A carbohydrate based approach towards the synthesis of aspercyclide C

Article abstract of DOI:10.1016/j.tetlet.2007.08.050

A formal total synthesis of aspercyclide C (3) is described in which d-ribose is employed as a chiral pool material. The key step is a ring closing metathesis.

Full text of DOI:10.1016/j.tetlet.2007.08.050

Tetrahedron Letters 48 (2007) 7524–7527
A carbohydrate based approach towards the synthesis
of aspercyclide C
C. V. Ramana,* Mohabul A. Mondal, Vedavati G. Puranik and Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 3 July 2007; revised 8 August 2007; accepted 13 August 2007
Available online 16 August 2007
Abstract—A formal total synthesis of aspercyclide C (3) is described in which D-ribose is employed as a chiral pool material. The key
step is a ring closing metathesis.
Ó 2007 Elsevier Ltd. All rights reserved.
Bioassay guided fractionation and screening of Aspergil-
lus sp. led to the isolation of three naturally occurring
compounds named aspercyclide A (1), B (2) and C (3)
as highly efficient binding inhibitors of the IgE recep-
tor.1 All are 11-membered macrolactones with an inte-
grated biaryl ether moiety. The important biological
activity, and interesting structural framework make the
aspercyclides interesting targets for total synthesis. An
expeditious synthesis of aspercyclide C was reported in
grating RCM with chiron approaches and the
synthesis of bioactive natural products, we have investi-
gated the synthesis of aspercyclides.3 Herein we report a
formal synthesis of aspercyclide C using a chiral pool
approach.
Employing RCM as the key macrocycle building re-
action (Fig. 1),4 3 was disconnected to key intermediates
5 and 6. D-Ribose acetonide 7 having the required two
contiguous stereocenters was selected as a starting point
for key coupling partner 5. The Ullmann coupling5 of
o-vanillin with the known iodobenzoate 8 followed by
2005 by Furstner and co-workers by taking advantage
¨
of an efficient ring closing metathesis to form the macro-
cycle.2 As a part of our long standing interest in inte-
OPMB
R
OH
OH
HO
O
O
O
O
O
O
OMe
O
OH
O
O
Me
Me
Me
4
Aspercyclide A (1) R = -CH2OH
Aspercyclide B (2) R = -CHO
Aspercyclide C (3)
HO
OPMB
O
I
O
OH
CO2Me
Me
+
O
+
CO2H
OMe
OH
OH
O
O
7
OMe
o-vanillin
5
8
Me
6
Figure 1. Aspercyclides A–C and a retrosynthetic strategy for aspercyclide C.
Keywords: Chiron approach; Ring closing metathesis (RCM); D-Ribose; Ullmann coupling; Mukaiyama reagent.
*
Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25902629; e-mail: vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.050

C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 7524–7527
7525
HO
O
HO
HO
OH
OH
OH
c
a
b
O
D-Ribose
O
O
O
O
O
12
O
O
10
9E /Z (3:7)
7
d
OPMB
OR
OH
e
13
+
+
(20%)
(41%)
R = H
(11%)
OPMB
OR
OH
13
14 R = H
14Ac R = Ac
5
f
f
5Ac R = Ac
O
OMe
I
OH
CHO
o-vanillin (9)
O
O
O
O
O
O
CO2Me
h
i
g
MeO
MeO
MeO
OMe
Me
OMe
Me
OH
Me
Me
8
15
16
6
Scheme 1. Reagents and conditions: (a) PPh3C4H9Br, tert-BuOK, THF, 0 °C ! rt, 16 h, 63%; (b) Raney-Ni, H2, ethanol, rt, 99%; (c) (i) MsCl, TEA,
CH2Cl2, 0 °C, 3 h; (ii) Zn, NaI, DMF, 155 °C, 2 h, 66%; (d) p-TSA, MeOH, rt, 24 h, 99%; (e) NaH, PMBCl, 0 °C ! rt, DMF, 10 h, 5 (41%), 14
(11%); (f) Ac2O, cat. DMAP, pyridine, 0 °C ! rt, 14Ac (91%), 5Ac (93%); (g) CuO, DMF, 140 °C, 50 h, 48%; (h) PPh3CH3I, n-BuLi, THF, 0 °C,
0.5 h, 82%; (i) NaOH, MeOH–H2O (6:4), 48 h, 99%.
