Total synthesis of (+)-massarinolin B and (+)-4-epi-massarinolin B, fungal metabolites from Massarina tunicata

Article abstract of DOI:10.1016/j.tet.2006.06.011

The Cr(II)- and Ni(II)-mediated coupling of several tricyclic chiral aldehydes with (E)-β-iodomethacrylates (Nozaki-Hiyama-Kishi reaction) was successfully applied to the preparation of some valuable key intermediates of our synthetic strategy to the fung

Full text of DOI:10.1016/j.tet.2006.06.011

Tetrahedron 62 (2006) 8095–8102
Total synthesis of (D)-massarinolin B and (D)-4-epi-massarinolin
B, fungal metabolites from Massarina tunicata
*
´
Marıa Rodrıguez Lopez and Francisco A. Bermejo
´
ꢀ
´
Departamento de Quımica Organica, Facultad de Quımicas, Universidad de Salamanca, Pza de la Merced s.n.,
ꢀ
´
37008 Salamanca, Spain
Received 11 March 2006; revised 1 June 2006; accepted 2 June 2006
Available online 27 June 2006
Abstract—The Cr(II)- and Ni(II)-mediated coupling of several tricyclic chiral aldehydes with (E)-b-iodomethacrylates (Nozaki–Hiyama–
Kishi reaction) was successfully applied to the preparation of some valuable key intermediates of our synthetic strategy to the fungal meta-
bolites (+)-massarinolin B, (+)-4-epi-massarinolin B and (+)-massarinolin C.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Although, the absolute configuration at C-4 of 2 and 3 has
been determined by NMR studies on (R)-phenylbutyric
acid (PBA) derivatives carried out by the discoverers,1 it
has not been possible yet to correlate the stereochemistry
of the tricyclic portion of 2 and 3 with that of the side chain,
so the absolute stereochemistry of the ring systems in mas-
sarinolins B and C still need to be ascertained. Since the ab-
solute stereochemistry of the bicyclo[3.1.1]heptane subunit
common to 2 and 3 has not yet been reported, the total syn-
thesis of these two sesquiterpenoids remains a challenge.
Massarinolins A–C (1–3) are novel bioactive sesquiterpe-
noids isolated from the freshwater aquatic fungus Massarina
tunicata Shearer & Fallah (A-25-1; Lophiostomataceae) by
Gloer and Shearer in 1999 (Fig. 1).1 Massarinolins A and B
are presumably cyclization products of massarinolin C and
all of them appear to be sesquiterpenoids biosynthesized
from a farnesyl-type precursor. Compounds 1 and 2 were
active against Bacillus subtillis (ATCC 6051), and possess
unusual tricyclic and bicyclic ring systems, exhibiting simi-
lar functionalization within the lateral chain derived from
(E)-4-hydroxy-2-methyl-2-pentenoic acid.
On the basis of our retrosynthetic analysis, access to the
lateral chain functionalities of these sesquiterpenoids was
O
O
OH
OH
OH
O
O
COOH
O
COOH
OH
(+)-Massarinolin C (3)
(+)-Massarinolin B (2)
(+)-Massarinolin A (1)
O
O
O
OH
O
O
O
COOH
CONH2
N
H
(+)-Pinthunamide (5)
6: (+)-Ampullicin (E)
(+)-4-epi-Massarinolin B (4)
7: (+)-Isoampullicin (Z)
O
I
HO
H
O
CHO
COOR
+
R= CH3
R= CH2CH2SiMe3
COOR
4
NHK
Figure 1. Bioactive sesquiterpenoids from Massarina tunnicata and Ampulliferina Sp 27. Retrosynthetic analysis of (+)-massarinolin B.
Keywords: Sesquiterpenes; b-Iodomethacrylates; (+)-Massarinolin B; R-(ꢀ)-carvone.
* Corresponding author. Tel.: +34 923 294481; fax: +34 923 294574; e-mail: fcobmjo@usal.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.011

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M. Rodrıguez Lopez, F. A. Bermejo / Tetrahedron 62 (2006) 8095–8102
8096
envisioned to take place by Cr(II)- and Ni(II)-mediated cou-
pling of the corresponding chiral aldehyde with (E)-b-iodo-
methacrylates (Nozaki–Hiyama–Kishi NHK reaction).2
DMF furnishes the functionalized chromium(III) organo-
metallics, which react with aldehydes to afford g-hydroxy-
a,b-unsaturated esters. This process appears to involve the
activation of the carbon–iodine bond via Ni(0) or Ni(I), trans-
metallation of Ni to Cr and carbon–carbon bond formation
via the organochromium reagent. The exceptional chemo-
and stereoselectivity displayed by the d3 organometallic
reagent precludes any protection of the ester group or the
double bond.
We wish to report the results obtained for the coupling reac-
tion of chiral aldehydes 12 and 15 with different (E)-b-iodo-
methacrylates and the application of these transformations
to the synthesis of (+)-massarinolin B (2), (+)-massarinolin
C (3) and (+)-4-epi-massarinolin B (4). The formal synthesis
of (+)-pinthunamide (5)3 will also be described as an appli-
cation of the same coupling process to the chiral aldehyde 9.
We first studied the coupling reaction of (E)-b-iodometha-
crylates 16–18 with an achiral aldehyde. The Cr(II)- and
Ni(II)-mediated coupling of b-iodomethacrylates 177 and
188 with benzaldehyde took place at room temperature in
DMF with moderate to excellent yields (See Scheme 2).
However, under these conditions the coupling with 16 failed.
2. Results and discussion
On the basis of our retrosynthetic analysis, access to the lat-
eral chain functionalities of sesquiterpenoids 3–5 was envi-
sioned to take place by Cr(II)- and Ni(II)-mediated coupling
of the corresponding chiral aldehyde with (E)-b-iodometha-
crylates (Nozaki–Hiyama–Kishi NHK reaction).
OH
CHO
CrCl2, NiCl2
DMF, rt, 2h
COOR
CH3
19: R= CH3 (65%)
20: R= C2H4SiMe3 (95%)
I
COOR
The preparation of the chiral aldehydes 9, 12 and 15 was eas-
ily achieved by multistep sequences starting from lactone 8
(Scheme 1), which was first described by Mori4 and we
have previously reported from R-(ꢀ)-carvone with occasion
of the synthesis of (+)-ampullicin (6) and (+)-isoampullicin
(7).5
(E)-ICH=C(CH3)COOR
16: R= Si tBuMe2
17: R= CH3
18: R= CH2CH2SiMe3
Scheme 2. Coupling reactions of (E)-b-iodomethacrylates with benz-
aldehyde.
Ozonolysis of 8 followed by treatment with dimethyl sulfide
afforded the aldehyde 9 in nearly quantitative yields.
Isolation of the methyl and trimethylsilylethyl esters 19 and
20 by flash chromatography9 on silica gel took place with 65
and 95% yields, respectively. Yields were lower in both THF
(15–45%) and CH3CN (5–15%).
The LAH reduction of 8 followed by tosylation of the pri-
mary alcohol 10 allowed us to isolate the tricyclic ether 11,
which was further ozonolyzed to yield aldehyde 12 with
80% overall yield.
The Cr(II)- and Ni(II)-mediated coupling of aldehydes 9, 12
and 15 with (E)-b-iodomethacrylates 17 and 18 took place
with moderate yields but with poor diastereoselectivity
(Table 1). However, the isolation and structural elucidation
of the reaction products was possible in all cases.
On the other hand the diol 10 was sequentially protected by
treatment with acetic anhydride followed by trimethylsilyl
chloride in triethyl amine and DMAP to afford the unsatu-
rated ester 14, which was further ozonolyzed to yield alde-
hyde 15 with 76% yield (three steps).
The Cr(II)- and Ni(II)-mediated coupling of aldehyde 9 with
b-iodomethacrylate 18 in DMF at room temperature afforded
a mixture of diastereomers (21:22¼1:1) with 56% yield.10
Isolation of both isomers by flash chromatography was
followed by Dess–Martin oxidation of each diastereomer to
afford the enone 23 with 75 and 80 yields, respectively.
