Total synthesis of (+)-cephalosporolide E and (-)-cephalosporolide F en route to bassianolone

Article abstract of DOI:10.1055/s-0029-1218538

A stereoselective synthesis of (+)-cephalosporolide E and (-)-cephalosporolide F en route to bassianolone is described. The key steps involve cross metathesis to get the desired β ,γ-unsaturated ester, asymmetric dihydroxylation to install the β-hydroxy-γ-lactone moiety and spiroketalization. Although attempts to get free bassianolone failed, the first total synthesis of natural cephalosporolides E and F has been achieved in nine steps and 6.3% and 3.5% overall yields, respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218538

1
58
LETTER
Total Synthesis of (+)-Cephalosporolide E and (–)-Cephalosporolide F en route
to Bassianolone
T
R
otal
S
ynthesis
o
o
f
(+)-Cephal
d
osporolide
E
n
and (–)-Cep
e
halosporoli
y
de
F
A. Fernandes,* Arun B. Ingle
Department of Chemistry, Indian Institute of Technology Bombay, Powai 400076 Mumbai, Maharashtra, India
Fax +91(22)25767152; E-mail: rfernand@chem.iitb.ac.in
Received 22 September 2009
4
clic core in several other isolated natural products aug-
ments that these could be of natural origin. We planned to
synthesize (+)-bassianolone (1) and found that, under nor-
Abstract: A stereoselective synthesis of (+)-cephalosporolide E
and (–)-cephalosporolide F en route to bassianolone is described.
The key steps involve cross metathesis to get the desired b,g-unsat-
urated ester, asymmetric dihydroxylation to install the b-hydroxy- mal laboratory conditions, it was indeed difficult to sup-
g-lactone moiety and spiroketalization. Although attempts to get press its spiroketalization, giving 2 and 3. Hence in this
free bassianolone failed, the first total synthesis of natural cepha-
paper we discuss the first total synthesis of natural cepha-
losporolides E and F has been achieved in nine steps and 6.3% and
losporolides E and F en route to bassianolone. There is
3
.5% overall yields, respectively.
only one synthesis reported in the literature on unnatural
–)-cephalosporolide E and (+)-cephalosporolide F.5
Key words: bassianolone, cephalosporolides, cross metathesis,
asymmetric dihydroxylation, spiroketalization
(
O
O
H
H
O
OH
O
1
O
O
In 2005, Oltra and co-workers isolated (+)-bassianolone
(
(
3
4
O
O
O
H
1), a rare antimicrobial precursor of cephalosporolides E
2) and F (3) from the entomoparasitic fungus Beauveria
bassiana (Figure 1). The chemical structure of 1 was es-
tablished by NMR study of its bisacetate derivative, and
the relative and absolute configuration was ascertained by
H
O
6
OH
O
1
9
2
H
3
H
(+)-bassianolone
(+)-cephalosporolide E
(–)-cephalosporolide F
1
Figure 1 (+)-Bassianolone and cephalosporolides E and F
chemical correlation with 2 and 3. It was also converted
into cephalosporolides E and F by passing through a pad
of silica gel where it undergoes spiroketalization. This Our synthesis is based on the separation of cepha-
confirmed the relative (3S*,4S*,9R*) configurations.1 losporolides E and F formed after spiroketalization of
Cephalosporolides E and F were isolated by Hanson and bassianolone (1) as shown in our retrosynthetic analysis
2
co-workers from the fungus Cephalosporium aphidicola (Scheme 1). Bassianolone (1) can be visualized to be ob-
3
and later by Rukachaisirikul and co-workers from the en- tained by asymmetric dihydroxylation of the b,g-unsatur-
tomopathogenic fungus Cordyceps militaris BCC 2816. ated ester 4 with concomitant lactonization. Compound 4
These are believed to be simple artifacts formed during can be assembled by a cross metathesis of olefin frag-
the isolation process. However, the presence of spirotricy- ments 5 and 6. The compound 5 can be derived from 7
O
O
O
O
H
H
O
3
OH
O
4
O
O
O
spiroketalization
H
H
6
O
OH
O
1
9
H
3
(
+)-bassianolone
2
H
(+)-cephalosporolide E
(–)-cephalosporolide F
asymmetric
dihydroxylation
OH
cross
metathesis
OH
OTBDMS
CO2Et
OH
5
+
O
CO2Me
O
CO2Me
7
8
MeO
O
4
6
Scheme 1 Retrosynthetic analysis of bassianolone and cephalosporolides E and F
SYNLETT 2010, No. 1, pp 0158–0160
x
x.
x
x.
