Towards the synthesis of the cornexistins

Article abstract of DOI:10.1055/s-2007-983769

A concise synthetic route to the carbocyclic core of the cornexistins is reported. The route is highlighted by a Diels-Alder cycloaddition/oxidative cleavage strategy to generate the central highly functionalized nine-member ring. A silyl-tethered ring-cl

Full text of DOI:10.1055/s-2007-983769

2388
PAPER
Towards the Synthesis of the Cornexistins
Towards
t
a
he Total Sy
m
nthesis of the Corne
e
xistins s C. Tung,a Wensheng Chen,a Bruce C. Noll,a Richard E. Taylor,*a Stephen C. Fields,b William H. Dent III,b
F. Richard Green IIIb
a
251 Nieuwland Hall of Science, University of Notre Dame, Notre Dame, IN 46556, USA
Discovery Research, Dow Agrosciences, Inc., 9330 Zionsville Road, Indianapolis, IN 46268-1054, USA
b
Fax +1(574)6316652; E-mail: taylor.61@nd.edu
Received 1 March 2007
Dedicated to Professor Paul Wender on the occasion of his 60th birthday
ities, and pendant alkyl groups. In contrast to other
nonadrides, cornexistin distinguishes its structure as a
consequence of significant biosynthetic oxidative pro-
cessing. Outside of the best-known example of the nona-
Abstract: A concise synthetic route to the carbocyclic core of the
cornexistins is reported. The route is highlighted by a Diels–Alder
cycloaddition/oxidative cleavage strategy to generate the central
highly functionalized nine-member ring. A silyl-tethered ring-clos-
ing metathesis strategy is utilized to control trisubstituted alkene ge- drides, the phomoidrides,4 this remains a relatively
ometry.
unexplored field in the synthetic community. Notable
amongst previous nonadride syntheses are Stork’s early
synthesis of byssochlamic acid,5 and White’s more recent
enantioselective total syntheses of byssochlamic acid.6
Clark has published synthetic routes to cornexistin, in-
cluding the use of ring-closing metathesis (RCM) technol-
ogy to close the nine-membered ring.7
Key words: Diels–Alder, oxidative cleavage, natural products, ring
expansion, ring-closing metathesis, carbocycle
Cornexistin (1) (Figure 1) was isolated by Sankyo and re-
ported in 1991.1 A fungal metabolite of Paecilomyces var-
iottii SANK 21086, cornexistin has potent herbicidal
activity against broadleaf weed species. At that level of
activity, maize plants are insensitive to cornexistin’s ef-
fects. In 1991, an additional metabolite was found by Dow
Agrosciences to be the 14-hydroxy analogue of cornexis-
tin;2 14-hydroxycornexistin (2) is at least as active as
cornexistin, if not more. Both of these molecules are of
practical interest to the agrochemical community and are
interesting to the synthetic community in terms of their
unique structure and functionality.
Our retrosynthesis of the cornexistins (Figure 2) began
with the recognition of inherent symmetry of functionality
within the nine-membered-ring system. By bisecting the
molecule horizontally and noting that oxidation state is
fungible, each substituent is mirrored across the ring with
the exception of the C3 propyl group. Such a reductionist
approach brought us to 3, where a chemoselective oxida-
tive cleavage would expose a nine-membered cyclic dike-
tone. This cyclohexa-1,4-diene could be clearly derived
from a Diels–Alder reaction of dienophile dimethyl acet-
ylenedicarboxylate and readily available 4 as the neces-
sary diene. This strategy is quite reminiscent of Wender’s
metathetical approach to medium-ring carbocycles.8
OH
OH
O
OH
O
O
8
OTBS
O
OH
O
1
O
O
MeO2C
MeO2C
O
O
O
O
OH
OH
OPMB
O
OH
1: cornexistin
2: 14-hydroxycornexistin
3
Figure 1 Cornexistin (1) and 14-hydroxycornexistin (2), herbicidal
natural products
OTBS
OPMB
CO2Me
CO2Me
Cornexistin is a member of the nonadride family, which
was defined by Barton and Sutherland3 as a class of mol-
ecules that have their biogenesis from the dimerization of
nine carbon maleic anhydride units. They typically con-
tain a nine-membered ring, maleic anhydride functional-
4
Figure 2 Retrosynthesis towards cornexistin via Diels–Alder/
oxidative cleavage strategy
SYNTHESIS 2007, No. 15, pp 2388–2396
Advanced online publication: 26.07.2007
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x.