The preparation of functionalized allylic alcohols has been
successfully achieved by Cr(II)- and Ni(II)-mediated cou-
pling of olefinic halides or triflates to aldehydes.6 The inser-
tion of chromium(II) chloride to b-iodomethacrylates in
O
OH
O
HO
O
O
g
c
a
X
X
8: X= CH2
9: X= O
11: X= CH2
12: X= O
10
b
h
R-(-)-carvone
d
OR1
R2O
X
13: R = Ac; R2= H; X= CH2
14: R1= Ac; R2 =SiMe3; X= CH2
e
f
1
15: R1= Ac; R2= SiMe3; X= O
Scheme 1. Reagents and conditions: (a) Ref. 5; (b) O3, ꢀ78 ꢁC, Me2S, 97%; (c) LAH, ether, rt, 91% (X¼CH2); (d) Ac2O, Py, 95%; (e) Me3SiCl, Et3N, DMAP,
CH2Cl2, 84%; (f) O3, ꢀ78 ꢁC, Me2S, 95%; (g) TsCl, Py, DMAP, CH2Cl2, rt, 90%; (h) O3, ꢀ78 ꢁC, Me2S, 98%.

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Table 1. Coupling reaction of aldehydes 9, 12 and 15 with (E)-b-iodomethacrylates 17 and 18a
R1O
R2
Y
Z
R1O
R2
I
COOR3
CrCl2, NiCl2, DMF, rt
CHO
COOR3
Aldehyde
Methacrylate
drb
Yield (%)c
9: R1,R2¼CO
18: R3¼CH2CH2SiMe3
17: R3¼CH3
21:22¼1:1
24:25¼3:2
27:28¼1.2:1
29:30¼1.2:1
56
65
95
87
12: R1,R2¼CH2
12: R1,R2¼CH2
18: R3¼CH2CH2SiMe3
17: R3¼CH3
15: R1¼SiMe3; R2¼CH2OAc
X
OAc
X
Y
Z
O
RO
Y
COOR
COOCH3
21: X= O; Y= OH, Z= H; R= CH2CH2Si(CH3)3
22: X= O ; Y= H, Z= OH; R= CH2CH2Si(CH3)3
24: X= H2; R= CH3; Y= OH, Z= H
29: R= SiMe3 ; X= OH; Y= H
30: R= SiMe3 ; X= H; Y= OH
25: X= H2; R= CH3; Y= H, Z= OH
27: X= H2; R= CH2CH2SiMe3; Y= OH; Z= H
28: X= H2; R= CH2CH2SiMe3; Y= H; Z= OH
23: X= O; Y, Z= O; R= CH2CH2Si(CH3)3
26: X= H2; Y, Z= O; R= CH3
31d: R= SiMe3 ; X= OSitBuPh2; Y= H
32d: R= H; X= OSitBuPh2; Y= H
a
All reactions were run in DMF at room temperature with CrCl2/haloester/aldehyde¼4:2:1 ratio.
Determined by GLPC (3% silicone OV-17, 1.5 m).
Isolated yields.
b
c
Transformation of the enone 23 into (+)-pinthunamide (5)
has been described previously.4
possible by flash chromatography and the structural elucida-
tion was based on full spectroscopic analysis and compari-
son with the spectroscopic evidence obtained for 24 and
25. Hydroxyester 29 is an advanced intermediate in the syn-
thesis of (+)-massarinolin C (3).15
The Cr(II)- and Ni(II)-mediated coupling of aldehyde 12
with each of the b-iodomethacrylates 17 and 18 afforded
mixtures of diastereomers [(24:25¼3:2) and (27:28¼
1.2:1)] with 65 and 95% isolated yields, respectively. Reac-
tion was fast in DMF, the usual solvent of choice. Further-
more, the reactions were slower in THF and CH3CN and
both solvents afforded similar stereoselectivities but with
lower reaction yields: THF, 47% (24+25) and 40%
(27+28); CH3CN, 48% (24+25) and 45% (27+28).
3. Conclusion
The Cr(II)- and Ni(II)-mediated coupling of chiral aldehydes
9, 12 and 15 with (E)-b-iodomethacrylates yielded the corre-
sponding g-hydroxy-a,b-unsaturated esters with moderate
yields but with poor stereoselectivity. Starting from the
allylic lactone 8, application of these transformations to
the synthesis of (+)-massarinolin B (2), (+)-4-epi-massarino-
lin B (4), (+)-pinthunamide (5) and the preparation of an
advanced intermediate (29) in the synthesis of (+)-massari-
nolin C (3) have been described.
Isolation of isomers was possible by flash chromatography
on silica gel.11 The spectroscopic data obtained for 24
were identical to those previously described for the methyl
ester of (+)-massarinolin B.1 Fluoride-promoted deprotec-
tion of 27 yielded the target molecule 2 with quantitative
yields. Analogously, deprotection of the silyl derivative 28
afforded 4-epi-(+)-massarinolin B (4) quantitatively.12
4. Experimental
4.1. General
Since the absolute stereochemistry of the starting material 8
is known,13 it is possible now to correlate the stereochemis-
try of the bicyclo[3.1.1]heptane portion of 2 with that of the
side chain, therefore, the absolute stereochemistry of 2 and 4
has been unambiguously established.
Melting points are uncorrected. 1H NMR spectra were
measured at either 200 or 400 MHz and 13C NMR were
measured at 50 or 100 MHz in CDCl3 and referenced to
TMS (1H) or solvent (13C), except where noted otherwise.
IR spectra were recorded for neat samples on NaCl plates,
unless otherwise noted. Standard mass spectrometry data
were acquired by using GC–MS system in EI mode with
the maximum m/z range of 600. Optical rotations were deter-
mined on a digital Perkin–Elmer 241 polarimeter in a 1 dm
cell. Tetrahydrofuran (THF) was purified by distillation from
sodium and benzophenone ketyl and degassed before use.
Dimethylformamide (DMF) was dried over CaH2, distd un-
der reduced pressure and degassed before use. Acetonitrile is
For preparative purposes, we attempted to enhance the dia-
stereomeric ratio in favour of 24 by a two-step oxidation–
reduction sequence via enone 26. Among the reagents
screened, neither L-Selectride nor zinc borohydride gave
acceptable results with respect to either chemo- or stereo-
selectivity.14
The coupling reaction of aldehyde 15 with b-iodomethacry-
late 17 gave a mixture of diastereoisomers (29:30¼1.2:1)
with 87% yield. Separation of both diastereomers was

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8098
fractionally distd after refluxing over CaH2. All reactions
were conducted under a positive pressure of argon, utilizing
standard bench-top techniques for handling air-sensitive ma-
terials. Chromatographic separations were carried out under
pressure on silica gel using flash column techniques.9 Rf
values refer to TLC carried out on 0.25 mm silica gel plates,
with the same eluant as that indicated for the column chro-
matography unless otherwise noted. Yields reported are for
chromatographically pure isolated products unless men-
tioned otherwise. Anhydrous CrCl2 and NiCl2 were pur-
chased from Aldrich and Strem Chemicals and were used
without purification.
(t), 38.05 (t), 39.60 (d), 50.72 (d), 54.96 (s), 70.46 (t),
86.77 (s), 116.62 (t), 134.74 (d) ppm. MS (EI) m/z (%):
178 (M+, 13.1), 67 (25), 79 (44), 95 (28.6), 107 (17), 123
(100), 163 (14.3). HRMS-EI (M+) calcd for C12H18O:
178.1358, found: 178.1348.
4.2.3. (1R,2R,5S,6S)-2-Hydroxy-2-methyl-6-(2-propenyl)-
bicyclo[3.1.1]hept-6-yl-methyl acetate 13. To a solution
of diol 10 (0.205 g, 1.0 mmol) in CH2Cl2 were successively
added pyridine (0.16 mL, 2.2 mmol) and acetic anhydride
(0.2 mL, 2.0 mmol). The reaction mixture was stirred for
12 h. Then, ether (5 mL) was added and the reaction mixture
was poured on satd NaHCO3 (5 mL) and stirred for 1 h. The
organic phase was successively washed with 2 N HCl
(3ꢂ10 mL), satd NaHCO3 (3ꢂ10 mL) and brine (3ꢂ
10 mL), dried (Na2SO4) and evaporated to yield a crude
product (0.260 g), which was fractionated by flash chroma-
tography on silica gel. By elution with hexane/ethyl acetate
8:2, acetate 13 (0.237 g, 95%) was obtained as a colourless
oil. [a]2D0 ꢀ5.05 (c 1.01, CHCl3). Rf 0.48 (hexane/ethyl ace-
tate 1:1). IR (CHCl3): n 3480, 3078, 2922, 1716, 1639, 1456,
1237, 1027, 962 cmꢀ1. 1H NMR (200 MHz, CDCl3): d 1.09
(d, 1H, J¼10.2 Hz), 1.28 (s, 3H), 1.27–2.35 (m, 7H), 2.04 (s,
3H), 2.45 (d, 2H, J¼7.52 Hz), 4.21 (dd, 2H, J1¼11.8 Hz,
J2¼36.8 Hz), 5.05 (m, 2H), 5.84 (m, 1H) ppm. 13C NMR
(50 MHz, CDCl3): d 15.04 (q), 23.73 (t), 27.44 (t), 31.47
(q), 31.95 (t), 37.47 (t), 37.95 (d), 43.23 (s), 50.75 (d),
65.70 (t), 75.21 (s), 116.97 (t), 134.81 (d), 170.79 (s) ppm.
