Gold(I)/copper(II)-cocatalyzed tandem cyclization/semipinacol reaction: Construction of 6-Aza/Oxa-Spiro[4.5]decane skeletons and formal synthesis of (±)-halichlorine

Article abstract of DOI:10.1002/adsc.201400932

A simple and efficient strategy for the construction of 6-aza/oxa-spiro[4.5]decane skeletons under the cocatalysis of gold(I)/copper(II) was developed, and its potential utility was demonstrated by a formal synthesis of the biologically active marine alkaloid (±)-halichlorine.

Full text of DOI:10.1002/adsc.201400932

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DOI: 10.1002/adsc.201400932
Gold(I)/Copper(II)-Cocatalyzed Tandem Cyclization/Semipinacol
Reaction: Construction of 6-Aza/Oxa-Spiro[4.5]decane Skeletons
and Formal Synthesis of (Æ)-Halichlorine
Dao-Yong Zhu,a Zhen Zhang,a Xue-Qing Mou,b Yong-Qiang Tu,a,c,*
Fu-Min Zhang,b Jin-Bao Peng,a Shao-Hua Wan,a,b,* and Shu-Yu Zhanga
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000 People’s Republic of China
School of Pharmacy, Lanzhou University, Lanzhou, 730000 People’s Republic of China
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300000 People’s Republic of China
b
c
Fax : (+86) 931-8912582; e-mail: tuyq@lzu.edu.cn or wangshh@lzu.edu.cn
Received: September 24, 2014; Revised: December 7, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400932.
Abstract: A simple and efficient strategy for the
construction of 6-aza/oxa-spiro[4.5]decane skeletons
under the cocatalysis of gold(I)/copper(II) was de-
veloped, and its potential utility was demonstrated
by a formal synthesis of the biologically active
marine alkaloid (Æ)-halichlorine.
a single step.[10–12] Selected examples for the construc-
tion of the aza-spiro[4.5]decane moiety include an ad-
dition/dipolar cycloaddition developed by Padwaꢀs
group, and Kibayashiꢀs intramolecular ene reac-
tion.[10,11] Therefore, the exploration for an alternative
efficient approach for the synthesis of the spirocyclic
scaffold remains highly desirable.
Keywords: cocatalysis; copper; gold; marine alka-
loid; spirocycle
Because of our fascination with these structures,
and our long-standing interest in the total synthesis of
natural products using the semipinacol reaction,[13,14]
we have previously developed a tandem intramolecu-
lar hydroamination/semipinacol rearrangement, which
has been successfully applied to the formal synthesis
The development of strategies for the efficient con- of (À)-cephalotaxine (eq. 1 in Scheme 1).[15] However,
struction of complex molecular skeletons is consis- this method is only effective for the synthesis of the
tently a popular topic in the synthetic community.[1] aza-spiro[4.4]nonane skeleton, and the attempts for
Especially with the rapid development of certain dis- the construction of another important type of spiro-
ciplines such as chemical biology and pharmaceutical skeleton, i.e., 6-aza/oxa-spiro[4.5]decane, have failed.
chemistry, and the appearance of modern tech- Based on the experimental results, we envisioned that
niques,[2] there has been significant growth in the the appropriate introduction of a carbonyl group in
demand for bioactive natural products and their de-
rivatives. Aza/oxa-spirocyclic skeletons, as key struc-
tural moieties, broadly exist in a number of bioactive
natural products, such as capillosanane Q, capillosa-
nane I,[3] cephalotaxin,[4] pinnaic acid,[5] and halichlor-
ine[6,7] (Figure 1). Because of the special bioactivity
and structural complexity of these molecules, particu-
larly their potential for future drug discovery, strat-
egies toward the syntheses of the relevant aza/oxa-spi-
rocyclic skeletons have attracted the attention of or-
ganic chemists. Therefore, a variety of methodologies
has been developed.[8,9] Among these methodologies,
a stepwise introduction of the required aza/oxa-tetra-
substituted-carbon center and the spirocyclic system
has generally been employed. Few reports are avail-
able for a more straightforward strategy that affords
the corresponding aza/oxa-spirocyclic skeleton in tures.
