Synthetic utility of sugar-derived cyclic nitrones: A diastereoselective synthesis of linear 4-azatriquinanes

Article abstract of DOI:10.1055/s-0031-1290375

A diastereoselective Pauson-Khand reaction has been utilized as the key step in the construction of azatriquinanes from sugar-derived nitrones. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290375

LETTER
▌1473
lSetyternthetic Utility of Sugar-Derived Cyclic Nitrones: A Diastereoselective
Synthesis of Linear 4-Azatriquinanes
Synthesis of Linear 4-Azatriquinanes
Anandaraju Bandaru, Krishna P. Kaliappan*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received: 02.02.2012; Accepted after revision: 12.04.2012
OH
H
O
H
Abstract: A diastereoselective Pauson–Khand reaction has been
utilized as the key step in the construction of azatriquinanes from
sugar-derived nitrones.
H
O
COOH
R
O
H
Key words: diastereoselectivity, sugar derivatives, nitrones,
Pauson–Khand reaction
O
OH
R = β-OH, hirsutic acid-C 1
R = O, complicatic acid 2
coriolin 3
O
H
Polyquinane1 natural products and their analogues have
attracted attention from the synthetic community owing to
their unique molecular architecture and interesting bio-
logical activities. Among the polyquinanes, natural prod-
ucts containing the triquinanes, especially some linearly
fused triquinanes, have elicited much interest due to their
promising biological activities (Figure 1). For example,
hirsutic acid (1) exhibits antibiotic activity, and coriolin
(3) shows antibacterial and antitumor activities.2 Deoxy-
hypnophilin (4) and hypnophilin (5) are active against the
Gram-positive bacterium Bacillus cereus, and spores of
Aspergillus niger, Aspergillus flavus, and Mucorrouxii,
with MIC values of 1–5 μg/mL.3 Moreover, highly func-
tionalized and biologically active linear triquinane natural
products are continuously being isolated from various
sources. Recently, connatusins A (6) and B (7) have been
isolated from the culture broth of the fungus Lentinus
conatus BCC 8996.4
H
OH
O
O
OH
H
H
R
HO
R = H, desoxyhypnophilin 4
R = OH, hypnophilin 5
(+)-connatusin A 6
H
R1
5
4
N
5a
6
7
3
O
R2O
2
8a
8b
O
H
1
8
OH
HO
OR3
R1 = H, CH2OBn or
O
OH
(+)-connatusin B 7
O
R2 = R3 = Bn or CMe2
linear 4-azatriquinane 8
Figure 1 Biologically active linear triquinanes and our designed lin-
ear 4-azatriquinanes
The hetero-analogues of carbocyclic triquinanes, namely
azatriquinanes5 and oxatriquinanes,6 have shown promis-
ing biological activities. Although several methods7 are
known to construct oxatriquinanes utilizing a sugar tem-
plate, to the best of our knowledge, there has been no re-
port on the construction of linear azatriquinanes with an
appended sugar unit. Furthermore, because of their known
polyhydroxylated carbon framework with multiple ave-
nues of chirality, sugar-derived nitrones8 have been wide-
ly used as chiral building blocks in the synthesis of several
biologically active compounds. Bearing in mind these
findings, in continuation of our interest in the synthesis of
natural-product-like molecular scaffolds,9 we developed
an interest in devising a simple and straightforward strat-
egy to synthesize a small set of azatriquinane scaffolds 8
(Figure 1).
According to our retrosynthesis, as delineated in Scheme
1, we envisaged that the hexahydrocyclopenta[a]pyrroli-
zin-7-one (15) could be obtained by an intramolecular
Pauson–Khand reaction10 of enyne 14, which, in turn,
could be generated from sugar-derived nitrone 9.8
O
N
N
H
BnO
BnO
H
BnO
OBn
BnO
OBn
15
14
O–
N
BnO
D-xylose
BnO
OBn
9
SYNLETT 2012, 23, 1473–1476
Advanced online publication: 29.05.2012
Scheme 1 Retrosynthetic analysis
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290375; Art ID: ST-2012-D0100-L
© Georg Thieme Verlag Stuttgart · New York

