Biomimetic Total Synthesis of Angiopterlactone B and Other Potential Natural Products

Article abstract of DOI:10.1021/acs.orglett.7b01525

A one-pot biomimetic synthesis of (-)-angiopterlactone B and its enantiomer (+)-angiopterlactone B has been accomplished via TBAF-catalyzed tandem ring contraction followed by oxa-Michael/Michael addition sequence. Comparison of specific optical rotations

Full text of DOI:10.1021/acs.orglett.7b01525

Letter
pubs.acs.org/OrgLett
Biomimetic Total Synthesis of Angiopterlactone B and Other
Potential Natural Products
Tharun K. Kotammagari,†,‡ Rajesh G. Gonnade, and Asish K. Bhattacharya*,†,‡
§
†
‡
§
Division of Organic Chemistry, Academy of Scientific and Innovative Research, and Centre for Material Characterization,
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
*
S Supporting Information
ABSTRACT: A one-pot biomimetic synthesis of (−)-angiopterlactone B and its enantiomer (+)-angiopterlactone B has been
accomplished via TBAF-catalyzed tandem ring contraction followed by oxa-Michael/Michael addition sequence. Comparison of
specific optical rotations, absolute configurations, and CD spectra of natural, synthesized (−)-angiopterlactone B and
(
+)-angiopterlactone B unequivocally proves that the isolated angiopterlactone B must be levorotatory. Synthesis of hitherto
undiscovered natural products 18 and 20 and analogues of angiopterlactone B demonstrate the versatility of this method.
1
(
+)-Angiopterlactone B (1) and angiopterlactone A (2) were
the isolation paper, the authors did not establish the stereo-
chemistries of lactones 3 and 4.
isolated from the Asian fern Angiopteris caudatiformis (Angiop-
terdaceae) by Zou et al. (Figure 1). Angiopterlactone B (1) has a
1
The unique structural features of angiopterlactone B (1) were
hitherto unknown in the literature, thus making this compound
an interesting target for total synthesis. In the isolation paper,
Zou et al. reported a negative Cotton effect for angiopterlactone
3
4a
1
B (1) [absolute configuration: 4R,5S,6S,2′R,3′R,4′S,6′S]. How-
2
0
ever, they mentioned that its optical rotation was [α]D +22 (c
0
.04, EtOAc). We wished to mimic the biosynthesis of
angiopterlactone B (1) and also to clear the ambiguity with its
specific rotation. While our manuscript was being prepared, we
4b
came across a publication from Lawrence et al. on the synthesis
of (−)-angiopterlactone B. Our retrosynthesis is depicted in
Scheme 1. We envisaged that angiopterlactone B (1) could be
obtained by intramolecular Michael addition of angiopterlactone
A (2). Angiopterlactone A (2) could potentially be synthesized
by the intermolecular oxa-Michael addition reaction of the five-
membered lactone 7 and the six-membered lactone 8. The six-
membered lactone 8, in turn, could be obtained from di-O-acetyl7-
L-rhamnal 6 by the application of Ferrier rearrangement
followed by C-4 epimerization using the Mitsunobu reaction.
The five-membered lactone 7 could be obtained from 6 by
oxidative rearrangement followed by hydrolysis and trans-
lactonization.
5
,6
Figure 1. Structure of angiopterlactone B (1) and co-occurring lactones
2−5 from A. caudatiformis.
unique structure; i.e., it is a tricyclic ring system (A/B/C) having
dual lactones flanking both sides of a tetrahydrofuran ring
containing seven contiguous stereocenters. Lactones 3 and 4
1
were reported to be naturally co-occurring along with
2
compounds 1 and 2, and it has been stated that angiopterlactone
A (2) is biosynthesized in the plant from compounds 3 and 4.
Further, Zou et al. reported that angiopterlactone A (2) could be
1
Received: May 20, 2017
a biosynthetic precursor of angiopterlactone B (1). However, in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01525
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Organic Letters
Letter
Scheme 1. Retrosynthetic Plan for Synthesis of
Angiopterlactone A (2) and Angiopterlactone B (1)
Scheme 4. Formation of Angiopterlactone B (1) via Tandem
Ring Contraction/Oxa-Michael/Michael Addition Sequence
unequivocally the structure of (−)-angiopterlactone B (1) by its
11
single-crystal X-ray analysis (Figure 2a).
The α,β-unsaturated γ-lactone 7 fragment for Michael addition
was prepared from the 3,4-di-O-acetyl-L-rhamnal 6 in three steps
(
Scheme 2). Oxidative rearrangement of 3,4-di-O-acetyl-L-
Scheme 2. Synthesis of Five-Membered α,β-Unsaturated γ-
Lactone 7
rahmnal 6 according to the method reported by Lichtenthaler
8
et al. furnished ene lactone 9 which on hydrolysis of the acetate
group and translactonization with barium hydroxide yielded the
desired α,β-unsaturated γ-lactone 10. The free secondary
hydroxyl group was protected as a TBS ether with tert-
butyldimethyl silyl chloride and imidazole in DMF at room
temperature to yield the five-membered α,β-unsaturated γ-
lactone 7.
