Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine

Article abstract of DOI:10.1021/jacs.1c01865

Here, we report the first asymmetric total synthesis of (+)-talassimidine and (+)-talassamine, two hetidine-type C20-diterpenoid alkaloids. A highly regio- and diastereoselective 1,3-dipolar cycloaddition of an azomethine ylide yielded a chiral tetracyclic intermediate in high enantiopurity, thus providing the structural basis for asymmetric assembly of the hexacyclic hetidine skeleton. In this key step, the introduction of a single chiral center induces four new continuous chiral centers. Another key transformation is the dearomative cyclopropanation of the benzene ring and subsequent SN2-like ring opening of the resultant cyclopropane ring with water as a nucleophile, which not only establishes the B ring but also precisely installs the difficult-to-achieve equatorial C7-OH group.

Full text of DOI:10.1021/jacs.1c01865

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Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid
Alkaloids: (+)-Talassimidine and (+)-Talassamine
Quanzheng Zhang,† Zhao Yang,† Qi Wang, Shuangwei Liu, Tao Zhou, Yankun Zhao, and Min Zhang*
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ABSTRACT: Here, we report the first asymmetric total synthesis
of (+)-talassimidine and (+)-talassamine, two hetidine-type C20-
diterpenoid alkaloids. A highly regio- and diastereoselective 1,3-
dipolar cycloaddition of an azomethine ylide yielded a chiral
tetracyclic intermediate in high enantiopurity, thus providing the
structural basis for asymmetric assembly of the hexacyclic hetidine
skeleton. In this key step, the introduction of a single chiral center
induces four new continuous chiral centers. Another key transformation is the dearomative cyclopropanation of the benzene ring and
subsequent SN2-like ring opening of the resultant cyclopropane ring with water as a nucleophile, which not only establishes the B
ring but also precisely installs the difficult-to-achieve equatorial C7−OH group.
Scheme 1. Background and Study Synopsis
INTRODUCTION
■
The C20-diterpenoid alkaloids constitute a large family of
natural products, which are mainly isolated from the Aconitum,
Consolidum, Delphinium, and Spiraea genera of plants that have
a history of use in traditional medicine.1 Architecturally, the
C20-diterpenoid alkaloids can be classified into several subtypes
(selected subtypes and representative hetidine-type members
are shown in Scheme 1A). Of the biosynthetically related
atisine-, hetidine-, and hetisine-type C20-diterpenoid alkaloids,
the hexacyclic hetidine core has a characteristic C14−C20
linkage; besides the C14−C20 linkage, the hetisine core has an
additional C6−N linkage, forming a complex heptacyclic
framework. The unique biological profiles and structural
complexity of C20-diterpenoid alkaloids render them highly
sought-after synthetic targets.2−10 Successful total syntheses of
hetisine-type alkaloids have been reported by the groups of
Muratake/Natsume, Gin, and Sarpong, as well as our group,4
reflecting considerable achievements toward total synthesis of
various C20-diterpenoid alkaloids in recent years.3−8 However,
there has been limited success in the synthesis of the seemingly
less complex hetidine-type alkaloids, despite considerable
efforts having been made toward this subtype.6,7 Guided by
network analysis, Sarpong’s group accomplished a unified total
synthesis of C18-, C19-, and C20-diterpenoid alkaloids2h,5c,8b,9e
and developed an elegant approach of Ga-catalyzed cyclo-
isomerization to synthesize dihydronavirine, a structurally very
similar analogue of navirine.6a,b Baran’s group applied a two-
phase synthetic strategy to synthesize the atisine alkaloids and
construct the hetidine skeleton from a readily available ent-
kaurane.3i Qin and Liu developed an efficient biomimetic
approach to access the denudatine- and atisine-type alkaloids
and the hetidine skeleton from an atisine-type precursor.3k Ma,
Liu, and colleagues used a hydrogen atom transfer-based
radical cyclization as the key step to build the hetidine scaffold
Received: February 17, 2021
Published: May 3, 2021
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and accomplished an efficient synthesis of the proposed
structure of navirine C.3l Recently, Li and co-workers reported
an elegant synthesis of septedine (2) and 7-deoxyseptedine
(3), which represents the first and only route to hetidine-type
C20-diterpenoid alkaloids reported to date (Scheme 1B).7 Key
steps of this synthesis included a Carreira polyene cyclization
to construct the core framework and a Sanford Csp3−H
functionalization to install the equatorial C7−OH.
