Total Synthesis of Hybridaphniphylline B

Article abstract of DOI:10.1021/jacs.8b01681

Hybridaphniphylline B (1) is a Daphniphyllum alkaloid possessing 11 rings and 19 stereocenters. Here we report the first total synthesis of 1 featuring a late-stage intermolecular Diels-Alder reaction of a fully elaborated cyclopentadiene and asperuloside tetraacetate. The diene was prepared on the basis of a scalable route to daphnilongeranin B (4). Claisen rearrangement of an allyl dienol ether was exploited as a key step; the subtle variation of the substrate and use of protic solvents suppressed the undesired Cope rearrangement. Daphniyunnine E (6) and dehydrodaphnilongeranin B (7), two congeners of 4, were also synthesized. The dienophile arose from (+)-genipin through glycosylation and lactonization. A one-pot protocol was developed for the diene formation and Diels-Alder reaction; one of the cycloadducts was converted into 1 through reductive desulfurization and global deacetylation.

Full text of DOI:10.1021/jacs.8b01681

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Communication
Total Synthesis of Hybridaphniphylline B
Wenhao Zhang, Ming Ding, Jian Li, Zhicong Guo, Ming
Lu, Yu Chen, Lianchao Liu, Yun-Heng Shen, and Ang Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01681 • Publication Date (Web): 01 Mar 2018
Downloaded from http://pubs.acs.org on March 1, 2018
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Total Synthesis of Hybridaphniphylline B
Wenhao Zhang,†,§ Ming Ding,†,§ Jian Li,†,§ Zhicong Guo,† Ming Lu,† Yu Chen,† Lianchao Liu,† Yunꢀ
Heng Shen,‡ and Ang Li*,†
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†State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shangꢀ
hai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡Department of Phytochemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai
200433, China
Supporting Information Placeholder
via a sequence of 1,2ꢀreduction of the α,βꢀunsaturated enone and
dehydration of the resultant allylic alcohol. Notably, [1,5]ꢀH shift
of the cyclopentadiene could occur under thermal conditions,19
which suggested that the starting positions of the two C=C bonds
should be inconsequential; therefore, 510b might serve as an
ABSTRACT: Hybridaphniphylline B (1) is a Daphniphyllum
alkaloid possessing 11 rings and 19 stereocenters. Here we report
the first total synthesis of 1 featuring a lateꢀstage intermolecular
Diels−Alder reaction of a fully elaborated cyclopentadiene and
asperuloside tetraacetate. The diene was prepared on the basis of a
scalable route to daphnilongeranin B (4). Claisen rearrangement
of an allyl dienol ether was exploited as a key step; the subtle
variation of the substrate and use of protic solvents suppressed the
undesired Cope rearrangement. Daphniyunnine E (6) and dehyꢀ
drodaphnilongeranin B (7), two congeners of 4, were also syntheꢀ
sized. The dienophile arose from (+)ꢀgenipin through glycosylaꢀ
tion and lactonization. A oneꢀpot protocol was developed for the
diene formation and Diels−Alder reaction; one of the cycloadꢀ
ducts was converted into 1 through reductive desulfurization and
global deacetylation.
OH
OH
H
H
O
O
OH
OH
OH
H
O
O
H
O
H
OH
O
H
OH
H
O
MeO2C
Me
Me
H
1: hybridaphniphylline B
12: (+)-genipin
N
Diels Alder
OH
OH
H
O
H
Me
O
O
OH
OH
Me
+
H
O
O
N
O
H
OH
3
2: deacetylasperuloside
The Daphniphyllum alkaloid family comprise more than 320
members with fascinating molecular architectures and diverse
biological activities.1 Synthetic chemists have been intrigued by
the challenges posed by these molecules.1–3 The groups of Heathꢀ
cock,4 Carreira,5 Smith,6 Fukuyama,7 Zhai,8 and Dixon9 accomꢀ
plished elegant syntheses of a dozen of Daphniphyllum alkaloids.