HRMS-EI (M+Na+) calcd for C14H22O3Na: 261.1461,
found: 261.1447.
4.2. Preparation of intermediates 10, 11, 13 and 14
4.2.1. (1R,2R,5S,6S)-2-Hydroxy-2-methyl-6-(2-propenyl)-
bicyclo[3.1.1]hept-6-yl-methanol 10. To an ice-cooled and
stirred solution of crude 8 (2 g, 10.41 mmol) in anhydrous
ether (45 mL) LiAlH4 (0.394 g, 10.41 mmol) was added.
The mixture was stirred at room temperature for 15 h. To
the ice-cooled mixture were added H2O (0.4 mL), 15%
NaOH (0.4 mL) and H2O (1.2 mL) successively. The mix-
ture was stirred at room temperature for 1 h and filtered
through Celite and eluted with ether. The filtrate was concen-
trated in vacuo and the residue was flash chromatographed
on silica gel. Elution with hexane/ethyl acetate 6:4 afforded
diol 10 (1.83 g, 91%) as a colourless oil. [a]2D0 ꢀ24.51
(c 1.04, CHCl3). Rf 0.33 (hexane/ethyl acetate 1:1). IR
(KBr): n 3365, 3081, 2973, 2931, 1637, 1471, 1261, 1121,
1
1029, 912, 803 cmꢀ1. H NMR (400 MHz, CDCl3): d 1.04
(d, 1H, J¼10.4 Hz), 1.33 (s, 3H), 1.75–2.10 (m, 5H), 2.16
(m, 1H), 2.25 (m, 1H), 2.4 (dd, 1H, J1¼7.5 Hz,
J2¼14.2 Hz), 2.65 (dd, 1H, J1¼7.2 Hz, J2¼14.16 Hz), 3.45
(d, 1H, J¼11.6 Hz), 3.9 (d, 1H, J¼11.6 Hz), 5.1 (m, 2H),
5.9 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 24.16
(t), 27.61 (t), 31.33 (q), 32.79 (t), 36.34 (d), 37.94 (t),
45.24 (s), 51.20 (d), 63.11 (t), 76.02 (s), 116.98 (t), 135.59
(d) ppm. MS (EI), m/z (%): 196 (M+, 2), 178 (10), 137
(35), 110 (35), 94 (100), 79 (85), 67 (55). HRMS-EI (M+)
calcd for C12H20O2: 196.1463, found: 196.1457.
4.2.4. (1R,2R,5S,6S)-2-Methyl-2-(trimethylsilyloxy)-6-(2-
propenyl)-bicyclo[3.1.1]hept-6-yl-methyl acetate 14. To
a solution of 13 (0.20 g, 0.84 mmol) in CH2Cl2 (25 mL) at
0 ꢁC were successively added Et3N (0.24 mL, 1.7 mmol),
DMAP (20.4 mg, 0.17 mmol) and Me3SiCl (0.16 mL,
1.25 mL). The reaction mixture was stirred for 12 h at
room temperature, diluted with ether (20 mL) and poured
on satd NaHCO3 (20 mL). The mixture was stirred for 1 h
and extracted with ether. The combined organic layers
were washed with brine, dried (Na2SO4) and evaporated to
yield a crude product (0.27 g), which was fractionated by
flash chromatography on silica gel. Elution with hexane/
ethyl acetate 8:2 afforded the silyl acetate 14 (0.22 g,
84%) as a colourless oil. [a]2D0 ꢀ10.95 (c 1.21, CHCl3). Rf
0.62 (hexane/ethyl acetate 7:3). IR (CHCl3): n 3075, 2961,
4.2.2. (1R,4S,6R,7S)-1-Methyl-9-oxa-7-(2-propenyl)-
tricyclo[4.3.0.04,7]nonane 11. To a solution of diol 10
(0.67 g, 3.42 mmol) in CH2Cl2 (50 mL) at 0 ꢁC, pyridine
(0.82 mL, 10.26 mmol), DMAP (0.084 g, 0.684 mmol) and
tosyl chloride (1.3 g, 6.84 mmol) were successively added.
The reaction mixture was stirred at room temperature for
48 h. Then, 10% NaHCO3 (10 mL) was added and the reac-
tion mixture was further stirred for 1 h. The crude mixture
was extracted with methylene chloride (3ꢂ25 mL) and the
combined organic layers were successively washed with
1 N HCl (3ꢂ10 mL), 10% NaHCO3 (3ꢂ10 mL) and brine
(3ꢂ10 mL). The organic phase was dried with Na2SO4 and
evaporated to yield a crude (1.5 g), which was fractionated
by flash chromatography on silica gel (hexane/ethyl acetate
9:1) to afford 11 (0.55 g, 90%) as a colourless oil. [a]D20
+17.9 (c 0.8, CHCl3). Rf 0.68 (hexane/ethyl acetate 1:1).
IR (neat): n 3077, 2926, 2866, 1726, 1642, 1452, 1375,
2928, 2873, 1739, 1381, 1250, 1130, 1004, 968, 840 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.11 (s, 9H), 1.5 (d, 1H,
J¼9.7 Hz), 1.28 (s, 3H), 1.15–2.25 (m, 7H), 2.01 (s, 3H),
2.44 (d, 2H, J¼7.35 Hz), 4.09 (dd, 2H, J1¼12.2 Hz,
J2¼76.6 Hz), 5.04 (m, 2H), 5.80 (m, 1H) ppm. 13C NMR
(50 MHz, CDCl3): d 2.53 (q), 20.87 (q), 23.97 (t), 27.06
(t), 30.57 (q), 33.47 (t), 37.65 (t), 38.33 (d), 43.24 (s),
51.66 (d), 66.02 (t), 78.34 (s), 116.76 (t), 135.28 (d),
170.95 (s) ppm. HRMS-EI (M+Na+) calcd for C17H30O3-
SiNa: 333.1856, found: 333.1821.
4.3. Ozonolysis of alkenes 8, 11 and 14. Obtention of
aldehydes 9, 12 and 15. General procedure
1
1032, 912, 849 cmꢀ1. H NMR (200 MHz, CDCl3): d 1.26
(s, 3H), 1.45 (m, 1H), 1.65–1.9 (m, 5H), 2.0–2.2 (m, 2H),
2.3–2.5 (m, 2H), 3.5 (d, 1H, J¼8.9 Hz), 3.74 (d, 1H,
J¼8.9 Hz), 5.05 (m, 2H), 5.7 (m, 1H) ppm. 13C NMR
(50 MHz, CDCl3): d 22.70 (t), 22.96 (t), 25.18 (q), 32.60
4.3.1. (1R,4S,6R,7S)-1-Methyl-9-oxa-8-oxo-tricyclo-
[4.3.0.04,7]non-7-yl-acetaldehyde 9. Ozone was bubbled
through a solution of 8 (2.5 g, 13.01 mmol) in 75 mL of

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8099
CH2Cl2 at ꢀ78 ꢁC until a blue-grey colouration developed.
Then, excess ozone was eliminated using argon, and then
SMe2 (2.85 mL, 39 mmol) was added. After stirring for 3 h
(from –78 ꢁC to room temperature) the solvent was evapo-
rated under reduced pressure. The residue was purified by
flash chromatography (hexane/ethyl acetate 6:4) to yield a
colourless oil 9 (2.4 g, 95%). [a]2D0 +49.06 (c 1.35, CHCl3).