Figure 1. Natural Products Containing Oxa/Aza-Spiro Struc-
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Table 1. Optimization of the Reaction Conditions.[a]
Entry Catalyst
T
Yield
[h] [%][b]
1
2
3
4
5
AuCl
PtCl2
8
8
8
8
8
9
0
15
25
28
[PPh3 AuCl]/AgOTf(1:1)
[PPh3 AuCl]/AgOTf/p-TsOH(1:1:1)
[(BINAP)(AuCl)2]/AgBF4/p-
TsOH(1:2:2)
Scheme 1. Tandem Cyclization/Semipinacol Reactions.
6
[(BINAP)(AuCl)2]/AgOTf/p-
TsOH(1:2:2)
[(BINAP)(AuCl)2]/AgBF4/p-
TsOH(1:2:2)
[(BINAP)(AuCl)2]/AgBF4/
Sc(OTf)3(1:2:2)
[(BINAP)(AuCl)2]/AgBF4/
In(OTf)3(1:2:2)
[(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:2)
[(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:1)
8
41
47
62
66
69
60
67
the substrates might facilitate the expected cycliza-
tion/rearrangement process through a dual-activation
mode, therefore providing an alternative strategy for
the synthesis of the related natural products. In this
study, we present our research results of this method-
ology and its application in the formal synthesis of
(Æ)-halichlorine (eq. 2 in Scheme 1).[7]
7
8
8
8
9
8
We commenced our investigation with compound
1a as the model substrate. As shown in Table 1, in the
initial tests using common p-acids, such as AuCl and
PtCl2, only the use of AuCl could afford the desired
spirocyclic product 2a in a very low yield of 9%, and
most of 1a was recovered.[16] Fortunately, when
[PPh3 AuCl]/AgOTf (1:1) was used as the catalyst, 2a
could be obtained in a slightly higher yield of 15%.
Based on this information and our previous experi-
ence with the semipinacol type vinylogous a-ketol re-
arrangements,[17] we assumed that the presence of an-
other Lewis/Brønsted acid might better promote the
reaction by coordinating to the carbonyl group ulti-
mately leading to a better outcome. Following this
speculation, we observed that the addition of p-TsOH
(10 mol%) into the reaction system clearly improved
the yield of 2a, and the use of p-TsOH/[PPh3 AuCl]/
AgBF4 (1:1:1) gave a yield of 28% in CH2Cl2. Addi-
tionally, the reactivity difference between AuCl and
[PPh3 AuCl]/AgOTf (1:1) further prompted the evalu-
ation of the corresponding ligand effect.[18] According-
ly, it was found that changing the ligand to BINAP
could further increase the yield of 2a to 47%. In-
trigued by these results, we tested the combination of
10
11[c]
12
12
12
12[d] [(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:3)
13
Cu(OTf)2
12
12
0
0
14[e] [(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:2)
15[f]
[(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:2)
12
18
38
45
16[g] [(BINAP)(AuCl)2]/AgBF4/
Cu(OTf)2(1:2:2)
[a]
Reaction conditions: 1a (0.1 mmol), catalyst (5 mol%),
o
and CH2Cl2 (1.0 mL) stirred at C under an argon atmos-
phere for 1 h, and then warmed to room temperature
until full consumption of 1a. p-TsOH=p-toluenesulfonic
acid.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
[(BINAP)(AuCl)2]/AgBF4/Cu(OTf)2 (1:2:1) (5 mol%).
[(BINAP)(AuCl)2]/AgBF4/Cu(OTf)2 (1:2:3) (5 mol%).
THF (1.0 mL) instead of CH2Cl2.
Toluene (1.0 mL) instead of CH2Cl2.
CHCl3 (1.0 mL) instead of CH2Cl2.
[g]
[(BINAP)(AuCl)2]/AgOTf (1:2) along with different when THF was used as the solvent, only substrate 1a
Lewis acids as the catalyst. Among the catalysts ap- was recovered from the reaction system.
