Synthesis of the 2-formylpyrrole spiroketal pollenopyrroside A and structural elucidation of xylapyrroside A, shensongine A and capparisine B

Article abstract of DOI:10.1039/c6ob01361a

A convergent synthesis of the 2-formyl pyrrole spiroketal pollenopyrroside A is reported. The key step involves a Maillard-type condensation of an amine derived from deoxy-d-ribose with a dihydropyranone to furnish the 2-formylpyrrole ring system. Spectroscopic and physical data of 9-epi-pollenopyrroside A are also provided, elucidating the structures of the previously isolated 2-formylpyrrole spiroketals capparisine B, shensongine A and xylapyrroside A.

Full text of DOI:10.1039/c6ob01361a

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DOI: 10.1039/C6OB01361A
Journal Name
ARTICLE
Synthesis of the 2-Formylpyrrole Spiroketal Pollenopyrroside A and
Structural Elucidation of Xylapyrroside A, Shensongine A and
Capparisine B
Received 00th January 20xx,
Accepted 00th January 20xx
James M. Wood,a Daniel P. Furkerta* and Margaret A. Brimblea,b*
DOI: 10.1039/x0xx00000x
A convergent synthesis of the 2-formyl pyrrole spiroketal pollenopyrroside A is reported. The key step involves a Maillard-
type condensation of an amine derived from deoxy-ᴅ-ribose with a dihydropyranone to furnish the 2-formylpyrrole ring
system. Spectroscopic and physical data of 9-epi-pollenopyrroside A are also provided, elucidating the structures of the
previously isolated 2-formylpyrrole spiroketals capparisine B, shensongine A and xylapyrroside A.
www.rsc.org/
O
O
O
O
9
R
Introduction
O
9R
O
9S
HO
HO
HO
12S
12R
12R
The spiroketal alkaloids pollenopyrroside A ((+)-1) and B
N
N
N
11R
11S
11S
HO
HO
HO
((+)-
campestris pollen in 2010 by Zhan et al.1 In the same year
acortatarin A ((+)- ) and B ((−)- ) were isolated from the
rhizome of Acorus tatarinowii2 and capparisine A ((−)-
) and B
((+)-
) from the fruits of Capparis spinosa.3 Peterson et al.4
reported the isolation of acortatarin A ((+)- ) from bread crust
in 2013. More recently, shensongine A ((−)- ), B ((−)- ) and C
((+)- ) were isolated from capsules of the anti-arrhythmic
Chinese medicine Shensong Yangxin5 and xylapyrroside A
((−)- ) and B ((−)- ) were isolated from the dried mycelia of
3) (Figure 1) were isolated from bee-collected Brassica
O
O
O
−
+
+
2
B
1
A1
2
A
-pollenopyrroside
shensongine A5
9-
epi
capparisine
at isolation3
( )-
( )- pollenopyrroside
( )-
3
5
proposed
A6
3
xylapyrroside
2
HO
HO
O
O
O
9R
O
9S
N
12R
12R
3
HO 11
HO 11S
S
2
4
N
6
O
O
−
( )-
3
B1
4 shensongine B5
+
( )- pollenopyrroside
2
4
acortatarin A11
B6
xylapyrroside
Xylaris nigripes.6 These tricyclic alkaloids share a common
carbon skeleton, which includes a 2-formylpyrrole and a
spiro-fused sugar-morpholine spiroketal subunit.
A3
capparisine
12R O
HO
12S O
O
HO
O
9S
11S
11R
9R
HO
HO
10R
To date, eight different compounds have been reported in
this compound class (Figure 1). Some compounds have been
isolated on more than one occasion and have subsequently
been assigned more than one name. Moreover, there are
instances of conflicting isolation and synthetic data between
different reports on the same compound. In this report we aim
to collate and clarify the literature surrounding this class of
compounds.