The limited success in the synthesis of hetidine-type
alkaloids can be attributed to the synthetic challenge associated
with the rigid hexacyclic cage-shaped skeleton and more
problematically, the different oxygen substitutions at various
positions of the core frameworks.2,6,7 To develop new synthetic
strategies to access diterpenoid alkaloids with complex oxygen
substitution patterns, we embarked on a synthetic program
toward the synthesis of talassimidine (4) and talassamine (5),
two hetidine-type alkaloids initially isolated from Aconitum
talassicum M. Pop. by Nishanov11a and then reisolated from
Delphinium campylocentrum Maxim. by Wang11b (Scheme 1A).
We report here the first asymmetric total synthesis of
(+)-talassimidine and (+)-talassamine through 1,3-dipolar
cycloaddition and cyclopropanation/ring opening as the key
transformations to build the polycyclic hetidine scaffold and to
install the oxygen functionalities (Scheme 1C).
tetracycle ( )-14 in good yield with a regioselectivity opposite
to the intrinsic selectivity observed in the intermolecular
reactions. In this key reaction, four continuous chiral carbon
centers at C6, C5, C10, and C20 were established in a single
step (in addition to the retained C14 chiral center). With
( )-14 as the key intermediate, the E ring was constructed by
an intramolecular alkylation. Thereafter, a SmI2-mediated free
radical addition to the arene moiety without prior dearoma-
tization was used as the second key reaction to build the B ring
(17 to 18). Last, a diastereoselective aldol reaction constructed
the remaining D ring of the hetisine core (19 to 20). Finally,
installation of requisite functionalities furnished ( )-spirasine
IV (21) and ( )-spirasine XI (22) in 0.88 and 0.73% total
yields from 10 over 22 and 23 total steps, respectively. From a
biogenetic perspective, the hetidine scaffold generates a
hetisine core via formation of a C6−N bond. Retrosyntheti-
cally, breakage of the C6−N bond of the hetisine scaffold
would lead to a hetidine core. On basis of these analyses, we
envisioned that using tetracycle 14 as the foundational
intermediate and breaking the C6−N bond at an appropriate
stage would provide a new strategy to access hetidine-type
alkaloids. Additionally, if tetracycle 14 could be prepared in
high enantiopurity, asymmetric synthesis of both hetisine- and
hetidine-type alkaloids could be achieved.
Retrosynthetic Analysis. Our retrosynthetic analysis of
hetidine-type alkaloids (+)-talassimidine (4) and (+)-talass-
amine (5) is illustrated in Scheme 3. Disassembly of the
RESULTS AND DISCUSSION
■
In 2018, our group realized the first racemic total synthesis of
hetisine-type alkaloids spirasine IV (21) and XI (22) (Scheme
2).4d Key reactions of the synthesis involve a diastereoselective
Scheme 3. Retrosynthetic Analysis of (+)-Talassimidine and
(+)-Talassamine
Scheme 2. Our Previous Synthesis of the Hetisine-Type C20-
Diterpenoid Alkaloids ( )-Spirasine IV and XI
bicyclo[2.2.2]octane motif in talassimidine and talassamine led
back to 23. Instead of the commonly used Diels−Alder
cycloaddition strategy,2 formation of the C12−C13 bond of 23
would give the bicyclo[2.2.2]octane motif and establish the