Rf 0.24 (hexane/ethyl acetate 1:1). IR (neat): n 2972, 2899,
2745, 1759, 1723, 1458, 1383, 1252, 1198, 1082, 939,
chromatography on silica gel (hexane/ethyl acetate 9:1)
afforded 0.16 g (65%) of the desired allylic alcohol 19 as a
colourless oil. Rf 0.37 (hexane/ethyl acetate 1:1). IR (neat):
n 3445, 3050, 2953, 1715, 1651, 1439, 1128, 1017 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 1.85 (s, 3H), 2.52 (s, 1H),
3.6 (s, 3H), 5.42 (d, 1H, J¼8.6 Hz), 6.79 (d, 1H,
J¼8.5 Hz), 7.22–7.29 (m, 5H) ppm. 13C NMR (50 MHz,
CDCl3): d 12.93 (q), 51.87 (q), 70.8 (d), 126.2 (d), 128.02
(d), 128.4 (s), 128.75 (d), 142.1 (d), 142.2 (s), 168.3
(s) ppm. MS-EI m/z (%): 206 (M+, 1.5), 51 (48), 77 (100),
79 (34), 105 (100), 117 (33), 145 (47), 159 (3), 174 (37.5),
188 (19), 191 (3). Anal. Calcd for C12H14O3: C, 69.88; H,
6.84. Found: C, 70.01; H, 6.96.
1
893 cmꢀ1. H NMR (200 MHz, CDCl3): d 1.49 (s, 3H),
1.72 (d, 1H, J¼10.7 Hz), 1.92 (s, 4H), 2.19 (m, 1H), 2.45
(m, 1H), 2.64 (t, 1H, J¼5.4 Hz), 2.83 (dd, 2H, J1¼18.2 Hz,
J2¼30.5 Hz), 9.74 (s, 1H) ppm. 13C NMR (50 MHz,
CDCl3): d 22.88 (t), 24.78 (q), 29.83 (t), 40.81 (d), 43.36
(t), 47.74 (d), 52.87 (s), 88.71 (s), 177.42 (s), 199.12
(d) ppm. HRMS-EI (M+H+) calcd for C11H15O3: 195.1016,
found: 195.0998.
4.4.2. (E)-4-Hydroxy-2-methyl-4-phenyl-2-butenoic acid
2-(trimethylsilyl)ethyl ester 20. Coupling of benzaldehyde
(0.118 g, 1.12 mmol) and (E)-haloester 18 (0.70 g,
2.24 mmol) afforded 0.320 g of crude product. Fractionation
by flash chromatography on silica gel (hexane/ethyl acetate
9:1) afforded 0.27 g (95%) of the desired alcohol 20 as a col-
ourless oil. Rf 0.27 (hexane/ethyl acetate 8:2). IR (CHCl3):
n 3455, 3030, 2955, 2899, 1709, 1649, 1452, 1252, 1036,
4.3.2. (1R,4S,6R,7S)-1-Methyl-9-oxa-tricyclo[4.3.0.04,7]-
non-7-yl-acetaldehyde 12. Ozonolysis of alkene 11 (1.5 g,
8.43 mmol) afforded aldehyde 12 (1.49 g, 98%) as a colour-
less oil. [a]2D0 +40.54 (c 1.07, CHCl3). Rf 0.33 (hexane/ethyl
acetate 1:1). IR (CHCl3): n 2928, 2870, 2726, 1721, 1452,
1
936, 856 cmꢀ1. H NMR (200 MHz, CDCl3): d 0.35 (s,
1377, 1024, 853 cmꢀ1
.
1H NMR (200 MHz, CDCl3):
9H), 1.01 (dd, 2H, J¼8.5 Hz), 1.94 (s, 3H), 4.2 (dd, 2H, J¼
8.45 Hz), 5.52 (d, 1H, J¼8.6 Hz), 6.68 (d, 1H, J¼8.7 Hz),
7.25–7.4 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3): d 1.57
(q), 12.85 (q), 17.3 (t), 62.98 (t), 70.73 (d), 126.12 (d),
127.87 (d), 128.6 (d), 128.61 (s), 141.89 (d), 142.16 (s),
167.97 (s) ppm. MS-EI m/z (%): 275.14 (M+Na, 17.5),
129.1 (100), 169.1 (7.4), 175.1 (10.1), 202.02 (3.7), 247.11
(9.2), 265.13 (5.5). Anal. Calcd for C16H24O3Si: C, 65.71;
H, 8.27. Found: C, 65.83; H, 8.37.
d 1.25 (s, 3H), 1.45 (d, 1H, J¼10.3 Hz), 1.7–2.25 (m, 7H),
2.75 (dd, 2H, J1¼18 Hz, J2¼30 Hz), 3.75 (d, 1H,
J¼9.3 Hz), 4.04 (d, 1H, J¼9.3 Hz), 9.74 (s, 1H) ppm. 13C
NMR (50 MHz, CDCl3): d 22.42 (t), 22.63 (t), 24.92 (q),
32.25 (t), 40.01 (d), 48.36 (t), 51.20 (d), 52.25 (s), 70.58
(t), 86.03 (s), 200.64 (d) ppm. HRMS-EI (M+H+) calcd for
C11H17O2: 181.1223, found: 181.1223.
4.3.3. (1R,2R,5S,6S)-2-Methyl-2-(trimethylsilyloxy)-6-(2-
oxoethyl)-bicyclo[3.1.1]hept-6-yl-methyl acetate 15. Ozo-
nolysis of alkene 14 (1 g, 3.22 mmol) yielded aldehyde 15
(0.950 g, 95%) as a colourless oil. [a]2D0 ꢀ22.32 (c 1.257,
CHCl3). Rf 0.46 (hexane/ethyl acetate 7:3). IR (KBr):
4.4.3. Hydroxyesters 21 and 22. Coupling of aldehyde 9
(0.110 g, 0.57 mmol) and (E)-haloester 18 (0.354 g,
1.14 mmol) afforded 0.25 g of crude product. Fractionation
by flash chromatography on silica gel (hexane/ethyl acetate
9:1) afforded 21 (0.06 g, 28%) and 22 (0.06 g, 28%).
n 2959, 2738, 1730, 1452, 1376, 1233, 1000, 956, 835 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.1 (s, 9H), 1.3 (s, 3H),
1.35 (d, 1H, J¼11.0 Hz), 1.9–2.4 (m, 7H), 2.0 (s, 3H),
2.6–2.8 (m, 2H), 4.15 (d, 1H, J¼12.2 Hz), 4.58 (d, 1H, J¼
12.1 Hz), 9.85 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3):
d 2.38 (q), 20.71 (q), 23.47 (t), 27.69 (t), 30.28 (q), 33.04
(t), 37.75 (d), 42.89 (s), 47.93 (t), 52.98 (d), 67.33 (t),
77.90 (s), 170.54 (s), 202.07 (d) ppm. HRMS-EI (M+Na+)
calcd for C16H28O4SiNa: 335.1649, found: 335.1639.
4.4.3.1. 2-(Trimethylsilyl)ethyl (10R,4S,40S,60R,70S)-
(E)-4-hydroxy-2-methyl-5-(10-methyl-90-oxa-80-oxo-tri-
cyclo[4.3.0.04,7]non-70-yl)-2-pentenoate 21. Colourless oil.
[a]2D0 ꢀ0.79 (c 1.305, CHCl3). Rf 0.40 (hexane/ethyl acetate
1:1). IR (CHCl3): n 3475, 3057, 2954, 2871, 1761, 1708,
1653, 1458, 1250, 1062, 942, 834 cmꢀ1
.
1H NMR
(200 MHz, CDCl3): d 0.04 (s, 9H), 1.01 (t, 2H, J¼8.3 Hz),
1.42–2.80 (m, 3H), 1.46 (s, 3H), 1.85 (s, 3H), 1.9 (m, 4H),
2.5 (m, 2H), 2.61 (m, 1H), 4.22 (t, 2H, J¼8.3 Hz), 4.69
(ddd, 1H, J1¼8.5 Hz, J2¼8.5 Hz, J3¼4.3 Hz), 6.66 (dq,
1H, J1¼8.5 Hz, J2¼1.2 Hz) ppm. 13C NMR (50 MHz,
CDCl3): d ꢀ1.65 (q), 12.62 (q), 17.26 (t), 22.74 (t), 22.75
(t), 24.74 (q), 29.66 (t), 36.46 (t), 42.06 (d), 47.18 (d),
54.33 (s), 62.87 (t), 65.97 (d), 88.40 (s), 128.70 (s), 142.09
(d), 167.76 (s), 179.15 (s) ppm. HRMS-EI (M+Na+) calcd
for C20H32O5NaSi: 403.1911, found: 403.1914.
