Unified total syntheses of structurally diverse akuammiline alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b02698

The unified total syntheses of structurally diverse akuammiline alkaloids deformylcorymine (1), strictamine (2), and calophyline A (3) are reported. The strategy mimics the biosynthesis in nature at a strategic level, which allows for structural diversification from a common synthetic precursor by late-stage ring migrations.

Full text of DOI:10.1021/acs.orglett.7b02698

Letter
pubs.acs.org/OrgLett
Unified Total Syntheses of Structurally Diverse Akuammiline
Alkaloids
Xiaoni Xie, Bei Wei, Guang Li, and Liansuo Zu*
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Tsinghua University, Beijing 100084, China
*
S Supporting Information
ABSTRACT: The unified total syntheses of structurally diverse akuammiline alkaloids deformylcorymine (1), strictamine (2),
and calophyline A (3) are reported. The strategy mimics the biosynthesis in nature at a strategic level, which allows for structural
diversification from a common synthetic precursor by late-stage ring migrations.
he akuammiline natural products are a family of
structurally intricate and bioactive monoterpene indole
Structurally, according to the ring connectivity around N4,
these natural products can be divided into three subclasses with
N4−C2, N4−C3, and N4−C14 linkages (Figure 1). These N−
C linkages along with varied oxidation states result in different
polycyclic ring systems of the akuammiline natural products.
Owing substantially to the efforts of leading chemists in this
area, several members of this alkaloid family have been
successfully synthesized, highlighting the power of a variety of
T
alkaloids that have become a popular research area in recent
1
years (Figure 1). The fascinating structural features of these
natural products, including their rigid and cagelike framework,
the bridged polycyclic ring system, and multiple stereogenic
centers, have presented significant challenges to chemical
synthesis and attracted the attention of synthetic chemists for
2
novel bond-forming strategies. While synthetic chemists
1
many years.
typically build individual linkages around N4, leading to the
total synthesis of natural products with “single connectivity”,
biosynthesis in nature provides an appealing alternative
involving structural diversification from a common biogenetic
precursor. In the context of akuammiline alkaloid biosynthesis,
nature generates all of the ring connectivities (N4−C2, N4−
1d,3
C3, and N4−C14) from rhazimal (Figure 1).
For example,
direct deformylation of rhazimal leads to strictamine (2) with a
N4−C3 linkage; the N4 migrations from C3 to C2 and C14 in
rhazimal generate the polycyclic ring system of deformylcor-
ymine (1) and calophyline A (3), respectively. The beauty of
such an approach endorsed by nature is remarkable. Inspired by
the brevity of nature’s way of making this class of natural
products, we envisioned that an advanced intermediate 4 could
serve as a potential common synthetic precursor to several
structurally diverse akuammiline alkaloids if the selective
migrations of N4 from C14 to C2 and C3 could be realized
(
Figure 1). While this concept features totally different modes
of ring migrations compared to nature’s biosynthesis, it
mimicks the biosynthesis at the strategic level, namely,
structural diversification from a common precursor by late-
stage ring migrations. Herein, we report the unified total
Figure 1. Representative akuammiline alkaloids: biogenetic precursor
and proposed synthetic precursor.
Received: August 30, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
syntheses of three structurally diverse akuammiline alkaloids
deformylcorymine (1), strictamine (2), and calophyline A (3).
We chose three akuammiline alkaloids (1−3) with different
ring connectivities (N4−C2, N4−C3, and N4−C14) as our
targets to demonstrate our strategy via bioinspired ring
migrations. Our retrosynthetic analysis of natural alkaloids 1−
Scheme 2. Synthesis of the Common Synthetic Precursor 4
3
is depicted in Scheme 1. We envisioned accessing calophyline
Scheme 1. Retrosynthetic Analysis of Akuammiline Alkaloids
−3
1
carbonylation reaction for the introduction of the signature
C16 methyl ester in akuammiline alkaloid total synthesis. The
common synthetic precursor 4 was then successfully prepared
from 7 by deprotection of the methyl carbamate and two site
oxidations using iodosobenzene and manganese oxide.