hetidine core. Inspired by our previous success in constructing
the B ring of hetisine through a dearomative free radical
addition, we posited that addition of a ketyl radical to the arene
moiety would yield the B ring and concurrently install a
hydroxyl group. The ketyl radical precursor could be formed
by single-electron reduction of an aldehyde, which can be
traced back to tetracyclic ester 25.12,14 Through the use of
tetracyclic 14 as the key intermediate, 25 can be obtained by a
sequence of C6−N cleavage and C19−N formation. The
fundamental step for our proposed scheme is the asymmetric
synthesis of 14. If chiral erosion of the potentially
intramolecular 1,3-dipolar cycloaddition of azomethine ylide to
access the tetracycle ( )-14 with linkages of C14−C20 and
C6−N and a SmI2-mediated, dearomative free radical addition
to the arene moiety to construct the B ring. Highly enolizable
aldehyde 8 was prepared in a racemic form via a modular
coupling of two simple building blocks, 11 and 12, with known
compound 10 as the starting material. Condensation of
aldehyde ( )-8 with the phosphinimine Ph3PCH2CO2Me
and subsequent treatment with AgOAc and DBU provided
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a
Scheme 4. Asymmetric Total Synthesis of (+)-Talassimidine and (+)-Talassamine
a
Reagents and conditions: (a) SOCl2, DMF, CH2Cl2, 0 °C to room temperature (rt), 4 h, then (S)-4-benzyl-2-oxazolidinone, nBuLi, THF, −78 °C,
1 h, 74%; (b) TiCl4, DIPEA, (HCHO)3, 0 to −20 °C, 1 h, 72%; (c) TIPSOTf, 2,6-lutidine, 0 °C to rt, 2 h, 83%, >20/1 dr; (d) NaBH4, MeOH/
THF, 0 °C to rt, 3 h, 73%; (e) nBuLi, nBu3SnCl, THF, −78 °C, 30 min, 65%; (f) 12, Pd(PPh3)4, CuBr, dioxane, 85 °C, 12 h, 77%; (g) TEMPO,
KBr, aqueous NaClO, NaHCO3, CH2Cl2/H2O, 0 °C to rt, 3 min, then NH2CH2COOMe·HCl, Et3N, MgSO4, CH2Cl2, 1 h, then AgOAc, DBU,
toluene, rt, 1 h, 60% (gram-scale yield), 6/1 dr; (h) BnBr, K2CO3, CH3CN, 80 °C, 5 h, 99%; (i) Ph3PCH2OMe·Cl, nBuLi, THF, −78 to 0 °C, 2 h,
t
96%; (j) SmI2, HMPA, HCl, MeOH/THF, 0 °C, 6 h, 87%; (k) TiCl4, H2O, CH2Cl2, 0 °C, 1 h, then MeI, BuONa, THF, 0 °C to rt, 10 h, 78%,
>20/1 dr; (l) NaBH4, MeOH, 0 °C, 30 min, then MsCl, Et3N, CH2Cl2, 0 °C to rt, 30 min, 73%; (m) NaOMe, MeOH, 90 °C (microwave), 2 h,
98%; (n) I2, NaHCO3, THF/H2O, rt, 1 h, then DIBAL-H, CH2Cl2, −78 °C, 10 min, 87%; (o) TsNHNH2, THF, rt, 1 h, then Rh2(Oct)4, K2CO3,
dioxane, 130 °C, 1.5 h, 85%; (p) DIBAL-H, toluene, 0 °C to rt, 2 h, 75%; (q) HBF4, THF/H2O, 60 °C, 1 h, 61%; (r) Ac2O, DMAP, Et3N, CH2Cl2,
rt, 90%, >20/1 dr; (s) H2, Pd(OH)2, MeOH, rt, 8 h, then Boc2O, Et3N, CH2Cl2, reflux, 24 h, 80%; (t) HF, H2O/THF, rt, 4 h, then Dess−Martin
periodinane, CH2Cl2, rt, 1 h, 95%; (u) pyrrolidine, AcOH, CH2Cl2, rt, 5 h, then MsCl, DMAP, Et3N, CH2Cl2, 0 °C to rt, 30 min, 90%; (v) KOH,
THF/H2O, 80 °C, 8 h, then Tebbe reagent, THF, rt, 2 h, 80%; (w) Li, liquid NH3, tBuOH, THF, −78 °C, 2 h, 83%; (x) SeO2, tBuOOH, CH2Cl2,
0 °C to rt, 30 min, 93%, >20/1 dr; (y) ZnBr2, CH2Cl2, rt, 3 h, then MnO2, CH2Cl2, rt, 4 h, 74% for 15-epi-talassamine (62), 62% for talassimidine
(4), 64% for talassamine (5); (z) SeO2, dioxane, 80 °C, 6 h, 71%; (aa) NaBH4, CeCl3·7H2O, MeOH, 0 °C, 30 min, 99%, >20/1 dr; (ab) Ac2O,
DMAP, Et3N, CH2Cl2, −30 °C, 30 min, 73%.