4.4. Coupling reactions between (E)-b-halo-acrylates
and aldehydes. General procedure
4.4.1. (E)-4-Hydroxy-2-methyl-4-phenyl-2-butenoic acid
methyl ester 19. A mixture of anhydrous CrCl2 (0.60 g,
4.9 mmol) and a catalytic amount of NiCl2 (3.2 mg,
0.02 mmol) in dry oxygen-free dimethylformamide (DMF,
10 mL) was stirred at 25 ꢁC for 10 min under argon atmo-
sphere. To the reagent at 25 ꢁC, solutions of benzaldehyde
(0.129 g, 1.02 mmol) in DMF (5 mL) and methyl-(E)-3-
iodomethacrylate 17 (0.554 g, 2.45 mmol) in DMF (5 mL)
were successively added. After stirring at 25 ꢁC for 4 h at
room temperature, the reaction mixture was diluted with
ether (20 mL), poured into water (20 mL) and extracted
with ether repeatedly. The combined extracts were dried
(Na2SO4) and concentrated. Purification by flash column
4.4.3.2. 2-(Trimethylsilyl)ethyl (10R,4R,40S,60R,70S)-
(E)-4-hydroxy-2-methyl-5-(10-methyl-90-oxa-80-oxo-tri-
cyclo[4.3.0.04,7]non-70-yl)-2-pentenoate 22. Colourless oil.
[a]2D0 +24.89 (c 0.953, CHCl3). Rf 0.46 (hexane/ethyl acetate
1:1). IR (CHCl3): n 3456, 3056, 2954, 2855, 1759, 1709,
1650, 1458, 1250, 1044, 986, 839 cmꢀ1
.
1H NMR
(200 MHz, CDCl3): d 0.04 (s, 9H), 1.02 (t, 2H, J¼8.3 Hz),

´
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M. Rodrıguez Lopez, F. A. Bermejo / Tetrahedron 62 (2006) 8095–8102
8100
1.48 (s, 3H), 1.74 (m, 1H), 1.85–2.10 (m, 6H), 1.88 (s, 3H),
1.98 (s, 4H), 1.9–2.35 (m, 3H), 2.25 (m, 1H), 2.57 (m, 1H),
2.7 (m, 1H), 4.22 (t, 2H, J¼8.6 Hz), 4.71 (ddd, 1H, J1¼
8.1 Hz, J2¼8.1 Hz, J3¼6.8 Hz), 6.71 (dq, 1H, J1¼8.1 Hz,
J2¼1.2 Hz) ppm. 13C NMR (50 MHz, CDCl3): d 1.63 (q),
12.62 (q), 17.27 (t), 22.78 (t), 22.99 (t), 24.74 (q), 29.66 (t),
36.25 (t), 40.57 (d), 49.13 (d), 55.33 (s), 62.80 (t), 66.24
(d), 89.28 (s), 128.14 (s), 142.91 (d), 167.90 (s), 179.56
(s) ppm. HRMS-EI (M+Na+) calcd for C20H32O5SiNa:
403.1911, found: 403.1900.
4.4.5.1. (10R,40S,4S,60R,70S)-(E)-4-Hydroxy-2-methyl-
5-(10-methyl-90-oxa-tricyclo[4.3.0.04,7]non-70-yl)-2-pente-
noic acid 2-(trimethylsilyl)ethyl ester 27. Colourless oil.
[a]2D0 +28.25 (c 0.89, CHCl3). Rf 0.37 (hexane/ethyl acetate
1:1). IR (CHCl3): n 3398, 2926, 1710, 1650, 1452, 1250,
1
1034, 935, 838 cmꢀ1. H NMR (400 MHz, CDCl3): d 0.06
(s, 9H), 1.04 (dd, 2H, J1¼8.6 Hz, J2¼1.8 Hz), 1.27 (s, 3H),
1.47 (d, 1H, J¼10.2 Hz), 1.65–2.00 (m, 6H), 1.87 (d, 3H, J¼
1.5 Hz), 2.1 (m, 1H), 2.15 (t, 1H, J¼5.6 Hz), 2.27 (m, 1H),
3.62 (d, 1H, J¼9.45 Hz), 3.90 (d, 1H, J¼9.45 Hz), 4.25 (m,
2H), 4.53 (ddd, 1H, J1¼8.4 Hz, J2¼8.4 Hz, J3¼4.4 Hz),
6.69 (dq, 1H, J1¼8.4 Hz, J2¼1.5 Hz) ppm. 13C NMR
(100 MHz, CDCl3): d ꢀ1.52 (q), 12.70 (q), 17.27 (t), 22.65
(t), 22.83 (t), 25.13 (q), 32.44 (t), 39.00 (d), 40.61 (t), 52.12
(d), 54.25 (s), 63.10 (t), 66.67 (d), 71.58 (t), 85.85 (s),
128.04 (s), 142.95 (d), 167.99 (s) ppm. HRMS-EI (M+Na+)
calcd for C20H34O4SiNa: 389.2118, found: 389.2127.
4.4.4. Hydroxyesters 24 and 25. Coupling of aldehyde
12 (0.124 g, 0.70 mmol) and (E)-haloester 17 (0.312 g,
1.38 mmol) afforded 0.228 g of crude product. Fractionation
by flash chromatography on silica gel (hexane/ethyl acetate
8:2) afforded 24 (0.075 g, 39%) and 25 (0.050 g, 26%).
4.4.4.1. Methyl (10R,40S,4S,60R,70S)-(E)-4-hydroxy-2-
methyl-5-(10-methyl-90-oxa-tricyclo[4.3.0.04,7]non-70-yl)-
2-pentenoate 24. Colourless oil. [a]2D0 +8.6 (c 1.1, CHCl3).
Rf 0.23 (hexane/ethyl acetate 1:1). IR (CHCl3): n 3408,
4.4.5.2. (10R,40S,4R,60R,70S)-(E)-4-Hydroxy-2-methyl-
5-(10-methyl-90-oxa-tricyclo[4.3.0.04,7]non-70-yl)-2-pente-
noic acid 2-(trimethylsilyl)ethyl ester 28. Colourless oil.
[a]2D0 ꢀ5.08 (c 0.47, CHCl3). Rf 0.42 (hexane/ethyl acetate
1:1). IR (CHCl3): n 3403, 2925, 2867, 1711, 16490, 1453,
1
2925, 2855, 1720, 1451, 1122 cmꢀ1. H NMR (400 MHz,
CD3OD): d 1.23 (s, 3H), 1.50 (m, 1H), 1.62 (m, 1H), 1.78
(m, 1H), 1.84 (m, 1H), 1.85 (d, 3H, J¼1.44 Hz), 1.88 (m,
1H), 1.89 (m, 1H), 1.98 (dd, 1H, J1¼14.1 Hz, J2¼4.0 Hz),
2.13 (m, 1H), 2.14 (m, 1H), 2.30 (m, 1H), 3.60 (d, 1H,
J¼9.45 Hz), 3.74 (s, 3H), 3.89 (d, 1H, J¼9.45 Hz), 4.46
(ddd, 1H, J1¼8.9 Hz, J2¼8.9 Hz, J3¼3.8 Hz), 6.67 (dq,
1H, J1¼8.9 Hz, J2¼1.4 Hz) ppm. 13C NMR (100 MHz,
CD3OD): d 12.78 (q), 23.53 (t), 23.75 (t), 25.35 (q), 33.41
(t), 40.24 (d), 41.72 (t), 52.45 (q), 53.55 (d), 55.53 (s),
66.94 (d), 72.76 (t), 87.62 (s), 127.95 (s), 145.59 (d),
169.95 (s) ppm. MS-EI m/z (%): 262 (M+ꢀH2O, 5), 247
(3), 225 (21), 207(46), 203 (10), 187 (8), 175 (21), 151
(37), 147(56), 133(29), 109 (26), 97 (100), 79 (78), 67
(65), 55 (80). Anal. Calcd for C16H24O4: C, 68.54; H,
8.63. Found: C, 68.61; H, 8.68.
1
1250, 1038, 936, 839 cmꢀ1. H NMR (400 MHz, CDCl3):
d 0.05 (s, 9H), 1.02 (dd, 2H, J1¼8.5 Hz, J2¼1.8 Hz), 1.25
(s, 3H), 1.47 (d, 1H, J¼10.1 Hz), 1.2–1.9 (m, 6H), 1.84 (d,
3H, J¼1.44 Hz), 2.09 (m, 1H), 2.15 (m, 1H), 2.27 (m, 1H),
3.55 (d, 1H, J¼9.04 Hz), 3.81 (d, 1H, J¼9.04 Hz), 4.22 (m,
2H), 4.52 (ddd, 1H, J1¼7.6 Hz, J2¼7.6 Hz, J3¼7.2 Hz),
6.63 (dq, 1H, J1¼7.6 Hz, J2¼1.4 Hz) ppm. 13C NMR
(100 MHz, CDCl3): d ꢀ1.52 (q), 12.76 (q), 17.29 (t), 22.67
(t), 22.73 (t), 25.16 (q), 32.38 (t), 40.16 (d), 40.74 (t), 52.08
(d), 53.92 (s), 63.12 (t), 67.45 (d), 70.81 (t), 86.44 (s),
128.52 (s), 142.57 (d), 167.86 (s) ppm. HRMS-EI (M+Na+)
calcd for C20H34O4SiNa: 389.2118, found: 389.2108.
