Stereoselective synthesis (+)-cephalosporolide D

Article abstract of DOI:10.1016/j.tetlet.2010.01.082

A simple and efficient stereoselective synthesis of macrolactone, (+)-cephalosporolide D has been accomplished in 13 steps from inexpensive and commercially available starting materials in an overall yield of 17%, respectively. This convergent synthesis u

Full text of DOI:10.1016/j.tetlet.2010.01.082

Tetrahedron Letters 51 (2010) 1723–1726
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Stereoselective synthesis (+)-cephalosporolide D
G. Venkateswar Reddy, R. Sateesh Chandra Kumar, Eppakayala Sreedhar, K. Suresh Babu,
*
J. Madhusudana Rao
Natural Products Laboratory, Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient stereoselective synthesis of macrolactone, (+)-cephalosporolide D has been accom-
plished in 13 steps from inexpensive and commercially available starting materials in an overall yield of
17%, respectively. This convergent synthesis utilizes Maruoka asymmetric allylation reaction, Grubb’s
cross metathesis for the formation of a fully functionalized acid, and Yamaguchi lactonization as key
steps.
Received 30 December 2009
Revised 20 January 2010
Accepted 25 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cephalosporolide D
Fungal metabolites
Maruoka asymmetric allylation
Grubb’s cross metathesis
CBS-reduction
Yamaguchi macrolactonization
Medium-sized ring systems are found in many biologically ac-
tive molecules and natural products.1 Medium ring compounds,
and particularly lactones, have become an important class of com-
pounds in organic chemistry, and now their chemistry cannot be
considered as marginal. Cephalosporolides are a group of naturally
occurring macrolides isolated from fermentation fungus, cephalo-
sporium aphidicola ACC 3490.2 The gross structures were estab-
lished by extensive, IR, mass spectroscopy and NMR (1D and 2D)
studies. Structurally, cephalosporolide D contains two chiral cen-
ters (C-4 and C-8) and unusual saturated eight-membered lactone
ring that represents a prominent member of the saturated eight-
membered lactone ring family of natural products that includes
octalactin A and octalactin B (Fig. 1).3 Because of their fascinating
structural features and interesting biological properties, cepha-
losporolides have solicited considerable interest among organic
chemists.4 As a consequence of the central role played by this lac-
tone ring system, numerous methods have been devised for the
asymmetric synthesis of cephalosporolides.
methyl) benzoic anhydride (TFBA).5 Also, Shiina has reviewed quite
recently on the synthesis of eight-membered lactones.6
Our research program directed toward the expedient synthesis
of polysubstituted piperidines from cheap and readily available
starting materials7a,d prompted us to develop a general approach
for the stereocontrolled synthesis of medium-sized lactone ring
compounds. The realization of this goal and an application to the
efficient synthesis of (+)-cephalosporolide D (1) is presented
herein.
During the course of our synthetic studies on developing simple
routes for the asymmetric synthesis of bioactive natural prod-
ucts,7b,c we found that Marouka asymmetric allylation of aldehyde
derivatives using (S)-BINOL and (R)-BINOL proceeded smoothly to
provide homoallylic alcohols with the desired enantioselectivity.7c
Thus, our retrosynthetic strategy (Scheme 1) relies on the Maruoka
allylation approach starting from the 1,3-propanediol and well-
known Grubb’s cross metathesis.
As outlined retrosynthetically in Scheme 1, cephalosporolide D
(1) could be obtained by Yamaguchi lactonization8 of acid 4, which
could be provided by the oxidation of 5. In the forward direction,
key fragment 5 containing two stereogenic centers was envisaged
to be obtained by Grubb’s cross metathesis reaction of two frag-
ments 6 and 7. Fragment 7, containing one stereogenic center,
could be derived from aldehyde 8 via Maruoka allylation, which
is conceived to be obtained through four-step sequence starting
from the inexpensive 1,3-propanediol (9). The highlight of present
total synthesis is the utilization of Maruoka asymmetric allylation
which directs the stereochemistry at C-7. More importantly, we
Interests of these compounds have largely focused on the con-
struction of eight-membered lactone ring system as well as the
structural moiety possessing the asymmetric centers bearing a hy-
droxyl group and methyl group. Shiina et al. reported the synthesis
of cephalosporolides which involved the eight-membered lactone
moiety by a novel mixed anhydride method using (4-trifluoro-
* Corresponding author. Tel.: +91 40 27193166; fax: +91 40 27160512.
E-mail address: janaswamy@iict.res.in (J.M. Rao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.082