Our endeavors in this area also resulted in the syntheses of several
members of this family.10 During the studies, we developed stratꢀ
egies such as 6π electrocyclization/aromatization for constructing
multisubstituted benzenes10a and alkyne cyclization for assemꢀ
bling azabicyclo[3.3.1]nonanes,10a,b which found further use in the
syntheses of other natural products.11,12 Hybridaphniphylline B (1,
Figure 1) is a complex Daphniphyllum alkaloids containing 11
rings and 19 stereogenic centers, which was isolated by Liu and
coꢀworkers from Daphniphyllum longeracemosum.13,14 Biogenetꢀ
ically, 1 may result from an intermolecular Diels−Alder reaction
of naturally occurring deacetylasperuloside (2) and a putative
cyclopentadiene 3.13,14 This diene shares a 6ꢀ6ꢀ5ꢀ7ꢀ5ꢀ5ꢀhexacyclic
skeleton with the calyciphylline A type Daphniphyllum alkaloids,
such as daphnilongeranin B15 (4), daphniynnine C (longeracinꢀ
phyllin A)16 (5), daphniyunnine E16a (6), and dehydrodaphniꢀ
longeranin B17 (7). Our experience with bioinspired Diels−Alder
cycloaddtion18 and Daphniphyllum alkaloid synthesis10 suggested
an opportunity for an expedient route to the undecacyclic scaffold
of 1. Here we report the first total synthesis of 1 as well as the
syntheses of 4, 6, and 7.
H
H
O
Me
Me
O
O
Me
Me
or
O
H
N
4: daphnilongeranin B
Pauson Khand/
N
H
H
5: daphniynnine C
(longeracinphyllin A)
C=C bond migration
Me
Me
O
O
8
Me
Me
N
N
H
H
8
9
Claisen
rearrangement
Me
O
H
O
H
Me
Me
Me
N
N
CO2Me
O
11
10
OH
Me
Me
O
O
Me
Me
O
O
N
N
H
H
6: daphniyunnine E
7: dehydrodaphnilongeranin B
Figure 1. The structure and retrosynthetic analysis of hybridaphꢀ
niphylline B (1).
We first undertook a retrosynthetic analysis of 1 (Figure 1). Inꢀ
spired by the biosynthetic hypothesis, 1 was disassembled to give
the Diels−Alder substrates 2 and 3. The latter may arise from 4
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Scheme 1. Total Syntheses of Daphnilongeranin B (4), Daphniyunnine E (6), and Dehydrodaphnilongeranin B (7)
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son−Khand/C=C bond migration22 strategies toward the synthesis
Table 1. Studies of the Claisen rearrangement of the allyl
dienol ethers
of calyciphylline A type alkaloids. We confirmed the stereochemꢀ
ical outcome of the Claisen rearrangement using an elaborated
tetracyclic substrate in a previous study.23 The dienophile 2 may
arise from comerically available (+)ꢀgenipin (12).
We first investigated the Claisen rearrangement for the conꢀ
struction of the quaternary C8 (Table 1). Dienol ether 13 (see the
SI for preparation) was initially used as a substrate (entries 1 and
2). Under the thermal conditions (entry 1), a trace amount of
Claisen product 14 (a single C8 diastereomer) was detected.
Compound 15 resulting from a Claisen/Cope cascade turned out
to be predominant; we observed the epimerization at C10 presumꢀ
ably through tautomerization at elevated temperature. Boeckman
and coꢀworkers exploited the combination of TiCl4 and AlMe3 to
solely accelerate the Claisen rearrangement of an allyl dienol
ether.24 Under these conditions (entry 2), we still obtained 15 (a
single C10 diastereomer; specified as 15r) as a major product,
along with a small amount of 14. An alternative substrate 16 was
then prepared (Scheme 1). 11 was subjected to Krapcho demethꢀ
oxycarbonylation to afford compound 17, which underwent αꢀ
selenation followed by oxidative elimination to give α,βꢀ
unsaturated enone 18. Treatment with KHMDS and allyl bromide
furnished the dienol ether, which was subjected to the convenꢀ
tional thermal conditions (entry 3). Claisen product 19 and
Claisen/Cope product 20 (specified as 20r) were isolated as single
diastereomers in 48% and 5% yields, respectively, and 38% of 16
was recovered. However, an attempt to improve the conversion of
16 by prolonging the reaction times resulted in production of a
significant amount of 20 (entry 4). To our delight, the Claisen
rearrangement proceeded smoothly in basic MeOH/water25 at 80
°C to provide 19 in 94% yield (entry 5); the Cope rearrangement
did not ensue. The reaction was performed on 5 gram scale.
