A relay ring-opening/double ring-closing metathesis strategy for the bicyclic macrolide-butenolide core structures

Article abstract of DOI:10.1039/c4ra10937f

A concise strategy has been developed for the synthesis of the bicyclic macrolide-butenolide core structures of various natural products with the macrolide ring size ranging from 12- to 16-membered. The bicyclic structure was easily assembled using the relay ring-opening/double ring-closing metathesis strategy. An efficient synthesis of (±)-desmethyl manshurolide has been achieved as an application of this strategy. This journal is

Full text of DOI:10.1039/c4ra10937f

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A relay ring-opening/double ring-closing
metathesis strategy for the bicyclic macrolide-
Cite this: RSC Adv., 2014, 4, 63342
butenolide core structures†
*
Mahesh B. Halle and Rodney A. Fernandes
A concise strategy has been developed for the synthesis of the bicyclic macrolide-butenolide core
structures of various natural products with the macrolide ring size ranging from 12- to 16-membered.
The bicyclic structure was easily assembled using the relay ring-opening/double ring-closing metathesis
strategy. An efficient synthesis of (ꢀ)-desmethyl manshurolide has been achieved as an application of
this strategy.
Received 22nd September 2014
Accepted 11th November 2014
DOI: 10.1039/c4ra10937f
www.rsc.org/advances
With our continued interest in the synthesis of g-lactones,
butenolides and strained macrolides6 and considering the
Introduction
importance of these bicyclic structures we embarked on devel-
oping a strategy to rapidly construct both the rings (butenolide
and macrolide) in an efficient manner based on a relay ring-
opening/multiple ring-closing metathesis.7
The bicyclic macrolide-butenolide core structure 1 is present in
many natural products (Fig. 1). The macrolide size may vary and
there could be the presence of one or more double bonds.
Selected examples are shown in Fig. 1 with the macrolide size
varying from 12- to 14-membered (2a–e) being the most
common. Gersemolide 2a (12-membered macrolide) is a pseu-
dopterane, isolated from the so coral Gersemia rubiformis.1
Manshurolide 2b, also a 12-membered macrolide is a sesqui-
terpene lactone isolated from the stems of Aristolochia man-
shuriensis.2 It has three trans-double bonds in the macrolide
ring (the butenolide double bond is apparently trans- in the
macrolide ring but geometrically cis- in the butenonide).
Okilactomycins C 2c and D 2d have a 13-membered bicyclic
macrolide-butenolide structure with an annulated cyclohexene
and additional spiro functionality. These were isolated from
Streptomyces scabrisporus.3 The cembranoid diterpenes, sar-
cophytonolides A-L were isolated from the so coral of the
genus Sarcophyton.4 These possess the 14-membered bicyclic
macrolide-butenolide structure. The simpler member is sar-
cophytonolide L 2e. The bicyclic macrolide-butenolide structure
is also present in many other natural products with various
substituents and functionalities. Oen there is the furan ring5
(or the oxidized diketo form) as another common feature in
most of them (Fig. 1). These could be the furano-pseudopterane
type 3a, furano-gersolene type 3b or the furano-cembrane type
3c (Fig. 1).5 The butenolide moiety gains it signicance in
medicinal chemistry as Michael acceptor to various biological
nucleophiles.
Results and discussion
As shown in the retrosynthetic analysis (Scheme 1) the core
structure 1 could be assembled through a double ring-closing
metathesis of the tetraene 4. However this design would
impose issues of regioselectivity in the ring-closure considering
the competition of three available terminal mono-substituted
double bonds. While the butenolide ring closure could occur
with ease, the macrolide ring closure would be challenging. The
latter would predominantly depend on ring size and would
occur separately of the rst ring-closure. We sought an alter-
native path to prevent competition by reducing the number of
double bonds and hence the triene 5 seemed obvious choice. In
this case during metathesis there would be carbene cascade
which appeared promising for the challenging macrolide ring
closure unlike the case of compound 4 where the two ring
closures would occur separately. The substrate 5 can be
considered as synthetic equivalent to compound 4. Compound
5 can easily be assembled through vinyl Grignard reaction on
aldehyde 6 (of varying chain length) followed by esterication
with cyclobutene carboxylic acid 7. An advantage of this strategy
is the ready adaptability for chiral version where in the inter-
mediate allyl alcohol 9 can be resolved through Sharpless
kinetic resolution.8
The forward synthesis towards the bicyclic core structure 1
with macrolide ring size varying from 12- to 16-membered is
shown in Scheme 2. The vinyl Grignard addition to various
aldehydes from the alcohols 8a–e gave the corresponding
allyl alcohols 9a–e in 84–89% yields. The esterication of 9a
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400
076, Maharashtra, India. E-mail: rfernand@chem.iitb.ac.in; Fax: +91-22-25767152;
Tel: +91-22-25767174
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all the compounds. See DOI: 10.1039/c4ra10937f
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Fig. 1 Bicyclic macrolide-butenolide natural products and related furano-structures.
