Synthesis of (+)-muricatacin and a formal synthesis of CMI-977 from l -malic acid

Article abstract of DOI:10.1055/s-0033-1338934

A total synthesis of (+)-muricatacin and a formal synthesis of CMI-977 have been achieved using commercially available l-malic acid based on our furan approach to oxacyclic systems, the proven scope of which is thus broadened. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338934

PAPER
▌1693
paper
Synthesis of (+)-Muricatacin and a Formal Synthesis of CMI-977 from L-Malic
Acid
(+)-Muricatacin from L-Malic Acid
Maria González, Zoila Gándara, Andrea Martínez, Generosa Gómez,* Yagamare Fall*
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(986)812262; E-mail: yagamare@uvigo.es; E-mail: ggomez@uvigo.es
Received: 15.03.2013; Accepted after revision: 16.04.2013
5 as previously described.3b We anticipated that once al-
Abstract: A total synthesis of (+)-muricatacin and a formal synthe-
cohol 5 had been transformed into chiral furan 16
sis of CMI-977 have been achieved using commercially available L-
(Scheme 2), the stage would be set for the synthesis of 1
malic acid based on our furan approach to oxacyclic systems, the
proven scope of which is thus broadened.
by what we call our furan approach to oxacyclic systems.3
Accordingly, alcohol 5 was protected as its pivaloyl ester
Key words: butenolide, oxygen, natural products, total synthesis,
6 (90% yield), and selective removal of the TBS protect-
ing group of 6 afforded alcohol 7 (95%), which upon
TEMPO oxidation gave aldehyde 8 in 91% yield. Wittig
reaction of aldehyde 8 with the phosphonium salt pre-
pared from decyltriphenylphosphonium iodide afforded
an 85% yield of alkene 9, which upon catalytic hydroge-
nation gave 10 in 99% yield. Deprotection of the primary
hydroxyl group of 10 afforded a 91% yield of alcohol 11,
and TEMPO oxidation of 11 gave an 86% yield of alde-
hyde 12. Treatment of 12 with the lithium derivative of al-
kyne 13 gave a mixture of epimeric propynyl alcohols 14,
which were hydrogenated over Lindlar catalyst, providing
a mixture of diastereoisomeric Z-alkenes 15, which were
used in the next reaction without further purification.
Treatment of allylic alcohols 15 with catalytic pyridinium
p-toluenesulfonate (PPTS) or HCl resulted in cyclisation
with loss of two molecules of ethanol, affording the de-
sired furan.4
oxidation
The biological activities of the natural products (+)-muri-
catacin (1) and CMI-977 (LDP-977) (2) (Figure 1) have
stimulated significant interest in their synthesis.1,2 While
(+)-muricatacin (1) displays potent cytotoxicity towards
several human tumour cell lines, CMI-977 proved to be a
promising candidate for chronic asthma.
O
O
OH
(+)-muricatacin (1)
O
O
O
N
NH2
H
H
OH
F
CMI-977 (LDP-977) (2)
With furan 16 in hand, the stage was set for the crucial ox-
idation step using singlet oxygen (Scheme 3). Furan 16
was subjected to singlet oxygen oxidation followed by so-
dium borohydride reduction under Luche’s conditions to
give an intermediate hydroxy acid, which underwent acid-
catalysed in situ lactonisation, affording butenolide 175 in
Figure 1 (+)-Muricatacin (1) and CMI-977 (LDP-977) (2)
Our retrosynthetic strategy for (+)-muricatacin (1) and the
alkyne precursor 3 of CMI-977 is depicted in Scheme 1.
The relatively inexpensive and readily available chiral re- 75% overall yield (3 steps).1a,6 Catalytic hydrogenation of
agent L-malic acid (4) was easily transformed into alcohol
O
O
H
H
F
3
OTBDPS
OH
O
HO
HO
OTBS
OH
5
O
4
O
O
OH
1
Scheme 1 Retrosynthetic analysis of (+)-muricatacin (1) and CMI-977 precursor 3
SYNTHESIS 2013, 45, 1693–1700
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338934; Art ID: SS-2013-Z0211-OP
© Georg Thieme Verlag Stuttgart · New York

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M. González et al.
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OH
O
OTBDPS
OTBDPS
OTBDPS
i
ii
iii
iv
HO
OH
HO
PivO
PivO
OTBS
OTBS
OH
O
4
5
6
7
OTBDPS
CHO
OTBDPS
OTBDPS
v
vi
vii
PivO
HO
PivO
PivO
C9H19
8
9
10
OTBDPS
OTBDPS
EtO
EtO
OTBDPS
viii
ix
x
O
C9H19
C9H19
C9H19
OEt
OEt
H
OH
11
12
14
13
OTBDPS
xi
C9H19
O
EtO
OTBDPS
OH
15
OEt
16
Scheme 2 Reagents and conditions: (i) see ref. 3b; (ii) PivCl, DMAP, pyr (99%); (iii) HF–pyr, THF, pyr, 0 °C to r.t. (95%); (iv) TEMPO,
BAIB, CH2Cl2 (91%); (v) C10H21IPPh3, n-BuLi, THF (85%); (vi) H2, Pd/C, MeOH, r.t. (99%); (vii) DIBAL-H, CH2Cl2, –78 °C (91%); (viii)
TEMPO, BAIB, CH2Cl2 (86%); (ix) 13, n-BuLi, THF, –78 to 0 °C (99%); (x) H2, Lindlar catalyst, hexane, r.t.; (xi) HCl, or PPTS (73%).
17 gave 18 in 82% yield. Treatment of 18 with TBAF af- For the synthesis of alkyne 3 the advanced intermediate
forded target compound 1 in 90% yield.
19 available from 53b was used (Scheme 4). Radical
deoxygenation8 of alcohol 19 led to tetrahydrofuran 21 in
74% overall yield. Removal of the silyl protecting group
of 21 afforded alcohol 22 (73% yield). Alcohol 22 was un-
eventfully converted into alkene 24 in 98% overall yield
by iodination followed by reaction with t-BuOK.9
The structure of 1 was unambiguously confirmed by X-
ray crystallographic analysis of crystals obtained by re-
crystallisation from hexane (Figure 2).7
Ozonolysis of alkene 24 gave an aldehyde, which under-
went an Ohira–Bestmann homologation10 to give target
alkyne 3 in 69% yield (2 steps). Alkyne 3 is an intermedi-
ate in the known synthesis of CMI-977;2 thus, a formal
synthesis of CMI-977 has been achieved.
In summary the synthesis of (+)-muricatacin (1) and the
alkyne 3 precursor of CMI-977 has been achieved using
commercially available L-malic acid. The structure of 1
was unambiguously confirmed by X-ray crystallographic
analysis.
Figure 2 X-ray structure of (+)-muricatacin (1)
O
ii
i
O
O
OTBDPS
OTBDPS
16
17
O
O
O
iii
O
OTBDPS
OH
18
(+)-muricatacin (1)
Scheme 3 Reagents and conditions: (i) (a) O2, MeOH, rose Bengal, Hünig’s base, hν; (b) NaBH4, CeCl3·7H2O, MeOH; (c) HCl, MeOH (75%,
3 steps); (ii) H2, Pd/C, MeOH, r.t. (82%); (iii) TBAF, THF, r.t. (90%).
