Concise stereoselective total synthesis of (+)-mueggelone

Article abstract of DOI:10.1080/00397911.2011.624395

A concise synthetic route has been reported for the total synthesis of (+)-mueggelone. The syntheses of fragments were initiated from commercially available and inexpensive starting materials. The synthesis involves key steps such as Sharpless epoxidation

Full text of DOI:10.1080/00397911.2011.624395

This article was downloaded by: [University of Sussex Library]
On: 28 February 2013, At: 12:29
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Concise Stereoselective Total Synthesis
of (+)-Mueggelone
Dachepally Aravind Kumar a & Harshadas Mitaram Meshram a
a Organic Chemistry Division I, Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 27 Feb 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Dachepally Aravind Kumar & Harshadas Mitaram Meshram (2013): Concise
Stereoselective Total Synthesis of (+)-Mueggelone, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:8, 1145-1154
To link to this article: http://dx.doi.org/10.1080/00397911.2011.624395
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 1145–1154, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.624395
CONCISE STEREOSELECTIVE TOTAL SYNTHESIS
OF (þ)-MUEGGELONE
Dachepally Aravind Kumar and Harshadas Mitaram Meshram
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A concise synthetic route has been reported for the total synthesis of (þ)-
mueggelone. The syntheses of fragments were initiated from commercially available and
inexpensive starting materials. The synthesis involves key steps such as Sharpless epoxida-
tion, Jacobsen resolution, lactonization, and cross metathesis.
Keywords Jacobsen resolution; (þ)-mueggelone; Sharpless epoxidation
INTRODUCTION
(þ)-Mueggelone was isolated by Konig and coworkers in 1995 from the
bloom-forming strain of Aphanizomenon flos-aquae.[1] (þ)-Mueggelone is reported
to show a significant ecologically important role in the inhibition of fish embryo lar-
val development. In particular, in mueggelone at a concentration of 10 ug=mL, zebra
fish larvae showed 45% mortality. Survivors showed edema in the heart region and
thrombosis. The key structural features of mueggelone are a 10-membered lactone
having a side chain with cis, trans double bonds and epoxide. The structure and
unique biological activity of 1 spurred considerable interest among synthetic organic
chemists. Ishigami et al. synthesized all the four possible stereoisomers of
mueggelone and determined its absolute configuration. Ishigami et al.[2a] and Yadav
et al.[2b] have reported the total synthesis of (þ)-mueggelone in 21 and 22 steps
respectively. We have planned a synthetic strategy to reduce the number of steps.
The carbon skeleton of (þ)-mueggelone suggests a convergent synthesis is desirable.
Received December 11, 2010.
Address correspondence to H. M. Meshram, Organic Division I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India. E-mail: hmmeshram@yahoo.com
1145

1146
D. A. KUMAR AND H. M. MESHRAM
RESULTS AND DISCUSSION
As outlined in retrosynthetic diagram in Scheme 1, the synthesis of fragment 2
commenced from commercially available (Z)-3-hexene1-ol 4. Thus, the alcohol was
oxidized with Dess–Martin periodinane to obtain aldehyde, which subsequently
underwent Witting olefination to give 6 in 89% yield.[3]
Reduction of 6 with diisobutyl aluminium hydride gave allylic alcohol 7 in 89%
yield, which was then transformed into epoxy alcohol 8 under Sharpless conditions.[4]
Conversion of epoxy alcohol 8 into 2 was accomplished in good yield by Swern
oxidation followed by 1C-Wittig homologation.[5]
A kinetic resolution of racemic epoxide 5 with the (R,R)-Jacobsen catalyst 15
(Fig. 1) furnished the optically active epoxide 9.[6] Treatment of epoxide 9 with tri-
methylsulfonium iodide and n-BuLi cleanly afforded secondary allylic alcohol 10 in
85% yield.[7] The secondary hydroxy group protected with tert-butyldiphenylsilyl
chloride gave the corresponding silyl ether 11. Deprotection of TBS with PPTS
resulted in to primary alcohol 12 in good yield.[8] Alcohol 12 was converted to acid
13 by treating with TEMPO and (bisiodobenzene diacetate) (BAIB) as co-oxidant.[9]
Removal of the TBDPS group with HF ꢀ pyridine gave a precursor of fragment 3.
Macrolactonization of hydroxy acid using 2-methyl-6-nitrobenzoic anhydride
(MNBA) under Shiina conditions gave a 10 membered lactone 3.[10] Assembly of
two terminal alkenes 2 and 3 was undertaken by cross metathesis using Grubbs
catalyst[11] 16 (Fig. 1), which afforded the target molecule with desired E-selectivity
along with the homo dimer as a side product, which was confirmed by mass
spectroscopy (Scheme 3). The desired molecule was confirmed by spectral data and
rotation, which are identical to the natural isomer.[2]
Scheme 1. Retrosynthetic analysis of (þ)-muggelone (1).
