Diastereoselective total synthesis of salvileucalin C

Article abstract of DOI:10.1021/ol501423t

A concise and efficient approach for the diastereoselective total synthesis of salvileucalin C, as well as their biosynthetically related diterpenoids salvileucalin D, salvipuberulin, isosalvipuberulin, and dugesin B, has been reported for the first time. The key features of the strategy are based on a Beckwith-Dowd ring expansion, a tandem diastereoselective Stille coupling/debromination/desilylation/lactonization reaction, and a photoinduced electrocyclic ring contraction.

Full text of DOI:10.1021/ol501423t

Letter
pubs.acs.org/OrgLett
Diastereoselective Total Synthesis of Salvileucalin C
Chenchen Fu, Yuanbao Zhang, Jun Xuan, Chenlong Zhu, Bingnan Wang, and Hanfeng Ding*
Department of Chemistry, Zhejiang University, 148 Tianmushan Road, Hangzhou 310028, P. R. China
S
* Supporting Information
ABSTRACT: A concise and efficient approach for the
diastereoselective total synthesis of salvileucalin C, as well as
their biosynthetically related diterpenoids salvileucalin D,
salvipuberulin, isosalvipuberulin, and dugesin B, has been
reported for the first time. The key features of the strategy
are based on a Beckwith−Dowd ring expansion, a tandem
diastereoselective Stille coupling/debromination/desilylation/
lactonization reaction, and a photoinduced electrocyclic ring contraction.
Salvia is one of the largest genera in the Labiatae family of both
economical and medicinal importance. Since ancient times,
many species of this widely distributed genus have been used in
folk medicine to treat a variety of illnesses.1 Isolation studies
targeting Salvia plants have yielded a wealth of structurally
intriguing and biologically active natural products.2 Recently,
efforts toward identifying novel diterpenoids as potential
medicinal leads resulted in the isolation of several new com-
pounds from Salvia leucantha that possess unusual structures.3,4
Salvileucalin C (1), a novel and highly rearranged neoclerodane
diterpene, and a structurally closely related salvileucalin D (2)
have recently been discovered (Scheme 1a).5
total synthesis. Herein, we report our recent efforts which
culminated in a concise and diastereoselective approach to this
diterpenoid, along with the total synthesis of salvileucalin D (2),
salvipuberulin (3),6 isosalvipuberulin (4)7,8a and dugesin B (5).8
Scheme 2 outlines our initial retrosynthetic analysis of
salvileucalin C (1). We rationalized that 1 might be synthesized
Scheme 2. Initial Retrosynthetic Analysis of Salvileucalin C (1)
Scheme 1. (a) Structures and Biosynthetic Relationship of
Salvileucalins C and D; (b) Structures of Salvipuberulin,
Isosalvipuberulin, and Dugesin B
from salvileucalin D (2) through cyclobutene formation by a
photoinduced 4π-electrocyclic ring closure,9 while the latter
could be derived from a 6π-electrocyclic ring-opening reaction
of a benzonorcaradiene moiety of salvipuberulin (3) followed
by [1,5]-sigmatropic hydrogen migration.10 For the construc-
tion of 3, we envisaged a radical initiated Beckwith−Dowd
ring expansion11 to forge the [5,6]-bicyclic framework of the
molecule. The essential [5,5]-bicycle of 6 could be prepared
through Heck cyclization12 of butenolide 7, which may in turn be
obtained from the readily available building blocks 813 and 9.14
The realization of our synthetic strategy commenced with
the construction of 4,5-dihydrosalvipuberulin (19, Scheme 3).
Zn(OTf)2 catalyzed Mukaiyama aldol reaction15 of silyloxyfuran
It was proposed that 2 is a biosynthetic precursor of 1, whose
bicyclo[3,2,0]hept-6-ene subunit was hypothesized to be formed
through bicyclization of the cycloheptadiene structure. Chal-
lenges in achieving a diastereocontrolled synthesis are foresee-
able since the two chiral centers at C(5) and C(12) locate far
away from each other on the flat scaffold of the molecule. The
unique structural feature of salvileucalin C (1) as well as their
interesting biosynthetic relationship to other constituents from
Salvia species6−8 (Scheme 1b) prompted us to embark on its
Received: May 18, 2014
© XXXX American Chemical Society
A
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Letter
Scheme 3. Synthesis of 4,5-Dihydrosalvipuberulin (19)
Scheme 4. Synthesis of Salvipuberulin (3) and Initial
Attempts in Its Conversion to Salvileucalin D (2)
of 20 (degassed solution) to UV-light irradiation (λ = 254 nm),
homolytic cleavage of the C−Se bond21 followed by β-hydrogen
radical abstraction occurred sequentially to afford salvipuberulin
(3) in 80% yield. Prolonged irradiation of 3 led to electrocyclic
ring opening of the benzonorcaradiene moiety together with
[1,7]-sigmatropic hydrogen migration of the resulting cyclo-
heptatriene 21, furnishing dugesin B (5) in 73% yield from 20.
