Cobalt-mediated synthesis of the tricyclo[5.2.1.01,6]decene framework in solanoeclepin A

Article abstract of DOI:10.1021/ol302432d

The stereocontrolled synthesis of the highly strained, tricyclo[5.2.1. 0^1,6]decene skeleton (C) of solanoeclepin A has been achieved through two key transformations: a [2,3]-Wittig rearrangement of allylpropargyl ether (A) to propargyl alcohol (B) having a trans-fused perhydroindane framework and the formation of the cyclobutane via a cobalt-mediated Hosomi-Sakurai type cyclization of an acetylene dicobalthexacarbonyl complex.

Full text of DOI:10.1021/ol302432d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Cobalt-Mediated Synthesis of the
Tricyclo[5.2.1.01,6]decene Framework in
Solanoeclepin A
Kuo-Wei Tsao, Chia-Yi Cheng, and Minoru Isobe*
Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu
Road, Hsinchu 30013, Taiwan
minoru@mx.nthu.edu.tw
Received September 2, 2012
ABSTRACT
The stereocontrolled synthesis of the highly strained, tricyclo[5.2.1.01,6]decene skeleton (C) of solanoeclepin A has been achieved through two
key transformations: a [2,3]-Wittig rearrangement of allylpropargyl ether (A) to propargyl alcohol (B) having a trans-fused perhydroindane framework and
the formation of the cyclobutane via a cobalt-mediated HosomiꢀSakurai type cyclization of an acetylene dicobalthexacarbonyl complex.
Solanoeclepin A (1; Figure 1) was first isolated by
Mulder in 1986 as the hatching stimulant principle parti-
cularly against the cyst nematodes (PCN; Globodera ros-
tochiensis and G. pallida).1 Its structure was elucidated by
Schenk in 1999 from X-ray crystallographic analysis.2 This
molecule has a tricyclo[5.2.1.01,6]decene unit which in-
cludes a highly strained cyclobutane, and a 7-oxabicyclo-
[2.2.1]heptanone moiety. PCNs can survive in the cyst over
years, and once they hatch in the field bearing crops, there
Figure 1. Solanoeclepin A, nematode hatching stimulant.
would be significant damage to the host plant (potato).
Damages to crops due to PCN have been reported in over
50 countries in the world. However, if 1 is first applied to
structure or framework that displays biological activity.
Many organic synthetic chemists such as the groups of
potato fields as a treatment prior to planting, the hatching
process will be initiated, followed by PCN death in 8 weeks
Hiemstra,3 Isobe,4 and AdachiꢀNishikawa5 have made
efforts in the challenge of synthesizing 1. Tanino, Miyashita
without any feeding on the host plants. While 1 is available
from nature in very small quantities (0.245 mg from
thousands of potato roots),1b organic synthesis of 1 would
contribute to solving this source problem.
ꢀ
(3) (a) Briere, J.-F.; Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel,
A. E.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2001,
2371–2377. (b) Hue, B. T. B.; Dijkink, J.; Kuiper, S.; van Schaik, S.; van
Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2006, 127–137. (c)
Lutteke, G.; Kleinnijenhuis, R. A.; Jacobs, I.; Wrigstedt, P. J.; Correia,
A. C. A.; Nieuwenhuizen, R.; Buu, H. B. T.; Goubitz, K.; Peschar, R.;
van Maareseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2011, 3146–
3155.
In the process of synthesizing solanoeclepin A and its
derivatives, it will be possible to assemble a structure
ꢀactivity relationship profile and find the most critical
(4) (a) Tojo, S.; Isobe, M. Synthesis 2005, 1237–1244. (b) Adachi, M.;
Yamauchi, E.; Komada, T.; Isobe, M. Synlett 2009, 1157–1161. (c) Tsao,
K.-W.; Isobe, M. Org. Lett. 2010, 12, 5338–5341. (d) Isobe, M.;
Niyomchon, S.; Cheng, C.-Y.; Hasakunpaisarn, A. Tetrahedron Lett.
2011, 52, 1847–1850.
