Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)-Haliclonin A?

Article abstract of DOI:10.1002/cjoc.202000291

We describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all-carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C₁N₁ building block to form the 3-azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3-alkenyl cyclohex-2-enone, and the first Pd-promoted intramolecular coupling of a thiocarbamate moiety onto an electron-deficient alkene (enone) to form the 3-azabicyclo[3,3,1]nonane core. The synthesis also features a SmI₂-mediated intermolecular reductive coupling of an enone with an aldehyde, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocycles, and an unprecedented direct transformation of enol into enone.

Full text of DOI:10.1002/cjoc.202000291

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product
()-Haliclonin A
Authors: Shi-Peng Luo, Xiong-Zhi Huang, Lian-Dong Guo, and Pei-Qiang Huang*
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This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000291.
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Chinese Journal
of Chemistry
Total synthesis, organocatalysis, alkyne metathesis, samarium diiodide,
marine natural products, biosynthetic hypothesis, Heck-type reactions
Report
CJC
中
国 化 学 - An International Journal
Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural
Product (−)-Haliclonin A
Shi-Peng Luo,†,a,b Xiong-Zhi Huang,†,a Lian-Dong Guo,†,a and Pei-Qiang Huang*,a
a Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian 361005, P. R. China
b School of Chemistry and Environmental Engineering, Jiangsu University of Technology, Changzhou 213001, P. R. China
Dedicated to the 70th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Cite this paper: Chin. J. Chem. 2020, 38, XXX—XXX. DOI: 10.1002/cjoc.202000XXX
Summary of main observation and conclusion We describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested
to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several
purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate
addition to forge the challenging all-carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule;
and (3) as a C1N1 building block to form the 3-azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel
organocatalytic asymmetric conjugate addition of nitromethane to 3-alkenyl cyclohex-2-enone, and the first Pd-promoted intramolecular coupling of a
thiocarbamate moiety onto an electron-deficient alkene (enone) to form the 3-azabicyclo[3,3,1]nonane core. The synthesis also features a SmI2-mediated
intermolecular reductive coupling of an enone with an aldehyde, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocycles, and
an unprecedented direct transformation of enol into enone.
In 2009, Shin and coworkers reported the isolation of the
macrocyclic alkaloid haliclonin A (3) from a marine sponge
Background and Originality Content
Containing more than 600 species, the marine sponge genus
Haliclona represents one of the most prolific sources of natural
products.[1] To date, more than 110 nitrogenous secondary
metabolites have been isolated from classified and unclassified
Haliclona sp.[1] Among them, the family of macrocyclic diamine
metabolites derived from 3-alkylpyridine dimers[2] comprises
structurally diverse groups as represented by manzamine A (1 in
Figure 1),[3] nakadomarin A, madangamine A, and sarain A (2).[4,5]
Following Baldwin’s seminal biosynthetic hypothesis in 1992,[6] it is
now well recognized that these apparently different polycyclic
alkaloids are closely related, with 3-alkyldihydropyridine dimer A
as the common biosynthetic precursor (Figure 1).[5] This family of
natural products exhibits a broad spectrum of bioactivities
including anticancer,[3,7] anti-HIV-1,[8] and antibacterial action.[9]
The intriguing structural features combined with the interesting
bioactivities established their “celebrity” status within the
synthetic community.[2a,5-13] However, their enantioselective total
synthesis presents a formidable synthetic challenge, especially for
sarain A.[11] Indeed, although tremendous efforts have been
devoted to the synthesis of sarain A,[12] its total synthesis was not
achieved until Overman et al.[13] published their results describing
the first enantioselective total synthesis of sarain A. Moreover, this
remains the only total synthesis to date.
Haliclona sp. collected from Korean waters.[14] A preliminary
assessment of bioactivity showed that haliclonin A exhibited
moderate antibacterial activity against several Gram-positive and -
negative bacteria, and displayed moderate cytotoxicity against the
K562 leukemia cell line, with an IC50 of 15.9 μg/mL (0.03 μmol). The
structural elucidation of haliclonin A (3) turned out to be
challenging because in the 13C and 1H NMR spectra, most of the
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haliclonin A not only come from the unprecedented tetracyclic
framework with delicate functionalities, but also from the
uncertainty about the relative stereochemistry for the skipped
diene moiety and about the absolute configuration. With our
longstanding interests in the synthesis of N-containing
compounds,[15,16] we have embarked on a synthetic study of
haliclonin A (3),[17a,c,e,18] which has resulted in the first total
synthesis of (−)-haliclonin A.[17d] In parallel[17a,b] with our own work,
significant progress has been made by Yokoshima, Fukuyama, and
coworkers, who very recently disclosed a racemic synthesis of 3-
azabicyclo[3.3.1]nonane skeleton with a bridge that forms the 17-
membered ring.[17f] Herein, we describe the full details of our
efforts to explore this intriguing molecule.
In view of the confusions discussed above regarding the
stereochemistries of natural haliclonin A, our adventure started
with selecting the displayed 1E,3R,4S,6R,11R,13Z,16Z stereoisomer
of haliclonin A (3 in Figure 1 and Scheme 1) as our synthetic target.
Our initial retrosynthetic analysis of 3 is outlined in Scheme 1. We
envisioned the formation of the Z-olefinic bond at C16–C17 and
thus the 15-membered ring by a macrocyclic ring-closing alkyne
metathesis (RCAM)[19] followed by a stereoselective Lindlar
reduction. Fürstner[19] extensively explored the chemistry of RCAM
from catalysts to reactions and its applications in the total synthesis
of natural products. Next, after a retro-aldol disconnection of the
side chain connected at C1, we anticipated the formation of the
saturated 17-membered macrocycle by a ring-closing metathesis
(RCM);[20] a methodology widely used for the construction of
macrocycles.[5a,11,13,21] A disconnection at the α,β-C–C bond of the
ketone is apparently simple and obvious, but the formation of this
C–C bond in a regio- and stereoselective manner might be
problematic. Hence the aldol reaction of 7 with 6b was envisioned
Baldwin's
part)
N
hypothesis (in
m
N
H
N
H
OH
N
n
n =
1
m,
N
N
A
Shin's
proposal
m = n =
3
5,
1
A
(+)-Manzamine ( )
(Z)
(Z)
δ−
13
O
N
HO (R)
15
11
H
6
N
H
(R)
(S)
+
N
δ
1
14
OH
17
(Z)
O
3
4
H
O
N
(R)
HO
CHO
(Z)
−
+
A 3
2
A
( )-Haliclonin ( )
( )-Sarain ( )
Figure 1 Biogenetic relationship within dimeric 3-alkyldihydropyridine
natural products.
proton and carbon signals were paired to each other. On the basis
of spectral investigations, Shin et al. suggested that compound 3
was a mixture of two rotamers with a ratio of 3:2. Moreover, the
geometries of the skipped diene could not be determined because
of the severe overlapping of the proton signals. A clever solution to
this puzzle came from the hypothesis that haliclonin A might
originate biosynthetically from 3-alkylpyridine dimers. Thus,
whereas the structure of haliclonin A features the unprecedented
3-azabicyclo[3.3.1]nonane framework with an enone-diamide
functionality, Shin et al suggested a possible retrobiosynthetic
pathway, which converges with that of sarain A on bispyridinium
intermediate A (Figure 1). Hence, the stereochemistry of the
skipped diene moiety in haliclonin A (3) was tentatively assigned by
analogy with that of sarain A (2). The absolute configuration of
as
a
stepwise
alternative.
Given
that
the
3-
azabicyclo[3.3.1]nonanone scaffold 7 contains a 1,4-dicarbonyl
motif, an umpolung method is required for its construction. We
thought that Bachi’s radical lactamization method[22] might suit this
need, which implied olefinic isocyanide 8 as an umpoled precursor.
Finally, as the key to our strategy, we opted for nitromethane as
both an umpolung surrogate of an aminomethanide[23] and a
pronucleophile for the envisioned catalytic enantioselective
conjugate addition to forge the challenging all-carbon quaternary
stereogenic center.[24,25] The established first chiral center was
expected to induce the formations of all the other three chiral
centers in haliclonin A.
haliclonin
A is another puzzle: i.e., the assigned one
(1E,3S,4R,6S,11S) is actually the antipode of that showed in Figure
1.[14] Consequently, the challenges for the total synthesis of
Scheme 1 Initial retrosynthetic analysis of haliclonin A (3)
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Running title
Chin. J. Chem.