plied, the use of [(BINAP)(AuCl)2]/AgBF4/Cu(OTf)2
With the determination of the optimized conditions
(1:2:2) resulted in the best yield of 69%.[19] Moreover, (Table 1, entry 10), we examined the generality of this
increasing the catalyst loading to 0.15 equiv did not tandem reaction. As summarized in Table 2, a variety
significantly affect the yield, whereas decreasing the of 6-aza/oxa-spiro[4.5]decanes could be obtained
amount of the catalyst to 0.05 equiv clearly led to from the corresponding propargyl alcohols using this
a lower yield (60%). Note that 2a was not detected method. In the case of the 5-hydroxy-1-(1-hydroxycy-
with Cu(OTf)2 as the sole catalyst. Additionally, a sol- clobutyl) pent-1-yn-3-ones, compounds with substitu-
vent effect was observed for this reaction. Among the ents at the C-5 position, which is closer to the reac-
solvents screened, the use of toluene and CHCl3 gave tion site, the change from the mono-methyl (1b) to
2a in a 38% and 45% yield, respectively. In contrast, the geminal dimethyl substitution (1c) reduced the re-
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Gold(I)/Copper(II)-Cocatalyzed Tandem Cyclization
Table 2. Substrate Scope of the Tandem Cyclization/Semipi-
nacol Reaction[a]
[a]
Reaction conditions: 1 (0.09–0.74 mmol), (5 mol%) [BI-
NAP(AuCl)2]/AgBF4/Cu(OTf)2(1:2:2) in CH2Cl2 (0.1–
0.75 mL) stirred at 08C for 1 h and then stirred at room
temperature for 11 h for an isolated yield.
For 120 h.
Refluxed for 24 h.
Scheme 2. Preliminary mechanistic studies.
[b]
NAP)(AuCl)2]/AgOTf (1:2) only gave 2e in very low
yield (eq. 2). Also, the reaction was carried out with
CH2Cl2/D2O (10:1) as solvent. Although the reaction
rate and yield were significantly affected in the pres-
ence of D2O, we could eventually manage to get the
[c]
[d]
At À158C for 1 h, and then stirred at room temperature
for 11 h.
action yield from 64% to 53% because of the possi- product 2e with a H/D ratio of ~1:1 at 2-position (eq.
ble existence of steric hindrance (Table 2, products 2b 3). Additionally, intermediate 2e’ was obtained with
vs. 2c). In contrast, the substituents at the C-4 posi- a H/D ratio of ~1:6.7 at 2-position without the use of
tion did not significantly affect the yield. Substrates Cu(OTf)2 (eq. 4). Moreover, in the same solvent, such
with a phenyl (1d), geminal dimethyl (1e) or geminal an intermediate 2eꢀ could be transformed to 2e with
diallyl group (1 f) at the C-4 position afforded the de- a H/D ratio of ~1:2.6 (eq. 5) at 2-position. All of
sired products in a good yield. Meanwhile, when the these results supported the initial design of such
geminal dialkyl substituents were replaced by a cyclo- a tandem reaction (Scheme 1, eq. 2). Additionally, the
pent-3-enyl moiety, the expected product was also iso- use of Cu(OTf)2 might more efficiently promote the
lated in good yield. In addition, the substrate scope rearrangement of reaction intermediate via the activa-
could be further expanded to the compounds with tion of corresponding carbonyl group.
a nitrogen atom as the nucleophilic center leading to
Encouraged by our experimental results, particular-
the efficient construction of the 6-aza-spiro[4.5]de- ly the successful synthesis of aza-spiro-ketone 2i, we
cane skeleton. Therefore, the subjection of substrates attempted the synthesis of a corresponding natural
1i and 1j to the standard reaction conditions pro- product with this methodology to demonstrate its util-
duced the expected products 2i (72% yield) and 2j ity. Therefore, halichlorine, a representative bioactive
(66% yield), respectively. Note that the reaction ex- marine alkaloid, was chosen as the target molecule.[7]
hibited excellent diastereoselectivity for the substrates The corresponding formal synthesis was started with
1b, 1d, 1h and 1j to give the corresponding products compound 2i, and primarily focused on the introduc-
as single diastereoisomers.[20]
tion of the required stereocenters to the spirocyclic
Besides, for some substrates, like 1e, we could iso- skeleton (Scheme 3). Because the carbonyl group on
late the reaction intermediate 2e’, which could be the piperidine ring would cause side reactions in the
converted to the desired product 2e in nearly quanti- subsequent nucleophilic steps, it was initially protect-
tative yield under the catalysis of Cu(OTf)2 ed through a Wittig reaction to give compound 3,
(Scheme 2, eq. 1). While treatment of 2e’ with [(BI- which could afford the amide 4 in a 65% yield in two
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Scheme 3. Formal Synthesis of (Æ)-Halichlorine.