x
x
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2
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DOI: 10.1055/s-2007-983769; Art ID: C00907SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Towards the Total Synthesis of the Cornexistins
2389
The synthesis of the cyclopentadiene (Scheme 1) began
with the aldehyde 5,9 which was reacted with lithiated
pentyne to give the desired alcohol in 91% yield. The re-
sulting alcohol was protected as the 4-methoxybenzyl
ether, the tert-butyldimethylsilyl ether was removed using
tetrabutylammonium fluoride, and the resulting alcohol
oxidized using Swern conditions to provide the desired al-
dehyde 7 in three steps in 70% yield. Aldehyde 7 was im-
mediately used in the following reaction, where it was
reacted with lithiated (trimethylsilyl)acetylene to provide
the syn- and anti-diastereomers.10 Through careful col-
umn chromatography, the diastereomers were separated
and the desired syn-diastereomer was obtained in good
yield. (A Mitsunobu inversion11 was used to convert the
anti-diastereomer into the syn in moderate yield.)
Figure 3 ORTEP representation of cyclohexadiene 3
With this key intermediate in hand, 3 was oxidatively
cleaved to reveal the diketone (Scheme 2). Despite the ex-
ploration of several different reagents and conditions for
alkenation of the C7 ketone, Tebbe’s reagent14 and an ex-
cess of pyridine gave the desired alkene 9 in moderate
yield. Then, sodium borohydride reduction of the C2 ke-
tone gave product alcohol 10 in excellent yield as a single
diastereomer.
The desilylation of the terminal alkyne was carried out
with tetrabutylammonium fluoride deprotection and the
free alcohol was protected under standard conditions as
the tert-butyldimethylsilyl ether. Diyne 8 was subjected to
Trost reductive cyclization12 conditions to provide the cy-
clopentadiene 4 in excellent yield. It was then reacted with
dimethyl acetylenedicarboxylate to provide the desired
cyclohexadiene 3 in moderate yield. The stereochemical
relationship between the propyl group and the 4-meth-
oxybenzyl (PMB) ether was under question and ROESY
analysis was unfortunately equivocal.
OTBS
OTBS
7
1. ozone
2. Tebbe
MeO2C
MeO2C
MeO2C
45%, 2 steps
2
MeO2C
OPMB
OPMB
O
OH
9
3
O
pent-1-yne, n-BuLi
TBSO
TBSO
91%
6
5
NaBH4
98%
1. PMBBr, NaH
2. TBAF
3. Swern [O]
70%, 3 steps
1. TMS-acetylene,
OTBS
OTBS
n-BuLi
2. TBAF
3. TBSCl
OPMB
OTBS OPMB
O
MeO2C
MeO2C
MeO2C
Ac2O
70%
1
2
8
3
2
OPMB
MeO2C
50%, 3 steps
7
OPMB
H
H
OAc
OH
10
H
11
Pd2(dba)3⋅CHCl3
Et3SiH, AcOH
98% yield
OTBS
10 Hz H–H
coupling
strong NOE,
2 Hz H–H
coupling
OTBS
OPMB
DMAD,
hydroquinone
Scheme 2
MeO2C
MeO2C
50%
A number of attempts were made to crystallize this prod-
uct, including derivatization to the 4-bromobenzoate or
the phenyl carbamate. Unfortunately, neither compound
was crystalline. NMR analysis of the corresponding ace-
tate 11 revealed a strong NOE between the C2 and C3 hy-
drogens. Additionally, the multiplicity of the C2 proton
supported the 1,2-trans-2,3-cis relationship. Moreover,
computer-based molecular modeling experiments provid-
ed a number of low energy conformations that fit this
analysis. Although this was not definitive proof, it sug-
gested the assignments of 10 and 11 in Scheme 2.
OPMB
4
3
Scheme 1
However, we were able to obtain a crystal for X-ray anal-
ysis. It revealed that the relationship between the propyl
group and the 4-methoxybenzyl ether was anti and thus
the facial selectivity of the cycloaddition was controlled
by the expected steric influences (Figure 3).13
Completion of the carbon skeleton of the cornexistins re-
quired stereoselective alkylation of the 1,1-disubstituted
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

2390
J. C. Tung et al.
PAPER
alkene. To achieve this aim, we considered the use of a
temporary silicon tether.15 Silyl group exchange provided
ring-closing metathesis precursor 13 (Scheme 3). Unfor-
tunately, only dimeric products were obtained regardless
of the choice of ring-closing metathesis catalyst.