Aldol
OH
13
12
OH
H
RCM
14
11
10
Ph
SO2
CHO
N
N
PhO
2S
N
(R)
N
Aldol
16
(R)
RCAM
1
5
(S)
17
(R)
O
O
O
N
N
9
O
O
O
PMB
3
( )
Haliclonin A
4
5
I
N
N
C
Ph
Ph
SO2
radical
+
6a
O
cyclization
O
N
umpolung
O
O
PMB
N
O
8
7
H
SO2
6b
OEt
N
O2
+
+
NO2
CH3
12
)
(R)
(
O
O
Asymmetric
conjugate
addition
O
BrMg
11
10
9
NH2
CH2
aminomethanide
to afford the bicyclic lactam (±)-17 in 80% yield.[18]
Results and Discussion
Synthesis of racemic 3-azabicyclo[3.3.1]nonane framework (7)
Scheme 2 Unanticipated formation of the hexahydro-1H-isoindole- 1,5(4H)-
dione
Radical approach. The synthesis started with commercially
available 3-ethoxycyclohex-2-enone (11) (Scheme 2). Addition of
Grignard reagent followed by acidic work-up afforded the desired
3-(hex-5-enyl)cyclohex-2-enone (10) in 84% yield. To test the
viability of our strategy, racemic substrate 9 was prepared and used
for our initial investigation. For the conjugate addition of
nitromethane to enone[23,26] 10, attempts using both organic bases
(NEt3, DBU, TMG) and inorganic bases (KF/Al2O3, NaOH) as well as
t-BuOK in THF failed to yield any adduct. Under Hanessian’s
asymmetric conjugate addition conditions[26a] except that racemic
proline was used as a catalyst, the desired adduct (±)-9 was
obtained in 15% yield, along with 84% of the recovered starting
material. After optimization of reaction conditions, the yield was
increased to 81% (98% BRSM, based on the recovered starting
material). Nicolaou’s method[27] was adopted for the
transformation of cyclohexanone into the corresponding enone.
Under the optimized conditions consisting of employing 4.0 equiv.
of N-methyl-morpholine N-oxide (IBX·NMO) complex in DMSO for
3 days at room temperature, the desired enone (±)-13 was
obtained in 60% yield. Acetalization of (±)-13 under Hwu’s
conditions[28] unexpectedly led to the olefinic bond migrated acetal
(±)-14 as the major product. At the time of our investigation, we
were unaware of this unexpected result, and proceeded to the
subsequent transformations.[18] Although this result did not allow
us to access the desired tropinone ring system, it offered us the
opportunity to examine Bachi’s lactamization method for our
synthesis.[22] Under Bachi’s conditions (with minor modification
mol%)
equiv)
(±)-Proline (40
NO
CH3
CH2=CH(CH
2 (4.0
2)4MgBr
B
trans
-2,5-dimethylpiperazine (
equiv)
)
12
11
(1.5
CHCl3 50 ºC,
~ rt
O
Et2
0
°C
O
,
7d
BRSM)
,
84%
10
81%
(98%
IBX·NMO
N
O2
N
O2
TMSO
equiv)
OTMS
(4.0
rt
DMSO,
60%
rt
TMSOTf, CH2Cl2
80%
,
O
O
±
±
9
13
( )-
( )-
OHC
N
H
N
O2
POCl3
rt, 2 h
LAH, Et
2O
1)
HCO Et, reflux
O
2)
2
O
two steps
85% for
O
±
O
±
15
14
( )-
( )-
N
,
O
H
HOCH2CH2SH
O
O
ACCN,
tol., 85 °C
NH
15
80%
O
(from
)
O
±
±
17
16
( )-
( )-
To circumvent the deconjugation of enone (±)-13 during the
subsequent transformations, an alternative route was investigated.
Thus, (±)-13 was subjected to sequential chemoselective Luche’s
employing 1,1′-azobis(cyclohexanecarbonitrile) as
a
radical
initiator), the reaction of isocyanide (±)-16, formed in situ by the
dehydration of formamide (±)-15 with POCl3, proceeded smoothly
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First author et al.
Report
reduction[29] of the enone (NaBH4, CeCl3·H2O, MeOH) and nitro
reduction (Zn, HCl, MeOH). N-formylation followed by oxidation of
the allylic alcohol with MnO2 afforded compound (±)-20 in 73%
overall yield from (±)-13. Treatment of (±)-20 with POCl3 yielded
isocyanide (±)-21, which was used without purification in the
Bachi’s reaction. To our disappointment, after many trials, the
desired cyclization product (±)-7a was always obtained in low yields
(15–25%).
O
N
X
PMB
O
Pd-catalyzed
radical
cyclization
N
O
PMB
or
O
7
.
.
=
=
22a
22b
X
X
PhS
ArSe
The synthesis of precursor (±)-22a is outlined in Scheme 5.
Reduction of the nitro group in (±)-14 with LiAlH4, followed by
reductive alkylation of the crude amine with anisaldehyde and
NaBH(OAc)3 in CH2Cl2 (room temperature, 4 h) furnished the
desired PMB-protected product (±)-23 in 82% yield over the two
steps. The latter was exposed to S-phenyl chlorothioformate,
prepared by Xu’s protocol,[35] to yield (±)-24. Deacetalization of 24
by PPTS-catalyzed hydrolysis in MeCN/H2O, followed by treating
the resulted β,γ-cyclohexenone with DBU (1.0 equiv) in CH2Cl2 (4 h,
room temperature) afforded the reconjugated enone (±)-22a in 83%
yield.
Scheme 3 Attempted construction of the 3-azabicyclo[3.3.1]nonane
skeleton by Bachi’s lactamization
OH
OH
NaBH4
CeCl3 MeOH;
,
HCOOEt
reflux
-
R
13
R
±)
(
Zn, 4 M
HCl
NHCHO
NH2
-
±
19
18
±)
( )-
(
O
O
MnO2
TEA
POCl3
,
R
R
CH2Cl2
73%
0 ºC, THF
80%
NHCHO
O
Scheme 5 Synthesis of the racemic cyclization precursor 22a as a model
compound
N
C
13
±
(from
)
20
( )-
±
21
( )-
HOCH2CH2SH
tol.
N
O2
PMBHN
4-MeOPhCHO
ACCN,
R
LiAlH4 Et
2O
,
=
R
O
O
85 ºC
15~25%
O
N
~
0 ° RT
NaBH(OAc)3
two steps
O
H
-
O
82% for
14
(±
7a
)-
±)
23
(
(±
)-
Considering that all successful Bachi’s reactions involve
substrates bearing an electron-rich olefin,[18,22] the observed low
yield in the formation of (±)-7a can be attributed to the electron-
deficient nature of the alkene (i.e., enone) in (±)-21. Thus, we had
to modify our strategy by developing another method to access the
3-azabicyclo[3.3.1]nonane framework 7.
PhS
O
PMBN
PPTS,
H
PhSCOCl
CH3CN/ 2O
1)
22a
(±
)-
Et
RT
DCM,
95%
3N,
DBU, DCM, RT
O
2)
two steps
83% for
O
Pd-mediated Heck-type reductive cyclization approach.
Although many methods have been developed for the synthesis of
the 3-azabicyclo[3.3.1]nonane framework,[30] asymmetric variants
are rare. Our new approach for the construction of 7 is outlined in
Scheme 4. The new design called for a radical[31] or a Pd-catalyzed
intramolecular coupling of thiocarbamate moiety onto an enone
(22) in a conjugate addition manner. While similar couplings using
vinyl or aryl halides as a coupling partner are well documented[32,33]
and a palladium-catalyzed cyclization of a carbamoyl chloride or a
S-phenyl carbamothioate onto electron-rich alkenes[34] has been
reported, a combination of the two partners, i.e., the coupling of a
carbamoyl chloride or a S-phenyl carbamothioate with an enone,
is, to our knowledge, without precedent. Nevertheless, this
transformation was crucial for our approach; therefore, we decided
to explore this chemistry.
24
(±
)-
Racemic (±)-22a was used for screening the reaction conditions.