4.4.6. Hydroxyesters 29 and 30. Coupling of aldehyde
15 (0.18 g, 0.6 mmol) and (E)-haloester 17 (0.26 g,
1.15 mmol) afforded 0.230 g of crude product. Fractionation
by flash chromatography on silica gel (hexane/ethyl acetate
9:1) afforded 29 (0.11 g, 46%) and 30 (0.1 g, 42%).
4.4.4.2. Methyl (10R,40S,4R,60R,70S)-(E)-4-hydroxy-2-
methyl-5-(10-methyl-90-oxa-tricyclo[4.3.0.04,7]non-70-yl)-
2-pentenoate 25. Colourless oil. [a]2D0 ꢀ0.78 (c 1.03,
CHCl3). Rf 0.28 (hexane/ethyl acetate 1:1). IR (CHCl3):
n 3407, 2925, 2849, 1717, 1655, 1437, 1265, 1141 cmꢀ1
.
4.4.6.1. Methyl (10R,20R,4S,50S,60S)-(E)-5-(60-acetoxy
methyl-20-trimethylsilyloxy-20-methyl-bicyclo[3.1.1]-hept-
60-yl)-4-hydroxy-2-methyl-2-pentenoate 29. Colourless
oil. [a]2D0 ꢀ40.81 (c 1.01, CHCl3). Rf 0.19 (hexane/ethyl ace-
tate 7:3). IR (CHCl3): n 3469, 2957, 2955, 2873, 1717, 1651,
1H NMR (400 MHz, CD3OD): d 1.23 (s, 3H), 1.50 (m, 1H),
1.61 (m, 1H), 1.78 (m, 1H), 1.84 (m, 1H), 1.85 (d, 3H, J¼
1.49 Hz), 1.88 (m, 1H), 1.89 (m, 1H), 2.09–2.25 (m, 3H),
2.4 (m, 1H), 3.54 (d, 1H, J¼9.01 Hz), 3.78 (s, 3H), 3.79 (d,
1H, J¼9.0 Hz), 4.5 (ddd, 1H, J1¼8.8 Hz, J2¼8.8 Hz, J3¼
6.4 Hz), 6.65 (dq, 1H, J1¼8.8 Hz, J2¼1.45 Hz) ppm. 13C
NMR (100 MHz, CD3OD): d 12.89 (q), 23.38 (t), 23.60 (t),
25.39 (q), 33.37 (t), 41.35 (d), 41.83 (t), 52.5 (q), 53.43 (d),
55.19 (s), 67.50 (d), 71.93 (t), 88.20 (s), 128.47 (s), 145.23
(d), 169.88 (s) ppm. MS-EI m/z (%): 262 (M+ꢀH2O, 3),
236 (2), 225 (16), 207 (54), 187 (10), 175 (17), 151 (37),
147 (60), 133 (32), 109 (27), 97 (100), 79 (90), 67 (67), 55
(84). Anal. Calcd for C16H24O4: C, 68.54; H, 8.63. Found:
C, 68.65; H, 8.70.
1
1437, 1251, 1043, 1003, 840 cmꢀ1. H NMR (200 MHz,
CDCl3): d 0.09 (s, 9H), 1.26 (s, 3H), 1.05–2.3 (m, 10H),
1.87 (d, 3H, J¼1.3 Hz), 2.03 (s, 3H), 3.75 (s, 3H), 4.3 (d,
1H, J¼12 Hz), 4.5 (d, 1H, J¼12 Hz), 4.65 (ddd, 1H, J1¼
8.4 Hz, J2¼8.4 Hz, J3¼4.4 Hz), 6.70 (dq, 1H, J1¼8.4 Hz,
J2¼1.3 Hz) ppm. 13C NMR (50 MHz, CDCl3): d 2.48 (q),
12.75 (q), 21.12 (q), 23.68 (t), 26.99 (t), 30.64 (q), 32.97
(t), 39.11 (d), 39.77 (t), 42.45 (s), 51.88 (q), 52.10 (d),
66.40 (d), 66.96 (t), 78.13 (s), 126.97 (s), 144.06 (d),
168.44 (s), 171.36 (s) ppm. HRMS-EI (M+Na+) calcd for
C21H36O6SiNa: 435.2173, found: 435.2169.
4.4.5. Hydroxyesters 27 and 28. Coupling of aldehyde
12 (0.110 g, 0.61 mmol) and (E)-haloester 18 (0.38 g,
1.2 mmol) afforded 0.37 g of crude product. Fractionation
by flash chromatography on silica gel (hexane/ethyl acetate
8:2) afforded 27 (0.12 g, 54%) and 28 (0.092 g, 41%).
4.4.6.2. Methyl (10R,20R,4R,50S,60S)-(E)-5-(60-acetoxy
methyl-20-trimethylsilyloxy-20-methyl-bicyclo[3.1.1]hept-
60-yl)-4-hydroxy-2-methyl-2-pentenoate 30. Colourless
oil. [a]2D0 ꢀ4.26 (c 0.59, CHCl3). Rf 0.32 (hexane/ethyl

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M. Rodrıguez Lopez, F. A. Bermejo / Tetrahedron 62 (2006) 8095–8102
ꢀ
8101
acetate 7:3). IR (CHCl3): n 3501, 2955, 2932, 2873, 1716,
1651, 1437, 1251, 1044, 1003, 840 cmꢀ1 1H NMR
4.5.4. Unsaturated ketoester 26 (from 25). Periodinane
oxidation of hydroxyester 25 (0.75 g, 0.26 mmol) afforded
26 (0.6 g, 81%).
.
(200 MHz, CDCl3): d 0.11 (s, 9H), 1.26 (s, 3H), 1.85 (d,
3H, J¼1.2 Hz), 1.8–1.9 (m, 4H), 1.99 (s, 3H), 2.0–2.2 (m,
4H), 2.21 (m, 1H), 2.4 (m, 1H), 3.74 (s, 3H), 4.03 (d, 1H,
J¼12.5 Hz), 4.62 (d, 1H, J¼12.4 Hz), 4.67 (ddd, 1H, J1¼
8.8 Hz, J2¼8.8 Hz, J3¼3.6 Hz), 6.7 (dq, 1H, J1¼8.8 Hz,
J2¼1.2 Hz) ppm. 13C NMR (50 MHz, CDCl3): d 2.49 (q),
12.61 (q), 20.92 (q), 23.85 (t), 26.81 (t), 30.48 (q), 32.92
(t), 38.70 (d), 40.02 (t), 42.27 (s), 51.88 (q), 53.25 (d),
66.56 (t), 66.60 (d), 78.28 (s), 126.93 (s), 144.22 (d),
168.39 (s), 170.88 (s) ppm. HRMS-EI (M+Na+) calcd for
C21H36O6SiNa: 435.2173, found: 435.2167.
4.6. Preparation of (D)-massarinolin B (2) and
4-epi-(D)-massarinolin B (4)
4.6.1. (D)-Massarinolin B (2). To an ice-cooled solution of
27 (0.083 g, 0.23 mmol) in anhydrous THF (1.5 mL) a solu-
tion of TBAF (0.180 g, 0.69 mmol) in THF (1 mL) was
added. The reaction mixture was stirred for 2 h at room tem-
perature, poured into water (25 mL), acidified with aq HCl
and extracted with ethyl acetate (3ꢂ25 mL). The combined
extracts were dried (Na2SO4) and concentrated in vacuo to
afford (+)-massarinolin B (2) (0.06 g, 99%). [a]2D0 +49.63
(c 0.72, MeOH). IR (CHCl3): n 3385, 2926, 1696, 1241,
1142, 1009 cmꢀ1. 1H NMR (400 MHz, CD3OD): d 1.23 (s,
3H), 1.51 (m, 1H), 1.61 (m, 1H), 1.77 (m, 1H), 1.83 (m,
1H), 1.84 (d, 3H, J¼1.2 Hz), 1.87 (m, 1H), 1.89 (m, 1H),
2.00 (dd, 1H, J1¼10.8 Hz, J2¼4.1 Hz), 2.13 (m, 1H), 2.15
(m, 1H), 2.30 (m, 1H), 3.60 (d, 1H, J¼9.4 Hz), 3.90 (d,
1H, J¼9.4 Hz), 4.45 (ddd, 1H, J1¼8.9 Hz, J2¼8.6 Hz,
J3¼4.0 Hz), 6.67 (dq, 1H, J1¼8.6 Hz, J2¼1.2 Hz) ppm.