The spectroscopic (1H and 13C NMR) and mass spectrometric
data of synthetic 3 and 5 were consistent with those reported
for the natural salvipuberulin and dugesin B, respectively.6,8
To our disappointment, all efforts on the isomerization of 5 to
salvileucalin D (2) proved fruitless. Worthy of note, during
attempts in the direct conversion of salvipuberulin (3) to
salvileucalin D (2), we found that both pure forms of individual
structures 3 and 12-epi-3 could be slowly epimerized by
treatment with catalytic pTsOH·H2O (20 mol %) in MeOH at
50 °C, resulting in a 1.3:1 (3/12-epi-3) mixture.22 A plausible
lactone opening and closure process via intermediate 22 accounted
for this transformation.
Having failed in accessing salvileucalin D (2) through a photo-
induced electrocyclic reaction, a revised strategy that involved
the base-promoted ring expansion of bromocyclopropane was
pursued (Scheme 5).23 In this instance, treatment of 13 with
freshly prepared Seyferth reagent24 (PhHgCBr3) gave dibromo-
cyclopropane 23 in 78% yield without any detectable
diastereomer.25 Subsequent demethylation of 23 followed by
triflation of the resulting phenol delivered triflate 25 in 90% yield
over the two steps, setting the stage for the γ-lactone installation.
Using conditions described for 16, the Stille coupling of 25
with stannane 17 followed by HF·Py-promoted lactonization
afforded products 27 and 12-epi-27 in 68% and 14% yields,
respectively (Table 1, entry 1). The improved diastereoselec-
tivity (ca. 5:1) compared with that of 16 to 19 is noteworthy,
and more detailed mechanistic studies are currently underway
in our laboratory. To our surprise, albeit in low yield, the forma-
tion of monobromocyclopropane 28 was also observed,26 which
led us to optimize this one-pot Stille coupling/debromination
reaction. Since the switch of the palladium catalyst did not affect
the debromination (entry 2), we envisioned that the presence of
8 and aldehyde 9 in aqueous media gave exclusively α-product
10 (72% yield), whose cyclization by the Nazarov reaction or
direct cyclodehydration to produce the requisite [5,5]-biyclic
skeleton was however unsuccessful. As an alternative, 10 was
iodinated in the presence of NIS and MeSO3H to afford the
precursor 7 in 75% yield. Although both radical and reductive
Heck cyclization approaches gave satisfactory outcomes, we were
interested in a more straightforward Heck reaction16 to construct
the C(2) ketone concomitantly. Pleasingly, under optimized
conditions [Pd(PPh3)2Cl2, 1,2,2,6,6-pentamethylpiperidine,
DMF, 130 °C], the challenging intramolecular Heck cyclization
of 7 proceeded smoothly to afford the desired indanone 6 in
76% yield. Subsequent iodomethylation of 6 provided iodide 11,
which was subjected to the Beckwith−Dowd ring-expansion
reaction (n-Bu3SnH, AIBN) to deliver 12 in 65% yield over
the two steps.17 A one-pot procedure involving ketone reduction
and elimination of the resulting alcohol gave 13 (75% yield),
which was then converted to 14 through CF3CO2H accelerated
cyclopropanation18 in 86% yield as a mixture of diastereomers
(dr = 5:1).
With the rapid construction of cyclopropane 14, the next
task was to install the remaining γ-lactone bearing a furanyl
moiety. Thus, triflate 16 was formed in two steps with 78%
yield following standard procedures. Palladium-catalyzed Stille
coupling19 of 16 with stannane 17 followed by liberation of the
TBS guarded secondary alcohol in 18 (HF·Py) resulted in
spontaneous lactonization to furnish 4,5-dihydrosalvipuberulin
(19) in 74% yield over the two steps as a separable mixture of
diastereomers at C12 (dr = 1.3:1; structure of 12-epi-19 was not
shown).