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Table 1. Optimization of the Asymmetric 1,3-Dipolar Cycloaddition
ab
,
cd
,
e
f
g
h
entry
[O]
amino ester source
base
yield (%)
dr
ee (%)
1
2
3
[DMP]
[DMP]
[DMP]
[DMP]
[TEMPO]
[TEMPO]
[TEMPO]
[TEMPO]
[TEMPO]
[TEMPO]
[TEMPO]
Ph3PNCH2CO2Me
Ph3PNCH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
NH2CH2CO2Me
Ph3PNCH2CO2Me
DBU
Et3N
Et3N
Et3N
Et3N
DIPEA
TMG
DBU
54
45
40
<5
51
53
56
65
37
42
45
7:1
5:1
4:1
45
54
50
i
4
i
5
4:1
4:1
4:1
6:1
4:1
4:1
5:1
>99
>99
>99
>99
>99
>99
36
i
6
i
7
i
8
i
9
Cs2CO3
K2CO3
DBU
i
10
11
i
a
b
[DMP] oxidation: 30 (0.1 mmol), Dess−Martin periodinane (0.15 mmol), CH2Cl2 (3 mL), rt, 0.5 h, chromatography on silica gel. [TEMPO]
oxidation: 30 (0.10 mmol), TEMPO (0.01 mmol), KBr (0.20 mmol), NaClO (10% in H2O, 0.20 mmol), NaHCO3 (saturated aqueous solution, 2
c
d
mL), CH2Cl2 (3 mL), 0 °C to rt, 3 min, aqueous workup. 8, N3CH2COOMe/PPh3 (0.11 mmol), CH2Cl2 (2 mL), 0 °C, 1 h. 8,
e
NH2CH2COOMe·HCl (0.20 mmol), Et3N (0.22 mmol), MgSO4 (0.60 mmol), CH2Cl2 (2 mL), 0 °C, 1 h. Crude 31, AgOAc (0.01 mmol), base
f
g
(0.11 mmol), toluene (2 mL), rt, 1 h. Isolated yield of the major diastereoisomer from 30. Ratio of yields of the two isolated diastereoisomers.
h
i
Of the major diastereoisomer; determined by chiral HPLC analysis. Crude 8 was used for the next step without chromatography purification.
racemization-prone azamethine ylide 13 or its precursors could
be avoided, then chiral 14 could be obtained through a regio-
and diastereo-selective intramolecular 1,3-dipolar cycloaddi-
tion of a chiral imino ester. Chiral aldehyde 8 for preparation
of the imino ester could be synthesized from chiral stannane
11 and commercially available bromide 12 through a Stille
coupling.
methyl glycinate and Et3N. However, the reaction outcome did
not improve (entries 2 and 3). Monitoring of the ee values of
all precursors and reacting intermediates throughout the
process indicated that silica gel chromatography of crude 8
resulted in its racemization. Hence, crude 8 was then used
directly in the next step without silica gel chromatography;
however, the cycloaddition was inhibited (entry 4). Thus, the
oxidation protocol for this step must directly provide 8 in the
required chemical purity without the need for silica gel
chromatography. After screening, we were delighted to find
that crude 8 prepared via a TEMPO-catalyzed oxidation
afforded 14 in good yield with >99% ee (entry 5).19 After
further investigation of various amino ester sources and bases
(entries 6−11), methyl glycinate and DBU were determined to
be the best options (entry 8). Through this protocol, we
smoothly prepared batches of chiral 14 on a gram scale.
Construction of the E Ring. Having successfully obtained
the fundamental framework of hetidine skeleton, we next
focused on construction of the E ring (Scheme 4B). After
benzyl protection and Wittig olefination, a SmI2-promoted
domino reductive elimination/lactamization afforded formal
skeleton-rearranged product 33 with breakage of the C6−N
bond.20 A sequence of enol ether hydrolysis and diaster-
eoselective methylation gave aldehyde 34 in 78% yield.