We first attempted the intramolecular radical cyclization
reaction.[31] When the (Me3Si)3SiH/ AIBN combination was used
(toluene, 110 °C), the starting material (±)-22a remained intact,
whereas the more reactive Bu3SnH/ AIBN combination led to
complex products. Therefore, we focused on transition metal-
mediated cyclization reactions.[32,33] After unsuccessful trials using
Pd(OAc)2 or Pd(dppb)Cl2 as a catalyst (cf. Table 1, entries 1, and 2),
we found that, in the presence of 20 mol% of Pd(Ph3P)4, the
reaction of (±)-22a in toluene at 110 °C for 12 h produced (±)-7 in
12% yield, along with 4% of the decarbonylative cyclization side-
product (±)-25, and 70% of recovered starting material (±)-22a
(Table 1, entry 3). The reaction was not improved by adding
triethylamine as an additive or ammonium formate as a reductant
(Table 1, entry 4). However, to our delight, the yield of the desired
product was improved by increasing the catalyst loading.
Meanwhile, an increased amount of the decarbonylative side-
product (±)-25 was obtained (Table 1, entries 5 and 6).
Scheme
4
Modified
retrosynthetic
analysis
for
the
3-
azabicyclo[3.3.1]nonane skeleton
These results indicated that no catalytic cycle was established
during the reaction. A plausible mechanism for this unprecedented
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Running title
Chin. J. Chem.
Heck-type Pd-mediated cyclization reaction is depicted in Scheme
6. The first step involves an oxidative addition of compound (±)-22a
with Pd(0) to give Pd-complex M1, from which two pathways are
possible. Path A is the desired one involving the intramolecular
insertion reaction leading to Pd-complex M2. However, because
the subsequent syn-β-elimination[35] from M2 would lead to an
anti-Bredt bridgehead enone[36] (±)-26, moreover, Pd and H are in
a trans-disposition, the syn-β-elimination is impossible. Hence Pd-
complex M2 can only undergo hydrolysis via its tautomer M2′ to
yield (±)-7 as the major product. Due to a lack of a syn-β-
elimination to regenerate and recycle the Pd(0) catalyst, a
stoichiometric amount of the catalyst is required for completion of
(±)-7 (50%), (±)-25
6
7
Pd(Ph3P)4 (1.0 equiv), PhMe, 110 °C
(28%)
Pd(Ph3P)4 (1.0 equiv), PhMe, DPPP (1.0 (±)-7 (58%), (±)-25
equiv), 110 °C
Pd(OAc)2 (1.0 equiv), DPPP (1.5 equiv),
CH3CN, rt − 90 °C
(15%)
8
NRb
Pd(OAc)2 (1.0 equiv), DPPP (1.5 equiv), (±)-7 (75%), (±)-25
CH3CN, 100 °C (5%)
Pd(OAc)2 (1.0 equiv), DPPP (2.0 equiv), (±)-7 (79%), (±)-25
CH3CN, 100 °C (trace)
9
10
a
b
Isolated yield; No Reaction. DMF = N,N-Dimethylformamide;
DPPB 1,3-bis(diphenylphosphino) butane; DPPP 1,3-
bis(diphenylphosphino) propane; Ac = acetyl.
the reaction. In path B, Pd-complex M1 undergoes
a
=
=
decarbonylation to give Pd-complex M3, which goes through an
intramolecular insertion reaction to give M4. Protolysis of Pd-
complex M4 produces the side-product (±)-25.
A concept for developing Pd-catalyzed Heck-type reductive
cyclization. In an effort to develop a catalytic version of the Pd-
catalyzed cyclization reaction, α-substituted cyclohexenone (±)-33
was conceived in the hope that the methylene would provide a
proton enabling a syn-β-elimination on the envisioned Pd
intermediate (cf. M5 and 7b in Scheme 8).[17e] For this purpose,
racemic substrate (±)-33 was prepared. The synthesis started from
the Morita–Baylis–Hillman reaction[37] of enone (±)-13 and
aldehyde 6b. Exposing a mixture of (±)-13 and 6b to Bu3P and
BINOL in THF (r.t., 7 days) resulted in the formation of adduct (±)-
27 in 85% yield. This result implied that the reaction conditions are
mild enough to avoid two possible competing side reactions; i.e., a
Henry reaction between the nitroalkane moiety and aldehyde, and
a bimolecular self-conjugate addition of the former with the enone
group.
Mesylation of (±)-27 with MsCl/ NEt3 followed by treating the
resultant mesylate with DBU afforded the elimination product (±)-
28 in 81% yield over two steps. In TFA, dienemide (±)-28 was
reduced with Et3SiH to produce α-substituted enone (±)-29 in 85%
yield. Sequential Luche’s reduction[29] and reduction of the nitro
group yielded amino cyclohexenol (±)-30, which was subjected to
reductive N-benzylation to yield benzylamine (±)-31.
On the basis of these considerations, we conceived that by
introducing a bidentate ligand, such as diphosphine dppp [1,3-
bis(diphenylphosphino)pro-pane)], and running the reaction in a
donor solvent, such as MeCN, one would be able to inhibit the
decarbonylation of the presumed Pd-complex M1 to give Pd-
complex M3, and thus prevent the formation of the side-product
(±)-25. Indeed, in the presence of 1.0 equiv of dppp, the ratio of
(±)-7/ (±)-25 was improved slightly (Table 1, entry 7). However,
because the polarity of the product is similar to that of the by-
product triphenylphosphine oxide (Ph3PO), their separation was
frustrating. To circumvent this problem, further optimization aimed
at a replacing of Pd(Ph3P)4 with Pd(OAc)2 was undertaken (Table 1,
entries 8–10). We were pleased to find that when a combination of
1.0 equiv of Pd(OAc)2 and 2.0 equiv of dppp was used as a source
of Pd(0), and MeCN as a chelating solvent, the reaction proceeded
smoothly at 100 °C to yield the desired product (±)-7 in 79%. In
such a manner, the side reaction leading to (±)-25 was almost
totally inhibited (Table 1, entry 10).
Table 1 Optimization of the Pd-mediated cyclization of carbamothioate-
enone 22a
O
PhS
Scheme 6 Plausible mechanisms of the Pd-mediated cyclization
of carbamothioate-enone 22a
N
PMB
conditions
+
O
O
N
N
PMB
25
O
PMB
O
7
22a
(±)-
(±)-
(±)-
Entry
Conditions
Yield (%)a
Pd(OAc)2 (0.2 equiv), Bu4NCl, HCOONH4,
1
NRb
DMF, 120 °C
Pd(dppb)Cl2 (0.2 equiv), PhMe, DPPB, 110
2
3
4
5
NRb
°C
(±)-7 (12%), (±)-25
(4%), (±)-22a (70%)
Pd(Ph3P)4 (0.2 equiv), PhMe, 110 °C
Pd(Ph3P)4 (0.2 equiv), Et3N or HCOONH4,
PhMe, 100 °C
Low yield
(±)-7 (28%), (±)-25
Pd(Ph3P)4 (0.5 equiv), PhMe, 110 °C
(10%), (±)-22a (45%)
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
Temporary in situ protection of the hydroxyl group (TMSCl, TEA,
DMAP), followed by carbamation with PhSC(O)Cl and regeneration
of the hydroxyl group (HCl aq.) afforded (±)-32 in one pot. As such,
(±)-32 was prepared from (±)-29 in an overall yield of 70%. Finally,
oxidation of the allylic alcohol with MnO2 in CH2Cl2 furnished the
desired cyclohexenone (±)-33 in 95% yield. To our dismay, when a
mixture of (±)-33 was treated with 5 mol% of Pd(PPh3) or Pd(OAc)2
and dppp in a sealed tube, no reaction took place. Even using a
stoichiometric amount of Pd(OAc)2/dppp, no desired cyclization
product (±)-34 was observed and only a trace amount of reductive
Heck-type coupling product (±)-35 was detected. The failure was
attributed to steric hindrance of the substrate. Notably, although
our efforts to develop a catalytic Pd-promoted intramolecular
Heck-type reaction was discontinued to focus on the total synthesis
of haliclonin A, both the stoichiometric reaction[17c,d] and the
concept for a catalytic reaction[17e] have inspired and prompted
Yang’s group to develop a catalytic version for related ring systems
(Scheme 8), which enabled them to accomplish the total synthesis
of lyconadins A–E.[38]
O
R
PhS
R
N
R
PMB
+
O
O
N
N
+
O
dppp
O
Pd(OAc)2
L
PMB
PMB
O
±
7
±
( )-
25
( )-
±
22a
( )-
O
L
Pd
- -
β
syn
elimination
PhS
Pd(0)
R
H
R
N
O
O
N
a
PMB
L
L
PMB
O
N
path
±
26
Pd
( )-
M2
H-trans
(Pd,
)
PhS
R
PMB
L
L
O
Pd
O
N
M1
PhS
R
hydrolysis
H
R
O
Given that we have succeeded in building the tropinone ring
system 7 by the Pd-promoted intramolecular Heck-type reaction,
the radical cyclization of 22b (Scheme 4) was not investigated. It is
worth mentioning that during the revision of this manuscript, this
chemistry has been elegantly realized by Ishihara and coworkers in
a tandem manner, which led them to achieve a formal total
synthesis of (−)-haliclonin A based on our total synthesis.[17g]
b
path
L
N
O
R
O
PMB
±
7
PMB
M2'
( )-
CO
PhS Pd
N
R
O
L
L
PMB
Pd
H
PhS
protolysis
R
O
O
N
N
M3
PMB
PMB
=
±
R
25
( )-
M4
Scheme 7 Concept for developing a new Heck-type Pd-catalyzed cyclization of carbamothioate-enone
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Chin. J. Chem. 2020, 38, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Ph
SO2
N
Ph
SO2
N
Ph
H
O
SO2
N
R
O
R
O
Bu
Binol
TEA;
MsCl,
3P,
R
+
HO
R
R
DBU
81%
R
THF, 7 days
85%
O
NO2
NO2
NO2
6b
13
-28
(±)-
-27
(±)
(±)
Ph
SO2
Ph
SO2
one-pot
N
N
•
R
O
NaBH CeCl 7H2O
R
,
OH
1)
4
3
Et
TFA
h
3SiH,
PhCHO, CH2Cl2
NaBH(OAc)3
MeOH
R
R
r.t., 2
85%
Zn,
HCl
2)
NO2
NH2
-29
-30
(±)
(±)
Ph
SO2
N
Ph
SO2
Ph
SO2
N
one-pot
TEA, DMAP
R
O
R
OH
N
R
OH
MnO2
TMSCl,
1)
R
R
Bn
CH2Cl2
95%
2) ArSC(O)Cl
Bn
R
N
HCl
N
aq.