Synthesis 2013, 45, 1693–1700
© Georg Thieme Verlag Stuttgart · New York

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(+)-Muricatacin from L-Malic Acid
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N
N
S
OH
OTBDPS
i
ii
O
O
OTBDPS
HO
O
OTBS
H
H
O
F
OTBDPS
O
5
19
H
H
F
20
O
O
iii
iv
v
OTBDPS
OH
O
O
H
H
H
H
F
F
21
22
O
O
O
vi
vii
I
O
O
O
H
H
H
H
H
H
F
F
F
3
23
24
ref. 2
O
O
O
N
NH2
H
H
OH
F
CMI-977 (LDP-977) (2)
Scheme 4 Synthesis of CMI-977 precursor 3. Reagents and conditions: (i) see ref. 3b; (ii) Im2C=S, THF, 70 °C (83%); (iii) n-Bu3SnH, AIBN,
toluene, 120 °C (89%); (iv) TBAF (73%); (v) I2, Ph3P, imidazole, THF, 0 °C (99%); (vi) t-BuOK, THF (99%); (vii) 1. O3, Ph3P, CH2Cl2, –78
°C, 2. (MeO)2P(=O)C(=N2)CO2Me, K2CO3, MeOH, 0 °C (69%, 2 steps).
Solvents were purified and dried by standard procedures. Flash
chromatography was performed on silica gel (Merck 60, 230–400
mesh). Analytical TLC was performed on plates precoated with sil-
ica gel (Merck 60 F254, 0.25 mm). Melting points were obtained
using a Gallenkamp apparatus and are uncorrected. Optical rota-
tions were obtained using a Jasco P-2000 polarimeter. IR spectra of
all liquid products were recorded as neat films between NaCl plates
on a Jasco FT/IR-6100 Type A spectrometer. 1H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Bruker ARX-
400 spectrometer using TMS as the internal standard; chemical
shifts (δ) are quoted in ppm and coupling constants (J) in Hz. Mass
spectrometry (MS and HRMS) was carried out a Hewlett-Packard
5988A spectrometer.
13C NMR (100 MHz, CDCl3): δ = 177.92 (C=O), 135.66 (CH, o-
Ph), 133.38 (C, Ph), 129.75 (CH, m-Ph), 127.75 (CH, p-Ph), 71.70
(CH-3), 65.23 (CH2-4), 59.41 (CH2-1), 38.89 (C-t-C4H9, Piv), 34.05
(CH2-2), 27.33 (CH3-t-C4H9, Piv), 26.81 (CH3-t-C4H9, TBDPS),
25.98 (CH3-t-C4H9, TBS), 19.31 (C-t-C4H9, TBDPS), 18.30 (C-t-
C4H9, TBS), –5.35 (CH3, TBS).
MS (ESI+): m/z (%) = 565.31 ([M + Na]+, 100), 543.33 ([M + 1]+,
45), 346.14 (3), 291.14 (2).
HRMS (ESI+): m/z calcd for C31H51O4Si2: 543.3320; found:
543.3328.
(S)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxybutyl Pivalate (7)
To a solution of 6 (115 mg, 0.212 mmol) in THF (2 mL) was added
pyridine (144 μL) and a solution 30% HF in pyridine (71 μL) at 0
°C and the mixture was stirred at r.t. for 6 h. The reaction was
quenched by the addition of EtOAc (3 mL) and sat. aq NaHCO3 (3
mL). After stirring for 10 min, the mixture was extracted with
EtOAc (3 × 5 mL), dried (Na2SO4), and the solvent evaporated un-
der reduced pressure. The residue was purified by chromatography
on silica gel (10% EtOAc–hexane) to afford 7; yield: 87 mg (95%);
colourless oil; Rf = 0.08 (10% EtOAc–hexane); [α]D23 –7.9 (c 1.02,
CHCl3).
(S)-2-(tert-Butyldiphenylsilyloxy)-4-(tert-butyldimethylsilyl-
oxy)butyl Pivalate (6)
To a solution of 5 (761 mg, 1.66 mmol) in pyridine (37mL) was
added a catalytic amount of DMAP and pivaloyl chloride (1.02 mL,
8.3 mmol) at 0 °C and the mixture was stirred at r.t. for 3 h. The re-
action was quenched by the addition of H2O (40 mL) and extracted
with Et2O (3 × 30 mL). The combined organic layers were washed
with 10% aq HCl (3 × 100 mL) and sat. aq NaHCO3 (3 × 100 mL),
dried (Na2SO4), and evaporated. Purification of the residue by silica
gel column chromatography (1% EtOAc–hexane) gave 6; yield:
894 mg (99%); colourless oil; Rf = 0.69 (10% EtOAc–hexane);
[α]D24 –13.9 (c 4.60, CHCl3).
IR (neat): 3760, 3452, 2958, 2932, 2857, 1729, 1589 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.62 (m, 4 H, CH, o-Ph), 7.39 (m,
6 H, CH, m,p-Ph), 4.19 (m, 1 H, H-4), 4.03 (m, 2 H, H-4, H-3), 3.70
(m, 2 H, H-1), 1.82 (m, 2 H, H-2), 1.20 (m, 9 H, t-C4H9, Piv), 1.17
(m, 9 H, t-C4H9, TBDPS).
13C NMR (100 MHz, CDCl3): δ = 178.36 (C=O), 135.52 (CH, o-
Ph), 133.71 (C, Ph), 129.64 (CH, m-Ph), 127.64 (CH, p-Ph), 68.98
(CH-3), 67.67 (CH2-4), 60.37 (CH2-1), 38.76 (C-t-C4H9, Piv), 37.03
IR (neat): 2957, 2931, 2857, 1730 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (m, 4 H, CH, o-Ph), 7.45 (m,
6 H, CH, m,p-Ph), 5.23 (m, 1 H, H-4), 4.17 (m, 1 H, H-4), 3.82 (m,
1 H, H-3), 3.71 (m, 2 H, H-1), 1.89 (m, 2 H, H-2), 1.24 (m, 9 H, t-
C4H9, Piv), 1.12 (m, 9 H, t-C4H9, TBDPS), 0.94 (m, 9 H, t-C4H9,
TBS), 0.11 (m, 6 H, CH3, TBS).
© Georg Thieme Verlag Stuttgart · New York
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(S)-2-(tert-Butyldiphenylsilyloxy)tetradecyl Pivalate (10)
Pd/C (10%, 21 mg) was added to a solution of 9 (179 mg, 0.324
mmol) in MeOH (20 mL) at r.t. The reaction mixture was stirred un-
der an atmosphere of H2 for 4 h after which time it was filtered and
concentrated in vacuo to give 10; yield: 179 mg (99%); colourless
oil; Rf = 0.63 (10% EtOAc–hexane); [α]D22 +2.3 (c 1.03, CHCl3).
(CH2-2), 27.18 (CH3-t-C4H9, Piv), 26.81 (CH3-t-C4H9, TBDPS),
19.34 (C-t-C4H9, TBDPS).
MS (ESI+): m/z (%) = 451.23 ([M + Na]+, 100), 429.25 ([M + 1]+,
32), 247.04 (11), 221.03 (5), 207.02 (7), 201.04 (40).
HRMS (ESI+): m/z calcd for C25H37O4Si: 429.2455; found:
429.2454.
IR (neat): 2956, 2927, 2855, 1731 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.73 (m, 4 H, CH, o-Ph), 7.43 (m,
6 H, CH, m,p-Ph), 4.02 (m, 3 H, H-1, H-2), 1.52 (dd, J = 5.9, 14.5
Hz, 2 H, H-3), 1.31 (m, 20 H, H-4 to H-13), 1.21 (d, J = 4.2 Hz, 9
H, t-C4H9, Piv), 1.10 (s, 9 H, t-C4H9, TBDPS), 0.93 (t, J = 6.8 Hz, 3
H, H-14).
13C NMR (100 MHz, CDCl3): δ = 178.47 (C=O), 135.91 (CH, o-
Ph), 134.11 (C, Ph), 129.68 (CH, m-Ph), 127.59 (CH, p-Ph), 71.27
(CH-2), 67.50 (CH2-1), 38.79 (C-t-C4H9, Piv), 34.17–29.41 (9
CH2), 27.21 (CH3-t-C4H9, Piv), 26.91 (CH3-t-C4H9, TBDPS), 24.65
(CH2), 22.74 (CH2), 19.31 (C-t-C4H9, TBDPS), 14.18 (CH3).
(S)-2-(tert-Butyldiphenylsilyloxy)-4-oxobutyl Pivalate (8)
To a solution of 7 (297 mg, 0.694 mmol) in CH2Cl2 (10 mL) was
added bis(acetoxy)iodobenzene (BAIB, 257 mg, 0.798 mmol) and
a catalytic amount of TEMPO. The reaction mixture was stirred at
r.t. for 5 h. Evaporation gave a residue, which was dissolved in t-
BuOMe (5 mL), and washed with 10% aq Na2S2O3 (3 × 5 mL) and
sat. aq NaHCO3 (3 × 5 mL). After drying (Na2SO4), and evaporation
of solvent under reduced pressure, the residue was purified by chro-
matography on silica gel (5% EtOAc–hexane) to give 8; yield: 270
mg (91%); orange oil; Rf = 0.42 (20% EtOAc–hexane); [α]D19 –9.8
(c 0.9, CHCl3).
MS (ESI+): m/z (%) = 575.38 ([M + Na]+, 71), 554.40 ([M + 1]+,
58), 234.21 (4), 201.04 (35).
IR (neat): 2946, 2878, 1735, 1716 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.72 (s, 1 H, H-1), 7.71 (m, 4 H,
CH, o-Ph), 7.44 (m, 6 H, CH, m,p-Ph), 4.43 (m, 1 H, H-3), 4.09 (m,
4 H, H-4, H-2), 1.20 (s, 9 H, t-C4H9, Piv), 1.08 (s, 9 H, t-C4H9,
TBDPS).
13C NMR (100 MHz, CDCl3): δ = 200.56 (C=O), 178.15 (C=O,
Piv), 135.85 (CH, o-Ph), 132.92 (C, Ph), 130.13 (CH, m-Ph), 127.79
(CH, p-Ph), 67.23 (CH2-2), 67.02 (CH-3), 48.18 (CH2-4), 38.83 (C-
t-C4H9, Piv), 27.17 (CH3-t-C4H9, Piv), 26.83 (CH3-t-C4H9, TBDPS),
19.22 (C-t-C4H9, TBDPS).
HRMS (ESI+): m/z calcd for C35H57O3Si: 553.4971; found:
553.4086.
(S)-2-(tert-Butyldiphenylsilyloxy)-1-tetradecanol (11)
To a solution of 10 (272 mg, 0.492 mmol) in CH2Cl2 (10 mL) was
added DIBAL-H (1 M in hexane, 1.8 mL) at –78 °C and the mixture
was stirred for 20 min. The reaction was quenched by the addition
of EtOAc (10 mL), and the mixture was washed with aq Rochelle
salt (3 × 10 mL), followed by brine (3 × 10 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue was pu-
rified by silica gel column chromatography (1% EtOAc–hexane) to
give 11; yield: 210 mg (91%); colourless oil; Rf = 0.43 (10%
EtOAc–hexane); [α]D21 +0.34 (c 1.3, CHCl3).
MS (ESI+): m/z (%) = 449.21 ([M + Na]+, 38), 427.23 ([M + 1]+,
57), 365.17 (8), 279.22 (5), 221.09 (6).
HRMS (ESI+): m/z calcd for C25H35O4Si: 427.2299; found:
427.2305.
IR (neat): 3582, 2954, 2926, 2855 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 4 H, CH, o-Ph), 7.44 (m,
6 H, CH, m,p-Ph), 3.70 (m, 2 H, H-1), 3.52 (m, 1 H, H-2), 2.53 (s,
1 H, OH), 1.35 (s, 22 H, H-3 to H-13), 1.11 (s, 9 H, t-C4H9, TBDPS),
0.91 (t, J = 6.4 Hz, 3 H, H-14).
13C NMR (100 MHz, CDCl3): δ = 135.58 (CH, o-Ph), 133.28 (C,
Ph), 129.81 (CH, m-Ph), 127.79 (CH, p-Ph), 72.01 (CH-2), 68.09
(CH2-1), 32.82–29.38 (7 CH2), 26.89 (CH3-t-C4H9, TBDPS), 25.54
(CH2), 22.71 (CH2), 19.27 (C-t-C4H9, TBDPS), 14.14 (CH3).
MS (ESI+): m/z (%) = 491.33 ([M + Na]+, 100), 391.30 (8), 226.95
(4).
HRMS (ESI+): m/z calcd for C30H48O2Si + Na: 491.3315; found:
491.3334.
(S)-2-(tert-Butyldiphenylsilyloxy)tetradec-4-enyl Pivalate (9)
To a solution of dried phosphonium salt (prepared from decyltriphe-
nylphosphonium iodide) (382 mg, 0.720 mmol) in THF (5.5 mL)
cooled to 0 °C was added dropwise n-BuLi (2.5 M in hexane, 202
μL, 0.504 mmol) and the solution was stirred for 1 h. To the orange
solution was added dropwise compound 8 (240 mg, 0.563 mmol)
dissolved in THF (3.6 mL). The mixture was stirred under the same
conditions for 15 min, and then sat. aq NaHCO3 (5 mL) was added,
and the mixture was extracted with EtOAc (3 × 5 mL). The com-
bined organic phases were washed with brine (3 × 5 mL), dried
(Na2SO4), and the solvent was evaporated under reduced pressure.
The residue was purified by chromatography on silica gel (0.5%
EtOAc–hexane) to afford 9; yield: 168 mg (85%); yellow oil; Rf =
0.73 (10% EtOAc–hexane); [α]D21 +11.6 (c 1.0, CHCl3).
IR (neat): 2957, 2927, 2856, 1731 cm–1.
(S)-2-(tert-Butyldiphenylsilyloxy)tetradecanal (12)
To a solution of 11 (106 mg, 0.227 mmol) in CH2Cl2 (4 mL) was
added BAIB (84 mg, 0.261 mmol) and a catalytic amount of TEMPO.
The reaction mixture was stirred at r.t. for 6 h. Evaporation gave a
residue, which was dissolved in t-BuOMe (5 mL), and washed with
a 10% aq Na2S2O3 (3 × 5 mL) and sat. aq NaHCO3 (3 × 5 mL). After
drying (Na2SO4) and solvent evaporation under reduced pressure,
the residue was purified by chromatography on silica gel (1%
EtOAc–hexane) to afford 12; yield: 91 mg (86%); orange oil; Rf =
0.83 (10% EtOAc–hexane); [α]D22 –3.8 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.72 (m, 4 H, CH, o-Ph), 7.43 (m,
6 H, CH, m,p-Ph), 5.36 (m, 2 H, H-5, H-4), 4.00 (m, 3 H, H-1, H-
2), 2.26 (m, 2 H, H-3), 1.91 (m, 2 H, H-6), 1.30 (m, 14 H, H-7 to H-
13), 1.20 (d, J = 2.8 Hz, 9 H, t-C4H9, Piv), 1.08 (s, 9 H, t-C4H9,
TBDPS), 0.91 (t, J = 6.8 Hz, 3 H, H-14).
13C NMR (100 MHz, CDCl3): δ = 178.43 (C=O), 135.85 (CH, o-
Ph), 133.89 (C, Ph), 132.80 (CH-5), 129.65 (CH, m-Ph), 127.61
(CH, p-Ph), 124.04 (CH-4), 71.21 (CH-2), 66.93 (CH2-1), 38.79 (C-
t-C4H9, Piv), 32.08 (CH2-3), 31.93–27.30 (7 CH2), 27.30 (CH3-t-
C4H9, Piv), 26.91 (CH3-t-C4H9, TBDPS), 19.31 (C-t-C4H9,
TBDPS), 14.16 (CH3).
IR (neat): 2954, 2926, 2855, 1736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.63 (s, 1 H, H-1), 7.66 (m, 4 H,
CH, o-Ph), 7.44 (m, 6 H, CH, m,p-Ph), 4.08 (t, J = 5.8 Hz, 1 H, H-
2), 1.65 (m, 2 H, H-3), 1.31 (s, 20 H, H-4 to H-13), 1.17 (s, 9 H, t-
C4H9, TBDPS), 0.93 (t, J = 6.8 Hz, 3 H, H-14).
MS (ESI+): m/z (%) = 573.37 ([M + Na]+, 59), 551.39 ([M + 1]+,
100), 481.19 (2), 473.34 (9), 403.25 (30).
13C NMR (100 MHz, CDCl3): δ = 204.04 (CH-1), 135.86 (CH, o-
Ph), 133.26 (C, Ph), 130.04 (CH, m-Ph), 127.83 (CH, p-Ph), 78.10
(CH-2), 32.92–29.42 (5 CH2), 27.00 (CH3-t-C4H9, TBDPS), 24.09
(CH2), 22.75 (CH2), 19.41 (C-t-C4H9, TBDPS), 14.19 (CH3).
HRMS (ESI+): m/z calcd for C35H55O3Si: 551.3915; found:
551.3926.
Synthesis 2013, 45, 1693–1700
© Georg Thieme Verlag Stuttgart · New York

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(+)-Muricatacin from L-Malic Acid
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MS (ESI+): m/z (%) = 489.31 ([M + Na]+, 31), 467.33 ([M + 1]+,
86), 403.25 (60), 389.28 (35).
cooled to –78 °C. At this temperature, DIPEA (89 μL, 0.513 mmol)
was added dropwise and the solution was stirred for 1 h under an at-
mosphere of O2 and irradiated with a 200 W lamp. Evaporation gave
a residue, which was dissolved in CH2Cl2 (5 mL) and a solution of
oxalic acid (77 mg in 6.6 mL H2O) was added. The mixture was
stirred for 2 h and extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried (Na2SO4) and the solvent evaporated un-
der reduced pressure to afford 4-hydroxybutenolide 16a (107 mg).
To a solution of 4-hydroxybutenolide 16a in anhyd MeOH (5 mL)
were added CeCl3·7H2O (2 mg, 0.006 mmol) and NaBH4 (18 mg,
0.488 mmol) at 0 °C. After stirring for 1 h, the reaction mixture was
acidified by adding concd HCl (pH 2) and stirred 17 h at r.t. The sol-
vent was evaporated under reduced pressure and the residue was pu-
rified by chromatography on silica gel (3% EtOAc–hexane) to give
17; yield: 48 mg (75%); orange oil; Rf = 0.71 (30% EtOAc–hexane);
[α]D20 –32.2 (c 1.0, CHCl3).
HRMS (ESI+): m/z calcd for C25H48O6 + Na: 467.3343; found:
467.3339.
(S)-5-(tert-Butyldiphenylsilyloxy)-1,1-diethoxyheptadec-2-yn-
4-ol (14)
To a solution of 3,3-diethoxyprop-1-yne (13; 29 μL, 0.204 mmol)
in THF (4.2 mL) cooled to –78 °C was added dropwise n-BuLi (2.5
M in hexane, 82 μL, 0.204 mmol) and the solution was stirred for 1
h at 0 °C. To the yellow solution cooled to –78 °C was added drop-
wise compound 12 (87 mg, 0.186 mmol) dissolved in THF (2.8
mL). The mixture was stirred at r.t. for 90 min. Evaporation gave a
residue, to which was added H2O (5 mL) and extracted with CH2Cl2
(3 × 5 mL).The combined organic phases were dried (Na2SO4) and
the solvent was evaporated under reduced pressure. The residue was
purified by chromatography on silica gel (5% EtOAc–hexane) af-
fording 14 as a mixture of two diastereoisomeric alcohols; yield:
110 mg (99%); yellow oil; Rf = 0.25 (10% EtOAc–hexane).
IR (neat): 3727, 3071, 2926, 2855, 2360, 2342, 1760 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J = 1.7, 7.7 Hz, 1 H, H-
4), 7.69 (m, 3 H, CH, Ph), 7.41 (m, 7 H, CH, Ph), 6.13 (dd, J = 2.0,
5.8 Hz, 1 H, H-3), 4.98 (td, J = 1.8, 3.7 Hz, 1 H, H-5), 4.01 (dd, J =
6.0, 10.1 Hz, 1 H, H-1′), 1.54 (m, 2 H, H-2′), 1.29 (s, 20 H, H-3′ to
H-12′), 1.08 (s, 9 H, t-C4H9, TBDPS), 0.92 (t, J = 6.8 Hz, 3 H, H-
13′).
13C NMR (100 MHz, CDCl3): δ = 172.98 (C=O), 154.31 (CH-
4),135.96 (CH, o-Ph), 133.42 (C, Ph), 130.08 (CH, m-Ph), 127.73
(CH, p-Ph), 122.71 (CH-3), 84.72 (CH-5), 72.62 (CH-1′), 32.81–
29.43 (CH2), 27.03 (CH3-t-C4H9, TBDPS), 26.62–19.72 (CH2),
19.48 (C-t-C4H9, TBDPS), 14.17 (CH3).
IR (neat): 3566, 2925, 2854 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (m, 8 H, CH, o-Ph), 7.45 (m,
12 H, CH, m,p-Ph), 5.34 (s, 2 H, H-1), 4.39 (m, 2 H, H-4), 3.79 (m,
4 H, H-1′), 2.54 (d, J = 7.7 Hz, 1 H, H-5), 2.44 (d, J = 7.8 Hz, 1 H,
H-5), 1.58 (m, 4 H, H-6), 1.25 (m, 26 H, H-2′, H-7 to H-16), 1.11 (s,
9 H, t-C4H9, TBDPS), 0.92 (t, J = 6.8 Hz, 3 H, H-17).
13C NMR (100 MHz, CDCl3): δ = 135.83 (CH, o-Ph), 133.69 (C,
Ph), 129.02 (CH, m-Ph), 127.83 (CH, p-Ph), 91.36 (CH-1), 83.45
(C-2), 81.61 (C-3), 76.06 (CH-5), 66.08 (CH-4), 64.85 (CH-4),
60.96 (CH2-1′), 60.83 (CH2-1′), 33.04, 29.67, 29.62, 29.51, 29.42,
29.35, 25.24, 22.73 (CH2-6 to -16), 27.06 (CH3-t-C4H9, TBDPS),
19.49 (C-t-C4H9, TBDPS), 15.11 (CH3), 14.16 (CH3).
MS (ESI+): m/z (%) = 543.32 ([M + Na]+, 100), 538.37 (55), 521.34
([M + 1]+, 6), 403.25 (32), 394.34 (29), 379.21 (10), 245.08 (11),
146.06 (18).
MS (ESI+): m/z (%) = 574.37 (36), 573.37 (100), 263.14 (64).
HRMS (ESI+): m/z calcd for C41H49O2: 573.3727; found: 573.3729.
HRMS (ESI+): m/z calcd for C39H43O2: 543.3257; found: 543.3251.
(S)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)tridecyl]dihydrofuran-
2(3H)-one (18)
(S)-tert-Butyl[1-(furan-2-yl)tridecyloxy]diphenylsilane (16)
Commercially available Lindlar catalyst (14 mg) was added to a so-
lution of 14 (69 mg, 0.115 mmol) in MeOH (3 mL) at r.t. The result-
ing suspension was stirred for 18 h under an atmosphere of H2. The
catalyst was filtered off through a pad of Celite, the solvent was
evaporated, and the residue was dissolved in CH2Cl2 (5 mL) and
washed with a solution 3 M aq HCl (3 × 5 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue was pu-
rified by flash chromatography (100% hexane) to afford 16; yield:
Pd/C (10%, 6 mg) was added to a solution of 17 (48 mg, 0.09 mmol)
in MeOH (6 mL) at r.t. The reaction mixture was stirred under an
atmosphere of H2 for 48 h after which time it was filtered and con-
centrated in vacuo to give 18; yield: 40 mg (82%); colourless oil;
Rf = 0.66 (30% EtOAc–hexane); [α]D20 +8.5 (c 1.0, CHCl3).
IR (neat): 2923, 2852, 1742, 1456 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (m, 4 H, CH, o-Ph), 7.43 (m,
6 H, CH, m,p-Ph), 4.54 (m, 1 H, H-5), 3.63 (m, 2 H, H-1′, H-3), 2.52
(m, 3 H, H-3, H-4), 2.17 (m, 2 H, H-2′), 1.16 (m, 29 H, H-3′ to H-
12′, t-C4H9, TBDPS), 0.91 (t, J = 6.6 Hz, 3 H, H-13′).
13C NMR (100 MHz, CDCl3): δ = 177.40 (C=O), 135.90 (CH, o-
Ph), 133.90 (C, Ph), 129.72 (CH, m-Ph), 127.71 (CH, p-Ph), 81.07
(CH-5), 74.90 (CH-1′), 32.59–28.58 (6 CH2), 27.04 (CH3-t-C4H9,
TBDPS), 26.58–22.71 (4 CH2), 19.53 (C-t-C4H9, TBDPS), 14.14
(CH3).
22
42 mg (73%); colourless oil; Rf = 0.86 (10% EtOAc–hexane); [α]D
–58.3 (c 0.9, CHCl3).
IR (neat): 3071, 2925, 2854, 2360 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 6.7 Hz, H-5, 2 H, CH,
o-Ph), 7.54 (d, J = 7.2 Hz, 2 H, CH, Ph), 7.45 (m, 5 H, CH, Ph), 7.31
(m, 2 H, CH, Ph), 6.23 (d, J = 1.9 Hz, 1 H, H-4), 5.97 (d, J = 3.0 Hz,
1 H, H-3), 4.68 (t, J = 6.5 Hz, 1 H, H-1′), 1.85 (dt, J = 6.4, 12.9 Hz,
2 H, H-2′), 1.26 (m, 20 H, H-3′ to H-12′), 1.08 (s, 9 H, t-C4H9, TB-
DPS), 0.94 (t, J = 6.7 Hz, 3 H, H-13′).
13C NMR (100 MHz, CDCl3): δ = 156.67 (C-2), 141.12 (CH-5),
135.79 (CH, o-Ph), 133.85 (C, Ph), 129.34 (CH, m-Ph), 127.31
(CH, p-Ph), 109.82 (CH-4), 106.40 (CH-3), 69.12 (CH-1′), 36.51–
29.36 (9 CH2), 26.97 (CH3-t-C4H9, TBDPS), 25.05 (CH2), 22.76
(CH2), 19.42 (C-t-C4H9, TBDPS), 14.19 (CH3).
MS (ESI+): m/z (%) = 545 ([M + Na]+, 100), 521 ([M – 1]+, 9), 510
(64), 279 (63), 445 (60).
HRMS (ESI+): m/z calcd for C33H50O3Si + Na: 545.3421; found:
545.3438.
(S)-5-[(S)-1-Hydroxytridecyl]dihydrofuran-2(3H)-one [1,
(+)-Muricatacin]
MS (ESI+): m/z (%) = 527.33 ([M + Na]+, 100), 503.23 ([M – 1]+,
5), 413.26 (25), 394.34 (64), 226.94 (28).
To a solution of 18 (40 mg, 0.077 mmol) in THF (2 mL) was added
TBAF (1 M in THF, 77 μL). The reaction mixture was stirred at r.t.
for 24 h. Evaporation gave a residue, which was purified by chro-
matography on silica gel (30% EtOAc–hexane) to afford (+)-muri-
catacin (1); yield: 20 mg (90%); white solid; mp 68–69 °C; Rf = 0.19
(30% EtOAc–hexane); [α]D23 +26.7 (c 1.8, CHCl3).
HRMS (ESI+): m/z calcd for C33H48O2Si + Na: 527.3315; found:
527.3313.
(S)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)tridecyl]furan-2(5H)-
one (17)
To a solution of 16 (62 mg, 0.122 mmol) in anhyd MeOH (5 mL)
was added Rose Bengal (3 mg) and the resulting pink solution was
IR (NaCl, neat): 3445, 2916, 2845, 1746, 1463 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1693–1700

1698
M. González et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 4.45 (m, 1 H, H-5), 3.60 (m, 1 H,
H-1′), 2.68 (m, 2 H, H-3), 2.20 (m, 2 H, H-4), 1.55 (m, 2 H, H-2′),
1.30 (s, 20 H, H-3′ to H-12′), 0.90 (t, J = 6.6 Hz, 3 H, H-13′).
13C NMR (100 MHz, CDCl3): δ = 177.1 (C=O), 82.9 (CH-5), 73.7
(CH-1′), 33.0–21.1 (13 CH2), 14.1 (CH3).
MS (ESI+): m/z (%) = 307 ([M + Na]+, 100), 285 ([M + 1]+, 20), 308
(18), 201 (16).
MS (ESI+): m/z (%) = 480.23 (3), 479.23 ([M – 1]+, 31), 478.23
([M]+, 100).
HRMS (ESI+): m/z calcd for C29H35FO3Si: 478.2339; found:
478.2333.
(2S,5S)-5-[(4-Fluorophenoxy)methyl]-2-[1′-hydroxyethyl]tetra-
hydrofuran (22)
To compound 21 (240 mg, 0.501 mmol) was added a 1 M solution
of TBAF in THF (501 μL, 0.501 mmol) and the mixture was stirred
for 20 h. The mixture was quenched with sat. aq NH4Cl (5 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic layers
were dried (Na2SO4), filtered, and the solvent was removed by rota-
ry evaporation to give a residue, which was chromatographed on sil-
ica gel using 30% EtOAc–hexane as eluent to afford 22; yield: 88
HRMS (ESI+): m/z calcd for C17H33O3: 285.2424; found: 285.2426.
O-(2R,3S,5S)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl)]-5-[(4-
fluorophenoxy)methyl]tetrahydrofuran-3-yl-1H-imidazole-1-
carbothioate (20)
To a solution of alcohol 19 (108 mg, 0.218 mmol) in THF (6 mL)
was added 1,1′-thiocarbonyldiimidazole (78 mg, 0.436 mmol) and
the mixture was heated to 70 °C for 1 day. EtOAc (5 mL) was added
and the organic layer was washed with brine (3 × 10 mL), dried
(Na2SO4), and the solvent was removed by rotary evaporation. The
residue was chromatographed on silica gel using 15% EtOAc–
hexane to afford 20; yield: 109 mg (83%); yellow oil; Rf = 0.45
(30% EtOAc–hexane); [α]D24 –16.97 (c 0.6, CHCl3).
23
mg (73%); colourless oil; Rf = 0.10 (30% EtOAc–hexane); [α]D
–4.24 (c 0.63, CHCl3).
IR (neat): 3662, 3197, 2955, 1691, 1505 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.95 (m, 2 H, H-3′′), 6.84 (m, 2 H,
H-2′′), 4.37 (tt, J = 5.2, 6.6 Hz, 1 H, H-5), 4.20 (tt, J = 5.3, 8.0, 1 H,
H-2), 3.90 (m, 2 H, CH2OPh), 3.76 (t, J = 5.8 Hz, 2 H, H-1′), 3.00
(br s, 1 H, OH), 2.11 (m, 2 H, H-3, H-4), 1.78 (m, 3 H, H-3, H-4, H-
2′), 1.62 (m, 1 H, H-2′).
13C NMR (100 MHz, CDCl3): δ = 158.48, 156.11 (d, J = 238.3 Hz,
C-4′′), 154.97 (C-1′′), 115.85, 115.64 (d, J = 20.8 Hz, CH-3′′),
115.62, 115.56 (d, J = 5.6 Hz, CH-2′′), 79.10 (CH-5), 77.45 (CH-2),
71.13 (CH2OPh), 61.10 (CH2-1′), 37.51 (CH2-2′), 32.04 (CH2-3),
28.23 (CH2-4).
IR (neat): 3060, 2938, 2862, 1742, 1598, 1505 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 Himidazolyl, H-2), 7.70 (dd,
J = 1.1, 6.7 Hz, 4 H, CH, o-Ph), 7.62 (s, 1 Himidazolyl, H-5), 7.43 (m,
6 H, CH, p,m-Ph), 7.07 (s, 1 Himidazolyl, H-4), 6.99 (t, J = 8.5 Hz, 2
H, H-2′′), 6.86 (m, 2 H, H-3′′), 5.80 (d, J = 6.5 Hz, 1 H, H-5), 4.65
(t, J = 6.6 Hz, 1 H, H-2), 4.50 (qd, J = 5.2, 10.3 Hz, 1 H, H-3), 4.07
(dd, J = 5.6, 9.7 Hz, 1 H, CH2OPh), 3.97 (dd, J = 5.0, 9.7 Hz, 1 H,
CH2OPh), 3.88 (m, 2 H, H-2′), 2.73 (m, 1 H, H-4), 2.27 (m, 1 H, H-
4), 1.87 (m, 2 H, H-1′), 1.09 (s, 9 H, t-C4H9, TBDPS).
MS (ESI+): m/z (%) = 529.56 (6), 481.24 (15), 263.10 ([M + Na]+,
1), 242.28 (100), 241.12 ([M + 1]+, 4).
13C NMR (100 MHz, CDCl3): δ = 183.16 (C=S), 158.69, 156.32 (d,
J = 238.6 Hz, C-4′′), 154.70 (C-1′′), 136.89 (CH-2, imidazolyl),
135.61, 135.59 (CH, o-Ph), 133.55, 133.48 (C, Ph), 131.03 (CH-4,
imidazolyl), 129.74 (CH, m-Ph), 127.73 (CH, p-Ph), 117.84 (CH-5,
imidazolyl), 116.06, 115.83 (d, J = 23.1 Hz, CH-3′′), 115.70, 115.62
(d, J = 8.0 Hz, CH-2′′), 87.29 (CH-3), 80.94 (CH-2), 75.67 (CH-5),
70.73 (CH2OPh), 60.20 (CH2-2′), 35.08, 33.71 (CH2-4 and -1′),
26.89 (CH3-t-C4H9, TBDPS), 19.20 (C-t-C4H9, TBDPS).
HRMS (ESI+): m/z calcd for C13H17FO3 + Na: 263.1053; found:
263.1051.
(2S,5S)-2-[(4-Fluorophenoxy)methyl]-5-[2′-(iodoethyl)]tetrahy-
drofuran (23)
To a solution of alcohol 22 (81 mg, 0.338 mmol) in THF (4 mL) was
added Ph3P (106 mg, 0.405 mmol) and imidazole (69 mg, 1.01
mmol). The mixture was cooled to 0 °C and I2 (94 mg, 0.372 mmol)
was added. After 4 h, the mixture was quenched with sat. aq
NaHCO3 (5 mL) and extracted with EtOAc (3 × 8 mL). The com-
bined organic layers were washed with 10% aq Na2S2O3 (3 × 8 mL),
dried (Na2SO4), filtered, and the solvent was removed by rotary
evaporation to give a residue, which was chromatographed on silica
gel using 7% EtOAc–hexane to afford 23; yield: 118 mg (99%); yel-
MS (ESI+): m/z (%) = 689.26 (32), 623.22 (43), 607.25 (42), 605.21
([M + 1]+, 13), 564.28 (33), 563.27 (100).
HRMS (ESI+): m/z calcd for C33H38FN2O4SSi: 605.2260; found:
605.2177.
23
(2S,5S)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluoro-
phenoxy)methyl]tetrahydrofuran (21)
low oil; Rf = 0.68 (30% EtOAc–hexane); [α]D +6.03 (c 0.26,
CHCl3).
To a degassed solution of 20 (271 mg, 0.448 mmol) in toluene (12
mL) was added, n-Bu3SnH (144 μL, 0.537 mmol) and AIBN (17
μL, 0.035 mmol). The mixture was heated to 120 °C for 3 h. The so-
lution was allowed to reach r.t. and the solvent evaporated. The re-
sulting residue was chromatographed on silica gel using 3%
EtOAc–hexane to afford 21; yield: 191 mg (89%); colourless oil;
Rf = 0.86 (30% EtOAc–hexane); [α]D24 –15.58 (c 0.33, CHCl3).
IR (neat): 2923, 2860, 1698, 1505 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.98 (m, 2 H, H-3′′), 6.88 (m, 2 H,
H-2′′), 4.37 (m, 1 H, H-5), 4.12 (tt, J = 5.7, 7.8 Hz, 1 H, H-2), 3.93
(qd, J = 5.1, 9.7 Hz, 2 H, CH2OPh), 3.27 (m, 2 H, H-2′), 2.09 (m, 4
H, H-3, H-4), 1.84 (m, 1 H, H-1′), 1.59 (m, 1 H, H-1′).
