Total Synthesis of (-)-Daphnezomines A and B

Article abstract of DOI:10.1021/jacs.0c06717

Daphnezomines A and B are structurally unusual Daphniphyllum alkaloids that contain a unique aza-adamantane core skeleton. Herein, a modular approach to these alkaloids is presented that exploits a diverse array of reaction strategies. Commencing from a chiral pool terpene-(S)-carvone, the azabicyclo[3.3.1]nonane backbone, which occurs widely in Daphniphyllum alkaloids, was easily accessed through a Sharpless allylic amination and a palladium-catalyzed oxidative cyclization. A protecting group enabled a stereoselective B-alkyl Suzuki-Miyaura coupling sequence and an Fe-mediated hydrogen atom transfer (HAT)-based radical cyclization were then applied to construct C6 and C8 stereocenters. A final epimer locking strategy enabled the assembly of the highly congested aza-adamantane core, thereby achieving the first total synthesis of (-)-daphnezomines A and B in 14 steps.

Full text of DOI:10.1021/jacs.0c06717

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Communication
Total Synthesis of (–)-Daphnezomines A and B
Guangpeng Xu, Jinbao Wu, Luyang Li, Yunan Lu, and Chao Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06717 • Publication Date (Web): 19 Aug 2020
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Journal of the American Chemical Society
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Total Synthesis of ( )-Daphnezomines A and B
Guangpeng Xu,†,§,‡ Jinbao Wu,§,‡ Luyang Li,§ Yunan Lu,§ Chao Li*,§,
∥
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†College of Life Sciences, Beijing Normal University, Beijing, 100875, China
§National Institute of Biological Sciences (NIBS), Beijing, 102206, China
∥Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China
ABSTRACT: Daphnezomines A and B are structurally unusual Daphniphyllum alkaloids that contain a unique aza-adamantane core
skeleton. Herein, a modular approach to these alkaloids is presented that exploits a diverse array of reaction strategies. Commencing
from a chiral pool terpene–(S)-carvone, the azabicyclo[3.3.1]nonane backbone, which occurs widely in Daphniphyllum alkaloids,
was easily accessed through a Sharpless allylic amination and a palladium-catalyzed oxidative cyclization. A protecting group enabled
a stereoselective B-alkyl Suzuki-Miyaura coupling sequence, and an Fe-mediated hydrogen atom transfer (HAT)-based radical cy-
clization were then applied to construct C6 and C8 stereocenters. A final epimer locking strategy enabled the assembly of the highly
congested aza-adamantane core, thereby achieving the first total synthesis of (-)-daphnezomines A and B in 14 steps.
The Daphniphyllum alkaloids are a structurally diverse and
complex family of natural products isolated from plants of the
genus Daphniphyllum. They exert a broad spectrum of biologi-
O
O
cal activities, including anticancer, anti-HIV, and antioxidant
N
N
N
effects.1 Their highly congested, polycyclic architectures have
long provided organic chemists with challenging targets for de-
velopment of innovative synthetic strategies and methodologies,
resulting in a number of elegant total syntheses (Figure 1).2,3 For
example, in the 1980s and 1990s, Heathcock and co-workers
completed several remarkable syntheses of daphniphylline-type,
secodaphniphylline-type, bukittinggine-type, and daphni-
lactone A-type alkaloids.4 More recently, many prominent total
syntheses of daphmanidin A-type, calyciphylline A-type, and
calyciphylline B-type alkaloids have been reported by the
groups of Carreira,5 Li,6 Smith,7 Fukuyama,8 Hanessian,9
Dixon,10 Zhai,11 Qiu,12 Xu,13a Gao,14 and Sarpong.15 In 2019, the
Xu group also reported a total synthesis of a bukittinggine-type
alkaloid.13c
secodaphniphylline-type
& Bukittinggine-type
(Heathcock, Xu)
daphniphylline-type
daphnilactone A-type
(Heathcock)
(Heathcock)
O
N
N
N
calyciphylline A-type
calyciphylline A-type
daphmanidin A-type
(Li, Fukuyama, Zhai, Qiu)
(Li, Zhai, Dixon, Xu, Gao)
(Carreira, Smith)
daphnezomine A-type
CO2X
CO2
5
N
OH
The Daphnezomine A-type alkaloids are a subfamily of
Daphniphyllum alkaloids with a rare aza-adamantane core skel-
eton. To date, only three members of this subtype are known,
including daphnezomines A (1) and B (2),16 as well as daphold-
hamine B (3).17 In 2019, the Xu group reported the first total
synthesis of dapholdhamine B (3) in 22 steps;13b however, daph-
nezomines A (1) and B (2) have not been prepared synthetically.