2
0
1
0
Advanced online publication: 01.12.2009
DOI: 10.1055/s-0029-1218538; Art ID: G30709ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-Cephalosporolide E and (–)-Cephalosporolide F
159
through allyl addition, and the latter can be readily elabo-
rated from commercially available (R)-methyl lactate (8),
which fixes the desired (9R) configuration.
OTBDMS
OTBDMS
a
b
OH
OH
CO2Me
We first attempted the synthesis of olefin fragment 5 as
shown in Scheme 2. Protection of the hydroxyl group in
1
0
1
5 (E/Z = 5:1)
(
R)-methyl lactate (8) as tert-butyldimethylsilyl ether fol-
c
OTBDMS
4
lowed by reduction of the ester, and Wittig olefination of
the resulting aldehyde provided ester 9 in 82% overall
6
d
mixture of
polar products
yield. Double-bond reduction by catalytic hydrogenation
gave the ester 7 in excellent yields (98%). Sequential re-
duction of the ester group in 7 to the aldehyde, subsequent
allyl Grignard addition to give the alcohol 10 (92% over
two steps), and further PCC oxidation gave the desired ke-
tone 11. All attempts to remove the TBDMS group either
using TBAF–THF or 2 M HCl–MeOH or PTSA–MeOH
to get 5 gave a complex mixture. Closer analysis of this
mixture indicated products formed by partial isomeriza-
tion of the double bond to the a,b-position and acetal for-
mation due to the g-hydroxyl group. To overcome this, the
ketone functionality was protected as ketal 12 in 77%
yield. Subsequent deprotection of the TBDMS ether af-
O
CO2Me
CO2Me
1
6
e
OTBDMS
O
OTBDMS
OH
f
O
O
O
g
O
18
1
7
O
OH
OH
h
O
OH
O
O
O
O
O
1
9
O
7
forded the alcohol 13. A cross-metathesis reaction of 13
g or i
OH
with 6 using Grubbs second-generation catalyst gave the
b,g-unsaturated ester 14 (76%), however, with poor E/Z
1
bassianolone
(
3:2) selectivity.
OH
OTBDMS
CO Et
OTBDMS
O
O
a
b
c
H
H
CO2Me
CO Et
2
2
O
O
H
O
O
8
9
7
H
O
OTBDMS
OTBDMS
OTBDMS
O
O
H
d
f
2
3
H
OH
(+)-cephalosporolide E
(–)-cephalosporolide F
10
O
O
12
11
Scheme 3 Synthesis of cephalosporolides E and F en route to bas-
sianolone. Reagents and conditions: (a) Grubbs II, 6 (5.0 equiv),
CH Cl , reflux, 12 h, 82%; (b) IBX (1.6 equiv), EtOAc, reflux, 6 h,
OH
e
g
OH
2
2
8
9%; (c) Bu NF (2.0 equiv), THF, r.t., 2 h; (d) K Fe(CN) , K CO ,
4
3
6
2
3
O
OH
MeSO NH , (DHQ) PHAL, K OsO ·2H O, t-BuOH–H O (1:1),
4 2 2 2 4 2 2
5
h
O
O
0
°C, 24 h; (e) (CH OH) (30.0 equiv), PTSA (cat.), C H , reflux, 14
2 2 6 6
h, 77%; (f) K Fe(CN) , K CO , MeSO NH , (DHQ) PHAL,
13
3
6
2
3
4
2
2
O
O
K OsO ·2H O, t-BuOH–H O (1:1), 0 °C, 24 h, 70%; (g) 2 N HCl,
2 4 2 2
CO2Me
1
4
MeOH, r.t., 8 h or PTSA (cat.), MeOH, r.t., 8 h; (h) Bu NF (1.5
4
(
E/Z = 3:2)
equiv), THF, r.t., 2 h, 70%; (i) CAN (2.5 equiv), MeCN–H O (1:1),
2
7
0 °C, 5 min, 2 (59%), 3 (33%).
Scheme 2 Attempted synthesis of 5 and cross metathesis. Reagents
and conditions: (a) (i) imidazole (1.2 equiv), TBDMSCl (1.1 equiv),
CH Cl , r.t., 12 h; (ii) DIBAL-H (1.0 equiv), CH Cl , –78 °C, 1.5 h;
forded the ketone 16 in good yields (89%). Further the re-
2
2
2
2
(
iii) Ph P=CHCO Et (1.2 equiv), THF, r.t., 12 h, 82% overall; (b) H / moval of TBDMS group failed to deliver compound 4.