bicyclic compounds 1a–e in 42–48% yields with E-selectivity
for the macrolide double bond.10 We believe, G-I catalyst is
known for ring-opening metathesis of strained small rings
(in this case the cyclobutene ring). Thus the above catalysts
combination worked well in this case. However, we did not
isolate any of the intermediate compounds in this relay
metathesis reaction which may require quenching with
ethylene.
The strategy was extended towards the protecting group
free synthesis of (ꢀ)-desmethyl manshurolide 11 as shown in
Scheme 3. Commercially available 5-hexene-1-ol 12 was
oxidized to aldehyde and the subsequent modied de-
carboxylative deconjugative Knoevenagel condensation11 with
half ester of malonic acid gave the ester 13 in 81% overall yield.
DiBAL-H reduction of the ester group to aldehyde and subse-
quent vinyl Grignard reaction furnished the triene 9f (89%
from 13). The esterication of 9f with the anhydride 10 using
LiHMDS gave 5f in 78% yield. The subsequent relay RO/DRCM
using G-I (10 mol%) and G-II (5 mol%) catalysts in toluene
solvent delivered (ꢀ)-desmethyl manshurolide 11 in 44%
yield.
Scheme 1 Retrosynthesis of bicyclic core structure 1.
with the cyclobutene carboxylic acid 7 using DCC gave the
corresponding ester 5a in 38% yield. The reaction using
Yamaguchi conditions9 delivered 5a in 51% yield. This was
further improved with the use of the anhydride of 7, i.e. 10,
and LiHMDS that delivered the ester 5a in good 79% yield.
Similarly, other esters 5b–e were prepared in 82–91% yields.
The relay ring-opening/double ring-closing metathesis (RO/
DRCM) reaction on 5a–e was carried out using Grubbs cata-
lysts (G-I and G-II) and Grubbs-Hoveyda catalysts (GH-I and
GH-II) in toluene, benzene and hexane solvent. The best
results were obtained through a sequential addition of rst
G-I catalyst (10 mol%) followed by addition of G-II catalyst (5
mol%) in toluene solvent providing the macrolide-butenolide
Conclusions
In conclusion an efficient strategy for bicyclic macrolide-
butenolide core structures of various natural products has
been developed. The macrolide rings ranging from 12- to 16-
membered have been synthesized. The efficiency of the relay
ring-opening/double ring-closing metathesis strategy was
further demonstrated by the protecting group free synthesis of
(ꢀ)-desmethyl manshurolide. The strategy has potential
towards the synthesis of bicyclic macrolide-butenolide natural
products.
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Scheme 2 Synthesis of the macrolide-butenolides 1a–e using the relay RO/DRCM strategy.
1
KMnO4 or by UV lamp. H NMR and 13C NMR were recorded
with Bruker AVANCE III 400 or 500 and 100 or 125 MHz,
respectively, and chemical shis are based on TMS peak at d ¼
0.00 pm for proton NMR and CDCl3 peak at d ¼ 77.00 ppm (t) in
carbon NMR. IR samples were prepared by evaporation from
CHCl3 on CsBr plates. High-resolution mass spectra were
obtained using positive electrospray ionization by TOF method.
General procedure for synthesis of allyl alcohols 9a–e
To a solution of alcohol 8 (2.0 mmol) in CH2Cl2 (20 mL) was
added Dess–Martin periodinate (DMP, 1.87 g, 4.40 mmol, 2.2
equiv.). The resulting mixture was stirred at room temperature
for 2 h. It was then quenched with a solution of 10% aq. Na2S2O3
and sat. aq. NaHCO3 (1 : 1, 15 mL) and the solution extracted
with CH2Cl2 (3 ꢁ 50 mL). The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated. The
residue was loaded on a short pad of silica gel and washed with
petroleum ether/EtOAc (2 : 1) to give the aldehyde which was
used directly for next step. Vinyl magnesium bromide (3.0 mL,
3.0 mmol, 1.5 equiv., 1 M solution in THF) was added to the
aldehyde dissolved in THF (30 mL) at 0 ꢂC. The reaction mixture
Scheme 3 Synthesis of (ꢀ)-desmethyl manshurolide 11.