13C NMR (100 MHz, CD3OD): d 12.77 (q), 23.55 (t),
23.78 (t), 25.35 (q), 33.44 (t), 40.27 (d), 41.78 (t), 53.59
(d), 55.54 (s), 67.08 (d), 72.77 (t), 87.65 (s), 128.37 (s),
145.44 (d), 171.37 (s) ppm. HRMS-EI (M+Na+) calcd for
C15H22O4Na: 289.1410, found: 289.1416.
4.5. Periodinane oxidations. General procedure
4.5.1. 2-(Trimethylsilyl)ethyl (10R,40S,60R,70S)-(E)-2-
methyl-5-(10-methyl-90-oxa-80-oxo-tricyclo[4.3.0.04,7]-
non-70-yl)-4-oxo-2-pentenoate 23. To a solution of hydroxy-
ester 21 (0.15 g, 0.40 mmol) in CH2Cl2 (5 mL) Dess–Martin
periodinane (0.25 g, 0.6 mmol) was added. The reaction
mixture was stirred for 5 h at room temperature. Then, 10%
NaCO3H (5 mL) and 10% Na2S2O3 (2.5 mL) were succes-
sively added. The reaction mixture was extracted with ether.
The combined organic layers were washed with brine, dried
(Na2SO4) and evaporated to give a crude product (0.16 g),
which was fractionated by flash chromatography on silica
gel. Elution with hexane/ethyl acetate 8:2 afforded ketoester
23 (0.112 g, 75%) as a colourless oil. [a]2D0 +52.045 (c 0.99,
CHCl3). Rf 0.45 (hexane/ethyl acetate 1:1). IR (KBr): n
3439, 2960, 2925, 1768, 1709, 1621, 1263, 1091, 1000,
4.6.2. 4-epi-(D)-Massarinolin B (4). Fluoride deprotection
of 28 (0.081 g, 0.22 mmol) afforded 4 (0.058 g, 99%). [a]D20
+8.71 (c 1.51, CHCl3). IR (CHCl3): n 3392, 2926, 2866,
1
925, 865, 835 cmꢀ1. H NMR (200 MHz, CDCl3): d 0.03
(s, 9H), 1.02 (dd, 2H, J¼8.6 Hz), 1.51 (s, 3H), 1.70 (d, 1H,
J¼10.0 Hz), 1.90 (s, 4H), 2.15 (m, 1H), 2.18 (s, 3H), 2.4
(m, 1H), 2.7 (m, 1H), 2.94 (d, 1H, J¼19.1 Hz), 3.14 (d, 1H,
J¼19.05 Hz), 4.25 (dd, 2H, J¼8.6 Hz), 7.04 (s, 1H) ppm.
13C NMR (50 MHz, CDCl3): d ꢀ1.67 (q), 14.31 (q), 17.20
(t), 22.66 (t), 22.84 (t), 24.74 (q), 29.87 (t), 40.44 (d), 43.88
(t), 47.31 (d), 53.57 (s), 63.79 (t), 88.25 (s), 130.99 (d),
141.97 (s), 167.41 (s), 177.47 (s), 198.15 (s) ppm. HRMS-
EI (M+Na+) calcd for C20H30O5SiNa: 401.1755, found:
401.1746.
1707, 1238, 1195, 1020 cmꢀ1 1H NMR (400 MHz,
.
CD3OD): d 1.22 (s, 3H), 1.47 (d, 1H, J¼10.2 Hz), 1.59
(m, 1H), 1.73–1.89 (m, 4H), 1.83 (d, 3H, J¼1.2 Hz), 2.09–
2.3 (m, 4H), 2.39 (m, 1H), 3.53 (d, 1H, J¼9.0 Hz), 3.79
(d, 1H, J¼9.0 Hz), 4.91 (ddd, 1H, J1¼9.2 Hz, J2¼9.2 Hz,
J3¼6.8 Hz), 6.63 (dq, 1H, J1¼9.2 Hz, J2¼1.2 Hz) ppm.
13C NMR (100 MHz, CD3OD): d 12.86 (q), 23.41 (t),
23.62 (t), 25.41 (q), 33.39 (t), 41.33 (d), 41.91 (t), 53.45
(d), 55.20 (s), 67.60 (d), 71.98 (t), 88.20 (s), 128.92 (s),
145.06 (d), 171.28 (s) ppm. HRMS-EI (M+Na+) calcd for
C15H22O4Na: 289.1410, found: 289.1409.
4.5.2. Unsaturated ketoester 23 (from 22). Periodinane
oxidation of hydroxyester 22 (0.12 g, 0.31 mmol) afforded
23 (0.096 g, 80%).
4.7. Methyl (10R,20R,4S,50S,60S)-(E)-5-(60-acetoxy methyl-
20-trimethylsilyloxy-20-methyl-bicyclo[3.1.1]hept-60-yl)-
4-tert-butyldiphenylsilyloxy-2-methyl-2-pentenoate 31
4.5.3. Methyl (10R,40S,60R,70S)-(E)-2-methyl-5-(10-methyl-
90-oxa-tricyclo[4.3.0.04,7]non-70-yl)-4-oxo-2-pentenoate
26. Periodinane oxidation of hydroxyester 24 (0.175 g,
0.62 mmol) afforded 26 (0.155 g, 89%). Mp 110–112 ꢁC
(hexane). [a]2D0 +41.7 (c 0.505, CHCl3). Rf 0.46 (hexane/ethyl
acetate 1:1). IR (CHCl3): n 3054, 2920, 2856, 1732, 1626,
To a solution of hydroxyester 29 (65 mg, 0.16 mmol) in
CH2Cl2 at 0 ꢁC were successively added Et3N (0.045 mL,
0.32 mmol), DMAP (4.8 mg, 0.039 mmol) and BuPh2SiCl
t
(0.062 mL, 0.24 mmol). The reaction mixture was stirred
for 48 h at room temperature, diluted with ether (5 mL) and
poured on satd NaHCO3 (5 mL). The mixture was stirred
for 30 min and extracted with ether. The combined organic
layers were successively washed with water and brine, dried
(Na2SO4) and evaporated to yield a crude product (0.23 g),
which was fractionated by flash chromatography on silica
gel. Elution with hexane/ethyl acetate 9:1 afforded 31
(60 mg, 59%) as a colourless oil. [a]2D0 ꢀ20.10 (c 1.25,
CHCl3). Rf 0.54 (hexane/ethyl acetate 7:3). IR (film):
n 2956, 2858, 1737, 1720, 1473, 1251, 859 cmꢀ1. 1H NMR
(400 MHz, CDCl3): d 0.05 (s, 9H), 1.03 (s, 9H), 1.05–2.19
1454, 1264, 1122 cmꢀ1 1H NMR (200 MHz, CDCl3):
.
d 1.26 (s, 3H), 1.5 (d, 1H, J¼10.1 Hz), 1.6–1.8 (m, 4H),
1.95–2.15 (m, 3H), 2.21 (s, 3H), 2.9 (dd, 1H, J1¼13.3 Hz,
J2¼66.7 Hz), 3.39 (d, 1H, J¼9.47 Hz), 3.81 (s, 3H), 4.15
(d, 1H, J¼9.45 Hz), 7.08 (s, 1H) ppm. 13C NMR (50 MHz,
CDCl3): d 14.14 (q), 22.47 (t), 22.76 (t), 24.98 (q), 32.25
(t), 39.67 (d), 49.59 (t), 51.39 (d), 52.39 (q), 52.99 (s),
70.99 (t), 85.74 (s), 131.96 (d), 140.60 (s), 167.80 (s),
200.15 (s) ppm. HRMS-EI (M+H+) calcd for C16H23O4:
279.1591, found: 279.1582.