3
2
2
8
Pd-C, EtOH, r.t., 12 h, 98%; (c) (i) DIBAL-H (1.05 equiv), CH Cl , –
7
(
8
h; or PTSA (cat), MeOH, r.t., 4 h; (f) (CH OH) (30.0 equiv), PTSA
(
7
2
2
Hence we attempted asymmetric dihydroxylation of ole-
8 °C, 1.5 h; (ii) allylMgCl (1.2 equiv), THF, 0 °C, 1 h, r.t., 1 h, 92%;
fin 16. This afforded an inseparable mixture of polar prod-
ucts. These could arise from initial dihydroxylation,
concomitant lactonization, and subsequent acetalization
of the C-3 hydroxy group with the ketone functionality.
However, the products formed at various stages of this se-
quence could not be separated for analysis. We then
moved our attention to protect the ketone functionality.
Thus ketalization of 16 with ethylene glycol provided 17
d) PCC (2.0 equiv), NaOAc (2.0 equiv), CH Cl , 0 °C to r.t., 4 h,
2
2
3%; (e) Bu NF (2.0 equiv), THF, r.t., 2 h; or 2 N HCl, MeOH, r.t., 4
4
2
2
cat), C H , reflux, 14 h, 77%; (g) Bu NF (2.0 equiv), THF, r.t., 2 h,
6
6
4
5%; (h) Grubbs II, 6 (5.0 equiv), CH Cl , reflux, 12 h, 76%.
2 2
We then moved our attention to the cross metathesis of
olefin fragments 10 and 6 (Scheme 3). Overwhelmingly,
compound 15 was obtained with improved E/Z selectivity
of calculated 5:1 (82%). IBX oxidation of alcohol 15 af-
(
77%). Subsequent asymmetric dihydroxylation of 17
cleanly afforded the lactone 18 as a single diastereomer in
Synlett 2010, No. 1, 158–160 © Thieme Stuttgart · New York

1
60
R. A. Fernandes, A. B. Ingle
LETTER
(4) (a) Seibert, S. F.; Krick, A.; Eguereva, E.; Kehraus, S.;
9
good yield (70%). The acid-catalyzed deprotection of
TBDMS ether and the ketal group failed to deliver free
bassianolone (1) in a single step. A stepwise removal of
TBDMS group first, followed by the ketal group, was ex-
ecuted. The compound 18 when treated with excess of
TBAF, deprotection of the ketal group was also observed
giving the mixture of 2 and 3, and no free bassianolone
was obtained. When compound 18 was treated with 1.5
equivalents of TBAF, the deprotection of only TBDMS
ether was observed to give 19 (70%). All attempts under
varied acid-catalyzed conditions to deprotect the ketal
functionality proved futile to obtain free bassianolone. In
all cases the mixture of 2 and 3 was obtained in variable
yields. In one of the attempts with CAN-mediated11
deprotection of the ketal functionality a cleaner deprotec-
tion–spiroketalization occurred affording 2 and 3 in high-
er yields. The crude mixture of 2 and 3 was easily
separated by flash column chromatography providing 2
Kónig, G. M. Org. Lett. 2007, 9, 239. (b) Li, X.; Yao, Y.;
Zheng, Y.; Sattler, I.; Lin, W. Arch. Pharm. Res. 2007, 30,
812. (c) Li, X.; Sattler, I.; Lin, W. J. Antibiot. 2007, 60, 191.
(5) Ramana, C. V.; Suryawanshi, S. B.; Gonnade, R. G. J. Org.
Chem. 2009, 74, 2842.
(
6) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org.
Chem. 1983, 48, 5180. (b) Kim, D.; Lee, J.; Shim, P. J.; Lim,
J. I.; Doi, T.; Kim, S. J. Org. Chem. 2002, 67, 772.
(
c) Stivala, C. E.; Zakarian, A. Org. Lett. 2009, 11, 839.
1
0
(7) For olefin cross metathesis, see: (a) Connon, S. J.; Blechert,
S. Angew. Chem. Int. Ed. 2003, 42, 1900. (b) Chatterjee,
A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360. (c) Lipshutz, B. H.;
Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org. Lett. 2008,
10, 1325; and references cited therein.
(
8) Reviews: (a) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006,
725. (b) Bolm, C.; Hildebrand, J. P.; Muniz, K. In
1
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: Weinheim, 2000, 399. (c) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
(
(
[
59%) and 3 (33%). The spectral and analytical data of
+)-cephalosporolide E (2) along with its optical rotation
a] +49.2 (c 0.25, CHCl ) were in excellent agreement
94, 2483. (d) Johnson, R. A.; Sharpless, K. B. Asymmetric
Catalysis in Organic Synthesis; Ojima, I., Ed.; VCH: New
2
5
York, 1993, 227.
