Unified total syntheses of (±)-sessilifoliamides B, C, and D

Article abstract of DOI:10.1021/acs.orglett.1c00895

The first total syntheses of the Stemona alkaloids sessilifoliamides B and D and the second synthesis of sessilifoliamide C have been completed from a simple pyrrole substrate. The bicyclic lactam core was prepared on a gram scale via a Br?nsted acid mediated cyclization and controlled oxidation with Dess-Martin periodinane. This delivered sessilifoliamide C (and its C-11 epimer) in 24% yield over 11 steps, and sessilifoliamides B and D in 13 and 17 steps, respectively.

Full text of DOI:10.1021/acs.orglett.1c00895

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Unified Total Syntheses of ( )-Sessilifoliamides B, C, and D
Wesley J. Olivier, Alex C. Bissember,* and Jason A. Smith*
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ABSTRACT: The first total syntheses of the Stemona alkaloids sessilifoliamides
B and D and the second synthesis of sessilifoliamide C have been completed
from a simple pyrrole substrate. The bicyclic lactam core was prepared on a gram
scale via a Brønsted acid mediated cyclization and controlled oxidation with
Dess−Martin periodinane. This delivered sessilifoliamide C (and its C-11
epimer) in 24% yield over 11 steps, and sessilifoliamides B and D in 13 and 17
steps, respectively.
he sessilifoliamide natural products are a class of
Tpolycyclic, lactam-containing alkaloids isolated from
Stemona sessilifolia and other plant species belonging to the
genus Stemona.1−6 Sessilifoliamides A−D (1−4) were first
isolated in 2003 and were the first sessilifoliamide-type
alkaloids discovered (Figure 1).1 These natural products are
structurally related by a common pyrrolo[1,2-a]azepine core.
Sessilifoliamides B−D each possess unique C-9 side chains;
however, sessilifoliamide A features a fused spirocyclic acetal.
While related Stemona alkaloids such as stenine (5) and
stemoamide (6) have garnered considerable attention as
targets for total synthesis,7,8 conspicuously few approaches to
sessilifoliamides A−D have been reported. To date, two total
syntheses of sessilifoliamide A and one total synthesis of
sessilifoliamide C have been published.8c,9,10 Sessilifoliamides
B and D have not yet succumbed to synthesis. Bioactivity
studies are yet to be conducted on sessilifoliamides B−D, and
thus, accessing these alkaloids synthetically would enable the
biological activity of these natural products to be compre-
hensively evaluated for the first time.
Wipf and Hoye’s pioneering total synthesis of enantioen-
riched (−)-sessilifoliamide C (3) realized the target in 18 steps
and commenced from chiral glutamic acid derivative 9 (Figure
2A).10 The construction of the azepine ring was achieved via
ring-closing metathesis (RCM) of a 4-pentenyl-5-vinylpyrroli-
dinone. Further elaboration of this intermediate, including a
key Ireland−Claisen rearrangement of a silyl ketene acetal,
provided bicyclic lactams 10 as a mixture of diastereomers in
14 steps from pyrrolidinone 9. Ester 10a was then efficiently
converted to sessilifoliamide C in four steps, which involved a
second RCM reaction to construct the lactone ring.
Pyrroles featuring pendant electrophilic moieties are known
to participate in intramolecular cyclizations to afford bicyclic
heterocycles such as 5,6,7,8-tetrahydroindolizines and pyrrolo-
[1,2-a]azepines.8c,11,12 This includes annulations via intra-
Received: March 16, 2021
Published: April 13, 2021
Figure 1. Examples of representative Stemona alkaloids.
https://doi.org/10.1021/acs.orglett.1c00895
© 2021 American Chemical Society
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alkaloids can be effected (Figure 1). Despite the considerable
interest this family of natural products has attracted as
synthetic targets,7,8 to our knowledge, only a handful of total
syntheses of Stemona alkaloids have employed pyrrolic
compounds as starting materials or key intermediates.8c,14
From our experience using conjugate addition chemistry to
form bicyclic pyrroles,15 we reasoned that substrate 11 could
facilitate expeditious total syntheses of sessilifoliamides B−D
by an original approach (Figure 2B).16 More specifically, this
derived from our findings that pyrrolo[1,2-a]azepine archi-
tecture can be efficiently constructed via the Brønsted acid
mediated intramolecular annulation of pyrrolic α,β-unsaturated
esters.15c Furthermore, we anticipated that γ-lactam ( )-12a
could be accessed by deploying Dess−Martin periodinane
(DMP) for the controlled oxidation of an appropriate bicyclic
pyrrole precursor using our established methodology.17
In this report, we confirm the viability of our above-
mentioned strategy which enabled the gram-scale synthesis of
the bicyclic core of sessilifoliamides B−D {( )-12} and
culminated in total syntheses of ( )-sessilifoliamides B−D.