one carbon Wittig homologation and saponification
the mixed anhydride in quantitative yields. Even our
should provide the requisite biaryl acid unit 6.
experiments to couple 5 and 6 under the conditions
reported by Furstner and co-workers using the Mukaiy-
¨
Scheme 1 summarizes our synthesis of key alcohol 5.
After substantial optimization using a variety of bases,
the 4-carbon Wittig homologation of ribose acetonide
76 was found to be facile with potassium t-butoxide
and provided a 3:7 E/Z-mixture of olefins. Hydrogena-
tion of the olefin using Raney-Ni in ethanol afforded
diol 10. Treatment of diol 10 with MsCl in the presence
of Et3N in dichloromethane followed by Zn-mediated
elimination7 of the resulting dimesylate gave olefin 12 ,
which was subjected to acid catalyzed hydrolysis to af-
ford diol 13 in 61% over the three steps. Allylic-OH pro-
tection of diol 13 using PMBCl and NaH in DMF
resulted in the preparation of key coupling partner 5
along with the other regiomer 14. The structures of 5
and 14 were analysed with the help of spectral and ana-
lytical data of the corresponding acetates 5Ac and 14Ac,
respectively.8
ama reagent12 met with poor yields. Notably, when 1
equiv of NaH was added, after initial salt formation,
the reaction proceeded smoothly and provided the key
diene ester 4 in 71% yield. Reflecting upon the observa-
tions of Furstner and co-workers,2 the RCM of 4 was
¨
carried out in toluene at 120 °C by adding the catalyst
using a syringe pump over 1 h to afford E-configured
macrocyclic lactone 18, exclusively.13
The E-configuration of the internal olefin was confirmed
by the large coupling constant (16.0 Hz) between the
1
olefinic protons in the H NMR spectrum of 18. Re-
moval of the methyl and PMB protecting groups was
attempted using excess BBr3.14 Our initial observation
of the disappearance of compound 18 within 5 min after
the addition of BBr3 at ꢀ78 °C, prompted us to quench
the reaction which gave macrolactone 19 in 91% yield as
a result of selective PMB deprotection alone. The spec-
tral and analytical data of compound 19 were in agree-
ment with the assigned structure, and this was further
substantiated by single crystal X-ray structural analysis
(Scheme 2).15–17 Attempted deprotections varying the
temperatures, reaction time and the amount of BBr3
resulted in the formation of aspercyclide C, however,
its separation from the complex mixture could not be
acheived.
To prepare biaryl ether 6, the Ullmann coupling of 89
and o-vanillin was carried out in DMF in the presence
of copper oxide to provide biaryl aldehyde 15. One car-
bon homologation of 15 using triphenylmethylphospho-
nium iodide and n-BuLi in THF at ꢀ78 °C resulted in
the formation of alkene 16 in 82% yield. Compound
16 was then subjected to the hydrolysis using NaOH
in MeOH–H2O to afford the second coupling partner,
acid 6 in good yield.10
In summary, we have reported a formal synthesis of
aspercyclide C using a chiral pool approach and ring
closing metathesis as the key reaction. Further applica-
tion of the key intermediate-alcohol 5 towards the
synthesis of other aspercyclides as well as analogues
of aspercyclides for structure activity studies is in
progress.