€
(1) (a) Mulder, J. G.; Diepenhorst, P.; Bruggemann-Rotgans,
I. E. M. PCT Int. Appl.WO 93/02,083. (b) Mulder, J. G.; Diepenhorst,
€
P.; Bruggemann-Rotgans, I. E. M. Chem. Abstr. 1993, 118, 185844z.
(2) Schenk, H.; Driessen, R. A. J.; de Gelder, R.; Goubitz, K.;
€
Nieboer, H.; Bruggemann-Rotgans, I. E. M.; Diepenhorst, P. Croat.
(5) Komada, T.; Adachi, M.; Nishikawa, T. Chem. Lett. 2012, 41,
287–289.
Chem. Acta 1999, 72, 593–606.
r
10.1021/ol302432d
XXXX American Chemical Society

and co-workers achieved the first asymmetric total synthe-
sis of solanoeclepin A in 2011.6
(Scheme 2) was found to generate the requisite trans-fused
rings in model experiments on 9a (X = H, Y = OTBS).
The terminal acetylenic moiety of 9a was first deproto-
nated with nBuLi and protected with TMSCl. Then a
smooth deprotonation of the propargylic proton took
place with the addition of a second equivalent of nBuLi
inTHF atꢀ78°C (ConditionsA), and a spontaneous[2,3]-
Wittig rearrangement proceeded at the same temperature
to provide the propargylic alcohol 10a as a single stereo-
isomer in one pot with an 85% overall yield. Furthermore,
after methylation and removal of the TMS group, the
NMR analysis of 12 revealed that the newly generated
stereogenic C11 was of an R-configuration.12 These experi-
ments also confirmed that the A/B rings of the hexahy-
droindene derivative 10 was trans-fused.
One of the challenges of synthesizing solanoeclepin
A is the construction of the highly strained tricyclo-
[5.2.1.01,6]decene skeleton 4, which includes four-, five-,
and six-membered rings and bears three contiguous qua-
ternary stereogenic centers. There have only been three
reports of the syntheses of the tricyclo[5.2.1.01,6]decane core
of solanoeclepin A to date: (i) intramolecular [2 þ 2] photo-
cycloaddition of alkene-dioxenone or allene butenolide,3 (ii)
base-induced intramolecular cyclization of an epoxynitrile,6
and (iii) 4-exo-trig radical cyclization of the cyclobutane.5
In this letter, we showcase a fourth example as an alter-
native synthesis of the tricyclic, cyclobutane-containing
framework 4 by exploiting a HosomiꢀSakurai type cycli-
zation of an acetyleneꢀdicobalthexacarbonyl complex.
The key step is generation of the Nicholas type carbenium
ion,7 which had been employed in our previous work as the
main strategy for the cyclization of seven-, eight-, and nine-
membered ether rings, in the total synthesis of ciguatoxin.8
In our retrosynthetic analysis of solanoeclepin A, the
functionalized seven-membered carbocyclic B-ring is
cleaved into two segments (Scheme 1): the 7-oxabicyclo-
[2.2.1]heptanone 2 and the highly strained tricyclic moiety
3 bearing three quaternary centers. We intended to develop
a stereocontrolled synthesis of the tricyclic subunit 4 and
envisaged that its cyclobutane moiety could be acquired by a
HosomiꢀSakurai type cyclization through a Nicolas cation
5 generated in situ from an acetyleneꢀdicobalthexacarbonyl
complex under Lewis acidic conditions. According to the
stereochemistry of the cyclobutyl moiety, a trans-stereo-
chemistry at the fused rings of 6 is required. Therefore,
the propargyl group at the C4 bridgehead position was
required to be trans with respect to the methyl group at the
C9 junction. This stereochemically defined intermediate 6
could be procured through a [2,3]-Wittig rearrangement9 of
β-propargyl ether 7, which could be prepared in turn from
HajosꢀParrish ketone 8.
