Stereocontrolled approach to the highly functionalized bicyclo[3.2.0] heptane core of bielschowskysin through intramolecular Cu(I)-catalyzed [2+2] photocycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.10.018

A direct route for the synthesis of highly functionalized bicyclo[3.2.0]heptane core containing the bridged lactone with the functionalized C-12 substituent of bielschowskysin is reported. The key step involves a stereoselective Cu (I)-catalyzed [2+2] photocycloaddition of a 1,6-diene embedded in a sugar derivative.

Full text of DOI:10.1016/j.tetlet.2012.10.018

Tetrahedron Letters 53 (2012) 6830–6833
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereocontrolled approach to the highly functionalized bicyclo[3.2.0] heptane
core of bielschowskysin through intramolecular Cu(I)-catalyzed [2+2]
photocycloaddition
⇑
Anupam Jana, Sujit Mondal, Md. Firoj Hossain, Subrata Ghosh
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct route for the synthesis of highly functionalized bicyclo[3.2.0]heptane core containing the bridged
lactone with the functionalized C-12 substituent of bielschowskysin is reported. The key step involves a
stereoselective Cu (I)-catalyzed [2+2] photocycloaddition of a 1,6-diene embedded in a sugar derivative.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 1 September 2012
Revised 2 October 2012
Accepted 4 October 2012
Available online 12 October 2012
Keywords:
Cycloaddition
Photochemistry
Stereocontrol
Terpenes
The marine diterpene bielschowskysin 11 isolated from Carib-
bean gorgonian octocoral Pseudopterogorgia kallos possesses a
highly oxygenated unprecedented novel [9.3.0.02,10] tetradecane
ring system. Seven of the eleven stereocenters present in it are con-
tiguous, six of which reside on the periphery of the bicy-
clo[3.2.0]heptane unit. It exhibits antiplasmodium activity
against Plasmodium falciparum and strong cytotoxicity against hu-
man lung cancer and renal cancer cell lines.1 Structural complexity
combined with its strong bioactivity profile, bielschowskysin elic-
ited considerable interest2 for developing synthetic strategies. Glo-
bal growing interest on synthetic approaches prompted us to
report preliminary results of our investigation leading to a stereo-
controlled route to the construction of highly functionalized bicy-
clo[3.2.0]heptane unit with the bridged lactone present in 1.
A major problem in the synthesis of 1 lies in the creation of
bridge head quaternary center (C-12) with a stereodefined hydro-
xyl group at C-13. A few approaches have been reported in the
literature for the synthesis of the bicyclo[3.2.0]heptane unit of 1.
However, some2a,b of the bicyclo[3.2.0]heptane derivatives
synthesized so far lack the C-12 appendage and will require an
unfavorable aldol reaction at the bridge head lactone enolate for
its attachment while the other ones2d will require chemo-and
1
O
2 R
3
H
H
R
R
O
O
6
+
1
9
H
13
12
O
H
O
OH
2
O
3
1
3
Me
OH
2a
, R = Me, R = OH, R =CH:CH2
b, R1 = R2 = R3 =H,
Me
H
H
H
OH
H
O
HO
9
6
3
2
O
12
1
13
H
O
H
OAc
O
1
2
R
3
R
R
4
1 : Bielschowskysin
4
R
O
1
We envisaged that coupling of the prebuilt bicyclo[3.2.0] hep-
tane unit 2a with the fragment 3 would be a feasible route to 1
(Scheme 1).
HO
2
O
O
4
⇑
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocsg@iacs.res.in (S. Ghosh).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.018

A. Jana et al. / Tetrahedron Letters 53 (2012) 6830–6833
6831
stereoselective nucleophilic addition to an aldehyde carbonyl at
C-13 for elaboration to 1. Thus the reported approaches have lim-
itations in generating C-12 quaternary center and the C-13 acetoxy
group. We initially focused on designing a route to construct a
bicyclo[3.2.0]heptane derivative containing the bridged lactone
with the C-12 appendage with simultaneous generation of the C-
13 OH group without employing the unfavorable aldol reaction
at the bridge head lactone enolate. We speculated that an intramo-
lecular Cu (I)-catalyzed [2+2] photocycloddition3 in the sugar
embedded diene 4 will set the stage for stereoselective4–6 genera-
tion of the bicyclo[3.2.0]heptane core with appropriately function-
alized substituents (C-12, C-13 of 1) in a single step. The C-1, C-2
sector of the glucose moiety in 4 is a latent carboxylic acid which
can be employed to construct the lactone unit while C-4 oxygen
of the sugar ring will provide the C-13 acetoxy group of 1. Use of
glucose will also provide the target in an enantiomerically pure
form. Realization of this concept is demonstrated here with the
synthesis of the bicyclo[3.2.0]heptane derivative 2b.