3)
NHBn
O
O
29
70%
(from
)
33
ArS
-31
-32
(±)-
ArS
(±)
(±)
PhO
R
2S
PhO
R
O
2S
N
N
R
H
H
R
Pd(OAc)2
O
O
or
100 mol%)
R
-
R
(5
H
L
syn
elimination
+
L
Pd
H
PhS
CH CN
R
H
R
dppp,
3
O
O
N
N
120
sealed tube
ºC,
=
O
Bn
Bn
O
N
O
N
P
7b
35
(trace)
-34
observed)
P
(±)-
(±)
(not
M5
=
Ar
R
Catalytic asymmetric total synthesis of haliclonin A.
O
O
[Pd(cinnamyl)Cl]2
mol%)
Organocatalytic construction of the quaternary stereogenic
carbon center. To develop a catalytic asymmetric synthesis of
haliclonin A (3), the first reaction that we needed to investigate was
the catalytic asymmetric conjugate addition of nitromethane to 3-
(hex-5-enyl)-cyclohex-2-enone (10). Considering the high acidity of
the α-protons of nitromethane, metal-catalyzed asymmetric
conjugate addition[39] would not be suitable for our reaction. A
survey of literature showed that only very few examples of highly
enantioselective organocatalytic conjugate addition of nitroalkanes
to β-substituted cyclic enones have been reported.[26b-d,f] These
include one example by Ley,[26b,c] the method of Ye,[26d] and
Kwiatkowski’s[26f] high-pressure (10 kbar) enhanced method. In
these methods, 5-pyrrolidin-2-yltetrazole (cat-2, Figure 2), the
(20
R2
R2
PPh3 Bu NBr, K PO
,
4
3
4
R1
R1
n
°
n
130
7-84%
C
H
xylene,
N
R
SPh
N
O
R
O
37
36
We first focused on investigating the organocatalytic
asymmetric conjugate addition of nitromethane to enone 10.
When Hanessian’s conditions were used [L-proline/B (trans-2,5-
dimethylpiperazine) in CHCl3], the desired adduct 9 was formed in
81% yield, 25% ee (Table 2, entry 1). Switching solvent to EtOAc
only resulted in a drop in yield (72%). With Ley’s catalytic system
cat-2/B, (R)-9 was obtained in 70% yield and 89% ee. Running the
reaction at 0 °C, the ee was increased to 92%; however, the yield
dropped to 45%. Three bifunctional amine-squaramides (cat-5, cat-
6, and cat-7)[41] were also examined, but all were ineffective
producing adduct 9 in less than 10% yield. We next turned our
attention to primary amine thiourea-type organocatalysts.[42] In
this context, Wang and coworkers demonstrated that trans-1,2-
diaminocyclohexane-based primary amine thiourea cat-8 afforded
interesting results in catalyzing the nitromethane addition to
primary amine-thiourea catalyst containing both
a
1,2-
diaminocyclohexane and a cinchona alkaloid moiety (cat-3),[26d]
and 9-amino-9-deoxy-epi-cinchonine (cat-4),[26e] were utilized as
the organocatalyst, respectively (Figure 2).[40]
Scheme 8 Recently realized Pd-catalyzed cyclization of carbamothioate-
enone by Yang’s group[38]
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
acyclic substrate 4-phenylbut-3-en-2-one (36% yield, 93% ee). They
further showed that by using ditrifluoromethyl derivative (S,S)-cat-
9,[26e] both the yield, and enantioselectivity were improved.
However, Ye and coworkers had reported that primary amine
thiourea cat-8 was inefficient (15% conversion) in catalyzing the
asymmetric addition of nitromethane to cyclohex-2-enone.[26d] In
view of the fact that cat-9[43] has not yet been used in the addition
of nitroalkanes to cyclohex-2-enones, we decided to examine the
(R,R)-cat-9-catalyzed asymmetric conjugate addition of
nitromethane to β-substituted cyclohexanone 10. Initial attempts
at running the reaction in the presence of 20 mol% of (R,R)-cat-9 in
CH2Cl2 for 48 h at r.t. produced the desired adduct (R)-9 in only 15%
yield; however, an excellent enantioselectivity of 98% ee was
observed. After many trials, it was found that by using
nitromethane as solvent, running the reaction at 45 °C for 7 days,
(R)-9 was formed in 80% yield and 97% ee. Importantly, even at a
10 mmol scale, both the high enantioselectivity (97% ee) and yield
of (R)-9 (88% based on the recovery of starting material, 20%) were
retained. By converting (R)-9 into indole derivative (R)-38, we were
able to obtain a single crystal, X-ray diffraction analysis of which
showed that, fortunately, the absolute configuration of 38 and thus
9 is R, which is the one that we need for the enantioselective total
synthesis of haliclonin A (3).
H
N
N
N
H
3C
COOH
N
N
H
N
N
H
NH
NH
cat-2/B
example
N
H
B
CH3
H2N
NH
cat-1
B
L-proline (
)/
N
N
(Hanessian)[26a]
1
NH
S
trans
-2,5-dimethyl
piperazine)
(
cat-3
cat-4
ee
91%
PhCO2H
64%
yield,
(Ley)[26b,c]
NH2
ee
96-99%
73-90%
yield,
kbar)
pressure
(10
70-82%
93-94%
yield
CF3
ee
high
(Kwiatkowski)[26f]
Ye)[26d]
(Liang,
O
F
3C
O
F
F
3C
F
3C
O
O
HN
O
HN
O
HN
HN
N
H
N
H
N
N
3C
F
3C
H
3CO
H
3CO
N
H
3C
cat-6
cat-7
cat-5
CH3
NH2
N
N
CF3
CF3
N
S
S
H
S
(S)
(S)
(R)
F
N
N
3C
N
N
(R)
cat-10 PhCOOH
H
H
F
N
H
N
3C
H
H
NH2
NH2
H
ee
Ye, 2015)[40]
52-92% 96-99%
yield,
(Dixon,
NH2
conversion
15%
for
4-phenylbut-3-en-2-one
cat-9
work:
cat-9
)-
This
Ye)[26d]
Wang)[26e]
(Duan,
R,R
(
cat-8
S,S
(Liang,
(
)-
Figure 2 Some reported organocatalysts that were screened in this work for the asymmetric conjugate addition of nitromethane to cyclic enones
98
97
97
9
Cat-9 (0.20), CH2Cl2, r.t. , 48 h
15
80
70 (88)f
Table 2 Screening of organocatalysts and conditions for the asymmetric
e
10
Cat-9 (0.20), CH3NO2 , 45 °C, 5 d
conjugate addition to β-substituted cyclohexenone
e
O2N
11
Cat-9 (0.20), CH3NO2 , 45 °C, 7 d
conditions
a Unless otherwise specified, the reaction of 10 (0.5 mmol) with
CH3NO2 (2.0 mmol) was carried out in 2 mL of solvent; b Isolated
yield; c Determined by chiral HPLC analysis; d Not detected. e CH3NO2
as solvent; f The reaction was carried out on a 10 mmol scale, yield
in parentheses is based on recovered starting material.