ꢂ
was stirred for 2 h at 0 C and warmed to room temperature.
Experimental section
General information
Saturated aq. NH4Cl (15 mL) was added and the mixture
extracted with EtOAc (3 ꢁ 50 mL). The combined organic layers
were washed with brine, dried (Na2SO4) and concentrated. The
residue was puried by silica gel ash column chromatography
using petroleum ether/EtOAc (4 : 1) as eluent to give the alco-
hols 9a–e in 84–89% yield.
Flasks were oven- or ame-dried and cooled in a desiccator. Dry
reactions were carried out under an atmosphere of Ar or N2.
Solvents and reagents were puried by standard methods. Thin-
layer chromatography was performed on EM250 Kieselgel 60
F254 silica gel plates. The spots were visualized by staining with
Deca-1,9-dien-3-ol (9a). Isolated yield of 9a (0.268 g, 87%);
colorless oil; IR (CHCl3): nmax 3417, 2925, 2851, 1637, 1459,
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1371, 1305, 1245, 1023, 910, 666 cmꢃ1 1H NMR (400 MHz,
;
Deca-1,9-dien-3-yl cyclobut-1-enecarboxylate (5a). Isolated
yield of 5a (0.185 g, 79%); colorless oil; IR (CHCl3): nmax 2927,
2854, 1730, 1646, 1462, 1367, 1250, 1173, 1114, 1050, 988, 966,
CDCl3, ppm) d 5.91–5.75 (m, 2H), 5.27–5.10 (m, 2H), 5.04–4.90
(m, 2H), 4.11 (brq, J ¼ 6.3 Hz, 1H), 3.30 (brs, 1H), 2.09–2.00 (m,
2H), 1.61–1.50 (m, 2H), 1.50–1.30 (m, 6H); 13C NMR (100 MHz,
CDCl3, ppm) d 141.3, 139.0, 114.5, 114.2, 73.2, 37.0, 33.7, 29.0,
28.8, 25.1; HRMS m/z calcd for [C10H18ONa]+ 177.1250, found
177.1256.
1
920, 695, 667 cmꢃ1; H NMR (400 MHz, CDCl3, ppm) d 6.77 (s,
1H), 5.84–5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.00–4.91 (m, 2H),
2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.09–2.01 (m, 2H), 1.61–
1.48 (m, 2H), 1.45–1.22 (m, 6H); 13C NMR (100 MHz, CDCl3,
ppm) d 161.7, 146.4, 139.0, 138.9, 136.6, 116.5, 114.3, 74.4, 34.1,
33.6, 29.7, 29.1, 28.8, 27.0, 24.8; HRMS m/z calcd for
[C15H22O2Na]+ 257.1512, found 257.1518.
Undeca-1,10-dien-3-yl cyclobut-1-enecarboxylate (5b). Iso-
lated yield of 5b (0.219 g, 88%); colorless oil; IR (CHCl3): nmax
2918, 2850, 1727, 1463, 1369, 1303, 1264, 1181, 1035, 984, 916,
666 cmꢃ1; 1H NMR (500 MHz, CDCl3, ppm) d 6.77 (s, 1H), 5.84–
5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.00–4.91 (m, 2H), 2.73–2.72
(m, 2H), 2.48–2.46 (m, 2H), 2.09–2.00 (m, 2H), 1.68–1.50 (m,
2H), 1.45–1.22 (m, 8H); 13C NMR (125 MHz, CDCl3, ppm) d
161.6, 146.3, 139.1, 138.9, 136.6, 116.5, 114.2, 74.4, 34.1, 33.7,
29.2, 29.1, 28.9, 28.8, 27.0, 24.0; HRMS m/z calcd for
[C16H24O2Na]+ 271.1669, found 271.1673.
