-pot manner by Et3-
SiH and catalytic amount of PdCl2 at À78 °C for 30 min. The result-
ing N-methylquinolone (À)-6 was obtained in 91% yield, [a]D À183
(c 0.5, MeOH). Another approach also tested consisted by using 5
and NaHMDS (1.1 equiv, 1 h, THF, À78 °C), followed by addition
of methyl iodide (À78 °C to rt, 2 h)11 affording (À)-6 in 90% yield
as the sole product, [a]D À185 (c 0.5, MeOH), Scheme 4.3
The Noyori hydrogenation of imine 2 was accomplished with
preformed (R,R)-TsDPEN-Ru(II) complex in DMF, and a HCO2H–
Et3N mixture6a that achieved amine (À)-3 in 89% yield and >90%
ee as determined by HPLC analysis using a ChiralPack OD column.
According to Noyori’s work, the absolute stereochemistry of 3 is
expected to be (S). The optical rotation, [a]D À83 (c 1.0, MeOH),
is in accordance with that reported in the literature for the
expected (S)-(À)-3.3,8 Another approach to 3 was using the chloro-
formate of 8-phenylmenthyl as chiral auxiliary (Scheme 3). The in
situ formation of the corresponding N-acyliminium ion 9 by adding
the chloroformate of 8-phenylmenthyl to imine 2 in CH2Cl2 at
room temperature, then cooling the mixture to À78 °C, and sub-
sequent Pd–H reduction using PdCl2/Et3SiH protocol9 afforded 4b
in good yield (88%). The absolute configuration of 4b was deter-
mined to be (R) after chiral auxiliary removal using HCl/CHCl3
(2 M) that gave (+)-3 in 89% yield, [a]D 65 (c 1.0, MeOH). As
mentioned above, the ee% for (+)-3 was 75% ee as determined by
HPLC, and it is in accordance with (R)-(+)-3. The chiral auxiliary
8-phenylmenthol was recovered in 95% yield with no decrease of
its optical rotation. The selectivity obtained in the chiral auxiliary
mediated reduction of 2 to 3 was rationalized by transition state
depicted in Scheme 3, which is in accordance with the reduction
of the N-acyliminium ion 9 through its Si-face.
With asymmetry incorporated in the pyrrolo–quinolone moi-
ety, we turned our attention to the exploration of anodic oxidation
method for a-oxidation of carbamate (À)-6. Previously, the feasibil-
ity of the oxidation route was evaluated through a model system
(Scheme 5) that would in turn be generated by electrochemically
functionalizing the corresponding proline derivative.12 The avail-
able N-Boc-proline under anodic oxidation conditions at À40 °C
gave the a-hydroxy-derivative 1113 that was oxidized under sev-
eral conditions: MnO2 and 65%, PDC and 75%, RuO2/NaIO4 and
93%.14 Finally, Swern conditions afforded 12 in 90% yield with no
epimerization of the proline center. Trying the direct oxidation of
N-Boc-proline ester to 12 with RuO2/NaIO4 gave a complex mix-
ture. This model study showed that although the anodic oxidation
can take place readily, temperature and reaction times needed to
be controlled. Regioselective hydroxylation occurred exclusively
at the less substituted carbon of the N-carbamate, and the hydro-
xy-derivative 11 showed to be very unstable to chromatography
purification in silica gel.
Further, with an efficient approach to the corrected asymmetric
center into the quinolactacin moiety secured by NAH, the stage
was now set for the Winterfeldt rearrangement. Treatment of
(À)-3 with (Boc)2O and Et3N in CH2Cl2 gave N-carbamate(À)-4a
in 99% yield (Scheme 2). Winterfeldt reaction of (À)-4 with 18-
crown-6-ether and NaO2 or KO2 gave quinolone (À)-5 in 75%
(>90% ee) and 73% (>90% ee), respectively, as depicted in Scheme
4.10 The enantiomeric excesses were determined by HPLC to assure
that no epimerization was occurred in the reaction due to basic
conditions. NMR and HRMS spectra were in agreement with previ-
ously reported.3,10 Then, the secondary amine (À)-5 was methyl-
Thus, with the electrolysis approach optimized we performed
the reaction with compound (À)-6. As expected by model studies,
Pt/W, 2e-
[O]
HO
CO2Me
CO2Me
O
CO2Me
N
N
N
H2O (10 eq.)