These spiroketal alkaloids have been isolated from plant or
fungal species used in traditional Chinese medicines which
possess biological activities including antioxidant, antitumor,
hypolipidemic and antihyperglycaemic effects.1,3 Xylapyrroside
10S
N
N
OH
OH
O
O
−
( )-
+
( )-
5
5 acortatarin B11
6
shensongine C
Figure 1. The pollenopyrrosides and other closely related spiroketal alkaloids
and shensongine A ((−)-
potential duration in rat myocardial cells.5 Acortatarin A ((+)-
and B ((−)- ) were found to inhibit the high-glucose-induced
production of reactive oxygen species in renal mesangial cells.2,7
As such, these compounds may provide a basis for drug
discovery directed towards therapeutic intervention of diabetic
nephropathy, the leading cause of end-stage renal disease.8–10
Early synthetic efforts towards 2-formylpyrrole spiroketals
2) and C ((+)-6) shortened action
3
)
5
A ((−)-2) and B ((−)-4) were shown to prevent oxidative stress-
induced cytotoxicity in A7r5 rat vascular smooth muscle cells6
were focused on the 5,6-spiroketals acortatarin A ((+)-
acortatarin B ((−)- ) (Figure 2). Initially assigned as enantiomer
(−)- using Mosher’s ester analysis, acortatarin A was later
revised to structure (+)-
3) and
5
3
a.School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland
1142, New Zealand.
E-mail: m.brimble@auckland.ac.nz
3
, based on the first total synthesis by
Sudhakar et al.11 Acortatarin B was also revised to structure
http://www.brimble.chem.auckland.ac.nz.
b.Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand.
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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2 and provided physical and spectroscopic
data in agreement with the isolated natDuOraI:l1c0o.1m03p9o/Cu6nOdB.0T13h6e1iAr
reported optical rotation [ꢀ]2D5 + 38.5 (c 0.05, MeOH) also
closely matched the natural material [ꢀ]2D5 + 34.5 (c 0.013,
MeOH).3 In this paper however, Zhao et al.16 did not specifically
address the revision of the absolute stereochemistry of
capparisine B (+)-
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HO
12S O
11R
O
O
9S
HO
12S
O
9R
HO
11R
N
HO
10R
N
OH
O
O
−
2
+
5 acortatarin B
( )-
3
3
A
proposed
capparisine proposed
acortatarin A
( )-
2
proposed
capparisine B to structure (−)-
originally proposed by Wang et al.3
Xylapyrroside ((−)- and shensongine
(Scheme 2) share the same relative configuration as the
proposed structure of capparisine B ((+)- ), supported by
identical 1H NMR data for all three isolated compounds3,5,6 and
X-ray crystal structures for isolated xylapyrroside A ((−)-
)6 and
capparisine B ((+)-
).3 Xylapyrroside A ((−)- [ꢀ]2D2 −189 (c 0.1,
MeOH)6 and shensongine A ((−)- [ꢀ]2D7 −12.7 (c 0.05, MeOH)5
have opposite signs of optical rotation to that of capparisine B
((+)-
[ꢀ]2D5 +34.5 (c 0.013, MeOH)3, however none of the three
values are in close agreement. Interestingly, Li et al.6
established that xylapyrroside was in fact
9-epi-pollenopyrroside A ((−)- ) from an X-ray crystal structure
and confirmed this by total synthesis from
(R)-isopropylideneglyceraldehyde (
) (Scheme 2).6 No optical
rotation was reported for synthetic xylapyrroside A ((−)- ); the
2 from that of structure (+)-2
HO
12R O
11S
O
O
9R
HO
12R
O
9S
HO 11S
A
2
)
A ((−)-2)
N
HO
10S
N
OH
O
O
2
−
11,13
3 acortatarin A revised11-15
+
5 acortatarin B
revised
( )-
( )-
B1
pollenopyrroside
2
2
2)
Figure 2. Initially proposed and revised structures of the acortatarins.
2
)
(−)-
5
from the initially proposed structure (+)-
5
.
Four
2
)
independent syntheses of acortatarin A ((+)-
confirming the revised absolute structure.12–15 Borero and
Aponick noted that the physical and spectroscopic data of
3
) followed,
A
2
acortatarin A ((+)-
((+)-
).12
The proposed absolute stereochemistry of capparisine A
((−)-
)3, determined using single crystal X-ray diffraction
analysis, is enantiomeric to acortatarin A ((+)- ). Capparisine A
((−)-
) has a reported optical rotation [ꢀ]2D5 +34.5 (c 0.013,
MeOH)3 which is of the same sign as acortatarin A ((+)-
[ꢀ]2D7 +178.4 (c 0.4, MeOH)2, but of much lower magnitude. As
such, capparisine A may be identical to acortatarin A ((+)- ),
however the difference in optical rotation has not been
addressed and the absolute structure of capparisine A has not
been revised to structure ((+)-3).
