Stereocontrolled entry to the tricyclo[3.3.0]oxoheptane core of bielschowskysin by a [2+2] cycloaddition of an allene-butenolide

Article abstract of DOI:10.1016/j.tetlet.2009.01.131

As part of ongoing transannulation studies, the practical synthesis of an allene-linked γ-butenolide from l-malic acid and its substrate-controlled [2+2] photocycloaddition to the tricyclic core of bielschowskysin (1) are described.

Full text of DOI:10.1016/j.tetlet.2009.01.131

Tetrahedron Letters 50 (2009) 1731–1733
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereocontrolled entry to the tricyclo[3.3.0]oxoheptane core of
bielschowskysin by a [2+2] cycloaddition of an allene-butenolide
*
Ru Miao, Subramanian G. Gramani, Martin J. Lear
Department of Chemistry and Medicinal Chemistry Program of the Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of ongoing transannulation studies, the practical synthesis of an allene-linked c-butenolide from
Received 16 December 2008
Revised 19 January 2009
Accepted 27 January 2009
Available online 30 January 2009
L-malic acid and its substrate-controlled [2+2] photocycloaddition to the tricyclic core of bielschowskysin
(1) are described.
Ó 2009 Elsevier Ltd. All rights reserved.
West Indian gorgonian octocorals are rich sources of terpenoids
with a high propensity to produce secondary metabolites with
promising pharmacological activities.1 In particular, the Rodríguez
group have reported several new classes of marine natural prod-
ucts from Pseudopterogorgia kallos; otherwise named Bielschowsky
after the discoverer of this Caribbean Sea plume.2,3 Bielschowsky-
sin4 (1) and providencin5 (2), for example, represent new founding
members of highly oxygenated cyclobutane-classes of
furanocembranoids.
cyclic core of bielschowskysin (cf. 4) via the [2+2] photocycloaddi-
tion of an allenyl-2(5H)-furanone (cf. 3) under high stereocontrol
(Fig. 1).
By considering the connective relationships between cembra-
noid natural products,1–5 we proposed to mold the bielschowsky-
ane ring system (4) through a formal [2+2] transannulation of an
allene-butenolide functionalised furanocembrane macrocycle
(3).7 Conceivably this may involve successive or concerted bond
formations between C7/C11 and C6/C12. Bray and Pattenden, for
example, have constructed the cyclobutane moiety of providencin
(2) by employing an intramolecular C–H insertion reaction.5 While
our work was ongoing,7 Doroh and Sulikowski published the valid-
ity of a [2+2]-photochemical approach to bielschowskysin (1) via
an enol ether appended butenolide.8 Indeed, literature examples
support similar intramolecular photocycloadditions of double-
bonds appended to cyclopentenones9, and an allene-butenolide
photocycloaddition10 has been applied to the synthesis of solanoe-
clepin A. Despite these related studies, our focus herein was to de-
velop a reproducible and practical synthesis that could be readily
accessed and exploited within a transannular bielschowskyane
manifold (cf. 3).
CO2Me
OH
OH
H
O
HO
O
O
OH
O
H
O
H
O
OAc
OAc
O
O
O
1:bielschowskysin
2:providencin
As a model system, we targeted the allene-butenolide 5 via the
benzylidene 6 (Schemes 1 and 2). First, commercially available L-
Besides the clear structural challenge, our interest with biels-
chowskysin (1) resides in unlocking the pharmacophoric features
and molecular targets that are responsible for its antiplasmodial
activity against several drug resistant strains of the malaria-caus-
malic acid (7) was reduced to triol 8 using borane-dimethyl sul-
fide.11 Protection of 8 in acetone with CuSO4 and a catalytic
ing protozoan parasite, Plasmodium falciparum (IC50 ꢀ 10
l
g mlꢁ1).
With a further view to expanding transannulation approaches to
natural product frameworks, we have embarked on the total syn-
thesis of 1, especially since re-isolation efforts from various P. kal-
los sources have proved unfruitful due to seasonal or chemotype
variations, and only trace amounts of natural 1 remain.6 Herein,
we describe a biomimetically inspired model study to fuse the tri-
H
7
6
H
H
7
6
·
transannular
[2+2]
H
11
12
12
11
H
H
O
O
O
O
3:furanocembrane
4:bielschowskyane
* Corresponding author. Tel.: +65 6516 3998; fax: +65 6779 1691.