Figure 1. (R,R) Jacobsen catalyst (15) and second-generation Grubbs catalyst (16).

SYNTHESIS OF (þ)-MUEGGELONE
1147
Scheme 2. Reagents and conditions: (a) (i) Dess–Martin oxidation, (ii) (EtO)2P(O)CH2CO2Et, n-BuLi,
THF, 0 ꢁC, 89%; (b) DIBAL-H, THF, 0 ꢁC, 89%; (c) (þ)-DIPT, Ti(iPrO)4, TBHP, CH2, 4 Aꢁ MS,
ꢂ20 ꢁC, 90%; (d) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢂ78 ꢁC, 1 h, 90%, (ii) PPh3CH3I, tBuOK, THF,
0–25 ꢁC, 2 h, 70%.
Scheme 3. Reagents and conditions: (a) (R,R)-Co salen complex, THF, H2O, 40%; (b) (CH3)3SþIꢂ,
n-BuLi, THF, ꢂ10 ꢁC to rt, 85%; (c) TBDPSCI, imidazole, CH2Cl2, rt, 92%; (d) PPTS, EtOH, rt, 90%;
(e) TEMPO, BAIB, CH3CN, H2O, 80%; (f) HF ꢀ Pyr, THF, 92%; (g) MNBA, DMAP, Et3N, CH2Cl2=
THF, 50 ꢁC, 77%; (h) 2, second-generation Grubbs catalyst, CH2Cl2, 25 ꢁC, 40%.
CONCLUSION
In summary, we have synthesized (þ)-mueggelone in comparably fewer steps.
Both fragments were synthesized from easily available starting materials. The
products are obtained in good yields. The synthesis was highlighted by Sharpless
epoxidation, Jacobsen resolution, lactonization, and cross metathesis as key steps.
This approach provides easy access to the synthesis of (þ)-mueggelone, which has
biological importance.
EXPERIMENTAL
All reactions were carried out under an inert atmosphere unless mentioned and
followed standard syringe septa techniques. Solvents were dried and purified by con-
ventional methods prior to use. The progress of all the reactions was monitored by

1148
D. A. KUMAR AND H. M. MESHRAM
thin-layer chromatography (TLC) using glass plates precoated with silica gel 60 F254
to a thickness of 0.5 mm (Merck). Column chromatography was performed on silica
gel (60 mesh) and neutral alumina using diethyl ether, ethyl acetate, and hexane as the
eluents. Optical rotation values were measured with a Perkin-Elmer P241 polarimeter
and Jasco DIP-360 digital polarimeter at 25 ꢁC. Infrared (IR) spectra were recorded
1
with a Perkin-Elmer Fourier transform (FT)–IR spectrophotometer. H and 13C
NMR spectra were recorded with Varian Gemini (200 MHz), Bruker Avance
(300 MHz), Varian Unity (400 MHz), or Varian Inova (500 MHz) spectrometers
using tetramethylsilane (TMS) as an internal standard in CDCl3. Mass spectra were
recorded on a Micromass VG-7070H for electron impact (EI) and VG Autospec M
for fast atom bombardment–mass spectrometry (FABMS).
(2E,5Z)-Octa-2,5-dienoic Acid Ethyl Ester
To a stirred solution of (Z)-hex-3-en1-ol 4 (1 g, 10 mmol) in dichloromethane
(1 mL), Dess–Martin periodinane (6.36 g, 15 mmol) was added portionwise, and the
resulting mixture was stirred for 30 min at 0 ꢁC. The reaction mixture was diluted with
ether and filtered, and the filtrate was washed with saturated aqueous sodium hydro-
gen carbonate and brine and dried over Na2SO4. Evaporation of the solvent gave a
residue, which, without further purification, was treated with triethyl phosphonoace-
tate (2.58 mL, 1.3 mmol) and n-butyllithium (1.6 M in n-hexane, 0.73 mL, 1.2 mmol)
in dry THF (5 mL) for 2 h at 0 ꢁC. After addition of saturated aqueous NH4Cl, the
mixture was extracted with diethyl ether. The extract was washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a residue that was purified by column
chromatography (n-pentane-diethyl ether, 30:1) to give 6 (1.49 g, 8.9 mmol, 89%) as
1
colorless oil. H NMR (300 MHz, CDCl3): (0.97 (t, 3H, J ¼ 7.5 Hz, CH3), 1.28 (t,
3H, J ¼ 7.2 Hz, CH3), 2.04–2.10 (m, 2H, CH2), 2.94 (dd, 2H, J ¼ 6.3, 7.1 Hz, CH2),
4.18 (q, 2H, J ¼ 7.2 Hz, OCH2), 5.35–5.41 (m, 1H, olefin), 5.55–5.62 (m, 1H, olefin),
5.83 (dt, 1H, J ¼ 1.7, 15.5 Hz, olefin), 6.95 (dt, 1H, J ¼ 6.3, 15.5 Hz, olefin); 13C NMR
(75 MHz, CDCl3): (13.9, 14.1, 20.4, 29.7, 60.1, 121.2, 123.5, 134.5, 147.2, 166.6; IR
(KBr): 1720, 1652,1464, 1400, 1368, 1325, 1308, 1272, 1234, 1208, 1165, 1120, 1096,
1047, 993, 930, 900 cmꢂ1; EI-MS: m/z 168 [Mþ]; ESI-HRMS: calculated for
C10H16O2: 168.1150; found: 168.1144.