entry
1a,b
2d
3a,f
4a,g
5i
S
conditions
oꢀDCB, 140 °C, 3 h
products (yield [%])
13
13
16
16
16
14 (<2)
14 (<5)
19 (48)
19 (46)
19 (94)
15c (31)
15e (47)
20e (5)
20h (27)
20 (0)
TiCl4, AlMe3, 0 °C
oꢀDCB, 120 °C, 12 h
oꢀDCB, 120 °C, 24 h
aq. NaOH/MeOH, 80 °C, 3 d
a47 mol% iꢀPr2NEt. b53% recovery of 13. c10R:10S = 1.7:1. d3.2 equiv [Ti], 3.2
e
f
equiv [Al], 100 wt% 4 Å MS, CH2Cl2. 10R only. 38% recovery of 16. g9%
recovery of 16. h10R:10S = 20:1. iv [aq. NaOH (0.010 M)]:v (MeOH) = 5:2.
alternative precursor of the diene. A robust route to 4 was reꢀ
quired for the study of the Diels−Alder reaction. We could also
exploit 4 as a versatile intermediate for the preparation of other
calyciphylline A type Daphniphyllum alkaloids, such as 6 and 7.
The bicyclo[3.3.0]octenone motif of
4 indicated a Pauꢀ
son−Khand/C=C bond migration20 strategy, leading to 1,6ꢀenyne
8 as a suitable precursor. Truncation of the side chain gave 1,5ꢀ
diene 9, the quaternary C8 of which could result from Claisen
rearrangement of allyl dienol ether 10. The challenge was to supꢀ
press the Cope rearrangement of 9 under the Claisen conditions.
Notably, the direct alkylation strategy to prepare 9 type intermeꢀ
diates was unsuccessful because the O and γꢀC of the dienolate
precursor turned out to be more nucleophilic than the αꢀC. 10 was
traced back to tetracycle 11, which had been prepared by us on a
large scale.10b It is noteworthy that Dixon and coꢀworkers contribꢀ
uted greatly to the development of the Claisen21 and Pauꢀ
The completion of the syntheses of 4, 6, and 7 was depicted in
Scheme 1. 1,5ꢀDiene 19 was elaborated into a Pauson−Khand
substrate 21. Selective hydroboration of the terminal C=C bond
with Cy2BH followed by oxidation afforded a primary alcohol,
which underwent Swern oxidation and Seyferth−Gilbert homoloꢀ
gation with 22 to give alkyne 23. Exposure of this compound to
Lawesson reagent furnished 21. A survey of Pauson−Khand conꢀ
ditions identified MeCN26 as an effective promoter for the transꢀ
formation from the the alkyne dicobalt complex [generated from
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Scheme 3. Preparation of the Dienophile
Scheme 2. Preparation of the Diene
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With the diene and dienophile in hand, we focused our attention
to the intermolecular Diels−Alder reaction for completing the
synthesis of 1 (Scheme 4). A convenient protocol was developed
for the in situ preparation of the dienes from their precursor 31:
MgSO4 was exploited as a mild yet efficient dehydrating reagent
at elevated temperature. In the presence of MgSO4 and BHT at
160 °C, cyclopentadiene 29 was generated in situ from 31 and
then reacted with 34 to give cycloadducts 35–37. A small amount
of cycloadduct 38 corresponding to diene 32 was also detected.
The yield of the four products reached ca. 79%, and the ratio was
determined to be ca. 3.9:1.7:2.7:1 by 1H NMR. When the mixture
of 29 and 32 (Scheme 2) were used, the cycloaddition efficiency
decreased (ca. 58% yield), while the ratio of the four products
remained unchanged. After HPLC purification, 35–38 was obꢀ
tained in 24%, 12%, 17%, and 8% overall yields from 31, respecꢀ
tively. The structures of 35 and 36 were confirmed by Xꢀray crysꢀ
tallographic analysis (Scheme 4), and those of 37 and 38 were
elucidated through extensive NMR studies.29 We then examined a
variety of Lewis acids as promoters for the Diels−Alder reaction.