E-mail address: chmlmj@nus.edu.sg (M.J. Lear).
Figure 1. Proposed biomimetic transannulation strategy.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.131

1732
R. Miao et al. / Tetrahedron Letters 50 (2009) 1731–1733
OH
O
OH
a
HO
OH
HO
OH
O
Me
H
CH2
H
HO
7
8
L
-malic acid ( )
H
b
c
O
O
O
O
H
O
O
O
OH
Me
17
9
10
Ph
Figure 2. X-ray structure of photoadduct 17.
O
O
d
HO Me
e
O
O
Me
HO
perature. Protection of the alcohol 14 as its TMS ether 15 and sub-
sequent homologation of the acetylene, with (CH2O)n, i-Pr2NH and
CuBr in refluxing dioxane,14 directly afforded the allene precursor 5
in 68% yield for cycloaddition studies.
11
6
Scheme 1. Reaction conditions: (a) BH3ꢃSMe2, rt, 16 h, 95%; (b) acetone, CuSO4,
p-TsOH, rt, 18 h, 67%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C, 1.5 h; MeMgBr, Et2O,
ꢁ78 °C, 3 h ; PCC, NaOAc, MS 4 Å, CH2Cl2, rt, 5 h, 43%, 3 steps; (d) ethynylmagne-
sium bromide, Et2O, ꢁ78 °C, 15 min, rt, 5 h, 72%; (e) PhCH(OMe)2, p-TsOH, CH2Cl2,
rt, 75%.
Initial thermal [2+2] cycloaddition studies on butenolides akin
to 5 were unproductive. Although the free-carbinol form of 5 was
found to undergo a photo-induced cyclisation, the silylated sub-
strate 5 cleanly underwent a [2+2] cycloaddition to the photoad-
duct 16. Conveniently, we found that the irradiation of 5 in a 1:1
(v/v) solution of dichloromethane/hexane could be performed reli-
ably with three conventional UV lamps (3 ꢂ 6 W, k = 254 nm) over
12 h.15 This gave a single diastereomeric photoadduct 16 in 70%
yield. The photoadduct 16 displayed all characteristic 1H and 13C
NMR cyclobutane peaks, which was confirmed unambiguously by
single-crystal X-ray analysis of its desilylated form 17 (Fig. 2).16
As anticipated,8,9 the incorporation of a tertiary carbinol into the
allenyl-arm of 5 favoured cyclisation to the tricyclo[3.3.0]oxohep-
tane ring structure 16, as opposed to alternative modes of closure.
Here, the combination of geminal-disubstituted and 1,3-allenylic
conformational effects are believed to play a role in determining
the stereochemical outcome. For instance, the six-membered cyc-
lised counterparts to 16 can also form with allene-substrates lack-
ing a quaternary centre, whereby exceptions to the ‘rule-of-five’
can occur and the exo-methylene of the allene can react with the
butenolide.9a
In summary, we have demonstrated the intramolecular feasibil-
ity of our biometically inspired strategy to form the tricyclic core
(17) of bielschowskysin (1) by virtue of a substrate-controlled
[2+2] photocycloaddition of an allene-butenolide (5). In practice,
gram-quantities of the butenolide 15 have been prepared repro-
ducibly, and transannular manifolds (cf. furanocembrane 3) to gen-
erate tetracyclo[9.3.3.0]tetradecanes (cf. bielschowskyane 4) are
being explored. Further efforts towards the total synthesis of biels-
chowskysin (1) are actively being pursued in our laboratories and
will be published in due course.
Ph
Ph
O
O
a
b
Me
O
O
6
Me
O
CO2CH3
12
13
Me
HO
Me
TMSO
c
d
O
O
H
H
O
O
14
15
Me
H
H
CH2
H
Me
TMSO
TMSO
·
CH2
O
e
f
H
H
O
H
O
5
O
16
Scheme 2. Reaction conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C, 1.5 h; (b)
BrꢃPh3PCH2CO2Me, Et3N, MeOH, 0 °C, 3 h, 60%, 2 steps (4:1 Z/E); (c) H2SO4, MeOH, rt,
overnight, 70 % (d) TMSOTf/2,6-lutidine, CH2Cl2, 0 °C to rt, 2 h, 62%, (e) (CH2O)n,
i-Pr2NH, CuBr, dioxane, reflux, 3 h, 68% (f) hm, hexane/CH2Cl2, rt, 12 h, 70%.