Reduction of the aldehyde group and subsequent mesylation
of the resulting hydroxyl group gave 35, which underwent a
cascade of lactam opening and intramolecular alkylation in the
presence of NaOMe to afford 25 with formation of the E ring.
Construction of the B Ring and Installment of the
C7−OH Group. Inspired by our experience with constructing
the B ring of hetisine-type alkaloids by a SmI2-mediated,
dearomative free radical addition to arene moiety, we initially
envisioned that a ketyl radical generated from an aldehyde
could undergo a dearomative addition to the phenyl ring, thus
constructing the B ring likewise and installing the C7−OH
group concurrently (Scheme 5A). However, our early attempts
Construction of the A/F/C Ring System. As depicted in
Scheme 4A, our synthetic efforts commenced with the
preparation of chiral precursor 30 from commercially available
acid (S)-4-benzyl-2-oxazolidinone. A sequence involving
amidation, Evans asymmetric aldol reaction,15 and silylation
of the resultant free hydroxyl group afforded chiral amide 28 in
good yield with a >20:1 diastereomeric ratio (dr). The
absolute configuration of the newly generated stereogenic
carbon center was determined by X-ray crystallographic
analysis.16,17 Reduction of amide 28 with NaBH4 provided
alcohol 29, which was transformed to 11 by treatment with
nBu3SnCl after a Br−Li exchange. A Stille coupling of 11 and
12 with Pd(PPh3)4 as the catalyst and CuBr as the cocatalyst
yielded 30 in 77% yield with >99% enantiopurity (ee).
With decagram quantities of chiral 30 in hand, we next
explored the feasibility of an asymmetric synthesis of tetracyclic
14 via 1,3-dipolar cycloaddition (Table 1). Aldehyde 8, imino
ester 31, and ylide 13 (structures are shown in Scheme 3) are
potentially prone to racemization; therefore, the protocols for
oxidation of alcohol 30, formation of imine ester 31, and Lewis
acid catalyzed 1,3-dipolar cycloaddition are key to successfully
preparing chiral 14. Initially, a sequence of oxidation of 30 with
Dess−Martin periodinane, imino ester formation with an aza-
Wittig reagent, and 1,3-dipolar cycloaddition with AgOAc/
DBU following our previous work produced 14 with low and
inconsistent ee values (entry 1). We posited that the basic aza-
Wittig reagent (i.e., Ph3PNCH2CO2Me)18 and DBU may
induce racemization and alternatively tested the less basic
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a
withTsNHNH2, which was then treated with a base and
Rh2(Oct)4 to give 47 in 85% yield along with 10% yield of a
1,2-H shift alkene byproduct. Using copper salts as the catalyst
in substitute for Rh2(Oct)4, only the alkene product was
observed.17 Amide reduction of 47 with DIBAL-H gave 48 in
good yield. We envisioned that opening the cyclopropane ring
with a hydroxyl nucleophile would not only establish the B ring
but also introduce a hydroxyl group at C7. As shown in
Scheme 6, a cascade of hydrolysis of the enol ether and SN2-
Scheme 5. Failed Attempts to Construct the B Ring
Scheme 6. Nucleophilic Ring Opening of the
a
Cyclopropane
a
Reagents and conditions: 47 or 48, acid (5 equiv), THF, 60 °C, 1 h.
49a (48% HBF4 in H2O, 80% yield, >20/1 dr); 49b (37% HCl in
H2O, 86% yield, >20/1 dr); 49c (57% HI in H2O, 83% yield, >20/1
dr); 50 (48% HBF4 in H2O, 61% yield, >20/1 dr).
a
Reagents and conditions: (a) I2, NaHCO3, THF/H2O, rt, 1 h, 97%;
(b) DIBAL-H, CH2Cl2, −78 °C, 10 min, 90%; (c) DIBAL-H,
CH2Cl2, −30 °C, 10 min, 94%; (d) NBS, Ph3P, rt, 1 h, 86%; (e) Na,
t
liquid NH3, BuOH, THF, −78 °C, 2 h, 85%; (f) PhOCSCl, DMAP,
CH2Cl2, rt, 2 h, 95%; (g) SmI2, HMPA, THF, rt, 2 h, 73%; (h) Na,
liquid NH3, BuOH, THF, −78 °C, 2 h, 78%.
like ring opening of cyclopropane moiety by treating 47 or 48
with an aqueous solution of HBF4 formed the B ring and
stereospecifically installed the problematic equatorial C7−OH.