(2E,5Z)-Octa-2,5-dien-1-ol (7)
Diisobutylaluminium hydride (20.6 mL, 19 mmol) was added dropwise to a stir-
red solution of 6 (1.49 g, 8.9 mmol) in dry diethylether (15 mL) and the resulting mix-
ture was stirred for 1 h at 0 ꢁC. After adding dropwise methanol–H2O (1:3), followed
by filtration of the mixture, the solvent was removed to give a residue that was
purified by column chromatography (n-pentane–diethyl ether, 2:1) to give 7 (1.0 g,
7.92 mmol, 89%) as a colorless oil. 1H NMR (300 MHz, CDCl3): (0.97 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.34 (brs, 1H, OH), 2.05 (dq, 2H, J ¼ 7.1, 7.4 Hz, CH2), 2.79–2.82
(m, 2H, CH2), 4.10 (m, 2H, OCH2), 5.40–5.51 (m, 2H, olefin), 5.68–5.79 (m, 2H,
olefin); 13C NMR (75MHz, CDCl3): (14.0, 20.3, 29.8, 63.3, 126.0, 129.1, 131.0, 132.6;
IR (KBr): 3320, 1670, 1652, 1432, 1374, 1304, 1225, 1090, 1072, 1005, 986 cmꢂ1; EI-MS:
m/z 126 [Mþ]. ESI-HRMS: calculated for C8H14O: 126.1045; found: 126.1052.

SYNTHESIS OF (þ)-MUEGGELONE
1149
((2S,3S)-3-((Z)-Pent-2-enyl)oxiran-2-yl)oxiran-2-yl)methanol (8)
˚
To a stirred suspension of activated 4 A molecular sieves (1.0 g) in CH2Cl2
(25 mL) was added L-(þ)-DIPT (0.16 mL, 0.942 mmol) and Ti (OiPr)4 (0.25 mL,
0.79 mmol) with stirring, and the resulting mixture was stirred for 30 min at
ꢂ20 ꢁC. The allyl alcohol 7 (1.0 g, 7.92 mmol) in dry CH2Cl2 (20 mL) was added drop-
wise and the resulting mixture was stirred for another 30 min at ꢂ20 ꢁC. TBHP
(5.3 mL, 3.0 M in toluene, 15.84 mmol) was then added, and the resulting mixture
was stirred at the same temperature for 8 h. It was then warmed to 0 ꢁC, quenched
with water (1 mL), and stirred for 2 h at room temperature. Aqueous NaOH solution
30% saturated with NaCl (3 mL) was then added, and the resulting mixture stirred
vigorously for another 30 min at room temperature. The resulting mixture was filtered
through celite, and the filter cake was washed well with CH2Cl2. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (3 ꢃ 10 mL).
Combined organic layers were washed with brine and dried over Na2SO4. Removal
of solvent under reduced pressure and purification by silica-gel column chromato-
graphy using ethyl acetate and hexane (2.5:7.5) afforded 8 (1.02 g, 7.12 mmol, 90%)
as a colorless viscous liquid. [(]D þ 18.0 (c ¼ 1.6, CHCl3); 1H NMR (300 MHz,
CDCl3): (0.98 (t, 3H, J ¼ 7.5 Hz, CH3), 1.97–2.11 (m, 2H, CH2), 2.18–2.47 (m, 2H,
CH2), 2.56 (br s, 1H, OH), 2.87–2.96 (m, 2H, epoxide), 3.57 (dd, 1H, J ¼ 3.7,
12.8 Hz, OCH), 3.85 (dd, 1H, J ¼ 2.2, 12.8 Hz, OCH), 5.26–5.39 (m, 1H, olefin),
5.44–5.59 (m, 1H, olefin); 13C NMR (75 MHz, CDCl3): (14.1, 20.6, 29.2, 55.5, 58.3,
61.7, 122.3, 134.8; IR (KBr) n ¼ 3440, 1590, 1257, 1450, 1050 cmꢂ1; EI-MS: m/z
142 [Mþ]. ESI-HRMS: calculated for C8H14O: 142.0993; found: 142.0099.