However, both substrates were labile under strongly acidic condiꢀ
21 and Co2(CO)8] to the desired products; 24 and 25 were
obatined in 73% yield in a ratio of ca. 2.4:1. This mixture was
subjected to K2CO3/trifluoroethanol for the C=C bond migration,
leading to more substituted enone 26 (63% overall yield from 21).
Raney Ni reduction of this thioamide rendered 4. The syntheses of
racemic and enantioenriched 4 were both achieved through the
described route, and the former synthesis was carried out on a
gram scale. Exposure of 4 to tꢀBuOK and O2 in the presence of
P(OEt)3 gave 6 in 61% yield as a single detectable diastereomer.
Treatment of the TFA salt of 6 with TsOH effected the dehydraꢀ
tion smoothly, providing 7 in 79% yield.
Having developed a robust route to 4, we moved forward to
prepare the diene segment (Scheme 2). Luche reduction of enone
27, a late intermediate in our recent synthesis of 5,10b followed by
mesylation and elimination, gave conjugated diene 28 which,
unfortunately, was not a suitable substrate for Diels−Alder reacꢀ
tion. Interestingly, enone 26, the immediate precursor of 4, unꢀ
derwent a similar sequence to afford an inseparable mixture of 29
and 30 in a ratio of ca 1:16, via the intermediary of allylic alcohol
31. At ambient temperature, the amount of 30 in the mixture
gradually decreased, while that of 29 increased. Meanwhile, anꢀ
other cyclopentadiene isomer, which was postulated to be 32,
emerged. These observations may be attributable to [1,5]ꢀH shift
processes.19 Upon heating at 80 °C for 5 min, the original mixture
turned into another inseparable mixture of 29 and 32 (ca. 2.6:1,
Scheme 2). Prolonged reaction times at this temperature resulted
in the generation of a fifth diene isomer 33, and the ratio of
29:32:33 reached ca. 2.6:1:2.1 after 4 h. We isolated 33 in a pure
form. This compound turned back into a mixture of 29, 32, and 33
(ca. 2.6:1:2.1) at 80 °C in 4 h, which indicated that the formation
of 33 should have essentially no bearing on the efficiency of the
Diels−Alder reaction under thermal conditions.
30
tions. Acetal tolerating Eu(fod)3 (DCE, 80 °C) led to a mixture
of cycloadducts in ca. 30% yield; the predominant component 36
was isolated in 21% yield. Finally, reduction of 35 with Raney Ni
followed by global deacetylation31 rendered 1 smoothly. Over 100
mg of 1 were prepared in total. The spectra and physical properꢀ
ties of synthetic 1, 4, 6, and 7 were identical to those reported for
their naturally occurring counterparts, respectively. The structures
of synthetic natural products 4, 6, and 7 and intermediates 14, 15r,
17, 19, 20r, 24, 25, 26, 28, 31, and 34 were verified by Xꢀray
crystallographic analysis.
In summary, we have accomplished the first total synthesis of 1
exploiting an bioinspired Diels−Alder strategy. To prepare the
diene, we developed a scalable route to 4 and achieved the first
syntheses of 6 and 7. The late stage cycloaddition of dienophile
34 and the in situ generated diene forged the highly congested
norbornene domain of 1.
Subsequently, we prepared asperuloside tetraacetate (34) as the
dienophile (Scheme 3). Known compound27 35 arising from (+)ꢀ
genipin (12) was subjected to a sequence of acetylation, silylation,
and selective deprotection of the less hindered silyl ether, to give
lactol 36 as a mixture of two anomers in a ca. 1:1 ratio. “Dynamic
kinetic” glycosylation of 36 with trichloroacetimidate 37 followed
by desilylation provided compound 38 as a single stereoisomer.