Although attempts to introduce fluoro, benzenesulfonyl, or
phenylthio groups at C7 were unfruitful, treatment of 47 with
an aqueous solution of HCl or HI generated 49b or 49c with a
halogen atom introduced, which would facilitate preparation of
natural product analogues with unnatural functionalities at
C7.13 The stereochemistry of the newly formed C7−OH of
49a was determined by X-ray crystallographic analysis, and the
same configuration was assigned to other products by
analogy.16,17
Construction of the D Ring. With the B ring established,
the next task was to construct the D ring. As shown in Scheme
7, our initial plan to construct the B ring was an intramolecular
alkylation. Mesylate 52 was prepared by a sequence of
desilylation, mesylation, cyclopropane ring opening, and
hydrogenation. To our surprise, attempts to construct the
bicyclo[2.2.2]octane motif by treatment of 52 with a base (e.g.,
LDA, tBuOK, NaH, and K2CO3) only resulted in generation of
54 with a four-membered ring. The structure of 54 was
confirmed by X-ray analysis of a single crystal of its derivative
56, which was prepared by sequential olefination and allylic
oxidation.16,17 Generally, formation of a six-membered ring is
favored over a four-membered ring. A possible rationale for
this unusual selectivity is the specific and rigid architecture of
compound 52. We next resorted to a reversible aldol reaction
with the expectation of generating the thermodynamically
favored six-membered ring product. As shown in Scheme 4C,
sequential reactions of acetylation, one-step alkene hydro-
genation/Bn-hydrogenolysis, and Boc-protection delivered 57,
which was then elaborated to aldehyde 58 via desilylation and
oxidation. Exposure of 58 to the classic aldol reaction
t
to prepare aldehyde 36 from ester 25 were unfruitful, and only
the suspected quaternary ammonium byproducts were
observed. This can be attributed to tendency toward
quaternization of the basic tertiary amine moiety of 25.
Accordingly, amine 25 was oxidized to amide 38 by treatment
with I2 (Scheme 5B). DIBAL-H reduction of the ester afford
aldehyde 39 in high yield. However, treatment of 39 with SmI2
under various conditions resulted in complex reaction mixtures
(Scheme 5B). To explore the feasibility of constructing the B
ring via dearomative addition with a primary free radical
intermediate, as we did previously, primary bromide 42 was
prepared from 38 by a sequential reduction and bromination
and was tested with SmI2 or Bu3SnH. However, only
unidentified products were generated (Scheme 5C). After
several unsuccessful dearomative additions, we then turned to
free radical addition to the alkene group after an arene
dearomatization. Thus, precursor 44 was prepared by a
sequence of Birch reduction and esterification and was then
subjected to SmI2. Notably, only 45 was isolated in a high yield
with formation of a five-membered ring (Scheme 5D).
Interestingly, Birch reduction of ester 38 led to compound
46 with a similar five-membered ring (Scheme 5E). We
hypothesized that formation of a five-membered ring is favored
over the six-membered ring without the tethering C6−N bond,
which is present in our hetisine-type alkaloid synthesis.
After unsuccessful attempts to construct the B ring via free
radical addition, we were ultimately drawn to a dearomative
cyclopropanation strategy. As indicated in Scheme 4B, the
diazo precursor was generated by condensation of aldehyde 39
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cyclopropanation strategy also allowed preparation of natural
product analogues with unnatural functionalities at C7.
Scheme 7. Failed Attempts to Construct the D Ring by
Alkylation
a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01865.