1474
A. Bandaru, K. P. Kaliappan
LETTER
During the course of our synthetic studies, a report on the
synthesis of hexahydrocyclopenta[a]pyrrolizin-7-one was
published by Vicario, Badía and co-workers using an or-
ganocatalytic [3+2] cycloaddition of azomethine ylides
with α,β-unsaturated aldehydes, and Pauson–Khand reac-
tion as key steps.11 An important advantage of our strategy
is that the structurally intriguing linear azatriquinanes, in
which the nitrogen atom is embedded in the cyclic frame-
work, could be easily obtained by utilizing nitrones as
appropriate precursors. Furthermore, the peripheral sub-
stitution around the cyclic nitrone governs the stereo-
chemical outcome of further synthetic transformations.
To this end, we selected a set of nitrones 9, ent-9, 10, 11,
12, and 13 as the basic building blocks, following litera-
ture procedures (Figure 2).8
OH
N
O
N
a
BnO
BnO
b
BnO
BnO
OBn
OBn
16
9
H
N
N
BnO
BnO
c
BnO
OBn
BnO
OBn
17
14
O
N
d
H
H
BnO
BnO
OBn
O
N
O
N
15
BnO
BnO
Scheme 2 Reagents and conditions: (a) CH2=CHMgBr, THF, 0 °C,
4 h, 97%; (b) Zn, In (cat.), MeOH, sat. NH4Cl, reflux, 12 h, 84%; (c)
3-bromoprop-1-yne, K2CO3, acetone, 92%; (d) i. [Co2(CO)8],
CH2Cl2; ii. toluene, DMSO, 80 °C, 69% (2 steps).
BnO
OBn
BnO
OBn
ent-9
9
O
O
rationalized on the basis of the approach of the alkene
from the less hindered side of the [Co2(CO)6]–alkyne
complex. The configuration of the newly generated ste-
reocenter was confirmed by COSY and NOESY experi-
ments (Figure 3).
N
N
BnO
BnO
BnO
OBn
BnO
OBn
10
11
O
N
O
N
O
O
O
H
N
H
BnO
BnO
H
H
BnO
OBn
O
O
H
BnO
13
12
Figure 3 NOE interactions between protons of 15
Figure 2 Sugar-derived nitrones
To expand the scope of our strategy, the sugar-derived ni-
trones ent-9, 10, 11, 12, and 13 (Figure 2) were then sub-
jected to the same synthetic sequence, which allowed the
efficient preparation of enyne 14 through vinyl Grignard
addition, N–O bond cleavage and N-propargylation, to
provide the enynes ent-14, 20, 24, 28, and 32, respective-
ly, in excellent yields (Table 1).
Thus, our synthesis of azatriquinanes as shown in Scheme
2, commenced with the addition of vinylmagnesium bro-
mide to a previously cooled solution of nitrone 9 in tetra-
hydrofuran (THF) at –20 °C to furnish the hydroxylamine
16 as a single diastereoisomer.8c–e The diastereoselectivity
of the reaction can easily be explained by anti attack of the
organometallic reagent with respect to the adjacent benzyl
ether, as a result of steric and stereoelectronic effects.
Amine 17, obtained through N–O bond cleavage of 16
with activated Zn (4 equiv) and saturated ammonium
chloride solution in the presence of a catalytic amount of
indium (18%),12 was further treated with propargyl bro-
mide in the presence of K2CO3,11 to afford enyne 14.
Having generated sufficient amounts of these enynes, they
were subjected to the Pauson–Khand reaction as de-
scribed for 14,14 and, pleasingly, we could isolate the de-
sired azatriquinanes ent-14, 21, 25, and 29 as single
diastereoisomers in all cases except for enyne 32, wherein
a separable mixture of diastereoisomers 33 and 34 was ob-
tained in a 4:1 ratio (Figure 4).
With enyne 14 in hand, the stage was set for the execution
of the Pauson–Khand reaction.13 Initially, when enyne 14
was treated with [Co2(CO)8] and subsequent treatment
with N-methylmorpholine N-oxide (NMO), an unidenti-
fied complex mixture was obtained. Pleasingly, replace-
ment of NMO with DMSO led to exclusive formation of
the desired azatriquinane 15 as a single diastereoisomer in
excellent yield.14 The observed diastereoselectivity can be
In conclusion, we have disclosed a simple approach to the
synthesis of a set of linear azatriquinanes from sugar-
derived nitrones using a diastereoselective Pauson–Khand
reaction as the key step. The requisite nitrones have been
prepared easily from inexpensive carbohydrate starting
materials. Using this approach, the desired linear aza-
triquinanes could be synthesized in good yields; the ste-
Synlett 2012, 23, 1473–1476
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Linear 4-Azatriquinanes
1475
Table 1 Synthesis of Azatriquinanesa
Sugar-derived nitrone
Hydroxylamine
Amine
Enyne
Azatriquinane
O
O
OH
N
H
N
N
N
N
BnO
BnO
H
BnO
BnO
BnO
H
BnO
OBn
BnO
BnO
OBn
OBn
BnO
OBn
BnO
OBn
ent-17 (80)
ent-9
ent-16 (94)
ent-15 (66)
ent-14 (91)
O
OH
N
O
N
H
N
N
N
BnO
BnO
H
BnO
BnO
BnO
H
BnO
OBn
BnO
BnO
OBn
OBn
BnO
OBn
BnO
OBn
19 (78)
10
18 (92)
21 (70)
20 (89)
O
OH
N
O
N
H
N
N
H
N
BnO
BnO
BnO
H
BnO
BnO
BnO
BnO
OBn
OBn
BnO
BnO
OBn
OBn
BnO
OBn
25 (68)
23 (81)
11
22 (97)
24 (90)
25 (68)
O
OH
N
O
N
H
N
N
N
H
H
BnO
OBn
BnO
OBn
BnO
OBn
BnO
OBn
BnO
OBn
27 (82)
12
26 (95)
29 (71)
28 (89)
O
N
OH
N
O
O
O
O
O
O
O
H
N
O
N
33/34
4:1
O
O
O
O
O
O
O
O
13
30 (87)
31 (72)
32 (89)
a Yield given in parenthesis.
Acknowledgment
O
O
O
O
We thank DST, New Delhi for financial support. K.P.K. thanks
DST for the Swarnajayanti fellowship. A.B. thanks CSIR, New Del-
hi for a fellowship.
O
O
N
N
H
H
H
H
O
O
O
O
Supporting Information for this article is available online at
4:1
34 (13)
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
33 (52)
Figure 4
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reochemistry of the newly formed stereocenter was
confirmed by COSY and NOESY experiments. The de-
scribed approach should open the way for the synthesis of
a library of linear azatriquinanes from a variety of appro-
priately functionalized sugar templates.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1473–1476