Exposure of 38 to Me3SnOH furnished the lactone moiety28 deꢀ
spite partial deacetylation; reꢀacetylation of the resultant mixture
afforded 34 smoothly.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Scheme 4. Completion of the Synthesis of Hybridaphniphylline B through an Intermolecular Diels−Alder Reaction
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(9) Shi, H.; Michaelides, I. N.; Darses, B.; Jakubec, P.; Nguyen, Q. N. N.;
AUTHOR INFORMATION
Paton, R. S.; Dixon, D. J. J. Am. Chem. Soc. 2017, 139, 17755.
(10) (a) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nat. Chem. 2013, 5, 679. (b) Li, J.;
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14893. (c) Chen, Y.; Zhang, W.; Ren, L.; Li, J.; Li, A. Angew. Chem., Int.
Ed. 2018, 57, 952.
(11) (a) Li, J.; Yang, P.; Yao, M.; Deng, J.; Li, A. J. Am. Chem. Soc. 2014,
136, 16477. (b) Meng, Z.; Yu, H.; Li, L.; Tao, W.; Chen, H.; Wan, M.;
Yang, P.; Edmonds, D. J.; Zhong, J.; Li, A. Nat. Commun. 2015, 6, 6096.
(c) Yang, M.; Li, J.; Li, A. Nat. Commun. 2015, 6, 6445. (d) Yang, M.;
Yang, X.; Sun, H.; Li, A. Angew. Chem., Int. Ed. 2016, 55, 2851. (e)
Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A. Angew. Chem., Int. Ed. 2016, 55,
6964. (f) Li, H.; Chen, Q.; Lu, Z.; Li, A. J. Am. Chem. Soc. 2016, 138,
15555.
(12) Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
(13) Wang, F.; Mao, M.ꢀF.; Wei, G.ꢀZ.; Gao, Y.; Ren, F.ꢀC.; Liu, J.ꢀK.
Phytochemistry 2013, 95, 428.
(14) For isolation of structurally related alkaloids, see: Di, Y.ꢀT.; Wee, C.ꢀ
S.; Li, C.ꢀS.; Kong, N.ꢀC.; Wang, J.ꢀS.; Fang, X.; Zhu, H.ꢀJ.; Wu, Y.ꢀD.;
Hao, X.ꢀJ. Tetrahedron 2014, 70, 4017.
(15) Yang, S.ꢀP.; Zhang, H.; Zhang, C.ꢀR.; Cheng, H.ꢀD.; Yue, J.ꢀM. J.
Nat. Prod. 2006, 69, 79.
(16) (a) Zhang, H.; Yang, S.ꢀP.; Fan, C.ꢀQ.; Ding, J.; Yue, J.ꢀM. J. Nat.
Prod. 2006, 69, 553. (b) Di, Y.ꢀT.; He, H.ꢀP.; Lu, Y.; Yi, P.; Li, L.; Wu,
L.; Hao, X.ꢀJ. J. Nat. Prod. 2006, 69, 1074.
(17) Zhang, H.; Zhang, D.ꢀD.; Li, J.ꢀY.; Shyaula, S. L.; Li, J.; Yue, J.ꢀM.
RSC Adv. 2016, 6, 44402.
(18) (a) Deng, J.; Zhou, S.; Zhang, W.; Li, J.; Li, R.; Li, A. J. Am. Chem.
Soc. 2014, 136, 8185. (b) Deng, J.; Zhu, B.; Lu, Z.; Yu, H.; Li, A. J. Am.
Chem. Soc. 2012, 134, 920.
Corresponding Author
*ali@sioc.ac.cn
Author Contributions
§W.Z., M.D., and J.L. contributed equally.
ACKNOWLEDGMENT
We thank Profs. JianꢀMin Yue and Dean Tantillo and Dr. David
Edmonds for discussions. Financial support was provided by the
National Natural Science Foundation of China (21525209,
21621002, 21772225, and 21761142003), the Chinese Academy
of Sciences (Strategic Priority Research Program XDB20000000
and Key Research Program of Frontier Sciences QYZDBꢀSSWꢀ
SLH040), Shanghai Science and Technology Commission
(15JC1400400 and 17XD1404600), and the K. C. Wong Educaꢀ
tion Foundation.
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