A convergent synthesis of the 2-formylpyrrole spiroketal natural product acortatarin A

Article abstract of DOI:10.1055/s-0031-1290508

A concise and flexible synthesis of the morpholine-spiroketal natural product acortatarin A, isolated from the traditional Chinese medicine Acorus tatarinowii, is reported. The key step involves a Maillard-type condensation of an amine derived from d-mannitol with a dihydropyranone. The approach also enables access to analogues of acortatarin A for biological evaluation and can be applied to the synthesis of related 2-formylpyrrole natural products. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0031-1290508

LETTER
▌855
lAetteCr onvergent Synthesis of the 2-Formylpyrrole Spiroketal Natural Product
Acortatarin A
Synthesis of the 2-Formylpyrrole Spiroketal Natural Product Acortatarin A
Hui Min Geng,a Jack Li-Yang Chen,a Daniel P. Furkert,a Shende Jiang,b Margaret A. Brimble*a
a
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
b
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. of China
Fax +64(9)3737422; E-Mail: m.brimble@auckland.ac.nz
Received: 27.01.2012; Accepted after revision: 09.02.2012
of this new template for drug discovery, directed towards
Abstract: A concise and flexible synthesis of the morpholine-spi-
therapeutic intervention in diabetic nephropathy (DN).5
roketal natural product acortatarin A, isolated from the traditional
During the course of our work, a synthesis of acortatarins
Chinese medicine Acorus tatarinowii, is reported. The key step in-
volves a Maillard-type condensation of an amine derived from D-
A and B was reported by Jagadeesh et al.6 that resulted in
mannitol with a dihydropyranone. The approach also enables access stereochemical revision of the original structures to struc-
to analogues of acortatarin A for biological evaluation and can be
applied to the synthesis of related 2-formylpyrrole natural products.
tures 1 aSnd 2, respectively (Figure 1). We herein report a
convergent synthesis of acortatarin A, confirming the re-
Key words: acortatarin, Chinese medicine, natural product synthe-
sis, spiroketal, 2-formylpyrrole, Maillard reaction
vised structure of the natural product.
OTBS
N
HO
O
O
O
O
Acortatarins A and B (Figure 1) were isolated in 2010
from the rhizome of Acorus tatarinowii, that is widely
used as a traditional Chinese medicine for the treatment of
central nervous system disorders.1 Both natural products
were examined for their antioxidant effects in high-glucose-
induced mesangial cells in a dose- and time-dependent
manner, with acortatarin A showing significant activity
against production of reactive oxygen species.
HO
O
N
CHO
OHC
acortatarin A (1)
TBDPSO
3
O
O
OH
O
HO
+
NH2
O
TBDPSO
OTBS
5
4
O
O
O
O
HO
HO
N
N
HO
HO
OH
O
O
OHC
OHC
O
HO
OTBS
acortatarin A (initial)
acortatarin B (initial)
CHO
7
6
O
O
O
O
HO
HO
Scheme 1 Retrosynthetic plan for the assembly of the acortatarin
framework
N
N
HO
HO
OH
OHC
OHC
Our retrosynthetic strategy (Scheme 1) aimed to access
the spiroketal core of acortatarin A (1) through an acid-
mediated cyclisation of the protected hydroxyketone 3.
Anticipating low yields in the N-alkylation of 2-formyl-
pyrrole derivatives,7 we envisioned that ketone 3 would
be available from a Maillard-type disconnection,8 leading
to amino alcohol 4 and sugar surrogate dihydropyranone
5.9 Amino alcohol 4 in turn is accessible using an ap-
proach based on initial diastereoselective allylation of a D-
mannitol-derived glyceraldehyde equivalent 6, while 5
would arise from Achmatowicz ring expansion of substi-
tuted furfuryl alcohol 7.10 We reasoned that this approach
would not only provide a convergent route to the acortata-
rins and close analogues thereof, but would also provide a
more convenient route to access a variety of other bioac-
tive 2-formylpyrrole-containing natural products (Figure
2).11
acortatarin A (1) (revised)
acortatarin B (2) (revised)
Figure 1 Initially proposed and revised structures of acortatarins A
(1) and B (2)
These spiroalkaloids possess a unique tricyclic structure
containing both a 2-formylpyrrole and a spiro-fused sug-
ar-morpholine spiroketal subunit. The morpholine phar-
macophore in particular is present in a number of
important enzyme inhibitors, including phosphoinositide
3 kinases,2 TNF-R converting enzyme,3 matrix metallo-
proteinases, and tumor necrosis factor.4 A practical asym-
metric synthesis of acortatarin A would allow evaluation
SYNLETT 204012, 236, 0855–0858
Advanced online publication: 16.03.2012
DOI: 10.1055/s-0031-1290508; Art ID: ST-2012-D0081-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

856
H. M. Geng et al.
LETTER
in 62% yield over two steps. Subsequent Achmatowicz
oxidation–rearrangement using MCPBA afforded 5 in
gram quantities for subsequent condensation with amino
alcohol 4.