(2S,3S)-2-((Z)-Pent-2-enyl)-3-vinyloxirane (2)
Dimethyl sulfoxide (1.13 mL, 16.0 mmol) was added to a solution of oxalyl
chloride (0.82 mL, 7.5 mmol) in CH2Cl2 (10 mL) at ꢂ78 ꢁC over 20 min. The resulting
mixture was stirred for an additional 15 min, and then alcohol 8 (710.9 mg, 5 mmol)
dissolved in CH2Cl2 (10 mL) was added dropwise. The mixture stirred for 30 min, and
triethylamine (3.47 mL, 25 mmol) was added dropwise. The reaction was allowed to
warm to room temperature and stirred for 30 min. After completion, the reaction
mixture was quenched with water (30 mL) and the aqueous phase was extracted with
CH2Cl2 (2 ꢃ 20 mL). The combined organic layers were washed with brine and dried
over anhydrous Na2SO4. Removal of solvent afforded aldehyde (0.560 g, 4.0 mmol,
90%) as a colorless liquid a solution of n-BuLi in hexane (7.5 mL, 1.6 M) was added
at 0 ꢁC to a solution of trimethylphosphonium iodide (4.84 g, 12.0 mmol) in THF
(35 ml), a and solution of aldehyde (0.560 g, 4.0 mmol) in THF (15 mL) was added
via cannula. Then reaction mixture was allowed to warm to rt and quenched with
water after 1 h. The solution was poured into water (50 ml) and extracted with ether
(3 ꢃ 40 mL). The combined organic extracts were washed once with brine (30 mL),
dried, filtered and concentrated. The product was purified by column chromato-
graphy (10% EtOAc in hexane) to afford 2 (0.386 g, 2.8 mmol, 70%) as yellow syrup.
[a]D þ 12.0 (c ¼ 1.4, CHCl3); 1H NMR (300 MHz, CDCl3): (0.99 (t, 3H, J ¼ 7.3 Hz,
25
CH3), 2.06 (quintet, 2H, J ¼ 7.3 Hz, CH2), 2.30–2.50 (m, 2H, CH2), 2.75 (dt, 1H,
J ¼ 5.2, 2.0 Hz, epoxide), 3.08 (dt, 1H, J ¼ 7.3, 1.3 Hz, epoxide), 5.22–5.61 (m, 5H,

1150
D. A. KUMAR AND H. M. MESHRAM
olefin); 13C NMR (75 MHz, CDCl3): (13.5, 20.6, 29.5, 58.1, 58.5, 121.2, 122.2, 134.8,
135.3; EI-MS: m/z 161 [M þ Na]þ. ESI-HRMS: calculated for C9H14ONa: 161.0942;
found: 161.0950.
(R)-tert-Butyldimethyl(8-(oxiran-2-yl)octyloxy)silane (9)
A flask (100 mL) equipped with a stir bar was charged with (R,R)-Co salen com-
plex (30 mg, 0.05 mmol). The catalyst was treated with racemic epoxide 5 (2.86 g,
10 mmol), AcOH (0.012 mL, 0.21 mmol), and 1 mL of THF. The reaction flask was
cooled to 0 ꢁC, and H2O (0.1 mL, 5.5 mmol) was added in one portion. The reaction
was allowed to warm to room temperature and stirred for 16 h. The recovered epoxide
was filtered through a silica plug to remove residual water, the THF was removed by
rotary evaporation, and the crude mixture was passed through column chromato-
graphy using ethyl acetate and hexane (0.5:9.5) to yield (R)-tert-butyldimethyl(8-
(oxiran-2-yl)silane 9 (1.14 g, 4.0 mmol, 97% ee, 40%). The catalyst was recovered by
suspension in MeOH and vacuum filtration. [a]D þ 2.0 (c ¼ 1.0, CHCl3); 1H
25
NMR (300 MHz, CDCl3): (0.05 [s, 6H, Si(CH3)2], 0.90 [s, 9H, (CH3)3CSi],
1.27–1.40 (m, 9H, aliphatic), 1.41–1.60 (m, 5H, aliphatic), 2.42–2.46 (m, 1H, epoxide),
2.70 (t, 1H, J ¼ 4.5 Hz, epoxide), 2.83–2.90 (m, 1H, epoxide), 3.60 (t, 2H, J ¼ 6.7 Hz,
OCH2); 13C NMR (75 MHz, CDCl3): (ꢂ5.3, 25.7, 25.9, 29.2, 29.3, 29.4, 32.4, 32.8,
47.0, 52.3, 63.2; IR (KBr) n ¼ 2929, 2856, 1426, 1252, 1098, 836, 775 cmꢂ1; EI-MS:
m/z 203 [M þ H]þ. ESI-HRMS: calculated for C10H23O2Si: 203.1467; found
203.1470.