The initial studies aiming at the total synthesis of salvileucalin
D (2) are depicted in Scheme 4. Phenylselenation of the pre-
formed TIPS enol ether20 gave selenide 20 in 94% yield. Although
oxidative elimination of organoselenium compounds has been
well established, we were delighted to find that, upon exposure
B
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Letter
synergistic effects from both the in situ generated bromide during
debromination and elevated temperature (30),28 thus enabling a
diastereoselective Stille coupling/debromination/desilylation/
lactonization cascade in one step. 12-epi-28 could be recycled
by epimerization as described for 12-epi-3, giving a 3.5:1 mixture
of diastereomers favoring 28. Fortunately, treatment of bro-
mocyclopropane 28 with aqueous sodium hydroxide solution in
the presence of Et3BnNCl afforded ring-expansion product
salvileucalin D (2) in 80% yield. Other bases such as LDA,
KHMDS, t-BuOK, K2CO3, DBU and pyridine, and silver salts
(Ag2O, Ag2CO3, AgNO3, AgO2CCF3) either caused decom-
position of 28 or gave a low yield of 2. Under thermodynamic
conditions, rapid conversion of salvileucalin D (2) to dugesin B
(5) was observed (95% yield). While treating with DBU at 0 °C,
2 was transformed into isosalvipuberulin (4) and dugesin B (5)
in 40% and 52% yields, respectively. Gratifyingly, upon UV-
light irradiation (λ = 365 nm), electrocyclic ring closure took
place smoothly and delivered salvileucalin C (1) in 84% yield.29
Scheme 5. Total Synthesis of Salvileucalin C (1)
1
Synthetic 1, 2, 4, and 5 exhibited H and 13C NMR spectra
identical in all respects to those reported for the natural products.4,8a
In summary, we have developed a concise and diastereo-
selective route to salvileucalin C, as well as their biosynthetically
related diterpenoids salvileucalin D, salvipuberulin, isosalvipu-
berulin, and dugesin B. The key steps of the strategy entail a
Beckwith−Dowd ring expansion, a tandem diastereoselective
Stille coupling/debromination/desilylation/lactonization reac-
tion, and a photoinduced electrocyclic ring contraction. The
asymmetric synthesis enabling further biological evaluation of
these molecules could be approached via the enantioselective
Mukaiyama aldol reaction15 of silyloxyfuran with aldehyde and
the following intramolecular Heck cyclization strategy.16b Studies
in this field are currently in progress and will be reported in due
course.
Table 1. Optimization of the One-Pot Stille Coupling/
Debromination Reaction
a
b
yield (%)
12-epi-
12-epi-
entry
[M], additive
Pd(PPh3)2Cl2
27
27
28
28
29
ASSOCIATED CONTENT
* Supporting Information
■
1
2
3
4
5
6
68
14
4
n.d.
n.d.
12
n.d.
n.d.
n.d.
54
S
Pd(PPh3)4
55
10
3
Detailed experimental procedures, characterizations, and
Pd(PPh3)2Cl2, n-Bu3SnH
Pd(PPh3)2Cl2, Et3SiH
Pd(PPh3)2Cl2, Ph3SiH
n.d.
27
n.d.
8
60
3
1
copies of H and 13C NMR spectra of all new compounds.
n.d.
13
This material is available free of charge via the Internet at
http://pubs.acs.org.
n.d.
n.d.
n.d.
n.d.
65
73
n.d.
n.d.
Pd(PPh3)2Cl2, CuI,
Ph3SiH
15
a
AUTHOR INFORMATION
Corresponding Author
Reaction conditions: 1) 25 (0.1 mmol), 17 (1.2 equiv), [Pd] (0.1 equiv),
■
CuI (0.1 equiv), n-Bu3SnH (1.2 equiv) or hydrosilane (1.2 equiv),
and LiCl (3.0 equiv) in DMF (3 mL) at 100 °C; 2) HF·Py, MeCN,
rt. n.d. = not detected. Isolated yields of two steps.
b
*E-mail: hfding@zju.edu.cn.
Notes
The authors declare no competing financial interest.
a trace amount of nBu3SnH in stannane 17 would be the critical
factor. Thus, stoichiometric nBu3SnH was employed as the
hydride source and the yield of 28 was indeed dramatically
improved to 60% (entry 3). In the presence of Et3SiH, simple
reductive detriflation product 29 was observed predominantly
(entry 4). Further studies showed Ph3SnH was a superior
hydride donor (entry 5).27 Moreover, catalytic CuI was found to
be an effective additive to this reaction, with which 28 and
12-epi-28 could be obtained in 73% and 15% yields, respectively
(entry 6).
Based on the encouraging results, stannane 26 with a more
labile trimethylsilyl group was employed in the Stille coupling
reaction instead of 17 (Scheme 5). Much to our delight, 28
was formed directly in 69% yield, accompanied by 12-epi-28
(13% yield). The γ-lactone formation was facilitated by deprotec-
tion of the TMS group, which was presumably the result of
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21202144, J1210042),
the Zhejiang Provincial NSFC (LQ12B02003), the Fundamental
Research Funds for the Central Universities (2014QNA3009),
the New Teacher’s Fund for Doctor Stations, Ministry of
Education (20120101120087), and Zhejiang University. We
gratefully acknowledge Professor Gang Xu of Kunming Institute
of Botany for kindly providing an authentic sample of
isosalvipuberulin and Dr. Chih-Chung Tseng (University of
Aberdeen, Foresterhill) for helpful discussions.
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D
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