Scheme 1. Retrosynthetic Analysis of Solanoeclepin A
In the [2,3]-Wittig rearrangement of 9b having a β-
substituent on C1 (X = ;CtC;SiMe3, Y = OTBS),
the rearrangement was impeded by the bulky β-TMS
acetylenic group. Under the same reaction conditions, only
a very small amount of the desired rearrangement product
10b was observed by TLC. When the reaction temperature
was raised from ꢀ78 to 28 °C for 3.5 h (Conditions B), a
9% yield of 10b was obtained, along with elimination
product 11b (75% yield) as the major product. On the
other hand, the reaction of 9c bearing an exocyclic olefin
(X = Y = ;CdCHCH2OTBS) at C1 provided the
desired [2,3]-Wittig rearrangement product 10c in 70%
yield over two steps (Conditions A).
Having accomplished the [2,3]-Wittig rearrangement to
give the desired trans-octahydroindene system, we pro-
ceeded to synthesize the right-hand segment 4 of solanoe-
clepin A from HajosꢀParrish ketone 8 (Scheme 3). First,
the R,β-unsaturated ketone was selectively protected
to give monoethylene-ketal 13 in 90% yield following
Wicha’s method using 1,2-bis(trimethylsiloxy)ethane and
The incorporation of substituents to generate the qua-
ternary C4 with the correct stereochemistry at the bridge-
head for producing the trans-fused octahydroindane ring
in solanoeclepin A was a synthetic challenge. Conjugate
addition of cuprates to 8 is known to produce the cis-fused
bicyclo[4.3.0] framework, except in the case of the Nagata-
hydrocyanation reaction,10 which also yielded a minor
amount of the trans-fused product. All attempts to use
[3,3]-sigmatropic rearrangements (e.g., the Irelandꢀ
Claisen rearrangement) failed to build the trans-fused ring
junction, including the use of 6-β-thiophenyl acetate.11
On the other hand, the use of a [2,3]-Wittig rearrangement
(6) Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.;
Miyashita, M. Nat. Chem. 2011, 3, 484–488.
(7) Connor, R. E.; Nicholas, K. M. J. Organomet. Chem. 1977, 124,
C45–C47.
(8) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–
2945.
(9) (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885–902. (b)
Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69, 595–600.
(10) Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255–476.
(11) See the Supporting Information.
(12) It is mechanistically assumed from Nakai et al. (ref 9) and
from similar [2.3]Wittig rearrangement product 22 and crystalline
compound 23.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Model Studies of [2,3]-Wittig Rearrangement
Scheme 3. Synthesis of the Precursor 7 of [2,3]-Wittig Rearran-
gement
TMSOTf at ꢀ78 °C.13 HornerꢀWadsworthꢀEmmons
(HWE) olefination of 13 proceeded in high yield and
predominantly provided the E-unsaturated ester (E/Z =
92:8) upon treatment with triethyl phosphonoacetate in
the presence of lithium chloride,14 which not only avoided
antagonizing the base-sensitive substrate but also in-
creased the reactivity of the phosphonium ylide. The
unstable ester was subsequently treated with pyridinium
p-toluenesulfonate to deprotect the ketal group to give the
corresponding ketone 14 in 97% overall yield over two
steps.
Bothcarbonylgroups in14werereducedsimultaneously
by treatment with DIBAL-H in THF at ꢀ78 °C to afford a
single isomer of a bis-allylic alcohol, in which the hydroxyl
group at C6 was exclusively R. The primary alcohol was
then protected with 1.05 equiv of TBSCl to give monosilyl
ether 15 selectively (92% yield in two steps). The stereo-
chemistries of the HWE olefination and reduction at C6
were determined by the NOESY correlations of β-H8 with
H11 and H6, respectively. A Mitsunobu reaction was
employed to invert the stereochemistry at C6 of 15. This
was followed by hydrolysis (K2CO3, MeOH) to give the
epimeric allyl alcohol 16 in 85% yield, and the stereo-
chemistry of 16 was confirmed by the NOESY correlation
between H6 and R-H7. An O-alkylation with propargyl
bromide provided β-propargyl ether 9c in 89% yield.
Desilylation of 9c with TBAF in the presence of Et3N
Compound 7 was subjected to the same reaction condi-
tions at ꢀ78 °C as in the model reaction of 9c to furnish
β-propargyl alcohol 18 as the expected product bearing the
trans-fusion and quaternary C4 in 83% yield (Scheme 4).