(R)-11-(tert-Butyldimethylsilyloxy)undec-1-3-ol (10)
n-BuLi (1.6 M in hexane, 7.43 mL, 11.9 mmol) was added to a suspension of
trimethyl sulfonium iodide (2.44 g, 12 mmol) in dry THF (36 ml) at ꢂ10 ꢁC. After
30 min, (R)-tert-butyldimethyl [8-(oxiran-2-yl)silane 9 (1.14 g, 4.0 mmol) in THF
(8 mL) was introduced, which produced a milky suspension. The reaction was allowed
to warm to 0 ꢁC over about 30 min, then to room temperature, and stirred for 2 h. The
reaction was quenched with water at 0 ꢁC and extracted with ether, and the combined
organic layers were dried over Na2SO4. Silica chromatography of the crude product
using ethylacetate and hexane (1:9) afforded (R)-11-(tert-butyldimethylsilyloxy)
25
undec-13-ol 10 (1.02 g, 3.4 mmol, 85%) as a colorless oil. [a]D ꢂ17.0 (c ¼ 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): (0.05 (s, 6H, Si(CH3)2], 0.90 [s, 9H,
(CH3)3CSi], 1.32–1.41 (m, 10H, aliphatic), 1.42–1.59 (m, 4H, aliphatic), 3.60 (t, 2H,
J ¼ 6.7 Hz, OCH2), 4.10 (m, 1H, OCH), 5.10 (d, 1H, J ¼ 10.5 Hz, olefin), 5.20 (d,
1H, J ¼ 16.6 Hz, olefin), 5.80–5.95 (m, 1H, olefin); IR (KBr) n ¼ 3377, 2930, 2858,
1641, 1463, 1253, 1100, 837 cmꢂ1; EI-MS: m/z 216 [M]þ; ESI-HRMS: calculated
for C11H24O4Si: 216.1546; found: 216.1552.
(R)-2,2,15,15,16,16-Hexamethyl-3,3-diphenyl-5-vinyl-4,14-dioxa-3,
15 disilaheptadecane (11)
TBDPSCl (1.02 g, 3.74 mmol) was added to a stirred solution of secondary
alcohol 10 (1.02 g, 3.4 mmol) and imidazole (0.57 g, 8.5 mmol) in CH2Cl2 (15 mL)

SYNTHESIS OF (þ)-MUEGGELONE
1151
at 0 ꢁC portionwise over a period of 10 min. The reaction mixture was stirred at room
temperature for 3 h. The mixture was then diluted with CH2Cl2 and washed with
water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatography using ethyl
acetate and hexane (0.2:9.8) to afford TBDPS-protected alcohol 11 (5.5 g, 3.12 mmol,
92%) as a colorless oil. [a]D ꢂ 12.0 (c ¼ 1.15, CHCl3); 1H NMR (300 MHz, CDCl3):
20
d 0.05 [s, 6H, Si(CH3)2], 0.92 [s, 9H, (CH3)3CSi], 1.10 [s, 9H, (CH3)3CSi], 1.12–1.54
(m, 14H, aliphatic), 3.60 (t, 2H, J ¼ 6.7 Hz, OCH2), 4.10 (m, 1H, OCH), 4.95–5.05
(m, 2H, olefin), 5.72–5.84 (m, 1H, olefin), 7.25–7.45 (m, 5H, ArH), 7.62–7.71 (m,
5H, ArH); 13C NMR (75 MHz, CDCl3): dꢂ5.2, 18.3, 19.3, 24.3, 25.7, 26.0, 27.0,
29.3, 29.4, 32.9, 37.5, 63.2, 74.6, 114.1, 127.3, 124.4, 129.3, 129.4, 134.2, 134.5,
135.8, 135.9, 140.9; IR (KBr) n ¼ 3050, 2958, 2858, 1598, 1260, 1272 cmꢂ1; EI-MS:
m/z 477 [M þ Na]þ. ESI-HRMS: calculated for C27H42O2Si2Na: 477.2621; found:
477.2618.
(R)-9-(tert-Butyldiphenylsilyloxy)undec-10-en-ol (12)
The bissilyl ether 11 (1.67 g, 3.12 mmol) was dissolved in absolute ethanol
(16 ml), and PPTS (0.235 g, 0.93 mmol) was added in one portion. The reaction mix-
ture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and
the residue was dissolved in ethyl acetate. The organic solution was washed with satu-
rated aqueous brine and water and then dried over anhydrous Na2SO4. The solvent
was evaporated in vacuum, and the crude product was purified by silica-gel column
using hexane–ethyl acetate (9:l) as eluent to get pure primary alcohol 12 (1.17 g,
25
1
2.87 mmol, 90%). [a]D ꢂ15.0 (c ¼ 1.0, CHCl3); H NMR (200 MHz, CDCl3): d1.1
[s, 9H, (CH3)3CSi], 1.12–1.58 (m, 14H, aliphatic), 3.6 (t, 2H, J ¼ 7.0 Hz, OCH2),
4.02–4.16 (m, 1H, OCH), 4.90–5.02 (m, 2H, olefin), 5.56–5.83 (m, 1H, olefin),
7.26–7.43 (m, 6H, ArH), 7.58–7.74 (m, 4H, ArH); 13C NMR (75 MHz, CDCl3):
(19.2, 24.2, 25.6, 26.9, 29.2, 29.3, 32.6, 37.4, 62.6, 74.5, 114.0, 127.2, 127.3, 129.3,
129.4, 134.1, 134.4, 135.7, 135.8, 140.8; IR (KBr) n ¼ 3428, 3042, 2940, 1572, 1270,
1102 cmꢂ1; EI-MS: m/z 424 [M]þ. ESI-HRMS: calculated for C21H28O2Si:
424.1859; found: 424.1866.
(R)-9-(tert-Butyldiphenylsilyloxy)undec-10-enoic acid (13)
TEMPO (0.090 g, 0.57 mmol) and BAIB (2.31 g, 7.17 mmol) were added to
a vigorously stirred solution of alcohol 12 (1.17 g, 2.87 mmol) in CH3CN (6 mL)
and H2O (3 mL). Stirring was allowed until TLC indicated complete conversion of
the starting material to product. The reaction mixture was quenched by addition
of saturated Na2S2O3 solution (5 mL). The reaction mixture was then extracted with
ethyl acetate (2 ꢃ 10 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated. The crude acid was purified by silica-gel column chroma-
tography using ethyl acetate and hexane (2:8) to get pure acid 13 (1.03 g, 2.43 mmol,
25
1
80%) as a colorless liquid. [a]D ꢂ13.9 (c ¼ 1.15, CHCl3); H NMR (300 MHz,
CDCl3): d1.10 [s, 9H, (CH3)3CSi], 1.12–1.4 (m, 10H, aliphatic), 1.60 (pent, 2H,
J ¼ 7.5 Hz, CH2), 2.30 [t, 2H, J ¼ 7.5 Hz, C(O)CH2], 4.10 (m, 1H, OCH), 4.90–5.10
(m, 2H, olefin), 5.70–5.85 (m, 1H, olefin), 7.35–7.42 (m, 6H, ArH), 7.60–7.70

1152
D. A. KUMAR AND H. M. MESHRAM
(m, 4H, ArH); 13C NMR (75 MHz, CDCl3): 19.3, 24.2, 24.5, 27.0, 28.8, 29.0, 29.1,
34.0, 37.4, 74.5, 114.1, 127.2, 127.3, 129.3, 129.4, 134.2, 134.4, 135.8, 135.9, 140.8,
179.8. IR (KBr) n ¼ 3442, 2930, 2858, 1710, 1625, 1425, 1106 cmꢂ1; EI-MS: m/z
405 [M þ Na]þ. ESI-HRMS: calculated for C23H30O3SiNa: 405.1862; found:
405.1869.