O
O
10
9
ee (%)c
26
Entry
Conditionsa ([equiv])
Yield (%)b
81
1
2
3
4
5
6
7
8
Cat-1 (0.40), B (1.5), CHCl3, 50 °C, 7 d
Cat-1 (0.40), B (1.5), EtOAc, 50 °C, 7 d
Cat-2 (0.15), B (1.5), CH2Cl2, r.t., 7 d
Enantioselective synthesis of 3-azabicyclo[3.3.1]nonane
framework (1S,5R)-7. After securing a robust method to access (R)-
9 in high enantioselectivity, its transformation into enone (R)-13
was investigated (Scheme 9). Although in the racemic series, this
was realized by a modification of Nicolaou’s method (Scheme 2),
this protocol presents severe limitations. First, the use of a large
excess of IBX⋅NMO complex (4.0 equiv.) not only resulted in low
atom-efficiency, but also introduced difficulties with respect to
work-up and product purification. Second, the reaction can only be
run on a small scale (0.5 mmol). To develop a scalable protocol to
25
72
89
70
80
Cat-2 (0.15), B (1.5), CHCl3, 50 °C, 4 d
Cat-2 (0.15), B (1.5), CH2Cl2, 0 °C, 7 d
Cat-5 (0.20), CH2Cl2, CH3NO2, r.t. to 40 °C, 7 d
Cat-6 (0.20), CH2Cl2, CH3NO2, r.t. to 40 °C, 7 d
Cat-7 (0.20), CH2Cl2, CH3NO2, r.t. to 40 °C, 7 d
75
92
45
NDd
NDd
NDd
<10
<10
<10
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Running title
Chin. J. Chem.
ensure our total synthesis, an alternative method was investigated.
Considering that nitroketone (R)-9 contains two types of acidic α-
protons, with those α- to the nitro group being much more acidic,
to enable an efficient conversion of the ketone to enone, it is
necessary to prevent possible deprotonation of nitro α-H that may
cause side reaction and may consume reagents. To tackle this
problem, a one-pot, two-step protocol involving chemoselective
ketone silyl enol ether (SEE) formation was envisioned. In this
regard, Nicolaou and coworkers have developed another method
for ketone dehydration via the intermediacy of SEEs by using a 4-
methoxypyridine-N-oxide (IBX⋅MPO) complex.[44] The authors have
elegantly proved that the oxidation of SEE involves a single electron
transfer. It occurred to us that this would be the method of choice
for our substrate. Considering the high price of MPO, in particular
for a large-scale synthesis, we opted for N-methylmorpholine N-
oxide (NMO) as a less-expensive alternative. In the event,
nitroketone (R)-9 was treated with TMSOTf and triethylamine (0 °C,
2 h), and the SEE formed in situ was added to a solution of IBX⋅NMO
complex in DMSO (50 °C, 8 h). In this manner, only 2.5 equiv. of
IBX⋅NMO complex was used, and the desired enone was obtained
in 72% yield. Further modification by replacing NMO with pyridine-
N-oxide (PNO) improved the yield to 79%. It is worth noting that
attempted Saegusa oxidation[45] with Pd(OAc)2 led to a complex
mixture of products.
Br
Br
cat-9
mol)
O
O
R,R
)-
(20%
(
NH2
N
H
NO2
(Z)
NO2
45 °C, 5 d
80%
NH
CH3
AcOH, 100 ºC
90%
R
R
)
10
R
)-
9
ee
(R)
(
O2N
(97%
TMSOTf
a)
38
79%
steps)
IBX·PNO
b)
(2
O
OH
NaBH4 CeCl
,
c)
NO2
3
NH2
then Zn, HCl
R
R
18
X-Ray structure of 38
13
)-
R
(
OH
PMB
TMSCl;
OH
H
e)
ArSC(O)Cl
SAr
O
MnO
95%
f)
2
PMPCHO
N
d)
N
PMB
then HCl
aq.
NaBH(OAc)3
R
R
13
73%
R
. =
40a Ar Ph
40b Ar
[from
O
(
)-
]
39
.
=
p
-tolyl
one
13
chromatography from
R
( )-
only
O
PMB
SAr
,
dppp
2
g) Pd(OAc)
N
=
R
R
O
75-82%
R
O
N
PMB
.
.
=
22a
22c
R
R
Ar Ph
(
(
)-
)-
=
Ar p-tolyl
7
R
)-
S
,5
(1
After sequential reduction of the ketone and nitro groups in (R)-
13, the resulting amino alcohol 18 was subjected to reductive
alkylation [PMPCHO, NaBH(OAc)3] to give N-PMB derivative 39. The
latter was converted into S-phenyl thiocarbamate 40a in a one-pot
reaction by sequential in situ protection of the hydroxyl group,
reaction with S-phenyl chlorothioformate, and chemoselective
removal of the silyl group. Note that only one chromatographic
purification was needed from compound (R)-13 to 40a (a 73%
overall yield of compound 40a was obtained). Oxidation of 40a with
MnO2 afforded enone (R)-22a in 95% yield, followed by the newly
developed Pd-mediated Heck-type cyclization reaction to afford
the desired product (1S,5R)-7 in 79%. To avoid the high toxicity and
repulsive odor of both benzenethiol and the corresponding S-
phenyl chlorothioformate, the reagents used for the preparation of
S-phenyl carbamothioate (R)-22a, we envisioned the use of 4-
methylbenzenethiol as a safer surrogate of benzenethiol. To our
delight, the corresponding S-(p-tolyl)carbamothioate (R)-22c was
prepared in a similar yield (75–82%), and the cyclization of (R)-22c
proceeded similarly. With the success in cyclization by Heck-type
reaction, the radical cyclization reactions[31] of (R)-22a, (R)-22b and
(R)-22c were not pursued.
Construction of the tricyclic core. Having developed a seven-
step enantioselective synthesis of the 3-azabicyclo[3.3.1] nonane
framework (1S,5R)-7 from 10, in which the key Heck-type
cyclization of (R)-22a,c can be run on a gram-scale, we then
pursued the total synthesis of halichonin A (3). Our next task was
the regioselective introduction of a side chain at the less-hindered
α-position of the ketone. The failure to achieve a direct
deprotonation–alkylation in a related ring system[18] prompted us
to investigate an indirect aldol addition-based method (cf. Scheme
1). Preliminary investigation on racemic 7[17c] allowed optimal
reaction conditions to be defined. Thus, TiCl4/ Hünig base-
mediated aldol addition[46] of (1S,5R)-7 with aldehyde 6b[18] gave
adduct 41 in 82% yield as a single regio- and diastereoisomer, the
stereochemistry of which has been confirmed previously[17c]
(Scheme 10). Subjecting diene 41 to the RCM reaction using Grubbs’
first generation catalyst[20] and high dilution technique (0.0003
mol/L in CH2Cl2, 40 °C, 24 h)[17c] produced cyclized product 42 as an
inseparable mixture of geometric isomers in 92% yield. The lack of
diastereoselectivity in this reaction is of no consequence since the
alkene will be saturated in a subsequent step. The subsequent
mesylation and elimination with DBU merit comments. Initial
attempts at mesylation of the geometric isomers 42 followed by
treatment of the resultant mesylate with 2.0 equiv of DBU afforded
a mixture of α,β-enone 43a and β,γ-enone 43b in a ratio of 1:1.