Figure 2. ORTEP diagrams of (a) (−)-angiopterlactone B (1), (b)
(
+)-angiopterlactone B (16), (c) compound 18, and (d) compound 20.
The key six membered lactone, fragment 8, was also
synthesized starting from 3,4-di-O-acetyl-L-rhamnal 6 by
9
It is interesting to mention here that compound 7 was
following a reported procedure (Scheme 3).
recovered unreacted from this reaction. This suggested that only
the six-membered lactone 8 provides both the five-membered
and six-membered partners to furnish compound 1. A screen of
Scheme 3. Synthesis of Six-Membered α,β-Unsaturated δ-
Lactone (8)
12
various bases ultimately revealed that TBAF was the best, with
compound 1 being formed in 62% yield (see the SI for full
13
details). Since six-membered lactones are sensitive to bases,
TBAF was selected as a mild base and found to efficiently catalyze
this tandem ring contraction/oxa-Michael/Michael addition
sequence.
Based on the results obtained in Scheme 4 (i.e., recovery of
unreacted compound 7), we propose a biomimetic path-
4b,14−16
way
for the formation of the tricyclic ring system (A/B/
C) of (−)-angiopterlactone B (1) by TBAF that follows a domino
reaction sequence, which has been delineated in Scheme 5. First,
the fluoride ion of TBAF abstracts a proton from the six-
membered lactone 8 leading to ring contraction to form the stable
five-membered α,β-unsaturated γ-lactone 10. Oxa-Michael
addition reaction between lactone 10 and the six-membered
lactone 8 then takes place to furnish intermediate A. The
intermediate A, on intramolecular Michael addition, furnishes
intermediate B which, on protonation, leads to the formation of
(−)-angiopterlactone B (1).
It is pertinent to mention here that our synthesized
angiopterlactone B (1) showed a negative Cotton effect in the
circular dichroism (CD) (see the SI for full details) spectrum with
as optical rotation [α]D25 −24 (c 0.04, EtOAc). However, Zou et
With both fragments in hand (7 and 8), we attempted to
synthesize angiopterlactone A (2) using intermolecular oxa-
Michael addition reaction. When a mixture of compounds 7 and 8
(
(
1.0 equiv each) was treated with NaH (0.5 equiv) in dry THF
Scheme 4), we obtained a single product. However, the product
1
did not show any peaks for the corresponding olefins in the H
NMR spectrum as required for the oxa-Michael addition product.
Instead, (−)-angiopterlactone B (1) was formed as evidenced by
1
1,4,10
the H NMR spectrum,
which was further corroborated by
1
3
C/HSQC and HMBC NMR experiments and HRMS (see the
Supporting Information, SI, for full details). Finally, we proved
B
DOI: 10.1021/acs.orglett.7b01525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Biomimetic Pathway for the Formation
of (−)-Angiopterlactone B (1)
Scheme 6. Synthesis of (−)-Angiopterlactone B (1) and
(+)-Angiopterlactone B (16) with TBAF
Scheme 7. Synthesis of Hitherto Unreported Natural Products
(Diastereomers of Angiopterlactone B)
1
al. reported a negative Cotton effect in the CD spectrum with
2
5
optical rotation [α]D +22 (c 0.04, EtOAc) for the isolated
natural 1. Angiopterlactone B (1) synthesized by us and
Lawrence et al. showed negative optical rotation. Since the
4
b
absolute configurations of natural angiopterlactone B isolated by
1
4b
Zou et al. and synthesized by Lawrence et al. and us were found
to be similar by single-crystal X-ray analysis, we opined that the
ambiguity revolved around its optical rotation only. We also
1
considered the possibility that Zou et al. might have obtained a
levorotatory sign for angiopterlactone B (1) but mistakenly
reported the wrong sign in their publication.
Since the discrepancy in the signs of synthesized angiopter1-
lactone B (1) (levorotatory) was observed with the isolated
angiopterlactone B (1) (dextrorotatory) (Table 1), we decided to
synthesize the other enantiomer of (−)-angiopterlactone B (1) in
order to clear the ambiguity. For this, we utilized 4-epi-
17
(
+)-osmundalactone 15, which is an enantiomer of lactone 8,
tandem reaction can be performed on gram-scale also, as the
synthesis of compound 18 has been accomplished on gram scale.