Our synthesis commenced with the one-pot reduction of
ester 11 with DIBAL-H, followed by Wadsworth−Emmons
olefination of the ensuing aldehyde with triethyl phosphonoa-
cetate (Scheme 1). This provided α,β-unsaturated esters 13 in
74% yield. The Brønsted acid mediated cyclization of
substrates 13 was facilitated by methanesulfonic acid and
furnished pyrroloazepine 14 in 80% yield.15c,18 The lithium
enolate of ester 14 was then treated with ethyl iodide to
provide C-alkylated product 15. Pleasingly, oxidation of
pyrrole 15 with DMP,17 followed by the elimination of
ensuing ester 16 with BF3·OEt2, provided lactam 17 very
efficiently (94% yield; 20-mg scale). This reaction was
Figure 2. Overview of the successful total syntheses of sessilifolia-
mides B−D (2−4).
molecular Friedel−Crafts-type acylations and alkylations,
oxidative arylations, conjugate additions, and palladium-
catalyzed couplings.11 Pyrrole rings are also amenable to
both reduction and (controlled) oxidation which provides
access to pyrrolidines and γ-lactams, respectively.13 These
properties should enable pyrroles to serve as attractive
substrates from which total syntheses of polycyclic Stemona
a
Scheme 1. Total Synthesis of ( )-Sessilifoliamide C (3) from Pyrrole 11
a
TEPA = triethylphosphonoacetate, MAA = methacryclic acid.
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Scheme 2. Total Syntheses of ( )-Sessilifoliamides B (2) and D (4) from Key Synthetic Intermediate ( )-20
successfully scaled-up, and in this way, we prepared lactam 17
from pyrrole 15 in 81% yield over 2 steps on a gram scale,
which illustrates the scalability of this DMP-controlled
oxidation.18,19 This method compares favorably to m-CPBA
oxidations of polycyclic pyrroles to unsaturated γ-lactams
employed in total syntheses of ( )-stemoamide (6) and
sessilifoliamide A (1).8c,20
sessilifoliamide B, rather than natural product 2,1 we opted to
synthesize sessilifoliamide B via a late-stage stereoselective
methylation of the lactone ring. To this end, vinyl alcohols 20
were treated with acryloyl chloride to furnish acrylate esters 23
(Scheme 2). The RCM and hydrogenation steps proceeded
efficiently to provide lactones 25 which were partially separable
by flash chromatography. α-Methylation of lactone 25a was
completed in 75% yield, thereby furnishing sessilifoliamide B
(2). The NMR spectroscopic data obtained for compound 2
were consistent with equivalent data for the isolated natural
product (see Supporting Information).1
In planning our approach to sessilifoliamide D (4) we
wondered whether the target could be accessed via the
nucleophilic opening (transesterification) of sessilifoliamide B
(2) by methanol/methoxide followed by oxidation of the
resulting hydroxy ester. To this end, we explored the viability
of various conditions on model lactone A. We found that
treatment with methoxide resulted in C-2 epimerization to
afford B, rather than nucleophilic acyl substitution (Table 1,
entry 1). Treatment of lactone A with catalytic DCl in
methanol-d4 (generated in situ from SOCl2) did not yield the
The palladium-catalyzed hydrogenation of diene 17
proceeded smoothly to furnish diastereomers 12 (5.7:1
ratio) quantitatively. By this approach, we successfully
obtained bicyclic-lactams ( )-12 on a gram scale in 41%
yield over 6 steps. Having reached key intermediate 12a, the
ethyl ester analogue of lactam 10a reported by Wipf and
Hoye,10 we based our end-game approach to sessilifoliamide C
on their efficient route. Specifically, esters 12 were reduced to
alcohols 18 with LiBH4. Wipf and Hoye employed LiBH4 (10
equiv) in THF over a two-day reaction time to achieve this.
We observed that the reduction of esters 12 also proceeded
very slowly under these conditions. However, by using LiBH4
(5 equiv) in an Et2O/methanol solvent mixture with mild
heating (35 °C) over 4.5 h, chromatographically separable
diastereomers 18 were obtained in 77% combined yield. The
Swern oxidation of alcohol 18a, followed by nucleophilic
addition of vinylmagnesium bromide to ensuing aldehyde 19,
furnished vinyl alcohols 20 quantitatively over two steps. These
substrates were then treated with methacryloyl chloride to give
chromatographically inseparable methacrylate esters 21.
Finally, an RCM promoted by the Grubbs second generation
catalyst furnished sessilifoliamide C (3) and its C-11 epimer
(22) in excellent yield. We obtained sessilifoliamide C and its
C-11 epimer in 24% yield from pyrrole 11 by this route. The
NMR spectroscopic data obtained for sessilifoliamide C were
consistent with equivalent data for the isolated natural product
(see Supporting Information).1
Table 1. Attempted Transesterification of Model Lactone A
a
entry
reaction conditions
outcome
b
1
NaOMe, MeOH, rt, 48 h
1:2 A/B
2
3
4
5
SOCl2, CD3OD, 40 °C, 24 h
DMAP, CD3OD, 40 °C, 24 h
DMAP, CD3OD, 65 °C, 24 h
H2SO4, CD3OD, 65 °C, 24 h
A + C
no reaction
no reaction
no reaction
After completing the synthesis of sessilifoliamide C (3) we
turned our attention to preparing sessilifoliamide B (2).