Although the two diastereomers are inseparable by flash
chromatography on silica gel, the observed characteristic coupling
Scheme 9 Construction of the azabicyclo[3.3.1]nonane skeleton based on
catalytic asymmetric conjugate addition and Pd-mediated cyclization
1
constant (J = 14.6 Hz) in the H NMR spectrum allowed the E-
geometry of the enesulfonamide moiety in 43b to be deduced. The
mixture of 43a and 43b was subjected to Pd-catalytic
hydrogenation to give a mixture of 44a and 44b in a 1:1 ratio. We
suspected that 44a and 44b were generated from 43a and 43b,
respectively. To confirm this hypothesis, an in situ monitoring by 1H
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
O
SO2Ph
N
NMR was undertaken. It was observed that the isolated olefinic
bond was saturated within 4 h, while that of enesulfonamide
required about 7 days. We also observed that solvent has a
profound impact on the reaction: in EtOAc, whereas the yield was
only 20%, in a 1:1 (v/v) mixture of EtOAc and MeOH, the yield was
50%. When the reaction was run in anhydrous THF, the yield was as
high as 95%, even on a gram scale. Interestingly, 44a was efficiently
converted into 44b upon treatment with t-BuOK in THF (95% yield).
1H NMR monitoring of the elimination reaction with DBU showed
that prolonging the reaction time also resulted in a conversion of
44a into 44b. Based on these findings, we developed a
chemoselective transformation of 42 into 43b that was achieved
simply by using 8.0 equiv of DBU for the elimination step (r.t., 16 h,
yield: 85%). Catalytic hydrogenation of 43b afforded 44b in 92%
yield with the desired aza-macrocycle in place.
8
TiCl4 NiPr Et
HO
,
a)
H
2
(S)
1
2
5
4
(R)
SO2Ph
N
O
N
O
O
N
6b
PMB
O
PMB
7
82%
S
,5
41
(1
R)-
Grubbs I 92%
b)
N
PhO2S
O
PhO2S
N
HO
43a
;
MsCl, TEA, CH2Cl2
DBU
N
O
equiv)
(2
=
dr 1:1
r.t., 4 h
O
PMB
+
N
O
PMB
88%
42
N
PhO2S
;
MsCl, TEA, CH2Cl2
O
85%
DBU
r.t., 16 h
To install an alkynyl group on the amide nitrogen, the PMB
group in 44b was oxidatively cleaved with CAN in a mixture of
MeCN/H2O solvents to give 45. We observed that the yield was
highly dependent on the ratio of mixed solvent. A 4: 1 (v/v) mixture
of MeCN/H2O produced 45 in 60% yield, along with imide 46 in 20%
yield, whereas with a 1: 1 (v/v) mixture of MeCN/H2O, the yield
dropped to 40%. A high yield of 88% was obtained when a 10: 1
(v/v) mixture of MeCN/H2O was used. Attempted direct N-
alkylation of 45 using alkynyl iodide 48 formed compound 50 in a
low yield (10%). Thus the ketone group was first protected to give
47 in 95% yield. N-Deprotonation with KHMSD followed by
alkylation with 48 gave the desired product 49 in 65% yield (80%
BRSM). An excellent yield of 90% was obtained when KH was used
as the base for the deprotonation.
(8 equiv),
43b
H2 Pd/C, THF, r.t., 7 days
,
N
O
PMB
92%
43a
+
N
N
PhO2S
43b
PhO2S
O
N
O
H2 Pd/C
,
+
THF, r.t., 7 days
O
:
=
:1
44a 44b
1
N
O
tBuOK, THF
PMB
44b
PMB
44a
95%
95%
PhO2S
N
PhO2S
N
CAN
eq.)
(4
+
Scheme 10 Stereoselective formation of the 17-membered macrocycle to
forge the tricyclic core
CH CN/H O
(10:1)
3
2
O
O
N
O
HN
OTMS
O
O
TMSO
46
PMP
45
(trace)
(88%)
ethylene glycol
95%
I
PhO2S
O
N
PhO2S
O
N
48
KH, THF
90%
O
N
O
HN
O
O
49
47
Construction of the multifunctional 15-membered ring. To
undertake an aldol reaction to introduce the side-chain for RCAM,
the acetal in 49 was cleaved with a 3 M HCl in acetone (r.t., 3 days),
which afforded keto-lactam 50 in 99% yield (Scheme 11).
Unexpectedly, under a variety of conditions, the aldol reaction of
50 with n-butanal used as a model aldehyde was unsuccessful.
Considering that the failure may be due to steric hindrance, the N-
phenylsulfonyl group in 49 was replaced with a formyl group (54)
via a three-step protocol consisting of desulfonylation (Mg, MeOH,
ultrasonic irradiation),[47] formylation (HCO2Et, TEA, reflux), and
deacetylation (3 M HCl). To our disappointment, an attempted
aldol reaction of functionalized ketone 54 was also unsuccessful.
Scheme 11 Attempted direct aldol addition reactions
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Running title
Chin. J. Chem.
diastereomeric ketones, 61a and 61b, were obtained in 45% and
22% overall yield, respectively, from 56. It is noteworthy that
although intramolecular reductive coupling of enones[50] with
aldehydes is known, the intermolecular version of the latter
reaction is unprecedented. The stereochemistries of the two newly
formed stereogenic centers were not determined at this stage, but
deduced from compound 67 at a later stage (vide infra). The major
diastereomer 61a was employed for the total synthesis.
PhO
O
N
2S
N
PhO
N
2S
N
3
M HCl, acetone
O
O
r.t., days
3
99%
O
O
49
50
MeOH,
CO2Et,
reflux
83%
steps)
a) Mg,
)))
TEA
n
various
conditions
-butanal
H
(2
b)
51
Scheme 12 Introduction of the chiral side-chain
PhO
O
PhO
2S
N
2S
OHC
PhO
OH
2S
N
N
N
OH
DBU;
TESOTf,
X
HCHO,
Sc(OTf)3
X
N
O
O
O
N
50
N
55
N
52
O
N
O
O
.
.
=
=
53
54
X+X
X+X
O
O
O
(CH2)2
3
M
HCl, acetone
95%
TEA; DBU
MsCl,
70%
50
(from
)
At this stage, a stepwise tactic employed by Li and Nicolaous in
the total syntheses of anominine and tubingensin A attracted our
attention.[48] Inspired by Li’s work,[49] an indirect approach was
pursued. Thus ketone 50 was treated with TESOTf/DBU, and the
resulting SEE was subjected to the Sc(OTf)3-promoted[48,49]
Mukaiyama aldol reaction with formaldehyde to give the presumed
α-hydroxymethylation product 55 (Scheme 12). We were unable to
isolate 55 in its pure form because partial epimerization and
elimination of 55 into 56 occurred during purification by column
chromatography. To our delight, subjecting the diastereomeric
mixture 55 to mesylation and elimination with DBU produced 56 in
70% overall yield from 50. Enone 56 and aldehyde 57a were
reductively coupled using SmI2 (Kagan’s reagent).[50] To our surprise,
the major product appeared to be enol 58. Although the lability of
enol 58 prevented its isolation in pure form, its structure was
tentatively assigned on the basis of an analysis of the mass
PhO
OH
2S
PhO
O
2S
CHO
N
TBSO
57a
TBSO
−
HO
SmI2 THF, 78 ºC
,
N
O
N
O
58
unstable)
(major product,
56
TESOTf,
−
57a
THF, 78 ºC
TEA
SmI
,
,
CHO
a)
b)
CH2Cl2
60% steps)
2
a)
TESO
•
HF
b)
Pyr.
57b
−
then 15% NaOH
(aq.)
N
(2
SmI2 THF, 78 ºC;
,
PhO
H
2S
PhO
2S
TBSO
N
OTES
HO
TESO
O
N
61a
TESO
59
O
spectrum and H/13C NMR spectra of the crude material. The
1
N
O
(45%)
+
following experimental evidence support this hypothesis. First,
when O-TES protected aldehyde 57b was successively subjected to
the SmI2-mediated reductive coupling with enone 56, and to O-
silylation of the resulting product with TESOTf, tris-O-TES-protected
SEE 59 was obtained as a separable mixture of two diastereomers
in a 2: 1 ratio. Second, in our previous effort to undertake a direct
aldol reaction of 50 (Scheme 11), we have observed the formation
of SEE 60 from the corresponding ketone 50 upon treatment with
TESOTf/DBU, and TESOTf/TEA was ineffective for this
transformation. These observations allowed us to deduce that SEE
59 was formed by silylation of the corresponding enol. Although
labile, the direct observation of the enol form of an unactivated
ketone is a rare phenomenon,[51] which turned out to be crucial for
us to achieve the total synthesis of haliclonin A (3) (vide infra).