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G. V. Reddy et al. / Tetrahedron Letters 51 (2010) 1723–1726
O
O
O
O
HO
HO
HO
HO
Me
O
H
O
OH
O
O
OH
OH
(+)-Cephalosporolide D (1)
O
H
Octalactin B (3)
Octalactin A (2)
Figure 1. Structures of (+)-cephalosporolide D (1) and similar 8-membered lactones, octalactin A (2) and octalactin B (3).
O
OBn
OMOM
O
OBn
OMOM
Me
OH
OH O
+
OTBDPS
OTBDPS
OH
6
7
OH
(+)-Cephalosporolide D (1)
4
5
O
HO
OH
H
OTBDPS
8
9
Scheme 1. Retrosynthetic analysis of 1.
The journey for the synthesis of segment 7 began with the
known 1,3-propanediol (9), which was selectively protected as
TBDPS ether 13 using TBDPSCl, DIPEA in dry CH2Cl2 (Scheme
2).10 IBX11 oxidation of 13 yielded aldehyde 8, which was subjected
to an enantioselective Maruoka allylation12 using titanium com-
plex (R,R)-I and allyltri-n-butyltin to furnish the homoallylic alco-
hol 14 in 86% yield with excellent enantioselectivity of 98% ee
(determined by chiral HPLC).13 The resultant homoallyalcohol
was orthogonally protected as its MOM ether 7 with MOMCl in
the presence of DIPEA in CH2Cl2 at 0 °C to room temperature
(90% yield).14 The conjunction of precursors 6 and 7 was then
investigated via olefin cross metathesis reaction. Treatment of
the precursors 6 and 7 with second generation Grubb’s catalyst
(5 mol % Grubbs II) in dichloromethane under reflux conditions
gratifyingly yielded 5 in 80% yield15 (see Scheme 3).
OBn
OBn
OBn
6
OH
c
b
H
a
OEt
OEt
O
O
11
O
10
12
Scheme 2. Reagents and conditions: (a) BnBr, Ag2O, Et2O, reflux, 12 h, 90%; (b)
DIBAL-H, CH2Cl2, ꢀ78 °C, 15 min, 88%; (c) CH3IPPh3, t-BuOK, toluene, 0 °C to rt, 1 h,
90%.
have successfully implemented a strategy that minimizes protect-
ing group manipulation in a unique fashion, a common and
unavoidable practice in cephalosporolide D synthesis.
The synthesis of cephalosporolide D commenced from commer-
cially available (S)-ethyl lactate (10) as chiral synthon. Thus, pro-
tection of the hydroxyl group with BnBr in the presence of Ag2O
in ether gave as its benzyl ether 11 in 90% yield,9 which on reduc-
tion with DIBAL-H at ꢀ78 °C in dichloromethane leading to the
corresponding aldehyde 12 in 88% yield.9 Wittig olefination of 12
with t-BuOK in toluene proceeded smoothly to yield 6 in excellent
yield (90%) (Scheme 2).
The key fragment 5 can also be synthesized from the protected
homoallyl alcohol 14 and hence this provides access to target com-
pound. Grubb’s cross metathesis reaction of 7 with methyl vinyl
ketone (2 equiv) led to the
a,b-unsaturated ketone 15 in 81%
yield.15 In our laboratory, we had previously demonstrated the
oxazaborolidine catalyst for applications in reduction reactions.7c
To our delight, the use of this catalyst with BH3ꢁDMS at ꢀ40 °C in
O
f
e
d
TBDPSO
H
TBDPSO
OH
HO
OH
OH
13
8
9
OMOM OBn
OMOM
h
g
TBDPSO
TBDPSO
TBDPSO
5
14
7
OiPr
O
O
Ti
O
O
O
Ti
PriO
( R,R)-I
Scheme 3. Reagents and conditions: (d) TBDPSCl, DIPEA, CH2Cl2, 0 °C to rt, 2 h, 95%; (e) IBX, DMSO, THF, rt, 1 h, 92%; (f) (R,R)-I (10 mol %), Bu3SnCH2CH@CH2, CH2Cl2, ꢀ15 °C
to 0 °C, 24 h, 86%; (g) MOMCl, DIPEA, CH2Cl2 0 °C to rt, 7 h, 90%; (h) compound 6 (2 equiv), 5 mol % Grubb’s second generation catalyst, CH2Cl2, reflux, 6 h, 80%.