We initially chose the diene 7 to demonstrate the feasibility of
the photocycloaddition event for accessing stereoselectively the
bicyclo[3.2.0]heptane core. The aldehyde 6 prepared from oxida-
tion of the known hydroxy-compound 55 with Dess–Martin peri-
odinane (DMP) was allowed to react with 1-butenyl-4-
magnesium bromide to provide the diene 77 along with its other
diastereomer in ca. 4:1 ratio in 82% yield (Scheme 2). The diene
7 was isolated in 65% yield as the major diastereoisomer by column
chromatography. The stereochemical assignment to the newly
generated stereocenter follows from addition of the Grignard re-
agent from the face opposite to the 1,2-acetonide moiety. The
diacetonide 7 was then transformed into diene 8 in 70% overall
yield through a three-step protocol involving selective deprotec-
tion of 5,6-acetonide moiety-periodate cleavage of the resulting
vicinal diol followed by reduction of the aldehyde. When a solution
of the diene 8 in diethyl ether was irradiated with a 450 W Hanovia
medium pressure mercury vapor lamp through a water cooled
quartz immersion well in the presence of 2CuOTf.C6H6 complex
as catalyst for 3 h, the cyclobutane derivative 9 was obtained in
75% yield (Scheme 2). The relative stereochemistry of the newly
generated stereocenters was established by comparison of the
hydrogens. That the cycloaddition took place from the face oppo-
site to the 1,2-acetonide moiety was based on analogy6 to the for-
mation of the adduct 11 from photocycloaddition of the
structurally analogous diene 10.
OH
H
O
H
O
O
O
O
H
O
O
O
OH
10
11
The synthesis of the bicyclo[3.2.0] heptane derivative 2b is
shown in Scheme 3. Photocycloaddition of the diene 7 in the pres-
ence of CuOTf as catalyst gave the cyclobutane derivative 12 in 65%
yield as a mixture of two diastereoisomers arising from transfor-
mation8 of the acetonide moiety of 7 to the acetal unit in 12. The
relatively less crowded 5,6-acetal unit compared to the 1,2-aceto-
nide unit of the glucofuranose moiety in 12 was selectively9 re-
moved on treatment with a catalytic amount of DDQ to afford
the cyclobutane derivative 13 as a single diastereoisomer demon-
strating that 12 was a diastereoisomeric mixture due to the pres-
ence of the C-5, C-6 acetal. The coupling constant (J = 3.3 Hz) of
the hydrogen
a to the hydroxyl group confirmed the relative ste-
reochemistry of the hydroxy-bicyclo[3.2.0]heptane unit in 13.
After establishing the stereochemical outcome in the photocyclo-
addition, we proceeded for the synthesis of the targeted intermedi-
ate 2b employing the photoadduct 12.
Cleavage of the vicinal diol in 13 with NaIO4 followed by Wittig
olefination of the resulting aldehyde produced the alkene 14 in 65%
overall yield. A three dimensional view generated by Chemdraw
3D reveals that the C-10 hydroxyl group is anti to the bond linking
the acetonide moiety. Thus an inversion of the configuration of the
C-10 hydroxyl group is required for lactonization with the
carboxylic acid to be generated from the acetonide moiety. For this
purpose an oxidation–reduction sequence was employed as
delineated in Scheme 3. Treatment of 14 with 4% aqueous H2SO4
followed by periodate cleavage of the resulting diol afforded
the hydroxy-aldehyde 15 in 80% yield. Treatment of the
coupling constant of the hydrogen
that reported in the literature. The coupling constant (J = 3 Hz)
observed for
is closely comparable with that reported4
(J = 4 Hz) for hydrogen to the hydroxyl group in exo-2-hydroxy
bicyclo[3.2.0]heptane and not with that (J = 8 Hz) reported for
the corresponding endo-hydroxy analogue. Thus the hydrogen
a to the hydroxyl group with
H
H
9
ii
i
O
HO
HO
O
7
HO
a
H
O
H
O
H
O
H
O
O
O
a
HO OH
to the hydroxyl group was assigned as anti to the ring junction
12
13
H
H
iv
iii
v
CHO
OCHO
O
H
O
H
O
O
H
O
H
O
HO
O
ii
iii
H
R
H
14
15
O
O
HO
iv
O
O
O
H
H
O
vi
H
CO2H
OCHO
5
, R = CH OH
6, R = CHO
OH
2
7
i
H
O
H
O
OR
O
H
2b, R = H
2c, R =
NO2
NO2
vii
16
O
H
HO
OC
O
H
O
H
O
HO
O
OH
O
9
8
Scheme 3. Reagents and conditions: (i) ht, CuOTf, Et2O, 3 h, 65%; (ii) DDQ, CH3CN-
H2O, 65 °C, 2 h, 88%; (iii) (a) NaIO4, THF-H2O, 0 °C, 1.5 h; (b) Ph3PCH3Br, KHMDS,
THF, ꢀ10 °C, 2 h; 65% from 13; (iv) (a) H2SO4, dioxane, 80 °C, 2 h; (b) NaIO4, THF-
H2O, 0 °C, 1.5 h, 80% from 14; (v) Jones’ reagent, acetone, 0 °C, 30 min, 88%; (vi)
NaBH4, MeOH, HCl, 0 °C to rt, 1.5 h, 91%; (vii) 3,5-dinitrobezoyl chloride, CH2Cl2,
Et3N, DMAP, rt, 5 min, 71%.