OHC
O
MeO
HO
N
N
H
OH
O
magnolamide
1) BuLi, THF
DMF, 65%
O
OHC
O
2) NaBH4,
MeOH, 95%
O
TBSO
OH
HO2C
N
TBSO
7
11
N
CHO
NH2
HO
O
HO
MCPBA
CH2Cl2
HO
pyrraline
(–)-funebral
O
Figure 2 Related 2-formylpyrrole natural products
95%
OTBS
5
The initial approach to build amino alcohol subunit 4 be-
gan with cyclohexylidene glyceraldehyde 6 prepared
from D-mannitol (Scheme 2). Allylation using allyl bro-
mide and zinc dust proceeded with excellent diastereose-
lectivity to afford anti-homoallylic alcohol 8 in good yield
(76%, dr 97:3).12 This result was substantially better than
that obtained with the more widely used acetonide glycer-
aldehyde,13 and also proved more convenient when con-
ducted on a multigram scale. Importantly, the minor
diastereomer was readily removed by standard column
chromatography. Cleavage of the cyclohexylidene was ef-
fected with methanolic HCl and the primary alcohol pro-
tected as a TBDPS ether in 77% yield over the two steps.
Treatment of the resultant anti-diol 9 with 2,2-dimethoxy-
propane and pyridinium p-toluenesulfonate (cat.) fol-
lowed by epoxidation of the olefin gave 10 in 95% yield
over two steps. Ring opening of the epoxide with sodium
azide afforded an azido alcohol that was reduced with tri-
methylphosphine in aqueous THF to provide the required
amino alcohol 4.
Scheme 3 Preparation of dihydropyranone 5
Initial investigations into the key condensation of amino
alcohol 4 with dihydropyranone 5 proved disappointing
(Table 1). Use of anhydrous dioxane as solvent did not af-
ford any of the desired product (Table 1, entry 1), but a
10% yield of 12 was obtained using undistilled solvent
(Table 1, entry 2).
Table 1 Maillard-Type Coupling of Amino Alcohol 4 with Dihy-
dropyranone 515
OTBS
O
OH
conditions
O
4
+
5
N
CHO
TBDPSO
12
Entry
4/5
Additive (equiv) Temp (°C) Yield (%)
0a
10
1
2
3
4
5
6
1:1
1:1
2:1
3:1
2:1
2:1
–
r.t.
r.t.
r.t.
r.t.
50
r.t.
Br
–
Zn
aq. NH4Cl
–
25
20
25
60
1) HCl, MeOH
O
O
O
O
2) TBDPSCl,
NaH, THF
–
76%, dr 97:3
8
–
6
O
77% (2 steps)
OH
Et3N (3.0)
1) MeC(OMe)2Me
PPTS, quant.
OH
O
O
O
a Anhydrous dioxane was used. All reactions were performed in undis-
tilled dioxane for 3 h unless indicated.
TBDPSO
2) MCPBA
CH2Cl2, 95%
OH
TBDPSO
9
10
1) NaN3,
EtOH, Δ
Increasing the quantity of amino alcohol 4 and the reac-
tion temperature (Table 1, entries 2–5) also offered some
improvement in yield. Finally, addition of triethylamine
(3 equiv; Table 1, entry 6) afforded the required 2-formyl-
pyrrole 12 in 60% yield together with the recovered amino
alcohol 4. With N-alkylation product 12 in hand, attention
turned to the assembly of the required spiroketal system.
