Total Synthesis and Stereochemical Revision of the 2-Formylpyrrole Alkaloid Hemerocallisamine i

Article abstract of DOI:10.1021/acs.jnatprod.7b00314

The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis features a key Maillard-Type condensation of a complex amine derived from cis-4-hydroxy-l-proline with a dihydropyranone, to directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis of optical rotation data obtained for the synthesized compound.

Full text of DOI:10.1021/acs.jnatprod.7b00314

Article
pubs.acs.org/jnp
Total Synthesis and Stereochemical Revision of the 2‑Formylpyrrole
Alkaloid Hemerocallisamine I
†
,†,‡
and Margaret A. Brimble*,†,‡
James M. Wood, Daniel P. Furkert,*
†
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
‡
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
*
S Supporting Information
ABSTRACT: The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis
features a key Maillard-type condensation of a complex amine derived from cis-4-hydroxy-L-proline with a dihydropyranone, to
directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis
of optical rotation data obtained for the synthesized compound.
he daylily (Liliaceae) is widely cultivated as an ornamental
plant in North America and Europe; however it has a long
exhibiting antioxidant, antitumor, hypolipidemic, and anti-
hyperglycemic effects.
4
T
history of use as a food and traditional medicine in Eastern
2-Formylpyrrole products result from the Maillard reaction, a
group of nonenzymatic reactions of reducing sugars with
amines that typically give rise to complex mixtures of
Asia. The edible flowers of the plant are known to be used as a
1
sleeping aid in Japan and also exhibit antidepressant effects. In
5
2
014, as part of studies to characterize the chemical
compounds. Interest in the synthetic application of the
constituents of the Hemerocallis fulva daylily flower and identify
sedative amino acid derivatives, Matsuda and co-workers
isolated the novel glutamine derivative hemerocallisamine I
Maillard reaction has recently led to the development of
conditions to synthesize 2-formylpyrroles directly from
reducing sugars and simple amines or amino acids in moderate
2
(1) (Figure 1).
6
yields. As part of our ongoing interest in the synthesis of 2-
formylpyrrole natural products, we have developed mild
Maillard-type condensation conditions to cleanly generate the
2
-formylpyrrole system from amines utilizing a dihydropyr-
7
anone as a sugar surrogate.
The relative configuration of hemerocallisamine I (1) was
established by X-ray crystallography and NMR analysis. The
absolute configuration of hemerocallisamine I (1) was
proposed to be (2R,4R)-1 on the basis of the Flack parameter
2
[
absolute structure parameter = −0.0(16)]. Given that 2-
formylpyrrole natural products arise from the reaction of sugars
and biologically common amines, the assignment of the
unnatural D-glutamine (2R,4R) configuration was unexpected.
We envisioned that a total synthesis from well-defined chiral
pool materials would allow unambiguous elucidation of the
absolute configuration of hemerocallisamine I (1) and provide
material for biological activity investigations.
Figure 1. Proposed structure of hemerocallisamine I, (2R,4R)-1. 2-
Formylpyrrole is in red.
Hemerocallisamine I (1) possesses a 2-formylpyrrole moiety
Figure 1, red) and a 4-hydroxyglutamine fragment. Glutamine
(
and its derivatives have an important role in the treatment of
3
many neurological conditions including sleep disorders. The 2-
formylpyrrole system, meanwhile, is present in a number of
natural products isolated from traditional Chinese medicines
Received: April 10, 2017
©
XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00314
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
9
b
RESULTS AND DISCUSSION
Retrosynthesis Analysis. Following our previous work
toward the synthesis of 2-formylpyrrole natural products, it
careful preparation under anhydrous conditions. In this event,
■
lactam 4 underwent facile ring opening by exposure to
concentrated NH OH in dioxane to afford terminal amide 6
7
4
in quantitative yield. Disappointingly, all attempts to remove
the N-Boc protecting group under acidic conditions resulted in
cyclization to give lactam 7 as the major product. Lowering the
temperature of the reaction failed to improve the ratio of the
target deprotected amine to the cyclized amide 7 and instead
only slowed the rate of the unwanted reaction.
It was anticipated that use of an electron-donating amide to
protect the terminal amide group might inhibit unwanted
competing cyclization of the α-amino group onto the terminal
amide. p-Methoxybenzyl (PMB) protected amide 8 was
accordingly prepared by aminolysis of lactam 4 with p-
methoxybenzylamine (Scheme 3). Pleasingly, this amide
was anticipated that the ring system of hemerocallisamine I (1)
could be constructed by a Maillard-type condensation of 4-
hydroxyglutamine derivative 2 with the known dihydropyr-
7
a
anone 3 (Scheme 1). The initial synthesis target was the
Scheme 1. Retrosynthesis Analysis of Hemerocallisamine I
1) Based on a Maillard-Type Condensation Strategy
(
Scheme 3. Preparation of Amines 9 and 10 by Aminolysis
and Boc Deprotection
enantiomer of the proposed absolute structure of hemerocallis-
amine I, (2S,4S)-1, which would require the preparation of
a
b
(2S,4S)-4-hydroxyglutamine derivative 2 rather than the
2R,4R)-4-hydroxyglutamine derivative. We postulated that
Reaction mixture was concentrated in vacuo directly. Aqueous
(
extraction was performed from a NaHCO solution.
3
the natural product in fact possessed the (2S,4S)-configuration,
and pursuit of this enantiomer would allow investigation of the
proposed synthesis route using readily accessible L-amino acid