Scheme 2. Reagents and conditions: (i) DMP, CH2Cl2, 0 °C, 1 h, 96%; (ii)
CH2:CHCH2CH2Br, Mg, THF, 0 °C, 1 h, 65%; (iii) (a) AcOH-H2O(4:1), rt; (b) NaIO4,
THF-H2O, 0 °C, 1.5 h; (c) LiAlH4, Et2O, 0 °C, 1.5 h, 70% from 7; (iv) ht, CuOTf, Et2O,
2 h, 75%.

6832
A. Jana et al. / Tetrahedron Letters 53 (2012) 6830–6833
H
6H
13
through an intramolecular stereoselective Cu(I)-catalyzed [2+2]
photocycloaddition of 1,6-diene embedded in a sugar derivative.
H
H
H10 O
OH
H O
Acknowledgments
Financial support from DST, Government of India through Grant
Nos. SR/S1/OC-19/2011 and SR/S2/JCB-83/2011 is gratefully
acknowledged. AJ and MFH are thankful to CSIR, New Delhi for re-
search fellowships. We are grateful to DBT for Single crystal X-ray
diffraction data collected at the DBT-funded CEIB program (Project
No. BT/01/CEIB/11/V/13) awarded to this Department.
Figure 1. NOESY for 2b.
H
H
H
H
H
O
OH
O
Supplementary data
Figure 2. COSY for 2b.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.018.
References and notes
1. Marrero, J.; Rodr´ıguez, A. D.; Baran, P.; Raptis, R. G.; Sa´nchez, J. A.; Ortega-
Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661.
2. (a) Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903; (b) Miao, R.; Gramani, S.
G.; Lear, M. J. Tetrahedron Lett. 2009, 50, 1731; (c) Nicolaou, K. C.; Adsool, V. A.;
Hale, R. H. Angew. Chem. Int. Ed. 2011, 50, 5149; (d) Farcet, J. B.; Himmelbauer,
M.; Mulzer, J. Org. Lett. 2012, 14, 2195.
3. For reviews on intramolecular Cu(I)-catalyzed [2+2] photocycloaddition of 1,6-
dienes see: (a) Salomon, R. G. Tetrahedron 1983, 39, 485; (b) Ghosh, S. In CRC
Hand Book of Organic Photochemistry and Photobiology; Horspool, W. M., Lenci,
F., Eds.; CRC Press: Boca Raton, Florida, 2004. Chapter 18.
4. Salomon, R. G.; Coughlin, D. J.; Ghosh, S.; Zagorski, M. G. J. Am. Chem. Soc. 1982,
104, 998.
5. (a) Patra, D.; Ghosh, S. J. Org. Chem. 1995, 60, 2526; (b) Ghosh, S.; Patra, D.;
Samajdar, S. Tetrahedron Lett. 1996, 37, 2073; (c) Holt, D. J.; Barker, W.; Jenkins,
P. R.; Ghosh, S.; Russell, D. R.; Fawcett, J. Synlett 1999, 1003; (d) Bannerjee, S.;
Ghosh, S. J. Org. Chem. 2003, 68, 3981; (e) Sarkar, N.; Nayek, A.; Ghosh, S. Org.
Lett. 2004, 6, 1903.