steps, i.e., deprotection of the Ts group and amidation oped and applied in the formal synthesis of halichlor-
with 2-bromoacetyl bromide. We encountered certain ine.[7] This methodology not only further enriched the
difficulties with the desired intramolecular Reformat- content of the semipinacol rearrangement but also
sky reaction under the standard reaction conditions.[21] provided an efficient method for the construction of
Among the solvents tested, such as toluene, 1,4-diox- the 6-aza/oxa-spiro[4.5]decane skeletons and the syn-
ane, dimethoxyethane and tetrahydrofuran, only tet- thesis of the related natural products.
rahydrofuran gave the desired product in a poor
yield. We also attempted to use zinc chloride and zinc
powder to further improve the yield of this reaction. Experimental Section
Unfortunately, the desired product was not obtained
except for the debromination product.[22] Fortunately, General procedure:
the expected intramolecular Reformatsky reaction
proceeded smoothly to produce the tricyclic inter-
of [(BINAP)(AuCl)2] (5.6 mg, 0.005 mmol, 0.5 equiv) in dry
AgBF4 (1.9 mg, 0.01 mmol, 1 equiv) was added to a solution
mediate 5 in a 60% yield with iodine as the initia-
tor.[23] Next, ozonolysis of the terminal olefin followed
by dehydration provided amide 7 in a 36% yield in
two steps.[24] The high-pressure hydrogenation condi-
tions successfully transformed compound 7 into com-
pound 8 in an 88% yield. A known three-step trans-
formation method, to introduce the desired carbon-
carbon double bond and a configuration reversion of
the C-14 methyl, was successfully achieved to give
amide 9, although in a relatively low yield of 25%.
Subsequently, intermediate 10 was obtained by a 1,4-
addition of amide 9 with allylstannane. Finally, pro-
tection of the carbonyl group of 10 with propane-1,3-
dithiol afforded amide 11, an advanced intermediate
reported by Padwaꢀs group toward the synthesis of
halichlorine, thus successfully completing the formal
synthesis.[11,25]
CH2Cl2 (0.5 mL). After the reaction mixture was stirred for
2 h at room temperature, the catalyst [(BINAP)Au2(BF4)2]
was obtained by filtering the mixture through a celite pad.
Next, [BINAP(AuBF4)2] (0.005 mmol) and Cu(OTf)2
(3.6 mg, 0.01 mmol) were added to a solution of 5-hydro-
xy-1-(1-hydroxycyclobutyl)pent-1-yn-3-one 1a (16.8 mg,
0.1 mmol) in anhydrous CH2Cl2 (1.0 mL) under argon. After
stirring for 1 h, the reaction mixture was allowed to warm to
room temperature until the substrates disappeared. The re-
action mixture was concentrated under vacuum. Purification
of the residue by column chromatography on silica gel (pe-
troleum/EtOAc=10:1) provided the desired product.
Acknowledgements
We would like to thank the Natural Science Foundation of
China (Nos. 21102061, 21202073, 21290180, 21272097,
In conclusion, a AuI/CuII-cocatalyzed tandem cycli-
zation/semipinacol reaction was successfully devel- 21372104, and 21472077), the ꢀꢀ111’ꢁ Program of MOE, and
4
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Gold(I)/Copper(II)-Cocatalyzed Tandem Cyclization
the Project of MOST (2012ZX 09201101–003), the funda-
mental research funds for the central universities (lzujbky-
2014-k20) for their financial support.
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[20] The relative configuration was confirmed by X-ray
crystallography. CCDC 1018381 (2b), CCDC 1001590
(2d), 1001591 (2h) and CCDC 1018382 (2j-2) contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge
Crystallographic Data
Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Gold(I)/Copper(II)-Cocatalyzed Tandem Cyclization/
Semipinacol Reaction: Construction of 6-Aza/Oxa-
Spiro[4.5]decane Skeletons and Formal Synthesis of (Æ)-
Halichlorine
7
Adv. Synth. Catal. 2015, 357, 1 – 7
Dao-Yong Zhu, Zhen Zhang, Xue-Qing Mou,
Yong-Qiang Tu,* Fu-Min Zhang, Jin-Bao Peng,
Shao-Hua Wan,* Shu-Yu Zhang
Adv. Synth. Catal. 0000, 000, 0 – 0
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