G. V. Reddy et al. / Tetrahedron Letters 51 (2010) 1723–1726
1725
OMOM
O
OMOM
OMOM
OH
b
c
a
5
TBDPSO
TBDPSO
TBDPSO
16
14
15
Scheme 4. Reagents and conditions: (a) Methyl vinyl ketone (2 equiv), 5 mol % Grubb’s II, CH2Cl2, reflux, 6 h, 81%; (b) R-CBS catalyst, THF, ꢀ40 °C, BH3ꢁDMS, 3 h, 90%, 97% de;
(c) NaH, BnBr, THF, 0 °C to rt, 3 h, 95%.
O
OMOM
OBn
OMOM
OBn
OMOM
OBn
i
j
HO
TBDPSO
HO
15
16
5
O
O
O
O
O
OMOM
OH
k
m
l
OH
HO
OMOM
17
1
18
Scheme 5. Reagents and conditions: (i) TBAF, THF, rt, 10 h, 91%; (j)TEMPO, BAIB, CH2Cl2–H2O (1:1), rt, 94%; (k) H2, Pd/C, EtOAc, rt, 12 h, 90%; (l) DIPEA, 2,4,6-Cl3C6H2COCl,
DMAP, PhH, 80 °C, 68%; (m) 4 N HCl, THF, 0 °C, 1 h, 85%.
the reduction16 of 15 furnished allyl alcohol 16 with an (S)-config-
2. Ackland, M. J.; Hanson, J. R.; Hitchcock; Ratcliffe, A. H. J. Chem. Soc., Perkin. Trans
1 1985, 843.
uration in 90% yield with 97% de.17 This presumably arises from the
3. (a) Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.; Shimazaki, T.; Takasuma,
‘diastereo selective’ reduction (as opposed to the over-reduction)
of 16 to the allyl alcohol, which spontaneously directs to form
the 16 as a single diastereomer. The resultant allylalcohol 16 pro-
tected as its benzyl ether using BnBr and NaH in THF to afford the
fragment 5 in 95% yield (Scheme 4).
Y.; Ibuka, R. Tetrahedron Lett. 2004, 45, 543; (b) Buszek, K. R.; Jeong, Y.; Sato, N.;
Still, P. C.; Muino, P. L.; Ghosh, I. Synth. Commun. 2001, 31, 1781.
4. Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.; Shimazaki, T.; Takasuma, Y.;
Ibuka, R. Chem. Eur. J. 2005, 11, 6601.
5. (a) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 1998,
831; (b) Shiina, I.; Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000, 52, 1105.
6. Shiina, I. Chem. Rev. 2007, 107, 239.
With the successful synthesis of the key fragment 5, we pro-
ceeded to macrolactonization via Yamaguchi lactonization as de-
picted in Scheme 5. Thus, removal of the TBDPS group with TBAF
followed by the oxidation (TEMPO, BAIB in DCM and water in 1:1
ratio) smoothly furnished acid 17 in 94% yield.18 Double bond
reduction followed by deprotection of benzyl group was accom-
plished by hydrogenation19 employing 10% Pd/C in ethyl acetate
to give alcohol 4 in 90% yield, which was then subjected to macrol-
actonization by using the Yamaguchi procedure to provide eight-
membered macrolactone 18. Finally, removal of the MOM group20
in 18 with 4 N HCl in THF furnished the (+)-cephalosporolide D (1)
in 80% yield.
7. (a) Kumar, R. S. C.; Sreedhar, E.; Reddy, G. V.; Babu, K. S.; Rao, J. M. Tetrahedron:
Asymmetry 2009, 20, 1160; (b) Sreedhar, E.; Kumar, R. S. C.; Reddy, G. V.;
Robinson, A.; Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 440; (c)
Reddy, G. V.; Kumar, R. S. C.; Babu, K. S.; Rao, J. M. Tetrahedron Lett. 2009, 50,
4117; (d) Kumar, R. S. C.; Reddy, G. V.; Shankariah, G.; Babu, K. S.; Rao, J. M.
Tetrahedron Lett. 2010, 51, 1114.
8. Inanaga, J.; Harata, K.; Saeki, H.; Katsaki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
9. Solladle-Cavallo, A.; Bonne, F. Tetrahedron: Asymmetry 1996, 7, 171.
10. Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1992, 57, 1722.
11. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
12. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708;
(b) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy, M. S. Tetrahedron
Lett. 2004, 45, 9299.
13. The enantiomeric excess (ee) of the homoallyl alcohol 14 was determined by
HPLC [Diacel OD-H column, 250 ꢃ 4.6 mm, 5
DMA) ethanol, 98% hexane, 20 L injection volume, flow rate 0.5 mL/min
retention time 9.39 and 10.46 min].
l, 254 nm; eluent, 2% (0.1% of
All the intermediate compounds including the cephalosporolide
D were fully characterized by IR, 1H NMR, 13C NMR, and mass spec-
tral data.21 Comparison of our physical and spectroscopic data with
l
14. Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275.
15. BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465. and references
cited therein.
16. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551; (b)
Corey, J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
17. The diastereoselectivity was determined by HPLC [Diacel OD-H column,
the published data3b confirmed our successful synthesis of (+)-
cephalosporolide D (½a D25
ꢂ
+ 45.2 (c 0.5, CHCl3); lit.
½
a 2D5
+ 47.5 (c
ꢂ
1
0.2, CHCl3)).
In conclusion, we have developed an efficient stereoselective
protocol for the synthesis of cephalosporolide D (1) by employing
Maruoka asymmetric allylation, and Grubbs cross metathesis reac-
tion and Yamaguchi lactonization as the key reaction steps. We be-
lieve that the presented synthetic method could be of value in the
development of novel eight-membered lactone ring-based ana-
logues for cephalosporolide research.
250 ꢃ 4.6 mm, 5
l
, 225 and 254 nm; eluent, 5% (0.1% of DMA) ethanol, 95%
hexane, 20
4.3 min].
lL injection volume, flow rate 1 mL/min retention time 3.1 and
18. (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org.
Chem. 1997, 62, 6974; (b) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293.
19. McNeill, A. H.; Thomas, E. J. Tetrahedron Lett. 1993, 34, 1669.
20. Meyers, A. I.; Durandetta, J. L.; Munavu, R. J. Org. Chem. 1975, 40, 2025.
21. Spectral Data for selected compounds:
Compound 6: oil, ½a D25
ꢀ25 (c 1, CHCl3); IR (KBr): 2976, 2859, 1446, 1090,
ꢂ
696 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.32–7.28 (m, 5H), 5.83–5.70 (m, 1H),
;
Acknowledgements
5.23–5.12 (m, 2H), 4.59–4.32 (m, 2H), 3.94–3.84 (m,1H), 1.28 (d, 3H,
J = 6.4 Hz); 13C NMR (75 MHz, CDCl3): d 139.9, 138.5, 127.8, 127.0, 126.8,
115.5, 75.7, 69.4, 21.1; HRESIMS m/z [M+Na]+; calcd for C11H14NaO: 185.0942,
found: 185.0939.
The authors gratefully acknowledge keen interest shown by Dr.
J. S. Yadav, Director, IICT, Hyderabad. G.V.R, R.S.C.K, and E.S. thank
CSIR and UGC, New Delhi, for financial support.
Compound 7: oil, ½a D25
ꢀ1.8 (c 1, CHCl3); IR (KBr): 3070, 2933, 2888, 1467,
ꢂ
1106, 702 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.64–7.51 (m, 4H), 7.35–7.20 (m,
;
6H), 5.80–5.60 (m, 1H), 5.01–4.90 (m, 2H), 4.53 (s, 2H), 3.83–3.58 (m, 3H), 3.21
(s, 3H), 2.25–2.15 (m, 2H), 1.71–1.58 (m, 2H), 0.96 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 135.43, 134.54, 133.74, 129.52, 127.56, 117.12, 95.60, 73.90, 60.37,
55.37, 39.20, 37.08, 26.79, 19.12; HRESIMS m/z [M+Na]+; calcd for
References and notes
1. For a recent review, see: Rosseau, G. Tetrahedron 1995, 51, 2777.