Dodeca-1,11-dien-3-yl cyclobut-1-enecarboxylate (5c). Iso-
lated yield of 5c (0.231 g, 88%); colorless oil; IR (CHCl3): nmax
2929, 2857, 1732, 1641, 1465, 1414, 1371, 1253, 1175, 1090, 991,
918, cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 6.77 (t, J ¼ 1.2 Hz,
1H), 5.85–5.73 (m, 2H), 5.31–5.14 (m, 3H), 5.01–4.90 (m, 2H),
2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.08–2.00 (m, 2H), 1.61–
1.48 (m, 2H), 1.46–1.22 (m, 10H); 13C NMR (100 MHz, CDCl3,
ppm) d 161.7, 146.3, 139.2, 138.9, 136.6, 116.5, 114.1, 74.4, 34.1,
33.8, 29.7, 29.3, 29.1, 29.0, 28.9, 27.0, 25.0; HRMS m/z calcd for
[C17H26O2Na]+ 285.1825, found 285.1818.
Trideca-1,12-dien-3-ylcyclobut-1-enecarboxylate (5d). Iso-
lated yield of 5d (0.215 g, 82%); colorless oil; IR (CHCl3): nmax
2928, 2851, 1731, 1644, 1459, 1374, 1308, 1251, 1171, 1127,
1045, 669, 631 cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 6.77 (s,
1H), 5.84–5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.02–4.91 (m, 2H),
2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.09–2.00 (m, 2H), 1.61–
1.48 (m, 2H), 1.45–1.22 (m, 12H); 13C NMR (100 MHz, CDCl3,
ppm) d 161.7, 146.3, 139.2, 138.9, 136.6, 116.5, 114.1, 74.4, 34.2,
33.8, 29.4, 29.36, 29.3, 29.1, 29.07, 28.9, 27.0, 25.0; HRMS m/z
calcd for [C18H28O2Na]+ 299.1987, found 299.1979.
Undeca-1,10-dien-3-ol (9b). Isolated yield of 9b (0.3 g, 89%);
colorless oil; IR (CHCl3): nmax 3367, 3076, 2927, 2854, 1637,
1464, 1440, 991, 911, 663 cmꢃ1; 1H NMR (500 MHz, CDCl3, ppm)
d 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H), 4.09
(brq, J ¼ 6.2 Hz, 1H), 3.35 (brs, 1H), 2.09–2.01 (m, 2H), 1.61–1.48
(m, 2H), 1.45–1.25 (m, 8H); 13C NMR (125 MHz, CDCl3, ppm) d
141.3, 139.1, 114.6, 114.2, 73.3, 37.0, 33.7, 29.4, 29.0, 28.8, 25.3;
HRMS m/z calcd for [C11H20ONa]+ 191.1395, found 191.1392.
Dodeca-1,11-dien-3-ol (9c). Isolated yield of 9c (0.313 g,
86%); colorless oil; IR (CHCl3): nmax 3369, 3071, 2926, 2854,
1640, 1464, 1437, 1259, 1166, 991, 911, 718 cmꢃ1; 1H NMR (400
MHz, CDCl3, ppm) d 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–
4.91 (m, 2H), 4.09 (brq, J ¼ 6.2 Hz, 1H), 3.35 (brs, 1H), 2.09–2.01
(m, 2H), 1.61–1.48 (m, 2H), 1.45–1.25 (m, 10H); 13C NMR (100
MHz, CDCl3, ppm) d 141.3, 139.2, 114.5, 114.1, 73.3, 37.0, 33.8,
29.5, 29.4, 29.0, 28.9, 25.3; HRMS m/z calcd for [C12H22ONa]+
205.1545, found 205.1539.
Trideca-1,12-dien-3-ol (9d). Isolated yield of 9d (0.334 g,
85%); colorless oil; IR (CHCl3): nmax 3364, 3071, 2927, 2855,
1640, 1462, 1434, 992, 911, 718 cmꢃ1; 1H NMR (400 MHz, CDCl3,
ppm) d 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H),
4.09 (brq, J ¼ 6.2 Hz, 1H), 2.09–2.01 (m, 2H), 1.61–1.48 (m, 2H),
1.45–1.25 (m, 12H); 13C NMR (100 MHz, CDCl3, ppm) d 141.3,
139.2, 114.5, 114.1, 73.3, 37.0, 33.8, 29.5, 29.5, 29.4, 29.1, 28.9,
25.3; HRMS m/z calcd for [C13H24ONa]+ 219.1702, found
219.1697.
Tetradeca-1,13-dien-3-ol (9e). Isolated yield of 9e (0.353 g,
84%); colorless oil; IR (CHCl3): nmax 3351, 3076, 2926, 2851,
1637, 1459, 1314, 990, 910 cmꢃ1 1H NMR (400 MHz, CDCl3,
;
ppm) d 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H),
4.09 (q, J ¼ 6.2 Hz, 1H), 2.09–2.00 (m, 2H), 1.61–1.48 (m, 2H),
1.45–1.25 (m, 14H); 13C NMR (100 MHz, CDCl3, ppm) d 141.3,
139.2, 114.5, 114.1, 73.3, 37.0, 33.8, 29.53, 29.5, 29.5, 29.45, 29.1,
28.9, 25.3; HRMS m/z calcd for [C14H26OK]+ 249.1621, found
249.1619.
Tetradeca-1,13-dien-3-yl cyclobut-1-enecarboxylate (5e). Iso-
lated yield of 5e (0.264 g, 91%); colorless oil; IR (CHCl3): nmax
2927, 2856, 1731, 1656, 1462, 1407, 1371, 1308, 1256, 1182,
1
1130, 1045, 968, 823 cmꢃ1; H NMR (400 MHz, CDCl3, ppm) d
General procedure for synthesis of esters 5a–e
6.77 (t, J ¼ 1.2 Hz, 1H), 5.85–5.75 (m, 2H), 5.30–5.15 (m, 3H),
5.01–4.91 (m, 2H), 2.73–2.71 (m, 2H), 2.47–2.45 (m, 2H), 2.09–
2.00 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.22 (m, 14H); 13C NMR
(100 MHz, CDCl3, ppm) d 161.7, 146.3, 139.2, 138.9, 136.6,
116.5, 114.1, 74.4, 34.2, 33.8, 29.4, 29.3, 29.1, 28.9, 27.0, 25.2,
25.18, 25.0; HRMS m/z calcd for [C19H30O2Na]+ 313.2116, found
313.2121.
To a solution of allyl alcohol 9a–e (1.0 mmol) in dry THF (15 mL)
at ꢃ78 ꢂC was gradually added LiHMDS (0.75 mL, 1.5 mmol, 1.5
equiv., 2 M solution in THF) over a period of 5 min. Aer stirring
for 15 min, a solution of anhydride 10 (0.267 g, 1.50 mmol, 1.5
equiv.) in dry THF (5 mL) was added and the reaction mixture
stirred for 4 h at ꢃ78 ꢂC. It was slowly warmed to room
temperature and a solution of sat. aq. NH4Cl (5 mL) was added.
The mixture was extracted with EtOAc (3 ꢁ 50 mL) and the
combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was puried by silica
General procedure for synthesis of macrolide-butenolides
1a–e
gel ash column chromatography using petroleum ether/EtOAc To a solution of 5a–e (0.20 mmol) in dry and degassed toluene
(4 : 1) as eluent to give the esters 5a–e in 79–91% yield.
(150 mL) was added Grubbs-I catalyst (16.5 mg, 0.02 mmol,
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10 mol%). The mixture was reuxed for 4 h under nitrogen
atmosphere and then cooled and Grubbs-II catalyst (8.5 mg,
0.01 mmol, 5 mol%) was added. The mixture was further
reuxed for 44 h under nitrogen atmosphere and then cooled
and concentrated. The residue was puried by silica gel ash
column chromatography using petroleum ether/EtOAc (4 : 1) as
eluent to give the macrolide-butenolides1a–e.
(E)-12-Oxabicyclo[9.2.1]tetradeca-1(14),4-dien-13-one (1a).
Isolated yield of 1a (17.3 mg, 42%); colorless oil; IR (CHCl3): nmax
3016, 2923, 2857, 1754, 1657, 1591, 1454, 1336, 1119, 971, 858,
669, 628 cmꢃ1; 1H NMR (500 MHz, CDCl3, ppm) d 6.90–6.87 (m,
1H), 5.26–5.13 (m, 2H), 5.12–5.08 (m, 1H), 2.67–2.56 (m, 1H),
2.48–2.38 (m, 1H), 2.36–2.29 (m, 2H), 2.20–2.11 (m, 2H), 1.70–
1.50 (m, 2H), 1.40–1.20 (m, 6H); 13C NMR (125 MHz, CDCl3,
ppm) d 173.8, 149.4, 133.9, 131.8, 130.0, 81.1, 31.6, 30.1, 29.9,
27.4, 25.7, 25.6, 21.7; HRMS m/z calcd for [C13H18O2Na]+
229.1199, found 229.1190.
