Concise enantioselective synthesis of cephalosporolide B, (4R)-4-OMe-cephalosporolide C, and (4S)-4-OMe-cephalosporolide C

Article abstract of DOI:10.1002/asia.201300332

Ring around the rosie: The effective enantioselective synthesis of the antimalarial nonenolide title compounds was achieved in a convergent strategy. Oxy-Michael addition reaction was used to introduce the chiral methoxy group at C-4, and ring-closing metathesis (RCM) reaction (53 % yield) facilitated the key construction of the 10-membered ring.

Full text of DOI:10.1002/asia.201300332

COMMUNICATION
DOI: 10.1002/asia.201300332
Concise Enantioselective Synthesis of Cephalosporolide B, (4R)-4-OMe-
Cephalosporolide C, and (4S)-4-OMe-Cephalosporolide C
Bin Ma,[a] Zhuliang Zhong,[a] Haitao Hu,[a] Huilin Li,[a] Changgui Zhao,[a]
Xingang Xie,*[a] and Xuegong She*[a, b]
The ascomycetous genus Cordyceps is an entomopatho-
genic fungus that has been widely used as food and herbal
medicine in Asia.[1] The Cordyceps genus is a rich source of
biologically active secondary metabolites,[2] among which
the ten-membered lactones are the most abundant and bio-
logically active.[3] This family of natural products displays
a wide range of pharmaceutical activities, such as antibacte-
rial and antifungal activity and the inhibition of cholesterol
biosynthesis.[3a] Over the past ten years, these secondary me-
tabolites have attracted many synthetic chemistsꢀ attention
due to their unique structures and special bioactivity.[4]
The compounds (4R)- and (4S)-4-OMe-cephalosporoli-
de C (1 and 2) were isolated from Cordyceps militaris BCC
ten-membered macrolactone core but differ in the absolute
configuration of C4 (1 vs. 2) or the oxidation states of C4
and C5 (1 and 2 vs. 3). To date, the synthesis of 1 and 3 has
not been reported, and only one total synthesis of 2 has
been reported, which used a 20-step reaction sequence in-
volving a Yamaguchi macrolactonization (48% yield) for
the construction of the key 10-membered ring in 2008.[4b] As
a part of our ongoing program on the syntheses of bioactive
macrolides,[6] compounds 1, 2, and 3 attracted our synthetic
interests. Herein, we report a facile and effective total syn-
thesis of compounds 1–3.
We envisioned that 1 and 2 could be obtained from 3 by
a stereoselective oxy-Michael addition reaction (Scheme 1).
Compound 3 belongs to the 10-membered lactone family
2816 in 2004, and both of them possessed moderate antima-
larial activity against Plasmodium falsifarum K1 (multidrug-
resistant strain).[5a] Cephalosporolide B (3) was isolated as
a white solid from the fungus C. aphidicola, ACC 3490 in
1985.[5b] Structurally, the three compounds share a common
Scheme 1. Retrosynthetic analysis of 1, 2, and 3.
and possesses a distinctive Z-configured enone subunit. Al-
though there are already some strategies for the construc-
tion of medium-sized rings, the synthesis of 10-membered
lactones remains a great challenge, in which destabilizing
nonbonding, transannular interactions and unfavorable en-
tropic factors must be overcome.[7,3b] And the distinctive Z-
configured enone subunit makes the ten-membered macro-
lide synthesis more challenging. Learning from our previous
experience on the construction of natural lactones using the
ring-closing metathesis (RCM) reaction,[8] we expected to
establish the ten-membered lactone core and the distinctive
Z-configured enone motif of 3 at the same time in an RCM
reaction from diene ester 4. The requisite precursor 4 for
RCM reaction could be obtained convergently from alcohol
5 and known carboxylic acid 6[6c] in an esterification reac-
[a] B. Ma, Z. Zhong, H. Hu, H. Li, C. Zhao, Dr. X. Xie, Prof. Dr. X. She
State Key Laboratory of Applied Organic Chemistry
Department of Chemistry, Lanzhou University
222 South Tianshui Road, Lanzhou, 730000 (P. R. China)
Fax : (+86)931-8912582
E-mail: xiexg@lzu.edu.cn
shexg@lzu.edu.cn
[b] Prof. Dr. X. She
State Key Laboratory of Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou, Gansu, 730000 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300332.
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Xingang Xie, Xuegong She et al.
tion. Alcohol 5 could be accessed from commercially avail-
able (R)-propylene oxide by a simple nucleophilic attack
with allyl magnesium bromide. (Scheme 2)
dented,[4] the RCM reaction between a free allylic alcohol
and an enone subunit was envisioned to be a significant
challenge. As shown in Table 1, we explored the use of
Table 1. Various reaction conditions used for the RCM reaction in 3 and
13.
Entry
Diene
Catalyst
t [h]
Yield [%]
3 or 13
14
1[a]
2[a]
3[a]
4[b]
5[b]
6[c]
7[b]
4
4
4
4
4
4
12
Grubbs I
Grubbs II
Hoveyda–Grubbs II
Grubbs II
Grubbs II
8
8
8
NR
30
21
44
52
NR
35
49
13
5
8
5.5
5.5
10
Grubbs II
Grubbs II
40
42 (13)
24
–
Scheme 2. Synthesis of the alcohol 5. a) allyl magnesium bromide, CuI,
THF, ꢀ408C to RT, 91%; b) i) TBSCl, imidazole, DMAP, CH2Cl2, RT,
overnight; ii) O3, PPh3, CH2Cl2, ꢀ788C, 95%, two steps; c) vinylmagnesi-
um bromide, THF, 08C, 2 h; d) i) Ac2O, NEt3,08C; ii) 1 m HCl (aq.),
MeOH, RT, 1 h, 83%, three steps. TBSCl=tert-butyldimethylsilyl chlo-
ride, DMAP=N,N-4-dimethylaminopyridine.
[a] c=1 mm, cat. 5 mol%. [b] c=0.5 mm, cat. 5 mol%. [c] c=0.5 mm, cat.
10 mol%. NR=no reaction.
Grubbs catalysts (the first and second generation,) and Hov-
eyda–Grubbs second-generation catalyst. Unfortunately, we
only got a little desired natural ten-membered lactone 3. In-
stead, because of the enthalpy and entropy factors, dimer-
ized product 14 was obtained as the main product (see crys-
tal structures in Figure 1). After screening the concentration
The synthesis of the requisite alcohol 5 began with com-
mercially available (R)-propylene oxide 7. Regioselective
epoxide ring-opening reaction of 7 by allyl magnesium bro-
mide in the presence of CuI yielded the corresponding sec-
ondary alcohol 8 in 91% yield. Alcohol 8 was subsequently
protected as TBS ether, ozonolysis of which gave aldehyde 9
in 95% yield over two steps. Compound 9 was then treated
with vinylmagnesium bromide to afford the allylic alcohol
10 as a mixture of two diastereomers. Protection of 10 by
Ac2O and removal of the TBS group produced alcohol 5 in
83% yield over three steps.
Compound 6 was prepared according to a literature pro-
cedure.[6c] With compounds 5 and 6 in hand (Scheme 3), an
esterification reaction was employed to furnish the diene
ester 11 under the classical conditions (DCC, DMAP, in
CH2Cl2). Removal of the protective acyl group of 11 afford-
ed the corresponding allylic alcohol, which was exposed to
IBX[9] to give vinyl ketone 12 in 85% yield over three steps.
Desilylation in the presence of HF (40% aq.)[10] led to the
requisite diene 4. Next, we attempted to construct a 10-
membered ring by RCM reaction. Although not unprece-
Figure 1. X-ray crystallographic structures of 3 and 14.[12]
of reaction mixtures, reaction time, and the amount of the
catalyst (Table 1), eventually the highest yield (52%) of
cephalosporolide B (3) was obtained when the reaction mix-
tureꢀs concentration was 0.5 mm in the presence of 5 mol%
Grubbs II catalyst for 5.5 h (Table 1, entry 5). The protected
precursor 12 was also tested under the optimal RCM condi-
tions and, as we expected, it afforded the desired cyclization
product 13 as the major product in a slightly lower yield
(Table 1, entry 7).
With cephalosporolide B (3) in hand, we expected to
access 1 and 2 through an oxy-Michael addition reaction;
the stereogenic center of C-4 could be induced by the hy-
droxy group at C-3. In a methanol solution of 7–10% Mg-
AHCTUNGTRENNUNG
(CH3O)2,[11] (4S)-4-OMe-cephalosporolide C (2) was ob-
tained smoothly through the chelating effect of the magnesi-
um cation on the oxygen atoms in the alkaline condition.
But it was disappointing that under acidic conditions we did
not get the compound 1 from 3; instead, we got a methylated
product at the hydroxy group of C-3 as the only product.
Fortunately, after several attempts we found that compound
13 could be converted to 1 directly using 1 m HCl (aq.) in
Scheme 3. Total synthesis of 3. a) DCC, DMAP, CH2Cl2, RT, 8 h;
b) i) K2CO3, MeOH, 08C; ii) IBX, EtOAc, reflux, 2 h, 85%, 3 steps;
c) 40% HFACHTUNGTRENNUNG(aq.), CH3CN, 08C, 2 h, 95%;d) Grubbs catalyst II, CH2Cl2,
0.5 mm, reflux, 5.5 h, 52%. DDC=dicyclohexylcarbodiimide, IBX=o-io-
doxybenzoic acid.
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Xingang Xie, Xuegong She et al.
(c 0.5, MeOH); 1H NMR (400 MHz, CDCl3): d=5.09–4.99 (m, 1H),
4.15–4.06 (m, 1H), 3.45 (s, 3H), 3.40–3.33 (m, 1H), 3.10 (s, 1H), 2.94 (dd,
J=17.5, 7.5, 1H), 2.87 (dd, J=17.4, 3.2, 1H), 2.63 (dd, J=17.4, 2.7, 1H),
2.52–2.38 (m, 2H), 2.38–2.29 (m, 1H), 2.17–2.07 (m, 1H), 2.08–1.97 (m,
1H), 1.28 ppm (d, J=6.4, 3H); 13C NMR (100 MHz, CDCl3): d=208.47,
169.17, 81.93, 71.62, 68.33, 57.38, 41.75, 40.34, 39.77, 33.15, 19.64 ppm; IR
(neat): n˜max =3664, 3641, 3579, 2957, 2919, 2850, 1853, 1729, 1711, 1574,
1466, 1256, 1090, 1039, 799 cmꢀ1; HR-MS (ESI-MS): calcd for C11H18O5
[M+H]+ 231.1227, found 231.1224.
Compound 1
HCl (1m, 2 drops) was added to a solution of 13 (31 mg, 0.1 mmol) in
MeOH (5 mL). The reaction mixture was allowed to stir at ambient tem-
perature for 12 h, and then the solvent was removed in vacuo. The resi-
due was dissolved in EtOAc, dried over anhydrous Na2SO4, filtered, and
concentrated. Purification of the residue by flash chromatography (hex-
anes/EtOAc, 2:1 to 1:1) afforded compound 1 (17 mg, 72%) as a colorless
oil. Data for 1: ½aꢁ2D0 =ꢀ328 (c=0.5, MeOH); 1H NMR (400 MHz,
CDCl3): d=5.15–5.04 (m, 1H), 4.29 (t, J=10.5, 1H), 4.00 (ddd, J=11.0,
4.5, 2.8, 1H), 3.39 (s, 3H), 2.81 (dd, J=17.7, 4.8, 1H), 2.71 (dd, J=16.5,
11.1, 1H), 2.63–2.47 (m, 3H), 2.47–2.37 (m, 1H), 2.37–2.25 (m, 1H),
2.15–2.05 (m, 1H), 2.04–1.98 (m, 1H), 1.25 ppm (d, J=6.3, 3H);
13C NMR (100 MHz, CDCl3): d=209.62, 169.84, 78.92, 71.94, 66.75, 57.39,
42.92, 40.50, 37.46, 34.00, 19.51 ppm; IR (neat): n˜max =3640, 3464, 2922,
2851, 1729, 1709, 1678, 1451, 1363, 1251, 1090, 970, 805 cmꢀ1; HR-MS
(ESI-MS): calcd for C11H18O5 [M+Na]+ 253.1046, found 253.1043.