OH
OH
1. DMP
2. NaBH4
MeO2C
MeO2C
MeO2C
60%, 2 steps
OPMB
MeO2C
OPMB
OAc
12
15
OAc
OTBS
OH
TBAF, THF
87%
MeO2C
MeO2C
MeO2C
MeO2C
allylSi(Me)2Cl, Et3N, CH2Cl2
50%
OPMB
OPMB
12
OAc
OAc
11
Si
O
Si
O
allylSi(Me)2Cl,
Et3N, CH2Cl2
50%
O
14, CH2Cl2,
reflux
MeO2C
MeO2C
MeO2C
MeO2C
Mes
Ph
N
N
Mes
Cl
quant.
OPMB
OPMB
Ru
P(Cy)3
CH2Cl2, reflux
14
Si
17
16
OAc
OAc
Cl
MeO2C
no reaction
Scheme 4
MeO2C
13
OPMB
OAc
In summary, we have generated complex nine-membered-
ring carbocycles through the use of a Diels–Alder strategy
and subsequent oxidative cleavage. This route has the
ability to install the required functionality towards the her-
bicidal natural products hydroxycornexistin and cornexis-
tin, including the use of ring-closing metathesis
technology to install the desired geometry of an exocyclic
ethylidene. Further efforts will be reported in due course.
Scheme 3
It was suspected that the molecule was in an inappropriate
conformation for the ring-closing metathesis. To alter the
conformation of 13, inversion of the alcohol stereocenter
at C8 was accomplished. While Mitsunobu inversion re-
sulted in elimination, an oxidation–reduction sequence
was quite fruitful. Dess–Martin oxidation of 12 followed
by simple sodium borohydride reduction provided the in-
verted C8 of 15 (Scheme 4) in good yield with a moderate
diastereomeric ratio (4:1). Silyl protection gave desired
Unless otherwise noted, all materials were used as received from a
commercial supplier and used without further purification. All reac-
tions were performed using oven-dried glassware and under an N2
atmosphere unless otherwise noted. THF, CH2Cl2, Et2O, and tolu-
allyldimethylsilyl ether 16 in 50% yield, which was re- ene were filtered through activated alumina under N2. DMSO was
purchased from a commercial supplier. All reactions were moni-
fluxed in dichloromethane with a catalytic amount of
Grubbs’ second-generation ruthenium catalyst 14;16 this
gave desired siloxacycle 17 in quantitative yield.
tored by E. Merck analytical TLC plates (silica gel 60 GF, glass
back) and analyzed with 254 nm UV light and anisaldehyde/H2SO4
treatment. Silica gel for column chromatography was purchased
Having generated 17 successfully, we turned to the ma-
nipulation of said siloxacycle to provide both cornexistin
and hydroxycornexistin. Initial attempts at protodesilyl-
ation of 17 have thus far demonstrated a surprising lack of
reactivity. However, inclusion of hydrogen peroxide led
to Tamao–Fleming oxidation and diol 18 was obtained in
quantitative yield (Scheme 5).15c,17
from E. Merck (Silica Gel 60, 230–400 mesh). Biotage chromatog-
raphy was performed using Flash 12+M, 25+S, 25+M, and 40+M
KP-Sil Silica (32–63 mM, 60 Å, nominally 500 m2/g silica) cartrid-
1
ges. All H and 13C NMR spectra were obtained on Varian Unity
Plus 300 and 500 spectrometers (operating at 299.701 and 499.864
MHz for 1H and 75.368 MHz and 125.706 MHz for 13C, respective-
ly); CHCl3 was used as an internal reference (1H: d = 7.26, 13C: d =
77.00). FT-IR spectra were obtained on a Perkin-Elmer Paragon
1000 spectrophotometer. MS (FAB) were obtained using 3-ni-
trobenzyl alcohol (NBA) as a matrix using either a JEOL
AX505HA or JEOL JMS-GCmate mass spectrometer.