6. Mondal, S.; Yadav, R. N.; Ghosh, S. Org. Biomol. Chem. 2011, 9, 4903.
7. All new compounds were characterized through spectroscopic data. Physical
characteristics for selected compounds: Compound 8. ½ ꢁ +131.3 (c 1.4,
a 2D5
CHCl3); 1H NMR (500 MHz, CDCl3) d 5.92 (1H, d, J = 4.5 Hz), 5.87–5.79 (1H, m),
5.61 (1H, d, J = 8.0 Hz), 5.23 (1H, d, J = 4.0 Hz), 5.04 (1H, dd, J = 1.5, 17.5 Hz),
4.98 (1H, d, J = 10.0 Hz), 4.84 (1H, s), 4.46 (1H, q, J = 7.0 Hz) 3.80 (1H, dd, J = 3.0,
12.3 Hz), 3.59 (1H, dd, J = 4.5, 11.8 Hz), 2.19 -2.07 (2H, m), 1.98 (2H, br s), 1.80–
1.73 (1H, m), 1.67–1.60 (1H, m), 1.49 (3H, s), 1.40 (3H, s); 13C NMR (125 MHz,
CDCl3) d 140.1 (C), 138.1 (CH), 130.6 (CH), 115.2 (CH2), 112.6 (C), 105.1 (OCHO),
81.2 (OCH), 78.9 (OCH), 69.0 (OCH), 64.5 (OCH2), 35.8 (CH2), 29.7 (CH2), 27.7
(CH3), 27.6 (CH3); HRMS (ESI) m/z Calcd for C14H22O5Na (M+Na)+, 293.1365;
Figure 3. ORTEP diagram of compound 2c.
hydroxy-aldehyde 15 with Jones’ reagent afforded the keto-acid 16
in ca. 88% yield. The rapidly decomposing formate in 16 (as re-
vealed by 1H and 13C NMR) led us to use the crude acid without fur-
ther purification for reduction of the carbonyl group. Treatment of
the keto-acid 16 with sodium borohydride followed the well estab-
lished trend4 of hydride addition from the least hindered exo face
of the bicyclo[3.2.0]heptane moiety resulting in the inversion of
configuration of the C-10 OH group which underwent spontaneous
found, 293.1366. Compound 9. ½a D25
ꢁ
+52.6 (c 1.2, CHCl3); 1H NMR (500 MHz,
CDCl3) d 5.63 (1H, d, J = 3.5 Hz), 4.62 (1H, d, J = 4.0 Hz), 4.27 (1H, d, J = 3.0 Hz),
4.12–4.08 (1H, m), 3.97–3.88 (2H, m), 2.90–2.65 (2H, br s), 2.71 (1H, t,
J = 7.5 Hz), 2.40 (1H, d, J = 7.0 Hz), 2.13–2.09 (2H, m), 2.02–1.97 (1H, m), 1.93–
1.86 (2H, m), 1.48 (3H, s), 1.28 (3H, s) 1.08 (1H, dd, J = 6.5, 13.3 Hz); 13C NMR
(125 MHz, CDCl3) d 112.3 (C), 104.0 (OCHO), 86.1 (OCH), 83.6 (OCH), 74.7
(OCH), 61.7 (OCH2), 49.3 (CH), 46.1 (C), 34.5 (CH), 33.6 (CH2), 30.1 (CH2), 27.9
(CH2), 26.9 (CH3), 26.5 (CH3); HRMS (ESI) m/z Calcd for C14H22O5Na (M+Na)+,
lactonization to afford directly the bridged c-butyrolactone 2b in
293.1365; found, 293.1365. Compound 14. ½a D27
ꢁ
+65.8 (c 2.25, CHCl3); 1H NMR
85% yield. The coupling constant (J = 5 Hz) observed for the C-10
H is closely comparable to that reported for endo-2-hydroxy
bicyclo[3.2.0]heptanes. This established that C-10 H is syn to the
ring fusion H’s as required for 1. Additional support in favor of
the stereochemical assignment to 2b was obtained with the aid
of 2D NMR spectroscopy (COSY, NOESY, and HSQC). Strong correla-
tion was observed between C-13 H and C-11 H as well as between
C-13 H with C-6 H in NOESY (Fig. 1). In COSY spectra (Fig. 2), strong
correlations were noted between the following pairs-C-7/C-11 H’s,
C-10/C-11 H’s, and C-13/C-14 H’s. Finally, the structure of 2b was
confirmed by single crystal X-ray (Fig. 3)10 of its 3,5-dinitrobenzo-
ate derivative 2c.