Removal of the TMS group from the acetylenic moiety
with K2CO3 in MeOH was followed by complexation with
dicobaltoctacarbonyl at room temperature to afford acet-
ylene dicobalthexacarbonyl complex 19 in 87% yield over
two steps.
Subsequently, 19 was treated with excess TMSOTf
at ꢀ20 °C, which generated the cobalt-stabilized propargyl
cation 5 in situ in dichloroethane solvent. To this reaction
mixture was further added THF as a cosolvent8 to sca-
venge the excess TMSOTf that prompted the Hosomiꢀ
Sakurai type cyclization to yield the strained tricyclic
cyclobutane 20 in 76% yield as a single isomer having
the three quaternary stereocenters.
Eventually, 20 was further transformed by hydrosilyla-
tion (HSiMe2Ph, bis(trimethylsilyl)acetylene) to trans-vi-
nylsilane 21 (85%) stereoselectively.16 Formation of the
tricyclic21wasverifiedbythreesetsof HMBC correlations
as shown in Scheme 5. The 13-R configuration was proven
from NOESY cross peaks between H13 and H11 as well as
H13 and H8.
Gold-catalyzed propargylic substitution with the nu-
cleophile of allyltrimethylsilane was reported by the Cam-
pagne group.17 Therefore, we attempted the gold-catalyzed
cyclization of propargylic alcohol 19 bearing allyltrimethyl-
silane for comparison with the above-mentioned results
˚
and 4 A molecular sieves produced allyl alcohol 17 in
92% yield. To furnish 7, the precursor to the [2,3]-Wittig
rearrangement, 17 was converted to the corresponding
allylsilane according to Smith’s method15 (76% yield in
two steps).
(13) Chochrek, P.; Kurek-Tyrlik, A.; Michalak, K.; Wicha, J. Tetra-
hedron Lett. 2006, 47, 6017–6020.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183–2186.
(15) Smith, J. G.; Drozda, S. E.; Petraglia, S. P.; Quinn, N. R.; Rice,
E. M.; Taylor, B. S.; Viswanathan, M. J. Org. Chem. 1984, 49, 4112–
4120.
(16) Isobe, M.; Nishizawa, R.; Nishikawa, T.; Yoza, K. Tetrahedron
Lett. 1999, 40, 6927–6932.
(17) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc.
2005, 127, 14180.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Cobalt Mediated Synthesis of Tricyclo-
[5.2.1.01,6]decene 20 and HMBC and NOESY Experiments of
Vinyl 21a
Scheme 5. Gold Catalyzed Cyclization to Tricyclic
Compound 23
and (ii) cobalt-mediated HosomiꢀSakurai type cyclization
ofanacetylene dicobalthexacarbonylcomplextoconstruct
thefour-memberedcarbocyclicring. Thecyclization wasin
effect accomplished via the Nicholas type cobalt-stabilized
propargylic cation with the bulky ligands, which facilitated
the intramolecular attack by the allytrimethylsilane. The
methodology is also amenable for gram-scale preparation
toward the synthesis of solanoeclepin A in our laboratory.
This research is in progress.
(Scheme 4). The treatment of 19 with 5 mol % of
PPh3AuNTf2 provided the unexpected formation of a five-
membered ring instead of four-membered ring (Scheme 5).
The absolute stereochemistry was established from X-ray
crystallographic analysis of corresponding p-nitrobenzoate
derivatives 23.18
In summary, we have achieved the stereocontrolled
synthesis of the highly strained tricyclo[5.2.1.01,6]decene
21 through two vital strategies: (i) [2,3]-Wittig rearrange-
ment that enabled the installation of the β-propargyl
alcohol on C4 trans with respect to the C9 methyl group
Acknowledgment. We gratefully acknowledge the Na-
tional Science Council, Taiwan, and National Tsing Hua
University for financial support.
1
Supporting Information Available. HNMR, 13CNMR,
2D NMR, X-ray crystallographic data, and typical experi-
mental details are supplied as Supporting Information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(18) Crystallographic data are also included in the Supporting In-
formation and have been deposited with the Cambridge Crystallo-
graphic Data Center as CCDC No. 887423.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX