Total synthesis of naturally occurring cephalosporolides E/F

Article abstract of DOI:10.1016/j.tet.2014.04.026

A modular total synthesis of cephalosporolides E/F featuring sequential epoxide-alkyne coupling and subsequent highly regioselective gold catalyzed alkynolcycloisomerization of the resulting alkynetetrol to construct the central spiroketal core has been documented.

Full text of DOI:10.1016/j.tet.2014.04.026

Tetrahedron 70 (2014) 3653e3656
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of naturally occurring cephalosporolides E/F
*
Chandrababu Naidu Kona, C.V. Ramana
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A modular total synthesis of cephalosporolides E/F featuring sequential epoxideealkyne coupling and
subsequent highly regioselective gold catalyzed alkynolcycloisomerization of the resulting alkynetetrol
to construct the central spiroketal core has been documented.
Received 7 March 2014
Received in revised form 7 April 2014
Accepted 9 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 13 April 2014
Keywords:
Cephalosporolide
Epoxide-alkyne coupling
Gold catalysis
Alkynetetrol
Spiroketalization
1. Introduction
2) and other related natural products. As shown in Fig. 1, keeping
the metal-mediated spiroketalization13,14 of an alkynediol as the
Cephalosporolides E and F were isolated from the industrial
fermentation of the fungus Cephalosporium aphidcola in 1985 and
later in 2004 from fungus Cordyceps militaris BCC 2816.1,2 Cepha-
losporolides E and F belong to a special class of natural products
possessing a rare spiral lactone skeleton. Ascospiroketals A/B,3
penisporolides A/B,4 cephalosporolides H/I5 also possess the simi-
lar spiral lactone skeleton with variations mainly either in the side
chain and/or the groups at the C2-methylene group. The cepha-
losporolides E and F are epimeric at the spiro-carbon center and
have a similar configuration at the other three stereogenic centers.
In 2009, we documented the total synthesis of unnatural enantio-
mers of the cephalosporolides E and F and proposed the absolute
configuration of these two natural products.6 The naturally occur-
ring cephalosporolides E/F have been synthesized first by Fernan-
dez’s group followed by the groups of Brimble, Dudley, and
Britton.7e11
key skeletal construct and considering the fact that all these natural
products differ mainly either in the side chain and/or the groups at
the C2-methylene group, the complete carbon framework has been
disconnected into two key oxirane fragments with the plan being to
couple the two by an ethylene unit by employing sequential
epoxideealkyne couplings. The glucose-diacetonide 3 has been
selected as the starting chiral-pool material for the synthesis of key
oxirane fragments. The functional group manipulations at C3 of this
acetonide should address the variations required at the C2 of these
natural products. On the other hand, the constitution and config-
uration of the R group will be addressed by the oxirane fragment
employed. Fig.1 reveals the general retrosynthetic scheme for these
natural products. To start in this direction, the total synthesis of
cephalosporolides E/F has been selected as an exploratory example.
The epoxides 4 and 5 have been identified as the key building
blocks in this context.
In our synthesis of cephalosporolides E/F, a Pd-catalyzed alky-
The complementary stereochemical relation between the C3/C4
in glucose acetonide 3 (used for the synthesis of ent-cepha-
laosporolides E/F) with that of C4/C5 in 4 (with a simple inversion
at C5) has been considered as a handle for the stereo-divergent
synthesis of naturally occurring cephalosporolides E/F(1/2).
nediol cycloisomerization12 has been used as the key reaction to
construct the central spirocyclic ketal unit. The D-glucose and L-
maleic acids have been employed as chiral-pool starting materials
in order to address the stereochemistry of the C(4), C(5), and C(10)
centers.6 In continuation, we have been interested in developing
a general strategy for the synthesis of the cephalosporolides E/F (1/
2. Results and discussion
The synthesis commenced with the opening of the known ep-
oxide 415 with lithiated trimethylsilylacetylene in the presence of
BF3$Et2O. The treatment of the resulting TMS alkynol 6 with NaH
* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail
address: vr.chepuri@ncl.res.in (C.V. Ramana).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.026

3654
C.N. Kona, C.V. Ramana / Tetrahedron 70 (2014) 3653e3656
Scheme 1. Total synthesis of cephalosporolides E/FdReagents and conditions: (a)
BuLi, BF3$Et2O, THF, 1 h; (b) BnBr, NaH, THF, 3 h; (c) BuLi, BF3$Et2O, THF, 1 h; (d) [i] 60%
AcOH, reflux, 6 h; [ii] NaBH4, MeOH, 3 h; (e) (5 mol %) Au(PPh3)Cl, (5 mol %) AgSbF6,
CH2Cl2, 2 h, 0 ꢂC; (f) [i] NaIO4, CH2Cl2, H2O, 1.5 h; [ii] NaClO2, NaH2PO4$2H2O, 2-methyl
2-butene, tBuOHþH2O, 5 h [iii] Pd(OH)2/C/H2, MeOH, 3 h.
3. Conclusion
In summary, a concise and short total synthesis of cepha-
losporolides E and F has been documented. The central bicyclic
ketal core has been constructed through a gold-catalyzed spi-
roketalization of an alkynetetrol 9 with complete regioselectivity.
Fig. 1. Spiral lactone natural products & a unified modular approach.
and benzyl bromide in DMF gave the benzyl ether 7 resulting from
the deprotection of the C-trimethylsilyl group during the benzyla-
tion. Subsequently, the alkyne 7 and the commercially available
(2S)-porolyene oxide 5 were subjected for the alkyne-epoxide
coupling under the established conditions to procure the alkynol
8. Alkynol 8 was converted to the alkynetetrol intermediate 9 (73%
over two steps) by following a sequence of acetonide hydrolysis and
subsequent reduction of the intermediate lactal with NaBH4
(Scheme 1).
Having the key alkynetetrol 9 in hand the next concern was
metal-catalyzed alkynediol spiroketalization. Our initial experi-
ments dealing with Pd[CH3CN]Cl2 as a complex gave the desired
spiroketals 10 in poor yields along with the formation of various
unidentifiable products. The reactions with the other [Pd]-
complexes are either sluggish or gave the products in poor
yields. In this context, we next screened various gold complexes
(See Table 1, SI) amongst, which the AuCl(PPh3)/AgSbF6 combi-
nation has been found to be the best for this purpose and the re-
quired spiroketals 10 were obtained in excellent yield. As the
resulting epimeric spiroketals are not separable, the mixture was
subjected for the next reaction directly. To this end, the cepha-
losporolides E/F (1/2) have been synthesized (3 steps, 55% overall
yields) from 10 by following a sequence of reactionsdi. diol
cleavage with NaIO4; ii. oxidation of intermediate aldehyde to acid
using Pinnic conditions; and iii. hydrogenation over 20% Pd(OH)2/C
in methanol. Both the cephalosporolides E and F were separated
and their spectral and physical data was in agreement with the
data reported.
4. Experimental section
4.1. General
Air and/or moisture sensitive reactions were carried out in
anhydrous solvents under an atmosphere of argon in oven-dried
glassware. All anhydrous solvents were distilled prior to use:
dichloromethane and DMF from CaH2; methanol from Mg cake;
THF on Na/benzophenone; triethylamine over KOH; Acetone on
KMnO4. Commercial reagents were used without purification.
Column chromatography was carried out by using Spectrochem
silica gel. Optical rotations were determined on a Jasco DIP-370
digital polarimeter. Specific optical rotations [
a
]
are given in
D
10ꢀ1ꢁdegꢁcm2ꢁgꢀ1. 1H and 13C NMR spectroscopy measurements
were carried out on Bruker AC 200 MHz, Bruker DRX 400 MHz, and
Bruker DRX 500 MHz spectrometers, and TMS was used as an in-
ternal standard. 1H and 13C NMR chemical shifts are reported in
parts per million downfield from Chloroform-d (
d
¼7.25) or TMS or
acetone-d6
(
d
¼2.05) and coupling constants (J) are reported
in Hertz (Hz). The following abbreviations are used to designate
signal multiplicity: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, and br¼broad. The multiplicity of 13C NMR
signals was assigned with the help of DEPT spectra and the ab-
breviations used: s¼singlet, d¼doublet, t¼triplet, and q¼quartet,
represent C (quaternary), CH, CH2, and CH3, respectively. Mass
spectroscopy was carried out on PI QStar Pulsar (Hybrid
Quadrupole-TOF LC/MS/MS) and 4800 plus MALDI TOF/TOF Ap-
plied Biosystem spectrometer.

C.N. Kona, C.V. Ramana / Tetrahedron 70 (2014) 3653e3656
3655
4.2. Synthesis of oxirane 4
residue by column chromatography (10:90% ethyl acetate/petro-
leum ether) affords compound 7 (1.5 g, 70% over all yield from two
25
To a solution of 3-deoxy-1,2-O-isopropylidiene-6-(tert-butyldi-
methylsilyl)-ribo-hexopyranose15 (9.0 g, 28.3 mmol) in CH2Cl2
(100 mL), Et3N (15.7 mL, 113.0 mmol) followed by CH3SO2Cl
(3.32 mL, 42.4 mmol) were added at 0 ꢂC and stirred for 3 h at rt.
The reaction mixture was poured into 100 mL of water and
extracted with CH2Cl2 (2ꢁ100 mL). The combined organic layer was
washed with saturated solution of NaHCO3 (100 mL), brine (50 mL),
and dried over (Na2SO4), evaporated under reduced pressure. The
resulting crude mesylate (10.2 g, 25.7 mmol) dissolved in THF
(100 mL), was added TBAF (16.8 g, 64.3 mmol) and allowed to stir
for 2 h at room temperature. THF removed under reduced pressure
and extracted with ethyl acetate. Organic layer was concentrated,
crude product was purified by column chromatography (30:70%
ethyl acetate/petroleum ether) to afford compound 4 (4.1 g, 78%
yield overall two steps) as a colorless oil. Rf (25% EtOAc/petroleum
steps) as a yellow syrup. Rf (10% EtOAc/petroleum ether) 0.4; [
a]
D
ꢀ23.3 (c 1.4, CHCl3); IR (CHCl3)
n
: 1H NMR (200 MHz, CDCl3):
d 1.31
(s, 3H), 1.49 (s, 1H), 1.72e1.81 (ddd, J¼4.8, 10.6,13.3 Hz, 1H),
1.84e1.96 (dd, J¼4.8, 20.0 Hz, 1H), 2.0 (t, J¼2.7 Hz, 1H), 2.51e2.55
(dd, J¼2.7 Hz, 2H), 3.53e3.61 (ddd, J¼4.3, 6.3, 12.5 Hz, 1H),
4.37e4.47 (dt, J¼4.6 Hz, 1H), 4.61e4.79 (m, 3H), 5.82 (d, J¼3.7 Hz,
1H), 7.29e7.36 (m, 5H); 13C NMR (50 MHz, CDCl3):
d 21.9 (t), 26.3
(q), 26.9 (q), 33.8 (t), 70.2 (d), 73.3 (t), 77.4 (d), 79.5 (d), 80.5 (d),
80.5 (s), 105.3 (d), 111.3 (s), 127.7 (d), 127.9 (d, 2C), 128.3 (d, 2C),
138.2 (s) ppm; HRMS (ESIþ): calcd for C18H22O4Na [MþþNa]
325.1410; found 325.1408.
4.5. (2R,7S)-7-(Benzyloxy)-7-((3aR,5S,6aR)-2,2-dimethyl tet-
rahydrofuro[2,3-d][1,3]dioxol-5-yl)hept-4-yn-2-ol (8)
ether) 0.5; [
a]
25 ꢀ26.9 (c 0.3, CHCl3); IR (CHCl3)
n
: 3438, 2990, 2063,
At ꢀ78 ꢂC, to a solution of alkyne 7 (1.0 g, 3.31 mmol) in THF
(10.0 mL) were added n-BuLi (2.1 mL, 1.6 M in hexane, 3.31 mmol)
and BF3$Et2O (0.4 mL, 3.31 mmol) followed by a solution of the
epoxide 5 (76 mg, 1.32 mmol) in anhydrous THF (1.0 mL) with
a 15 min interval. The stirring was continued for another 30 min at
ꢀ78 ꢂC and then quenched with NH4Cl (5 mL). The reaction mixture
was allowed to reach room temperature and partitioned between
ethyl acetate (25 mL) and water (25 mL). The aqueous layer was
extracted with ethyl acetate (2ꢁ25 mL) and the combined organic
layer was washed with brine, dried over Na2SO4, and concentrated.
Purification of the crude product by column chromatography (silica
230e400 mesh, 25:75 ethyl acetate/petroleum ether) to afford
compound 8 (418 mg, 87% yield) as a colorless liquid. Rf (30% EtOAc/
D
1634, 1456, 1383, 1324, 1217, 1021, 928, 855, 765, 649, 600,
501 cmꢀ1 1H NMR (200 MHz, CDCl3):
; d 1.28 (s, 3H), 1.46 (s, 3H),
1.73e1.87 (d, J¼8.1 Hz, 1H), 2.08e2.17 (dd, J¼4.7, 13.4 Hz, 1H),
2.75e2.80 (m, 2H), 2.97e3.03 (m, 1H), 4.08e4.18 (dt, J¼4.6, 1H),
4.71 (t, J¼4.2 Hz, 1H), 5.77 (d, J¼3.7 Hz, 1H); 13C NMR (50 MHz,
CDCl3):
d 26.1 (q), 26.7 (q), 35.5 (t), 44.3 (t), 52.2 (d), 76.9 (d), 80.2
(d), 105.5 (d), 111.3 (s) ppm; HRMS (ESIþ): calcd for C9H14O4Na
[MþþNa] 209.0784; found 209.0784.
4.3. (S)-1-((3aR,5S,6aR)-2,2-Dimethyltetrahydrofuro[2,3-d]
[1,3]dioxol-5-yl)-4-(trimethylsilyl)but-3-yn-1-ol (6)
At ꢀ78 ꢂC, to a solution of TMS alkyne (1.5 mL,10.7 mmol) in THF
(7.0 mL) were added n-BuLi (6.7 mL, 1.6 M in hexane, 10.7 mmol)
and BF3$Et2O (1.14 mL, 10.7 mmol) followed by a solution of the
epoxide 4 (1.0 g, 5.37 mmol) in THF (8 mL) with a 15 min interval.
The stirring was continued for another 30 min at ꢀ78 ꢂC and then
quenched with NH4Cl (5 mL). The reaction mixture was allowed to
reach room temperature and partitioned between ethyl acetate
(25 mL) and water (25 mL). The aqueous layer was extracted with
ethyl acetate (2ꢁ25 mL) and the combined organic layer was
washed with brine, dried over Na2SO4 and concentrated. Purifica-
tion of the crude product by column chromatography (silica
230e400 mesh, 20:80 ethylacetate/petroleum ether) afford the
petroleum ether) 0.4; [
a]
23 ꢀ12.4 (c 0.16, CHCl3); IR (CHCl3)
n
: 3565,
D
2928, 1722, 1373, 1217, 849, 754, 468 cmꢀ1
;
1H NMR
(200 MHz,CDCl3):
d
1.21 (d, J¼6.2 Hz, 3H), 1.30 (s, 3H), 1.48 (s, 3H),
1.71e1.85 (m, 1H), 1.92e2.01 (m, 1H), 2.15e2.23 (m, 1H), 2.25e2.33
(m, 2H), 2.49e2.52 (dd, J¼4.0 Hz, 1H), 2.53e2.55 (dd, J¼2.0, 2.3 Hz,
1H), 3.48e3.58 (ddd, J¼4.3, 6.3, 10.6 Hz, 1H), 3.80e3.95 (m, 1H),
4.37e4.46 (ddd, J¼4.4, 9.1, 10.5 Hz, 1H), 4.59 (d, J¼12.0 Hz, 1H),
4.67e4.76 (m, 2H), 5.81 (d, J¼3.8 Hz, 1H), 7.26e7.37 (m, 5H); 13C
NMR (50 MHz, CDCl3): d 21.4 (t), 22.3 (q), 26.2 (q), 26.7 (q), 29.4 (t),
34.5 (t), 66.3 (d), 72.5 (t), 77.5 (d), 78.3 (s), 79.0 (d), 80.2 (d), 105.3
(d), 111.1 (d), 127.7 (d), 127.9 (d, 2C), 128.3 (d, 2C), 138.02 (d), ppm;
HRMS (ESIþ): calcd for C21H28O5Na [MþþNa] 383.1829; found
383.1826.
alkynol 6 (1.1 g, 72% yield) as a white color solid. Mp¼243 ꢂC; Rf
25
(25% EtOAc/petroleum ether) 0.4; [
a
]
þ12.3 (c 0.18, CHCl3); IR
D
(CHCl3)
n
: 3418, 2989, 2170, 1634, 1381, 1251, 1162, 1027, 924, 842,
4.6. (2R,4S,5S,10R)-5-(Benzyloxy)undec-7-yne-1,2,4,10-tetraol
(9)
760, 498 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
0.13 (t, J¼3.5 Hz, 9H),
1.32 (s, 3H), 1.51 (s, 3H), 1.79e1.87 (m, 1H), 2.06e2.10 (dd, J¼4.6 Hz,
1H), 2.24 (d, J¼6.8 Hz, 1H), 2.45e2.51 (dd, J¼7.0, 17.0 Hz, 1H),
2.52e2.58 (dd, J¼6.5, 16.8 Hz 1H), 3.64e3.70 (m, 1H), 4.32e4.36 (dt,
J¼4.3 Hz, 1H), 4.75 (t, J¼4.2 Hz, 1H), 5.80 (d, J¼3.6 Hz, 1H); 13C NMR
A solution of alkynol 8 (500 mg, 1.39 mmol) in 60% aq acetic acid
(10 mL) was refluxed for 7 h. Acetic acid was evaporated under
reduced pressure and resulting crude (320 mg) was dissolved in
15 mL methanol and sodium borohydride (113 mg, 3 mmol) was
added at 0 ꢂC in portion wise and allowed to stir for 4 h at rt. The
reaction mixture was quenched with satd NH4Cl solution (2 mL)
and methanol was evaporated under reduced pressure. The crude
product was purified by column chromatography (100e200 silica
gel, 1:9% methanol/CH2Cl2) afford tetrol 9 (210 mg, 73% yield over
(101 MHz, CDCl3):
d 0.0 (q), 25.8 (t), 26.3 (q), 26.8 (q), 34.8 (t), 70.7
(d), 79.4 (d), 80.8 (d), 87.2 (s), 102.5 (s), 105.4 (d), 111.5 (s) ppm;
HRMS (ESIþ): calcd for C14H24O4NaSi [MþþNa] 307.1336; found
307.1334.
4.4. (3aR,5S,6aR)-5-((S)-1-(Benzyloxy)but-3-yn-1-yl)-2,2-
dimethyl tetrahydrofuro[2,3-d][1,3]dioxole (7)
two steps) as a colorless gum; Rf (100% EtOAc) 0.3; [
CHCl3); IR (CHCl3)
665, 505, 466 cmꢀ1
a
]
25 þ7.0 (c 0.1,
D
n
: 3400, 2924, 1645, 1401, 1069, 939, 755, 698,
To a solution of alcohol 6 (2 g, 7.0 mmol) in anhydrous THF
(15 mL), sodium hydride (60% oil suspension, 562 mg, 14.1 mmol)
was added at 0 ꢂC and allowed to stir for 20 min. To this cooled
reaction mixture, benzyl bromide (1.25 mL, 10.5 mmol) was added
slowly and stirred at room temperature for 2 h. The reaction mix-
ture was partitioned between ethyl acetate (50 mL) and water
(50 mL). The organic layer was separated, washed with ethyl ace-
tate, brine, dried (Na2SO4), and concentrated. Purification of the
;
1H NMR (200 MHz, acetone-d6):
d
1.18 (d,
J¼6.1 Hz, 3H), 1.62e1.58 (m, 1H), 1.80 (dt, J¼3.66, 1H), 2.23e2.18 (m,
1H), 2.33e2.28 (m, 1H), 2.47e2.41 (m, 1H), 2.56 (dq, J¼5.2, 2.7 Hz,
1H), 3.48e3.41 (m, 2H), 3.54e3.50 (dd, J¼6.1, 10.7 Hz, 1H),
3.86e3.82 (m, 1H), 3.91 (d, J¼4.9 Hz, 1H), 4.01 (m, 1H), 4.13 (d,
J¼4.9 Hz, 1H), 4.17 (d, J¼3.4 Hz, 1H), 4.61(d, J¼11.6 Hz, 1H), 4.77 (d,
J¼11.6 Hz, 1H), 7.41e7.25 (m, 5H); 13C NMR (acetone-d6, 50 MHz):
20.7 (t), 23.0 (q), 30.1 (t), 36.5 (t), 67.1 (d), 67.3 (t), 72.2 (d), 72.4 (d),

3656
C.N. Kona, C.V. Ramana / Tetrahedron 70 (2014) 3653e3656
73.0 (t), 79.4 (s), 79.9 (s), 81.8 (d), 128.3 (d), 128.7 (d, 2C), 129.1 (d,
2C), 140.1 (s) ppm; HRMS (ESIþ): calcd for C18H26O5Na [MþþNa]
345.1672; found 345.1670.
J¼6.2 Hz, 3H), 1.68e1.75 (m, 1H), 1.96e2.02 (m, 1H), 2.04e2.09 (m,
1H), 2.12e2.16 (m, 1H), 2.30e2.34 (dd, J¼2.3, 15.0 Hz, 1H),
2.48e2.52 (dd, J¼6.6,14.6 Hz,1H), 2.66 (d, J¼18.4 Hz,1H), 2.71e2.76
(dd, J¼5.6, 18.7 Hz, 1H), 4.15e4.22 (m, 1H), 4.78 (dt, J¼4.54, 5.36 Hz,
1H), 5.08 (sp., J¼2.3, 4.5, 6.6 Hz, 1H); 13C NMR (125 MHz, CDCl3):
4.7. 3-((2S,3S,7R)-3-(Benzyloxy)-7-methyl-1,6-dioxaspiro[4.4]
nonan-2-yl)propane-1,2-diol (10)
d 22.8 (q), 32.4 (t), 36.0 (t), 36.9 (t), 42.1 (t), 76.5 (d), 76.9 (d), 83.8
(d), 115.5 (s), 175.6 (s) ppm; HRMS (ESIþ): calcd for C10H14O4Na
To a solution of alkynetetrol 9 (140 mg, 0.43 mmol) in
dichloromethane (20 mL) was added catalyst solution prepared by
[MþþNa] 221.0784; found 221.0782.
dissolving Au(PPh3)Cl (10.7 mg, 21.7
mmol) and AgSbF6 (7.4 mg,
Acknowledgements
21.7
m
mol) in CH2Cl2 (10 mL)] at 0 ꢂC and the reaction mixture was
allowed to stir for 1 h at room. The reaction mixture was concen-
trated under reduced pressure and purified by silica gel column
chromatography (20:80% ethyl acetate/petroleum ether) gave the
The authors would like to acknowledge Council of Scientific and
Industrial Research (India) (CSC0108) for funding this project under
ORIGIN program of 12FYP and also for a research fellowship to C.N.K.
spiroketal diols 10 (120 mg, 85% yield) as yellow oil. Rf (50% EtOAc/
23
petroleum ether) 0.3; [
NMR (200 MHz, CDCl3):
a
]
D
þ7.0 (c 0.03, CHCl3); IR (CHCl3)
n:
1H
Supplementary data
d
1.19 (d, J¼6.1 Hz, 1H), 1.26 (d, J¼6.1 Hz,
3H), 1.63e1.78 (m, 4H), 1.88e1.98 (m, 2H), 2.0e2.09 (m, 2H),
2.12e2.16 (m, 2H), 2.18e2.30 (m, 2H), 2.32e2.37 (m, 1H), 3.51e3.55
(m, 2H), 3.59e3.64 (m, 1H), 3.90e3.94 (m, 1H), 4.10e4.17 (m, 2H),
4.19e4.22 (m, 0.3H), 4.26e4.35 (m, 1H), 4.39 (d, J¼11.9 Hz, 1H), 4.43
(d, J¼12.3 Hz, 0.3H), 4.54 (d, J¼11.9 Hz, 1H), 4.61 (d, 12.3 Hz, 0.3H),
NMR spectra of all the new compounds. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.04.026.
References and notes
7.28e7.35 (m, 6H); 13C NMR (50 MHz, CDCl3):
d 21.4 (q), 22.9 (q),
31.4 (t), 32.5 (t), 32.8 (t), 33.0 (t), 37.4 (t), 37.8 (t), 40.7 (t), 41.3 (t),
66.6 (t), 66.7 (t), 70.8 (d), 70.9 (d), 71.3 (t), 71.4 (t), 75.3 (d), 76.4 (d),
78.1 (d), 79.1 (d), 79.3 (d), 79.9 (d), 113.9 (s), 127.5 (d, 2C), 127.7 (d),
128.4 (d, 2C), 137.9 (s) ppm: HRMS (ESIþ): calcd for C18H26O5Na
[MþþNa] 345.1672; found 345.1670.
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239e242.
4. Li, X.; Sattler, I.; Lin, W. J. Antibiot. 2007, 60, 191e195.
5. Li, X.; Yao, Y. H.; Zheng, Y. A.; Sattler, I.; Lin, W. H. Arch. Pharm. Res. 2007, 30,
812e815.
4.8. Synthesis of (D)-cephalosporolide E and (L)-cepha-
6. Ramana, C. V.; Suryawanshi, S. B.; Gonnade, R. G. J. Org. Chem. 2009, 74,
2842e2845.
losporolide F
7. Fernandes, R. A.; Ingle, A. B. Synlett 2010, 158e160.
8. Brimble, M. A.; Finch, O. C.; Heapy, A. M.; Fraser, J. D.; Furkert, D. P.; O’Connor, P.
D. Tetrahedron 2011, 67, 995e1001.
9. Tlais, S. F.; Dudley, G. B. Beilstein J. Org. Chem. 2012, 8, 1287e1292.
10. Chang, S.; Britton, R. Org. Lett. 2012, 14, 5844e5847.
11. Brimble, M. A.; Finch, O. C.; Furkert, D. P.; O’Connor, P. D. Tetrahedron 2014, 70,
590e596.
To an ice cooled solution of spiroketals 10 (120 mg, 0.30 mmol)
in dichloromethane NaIO4 (240 mg, 1.13 mmol) was added and
stirred for 2 h at room temperature. Then the reaction mixture was
filtered through Celite pad and concentrated under reduced pres-
sure. The resulting crude aldehyde (96 mg, 0.33 mmol) was dis-
t
12. For selected papers on transition metal-mediated alkynediol cyclo-
isomerizations see: (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew.
Chem., Int. Ed. 2002, 41, 4563e4565; (b) Hartman, J. W.; Sperry, L. Tetrahedron
Lett. 2004, 45, 3787e3788; (c) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P.
J. Am. Chem. Soc. 2005, 127, 9976e9977; (d) Liu, B.; De Brabander, J. K. Org. Lett.
2006, 8, 4907e4910; (e) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006, 78,
385e390; (f) Oh, C. H.; Yi, H. J.; Lee, J. H. New J. Chem. 2007, 31, 835e837; (g)
Ramana, C. V.; Patel, P.; Gonnade, R. G. Tetrahedron Lett. 2007, 48, 4771e4774;
solved in a mixture of BuOH:H2O (4:1), NaH2PO4$2H2O (154 mg,
0.99 mmol) was added at 0 ꢂC and the contents stirred for 10 min at
the same temperature. To this suspension, were added NaClO2
(89.7 mg, 0.99 mmol) followed by 2-methyl 2-butene (0.4 mL,
3.3 mmol) at 0 ꢂC. The reaction temperature was slowly increased
to room temperature and was stirred for additional 5 h. After the
completion of the reaction as indicated by TLC, tBuOH was removed
under vacuum and extracted with ethyl acetate, washed with brine,
dried over sodium sulfate and concentrated under reduced pres-
sure. The resulting crude spiroacid (75 mg) was subjected for hy-
drogenation with 20% Pd(OH)2/C (10 mg) in methanol (10 mL)
under balloon pressure procure the naturally occurring spi-
rolactones (þ)-cephalosporolide E (12 mg) and (ꢀ)-cephalospor-
olide F (15 mg) as colorless liquids (total 27 mg, 55% yield over three
steps) after chromatography purification.
ꢀ
ꢀ
(h) Dieguez-Vazquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew. Chem.,
Int. Ed. 2008, 47, 209e212; (i) Ramana, C. V.; Mallik, R.; Gonnade, R. G. Tetra-
hedron 2008, 64, 219e233; (j) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett
2008, 940e944; (k) Selvaratnam, S.; Ho, J. H. H.; Huleatt, P. B.; Messerle, B. A.;
Chai, C. L. L. Tetrahedron Lett. 2009, 50, 1125e1127; (l) Hashmi, A. S. K.; Buhrle,
M.; Wolfle, M.; Rudolph, M.; Wieteck, M.; Rominger, F.; Frey, W. Chem.dEur. J.
2010, 16, 9846e9854; (m) Alcaide, B.; Almendros, P.; Alonso, J. M. Molecules
2011, 16, 7815e7843; (n) Volchkov, I.; Sharma, K.; Cho, E. J.; Lee, D. Chem.
dAsian J. 2011, 6, 1961e1966; (o) Ravindar, K.; Reddy, M. S.; Deslongchamps, P.
Org. Lett. 2011, 13, 3178e3181; (p) Alcaide, B.; Almendros, P.; Carrascosa, R.
Tetrahedron 2012, 68, 9391e9396; (q) Das, S.; Induvadana, B.; Ramana, C. V.
Tetrahedron 2013, 69, 1881e1896; (r) Kotikalapudi, R.; Swamy, K. C. K. Tetra-
hedron 2013, 69, 8002e8012; (s) Allegretti, P. A.; Ferreira, E. M. J. Am. Chem. Soc.
2013, 135, 17266e17269; (t) Quach, R.; Furkert, D. P.; Brimble, M. A. Tetrahedron
Lett. 2013, 54, 5865e5868.
4.8.1. (þ)-Cephalosporolide E (1). Rf (20% EtOAc/petroleum ether)
0.4; [
a
]
25 þ27.4 (c 0.4, CHCl3); IR (CHCl3)
n: 2969, 1780, 1402, 1303,
D
13. For representative total synthesis employing alkynediol cycloisomerizations
and spiroketalization see: (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845e1852;
(b) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42,
5987e5990; (c) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46,
7664e7666; (d) Ramana, C. V.; Induvadana, B. Tetrahedron Lett. 2009, 50,
271e273; (e) Commandeur, M.; Commandeur, C.; Cossy, J. Pure Appl. Chem.
2012, 84, 1567e1574.
1157, 1098, 1056, 918, 825 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 1.18
(d, J¼6.0 Hz, 3H), 1.42e1.48 (m, 1H), 2.03e2.14 (m, 4H), 2.44 (d, 1H),
2.64 (d, 18.5 Hz, 1H), 2.71e2.77 (dd, J¼7.8 Hz, 1H), 4.13e4.21 (m,
1H), 4.87e4.90 (m, 1H), 5.15 (t, J¼5.8 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d 20.9 (q), 31.3 (t), 34.2 (t), 37.6 (t), 41.6 (t), 75.1 (d), 77.3 (d),
14. Selected reviews: (a) Muzart, J. Tetrahedron 2005, 61, 5955e6008; (b) Kirsch, S.
F. Synthesis 2008, 3183e3204; (c) Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron
2008, 64, 2683e2723; (d) Alcaide, B.; Almendros, P.; Alonso, M. J. Org. Biomol.
Chem. 2011, 9, 4405e4416; (e) Zeng, X. Chem. Rev. 2013, 113, 6864e6900.
15. For synthesis of epoxide 4 see: (a) Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc.
1981, 103, 932e933; (b) Rondot, B.; Durand, T.; Rossi, J. C.; Rollin, P. Carbohydr.
Res. 1994, 261, 149e156; (c) Falck, J. R.; Reddy, L. M.; Byun, K.; Campbell, W. B.;
Yi, X.-Y. Bioorg. Med. Chem. Lett. 2007, 17, 2634e2638.
83.4 (d), 115.0 (s), 175.9 (s) ppm; HRMS (ESIþ): calcd for
C
10H14O4Na [MþþNa] 221.0784; found 221.0782.
4.8.2. (ꢀ)-Cephalosporolide F (2). Rf (20% EtOAc/petroleum ether)
0.4; [
a
]
25 ꢀ34.0 (c 0.8, CHCl3); IR (CHCl3)
n
: 3020, 1781, 1403, 1216,
1.26 (d,
D
1167, 1096, 1061, 927 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d