More recent synthetic work has focused on elucidation of
the absolute stereochemistry of the 2-formylpyrrole
6,6-spiroketals. Zhao et al.16 reported the first total synthesis of
pollenopyrroside A ((+)-
the structure initially proposed by Zhan et al.1 The synthesis
utilised ᴅ-fructose ( ) as a chiral pool starting material to
establish the C-11 and C-12 stereocentres, furnishing both
3) matched that of pollenopyrroside B
3
9
2
3
authors stated that all spectroscopic and physical
characteristics of the synthetic product matched the material
they had isolated. Published shortly after the first synthesis of
3
3
3
)
9-epi-pollenopyrroside A ((−)-2
) y Zhao et al.,16 this second
synthesis by Li et al.6 makes no reference to the former and
does not address the conflicting reports of the optical rotation
and relationship to capparisine B. The absolute
3
stereochemistries of capparisine B, shensongine
A and
xylapyrroside A therefore still remain to be confirmed
unequivocally.
O
OH
O
I
1
) in early 2015 (Scheme 1), confirming
O
O
O
O
7
9
10
pollenopyrroside
A
((+)-
1
)
and its C-9 epimer
H
N
OR
O
O
O
9S
HO
HO
12R
O
H
O
9R
O
N
11S
11
HO
N
OH
HO
12R
+
N
11S
O
HO
OH
HO
−
( )-
OH
2
A
9-
epi
-pollenopyrroside
shensongine A5
O
D
-fructose
7
( )
1
A
pyrrole
8
( )
(+)- pollenopyrroside
+
A6
xylapyrroside
capparisine
B revised16
O
O
9S
HO
Scheme 2. Total synthesis of 9-epi-pollenopyrroside
xylapyrroside A, shensongine A) by Li et al.6
A
((−)-2) (alternatively
12R
O
O
9R
HO
N
11S
12S
HO
N
11R
HO
O
To summarise, two syntheses of 9-epi-pollenopyrroside A
((−)- ) have been reported to date. The absolute configurations
of capparisine B ((+)- ), shensongine A ((−)- ) and xylapyrroside
A ((−)- ) have not been confirmed as the reported physical
. The authors claimed this C-9 epimer was in fact properties of 9-epi-pollenopyrroside A ((−)-
) are in conflict.6,16
In light of this we aimed to develop an enantioselective
synthesis of pollenopyrroside ((+)- and
9-epi-pollenopyrroside A ((−)- ) using a Maillard-type strategy,
−
2
A
-pollenopyrroside
shensongine A5
9-
epi
O
( )-
2
+
2
B
capparisine
at isolation3
( )-
A6
2
2
xylapyrroside
capparisine
proposed
B revised16
2
(−)-
2
2
Scheme 1. The first reported synthesis of pollenopyrroside
9-epi-pollenopyrroside A ((−)-
) by Zhao et al.16
A ((+)-1) and
A
1)
2
2
2 | J. Name., 2012, 00, 1-3
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previously implemented by our group for the synthesis of Synthesis
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acortatarin A ((+)-
This modular
3
) and other 2-formylpyrrole compounds.17–19
approach would generate the
Initial efforts focused on the synthesis oDf OdIi:h1y0d.1r0o3p9/yCr6aOnBo0n1e36114A
(Scheme 4). Aldehyde 18 was obtained by dehydration of
fructose to give hydroxymethyl furfural22 followed by silyl
protection of the primary alcohol. This approach was highly
scalable, proving amenable to the synthesis of >10 g batches of
the aldehyde 18. Reduction of aldehyde 18 with sodium
borohydride provided alcohol 17 23
Achmatowicz rearrangement upon oxidation with m-CPBA to
provide dihydropyranone 14 15
2-formyl-5-hydroxymethyl pyrrole ring in a single step, avoiding
tedious functionalization of the pyrrole ring. It would also allow
the future synthesis of analogues in order to probe the
biological activity of these compounds through structure-
activity relationship studies. We herein report the successful
,
which then underwent
total synthesis of pollenopyrroside
9-epi-pollenopyrroside A ((−)- ). We further establish that
xylapyrroside and shensongine are in fact
9-epi-pollenopyrroside A ((−)- ), while also providing evidence
to support that capparisine B is not 9-epi-pollenopyrroside A
((−)- ), but in fact the enantiomer (+)-
A
((+)-
1
)
and
2
.