They each possess an aza-adamantane core bearing a carbino-
lamine bridge system, and were first isolated by Kobayashi and
co-workers from the leaves of Daphniphyllum humile in 1999.16
Daphnezomine B (2) was found to exert notable cytotoxicity in
murine lymphoma L1210 cells, with an IC50 at 1.3 µM.16 Given
their intricate architecture and biological potential, our aim in
the present study was to devise a novel and concise approach to
access these natural products. We here report the first total syn-
thesis of (-)-daphnezomines A (1) and B (2) based on a modular
synthetic strategy.18
N
HN
calyciphylline B-type
ꢀHanessian (5-epi),
Sarpong]
OH
dapholdhamine B (3)
X = H, daphnezomine A (1)
X = Me, daphnezomine B (2)
(Xu, 2019, 22 steps)
Figure 1. Frameworks of previously synthesized Daphniphyllum
alkaloids, and the structures of daphnezomine A-type alkaloids.
Retrosynthetically, we envisioned that daphnezomines A (1)
and B (2) could be accessed from keto amine tautomer (4) via a
keto amine-carbinolamine tautomerization.19 We also used top-
ological strategies in planning,20 which identified the oppor-
tunity to disconnect the topologically strategic C8–C9 bond of
4—breaking a bridged 6-membered ring—to substantially sim-
plify the overall synthetic route. We speculated that it may be
possible to address construction of the bridgehead C8 all-carbon
quaternary stereocenter by employing hydrogen atom transfer
(HAT)-initiated intramolecular radical conjugate addition, us-
ing alkene 5.21 Alternatively, keto amine 4 might also be gener-
ated from 5 via a stepwise strategy, perhaps using acid or base-
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promoted intramolecular cyclization followed by a hydrogena-
Page 2 of 7
a combination of 2-methoxy-5,5-dimethyl 1,3-dioxane and 2,2-
dimethylpropane-1,3-diol in the presence of a catalytic amount
of p-TsOH at 50 °C produced the bulky ketal 13 in 80% yield
(Scheme 2). Note that the exo-methylene of 7 is prone to mi-
grate to its endo-isomer under acidic conditions over 50 °C.
Next, we initially used a single isomer–(R)-2-iodocyclohex-2-
enol [(R)-14, 94% ee] as the coupling partner in the following
B-alkyl Suzuki-Miyaura coupling reaction. Our major goal here
was to generate a relatively simple reaction mixture to facilitate
isolation and elucidation of the product structure(s). Gratify-
ingly, treatment of 13 with 9-BBN, followed by standard Su-
zuki-Miyaura coupling conditions with (R)-14, gave rise to the
desired product 15 in 71% NMR yield with high diastereoselec-
tivity (> 20:1). The stereochemistry at C6 of 15 was further con-
firmed by X-ray crystallographic analysis of 16, which was pro-
vided by Dess-Martin oxidation of 15. We also noted that the
addition of coligand AsPh3 in the Suzuki-Miyaura reaction was
essential for reproducibility at scale; it could increase the turn-
over rate of the Pd catalyst (see SI for details).27
1
2
3
4
5
6
7
8
tion. Alkene 5 could be further disconnected to ketone 6, which
could in turn be assembled through a stereoselective B-alkyl Su-
zuki-Miyaura coupling reaction from exo-olefin 7.22 The azabi-
cyclo[3.3.1]nonane ring system of 7, which occurs widely in the
Daphniphyllum alkaloids, could be obtained from 8 through a
palladium-catalyzed oxidative cyclization,23 which would con-
struct another all-carbon quaternary stereocenter at C5. Com-
pound 8 could be easily prepared from 9, which is a known
compound synthesized by Magnus and co-workers from the si-
lyl enol ether 10 through a Sharpless allylic amination.24 Com-
pound 10 could be readily traced back to a commercially avail-
able chiral pool terpene–(S)-carvone (11).25
9
10
11
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Scheme 1. Retrosynthetic Analysis
CO2X
CO2X
keto amine–carbinolamine
tautomerization
8
9
H
H+
HN
HN
tautomer-locked
Although the 1,3-dioxane protecting group at C8 could facil-
itate the diastereoselective installation of the cyclohexene moi-
ety, removal proved to be unexpectedly challenging, owing to
the lability of the C11 allylic alcohol of 15 in acid conditions.