Having synthesized 5 and 6, we proceeded further with
their coupling and the ring closing metathesis. There
are several observations regarding the coupling of 5
and 6 that deserve mention. Coupling using standard re-
agents such as DCC and EDCI met with failure.11 In the
case of the Yamaguchi reagent,11c we could only isolate

7526
C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 7524–7527
MeO
a
MeO
HO
O
O
+
OPMB
O
OH
OPMB
+
5
N
Cl
I-
Me
O
4
Me
O
17
Me
6
b
MeO
MeO
c
O
O
OPMB
OH
O
O
ORTEP structure of 19
O
O
Me
Me
18
19
Scheme 2. Reagents and conditions: (a) 17, TEA, toluene, 120 °C, 1 h, then NaH, 0 °C ! rt, 2 h, 71%; (b) Grubbs’ 2nd gen. catalyst, toluene, reflux,
3 h, 71%; (c) BBr3, CH2Cl2, ꢀ78 °C, 5 min, 91%.
(q), 69.9 (t), 74.8 (d), 80.7 (d), 113.7 (d), 119.3 (t), 129.3
(d), 130.3 (s), 135.3 (d), 159.1 (s), 170.4 (s); ESI-MS:
m/z = 321.3 (40%, [M+H]+), 343.3 (100%, [M+Na]).
Anal. Calcd for C19H28O4: C, 71.22; H, 8.81. Found: C,
Acknowledgement
Financial support from CSIR (New Delhi) in the form
of a research fellowship to M.A.M. is gratefully
acknowledged.
25
71.31; H, 8.88; (b) Spectral data of 14Ac: ½aꢁD ꢀ22.7 (c 1.1,
CHCl3); IR (CHCl3): m 1035, 1244, 1465, 1514, 1613,
1741 cmꢀ1 1H NMR (200 MHz, CDCl3) d: 0.91 (t,
;
J = 6.2 Hz, 3H), 1.27–1.34 (m, 6H), 1.43–1.56 (m, 2H),
2.13 (s, 3H), 3.50 (dt, J = 3.3, 7.8 Hz, 1H), 3.84 (s, 3H),
4.47 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 5.28–
5.37 (m, 2 H), 5.49 (dd, J = 2.7, 7.8 Hz, 1H), 5.91 (ddd,
J = 6.4, 10.5, 17.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 7.29
(d, J = 8.2 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3) d:
14.1 (q), 21.2 (q), 22.6 (t), 25.4 (t), 30.5 (t), 31.7 (t), 55.2
(q), 72.0 (t), 75.8 (d), 79.7 (d), 113.7 (d), 118.3 (t), 129.6
(d), 130.5 (s), 133.1 (d), 159.2 (s), 170.0 (s) ppm. ESI-MS:
m/z = 343.3 (100%, [M+Na]) Anal. Calcd for C19H28O4:
C, 71.22; H, 8.81. Found: C, 71.35; H, 8.66.
References and notes
1. Singh, S. B.; Jayasuriya, H.; Zink, D. L.; Polishook, J. D.;
Dombrowski, A. W.; Zweerink, H. Tetrahedron Lett.
2004, 45, 7605–7608.
2. Furstner, A.; Muller, C. Chem. Commun. 2005, 5583–
¨
¨
5585.
3. (a) Ramana, C. V.; Salian, S. R.; Gurjar, M. K.
Tetrahedron Lett. 2007, 48, 1013–1016; (b) Ramana, C.
V.; Mondal, M. A.; Puranik, V. G.; Gurjar, M. K.
Tetrahedron Lett. 2006, 47, 4061–4064; (c) Gurjar, M. K.;
Nayak, S.; Ramana, C. V. Tetrahedron Lett. 2005, 46,
1881–1884; (d) Gurjar, M. K.; Nagaprasad, R.; Ramana,
C. V. Tetrahedron Lett. 2003, 44, 2873–2875.
`
9. Masurier, N.; Estour, F.; Froment, M.-T.; Lefevre, B.;
Debouzy, J.-C.; Brasme, B.; Masson, P.; Lafont, O. Eur. J.
Med. Chem. 2005, 40, 615–623.