Calophylina A (3) was isolated by Li, Zou, and co-workers in
6
2
012. This is the only member of the alkaloid family that
contains a unique N4−C14 linkage and an inner salt, which
resulted in a distinct polycyclic ring system associated with this
member of the family. Our group reported the first, and so far
4
only, total synthesis of this natural product in 2016. We
envisioned that the identification and utilization of 4 as the key
intermediate would minimize several unnecessary functional
group transformations in our previous synthetic route and thus
realize an improved total synthesis of this challenging natural
product.
Structurally, calophyline A (3) has the same ring connectivity
as that of 4 (N4−C14, Scheme 3). The remaining task was to
A (3) from 4 by a late-stage aldol-cyclization reaction with
formaldehyde. Deformylcorymine (1) and strictamine (2)
could be furnished from 5 and 6, respectively, which in turn
could be generated from 4 by the selective ring migrations of
N4 from C14 to C2 and C3. The common synthetic precursor
Scheme 3. Total Synthesis of Calophyline A (3)
4
could be prepared by the oxidation-state adjustment of 7,
which could be assembled from 8 by a highly efficient nickel-
mediated tandem Heck-carbonylation reaction. Finally, the
synthesis of 8 could be traced back to 9, which we previously
4
utilized for the first total synthesis of calophyline A.
Our synthetic studies commenced with the preparation of
the common synthetic precursor 4 (Scheme 2). From 9, vinyl
triflate formation followed by palladium-catalyzed reduction
furnished alkene 10, which was further attached to the vinyl
iodide side chain to generate intermediate 8. At this stage, one
of the key reactions in our synthesis would be the direct
construction of the fused five-membered ring and installation of
the required methyl ester in 7 by a tandem Heck-carbonylation
reaction. Our initial attempts using palladium-based catalysts
for this reaction proved fruitless under a variety of conditions.
To our delight, the transformation of 8 to 7 could be achieved
by the nickel-promoted Heck-carbonylation reaction developed
by the group of Delgado. After further optimization of the
reported reaction conditions, we were able to synthesize the
polycycle 7 in 83% yield using MeCN/DMF (2:1) as the mixed
solvents. This highly efficient process enabled the simultaneous
generation of both the fused five-membered ring and a methyl
ester at C16 without the prefunctionalization of alkene 8. To
our knowledge, this is the first utilization of a tandem Heck-
build the neopentyl quaternary stereocenter C16 and an
additional oxygen-containing bridged [3.2.1] bicycle. Appa-
rently, both could be achieved by a late stage aldol reaction with
formaldehyde. However, the late stage decoration of C16 has
been very challenging in akuammiline alkaloid synthesis due to
the extremely congested architecture. Not surprisingly, the
reaction of 4 with formaldehyde under a variety of conditions
using different bases was unsuccessful. Gratifyingly, by using
NaH as the base and DMF as the solvent, the formation of 11
was achieved in 34% yield involving A as the intermediate.
5a
B
DOI: 10.1021/acs.orglett.7b02698
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Organic Letters
Letter
Finally, inner salt generation involving N-methylation and
saponification delivered natural product calophyline A (3).
the only epimer in 70% yield over two steps. Our synthesis
represents the first total synthesis of this natural alkaloid.
7
11
Deformylcorymine (1) is structurally similar to vincorine
Strictamine (2) was first isolated in 1966 and had been a
12
(
Figure 1) with an additional hydroxyl group at C3. While the
long-standing synthetic target for many years. The first total
8
total synthesis of vincorine has been elegantly accomplished by
the groups of Qin, Ma, and MacMillan, the site-specific and
stereoselective introduction of a hydroxyl group at C3 has been
challenging. Most recently, the group of Li and Sun reported
the creative total synthesis of another structurally related
natural product corymine (Figure 1) in 21 steps from readily
synthesis of strictamine was achieved by the groups of Garg and
12a,b
Zhu independently in 2016.
Later, the groups of Fujii and
Ohno, Gaich, and Snyder reported the formal total synthesis of
12c−f
this strained natural alkaloid.
Except for Garg’s synthesis,
all the other synthetic routes relied on a reductive Heck
cyclization developed by Zhu to build the bridged 6-membered
ring D (Scheme 5). However, the high strain associated with
9
available starting materials.