A
A
2
OH
OH
TBSO
O
O
OH
ii)
iii)
i),
O
HO
2
2.
HO
7
18
O
Results and discussion
Retrosynthetic strategy
TBSO
OH
iv)
O
O
TBSO
OH
Our retrosynthetic strategy (Scheme 3) involved
construction of the spiroketal core of pollenopyrroside A
17
14
Scheme 4. Synthesis of dihydropyranone 14. Reagents and conditions: i) (CO2H)2
(10 mol %), DMSO, 150 °C, 6 h; ii) TBSCl, imidazole, CH2Cl2, r.t., 18 h, 92 % over two
steps; iii) NaBH4, MeOH, 0 °C, 15 min, 98 %; iv) m-CPBA, CH2Cl2, r.t., 1 h,
86 %.
((+)-
dihydroxyketone 12 18
available in a convergent manner from amino alcohol 13 and
dihydropyranone 14 by modified Maillard-type
1
)
by acid-catalysed cyclisation of protected
.
We envisioned ketone 12 would be
With dihydropyranone 14 in hand, attention was focused on
the synthesis of amino alcohol 13 (Scheme 5) for use in the key
Maillard-type condensation. The approach to amino alcohol 13
involved protection and Wittig methylenation of deoxy-ᴅ-ribose
16) as described initially by Geng and Danishefsky24 and more
recently by Banwell et al.25 Adoption of deoxy-ᴅ-ribose (16) as
a chiral pool material ensured both the 11S and 12R
a
condensation.20 Amino alcohol 13 would be accessible from
olefin 15 by epoxidation followed by regioselective azide ring
opening. In turn, olefin 15 could be generated by Wittig
(
methylenation
dihydropyranone 14 would be formed by Achmatowicz ring-
expansion of furfuryl alcohol 17 21
Furfuryl alcohol 17 could in
).
of
deoxy-ᴅ-ribose
(16).
Meanwhile,
.
stereocentres of pollenopyrroside
A
((+)-
1
)
were
turn be generated from ᴅ-fructose (
7
unambiguously set from the beginning of the synthesis. The
acetonide protection was carried out at −10 °C as described by
Banwell et al.,25 which proved crucial in order to prevent
formation of the methyl glycoside side-product 21. Wittig
methylenation of the masked aldehyde and silyl protection
proceeded without difficulty to provide olefin 15 in 58 % yield
over three steps.
O
acid-catalysed
spirocyclisation
O
O
O
O
N
O
PO
9R
HO
N
12R
O
11S
HO
TBSO
12
1
(+)-
O
Maillard-type
condensation,
oxidation
O
OH
TBSO
O
O
i)-iii)24-25
+
iv)
OH
O
HO
O
O
PO
TBSO
OR
NH2
OH
13
14
16
15
TBSO
Achmatowicz
rearrangement
N3
5
TBSO
O
v)
OH
O
O
O
O
TBSO
OH
O
O
O
19
20
PO
17
15
NH2
5
TBSO
O
OMe
vi)
Wittig
OH
O
O
methylenation
O
O
O
OH
OH
OH
O
OH
13
21
HO
HO
HO
Scheme 5. Synthesis of amino alcohol 13
. Reagents and conditions:
i) 2,2-dimethoxypropane, PTSA, CaCO3, DMF, −10 °C, 24 h, 98%; ii) MePPh3Br,
n-BuLi, −78 °C, 16 h, r.t. 69 %; iii) TBSCl, imidazole, CH2Cl2, r.t., 2 h, 86 %;
iv) m-CPBA, CH2Cl2, r.t., 16 h, 94 % (dr 1.3:1); v) NaN3, NH4Cl, DMF/H2O 9:1, 80 °C,
16 h, (5S)-20 48 %, (5R)-20 36 %; vi) Pd/C, H2, MeOH, r.t., 90 % for (5S)-13, 79 %
OH
16
7
for (5R)-13
.