1476
A. Bandaru, K. P. Kaliappan
LETTER
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(14) Genaral Procedure for Pauson–Khand Reaction:
To a stirred solution of enyne (1 mmol) in CH2Cl2 (30 mL),
[Co2(CO)8] (1.2 mmol) was added under a nitrogen
atmosphere at 25 °C. After stirring at 25 °C for 1 h, the
solvent was removed to obtain the crude product. To a
solution of the above crude product in toluene (20 mL),
DMSO (10 mmol) was added and the solution was heated at
reflux overnight at 80 °C. After completion, the reaction
mixture was quenched with 1% HCl (50 mL) (except for
compounds 33 and 34, which were quenched with water)
and extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4) and concentrated. The crude product
was purified by basic alumina column chromatography.
Data for (1S,2S,3S,8aS,8bS)-1,2-bis(benzyloxy)-3-
(benzyloxymethyl)-1,2,3,8,8a,8b-hexahydrocyclo-
penta[a]pyrrolizin-7(5H)-one (15): Rf = 0.4 (EtOAc–
hexanes, 50%); [α]D20 –9.8 (c 1.00, CHCl3); 1H NMR
(CDCl3, 400 MHz): δ = 7.37–7.26 (m, 15 H), 6.0–5.99 (m,
1 H), 4.69–4.44 (m, 6 H), 4.08–4.02 (m, 3 H), 3.71 (d,
J = 16.9 Hz, 1 H), 3.62 (dd, J = 9.4, 4.5 Hz, 1 H), 3.52 (dd,
J = 9.4, 6.5 Hz, 1 H), 3.29–3.24 (m, 1 H), 3.19 (dd, J = 10.5,
3.3 Hz, 1 H), 3.12–3.08 (m, 1 H), 2.60 (dd, J = 17.6, 6.2 Hz,
1 H), 2.10 (dd, J = 17.6, 3.3 Hz, 1 H); 13C NMR (100 MHz,
CDCl3): δ = 209.3, 186.9, 138.4, 138.1, 137.7, 128.7, 128.6,
128.5, 128.1, 128.0, 127.9, 127.8, 125.1, 86.8, 86.1, 73.6,
73.0, 72.7, 72.5, 72.3, 70.2, 54.2, 48.5, 40.6; IR (neat): 3872,
3030, 2924, 2854, 2109, 1966, 1703, 1646, 1454, 1367,
1306, 1215, 1106, 1028, 754, 698 cm–1; HRMS (ESI): calcd
for C32H34NO4 [M + 1]+ 496.2488; found 496.2469.
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Synlett 2012, 23, 1473–1476
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