Happily, after extensive screening of reaction conditions, we
found that treatment of 15 with TFA led to i) initial formation
of a relatively stable C11 trifluoroacetate intermediate, fol-
lowed substantially later by ii) removal of 1,3-dioxane. This in
situ generated trifluoroacetate intermediate could be hydrolyzed
facilely via a basic workup process. Interestingly, the desired
product 6 was afforded in good yield but as 1:1 diastereomers
at C11, which indicated that the esterification of the C11 allylic
alcohol underwent a classic SN1 reaction. Having elucidated the
aforementioned diastereoselective hydroboration and racemiza-
tion of the C11 allylic alcohol, we eventually opted to use the
easily prepared rac-14 in the preceding Suzuki-Miyaura reac-
tion. Thus, the desired product 6 was delivered after a deprotec-
tion process in 58% overall yield from 13 at gram scale.
H
OH
O
X = H
daphnezomine A (1)
X = Me
4
HAT-based
radical cyclization
daphnezomine B (2)
CO2Me
O
8
olefination
9
TsN
HN
HO
6
O
5
stereoselective B-alkyl
Suzuki–Miyaura coupling
OTIPS
palladium-catalyzed
O
Ts
N
oxidative cyclization
5
TsN
7
8
O
OTIPS
OTIPS
Sharpless
allylic amination
TsHN
With the requisite ketone 6 in hand, we turned our attention
to installation of the 3-carbon side chain at C8. However, at-
tempts to perform this transformation via direct olefination
failed, owing to the strongly sterically hindered C8 ketone.
Thus, we adopted a two-step sequence involving initial nucleo-
philic addition to the ketone, followed by a dehydration. Addi-
tion of Grignard regent 17 to ketone 6 afforded 18 as a mixture
of epimers at C8 in 80% yield. The presence of Knochel’s salt
(LaCl3•2LiCl) was required;28 otherwise, the sterically hindered
C8 ketone of 6 was easily reduced by the Grignard regent via a
b-hydride transfer process. It is also noteworthy that: i) direct
addition of Grignard regent 17 to ketone 7 followed by a B-alkyl
Suzuki-Miyaura reaction led to either no reaction or poor dia-
stereoselectivity at C6 (Scheme S3); ii) the C11 alcohol of 6
could exert some directing effect on the 1,2-addition of 17 to
the C8 ketone of 6 (Scheme S6).
(S)-(+)-carvone
9
10
11
As shown in Scheme 2, we started our venture with the initial
aim of obtaining the azabicyclo[3.3.1]nonane 7. Global hydro-
genation of the alkenes in 11,26 followed by exposure of the en-
suing ketone to TIPSOTf and Et3N provided silyl enol ether 10
in 80% yield. Compound 10 was then treated with a freshly pre-
pared Sharpless aminating reagent using a modified Magnus’s
procedure to afford the amination product 9 in 41% yield at
decagram scale.24b Treatment of 9 with NaH, followed by the
addition of allyl bromide, gave rise to 8 in 93% yield. Next,
having drawn inspiration from Magnus’s elegant investiga-
tion,24b we were pleased to find that the desired azabicy-
clo[3.3.1]nonane ring system could be made successfully by ex-
posing 8 to a catalytic amount of Pd(OAc)2 (20 mol%) under O2
atmosphere;23 the desired product 7 was obtained in excellent
yield at decagram scale.
Now in possession of the intermediate 18—which contains
all of the carbon and nitrogen atoms of the natural products—
we focused our efforts on the construction of the aza-adaman-
tane ring system. Removal of the Ts group and reprotection of
the resulting free amine with Boc group followed by a Dess-
Martin oxidation of the C11 alcohol furnished enone 19 in 79%
overall yield as a mixture of diastereomers (C8 d.r. = 2.5:1).
Notably, these two diastereomers converged to a single com-
pound after dehydration with Burgess reagent, and the
With access to bridged bicycle 7 secured, we next investi-
gated the stereoselective installation of the cyclohexene side
chain. We reasoned that protection of the bridgehead ketone 7
prior to hydroboration would be a strategic maneuver. A bulky
ketal protecting group could increase the steric hindrance of the
convex face of 7, thereby promoting the diastereoselective hy-
droboration from the desired concave face. Treatment of 7 with
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Scheme 2. Total Synthesis of Daphnezomines A (1) and B (2)
1
2
3
4
O
OTIPS
OTIPS
Ts
N
4.
1ꢀ H2, Rh/Alumina,
then TIPSOTf, Et3N, 80%
O
8
TsHN
3. allyl bromide
Pd(OAc)2, O2
TsN
2. Se, Chloramine-T
41%, Ref. 24b
91%
O
O
NaH, 93%
5.