A screen of several oxidants (e.g., PCC, PDC, IBX, DMP)
established that TPAP/NMO was the reagent of choice for
oxidation of the secondary alcohol 12 to the correspond-
ing ketone 3 (Scheme 4). Exposure of 3 to mildly acidic
conditions (PPTS, PTSA, dilute aq HCl, CSA) cleanly re-
O
OH
O
NH2
2) Me3P,
aq THF
TBDPSO
50% (2 steps)
4
Scheme 2 Synthesis of amino alcohol 4
Synthesis of dihydropyranone 5 (Scheme 3) started with
TBS ether 11 derived from commercially available furfu-
ryl alcohol.14 Regioselective lithiation of 11 and for-
mylation with DMF followed by borohydride reduction of
the carbonyl group proceeded uneventfully, delivering 7
Synlett 2012, 23, 855–858
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the 2-Formylpyrrole Spiroketal Natural Product Acortatarin A
857
moved the TBS protecting group to afford a hemiacetal natural product acortatarin A (1). Towards this end, a fur-
but failed to remove the acetonide group. Of the harsher ther isomeric analogue 15 of amino ketone 3 was prepared
acidic reagents evaluated, use of 4 M aqueous HCl in THF from L-tartaric acid using a reaction sequence similar to
proved to be the most effective, affording a 3:2 mixture of the one described above. Accordingly, L-tartaric acid was
the desired TBDPS spiroketals 13 (epimeric at the spiro- subjected to esterification, acetonide protection, reduction
centre) in 80% yield. Disappointingly, little diastereose- of the carboxylic acid groups, and mono-TBDPS protec-
lectivity at the spirocentre was observed. Nevertheless, tion to afford alcohol 17 in 52% yield over four steps. Al-
this isomeric mixture was deprotected using TBAF to af- cohol 17 was then transformed into the corresponding
ford the corresponding spiroketal alcohols 1 and 14 that iodide under standard Appel reaction conditions. Subse-
were separable by careful column chromatography.
quent halide displacement with vinylmagnesium bromide
provided olefin 18. Treatment of 18 with MCPBA afford-
ed an epoxide that underwent nucleophilic opening with
sodium azide followed by Staudinger reduction to deliver
the required amino alcohol for subsequent Maillard con-
densation with dihydropyranone 5. Following oxidation
of the resulting alcohol, ketone 15 was subjected to a se-
quence of acid-mediated deprotection–cyclisation and
desilylation, leading to the acortatarin A analogues 16 and
epi-16 in good yield (Scheme 5).17
OTBS
TPAP, NMO,
MS, CH2Cl2
O
O
O
12
N
99%
CHO
TBDPSO
3
TBDPSO
O
O
4 M HCl, THF
80%, dr 3:2
HO
In summary, a convergent synthetic strategy to construct
the acortartarin family of natural products is described.
The key Maillard-type condensation of chiral amino alco-
hol 4 with dihydropyranone building block 5 demonstrat-
ed herein is amenable to the efficient synthesis of a
focused library of morpholine-spiroketals to further probe
their potential as agents to treat diabetic nephropathy. In
addition we anticipate that dihydropyranone 5 may find
wider utility in the synthesis of related 2-formylpyrrole
systems.
N
OHC
O
13
HO
HO
TBAF
O
O
O
THF
2
2
+
HO
HO
N
67%
N
dr 3:2
OHC
OHC
acortatarin A (1)
2-epi-acortatarin A (14)
Scheme 4 Elaboration to acortatarin A (1)
Acknowledgment
Comparison of the NMR spectra of synthetic 1 and 1416
with those reported in the literature established that the
major deprotection product was identical in all respects
with acortatarin A (1).1,6 The minor spiroketal epimer 14
(2-epi-acortatarin A) differed only in the configuration at
the spiroketal centre.
The authors wish to thank the New Zealand Ministry for Science
and Innovation for an International Investment Opportunities Fund
(IIOF) grant and the China Scholarships Council.
References and Notes
(1) Tong, X. G.; Zhou, L. L.; Wang, Y. H.; Xia, C.; Wang, Y.;
Liang, M.; Hou, F. F.; Cheng, Y. X. Org. Lett. 2010, 12,
1844.
Having established a practical and convergent route to the
acortatarin framework, we aimed to prepare a small li-
brary of analogues for biological evaluation alongside the
(2) Verheijen, J. C.; Zask, A. Drugs Future 2007, 32, 537.
1) MCPBA
CH2Cl2
2) NaN3, EtOH
1) EtOH, HCl
2) MeC(OMe)2Me,
PTSA, Δ
1) I2, Ph3P
imidazole
toluene
OH
O
O
O
CO2H
O
OH
HO2C
3) LiAlH4, THF, Δ
4) NaH, TBDPSCl
2)
3) Me3P, THF–H2O
4) 5, Et3N (3.0 equiv)
dioxane, 3 h
5) TPAP, NMO
MS, CH2Cl2
MgBr
OH
THF–DMPU
TBDPSO
TBDPSO
L-tartaric acid
17
18
52% (4 steps)
56% (2 steps)
31% (5 steps)
O
O
OTBS
HO
HO
O
TBDPSO
O
O
TBAF
THF
O
4 M HCl
THF
O
O
O
TBDPSO
2
4
2
2
4
4
+
HO
53%
N
80%
dr 3:2
HO
HO
N
N
N
(16, major)
OHC
2-epi-16
OHC
OHC
OHC
15
19
16
Scheme 5 Synthesis of spiroketals 16 and 2-epi-16 from L-tartaric acid
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 855–858

858
H. M. Geng et al.
LETTER
(3) Levin, J. I.; Chen, J. M.; Laakso, L. M.; Du, M.; Du, X.;
Venkatesan, A. M.; Sandanayaka, V.; Zask, A.; Xu, J.; Xu,
W.; Zhang, Y.; Skotnicki, J. S. Bioorg. Med. Chem. Lett.
2005, 15, 4345.
(4) Almstead, N. G.; Bradley, R. S.; Pikul, S.; De , B.; Natchus,
M. G.; Taiwo, Y. O.; Gu, F.; Williams, L. E.; Hynd, B. A.;
Janusz, M. J.; Dunaway, C. M.; Mieling, G. E. J. Med.
Chem. 1999, 42, 4547.
3.73 (d, J = 10.4 Hz, 1 H), 3.97 (br s, 1 H), 4.11 (d, J = 16.8
Hz, 1 H), 4.54 (d, J = 16.8 Hz, 1 H), 6.08 (d, J = 10.0 Hz, 1
H), 6.80 (d, J = 10.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 195.3 (C), 146.3 (CH), 128.2 (CH), 92.6 (C), 67.9 (CH2),
66.5 (CH2), 25.7 (CH3), 18.3 (C), –5.3 (CH3). IR (film):
3242, 295, 2929, 2857, 1677, 1244, 1114, 1061, 830, 773
cm–1. ESI-HRMS: m/z calcd for C12H23SiO4 [M + H]+:
259.1360; found: 259.1365.
(5) (a) Rosen, P.; Nawroth, P. P.; King, G.; Moller, W.;
Tritschler, H. J.; Packer, L. Diabetes Metab. Res. Rev. 2001,
17, 189. (b) Ha, H.; Lee, H. B. Kidney Int. 2000, 58, S19.
(c) Lee, H. B.; Yu, M. R.; Yang, Y.; Jiang, Z.; Ha, H. J. Am.
Soc. Nephrol. 2003, 14, 241. (d) Shi, X. Y.; Hou, F. F.; Niu,
H. X.; Wang, G. B.; Xie, D.; Guo, Z. J.; Zhou, Z. M.; Yang,
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(8) Ledl, F.; Schleicher, E. Angew. Chem., Int. Ed. Engl. 1990,
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(16) Synthesis of Acortatarin (1) and 2-epi-Acortatarin (14)
To a stirred solution of 13 (20 mg, 0.04 mmol) in THF (0.5
mL) was added TBAF (1 M in THF, 0.5 mL, 0.5 mmol)
under N2. The reaction mixture was stirred for 2.5 h at r.t.
then concentrated in vacuo The residue was purified by
preparative TLC (hexane–EtOAc = 1:5) to afford acortatarin
(1, 4 mg, 0.016 mmol, 40%) as a white solid and 2-epi-
acortatarin (14, 2.7 mg, 0.011 mmol, 27%) as a yellow oil.
Compound 1 (major): [α]D20 +194.8 (c 0.15, MeOH) {lit.6
[α]D +191.4 (c 0.27, MeOH)}. 1H NMR (400 MHz,
CD3OD): δ = 2.10 (dd, J = 14.0, 2.8 Hz, 1 H), 2.30 (dd,
J = 14.0, 8.4 Hz, 1 H), 3.58 (dd, J = 12.0, 4.8 Hz, 1 H), 3.67
(dd, J = 12.4, 3.6 Hz, 1 H), 4.02 (ddd, J = 6.9, 3.9, 2.9 Hz, 1
H), 4.18 (d, J = 14.0 Hz, 1 H), 4.24 (ddd, J = 8.9, 6.9, 3.9 Hz,
1 H), 4.55 (d, J = 10.0 Hz, 1 H), 4.81 (d, J = 16.8 Hz, 1 H),
4.97 (d, J = 16.8 Hz, 1 H), 6.03 (d, J = 4.4 Hz, 1 H), 6.98 (d,
J = 4.4 Hz, 1 H), 9.32 (s, 1 H). 13C NMR (100 MHz,
CD3OD): δ = 180.2 (CH), 137.6 (C), 132.4 (CH), 125.9
(CH), 106.1 (C), 104.5 (C), 89.4 (CH), 72.2 (CH), 63.0
(CH2), 58.7 (CH2), 52.0 (CH2), 45.9 (CH2). IR (film): 3360,
2921, 2851, 1736, 1659, 1412, 1260, 1036, 796 cm–1. ESI-
HRMS: m/z calcd for C12H15NNaO5 [M + Na]+: 276.0842;
found: 276.0843.Compound 14 (minor): [α]D20 –85.0 (c 0.2,
MeOH) {lit.6 [α]D –57.8 (c 0.04, MeOH)}. 1H NMR (400
MHz, CD3OD): δ = 2.10 (dd, J = 12.0, 6.8 Hz, 1 H), 2.45
(dd, J = 13.2, 6.8 Hz, 1 H), 3.55 (dd, J = 11.6, 2.8 Hz, 1 H),
3.65 [dd, J = 11.6, 4.4 (18) Hz, 1 H], 3.96 (ddd, J = 10.8, 8.8,
2.8 Hz, 1 H), 4.18 (d, J = 13.6 Hz, 1 H), 4.33 (ddd, J = 12.4,
5.6, 1.6 Hz, 1 H), 4.63 (d, J = 13.6 Hz, 1 H), 4.75 (d, J = 16.8
Hz, 1 H), 5.05 (d, J = 16.8 Hz, 1 H), 6.01 (d, J = 4.4 Hz, 1
H), 6.98 (d, J = 4.4 Hz, 1 H), 9.33 (s, 1 H). 13C NMR (100
MHz, CD3OD): δ = 180.2 (CH), 137.5 (C), 132.4 (CH),
126.1 (CH), 106.1 (C), 104.2 (C), 89.6 (CH), 72.2 (CH), 64.3
(CH2), 59.2 (CH2), 52.6 (CH2), 45.8 (CH2). IR (film): 3351,
2910, 2837, 1733, 1645, 1412, 1260, 1038, 796 cm–1. ESI-
HRMS: m/z calcd for C12H15NNaO5 [M + Na]+: 276.0842;
found: 276.0850.
(9) Maeba, I.; Takeuchi, T.; Iijima, T.; Furukawa, H. J. Org.
Chem. 1988, 53, 1401.
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Zwierzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27,
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(11) (a) Yu, H. J.; Chen, C. C.; Shieh, B. J. J. Nat. Prod. 1998, 61,
1017. (b) Tamura, O.; Iyama, N.; Ishibashi, H. J. Org. Chem.
2004, 69, 1475. (c) Hellwig, M.; Geissler, S.; Matthes, R.;
Peto, A.; Silow, C.; Brandsch, M.; Henle, T. ChemBioChem
2011, 12, 1270.
(12) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
(13) Jackson, D. Y. Synth. Commun. 1988, 18, 337.
(14) Celanire, S.; Marlin, F.; Baldwin, J. E.; Adlington, M. R.
Tetrahedron 2005, 61, 3025.
(15) Synthesis of Dihydropyranone 5
To a stirred solution of 7 (0.60 g, 2.5 mmol) in CH2Cl2 (50
mL) at 0 °C MCPBA was added in one portion (0.70 g, 3.2
mmol). The solution was stirred at 0 °C for 30 min then for
a further 4 h at r.t. The reaction was quenched by addition of
sat. aq Na2SO3 (30 mL) and neutralised to pH 7–8 with 1 M
NaOH solution. The reaction mixture was extracted with
CH2Cl2 (2 × 50 mL), and the combined organic phases were
washed with brine and dried over Na2SO4. Concentration in
vacuo and column chromatography (hexane–EtOAc = 7:1)
afforded the title compound 5 as a white solid (0.63 g, 2.4
mmol, 92%); mp 54–55 °C. 1H NMR (400 MHz, CDCl3):
δ = 0.07 (s, 6 H), 0.88 (s, 9 H), 3.65 (d, J = 10.4 Hz, 1 H),
(17) It did not prove possible to invert the C4 stereochemistry of
16 via a Mitsunobu sequence to access ent-1, possibly due to
the steric bulk of the TBDPS group.
grap
Synlett 2012, 23, 855–858
© Georg Thieme Verlag Stuttgart · New York

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