(E)-13-Oxabicyclo[10.2.1]pentadeca-1(15),4-dien-14-one (1b).
Isolated yield of 1b (19.8 mg, 45%); colorless oil; IR (CHCl3):
nmax 2922, 2846, 1755, 1646, 1459, 1369, 1333, 1242, 1094, 1042,
965, 858, 694 cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 7.00 (d, J
¼ 1.3 Hz 1H), 5.43–5.33 (m, 1H), 5.30–5.22 (m, 1H), 5.06–5.01
(m, 1H), 2.58–2.45 (m, 2H), 2.36–2.25 (m, 2H), 2.10–2.0 (m, 2H),
1.82–1.71 (m, 2H), 1.45–1.10 (m, 8H); 13C NMR (125 MHz,
CDCl3; ppm) d 174.3, 149.4, 133.9, 132.9, 128.8, 80.8, 33.2, 31.0,
29.6, 29.0, 28.7, 25.8, 24.5, 21.5; HRMS m/z calcd for
[C14H20O2Na]+ 243.1333, found 243.1327.
(E)-14-Oxabicyclo[11.2.1]hexadeca-1(16),4-dien-15-one (1c).
Isolated yield of 1c (22.5 mg, 48%); colorless oil; IR (CHCl3): nmax
2923, 2851, 1755, 1646, 1456, 1437, 1369, 1242, 1094, 1042, 965,
691 cmꢃ1;1H NMR (400 MHz, CDCl3, ppm) d 7.00 (d, J ¼ 1.4 Hz,
1H), 5.43–5.28 (m, 1H), 5.28–5.22 (m, 1H), 5.04–4.99 (m, 1H),
2.58–2.45 (m, 1H), 2.36–2.25 (m, 3H), 2.10–1.98 (m, 2H), 1.83–
1.71 (m, 2H), 1.45–1.10 (m, 10H); 13C NMR (100 MHz, CDCl3,
ppm) d 174.2, 149.3, 133.4, 132.7, 129.5, 80.8, 31.7, 29.7, 29.65,
26.7, 25.0, 24.4, 23.9, 18.4; HRMS m/z calcd for [C15H22O2Na]+
257.1512, found 257.1518.
(E)-15-Oxabicyclo[12.2.1]heptadeca-1(17),4-dien-16-one (1d).
Isolated yield of 1d (23.5 mg, 48%); colorless oil; IR (CHCl3):
nmax 2929, 2857, 1748, 1621, 1459, 1108, 872, 666, 603 cmꢃ1; 1H
NMR (400 MHz, CDCl3, ppm) d 7.00 (d, J ¼ 1.3 Hz, 1H), 5.45–
5.36 (m, 1H), 5.35–5.25 (m, 1H), 5.02–4.95 (m, 1H), 2.53–2.45
(m, 2H), 2.42–2.30 (m, 2H), 2.10–2.00 (m, 2H), 1.89–1.79 (m,
2H), 1.45–1.25 (m, 12H); 13C NMR (125 MHz, CDCl3, ppm) d
174.2, 148.4, 133.5, 132.1, 129.2, 81.2, 31.7, 31.3, 29.0, 28.2, 27.9,
27.1, 27.0, 25.8, 24.3, 21.1; HRMS m/z calcd for [C16H24O2Na]+
271.1669, found 271.1662.
(E)-16-Oxabicyclo[13.2.1]octadeca-1(18),4-dien-17-one (1e).
Isolated yield of 1e (23.6 mg, 45%); colorless oil; IR (CHCl3): nmax
2923, 2851, 1755, 1592, 1436, 1259, 1094, 1043, 960, 872, 771,
592 cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 7.06 (d, J ¼ 1.5 Hz,
1H), 5.48–5.41 (m, 1H), 5.32–5.25 (m, 1H), 4.92–4.85 (m, 1H),
2.52–2.41 (m, 2H), 2.40–2.25 (m, 2H), 2.06–1.95 (m, 2H), 1.88–
1.78 (m, 2H), 1.48–1.15 (m, 14H); 13C NMR (100 MHz, CDCl3,
ppm) d 173.9, 149.0, 133.4, 132.2, 128.4, 81.2, 32.3, 31.4, 29.4,
27.9, 26.9, 26.6, 26.3, 25.4, 25.38, 24.8, 21.8; HRMS m/z calcd for
[C17H26O2Na]+ 285.1802, found 285.1810.