6
[decagram scale]
O
p-TsOH
80%
5
6
7
[decagram scale]
(S)-(+)-carvone
9
8
7
11
12
OBn
6ꢀ 9-BBN
then 14, Pd(dppf)Cl2
aq. NaOHꢀ AsPh3
C6 d. r. > 20:1
8
9
O
O
8
7. TFA, then aq. NaOH
O
8. LaCl3•2LiCl, 80%
8
C11 d. r. = 1:1
O
OH
TsN
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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TsN
TsN
6
11
61% over 2 steps from
(R)-14
TsN
BrMg
OBn
[gram scale]
11
H
11
H
17
6
H
HO
58% over 2 steps from
rac-14
I
HO
HO
6
15
(R)-14, 94% ee
or rac-14
18
13
DMP
81%
9. Na, Naphthalene, then Boc2O, Et3N
then DMP, 79%, C8 d. r. = 2.5:1
HO
16 [X-ray]
AcHN
OBn
BF4
N
OBn
O
21
CO2Me
CO2Me
H
10.
11. Bobbitt’s salt (21)
H
2
H
8
13. See Table 1
Burgess reagent
noe
4
12. TMSCHN2, then TFA
OH
5
6
H2N
H
BocN
H
BocN
H
90%
TFA
61% over 2 steps
HN
H
10
12
[gram scale]
O
O
O
O
22 [X-ray]
19
5
20
conditions
1
2
14.
TFA/CH3CN/H2O 53% 0%
TFA/MeOH/H2O 34% 54%
conditions
CO2H
CO2Me
ArCOCl
DMAP
22
TMSCHN2
95%
TEA, 71%
Ar =
HN
HN
TFA
TFA
2,4-di-NO2-C6H3
OH
OH
X-ray of 16
X-ray of 24
X-ray of 2•HBr
daphnezomine B (2) [X-ray]
daphnezomine A (1)
Table 1. Investigation of the 6-endo-trig Cyclization
At this stage, we concentrated our efforts on the challenging
6-endo-trig cyclization. We considered three different tactics to
deliver the cyclized products 23, 22, or 2 (Table 1): i) Lewis
acid-promoted ene cyclization;30 ii) base-mediated anionic cy-
clization; and iii) HAT-initiated radical conjugate addition.21
However, numerous studies with the first two reaction types
proved unfruitful (entries 1 and 2, Table S1 and S2), presuma-
bly due to the steric crowding of C8. Fortunately, the desired
cyclization could be achieved successfully using Baran’s HAT-
initiated radical conjugate addition conditions (entry 3), and the
trans-fused adduct 22 was afforded as the sole cyclized product.
Notably, the success of this third reaction is consistent with the
knowledge that free radical reactions are generally less sensitive
to steric constraints.31
CO2Me
CO2Me
H
H
6-endo-trig
H
2
H
8
2
8
5
cyclization
H
4
4
5
+
ꢀꢁ
2
H
5
conditions
HN
HN
H
6
O
6
12
H
O
12
23
Conditionsa
22
23
Entry
1
22b
2
Lewis acids: BF3•2AcOH, BF3•Et2O, FeCl3,
AgOTf, AlCl3 et al. (for details, see Table S1)
bases: Et3N, Pyridine, DBU, LDA, LiHMDS
KHMDS et al. (for details, see Table S2)
Fe(acac)3, PhSiH3, EtOH, 60 ℃
0
-
-
2
0
-
-
-
-
-
-
-
-
3
4
5
6
7
8
16%
17%
5%
ND
ND
ND
ND
ND
ND
Fe(acac)3, Ph(i-PrO)SiH2, EtOH, 60 ℃
Fe(dibm)3, Ph(i-PrO)SiH2, EtOH, 60 ℃
The structure of 22 was elucidated by NMR analysis, and was
further confirmed by X-ray crystallographic analysis of a 2,4-
dinitrobenzoyl derivative 24 (Scheme 2). We speculate that the
C10–H in 22 was delivered from the ammonium proton in 5
through a 1,5-proton transfer, which resulted in a trans-fused
ring junction of the product (Scheme S5). This hypothesis could
also explain our observation that 22 was generated in a free
amine form after the cyclization reaction. Extensive screening
of conditions for reductive olefin coupling (Table S3) revealed
that treatment of 5 with Fe(acac)3 and Ph(i-PrO)SiH2 in
THF/EtOH at low concentration provided the highest yield of
22 (32%, Table 1, entry 8). Note that the unprotected amine was
needed for successful cyclization, owing to its reduced steric
profile and its ability to provide a proton. A crude NMR analy-
sis explained the relatively low yield, the reduction of the enone
Fe(acac)3, Ph(i-PrO)SiH2, EtOH/(CH2OH)2, 60 ℃
Fe(acac)3, Ph(i-PrO)SiH2, THF/EtOH (0.02 M), 60 ℃
Fe(acac)3, Ph(i-PrO)SiH2, THF/EtOH (0.001 M), 60 ℃
22%
26%
31%(32%c)
aSee SI for details bYield determined by 1H NMR with CH2Br2 as
an internal standard. cIsolated yield.