Scheme 3. Retrosynthetic analysis of pollenopyrroside A (+)-
1
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Elaboration of olefin 15 to amino alcohol 13 was achieved using
methods previously employed in our synthesis of acortatarin A elaboration to pollenopyrroside A ((+)-1)DrOeIq: u10ir.1e0d39o/Cxi6dOaBt0io13n6t1oA
((+)-
).15,17 Epoxidation of olefin 15 using m-CPBA and the dihydroxyketone and spirocyclisation (Scheme 6). Ley-
With reliable access to Maillard product 23 secured,
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3
subsequent ring-opening with sodium azide gave azido alcohol Griffith oxidation26 followed by TBS deprotection afforded a
20 as a mixture of C-5 epimers which were isolated and taken complex mixture of hemiacetal products along with the
forward separately. Staudinger reduction and palladium- deprotected dihydroxyketone. Treatment of this mixture with
catalysed hydrogenation of azido alcohol 20 were both catalytic PPTS promoted cyclisation to give spiroketals 24 as a
investigated, with hydrogenation providing amino alcohol 13 in 1.5:1 mixture of diastereomers. Removal of the acetonide with
higher yields.
The Maillard-type condensation of amino alcohol 13 with
PPTS in methanol afforded a mixture of pollenopyrroside A ((+)-
and 9-epi-pollenopyrroside ((−)- in 7:1 ratio.
1
)
A
2
)
a
dihydropyranone 14 proved challenging. The Maillard reaction Interestingly, no products containing a 5,6-spiroketal ring
is sensitive to pH and temperature, hence two conditions system were observed.
previously developed by our group for similar reactions were
1
and 2).15,18 Disappointingly, these
O
O
O
O
O
O
evaluated (entries
OH
O
i)
conditions only afforded 2-formylpyrrole 23 in poor yields along
with polar side products. In an attempt to increase the
selectivity of the reaction, dihydropyranone 14 was converted
to its acetate derivative 22 providing a better leaving group.
Acetate 22 proved less reactive under basic conditions (entry 3),
however it gave the desired 2-formylpyrrole 23 cleanly in
moderate yields in the presence of catalytic acid (entry 4). These
catalytic acidic conditions were applied to dihydropyranone 14
unsuccessfully (entry 5), establishing the importance of the
acetate group to achieve effective Maillard-type condensation.
TBSO
TBSO
N
N
TBSO
TBSO
23
12
O
iv)
iii)
ii),
N
O
O
O
O
24
O
O
Table 1. Maillard-type condensation of amino alcohol 13
N
N
O
+
O
9R
9R
HO
HO
O
12R
12R
O
O
11S
11S
O
O
HO
HO
+
OH
O
9-
A
A
epi
-pollenopyrroside
shensongine A
pollenopyrroside
TBSO
1
NH2
((+)- )
TBSO
OR
=
H
A
xylapyrroside
−
:
:
14 R
2
i
(( )- )
13
=
22 R Ac
Scheme 6. Synthesis of (+)-
(5 mol %), NMO, 4Å mol sieves, CH2Cl2, r.t., 30 min, 77 %; ii) 3HF·Et3N, THF, r.t.
24 h; iii) PPTS (50 mol %), CH2Cl2, r.t., 72 h, 59 % over two steps (1.2:1 dr);
iv) PPTS (1 equiv.), MeOH, r.t., 48 h, (+)- 71 %, (−)- 10 %.
1 and (−)-2. Reagents and conditions: i) TPAP
see
Table 1
1
2
The spectroscopic and optical rotation data for
pollenopyrroside A ((+)- ) were in agreement with that
previously Spectroscopic data for
reported.1,16
O
O
O
OH
1
TBSO
N
9-epi-pollenopyrroside A ((−)-
2
) in CDCl3 matched that of both
TBSO
3
6
capparisine B ((+)-
2
)
and xylapyrroside A ((−)-
2
)
(Table 2)
23
further establishing that they have the same relative structure.