Acknowledgements
amount of PTSA subsequently produced the acetonide 9 in 67%
yield.12
We thank the Ministry of Education of Singapore for funding
(AcRF Tier-2 Grant T206B1112) and a postdoctoral scholarship
(to R.M.). We further thank the National University of Singapore
for a Graduate Scholarship (to S.G.G.) and Tan Geok Kheng for solv-
ing the X-ray crystal structure of photoadduct 17. Appreciation
goes to James J. La Clair and Abimael D. Rodríguez for their dedi-
cated re-isolation efforts to obtain trace amounts of bielschowsky-
sin (1) from various P. kallos sources.
Swern oxidation of 9 followed by the addition of methyl magne-
sium bromide and subsequent PCC oxidation afforded the methyl
ketone 10 in 43% overall yield. Under chelation control, the Grig-
nard addition to ketone 10 with ethynylmagnesium bromide pro-
vided a 4:1 separable mixture of propargylic alcohols, giving the
major diastereomer 11 in 72% yield. Treatment of the ethynyl car-
binol 11 with benzaldehyde dimethylacetal in the presence of
p-TsOH transformed the acetonide 11 smoothly to the more stable
six-membered benzylidene acetal 6.13
Supplementary data
Aldehyde formation of 12 from alcohol 6 followed by Wittig
homologation in methanol produced a 4:1 cis/trans mixture of
Experimental procedures and characterisation data for com-
pounds 5, 6, 10, 11 and 13–17. Coordinates for 17 have been up-
loaded to the Cambridge Crystallographic Data Centre (http://
a
,b-unsaturated esters, with the cis-isomer 13 predominating
(Scheme 2). The -butenolide 14 was then prepared in 70% yield
by cyclising 13 in aqueous sulfuric acid in methanol at room tem-
c

R. Miao et al. / Tetrahedron Letters 50 (2009) 1731–1733
1733
12. Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Tetrahedron
2004, 60, 43.
13. Mayer, A. J.; Lawson, J. P.; Walker, D. G.; Linderman, P. J. J. Org. Chem. 1986, 51,
5111.
www.ccdc.cam.ac.uk/). Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.01.131.
14. Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbé, P. J. Chem. Soc.,
Perkin Trans. 1 1984, 747.
References and notes
15. Experimental procedure to photoadduct 16: The allene-butenolide 5 (15 mg,
0.06 mmol) was dissolved in a 1:1 (v/v) solvent mixture of hexane/CH2Cl2
(2 mL), and the resulting solution was bubbled with N2 for 15 min. This
solution was then irradiated with three UV lamps (3 ꢂ 6 W, k = 254 nm) in a
quartz test tube without stirring for 12 h. After consumption of the starting
material, as indicated by TLC, the solvent was removed and the residue was
purified by chromatography (hexane/ethyl acetate = 6:1, v/v) to give the
1. (a) Cases, M.; Gonzalez-Lopez de Turiso, F.; Hadjisoteriou, M. S.; Pattenden, G.
Org. Biomol. Chem. 2005, 3, 2786; (b) Roethle, P. A.; Trauner, D. Nat. Prod. Rep.
2008, 25, 298.
2. (a) Look, S. A.; Burch, M. T.; Fenical, W. J. Org. Chem. 1985, 50, 5741; (b)
Rodríquez, A. D. Tetrahedron 1995, 51, 4571; (c) Marrero, J.; Rodríguez, A. D.;
Baran, P.; Raptis, R. G. J. Org. Chem. 2003, 68, 4977; (d) Marrero, J.; Rodríguez, A.
D.; Baran, P.; Raptis, R. G. Org. Lett. 2003, 5, 2551; (e) Marrero, J.; Rodríguez, A.
D.; Baran, P.; Raptis, R. G. Eur. J. Org. Chem. 2004, 3909.
3. Marrero, J.; Benítez, J.; Rodríguez, A. D.; Zhao, H.; Raptis, R. G. J. Nat. Prod. 2008,
71, 381.
4. Marrero, J.; Rodríguez, A. D.; Baran, P.; Raptis, R. G.; Sánchez, J. A.; Ortega-
Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661.
5. Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 3937.