chiral pool reagents. 4-Hydroxy-L-glutamine derivative 2 could
potentially be obtained by aminolysis of known lactam 4, which
in turn could be prepared from commercially available cis-4-
underwent Boc-deprotection of the α-amino group with no
observed cyclization onto the protected amide function. Direct
concentration of the reaction mixture in vacuo resulted in
cleavage of the tert-butyldimethylsilane (TBDMS) protecting
group, although this could be prevented by prior neutralization
8
hydroxy-L-proline (5) by known methods. This synthesis
of the reaction mixture with a saturated NaHCO solution.
3
approach would enable the establishment of both stereocenters
of hemerocallisamine I (1) at the outset of the synthesis.
Synthesis of the Glutamine Fragment. Lactam 4 was
prepared over four steps from cis-4-hydroxy-L-proline (5) using
Generation of the 2-Formylpyrrole System. With the
free amines 9 and 10 in hand, attention turned to the key
Maillard-type condensation step. Both amines underwent
7a
condensation with dihydropyranone 3 in the presence of
8
established methods (Scheme 2). Preparation of the terminal
pyridinium p-toluenesulfonate in pyridine to give their
respective 2-formylpyrroles 11 and 12 (Scheme 4). It was
found that amine 9 underwent the condensation reaction more
readily than its TBDMS-protected counterpart 10, furnishing
the 2-formylpyrrole product 11 in 37% yield. Comparable
yields for the TBDMS-protected derivative 12 could be
achieved only when two equivalents of the amine 10 were
used relative to dihydropyranone 3. Previous applications of
this reaction have resulted in imine side products from the
condensation of the 2-formypyrrole product with a further
amide required aminolysis of the lactam in the presence of the
methyl ester moiety. Aminolysis of N-Boc-protected lactams in
9a
the presence of esters often requires use of catalytic KCN or
aluminum Lewis acid−ammonia conjugates, which require
Scheme 2. Aminolysis of Lactam 4 and the Unwanted
Lactamization of Amide 6
7b
equivalent of the amine coupling partner; however no imine
1
side products were observed in the H NMR spectra of either
crude reaction mixture. Although the yield appears moderate,
this was readily compensated for by the overall efficiency and
functional group tolerance of the Maillard condensation, to
directly install the functionalized pyrrole group in a single step.
Having constructed the 2-formylpyrrole system, elaboration
to the proposed natural product hemerocallisamine I (1)
required only deprotection of the PMB and TBDMS groups
and selective methylation of the primary hydroxy group. It has
B
DOI: 10.1021/acs.jnatprod.7b00314
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Scheme 4. Maillard-Type Condensation of Amines 9 and 10 with Dihydropyranone 3 and Elaboration to Hemerocallisamine I
(1)
previously been observed by Okada et al. that conversion of an
acid-labile protecting group for the 5-hydroxymethylpyrrole
substituent into an alkyl ether can be achieved directly under
configuration of hemerocallisamine I from (2R,4R)-1 to
(2S,4S)-1. The synthesis has also provided reliable access to
the revised natural product, which will enable biological activity
investigations.
10
acidic conditions in the presence of an alcohol. Accordingly,
treatment of TBDMS ether 11 with catalytic para-toluene-
sulfonic acid in MeOH and CH Cl cleanly afforded methyl
ASSOCIATED CONTENT
Supporting Information
2
2
■
ether 13, with no free alcohol side product being observed
Scheme 4). The final deprotection of the PMB amide was
S
*
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00314.
initially attempted using ceric ammonium nitrate, but the 5-
methoxymethyl substituent of the pyrrole moiety underwent
oxidation to afford the diformyl compound 14 as the major
1
Experimental procedures and analytical data ( H NMR,
1
product. This transformation was supported by the H NMR
13
C NMR, MS) for all new compounds (PDF)
spectrum of the crude reaction mixture, which showed the
disappearance of characteristic doublets resonating at δ 7.01 (J
AUTHOR INFORMATION
Corresponding Authors
*Tel: +64 9 373 7599, ext. 88259. Fax: +64 9 373 7422. E-mail:
d.furkert@auckland.ac.nz.
*E-mail: m.brimble@auckland.ac.nz.
ORCID
Daniel P. Furkert: 0000-0001-6286-9105
Margaret A. Brimble: 0000-0002-7086-4096
Notes
=
3.6 Hz) and 6.33 (J = 3.6 Hz) corresponding to the pyrrole
■
protons of the starting material and the appearance of a new
singlet resonating further downfield at δ 7.11. This new pyrrole
resonance at δ 7.11 and the formyl proton singlet at δ 9.77 both
integrated for two protons relative to the other characteristic
methine protons. These signals suggested the presence of a
symmetrical bisformylpyrrole system, which was confirmed by+
HRMS with a sodium adduct molecular ion [M + Na]
observed at m/z 305.0744, corresponding to a molecular
formula of C H N NaO .
12
14
2
6
The authors declare no competing financial interest.
Pleasingly, deprotection of PMB−amide 13 proceeded
cleanly using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, with
the addition of pH 7 phosphate buffer to suppress lactonization
of the γ-hydroxy ester. The spectroscopic and physical
properties of the synthesized hemerocallisamine I (1) agreed
with those reported for isolated hemerocallisamine I (1). Most
significantly, the sign of the specific rotation of the synthesized
ACKNOWLEDGMENTS
The authors would like to thank The University of Auckland
for the award of an Auckland Doctoral Scholarship to J.M.W.
■
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■
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DOI: 10.1021/acs.jnatprod.7b00314
J. Nat. Prod. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.jnatprod.7b00314
J. Nat. Prod. XXXX, XXX, XXX−XXX