´
ꢀ
M. Rodrıguez Lopez, F. A. Bermejo / Tetrahedron 62 (2006) 8095–8102
8102
2. For reviews see: (a) Cintas, P. Synthesis 1992, 248–257;
(b) Hodgson, D. M. J. Organomet. Chem. 1994, 476, 1–5;
(c) Hashmi, A. S. K. J. Prakt Chem. 1996, 491–495; (d)
F€urstner, A. Chem.—Eur. J. 1988, 4, 567–570; (e) F€urstner,
A. Chem. Rev. 1999, 99, 991–1045; (f) Wessjohann, L. A.;
Scheid, G. Synthesis 1999, 1–36; (g) Avalos, M.; Babiano,
(m, 9H), 1.22 (d, 3H, J¼1.2 Hz), 1.89 (s, 3H), 2.26 (dd, 1H,
J1¼5.6 Hz, J2¼14.4 Hz), 3.63 (s), 3.93 (d, 1H, J¼12.3 Hz),
4.37 (d, 1H, J¼12.3 Hz), 4.58 (m, 1H), 6.59 (dq, 1H,
J1¼1.4 Hz, J2¼9.4 Hz), 7.32–7.66 (m, 10H) ppm. 13C
NMR (100 MHz, CDCl3): d 2.43 (q), 12.38 (q), 19.19 (s),
20.95 (q), 23.59 (t), 26.93 (q), 30.71 (q), 32.64 (t), 39.13
(d), 40.51 (t), 41.80 (s), 51.61 (q), 52.05 (d), 66.26 (t),
68.24 (d), 78.07 (s), 125.87 (s), 127.33 (d), 127.54 (d),
129.47 (d), 129.62 (d), 133.66 (s), 133.92 (s), 135.85 (d),
143.98 (d), 168.19 (s), 170.96 (s) ppm. HRMS-EI (M+Na+)
calcd for C37H54O36Si2Na: 673.3351, found: 673.3370.
ꢀ
R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Chem. Soc. Rev.
1999, 28, 169–177; (h) Takai, K.; Nozaki, H. Proc. Jpn.
Acad., Ser. B 2000, 76, 123–131; (i) Bandini, M.; Cozzi,
P. G.; Umani-Ronchi, A. Chem. Commun. 2002, 919–927.
3. Kimura, Y.; Nakajima, H.; Hamasaki, T.; Sugawara, F.;
Parkanyi, L.; Clardy, J. Tetrahedron Lett. 1989, 30, 1267–1270.
4. Mori, K.; Matsushima, Y. Synthesis 1993, 406–410.
5. (a) Bermejo, F. A.; Rico-Ferreira, R.; Bamidele-Sanni, S.;
Garcia-Granda, S. J. Org. Chem. 2001, 66, 8287–8292; (b)
Rico, R.; Zapico, J.; Bermejo, F.; Bamidele-Sanni, S.;
4.8. Methyl (10R,20R,4S,50S,60S)-(E)-5-(60-acetoxy methyl-
20-hydroxy-20-methyl-bicyclo[3.1.1]-hept-6-yl)-4-tert-
butyldiphenylsilyloxy-2-methyl-2-pentenoate 32
´
Garcıa-Granda, S. Tetrahedron: Asymmetry 1998, 9, 293–303.
To a solution of 31 (130 mg, 0.20 mmol) in MeOH (5 mL)
PPTS (50.3 mg, 0.2 mmol) was added. The mixture was
stirred for 30 min. To the ice-cooled mixture was added
satd NaHCO3 (5 mL) and the reaction mixture was further
stirred for 30 min. The crude mixture was extracted with
ether and the combined organic layers were washed with
brine. The organic phase was dried with Na2SO4 and evapo-
rated to yield a crude (0.13 g), which was fractionated by
flash chromatography on silica gel (hexane/ethyl acetate
8:2) to afford 32 (60 mg, 52%). [a]2D0 +9.9 (c 0.78, CHCl3).
Rf 0.37 (hexane/ethyl acetate 1:1). IR (film): n 3350, 2858,
6. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644–5646; (b) Takai, K.; Tagashira, M.; Kuroda,
T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc.
1986, 108, 6048–6050; (c) Knochel, P.; Rao, C. J.
Tetrahedron 1993, 49, 29–48.
7. Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1995,
5386–5387.
8. Obtained by DCC coupling of (E)-3-iodo-2-methylpropen-
2-oic acid with 2-(trimethylsilyl)ethanol. See: Sieber, P.
Helv. Chim. Acta 1977, 60, 2711–2716.
1737, 1720, 1473, 1251, 1050, 859 cmꢀ1 1H NMR
.
9. Still, W. C.; Kahn, M.; Mitra, A. R. J. Org. Chem. 1978, 43,
2923–2925.
(200 MHz, CDCl3): d 1.03 (s, 9H), 1.19 (d, 3H, J¼12 Hz),
1.25–2.30 (m, 10H), 1.91 (s, 3H), 3.63 (s, 3H), 4.24 (s,
2H), 4.58 (q, 1H, J1¼6.7 Hz, J2¼15.3 Hz), 6.59 (d, 1H,
J¼9 Hz), 7.30–7.66 (m, 10H) ppm. 13C NMR (50 MHz,
CDCl3): d 12.32 (q), 19.19 (s), 20.80 (q), 23.58 (t), 27.00
(q), 27.54 (t), 29.63 (t), 31.71 (q), 38.88 (d), 40.33 (t),
42.16 (s), 51.55 (q), 51.55 (d), 66.21 (t), 68.44 (d), 75.18
(s), 125.92 (s), 127.34 (d), 127.60 (d), 129.56 (d), 129.69
(d), 133.68 (s), 133.93 (s), 135.92 (d), 144.18 (d), 168.23
(s), 170.73 (s) ppm. HRMS-EI (M+Na+) calcd for C34H46O6-
Si2Na: 601.2956, found: 601.2965.
10. Satisfactorial spectroscopic data for compounds described in
Table 1 and Schemes 1 and 2 have been obtained. See Section 4.
11. Transformation of the mixture of diastereomers 24 and 25 into
the corresponding a-O-acetyl-mandelic esters gave no results
in terms of a more efficient chromatographic separation. The
mixture of 24 and 25 was treated with (S)-(+)-O-acetylman-
delic acid, DCC and DMAP in THF at room temperature for
15 h to yield a mixture of (S)-(+)-O-acetylmandelic esters
with 72% yield. See: Bandini, M.; Cozzi, P. G.; Umani-
Ronchi, A. Angew. Chem., Int. Ed. 2000, 39, 2327–2330.
12. The spectroscopic data obtained for synthetic (+)-(2) were su-
perimposable over those described by Gloer for (+)-massarino-
lin B. [a]2D0 +50 (c 0.72 g/dL, CH3OH); lit. [a]2D0 +54 (c 0.65 g/
dL, CH3OH). Structural assignments of 2 and 4 were based
mainly on HMQC, HMBC and ROESY experiments.
13. The absolute stereochemistry of the tricyclic core of synthetic
(+)-isoampullicin (7) has been correlated with that of R-(ꢀ)-
carvone through a stereocontrolled multistep synthetic se-
quence. Furthermore, the X-ray analysis of 7 has been reported
(see Ref. 5a).
Acknowledgements
We are grateful for the financial support for this work from
ꢀ
ꢀ
´
the Spanish Direccion General de Investigacion Cientıfica
y Tecnica (DGICYT PPQ2002-00290) and the Junta de
ꢀ
ꢀ
Castilla y Leon (SA027/03).
Supplementary data
14. Paterson, I.; Bergmann, H.; Menche, D.; Berkessel, A. Org.
Lett. 2004, 6, 1293–1295.
Spectroscopic data for compounds described in Schemes 1
and 2 and Table 1. HMQC, HMBC, COSY and ROESY
experiments for 27, 28, 29, 30, 2 and 4. Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2006.06.011.
15. Hydroxyester 29 was sequentially transformed (two steps) into
hydroxyester 32 with excellent yields (65% isolated yield).
Unfortunately, the stereochemical integrity at C-4 did not sur-
vive even under mild dehydration conditions (treatment of 32
with trifluoromethylsulfonic anhydride and dimethyl amino-
pyridine in methylene chloride at room temperature took 5
days for completion) and afforded only untreatable mixtures
of diastereomers belonging to the a and b series of the dehy-
drated products.
References and notes
1. Oh, H.; Gloer, J. B.; Shearer, C. A. J. Nat. Prod. 1999, 62,
497–501.