desired product 20 was afforded in 90% yield. We anticipated
that removal of the benzyl group of 20 in a manner that would
not disturb the alkene, the enone, or the acid sensitive Boc group
would be challenging. Surprisingly, oxidation of 20 with Bob-
bitt’s salt (21) afforded the carboxylic acid directly, with good
chemoselectivity.29 Esterification of the resulting acid with
TMSCHN2 followed by deprotection of the Boc group with
TFA produced 5 in 61% overall yield from 20 (gram-scale).
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moiety by Fe-H was dominant over the sterically hindered tri-
substituted bridgehead alkene. The steric hindrance of the al-
kene is caused by the vicinal C5 quaternary carbon as well as
the 1,3-diaxial strain resulting from the C2–H, C4–H, and C6–
C12 bonds. To complete the syntheses, our plan to convert keto
amine 22 to the carbinolamine-containing natural products
drew inspiration from Heathcock and Lei’s elegant studies of
carbinolamine locking strategies for the synthesis of Lycopo-
dium alkaloids.19 Treatment of keto amine 22 with TFA led to
C10 epimerization and produced daphnezomines A (1) and B
(2) bearing the TFA-locked aza-adamantane core (Scheme 2).
Although the NMR data of 1•TFA was slightly different from
that reported for natural zwitterion form of 1, treatment of
1•TFA with TMSCHN2 could provide 2•TFA in 95% yield. All
physical and spectroscopic data of the synthetic 2•TFA were in
good accordance with those reported for natural daphnezomine
B. Moreover, the structure of our synthetic daphnezomine B
was elucidated unambiguously by X-ray crystallographic anal-
ysis of its hydrobromide salt.16
1
2
3
4
5
6
7
8
sion (Z181100001318008), MOST of China, and Tsinghua Insti-
tute of Multidisciplinary Biomedical Research, Tsinghua Univer-
sity. We thank Dr. Xiaobo Wan and Mr. Jincai Yang (NIBS) for
DFT-calculations. We are grateful to Dr. Kyle S. McClymont and
Dr. John H. Snyder for editorial advice on manuscript preparation.
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(2) (a) Kang, B.; Jakubec, P.; Dixon, D. J. Strategies towards the
Synthesis of Calyciphylline A-type Daphniphyllum Alkaloids. Nat.
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In summary, we achieved the first total synthesis of daphne-
zomines A and B via a modular synthetic strategy involving 14
steps. The decagram-scale preparation of azabicyclo[3.3.1]non-
ane 7, featuring a Sharpless amination and a palladium-cata-
lyzed oxidative cyclization, was an enabling basis for the total
synthesis. The key stereochemistry at C6 was generated by a
stereoselective B-alkyl Suzuki-Miyaura coupling reaction. Fi-
nally, the late-stage construction of the aza-adamantane core
was achieved through a HAT-initiated intramolecular radical
conjugate addition and an epimer locking strategy. This synthe-
sis also illustrates that a classic topological strategy, used in
combination with a modern radical coupling reaction, repre-
sents a powerful strategy for achieving the concise total synthe-
sis of polycyclic natural products. Importantly, our early-stage
strategy in this synthesis should be immediately extendable for
the syntheses of other highly congested Daphniphyllum alka-
loids; such work is under way and will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications
Experimental details, spectroscopic data for all new compounds
(PDF)
website.
X-ray crystallographic data for 16 (CIF)
X-ray crystallographic data for 24 (CIF)
X-ray crystallographic data for 2•HBr (CIF)
AUTHOR INFORMATION
Corresponding Author
*lichao@nibs.ac.cn
Author Contributions
‡G.X. and J.W. contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We appreciate Prof. Phil S. Baran (Scripps Research) and Dr. Ming
Yan for helpful discussion. Financial support for this work was
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