OH
Si
KF, H2O2,
KHCO3,
THF, MeOH
O
OH
1-(tert-Butyldimethylsiloxy)oct-4-yn-3-ol (6)
To a soln of pent-1-yne (6.09 mL, 0.062 mol, 1.2 equiv) in THF (50
mL) cooled to –78 °C was added 2.5 M BuLi in hexanes (26.83 mL,
0.067 mol, 1.3 equiv) and the mixture was stirred for 30 min. The
bath temperature was then warmed to 0 °C for 5 min and then re-
cooled to –78 °C. 3-(tert-Butyldimethylsiloxy)propanal (5, 9.7 g,
0.052 mol) in THF (25 mL) was added slowly to the mixture. The
round-bottom flask was transferred to a 0 °C ice bath and stirred for
4 h. After TLC analysis revealed the completion of the reaction, the
MeO2C
MeO2C
MeO2C
MeO2C
quant.
OPMB
OPMB
OAc
OAc
17
18
Scheme 5
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

PAPER
Towards the Total Synthesis of the Cornexistins
2391
reaction was quenched using sat. NH4Cl soln and diluted with
EtOAc. The aqueous layer was extracted with EtOAc and the com-
bined organic layers were washed with sat. NaHCO3 soln, brine,
and H2O. After drying (MgSO4), the organic layer was concentrated
to give a crude yellow oil (12.24 g, 91%). The material was used
further without purification.
(d, J = 11.4 Hz, 1 H, OCH2C6H4OMe), 4.48–4.44 (d, J = 11.4 Hz,
1 H, OCH2C6H4OMe), 4.30–4.28 [tt, J = 5.86, 1.96 Hz, 1 H,
CH(OPMB)], 3.90–3.80 (m, 1 H, CH2OH), 3.80 (s, 3 H,
C6H4OCH3), 3.80–3.70 (m, 1 H, CH2OH), 2.27–2.20 (td, J = 6.96,
1.96 Hz, 2 H, C≡CCH2CH2CH3), 2.01–1.90 [dd, J = 5.62, 11.36 Hz,
2 H, CH2CH(OPMB)], 1.61–1.50 (sextet, 2 H, C≡CCH2CH2CH3),
1.0 (t, J = 7.2 Hz, 3 H, C≡CCH2CH2CH3).
13C NMR (75 MHz, CDCl3): d = 159.6, 130.0, 129.9, 114.1, 87.5,
78.6, 70.4, 68.0, 60.7, 55.5, 38.5, 22.4, 21.0, 13.8.
HRMS-FAB: m/z [M]+ calcd for C16H22O3: 262.1553; found:
262.1569.
IR (thin film): 2957, 2931, 2857, 2234, 1613, 1586, 1514, 1463,
1249, 1098, 1038, 834, 776 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.64–4.54 (m, 1 H, CHOH), 4.08–
3.98 (m, 1 H, CH2OTBS), 3.86–3.75 (m, 1 H, CH2OTBS), 3.30 (d,
J = 5.12 Hz, 1 H, CHOH), 2.19 (dt, J = 6.96, 2.2 Hz, 2 H,
CH2CHOH), 2.02–1.88 (m, 2 H, C≡CCH2CH2CH3), 1.54 (sextet,
J = 6.96 Hz, 2 H, C≡CCH2CH2CH3), 1.0 (t, J = 7.2 Hz, 3 H,
C≡CCH2CH2CH3), 0.93 [s, 9 H, OSi(C(CH3)3)Me2], 0.1 [s, 6 H,
OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3): d = 86.6, 79.5, 70.3, 55.5, 39.5, 26.2,
22.5, 21.0, 13.8, –5.1.
HRMS-FAB: m/z [M + H]+ calcd for C14H29O2Si: 257.1921; found
257.1937.
3-(4-Methoxybenzyloxy)oct-4-ynal (7)
To a soln of oxalyl chloride (0.745 mL, 8.69 mmol, 1.6 equiv) dis-
solved in CH2Cl2 (15.4 mL, cooled to –78 °C) was added dropwise
DMSO (1.22 mL, 17.1 mmol, 3.13 equiv). The mixture was stirred
for 30 min and then 3-(4-methoxybenzyloxy)oct-4-yn-1-ol (1.43 g,
5.45 mmol) in CH2Cl2 (2 mL) was added followed immediately by
the addition of Et3N (2.5 mL, 17.9 mmol). After 15 min (and the for-
mation of a white slurry in the mixture), Et3N (2.5 mL, 17.9 mmol)
was again added and the reaction was warmed to 0 °C and stirred
for 1 h. The mixture was then diluted with Et2O (40 mL) and washed
with sat. NaHCO3, brine, and H2O, dried and concentrated to give a
brown oil that was subjected to column chromatography (silica gel).