D
3
2
30
2
9) 1H NMR and 13C NMR studies of purified product indicated
(
with that reported {lit. [a] +51.3 (c 0.42, CHCl )}.
D
3
2
5
single diastereomer.
Similarly, (–)-cephalosporolide F (3) had [a]
–69.1 (c5
D
1
25
Data for 18
0
.15, CHCl ) {lit. [a] –33.3 (c 0.79, CHCl ) and lit.
D
3
D
3
25
Colourless oil; [a]D +10.2 (c 0.2, CHCl ). IR (CHCl ):
25
3
3
[
a] +95.2 (c 0.9, CHCl ) for its enantiomer}. The spec-
3
n = 3463, 3022, 2973, 1772, 1646, 1528, 1421, 1347, 1216,
tral data for (–)-cephalosporolide F (3) matched well with
–1 1
1
045, 927, 669 cm . H NMR (400 MHz, CDCl /TMS):
3
2
that reported.
d = 0.02 (s, 3 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 1.11 (d, J = 6.1
Hz, 3 H), 1.43–1.49 (m, 2 H), 1.50–1.58 (m, 1 H), 1.72–1.80
In summary, the first total synthesis of natural (+)-cepha-
losporolide E and (–)-cephalosporolide F has been
achieved starting from (R)-methyl lactate and employing
cross metathesis, asymmetric dihydroxylation, and
spiroketalization as the key steps. The synthesis is com-
pleted in nine steps and overall yields of 6.3% and 3.5%
for 2 and 3, respectively.
(
(
m, 1 H), 2.24–2.37 (m, 2 H), 2.54 (d, J = 17.7 Hz, 1 H), 2.72
dd, J = 17.7, 5.8 Hz, 1 H), 3.44 (br s, OH), 3.75–3.80 (m, 1
H), 3.93–4.02 (m, 4 H), 4.36–4.38 (m, 1 H), 4.55–4.60 (m, 1
1
3
H). C NMR (100 MHz, CDCl ): d = –4.83, –4.39, 18.0,
3
23.6, 25.7 (3 C), 32.7, 33.7, 34.1, 37.7, 64.1, 64.5, 67.9, 68.3,
80.9, 110.1, 175.3. HRMS (ESI-TOF): m/z calcd for
C H O Si + Na: 397.2022; found: 397.2028.
18 34
6
(
10) Data for 19
Colourless oil; [a]D –20.4 (c 0.1, CHCl ). IR (CHCl ):
2
5
3
3
n = 3440, 3018, 2965, 2931, 1773, 1636, 1458, 1407, 1378,
Acknowledgment
–
1 1
1
216, 1160, 1062, 949, 668 cm . H NMR (400 MHz,
Financial support by IRCC, Indian Institute of Technology Bombay
is gratefully acknowledged. A.B.I. thanks CSIR New Delhi for a
research fellowship.
CDCl /TMS): d = 1.21 (d, J = 6.4 Hz, 3 H), 1.47–1.57 (m, 2
3
H), 1.79–1.87 (m, 2 H), 2.33–2.36 (m, 2 H), 2.56 (d, J = 17.7
Hz, 1 H), 2.76 (dd, J = 17.8, 5.9 Hz, 1 H), 3.36–3.45 (br s,
OH), 3.78–3.82 (m, 1 H), 3.98–4.06 (m, 4 H), 4.39–4.41 (m,
1
3
1
H), 4.56–4.61 (m, 1 H). C NMR (100 MHz, CDCl3):
References and Notes
d = 23.6, 33.3 (2 C), 34.3, 37.9, 64.3, 64.7, 67.6, 68.5, 81.1,
1
10.1, 175.5. HRMS (ESI-TOF): m/z calcd for C H O +
(
(
(
1) Oller-López, J. L.; Iranzo, M.; Mormeneo, S.; Oliver, E.;
Cuerva, J. M.; Oltra, J. E. Org. Biomol. Chem. 2005, 3, 1172.
2) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. B.; Ratcliffe,
A. H. J. Chem. Soc., Perkin Trans. 1 1985, 843.
12 20 6
H: 261.1338; found: 261.1341.
(
11) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel,
Y.; Vanherck, J.-C.; Markó, I. E. Tetrahedron 2003, 59,
8989.
3) Rukachaisirikul, V.; Pramjit, S.; Pakawatchai, C.; Isaka, M.;
Supothina, S. J. Nat. Prod. 2004, 67, 1953.
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