13C NMR (100 MHz, CDCl3): δ = 158.50, 156.13 (d, J = 238.4 Hz,
C-4′′), 155.02 (C-1′′), 115.87, 115.69 (d, J = 18.5 Hz, CH-3′′),
115.64, 115.61 (d, J = 3.4 Hz, CH-2′′), 79.40 (CH-5), 76.90 (CH-2),
71.24 (CH2OPh), 39.73 (CH2-1′), 31.24 (CH2-3), 28.47 (CH2-4),
2.39 (CH2-2′).
IR (neat): 3060, 2935, 2865, 1505 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 4 H, CH, o-Ph), 7.41 (m,
6 H, CH, p,m-Ph), 6.95 (m, 2 H, H-3′′), 6.87 (m, 2 H, H-2′′), 4.35
(m, 1 H, H-5), 4.23 (dt, J = 6.3, 12.5 Hz, 1 H, CH2OPh), 3.92 (m, 2
H, H-2′), 3.81 (m, 2 H, H-2 and CH2OPh), 2.12 (m, 2 H, H-4, H-3),
1.95 (qd, J = 6.1, 12.6 Hz, 1 H, H-3), 1.79 (m, 2 H, H-1′, H-4), 1.63
(m, 1 H, H-1′), 1.07 (s, 9 H, t-C4H9, TBDPS).
13C NMR (100 MHz, CDCl3): δ = 158.46, 156.10 (d, J = 237.9 Hz,
C-4′′), 155.10 (C-1′′), 135.60 (CH, o-Ph), 133.94, 133.85 (C, Ph),
129.59 (CH, m-Ph), 127.74, 127.64 (CH, p-Ph), 115.83, 115.63 (d,
J = 10.6 Hz, CH-3′′), 115.60, 115.55 (d, J = 5.01 Hz, CH-2′′), 77.00
(CH-5), 76.50 (CH-2), 71.39 (CH2OPh), 61.32 (CH2-2′), 38.50
(CH2-1), 31.93 (CH2-3), 28.65 (CH2-4), 26.58 (CH3-t-C4H9,
TBDPS), 19.22 (C-t-C4H9, TBDPS).
MS (ESI+): m/z (%) = 351.02 ([M + 1]+, 100), 279.09 (33), 236.01
(6), 206.18 (22).
HRMS (ESI+): m/z calcd for C13H17FIO2: 351.0251; found:
351.0267.
(2S,5S)-2-[(4-Fluorophenoxy)methyl]-5-vinyltetrahydrofuran
(24)
To a solution of iodide 23 (64 mg, 0.181 mmol) in THF (3 mL)
cooled to 0 °C was added t-BuOK (81 mg, 0.724 mmol). The mix-
ture was stirred at r.t. for 2 days. Then, sat. aq NH4Cl (5 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 5 mL). The
Synthesis 2013, 45, 1693–1700
© Georg Thieme Verlag Stuttgart · New York

PAPER
(+)-Muricatacin from L-Malic Acid
1699
combined organic layers were dried (Na2SO4) and filtered. The sol-
vent was removed by rotary evaporation to give a residue, which
was chromatographed on silica gel using 3% EtOAc–hexane to af-
ford 24; yield: 40 mg (99%); yellow oil; Rf = 0.38 (10% EtOAc–
hexane); [α]D25 +4.05 (c 1.0, CHCl3).
MS (ESI+): m/z (%) = 243.08 ([M + Na]+, 100), 239.12 (57), 221.09
([M + 1]+, 95), 220.11 ([M]+, 13), 201.07 ([M – F]+, 1), 151.05 (35).
HRMS (ESI+): m/z calcd for C13H14FO2: 221.0972; found:
221.0977.
IR (neat): 3073, 2936, 2879, 1609, 1506 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 6.97 (m, 2 H, H-3′′), 6.87 (m, 2 H,
H-2′′), 5.88 (ddd, J = 6.3, 10.3, 17.0 Hz, 1 H, H-1′), 5.28 (dd, J =
1.2, 17.1, 1 H, H-2′), 5.13 (dd, J = 1.0, 10.3 Hz, 1 H, H-2′), 4.51 (m,
1 H, H-2), 4.43 (m, 1 H, H-5), 3.95 (dq, J = 5.1, 9.6 Hz, 2 H,
CH2OPh), 2.17 (m, 2 H, H-3, H-4), 1.87 (m, 1 H, H-3), 1.76 (m, 1
H, H-4).
13C NMR (100 MHz, CDCl3): δ = 158.48, 156.11 (d, J = 240.3 Hz,
C-4′′), 155.06 (C-1′′), 138.79 (CH-1′), 115.84, 115.61 (d, J = 18.5
Hz, CH-3′′), 115.53 (CH-2′′), 115.50 (CH2-2′), 80.52 (CH-2), 77.12
(CH-5), 71.22 (CH2OPh), 32.21 (CH2-3), 28.48 (CH2-4).
This work was supported financially by the Xunta de Galicia (Nº
EXPTE. CN 2012/184). The NMR, X-ray, and MS services of the
University of Vigo (CACTI) are also gratefully acknowledged. Zoila
Gándara thanks the Xunta de Galicia for an Angeles Alvariño
contract and María González, the University of Vigo for a Ph.D.
fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
MS (ESI+): m/z (%) = 245.09 ([M + Na]+, 6), 222.09 ([M]+, 31),
221.10 ([M – 1]+, 100), 151.05 (95).
References
HRMS (ESI+): m/z calcd for C13H16FO2: 223.1128; found:
223.1132.
(1) For recent synthesis of muricatacin, see: (a) González, M.;
Gándara, Z.; Covelo, B.; Gómez, G.; Fall, Y. Tetrahedron
Lett. 2011, 52, 5983. (b) Kumarasway, G.; Ramakrishna, D.;
Santhakumar, K. Tetrahedron: Asymmetry 2010, 21, 544.
(c) Ghosal, P.; Kumar, V.; Shaw, A. K. Carbohydr. Res.
2010, 345, 41. (d) Barros, M. T.; Charmier, M. A. J.;
Maycock, C. D.; Michaud, T. Tetrahedron 2009, 65, 396.
(e) Prasad, K. R.; Gandi, V. Tetrahedron: Asymmetry 2008,
19, 2616. (f) Ferrié, L.; Reymond, S.; Capdevielle, P.;
Cossy, J. Synlett 2007, 2891. (g) Prasad, K. R.; Anbarasan,
P. Tetrahedron: Asymmetry 2006, 17, 2465. (h) Ahmed, Md.
M.; Cui, H.; O’Doherty, G. A. J. Org. Chem. 2006, 71, 6686.
(i) Popsavin, V.; Krstić, I.; Popsavin, M.; Srećo, B.;
Benedeković, G.; Kojić, V.; Bogdanović, G. Tetrahedron
2006, 62, 11044. (j) Quinn, K. J.; Isaacs, A. K.; Arvary, R.
A. Org. Lett. 2004, 6, 4143. For a study of the structure-
activity relationships of muricatacin and analogues, see:
(k) Cavé, A.; Chaboche, C.; Figadère, B.; Harmange, J. C.;
Laurens, A.; Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-
Lafitte, J.; Quéro, A. M. Eur. J. Med. Chem. 1997, 32, 617.
For a recent review on the synthesis of muricatacin and
related compounds, see: (l) Csákÿ, A. G.; Moreno, A.;
Navarro, C.; Murcia, M. C. Curr. Org. Chem. 2010, 14, 15.
(2) For recent syntheses of CMI-977, see: (a) Sharma, G. V. M.;
Punna, S.; Rajendra Prasad, T.; Krishna, P. R.; Chorgade, M.
S.; Ley, S. V. Tetrahedron: Asymmetry 2005, 16, 1113.