Because the palladium-catalyzed hydrogenation of sessilifolia-
mide C was shown to selectively deliver the C-13 epimer of
a
b
Reaction monitoring by 1H NMR spectroscopy. Reaction was
monitored by TLC and analyzed by 1H NMR spectroscopy after
aqueous workup.
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Author
desired hydroxy ester (entry 2). Instead, partial conversion to
chloride C occurred. Attempts to effect DMAP and sulfuric
acid catalyzed transesterifications (entries 3−5) also proved
unsuccessful. Although these observations suggested that the
transesterification of sessilifoliamide B (2) was not likely to
deliver target 4, we reacted substrate 2 with K2CO3 in
methanol. This resulted in the epimerization at C-13 and the
desired hydroxy-ester was not formed, which was consistent
with our expectations following experiments using model
system A.
Wesley J. Olivier − School of Natural Sciences − Chemistry,
University of Tasmania, Hobart, Tasmania 7001, Australia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00895
Notes
The authors declare no competing financial interest.
Our above-mentioned observations dictated that the route
to sessilifoliamide D (4) should proceed via 1,4-diol 26, which
could be accessed by the reduction of sessilifoliamide B (2)
(Scheme 2). The reaction of lactone 2 with LiBH4 proceeded
smoothly to afford 1,4-diol 26; however, the Swern oxidation
of substrate 26 to ketoaldehyde 27 was inefficient.21 This may
have derived from the small reaction scale (9 mg of 26).
Nevertheless, the subsequent Pinnick oxidation of ketoalde-
hyde 27 and O-methylation of keto acid 26 with iodomethane
proceeded without complication to furnish sessilifoliamide D
(4) in 18% yield over 4 steps from sessilifoliamide B (2). The
NMR spectroscopic data obtained for compound 4 were
consistent with equivalent data for the isolated natural product
(see Supporting Information).1
In summary, we have successfully completed the second
total synthesis of sessilifoliamide C (3), and the first total
syntheses of sessilifoliamides B (2) and D (4) via common
intermediate 20 accessed from an inexpensive pyrrole
substrate. Key bicyclic lactam core structure ( )-12 was
obtained on a gram scale via a Brønsted acid mediated
intramolecular conjugate addition and the controlled oxidation
of pyrrole 15 with DMP. Both of these lynchpins were high-
yielding (≥80%). Sessilifoliamide C along with C-11 epimer
was obtained in 24% yield over 11 steps while sessilifoliamides
B and D were synthesized in 13 and 17 steps, respectively.
Although the natural products that formed the basis of this
study were prepared racemically, we anticipate that our
approach could be modified to achieve enantioselective
syntheses, for example, by employing the Evans oxazolidinone
to facilitate the stereoselective ethylation of pyrrole 14, or
using this chiral auxiliary to facilitate the diastereoselective
epimerization of lactam 17.22
ACKNOWLEDGMENTS
■
The authors thank the University of Tasmania School of
Natural Sciences − Chemistry for funding and the University
of Tasmania Central Science Laboratory for providing access
to NMR spectroscopy services. W.J.O. thanks the Australian
Government for a Research Training Program Scholarship.
REFERENCES
■
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00895.
Additional experimental information and compound
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Alex C. Bissember − School of Natural Sciences − Chemistry,
University of Tasmania, Hobart, Tasmania 7001, Australia;
orcid.org/0000-0001-5515-2878;
Email: alex.bissember@utas.edu.au
(9) Hou, Y.; Shi, T.; Yang, Y.; Fan, X.; Chen, J.; Cao, F.; Wang, Z.
Asymmetric total syntheses and biological studies of tuberostemoa-
mide and sessilifoliamide A. Org. Lett. 2019, 21, 2952−2956.
(10) Hoye, A.; Wipf, P. Total synthesis of (−)-sessilifoliamide C and
(−)-8-epi-stemoamide. Org. Lett. 2011, 13, 2634−2637.
Jason A. Smith − School of Natural Sciences − Chemistry,
University of Tasmania, Hobart, Tasmania 7001, Australia;
orcid.org/0000-0001-6313-3298; Email: jason.smith@
utas.edu.au
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has been deployed in a total synthesis of a natural product.
(20) In ref 8c, the authors noted that low yields were obtained if
commercially available m-CPBA was used as received. Lactam yields
were improved (40−65%) by employing purified m-CPBA at −35 °C
in DCE on <50 mg scales.
(21) Before embarking on the synthesis of target 4, we screened a
range of oxidation conditions using a 1,4-diol model substrate (see
Supporting Information). The two-step Swern and Pinnick oxidation
route was informed by the results of these studies.
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