(E)-Methyl octa-3,7-dienoate (13). To a solution of alcohol 12
(0.6 g, 6.0 mmol) in CH2Cl2 (30 mL) was added Dess–Martin
periodinate (5.1 g, 12.0 mmol, 2.0 equiv.). The resulting mixture
was stirred at room temperature for 2 h. It was then quenched
with a solution of 10% aq. Na2S2O3 and sat. aq. NaHCO3 (1 : 1,
15 mL) and the solution extracted with CH2Cl2 (3 ꢁ 50 mL). The
combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was loaded on a short
pad of silica gel and washed with petroleum ether/EtOAc (2 : 1)
to give the aldehyde which was used for the next step. To the
aldehyde (0.582 g) was added mono methylmalonate (1.06 g, 9.0
mmol, 1.5 equiv.) followed by Et3N (1.2 mL, 12.0 mmol, 2.0
equiv.). The reaction mixture was reuxed for 12 h. It was then
cooled and concentrated. The residue was puried by silica gel
ash column chromatography using petroleum ether/EtOAc
(9 : 1) as eluent to give ester 13 (0.748 g, 81%) as colorless oil
(analysis showed it to contain <9% a,b-unsaturated isomer. This
was accounted for yield calculation). IR (CHCl3): nmax 3070,
2926, 2849, 1741, 1641, 1437, 1256, 1199, 1164, 996, 971, 914,
667 cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 5.81–5.71 (m, 1H),
5.52–5.50 (m, 2H), 4.99–4.90 (m, 2H), 3.63 (s, 3H), 2.99 (d, J ¼ 5.0
Hz, 2H), 2.10–2.02 (m, 4H); 13C NMR (100 MHz, CDCl3, ppm) d
172.4, 137.9, 133.8, 121.9, 114.6, 51.6, 37.7, 33.2, 31.7; HRMS m/
z calcd for [C9H14O2Na]+ 177.0863, found 177.0859.
(E)-Deca-1,5,9-trien-3-ol (9f). To a solution of the ester 13
(0.51 g, 3.3 mmol) in CH2Cl2 (20 mL) was added DIBAL-H (3.6
mL, 3.6 mmol, 1.1 equiv., 1 M solution in toluene) drop wise at
ꢂ
ꢃ78 C. The reaction mixture was stirred for 1 h. It was then
quenched by adding a saturated aq. solution of potassium–
sodium-tartrate (10 mL) and stirred for 2 h. It was then extracted
with CH2Cl2 (3 ꢁ 20 mL) and the combined organic extracts
were washed with water, brine, dried (Na2SO4), and concen-
trated. The residue was used for next reaction without further
purication.
To a solution of above aldehyde in THF (15 mL) was added
vinyl magnesium bromide (5.0 mL, 5.0 mmol, 1.51 equiv., 1 M
solutꢂion in THF) at 0 ꢂC. The reaction mixture was stirred for 2 h
at 0 C and then warmed to room temperature. Saturated aq.
NH4Cl (10 mL) was added and the mixture extracted with EtOAc
(3 ꢁ 20 mL). The combined organic layers were washed with
brine, dried (Na2SO4) and concentrated. The residue was puri-
ed by silica gel ash column chromatography using petroleum
ether/EtOAc (4 : 1) as eluent to give the allyl alcohol 9f (0.448 g,
89%) as colorless oil. IR (CHCl3): nmax 3444, 3077, 2926, 2855,
1641, 1618, 1577, 1481, 1467, 1378, 1252, 1176, 1127, 1070, 971,
914, 810, 694 cmꢃ1; 1H NMR (400 MHz, CDCl3, ppm) d 5.90–5.83
(m, 1H), 5.82–5.75 (m, 1H), 5.57–5.53 (m, 1H), 5.44–5.37 (m,
1H), 5.24 (dt, J ¼ 17.2, 1.5 Hz, 1H), 5.13 (dt, J ¼ 10.5, 1.4 Hz, 1H),
5.03–4.94 (m, 2H), 4.1 (brd, J ¼ 1.6 Hz, 1H), 2.31–2.19 (m, 1H),
2.18–2.16 (m, 1H), 2.14–2.12 (m, 4H), 1.7 (brs, 1H); 13C NMR
(125 MHz, CDCl3, ppm) d 140.4, 138.3, 134.1, 125.6, 114.8,
114.6, 71.8, 40.5, 33.6, 32.0; HRMS m/z calcd for [C10H16ONa]+
175.1093, found 175.1085.