(b) Sharma, G. V. M.; Punna, S.; Krishna, P. R.; Chorghade,
M. S.; Ley, S. V. Tetrahedron: Asymmetry 2005, 16, 1125.
(c) Gurjar, M. K.; Murugaiah, A. M. S.; Radhakrishna, P.;
Ramana, C. V.; Chorghade, M. S. Tetrahedron: Asymmetry
2003, 14, 1363.
(3) (a) Canoa, P.; Gándara, Z.; Pérez, M.; Gago, R.; Gómez, G.;
Fall, Y. Synthesis 2011, 431. (b) Álvarez, C.; Pérez, M.;
Zúñiga, A.; Gómez, G.; Fall, Y. Synthesis 2010, 3883.
(c) Canoa, P.; Pérez, M.; Covelo, B.; Gómez, G.; Fall, Y.
Tetrahedron Lett. 2007, 48, 3441. (d) García, I.; Gómez, G.;
Teijeira, M.; Terán, C.; Fall, Y. Tetrahedron Lett. 2006, 47,
1333. (e) Teijeira, M.; Suárez, P. L.; Gómez, G.; Terán, C.;
Fall, Y. Tetrahedron Lett. 2005, 46, 5889. (f) Alonso, D.;
Pérez, M.; Gómez, G.; Covelo, B.; Fall, Y. Tetrahedron
2005, 61, 2021. (g) Pérez, M.; Canoa, P.; Gómez, G.; Terán,
C.; Fall, Y. Tetrahedron Lett. 2004, 45, 5207. (h) Fall, Y.;
Vidal, B.; Alonso, D.; Gómez, G. Tetrahedron Lett. 2003,
44, 4467.
(2S,5S)-2-Ethynyl-5-[(4-fluorophenoxy)methyl]tetrahydrofu-
ran (3)
To a solution of 24 (65 mg, 0.292 mmol) in CH2Cl2 (20 mL) was
bubbled ozone gas at –78 °C. After 5 min of stirring at that temper-
ature, Ph3P (101 mg, 0.386 mmol) was added and the mixture was
stirred overnight at –10 °C. The reaction was quenched with sat. aq
NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were washed with brine (3 × 5 mL), dried
(Na2SO4), filtered, and the solvent was removed in vacuo. The res-
idue was purified by column chromatography on silica gel using
50% EtOAc–hexane to give the expected aldehyde; colourless oil;
Rf = 0.15 (30% EtOAc–hexane).
Intermediate Aldehyde
1H NMR (400 MHz, CDCl3): δ = 9.69 (d, J = 1.6 Hz, 1 H, H-1′),
6.95 (m, 2 H, H-3′′), 6.85 (m, 2 H, H-2′′), 4.45 (m, 2 H, H-5, H-2),
3.98 (m, 2 H, CH2OPh), 2.26 (m, 1 H, H-3), 2.07 (m, 2 H, H-3, H-
4), 1.91 (m, 1 H, H-4).
13C NMR (100 MHz, CDCl3): δ = 202.31 (C=O), 158.58, 156.21 (d,
J = 235.9 Hz, C-4′′), 154.80 (C-1′′), 115.93, 115.70 (d, J = 23.21 Hz,
CH-3′′), 115.64, 115.56 (d, J = 7.87 Hz, CH-2′′), 83.38 (CH-2),
78.88 (CH-5), 70.66 (CH2OPh), 27.69, 27.14 (CH2-3, -4).
To a solution of the above obtained aldehyde in MeOH (6 mL)
cooled to 0 °C was added ethyl 2-diazo-2-(dimethoxyphospho-
ryl)acetate (630 mg, 2.92 mmol) in MeOH (6 mL) and K2CO3 (403
mg, 2.92 mmol), and the mixture was stirred at r.t. for 18 h. The re-
action was quenched with H2O (5 mL) and extracted with EtOAc (3
× 5 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and the solvent was removed in vacuo. The residue was puri-
fied by column chromatography on silica gel using 3% EtOAc–
hexane to give 3; yield: 44 mg (69%, 2 steps); colourless oil; Rf =
0.85 (EtOAc); [α]D22 –26.47 (c 1.0, CHCl3).
3
IR (neat): 3294, 3061, 2932, 2863, 1505 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.97 (m, 2 H, H-3′′), 6.86 (m, 2 H,
H-2′′), 4.78 (m, 1 H, H-2), 4.51 (m, 1 H, H-5), 3.96 (d, J = 4.7 Hz,
2 H, CH2OPh), 2.48 (d, J = 2.0 Hz, 1 H, H-2′), 2.29 (m, 2 H, H-3,
H-4), 2.09 (m, 1 H, H-3), 1.90 (m, 1 H, H-4).
13C NMR (100 MHz, CDCl3): δ = 158.54, 156.17 (d, J = 238.2 Hz,
C-4′′), 154.94 (C-1′′), 115.89, 115.66 (d, J = 23.3 Hz, CH-3′′),
115.63, 115.55 (d, J = 8.1 Hz, CH-2′′), 83.47 (CH-5), 77.06 (CH-2),
72.91 (C-1′), 70.60 (CH2OPh), 68.61 (CH2-2′), 33.20 (CH2-4),
27.66 (CH2-3).
(4) (a) Canoa, P.; Vega, N.; Pérez, M.; Gómez, G.; Fall, Y.
Tetrahedron Lett. 2008, 49, 1149. (b) Kocienski, P. J.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1693–1700

1700
M. González et al.
PAPER
Brown, R. C.; Pommier, A.; Procter, M.; Schmidt, B.
J. Chem. Soc., Perkin Trans. 1 1998, 9.
calculations on F2 using the program SHELXL97. Hydrogen
atoms were inserted at calculated positions and constrained
with isotropic thermal parameters. The structural data have
been deposited with the Cambridge Crystallographic Data
Centre (CCDC) with reference number CCDC 826376.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ
[FAX: +44(1223)336033; E-mail:
(5) For a synthesis of butenolide 17, see: Szlosek, M.; Franck,
X.; Figadère, B.; Cave, A. J. Org. Chem. 1998, 63, 5169.
(6) (a) González, M.; Gándara, Z.; Pazos, G.; Gómez, G.; Fall,
Y. Synthesis 2013, 45, 625. (b) Teijeira, M.; Suárez, P-L.;
Gómez, G.; Terán, C.; Fall, Y. Tetrahedron Lett. 2005, 46,
5889.
(7) Crystallographic data were collected on a Bruker Smart
1000 CCD diffractometer at CACTI (Universidade de Vigo)
at 20 °C using graphite monochromated MoKα radiation
(λ = 0.71073 Å), and were corrected for Lorentz and
polarisation effects. The frames were integrated with the
Bruker SAINT software package and the data were corrected
for absorption using the program SADABS. The structures
were solved by direct methods using the program
deposit@ccdc.cam.ac.uk].
(8) (a) Barton, D. H. R.; Dorchak, J.; Jaszberenyl, J. C.
Tetrahedron 1992, 48, 7435. (b) Barton, D. H. R.;
McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975,
1574.
(9) Zúñiga, A.; Pérez, M.; González, M.; Gómez, G.; Fall, Y.
Synthesis 2011, 3301.
(10) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, J. Synlett
1996, 521.
SHELXS97. All non-hydrogen atoms were refined with
anisotropic thermal parameters by full-matrix least-squares
Synthesis 2013, 45, 1693–1700
© Georg Thieme Verlag Stuttgart · New York