To simplify product isolation and characterization, a protocol
was developed to allow the isolation of the product in pure ketone
form. The protocol comprised the SmI2-mediated reductive
coupling with aldehyde 57a, O-silylation of the crude material with
TBSOTf, selective mono-desilylation of the primary silyl ether with
Olah’s reagent (HF⋅Pyr.) in THF, and a basic work-up with a 15%
aqueous solution of NaOH. In such a manner, two separable
=
dr
2:1)
(
PhO
2S
PhO
2S
N
N
H
TESOTf
DBU
OTBS
50
HO
TESO
O
N
N
O
O
61b
60
(22%)
To introduce the enyne moiety, required for the RCAM[19]
reaction, diastereoisomer 61a was subjected to successive Dess-
Martin oxidation and Wittig reaction with ylide generated in situ
from 62[52] to afford enediyne 63a in 75% yield over two steps
(Scheme 13). Under Fürstner’s alkyne metathesis conditions using
Fürstner’s catalyst generated in situ from precursor 64 and MnCl2,
RCAM of compound 63a proceeded smoothly to give the tetracyclic
framework of haliclonin A (65a) in 70% yield.[53] Controlled
hydrogenation of the alkynyl group in 65a using Lindlar catalyst
afforded tetracyclic diene (13Z,16Z)-66a in 95% yield.[54] It is worth
noting that over-reduction is a common problem in the Lindlar
reduction. We tackled this problem by using a mixed solvent system
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EtOAc/1-hexene (1:1, v/v). Following the same sequence, the
minor diastereoisomer 61b was converted into 66b in a similar
overall yield. However, this diastereoisomer (65b) is less reactive
towards Lindlar reduction, which required the use of 300% w.t. of
Lindlar catalyst and a 3:1 (v/v) EtOAc/1-hexene solvent system.
Compound 65a was hydrogenated to give 67 to confirm its
structure by single-crystal X-ray diffraction analysis. The result
indicates that the configuration at C11 is R, and the relative
stereochemistry around the tetracyclic core is in agreement with
that reported for the natural product. The determined absolute
configuration 3R,4S,6R,11R is consistent with the displayed
structure, but opposite to that descibed in the text of ref. 14.
Scheme 13 Formation of the 15-membered macrocycle to build the tetracyclic core
PhO
H
2S
PhO
H
2S
PhO
H
2S
H
2 Lindlar cat.
d)
N
N
N
TBSO
TBSO
TBSO
w.t.
w.t.
65a
65b
)
for
for
(50%
(300%
)
11
DMP, NaHCO
64 MnCl
a)
b)
3
,
2'
c)
2
2'
HO
EtOAc/1-hexene
(1:1,
(3:1,
M
S
4Å
MS
5Å,
PPh
3 I
O
O
O
65a
65b
v/v for
v/v for
)
)
OMe
62
NaHMDS
N
N
N
O
O
O
95%
92%
.
.
.
.
61a
61b
75% steps
61a
)
.
.
S
R
from
from
63a
63b
65a
65b
S
R
S
R
70%
65%
(2'
(2'
)
)
(2
(11
(11
)
)
(2'
(2'
)
)
OSiPh3
N
Ph3SiO
steps
61b
80%
(2
)
Mo
Ph3SiO
N
H
e)
2
100%
64
10% Pd/C
PhO
H
2S
PhO2S
N
TBSO
N
TBSO
PhO
H
2S
H
11
TBSO
(R)
N
HMDS
TMSI,
11
(R)
CH3CN, reflux
quant.
(R)
O
RO
N
N
(S)
(R)
O
O
O
N
O
=
=
68
69
66a
)
.
.
TMS, from
H)
66a
66b
S
R
(R
(R
(11
(11
)
)
67
65a
X-ray structure 67
of
(from
)
Completion of the total synthesis of (−)-haliclonin A: The end
game. Although we were very close to the target, the last battle,
the dehydration of ketone to form the enone moiety turned out to
be quite challenging. After many unsuccessful attempts for a direct
dehydration of 66a using IBX,[27] Pd(TFA)2,[55] DDQ, etc., we
investigated an indirect method via silyl enol ethers. To our surprise,
compound 66a was reluctant to deprotonation with a strong base
(LDA, KH) at –78 °C, whereas at a temperature higher than –30 °C,
the substrate was destroyed. An alternative method utilizing
TMSOTf-TEA combination was also unrewarding. Finally, we were
pleased to find that compound 66a could be quantitatively
converted into the corresponding SEE 68 by exposure to TMSI/
HMDS in refluxing MeCN,[56] as confirmed by 1H NMR spectroscopic
analysis. Attempts to purify the product by flash chromatography
on SiO2 resulted in partial decomposition to give the corresponding
enol 69, possibly stabilized by H-bonding with the nitrogen atom of
the lactam. For the subsequent oxidation of SEE to enone, as shown
in Table 3, more than fifteen methods and conditions[30,44,17e,57]
were tried, but all failed to yield the desired enone 70.
Nevertheless, careful analysis of the results gave us useful
PhO
2S
PhO
H
2S
N
N
TBSO
TBSO
H
conditions
TMSO
O
N
N
O
O
68
70
Entry
1
Conditions (equiv.)
Yield (%)a
Pd(OAc)2 (5.0), CH3CN, r.t.
Pd(OTFA)2 (5.0), CH3CN, r.t.
Pd(OAc)2 (5.0), DMSO, r.t.
0b
2
Decomposed
3
0
4
Pd(OAc)2 (5.0), DMSO, 80 °C
Decomposed
5
Pd2(dba)3 (0.2), 71c (5.0), CH3CN, reflux
PhSeCl (2.0), DCM, –78 °C to –20 °C
PhSeCl (1.1), DCM, r.t.
NRd
6
NR
7
0
NR
8
IBX (2.5), PNO (2.6), DMSO, r.t.
IBX (2.5), PNO (2.6), DMSO, 80 °C
DDQ (4.0), CH3CN, r.t.
information. As can be seen from entries 1, 14, and 15, although
[45]
the oxidation with Pd(OAc)2
and AZADO+BF4 (Iwabuchi’s
9
Decomposed
NR
oxidant)[57] failed to give any product, a combination of the two
10
11
12
13
reagents led to the formation of enone 70, albeit in only 5% yield.
DDQ (4.0), CH3CN, reflux
Decomposed
Decomposed
NR
Table 3 Attempted conversion of SEE 68 into enone 70
CAN (2.5), DMF, 0 °C
72e (1.5), DCM, r.t.
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Running title
Chin. J. Chem.
To complete the total synthesis, compound 66a was
desulfonylated by reaction with Mg in methanol under ultrasonic
irradiation,[47] and the resulting crude amine was formylated with
ethyl formate/ pyridine to give diamide 73 in 82% yield over two
steps (Scheme 15). Ketone 73 was treated with TMSI-HMDS in
refluxing acetonitrile[56] to yield enol 75, and the latter was exposed
to HOAc/ silica gel to give enol 75. Oxidation of enol 75 produced
the desired enone 76 in 68% yield. The geometry of the enone 76
was not determined at this stage, but deduced from the final
product 3. To the best of our knowledge, this represents the first
example of direct conversion of an enol into an enone. Finally
14
15
72 (1.5), CH3CN, r.t.
NR
5b,f
72 (1.5), Pd(OAc)2 (2.0), CH3CN, r.t.
a
1
b
Crude yield determined by H NMR spectroscopic analysis;
Compound 68 partially decomposed; 71: Diallyl carbonate; d No
c
reaction; e 72: AZADO+BF4– (Iwabuchi’s oxidant); f Enone 70 is labile.