After the construction of the common synthetic precursor 4
and total synthesis of calophyline A (3), we next examined the
selective ring migration of 4 (N4 from C14 to C2) to furnish
the ring connectivity shown in deformylcorymine (1) (Scheme
Scheme 5. Total Synthesis of Strictamine (2)
4). We envisioned that this type of ring migration could be
Scheme 4. Total Synthesis of Deformylcorymine (1) and the
C3-Epimer of Demethyldeformylcorymine
the cagelike architecture of strictamine rendered the process
12b
very challenging (about 10% yield). We envisioned that our
strategy could address this problem by first making the fused
ring E in 4, which was then migrated to form the bridged ring
D in strictamine.
Then we turned to the construction of the ring connectivity
of strictamine (2) by the ring migration of 4 (N4 from C14 to
C3, Scheme 5). Our hypothesis was that 4 could be first
reduced to 5 (Scheme 4) followed by the further reduction by
achieved by the reductive cleavage of the N4−C14 bond
followed by the subsequent N-cyclization to C2. For that
purpose, we were inspired by the ability of SmI in reducing α-
2
10
amino carbonyls under mild reaction conditions. Indeed, the
ring migration of 4 to 5 proceeded smoothly in the presence of
SmI to form anionic intermediate F, which would facilitate the
subsequent reductive cleavage of the N4−C2 bond and N-
cyclization to C3 to furnish hemiketal 6. Thus, we carried out
2
SmI in 59% yield along with the 23% recovery of starting
2
material 4. Thus, the core architecture of deformylcorymine
was successfully assembled by the skeletal rearrangement of 4
involving N4 migration from C14 to C2. Mechanistically, 4 was
presumably first reduced via single-electron transfer to form
the reaction in the presence of large amounts of SmI (15.0
2
equiv); the direct transformation of 4 to 6 occurred smoothly
in 68% yield. Thus, the successful ring migration of N4 from
C14 to C3 built up the architecture of strictamine. Finally,
reduction of the hemiketal by triethylsilane followed by the
oxidation by iodosobenzene produced natural product strict-
amine (2).
In summary, we have developed a unified strategy to
structurally diverse akuammiline alkaloids by bioinspired ring
migrations. The common synthetic precursor 4 served as a
springboard to different ring connectivities of this class of
natural products. Our approach strategically mimics biosyn-
thesis in nature, which allows for structure diversification from a
common precursor and the unified total synthesis of
deformylcorymine (1), strictamine (2), and calophyline A (3).
ketyl radical B, which was further reduced by SmI to furnish
2
anionic intermediate C. Subsequent N4−C14 bond cleavage by
elimination followed by N-cyclization to C2 facilitated the
observed ring migration. Next, direct reduction of the ketone
group in 5 with NaBH4 delivered 12, the C3-epimer of
demethyldeformylcorymine. Attempts to reverse the diaster-
eoselectivity of the reduction by using bulkier L-Selectride were
unsuccessful. The dominant diastereoselectivity was presum-
ably due to the directive reduction by the NH group or subtle
steric effect. To our delight, methylation of 5 via reductive
amination followed by the reduction of the ketone with L-
Selectride furnished natural product defromylcorymine (1) as
C
DOI: 10.1021/acs.orglett.7b02698
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Organic Letters
Letter
Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126−9129. (c) Horning,
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
9) Zhang, B.; Wang, X.; Cheng, C.; Sun, D.; Li, C. Angew. Chem., Int.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02698.
Ed. 2017, 56, 7484−7487.
(10) For a review, see: Honda, T. Heterocycles 2011, 83, 1.
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Detailed experimental procedures, characterization data,
(
1
13
and H and C spectra of all products (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
1
(
817.
12) For chemical synthesis of strictamine, see: (a) Moreno, J.;
Picazo, E.; Morrill, L. A.; Smith, J. M.; Garg, N. K. J. Am. Chem. Soc.
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*E-mail: zuliansuo@biomed.tsinghua.edu.cn.
2
ORCID
Int. Ed. 2016, 55, 3500−3503. (c) Nishiyama, D.; Ohara, A.; Chiba,
H.; Kumagai, H.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2016, 18,
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Liansuo Zu: 0000-0001-7747-2979
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (21672123) for financial support.
■
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DOI: 10.1021/acs.orglett.7b02698
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