CH2Cl2
RuO2/NaIO4: 93%
PDC: 75%
MnO2: 65%
Boc
11
Boc
Boc
12
Swern: 90%
Scheme 5. Model studies of anodic/Swern oxidations with N-Boc-proline ester.
O
a)
R*
Cl
O
HCl/CHCl
3
H
N
N
O
NH
(89%)
N
N
R*
N
b)
PdCl , Et SiH
2
3
H
H
H
Et N, CH Cl
R
4b
O
H
3
2
2
o
2
−78 C, 88%
(+)-3a
R*= 8-phenylmenthyl
Nu
Si face
R
O
H
N
N
O
+
9
Scheme 3. Proposed facial discrimination in the chiral auxiliary-mediated Pd-hydride reduction of the N-acyliminium ion derived from 2.
1) HCHO, CH2Cl2, rt
2) Et3SiH, PdCl2, -78 o
(91%)
O
O
C
Ref.
3,10
N
Boc
N
Boc
or
4a
N
N
H
1) 1.1 equiv. NaHMDS
THF, -78 oC, 1 h
2) 3.0 equiv. MeI
-78 oC to rt, 2 h
(90%)
Me
6
5
Scheme 4. Winterfeldt oxidation and N-methylation to give (À)-6.

N. Shankaraiah et al. / Tetrahedron Letters 49 (2008) 4289–4291
4291
O
O
O
O
OH
N
+
N
+
Boc
N
Boc
Boc
N
Boc
6
N
N
N
N
OH
Me
Me
Me
Me
11a
7a
7b
11b
Scheme 6. Proposed intermediates for the formation of 8 from 11a and ( )-6 from 11b.
Acknowledgements
O
O
O
O
Anodic
ZnBr2
CH2Cl2
rt
Boc
a)
b)
Oxidation
L.S.S. thanks FONDECYT (Project 1085308), IFS (F/4195-1), the
Organisation for the Prohibition of Chemical Weapons, and Progra-
ma de Investigación en Productos Bioactivos-UTalca for support of
research activity. PBCT (PSD-50) was also acknowledged for finan-
cial support to S.N., C.K.Z.A. and W.A.S. thank CNPq for financial
assistance.
N
H
6
N
Swern
(65 %)
N
N
(94%)
Me
Me
1
8
(
S
)-(−
)-Quinolactacin B
[α]D −4.0 (c 0.2, DMSO)
[α]Dlit. −3.3 (c 0.15, DMSO)
Supplementary data
Scheme 7. Anodic/Swern oxidations of 6 followed by ZnBr2 deprotection to give
(À)-quinolactacin B.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.04.130.
the anodic oxidation proceeded smoothly at À78 °C giving an
unstable product, which was then readily converted into the
desired pyrrolo compound (À)-8, [a]D À85 (c 0.5, MeOH), as
depicted in Scheme 7. The expected regioselectivity of hydroxyl-
ation to less substituted a-nitrogen carbon in cyclic carbamates
has been extensively studied.13 The mechanism behind the high
regiocontrol to N-protected carbamates was recently proposed by
Onomura,13h and suggested that stabilities of iminium ions might
determine the regioselectivities observed. N-acyliminium ion 7a
is somewhat stable compared with 7b by DFT calculations, thereby
affording to hydroxylation on the less substituted side (Scheme 6).
As an interesting side note, it was found that temperatures higher
than À30 °C and longer reaction times in the anodic oxidation led
to a decrease in the yields (determined by gas-chromatography),
and formation of ( )-6 was also observed.
The unusual formation of ( )-6 could be explained by a radicalar
process involving 6 or intermediates 7b/11b in the electrochemical
cell, Scheme 6. Herein, on-line ESI-MS analysis15 of the reaction
mixture suggested that a hydroxylated by-product at the tertiary
carbon presenting a structure as 11b was also formed. It was ratio-
nalized that kinetic formation of the a-hydroxy-N-carbamate was
reversible under the reaction conditions. In accordance with time,
the initial N-acyliminium ion 7a would be, isomerized and might
be trapped hydroxy at C-2 to give 7b. Fortunately, it was possible
to address both of these regioselectivity issues due to electron-
withdrawing nature of the tert-butyl ester, regeneration of the
iminium ion toward C-2 would be expected to be slow, effectively
stopping the reaction.
References and notes
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Finally, deprotection of 8 to (À)-quinolactacin B requires only
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Synthetic 1 displayed the same absolute configuration, [a]D À4.0
(c 0.2, DMSO), when compared to natural 1, [a]D À3.3 (c 0.13,
DMSO).1
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