(E)-Deca-1,5,9-trien-3-yl cyclobut-1-enecarboxylate (5f). To a
solution of allyl alcohol 9f (0.1 g, 0.657 mmol) in dry THF (10
mL) at ꢃ78 ꢂC was gradually added LiHMDS (0.5 mL, 1.0 mmol,
63346 | RSC Adv., 2014, 4, 63342–63348
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1.52 equiv., 2 M soln. in THF) over a period of 5 min. Aer
stirring for 15 min, a solution of anhydride 10 (0.176 g, 0.985
mmol, 1.5 equiv.) in dry THF (5 mL) was added and the reaction
mixture stirred for 4 h at ꢃ78 ꢂC. It was warmed to room
temperature and a solution of saturated aq. NH4Cl (5 mL) was
added. The mixture was extracted with EtOAc (3 ꢁ 30 mL) and
the combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was puried by silica
gel ash column chromatography using petroleum ether/EtOAc
(4 : 1) as eluent to give the ester 5f (0.12 g, 78%) as colorless oil.
IR (CHCl3): nmax 3075, 2929, 2857, 1731, 1641, 1464, 1252, 1180,
1046, 991, 917, 668 cmꢃ1;1H NMR (500 MHz, CDCl3, ppm) d 6.8
(s, 1H), 5.86–5.76 (m, 2H), 5.55–5.45 (m, 1H), 5.41–5.33 (m, 1H),
5.32–5.22 (m, 2H), 5.21–5.16 (m, 1H), 5.08–4.82 (m, 2H), 2.78–
2.70 (m, 2H), 2.49–2.44 (m, 2H), 2.40–2.30 (m, 2H), 2.12–2.00
(m, 4H); 13C NMR (125 MHz, CDCl3, ppm) d 161.5, 146.4, 138.9,
138.2, 136.1, 133.3, 124.8, 116.6, 114.6, 73.8, 37.6, 33.6, 32.0,
29.7, 27.0; HRMS m/z calcd for [C15H20O2Na]+ 255.1356, found
255.1361.
(4E,8E)-12-Oxabicyclo[9.2.1]tetradeca-1(14),4,8-trien-13-one
(11). To a solution of 5f (0.050 g, 0.213 mmol) in dry and
degassed toluene (150 mL) was added Grubbs-I catalyst (17.5
mg, 0.0213 mmol, 10 mol%). The mixture was reuxed for 4 h
under nitrogen atmosphere and then cooled and Grubbs-II
catalyst (9.1 mg, 0.0107 mmol, 5 mol%) was added. The
mixture was further reuxed for 44 h under nitrogen atmo-
sphere and then cooled and concentrated. The residue was
puried by silica gel ash column chromatography using
petroleum ether/EtOAc (4 : 1) as eluent to give the desmethyl
manshurolide 11 (19.1 mg, 44%) as colorless oil. IR (CHCl3):
nmax 2923, 2851, 1753, 1651, 1593, 1434, 1360, 1259, 1122, 1091,
1039, 1017, 957, 932, 869, 666 cmꢃ1; 1H NMR (400 MHz, CDCl3,
ppm) d 6.75 (s, 1H), 5.18–5.11 (m, 1H), 5.06–5.02 (m, 2H), 5.00–
4.98 (m, 2H), 2.80–2.75 (m, 1H), 2.56–2.52 (m, 1H), 2.36–2.18
(m, 6H), 1.88–1.79 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm) d
173.8, 150.5, 135.3, 133.7, 132.9, 129.8, 123.3, 80.1, 34.1, 31.8,
31.5, 29.7, 25.5; HRMS m/z calcd for [C13H16O2Na]+ 227.1043,
found 227.1044.
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Acknowledgements
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We thank the Board of Research in Nuclear Sciences (BRNS),
Government of India (Basic Sciences, Grant no. 2013/37C/59/
BRNS/2443) for nancial support. M.B.H. thanks the Council
of Scientic and Industrial Research (CSIR), New Delhi for
senior research fellowship.
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Paper
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10 The (E)-selectivity was arrived at by comparison of similar 11 For Knoevenagel condensation see: (a) H. Yamanaka,
ring closure and appearance of peaks (d values) in the 1H
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M. Yokoyama, T. Sakamoto, T. Shiraishi, M. Sagi and
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63348 | RSC Adv., 2014, 4, 63342–63348
This journal is © The Royal Society of Chemistry 2014