In conclusion, we have developed a stereocontrolled route to a
bicyclo[3.2.0]heptane core with the bridge head lactone with the
C-12 appendage present in bielschowskysin 1. The attractive
feature of this route is that it directly provides the bicy-
clo[3.2.0]heptane moiety with stereoselective generation of the
C-12 quaternary center with stereodefined C-13 hydroxyl group
(CDCl3, 300 MHz) d 6.00 (1H, ddd, J = 6.4, 10.7, 17.1 Hz), 5.65 (1H, d, J = 3.5 Hz),
5.48 (1H, dt, J = 1.5, 17.2 Hz), 5.36 (1H, dt, J = 1.4, 10.6 Hz), 4.65 (1H, d,
J = 4.1 Hz), 4.43 (1H, d, J = 6.2 Hz), 4.32 (1H, d, J = 3.5 Hz), 2.63–2.57 (1H, m),
2.29 (1H, d, J = 6.8 Hz), 2.09–2.00 (2H, m), 1.94–1.83 (2H, m), 1.67 (1H, br s),
1.49 (3H, s), 1.49–1.42 (1H, m), 1.30 (3H, s), 1.08 (1H, dd, J = 6.3, 9.1 Hz); 13C
NMR (CDCl3, 75 MHz) d 132.6 (CH), 119.2 (CH2), 112.1 (C), 104.0 (OCHO), 85.5
(OCH), 83.7 (OCH), 75.0 (OCH), 49.3 (CH), 47.7 (C), 34.9 (CH2), 33.2 (CH), 30.0
(CH2), 28.0 (CH2), 26.9 (CH3), 26.5 (CH3); HRMS (ESI) m/z Calcd for C15H22O4Na
(M+Na)+, 289.1416; found, 289.1414. Compound 2b. ½a 2D7
ꢀ53.9 (c 0.56, CHCl3);
ꢁ
t
max (neat) 3445, 2926, 1746 cmꢀ1 1H NMR (500 MHz, CDCl3) d 5.96 (1H, ddd,
;
J = 6.5, 10.5, 17.0 Hz), 5.42 (1H, d, J = 17.5 Hz), 5.30 (1H, d, J = 10.5 Hz), 5.00 (1H,
t, J = 5.0 Hz), 4.34 (1H, d, J = 6.0 Hz), 3.18 (1H, t, J = 7.5 Hz), 2.75 (1H, dd, J = 9.5,
11.0 Hz), 2.70–2.63 (1H, m), 2.27 (1H, dd, J = 6.5, 10.0 Hz), 2.20–2.13 (2H, m),
1.87–1.60 (2H, m), 1.27–1.24 (1H, m); 13C NMR (125 MHz, CDCl3) d 181.1 (CO),
135.2 (CH), 118.3 (CH2), 85.3 (OCH), 72.7 (CHO), 49.4 (C), 45.8 (CH), 36.3 (CH2),
32.6 (CH), 32.2 (CH2), 31.3 (CH2); HRMS (ESI) m/z Calcd for C11H14O3Na
(M+Na)+, 217.0841; found, 217.0842.
8. Mondal, S.; Yadav, R. N.; Ghosh, S. Tetrahedron Lett. 2010, 51, 4452.
´
9. Fernàndez, J. M. G.; Mellet, C. O.; Marin, A. M.; Fuentes, J. Carbohydr. Res. 1995,
274, 263.
10. Crystal data: Compound 2c. Colorless, needle shaped crystal. Empirical formula
C
18H16N2O8, Mr = 388.33, Orthorhombic space group P212121, a = 5.830 (3),
b = 9.556 (4), c = 31.119 (14) Å,
v
= 1733.7 (14) Å3, z = 4, T = 150 K,

A. Jana et al. / Tetrahedron Letters 53 (2012) 6830–6833
6833
q
calcd = 1.488 g cmꢀ3, F(000) = 808.0, k (Mo-K
2hmax = 50.0°, 4171 total reflections, 2858 unique reflections, 1802 observed
(I > 2 (I)), 253 refined parameter, R1 = 0.0596, wR2 = 0.1866, with GOF = 0.999.
X-ray single crystal data were collected using MoK (k = 0.7107 Å) radiation on
SMART APEX II diffractometer equipped with CCD area detector. Data
a
) = 0.71073 Å,
l
mmꢀ1 = 0.119,
direct method and refined in a routine manner. Non hydrogen atoms were
treated anisotropically. The hydrogen atoms were geometrically fixed. CCDC
(CCDC No. 902058 for 2c) contains the supplementary crystallographic data for
this Letter. These data can be obtained free of charge via http://
r
a
a
www.ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge
collection, data reduction, and structure solution/refinement were carried out
using the software package of SMART APEX. The structure was solved by the
Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
(+44) 1223 336 033; or deposit@ccdc.cam.ac.uk.