1726
G. V. Reddy et al. / Tetrahedron Letters 51 (2010) 1723–1726
C24H34NaO3Si: 421.2175; found: 421.2164.
550.3351.
Compound 5: ½a 2D5
ꢂ
ꢀ17.4 (c 1, CHCl3); IR (KBr): 2930, 2856, 1427, 1110,
Compound 17: ½a 2D5
ꢂ
+1.7 (c 1, CHCl3); IR (KBr): 3462, 2923, 2852, 1715,
703 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.76–7.48 (m, 4H), 7.35–7.05 (m, 11H),
1038 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.65–4.51 (m, 2H), 3.96–3.84 (m, 1H),
;
5.58–5.24 (m, 2H), 4.54–4.37 (m, 3H), 4.29–4.13 (m, 1H), 3.83–3.54 (m, 3H),
3.17 (s, 3H), 2.41–2.34 (m, 2H), 1.69–1.53(m, 2H), 1.15 (d, 3H, J = 6.42 Hz), 0.96
(s, 9H); 13C NMR (75 MHz, CDCl3): d 138.8, 135.5, 134.8, 133.7, 129.6, 129.5,
128.6, 128.2, 127.6, 127.3, 95.5, 75.5, 74.1, 69.6, 60.4, 55.3, 37.67, 26.69, 21.8,
19.2; HRESIMS m/z [M+NH4]+; calcd for C33H48NO4Si: 550.3353; found:
3.80–3.65 (m, 1H), 3.29 (s, 3H), 2.60–2.32 (m, 2H), 1.44–1.32 (m, 4H), 1.23–
1.15 (m, 2H), 1.12 (d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3): d 176.2, 95.96,
74.6, 67.7, 55.5, 38.9, 34.7, 29.7, 23.5, 21.3; HRESIMS m/z [M+Na]+; calcd for
C10H20NaO5: 243.1208; found: 243.1200.