Scheme 4. Total synthesis of 1 and 2: a) 7–10% MgACHTNUGTRNEG(UN CH3O)2, MeOH,
reflux, 8 h, 80%; b) cat. 1m HCl (aq.), MeOH, RT, 12 h, 72%.
methanol, and the diastereomeric stereoselectivity of the
OMe group could be controlled by the action of a hydrogen
bond (Scheme 4).
In conclusion, a facile and effective collective synthesis of
three natural ten-membered lactones 1, 2, and 3 has been
achieved from commercially available (S)-propylene oxide
and known compound 6 in 18, 24, and 30% overall yields,
respectively. The notable features of our synthesis are:
1) the use of an RCM reaction to establish the requisite Z-
enone and ten-membered lactone core of cephalosporoli-
de B (3) in one step; 2) assembling two diastereomeric OMe
groups at the C-4 atom of compound 3 to give (4R)- and
(4S)-4-OMe-cephalosporolide C (1 and 2) controlled by the
reaction conditions.
Acknowledgements
We are grateful for the generous financial support from the MOST
(2010CB833200), PCSIRT (IRT1138), the NSFC (21125207, 21102062,
21072086), the FRFCU (lzujbky-2013-49, lzujbky-2013-ctoz) and program
111.
Experimental Section
Compound 3
Keywords: lactones · macrocycles · metathesis · Michael
addition · total synthesis
Under argon, compound 4 (113 mg, 0.5 mmol) in anhydrous CH2Cl2
(100 mL) was added over 10 min to a solution of Grubbs second-genera-
tion catalyst (22 mg, 0.025 mmol) in anhydrous CH2Cl2 (900 mL) at
reflux and the mixture was stirred at reflux for 5.5 h. After that, the reac-
tion system was exposed to air stirring overnight. Solvent was removed in
vacuo and the residue was purified by flash column chromatography
(silica gel, hexane/EtOAc 3:1 to 1:1) to afford 3 as colorless acicular crys-
tals (51 mg, 52%). Data for 3: colorless crystals (hexane/EtOAc), mp
118–1218C; ½aꢁ2D0 = +848 (c=0.1, CHCl3); 1H NMR (400 MHz, CDCl3):
d=6.19 (dd, J=11.8, 0.9, 1H), 5.74 (dd, J=11.8, 9.2, 1H), 5.24–5.13 (m,
1H), 5.00 (dqd, J=12.7, 6.4, 3.2, 1H), 2.91 (dd, J=15.0, 5.6, 1H), 2.70 (s,
1H), 2.52–2.43 (m, 1H), 2.43–2.33 (m, 2H), 2.15–2.04 (m, 1H), 2.04–1.94
(m, 1H), 1.25 ppm (d, J=6.4, 3H); 13C NMR (100 MHz, CDCl3): d=
205.40 (Ref. [5b] 207.7), 168.75, 138.61, 132.57, 71.41, 63.94, 43.17, 38.56,
32.27, 19.02 ppm; IR (neat): n˜max =3663, 3464, 2975, 2919, 2849, 1733,
1659, 1612, 1429, 1278, 1154, 1126, 1075, 1025, 893, 748, 483 cmꢀ1; HR-
MS (ESI-MS): calcd for C10H14O4 [MꢀH2O+H]+ 181.0859, found
181.0855.
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Received: March 13, 2013
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