9-Hydroxyundec-10-enoic acid (14)
To a solution of acid 13 (1.03 g, 2.43 mmol) in THF (8 mL), 70% HF-Py com-
plex (1.7 mL, 12.4 mmol) was added at room temperature. The mixture was stirred
for 24 h and quenched with cold water (12 mL). The resulting mixture was diluted
with Et2O (50 mL). The organic phase was successively washed with water and brine
(5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography using ethyl acetate
25
and hexane (4:6) to afford seco acid 14 (0.406 g, 2.18 mmol, 92%). [a]D ꢂ15.4
(c ¼ 1, CHCl3);1H NMR (300 MHz, CDCl3): (1.23–1.64 (m, 12H, aliphatic), 2.32
[t, 2H, J ¼ 7.5 Hz, C(O)CH2], 4.02–4.13 (m, 2H, aliphatic), 5.06 (d, 1H, J ¼ 16.6 Hz,
Hz, olefin), 5.18 (d, 1H, J ¼ 16.6 Hz, olefin), 5.77–5.88 (m, 1H, olefin); IR (KBr)
n ¼ 3432, 2928, 2854, 1706, 1419, 1102, 1035 cmꢂ1. EI-MS: m/z 223 [M þ Na]þ.
ESI-HRMS: calculated for C17H27O4Na: 223.1310; found: 223.1304.
(R)-10-Vinyloxecan-2-one (3)
A solution of seco-acid 14 (100 mg, 0.543 mmol) in THF (16.3 mL) with
a mechanically driven syringe was slowly added to a solution of MNBA (0.205 g,
0.597 mmol), DMAP (0.013 g, 0.108 mmol), and triethylamine (2.25 mL, 1.62 mmol)
in dichloromethane (9.6 mL) at 50 ꢁC over a 12-h period. After the reaction mixture
had been stirred for 1 h at room temperature, saturated aqueous sodium hydrogen-
carbonate was added at 0 ꢁC. The mixture was extracted with dichloromethane
(15 mL), and the organic layer was washed with water and brine and dried over
sodium sulfate. After filtration of the mixture and evaporation of the solvent, the
crude product was purified by column chromatography (eluant; hexane–ethyl acetate
25
3=1) to afford lactone 3 (0.076 g, 0.418 mmol, 77%). [a]D ꢂ10.6 (c ¼ 0.8, CHCl3);
1H NMR (300 MHz, CDCl3): (1.27–1.81 (m, 10H, aliphatic), 2.04–2.57 (m, 4H,
aliphatic), 5.17–5.36 (m, 3H), 5.83–5.94 (m, 1H, olefin); IR (KBr) n ¼ 2934, 1728,
1469, 1229, 1069, 973 cmꢂ1; EI-MS: m/z 205 [M þ Na]þ. ESI-HRMS: calculated
for C11H18O2Na: 205.1204; found: 205.1214.
(R)-10-((E)-2-((2S,3S)-3-((Z)-Pent-2-enyl)oxiran-2-yl)vinyl)oxecan-2-
one (1)
To a solution of 3 (0.018 g, 0.1 mmol) and 2 (0.069 mg, 0.05 mmol) in freshly
distilled degassed anhydrous CH2Cl2 (0.5 mL), Grubbs second-generation catalyst
(0.017 mg, 0.02 mmol) was added and stirred at 40 ꢁC for 2 h under an argon atmos-
phere until the complete consumption of starting material (monitored by TLC).
The solvent was evaporated to a brown residue, which was purified by column
chromatography (silica gel, 60–120 mesh, 10% ethyl acetate–hexane) to afford 1

SYNTHESIS OF (þ)-MUEGGELONE
1153
(5 mg, 0.02 mmol) as colorless oil. [a]D20: þ28.2(c ¼ 0.6, CHCl3); 1H NMR (300 MHz,
DMSO): (0.97 (t, 3H, J ¼ 7.5, CH3), 1.00–1.80 (m, 10H, aliphatic), 1.95–2.15 (m, 4H,
aliphatic), 2.20 (ddd, 1H, J ¼ 15.5, 11.8, 2.6 Hz, aliphatic), 2.36 (m, 2H, aliphatic),
2.52 (ddd, 1H, J ¼ 15.5, 6.2, 3.0 Hz, aliphatic), 2.87 (dt, 1H, J ¼ 5.3, 2.20 Hz, epoxide),
3.15 (dd, J ¼ 7.8, 2.2 Hz, 1H, epoxide), 5.30–5.42 (m, 2H, olefin), 5.54 (m, 1H, olefin),
5.94 (dd, 1H, J ¼ 15.6, 5.1 Hz, olefin); 13C NMR (75 MHz, DMSO-d6): (13.7, 20.9,
23.5, 23.7, 24.3, 27.2, 29.8, 33.9, 35.0, 35.3, 57.1, 58.6, 74.7, 121.5, 128.6, 132.7,
133.0, 172.6; IR (KBr) n ¼ 2931, 1738, 1465, 1236, 1068, 969 cmꢂ1; EI-MS: 293
[MþH]þ; ESI-HRMS: calculated for C18H29O3: 293.2116; found: 293.2120.