■
sı
Experimental procedures and compound characteriza-
tion (PDF)
Accession Codes
CCDC 2059195, 2059198, 2059200, 2059202, 2070613,
2070620, and 2070622 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
Reagents and conditions: (a) TBAF, THF, 70 °C, 4 h, then MsCl,
DMAP, Et3N, CH2Cl2, rt, 3 h, 90%; (b) HBF4, THF/H2O, 60 °C, 1 h,
80%; (c) Pd(OH)2, H2, MeOH, rt, 2 h, 82%; (d) K2CO3, MeOH, 75
°C, 3 h, 95%; (e) Tebbe reagent, THF, rt, 2 h, 81%; (f) SeO2,
tBuOOH, CH2Cl2, 0 °C to rt, 30 min, 96%.
AUTHOR INFORMATION
Corresponding Author
■
Min Zhang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, China;
orcid.org/0000-0002-3851-7836; Email: minzhang@
cqu.edu.cn
conditions of pyrrolidine/AcOH and subsequent treatment
with MsCl provided mesylate 59 with the D ring successfully
constructed, thus completing the hetidine core.
Total Synthesis of (+)-Talassimidine and (+)-Talass-
amine. With the hetidine core constructed, the remaining task
for completion of the synthesis of (+)-talassimidine and
(+)-talassamine was the installation of the requisite function-
alities (Scheme 4C). Mesylate 59 was transformed to 61 by
sequential deacetylation, olefination, and sulfonate reduction.
Using 61 as the branch point, we prepared 15-epi-talassamine
62, a natural product analogue, by a sequence of diaster-
eoselective allylic oxidation with SeO2/tBuOOH at 0 °C, Boc
deprotection, and amine oxidation; the total synthesis of
(+)-talassamine 5 was achieved by reactions including allylic
oxidation with SeO2 at 80 °C, diastereoselective Luche
reduction of the resultant ketone, Boc deprotection, and
amine oxidation. The total synthesis of (+)-talassimidine 4 was
achieved by a similar reaction sequence except with an
additional acetylation of C15−OH. The structure of our
synthetic talassamine 5 and 15-epi-talassamine 62 were
unambiguously confirmed by X-ray crystallographic anal-
ysis.16,17 Notably, the ee values of the final products, as
measured by chiral HPLC analysis, indicated that our synthetic
approach provided (+)-talassimidine 4 and (+)-talassamine 5
with 99% ee.
Authors
Quanzheng Zhang − Chongqing Key Laboratory of Natural
Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing
401331, China
Zhao Yang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, China
Qi Wang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, China
Shuangwei Liu − Chongqing Key Laboratory of Natural
Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing
401331, China
Tao Zhou − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, China
Yankun Zhao − Chongqing Key Laboratory of Natural
Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing
401331, China
CONCLUSION
■
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01865
We have accomplished the first asymmetric total synthesis of
(+)-talassamine and (+)-talassimidine in 0.28 and 0.20% total
yields from known compound 26 over 26 and 27 total steps,
respectively. A regio- and diastereo-selective 1,3-dipolar
cycloaddition of azomethine ylide generated the fundamental
tetracyclic skeleton with five continuous stereogenic carbon
centers in high enantiopurity (>99% ee). Besides the hetidine-
type alkaloids, this chiral tetracyclic intermediate should also
enable asymmetric access to the hetisine-type alkaloids. An
efficient sequence of dearomative cyclopropanation of the
benzene ring and subsequent SN2-like ring opening of the
cyclopropane moiety with a water nucleophile was developed
to stereospecifically install the challenging equatorial C7−OH
group and to concurrently construct the B ring. This
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21672029, 21871033, and
21922102) and the Fundamental Research Funds for the
Central Universities (2020CQJQY-Z002). We are grateful to
Xiangnan Gong (CQU) for X-ray crystallographic analysis.
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Article
ramilactone B, ( )-Spiraminol, ( )-Dihydroajaconine, and ( )-Spi-
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ABBREVIATIONS
■
DIPEA, N,N-diisopropylethylamine; TIPS, triisopropylsilyl;
TEMPO, 2,2,6,6-tetramethylpiperidine 1-oxide; Tebbe re-
agent, bis(cyclopentadienyl)-μ-chloro(dimethylaluminum)-μ-
methylenetitanium
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