10. Spectral data of Compound 6: IR (CHCl3): m 757, 1067,
4. (a) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–
1215, 1461, 1705, 1740, 3368 (br) cmꢀ1 1H NMR
;
´
3765; (b) Gradillas, A.; Perez-Castells, J. Angew. Chem.,
(200 MHz, CDCl3) d: 2.54 (s, 3H), 3.77 (s, 3H), 5.33 (d,
J = 11.1 Hz, 1H), 5.83 (d, J = 17.5 Hz, 1H), 6.39 (d,
J = 8.3 Hz, 1H), 6.83–6.97 (m, 3H), 7.08–7.29 (m, 3H);
13C NMR (50 MHz, CDCl3) d: 20.3 (q), 56.0 (q), 111.7 (d),
111.8 (d), 116.7 (t), 118.1 (d), 121.9 (s), 124.4 (d), 125.9 (d),
130.2 (d), 130.8 (d), 132.7 (s), 138.8 (s), 140.6 (s), 151.9 (s),
155.9 (s), 169.9 (s) ppm; ESI-MS: m/z = 285.1 (6%,
[M+H] ), 307.1 (100%, [M+Na]). Anal. Calcd for
C17H16O4: C, 71.82; H, 5.67. Found: C, 71.69; H, 5.61.
11. (a) Dhimitruka, I.; Santa Lucia, J., Jr. Org. Lett. 2006, 8,
47–50; (b) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105,
4348–4378; (c) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki,
T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
Int. Ed. 2006, 45, 6086–6101; (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450; (d) Furstner, A.;
Langemann, K. Synthesis 1997, 792–803.
¨
5. (a) Frlan, R.; Kikelj, D. Synthesis 2006, 2271–2285; (b)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337–2364; (c) Kunz, K.; Scholz, U.; Ganzer,
D. Synlett 2003, 2428–2439.
6. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95–101.
7. (a) Ramana, C. V.; Reddy, B. S.; Gurjar, M. K.
Tetrahedron Lett. 2004, 45, 2817–2819; (b) Gurjar, M.
K.; Patil, V. J.; Pawar, S. M. Carbohydr. Res. 1987, 165,
313–317.
25
8. (a) Spectral data of 5Ac: ½aꢁD ꢀ51.2 (c 1.3, CHCl3); IR
(CHCl3): m 758, 1036, 1070, 1247, 1514, 1374, 1514,
12. (a) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18,
707–721; (b) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada,
E.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1977, 50, 1863–
1866; (c) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo,
K. Chem. Lett. 1975, 1045–1048.
1735 cmꢀ1 1H NMR (200 MHz, CDCl3) d: 0.87 (t,
;
J = 6.2 Hz, 3H), 1.20–1.35 (m, 6H), 1.50–1.65 (m, 2H),
2.01 (s, 3H), 3.74 (dd, J = 5.0, 7.6 Hz, 1H), 3.80 (s, 3H),
4.30 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.94
(dt, J = 5.0, 7.6 Hz, 1H), 5.20–5.33 (m, 2H), 5.75 (ddd,
J = 7.7, 10.6, 17.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.22
(d, J = 8.6 Hz, 2H) ppm; 13C NMR (50 MHz, CDCl3) d:
14.1 (q), 21.1 (q), 22.6 (t), 25.1 (t), 29.7 (t), 31.7 (t), 55.1
25
13. Spectral data of Compound 18: ½aꢁD +148.6 (c 0.4, CHCl3);
IR (CHCl3): m 757, 1081, 1251, 1460, 1514, 1585, 1610,
1735 cmꢀ1 1H NMR (500 MHz, CDCl3) d: 0.91 (t,
;
J = 7 Hz, 3H), 1.29–1.54 (m, 6H), 1.55–1.62 (m, 1H),

C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 7524–7527
7527
1.99–2.05 (m, 1H), 2.33 (s, 3H), 3.74 (t, J = 9.6 Hz, 1H),
3.80 (s, 3H), 3.91 (s, 3H), 4.32 (d, J = 11.5 Hz, 1H), 4.58
(d, J = 11.5 Hz, 1H), 5.29 (dt, J = 2.4, 9.6 Hz, 1H), 5.95