6
Reported NMR data for xylapyrroside A in CD3OD ((−)-
matches that of shensongine A ((−)-
established that 9-epi-pollenopyrroside A ((−)-
relative structure as shensongine A ((−)-
).‡
The measured optical rotation
9-epi-pollenopyrroside ((−)-
was the same sign as shensongine A ((−)-
(c 0.05, MeOH)5 and xylapyrroside A ((−)-
(c 0.1, MeOH)6 and opposite to capparisine
2)
Reagents and conditions: i) Ac2O, pyridine, DMAP, CH2Cl2, 0 °C, 1.5 h, 91 %
2
)5, therefore it can be
) is the same
2
Entr
y
Temperatur
e
Additive
(equiv.)
R
H
H
Solvent
Yield (%)
2
1
2
3
4
5
Dioxane
r.t.
50 °C
50 °C
r.t.
Et3N (3.0)
AcOH[a]
32
9
of
synthetic
2)
[ꢀ]2D2.2 −135.2 (c 0.071, MeOH)
THF/H2
O 1:1
2
)
[ꢀ]2D7 −12.7
[ꢀ]2D2 −189
A
c
A
c
2
)
Dioxane
CH3CN
CH3CN
Et3N (3.0)
PPTS (0.25)
PPTS (0.25)
14
47
11
B
((+)-
[ꢀ]2D5 + 34.5 (c 0.013, MeOH)3. Surprisingly, the magnitude of
optical rotation of synthetic 9-epi-pollenopyrroside ((−)-
2
)
2
)
showed no close agreement with any of these previously
reported values. Most interestingly, the reported optical
H
r.t.
rotation for 9-epi-pollenopyrroside ((−)-2)
[ꢀ]2D5 + 38.5 (c 0.05,
All reactions performed with a 2:1 ratio of amino alcohol 13:dihydropyranone 14
or 22. [a]Maintained at pH 5
MeOH) previously synthesised by Zhao et al.16 was opposite in
4 | J. Name., 2012, 00, 1-3
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Table 2. 1H (400 MHz) and 13C (100 MHz) NMR data of synthesised 9-epi-pollenopyrroside A ((−)-2) in CDCl3
δH (J values in Hz)
δC
No.
9-epi-pollenopyrroside A (−)-2
capparisine B3
xylapyrroside A6
9-epi-pollenopyrroside A (−)-2
capparisine B3
131.2
2
-
-
-
131.3
3
4
6.91 (d, 4.1)
6.01 (d, 4.1)
-
6.92 (d, 3.8)
6.01 (d, 3.5)
-
6.90 (d, 4.0)
5.99 (d, 4.0)
-
124.2
105.0
124.0
104.8
5
6
134.2
57.9
134.1
57.8
4.78 (d, 15.6)
4.70 (d, 15.6)
4.82 (d, 15.2)
4.74 (d, 15.7)
4.80 (d, 15.6)
4.71 (d, 15.6)
7
8
9.45 (s)
9.45 (s)
9.42 (s)
178.9
52.3
178.8
52.2
4.70 (d, 14.2)
4.02 (d, 14.2)
4.70 (d, 14.4)
4.02 (d, 13.8)
4.70 (d, 13.9)
4.03 (d, 13.9)
9
-
-
-
95.5
35.9
95.4
35.8
10
1.91 (dd, 12.9, 11.8)
2.04 (dd, 12.9, 5.4)
1.91 (dd, 12.6, 11.8)
2.04 (dd, 12.8, 5.3)
1.90 (dd, 12.8, 11.6)
2.02 (dd, 12.8, 5.6)
11
4.17 (m)
4.14 (m)
3.88 (m)
4.14 (ddd, 11.6, 5.6, 2.8)
3.87 (m, overlapped)
65.2
65.1
12
13
3.88 (m, overlapped)
67.5
64.7
67.4
64.5
3.89 (dd, overlapped)
3.81 (dd, 12.7, 1.2)
3.89 (d, 12.1)
3.81 (d, 12.1)
3.87 (dd, overlapped)
3.78 (dd, 12.8, 1.2)
sign to ours and significantly smaller in magnitude. The reason
for the discrepancies in these reported values is unclear and
requires further attention. However, we propose on the basis
of matching spectroscopic data and the sign of optical rotation
that shensongine A and xylapyrroside A are identical to
Notes and references
‡ See supporting information for comparison of spectroscopic
data for shensongine A ((−)- ) and xylapyrroside A ((−)- ).
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