Considering the lability of SEE 68, we supposed that Pd(OAc)2
might play the role of promoting the cleavage of SEE 68 to give enol
69, and the latter was oxidized by AZADO+BF4. To test this idea, SEE
68 was treated with HOAc/ SiO2, which gave enol 69 in 86% yield
from 66a. Enol 69 is sufficiently stable to allow a chromatographic
desilylation
of
76
with
tris(dimethylamino)sulfonium
difluorotrimethylsilicate (TASF)[58] afforded (–)-haliclonin A (3) in 82%
yield. The sense of optical rotation and spectral (1H and 13C NMR,
the ratio of rotamers = 3: 2) data of our synthetic compound fully
matched those reported for the natural haliclonin A (3), but a
difference exists for the values of specific rotation {synthetic 1:
purification. To our delight, oxidation of enol 69 with AZADO+BF4
–
(72) at 0 °C furnished the desired enone 70 in 63% yield.
Scheme 14 Conversion of ketone 66a into enone 70
20
20
PhO
2S
[α]D –42.1 (c 1.0, MeOH); natural 1: [α]D –23.6 (c 0.14,
MeOH)[14]}. The fact that the synthetic compound displayed the
same sign of optical rotation as that of the natural product implies
that the absolute configuration of natural (–)-haliclonin A (3) is
3R,4S,6R,11R, which is in agreement with the structure displayed
in Figure 1 of ref. 14 (cf. Figure 1), but different from that suggested
in the text of ref. 14 (3S,4R,6S,11S).
N
TBSO
H
HMDS
TMSI,
HOAc, SiO2
CH2Cl2
68
66a
CH3CN, reflux
O
H
86% steps)
(2
N
O
69
BF4
PhO
H
2S
N
TBSO
N
O
72
CH2Cl2 0 ºC
,
O
N
63%
O
70
Scheme 15 Completion of the total synthesis of (–)-haliclonin A
PhO
H
2S
OHC
OHC
TBSO
TBSO
TBSO
N
N
N
H
H
AcOH
d)
SiO2
TMSI
c)
HMDS
MeOH
a) Mg,
85%
HC Et,
O2
O
O
TMSO
b)
Pyr.
66a
N
N
N
(from
)
O
O
O
82% steps)
(2
73
74
66a
H
OHC
OHC
O
H
17
TBSO
HO
N
TBSO
N
N
BF4
e)
H
H
N
O
TASF
f)
72
15
O
HO
O
82%
N
N
68%
N
O
O
O
−
75
A 3
( )-haliclonin ( )
76
synthesis of (–)-haliclonin A (3). Through this campaign, the
structure of natural haliclonin A (3) including the stereochemistry
of the skipped diene moiety has been confirmed, and its absolute
configuration was clarified as 1E,3R,4S,6R,11R,13Z,16Z. This
Conclusions
We have accomplished the catalytic enantioselective total
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
conclusion in turn confirmed Shin’s hypothesis about the
biosynthetic relationship between haliclonin A and sarain A. In the
course of this work, some new chemistries have been developed,
which include the thiourea (R,R)-cat-9-catalyzed asymmetric
conjugate addition of nitromethane with 3-substituted cyclohex-2-
enone, Pd-promoted intramolecular coupling of thiocarbamate
moiety with an enone in a conjugate addition manner, SmI2-
mediated bimolecular reductive coupling of enone with aldehyde,
and direct transformation of enol into enone. The value of these
methods and/ or concepts is highlighted by the development of a
catalytic version of the Pd-catalyzed intramolecular coupling of
thiocarbamates with enones developed by Yang and coworkers.
Chemistry and Biology; vol. 73, 223−329. Hans-Joachim, K., Ed.;
Academic Press: London, 2014.
(a) Baldwin, J. E.; Whitehead, R. C. On the Biosynthesis of Manzamines.
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R. C.; Boughtflower, R. J.; Mutton, I. M.; Upton, R. J. Investigations into
the Manzamine Alkaloid Biosynthetic Hypothesis. Angew. Chem. Int.
Ed. 1998, 37, 2661−2663. For a review, see: (c) Duval, R.; Poupon, E.
Biomimetic Synthesis of Manzamine Alkaloids. in Biomimetic Organic
Synthesis. pp 181−224; Biomimetic Organic Synthesis. Eds. Poupon, E.
and Nay, B. Wiley-VCH: Weinheim, 2011.
Karan, D.; Dubey, S.; Pirisi, L.; Nagel, A.; Pina, I.; Choo, Y. M.; Hamann,
M. T. The Marine Natural Product Manzamine A Inhibits Cervical
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Alkaloids from An Indo-Pacific Sponge. Pharmacokinetics, Oral
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Experimental
The general procedure and all the characterization data of the
synthetic intermediates as well as the procedures used to prepare
them are listed in the Supporting Materials online. Known
compounds were recorded in the previous report.[17c,d,18]
Crystallographic data for compounds 38 (CCDC 1442504) and
67 (CCDC 1442503) have been deposited at the Cambridge
Crystallographic Data Centre.
Hamann, M. T. The Manzamines as an Example of the Unique
Structural Classes Available for the Discovery and Optimization of
Infectious Disease Controls Based on Marine Natural Products. Curr.
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Supporting Information
For a review on synthetic studies, see: Matzanke, N.; Gregg, R. J.;
Weinreb, S. M. Biomimetic and Synthetic Approaches to Marine
Sponge Alkaloids Derived from Bis-pyridine Macrocycles. A review.
Org. Prep. Proced. Int. 1998, 30, 1−51.
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2020xxxxx.
Acknowledgement
For enantioselective total syntheses: Madangamines: (a) Ballette, R.;
Perez, M.; Proto, S.; Amat, M.; Bosch, J. Total Synthesis of (+)-
Madangamine D. Angew. Chem. Int. Ed. 2014, 53, 6202−6205.
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Manzamine A. J. Am. Chem. Soc. 2010, 132, 10233−10235. (c)
Humphrey, J. M.; Liao, Y.-S.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.;
Courtney, A. K.; Martin, S. F. Enantioselective Total Syntheses of
Manzamine A and Related Alkaloids. J. Am. Chem. Soc. 2002, 124,
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(−)-Nakadomarin A. Angew. Chem. Int. Ed. 2016, 55, 4332–4335. (e)
Bonazzi, S.; Cheng, B.; Wzorek, J. S.; Evans, D. A. Total Synthesis of (−)-
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B.; Wu, F.-F.; Yang, X.-B.; Zhou, Y.-D.; Wan, X.-L.; Zhai, H.-B. Efficient
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The authors are grateful for financial support from the National
Natural Science Foundation of China (Grant No. 21672176,
21931010, and 21472153), the National Basic Research Program
(973 Program) of China (Grant No. 2010CB833200), and the
Program for Changjiang Scholars and Innovative Research Team in
University (PCSIRT) of Ministry of Education, China. Ms. Yan-Jiao
Gao is thanked for assisting in the submission of this manuscript.
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Running title
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
Entry for the Table of Contents
H
Direct oxidation of
New
Page No.
organocatalytic asymmetric
addition
enol
enone
to
conjugate
creacted
Catalytic Asymmetric Total Synthesis of
Macrocyclic Marine Natural Product (–)-
Haliclonin A
RCM
O
17
N
OH
H
1 all-C* to
induce 3 chiral C*enters
SmI2
13
11
N
O2 CH3
(R)
(Z)
New Pd-mediated Heck-type
addition of thiocarbamate
15
(R) (S)
O
16
conjugate
(Z)
N
a
version
Concept for catalytic
O
on
Mo-catalyst
RCAM
Shin's
the
and sarain
relationship
A confirmed
−
hypothesis
between haliclonin A
biosynthetic
A
( )-Haliclonin
A crucial synergism of organo- and metal catalysis: The campaign of the catalytic asymmetric total
synthesis of (–)-haliclonin A started from an organocatalytic asymmetric conjugate addition, and
ended with the oxidation of an enol to the final enone with Iwabuchi’s oxoammonium salts. The
total synthesis is also highly reliant on metal catalysis: e.g., Pd-mediated Heck-type conjugate
addition, RCM with Grubbs’ Ru-catalyst, RCAM with Fürstner’s Mo-catalyst, and enone-aldehyde
reductive cross-coupling with Kagan’s reagent (SmI2).
Shi-Peng Luo,† Xiong-Zhi Huang,† Lian-Dong Guo,†
and Pei-Qiang Huang*
www.cjc.wiley-vch.de
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2020, 38, XXX－XXX
This article is protected by copyright. All rights reserved.