6. Access to the original location of specimens of P. kallos that actively produces
bielschowskysin (1) is unlikely since the Columbian waters off Old Providence
Island in the Southwestern Caribbean Sea are now closed to foreign scientific
expeditions.
7. Preliminary studies to our [2+2] approach were presented at the Singapore
International Chemical Conference-4, 8–10 December 2005, Shangri-La Hotel,
Singapore (Abstract 81-OS-A0357).
photoadduct 16 as a colourless oil in 70% yield. ½a D25
ꢄ
ꢁ23.4 (c 0.47, CH2Cl2). 1
H
NMR (CDCl3, 500 MHz): 5.30 (d, J = 0.9 Hz, 1H), 5.25 (ddd, J = 2.3, 5.7, 8.0, 1H),
5.15 (d, J = 0.9, 1H), 3.58 (dt, J = 2.3, 7.1, 1H), 3.49 (m, 1H), 3.24 (dt, J = 2.3, 3.9,
1H), 2.48 (ddd, J = 1.6, 8.0, 14.6, 1H), 1.95 (dd, J = 5.7, 14.6, 1H), 1.42 (s, 3H),
0.12 (s, 9H); 13C NMR (CDCl3, 125 Hz): d 176.0, 142.6, 114.6, 85.1, 84.9, 58.7,
49.4, 45.0, 42.1, 23.2, 2.2; IR(CH2Cl2): 2958, 1770, 1252, 1149, 1045, 841; MS
(FAB): [M+H]+ 253.1; HRMS (FAB) [M+H]+ calcd for C13H21O3Si 253.1254, found
253.1248.
16. Experimental procedure to photoadduct 17: Catalytic CSA was added to
a
solution of compound 16 (10 mg, 0.04 mmol) in 0.5 mL of ethanol, and the
resulting mixture was stirred for 2 h. After completion of starting material, as
monitored by TLC, the solvent was removed and the residue was purified by
chromatography (hexane/ethyl acetate = 1/1, v/v) to give compound 17 as a
white solid in 85% yield. This solid was dissolved in a minimal amount of
acetone, then CH2Cl2 and hexane were added. Slow evaporation at room
temperature afforded orthorhombic single crystals (mp = 125–126 °C), one of
8. Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903.
which was subjected to X-ray crystallography (cf. Supplementary data). ½a D25
ꢄ
9. (a) Dauben, W. G.; Rocco, V. P.; Shapiro, G. J. Org. Chem. 1985, 50, 3155; (b) De
Gregori, A.; Jommi, G.; Sisti, M.; Gariboldi, P.; Merati, F. Tetrahedron 1998, 44,
2549; (c) Tanaka, M.; Tomioka, K.; Koga, K. Tetrahedron 1994, 50, 12829; (d)
Booker-Milburn, K. I.; Cowell, J. K. Tetrahedron Lett. 1996, 37, 2177.
10. Hue, B. T. B.; Dijkink, J.; Kuiper, S.; Larson, K. K.; Guziec, F. S., Jr.; Goubitz, K.;
Fraanje, J.; Schenk, H.; van Maarseveen, J. H.; Hiemstra, H. Org. Biomol. Chem.
2003, 1, 4364.
ꢁ34.4 (c 0.5, CH2Cl2). 1H NMR (CDCl3, 500 MHz): 5.35 (d, J = 2.5 Hz, 1H), 5.25
(ddd, J = 2.5, 5.1, 8.0, 1H), 5.19 (d, J = 2.5, 1H), 3.63 (dt, J = 2.5, 7.0, 1H), 3.58 (m,
1H), 3.21 (dt, J = 1.9, 5.7, 1H), 2.45 (ddd, J = 1.9, 7.6, 15.1, 1H), 2.05 (dd, J = 5.1,
15.1, 1H), 1.43 (s, 3H); 13C NMR (CDCl3, 125 Hz): 175.8, 142.2, 115.0, 84.8, 82.6,
58.3, 48.5, 45.2, 42.1, 23.8; IR: IR(CH2Cl2): 3406, 2961, 2922, 1746, 1258, 1150,
1011, 798; MS (FAB): [M+H]+ 181.1; HRMS (FAB): [M+H]+ calcd for C10H13O3
181.0865, found 181.0857.
11. Shiina, I.; Kikuchi, T.; Sasaki, A. Org. Lett. 2006, 8, 4955.