ACKNOWLEDGMENT
D. A. thanks the Council of Scientific and Industrial Research, New Delhi, for
the award of a fellowship.
REFERENCES
1. Olaf, P.; Gabriele, M. K.; Anthony, D. W.; Ingrid, C.; Axel, O. Mueggelone, a novel
inhibitor of fish development from the fresh water cyanobacterium Aphanizomenon flos
aquae. J. Nat. Prod. 1997, 60, 1298–1300.
2. (a) Ishigami, K.; Motoyoshi, H.; Kithara, T. First total synthesis and determination of the
absolute configuration of mueggelone. Tetrahedron 2001, 57, 3899–3908; (b) Yadav, J. S.;
Somaiah, R.; Ravindar, K.; Chandraiah, L. Stereoselective total synthesis of (þ)-
mueggelone, a novel inhibitor of fish development. Tetrahedron Lett. 2008, 49, 2848–
2850; (c) Ishigami, K.; Motoyoshi, H.; Kithara, T. First total synthesis of mueggelone.
Tetrahedron Lett. 2000, 41, 8897–8901.
3. Toshio, H.; Mai, O.; Hirotake, M. Enantiocontrolled synthesis of naturally occurring
octadecadienoic acid derivatives, self-defensive substances against rice blast disease, by
means of the Sharpless asymmetric epoxidation of unsymmetrical divinylmethanol.
J. Chem. Soc., Perkin Trans. 1 1999, 23–30.
4. (a) Sharpless, K. B.; Katsuki, T. The first practical method for asymmetric epoxidation.
J. Am. Chem. Soc. 1980, 102, 5974–5976; (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.;
Ko, S. Y.; Masamune, H.; Sharpless, K. B. Catalytic asymmetric epoxidation and kinetic
resolution: Modified procedures including in situ derivatization. J. Am Chem. Soc. 1987,
109, 5765–5780.
5. Corey, E. J.; Martaf, A.; Laguzza, B. C. Total synthesis of 5s,12s-dihydroxy-6,10-
E,8,14-Z-eicosatetraenoic acid (5S,12S-di-hete) (2), a new human metabolite of arachido-
nic acid. Tetrahedron Lett. 1981, 22, 3339–3342.
6. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.;
Furrow, M. E.; Jacobsen, E. N. Highly selective hydrolytic kinetic resolution of terminal
epoxides catalyzed by chiral (salen)CoIII complexes: Practical synthesis of enantioenriched
terminal epoxides and 1,2-diols. J. Am. Chem. Soc. 2002, 124, 1307–1315.
7. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D. S.; Falck,
J. R. Novel conversion of epoxides to one carbon homologated allylic alcohols by
dimethylsulfonium methylide. Tetrahedron Lett. 1994, 35, 5449–5452.
8. Prakash, C.; Saleh, S.; Blair, I. A. Selective de-protection of silyl ethers. Tetrahedron Lett.
1989, 30, 19–22.
9. (a) Van den Bos, L. J.; Litjens, R. E. J. N.; Van den Berg, R. J. B. H. N.; Verkleeft, H. S.;
Vander Marel, G. A. Preparation of 1-thio uronic acid lactones and their use in oligosac-
charide synthesis. Org. Lett. 2005, 7, 2007–2010; (b) Yadav, J. S.; Reddy, Ch. S. Highly

1154
D. A. KUMAR AND H. M. MESHRAM
enantioselective construction of axial chirality by palladium-catalyzed cycloisomerization
of N-alkenyl arylethynylamides. Org. Lett. 2009, 11, 1805–1808.
10. (a) Shiina, I.; Kikuchi, T.; Sasaki, A. The first total synthesis of (ꢂ) and (þ)-2-hydroxy-24-
oxooctacosanolide using an effective lactonization. Org. Lett. 2006, 8, 4955–4958; (b)
Shiina, I.; Ibuka, R.; Kubota, M. A new condensation reaction for the synthesis of car-
boxylic esters from nearly equimolar amounts of carboxylic acids and alcohols using
2-methyl-6-nitrobenzoic anhydride. Chem. Lett. 2002, 286–287; (c) Shiina, I.; Kubota,
M.; Oshiumi, H.; Hashizume, M. An effective use of benzoic anhydride and its derivatives
for the synthesis of carboxylic esters and lactones: a powerful and convenient mixed
anhydride method promoted by basic catalysts. J. Org. Chem. 2004, 69, 1822–1830.
11. McDonald, F. E.; Wei, X. Concise, regioselective synthesis of the abc tristetrahydropyran
of thyrsiferol and venustatriol. Org. Lett. 2002, 4, 593–595.