(dd, J = 9.6, 16.0 Hz, 1H), 6.26 (d, J = 16.0 Hz, 1H), 6.55
(d, J = 8.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.80 (d,
J = 7.6 Hz, 1H), 6.84 (t, distorted, J = 2 Hz, 1H), 6.86 (t,
distorted, J = 2.5 Hz, 1H), 6.93 (dd, J = 1.2, 8.3 Hz, 1H),
7.06 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.21 (t,
distorted, J = 2.2 Hz, 1H), 7.23 (t, distorted, J = 2.2 Hz,
1H). 13C NMR (125 MHz, CDCl3) d: 14.1 (q), 19.3 (q),
22.6 (t), 25.3 (t), 31.7 (t), 32.0 (t), 55.2 (q), 56.1 (q), 70.5 (t),
75.7 (d), 82.9 (d), 111.7 (d), 113.8 (d), 114.3 (d), 121.7 (d),
123.7 (d), 125.4 (d), 126.8 (s), 129.4 (d), 129.6 (2d), 130.1
(s), 133.8 (s), 134.7 (s), 136.9 (d), 143.2 (s), 153.9 (s), 154.1
(s), 159.3 (s), 167.5 (s). ESI-MS: m/z = 539.1 (100%,
[M+Na]). Anal. Calcd for C32H36O6: C, 74.39; H, 7.02.
Found: C, 74.13; H, 7.28.
J = 8.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d: 14.1 (q), 19.4 (q), 22.6 (t), 25.4 (t),
31.7 (t), 31.8 (t), 56.1 (q), 76.9 (d), 77.2 (d), 111.8 (d), 114.4
(d), 121.6 (d), 123.7 (d), 125.5 (d), 126.7 (s), 127.9 (d),
129.7 (d), 133.6 (s), 134.7 (s), 137.8 (d), 143.2 (s), 153.8
(s), 154.1 (s), 167.7 (s) ppm. ESI-MS: m/z = 397.3
(5%, [M+H]), 419.2 (100%, [M+Na]). Anal. Calcd
for C24H28O5: C, 72.70; H, 7.12. Found: C, 72.82; H,
7.36.
16. (a) X-ray intensity data of compound 19 was collected on
a Bruker SMART APEX CCD diffractometer with omega
˚
and phi scan mode, kMoKa = 0.71073 A at T = 293 (2) K.
All the data were corrected for Lorentzian, polarisation
and absorption effects using Bruker’s SAINT and SADABS
programs. The crystal structure was solved by direct
methods using SHELXS-97 and the refinement was per-
formed by full matrix least squares of F2 using SHELXL-97.
Hydrogen atoms were included in the refinement as per the
riding model except for the hydroxyl group, which is
located in the difference Fourier map. (b) G. M. Sheldrick,
SHELX-97 program for crystal structure solution and
refinement, University of Go¨ttingen, Germany, 1997.
17. The crystallographic data of compound 19 has been
deposited with the Cambridge Crystallographic Data
Centre as deposition No. CCDC 656253. Copies of these
data can be obtained, free of charge, on application to the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk].
14. Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 1372.
25
15. Spectral data of Compound 19: ½aꢁD +330.5 (c 0.8, DCM);
IR (CHCl3): m 759, 1080, 1215, 1461, 1584, 1601,1722,
3445 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 0.93 (t,
;
J = 6.6 Hz, 3H), 1.26–1.45 (m, 4H), 1.50–1.60 (m, 1H),
1.63–1.73 (m, 2H), 2.03–2.10 (m, 1H), 2.35 (s, 3H), 3.90 (s,
3H), 4.03 (t, J = 9.0 Hz, 1H), 5.19 (t, 9.2 Hz, 1 H), 5.99
(dd, J= 9.2, 15.6 Hz, 1H), 6.27 (d, J = 15.6 Hz, 1H), 6.57
(d, J = 8.3 Hz, 1H), 6.73 (d, J= 7.53 Hz, 1H), 6.82 (d,
J = 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.07 (d,