Compounds 18 and 20 are enantiomers of each other, and their
complete structure was elucidated using NMR spectroscopy and
for the base-catalyzed (TBAF) tandem ring contraction/oxa-
Michael/Michael addition sequence to afford (+)-angiopterlac-
tone B (16) (Scheme 6). The complete structure was elucidated
11
11
by NMR spectroscopy and by single-crystal X-ray analysis
by their single-crystal X-ray analyses (Figure 2c,d). The
(
Figure 2b). Indeed, our supposition was proven correct with
enantiomers, compounds 18 and 20, showed a negative Cotton
(+)-angiopterlactone B (16) showing a positive Cotton effect
effect with optical rotation [α]D25 −106 (c 0.1, acetone) and a
2
5
25
with optical rotation [α]D +33 (c 0.04, EtOAc) (see the SI for
full details). Our synthesis of (+)-angiopterlactone B (16) has
now cleared the ambiguity in the signs of the optical rotation and
proves unequivocally that the natural angiopterlactone B (1)
must be levorotatory (Table 1). The other possible diastereomers
of (−)-angiopterlactone B (1) were synthesized by base-
catalyzed (TBAF) tandem ring contraction/oxa-Michael/
Michael addition reactions on 5,6-dihydropyran-2-one (17)
and (+)-osmundalactone (19)
2
positive Cotton effect with optical rotation [α]D +105 (c 0.7,
acetone), respectively, in the circular dichroism (CD) spectra
(see the SI for full details). Interestingly, diastereomers 18 and 20
are yet to be isolated from natural sources. However, our
synthesis adds to the growing number of instances of natural
product anticipation through biomimetic synthesis.
Various substituted 5,6-dihydropyran-2-ones were synthesized
from tri-O-acetyl-D-glucal (see the SI for full details) in order to
generalize the base-catalyzed tandem ring contraction/oxa-
Michael/Michael addition reactions that furnish tricyclic ring
9
17,18
to furnish compounds 18 and
0, respectively (Scheme 7). This biomimetic base-catalyzed
Table 1. Absolute Configurations, Specific Rotations, and CD Spectra of Natural and Synthetic Angiopterlactone B
absolute configuration
4R,5S,6S,2′R,3′R,4′S,6′S
specific rotation
[α]20 = +22 (c 0.04, EtOAc)
circular dichroism
1
Zou et al. (isolation)
negative Cotton effect
D
4
b
Lawrence et al. (through biomimetic synthesis)
−)-angiopterlactone B
this work (through biomimetic synthesis)
(
4R,5S,6S,2′R,3′R,4′S,6′S
[α]20 = −25 (c 0.04, EtOAc)
D
(
(
−)-angiopterlactone B
+)-angiopterlactone B
4R,5S,6S,2′R,3′R,4′S,6′S
4S,5R,6R,2′S,3′S,4′R,6′R
[α]25 = −24 (c 0.04, EtOAc)
negative Cotton effect
positive Cotton effect
D
[α]25 = +33 (c 0.04, EtOAc)
D
C
DOI: 10.1021/acs.orglett.7b01525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
system (A/B/C) having dual lactones. These substituted 5,6-
dihydropyranones, on reaction with TBAF in dry THF, afforded
the corresponding analogues of angiopterlactone B (1) (Scheme
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: ak.bhattacharya@ncl.res.in.
ORCID
8
). The synthesis of diverse analogues demonstrates the
Scheme 8. Synthesis of Analogues with Substituted
Dihydropyrones
Rajesh G. Gonnade: 0000-0002-2841-0197
Asish K. Bhattacharya: 0000-0002-9162-522X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a Council of Scientific and Industrial
Research (CSIR), New Delhi, sponsored network project
■
(
NaPAHA, CSC0130). T.K.K. is grateful to the University
Grants Commission (UGC), New Delhi, for the award of a
Senior Research Fellowship (SRF).
DEDICATION
■
Dedicated to Prof. Krishna N. Ganesh, IISER-Pune, on the
occasion of his 65th birthday.
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1
5
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3
3
6
6
(16). Diastereomers (18 and 20) of angiopterlactone B (1),
4b
which are hitherto undiscovered natural products, were also
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starting materials to synthesize complex tricyclic ring system in
one step. The fusion of two lactones (A and C) to form the core
tricyclic ring was found to be cis in all of the synthesized
compounds irrespective of the streochemistries of the starting
have also recorded NMR spectra of their synthesized (−)-angiopterlac-
tone B in CD OD. Hence, we have recorded our NMR spectra in
3
CD OD for comparison (see comparison table provided in the
3
Supporting Information).
(11) Crystallographic data (excluding structure factors): CCDC-
1
525957−1525961 contains the supplementary crystallographic data for
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(
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6
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(
́ ́
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(
2
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S
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Experimental procedures and analytical data for all
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D
DOI: 10.1021/acs.orglett.7b01525
Org. Lett. XXXX, XXX, XXX−XXX