This gave 7 as a pale yellow oil (1.02 g, 72% yield), which was sub-
jected immediately to the following reaction.
1-(tert-Butyldimethylsiloxy)-3-(4-methoxybenzyloxy)oct-4-yne
To a soln of 6 (4 g, 0.016 mol) in anhyd DMF (40 mL) at –10 °C
was added slowly NaH (95%, 1.49 g, 4 equiv) and the mixture was
stirred for 30 min. A soln of 4-methoxybenzyl bromide (4.7 g, 0.023
mol) dissolved in anhyd THF (20 mL) was added slowly to the soln
with a catalytic amount of TBAI and the reaction was stirred at 0 °C
for 2 h. After TLC analysis revealed that the reaction was complete,
the reaction was quenched very slowly with sat. NaHCO3 (10 mL)
and diluted with Et2O. The aqueous layer was extracted with Et2O
and the combined organic layers were washed with brine and H2O
(3 ×). After drying (MgSO4), the organic layer was concentrated to
give a pale-yellow oil, which was purified by chromatography (sil-
ica gel) to give the desired product (5.64 g, 94%).
IR (thin film): 2963, 2934, 2871, 2837, 2727, 2231, 1728, 1613,
1514, 1464, 1336, 1302, 1249, 1174, 1073, 1035, 823, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.34 (t, J = 2.24 Hz, 1 H,
CH2CHO), 7.29 (d, J = 8.8 Hz, 2 H, C6H4OMe), 6.89 (d, J = 8.8
Hz, 2 H, C6H4OMe), 4.79 (d, J = 11.4 Hz, 1 H, OCH2C6H4OMe),
4.45 (d, J = 11.4 Hz, 1 H, OCH2C6H4OMe), 4.52 [tt, J = 5.86, 1.96
Hz, 1 H, CH(OPMB)], 3.80 (s, 3 H, C6H4OCH3), 2.86–2.68 [m, 2
H, CH(OPMB)CH2CHO], 2.27 (td, J = 6.96, 1.96 Hz, 2 H,
IR (thin film): 2957, 2931, 2857, 2234, 1613, 1586, 1514, 1463,
1249, 1098, 1038, 834, 776 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32 (d, J = 8.5 Hz, 2 H,
C6H4OMe), 6.90 (d, J = 8.5 Hz, 2 H, C6H4OMe), 4.71 (d, J = 11
C≡CCH2CH2CH3), 1.61 (sextet, J = 7.25 Hz,
2
H,
C≡CCH2CH2CH3), 1.0 (t, J = 7.2 Hz, 3 H, C≡CH2CH2CH3).
13C NMR (75 MHz, CDCl3): d = 200.6, 159.6, 130.0, 129.8, 114.0,
88.4, 76.9, 70.4, 63.5, 55.5, 49.4, 22.3, 20.9, 13.7
HRMS-FAB: m/z [M]+ calcd for C16H20O3: 260.1412, found:
260.1426.
Hz,
1 H, OCH2C6H4OMe), 4.45 (d, J = 11 Hz, 1 H,
OCH2C6H4OMe), 4.29 [ddd, J = 7.5, 6, 2.2 Hz, 1 H, CH(OPMB)],
3.79–3.69 (m, 2 H, CH2OTBS), 3.80 (s, 3 H, C6H4OCH3), 2.33 [dt,
J = 6.96, 1.95 Hz, 2 H, CH2CH(OPMB)], 2.05–1.80 (m, 2 H,
C≡CCH2CH2CH3), 1.61–1.50 (sextet, 2 H, CCCH2CH2CH3), 1.0 (t,
5-(4-Methoxybenzyloxy)-1-(trimethylsilyl)deca-1,6-diyn-3-ol
To a soln of (trimethylsilyl)acetylene (0.82 mL, 5.77 mmol, 1.2
equiv) dissolved in anhyd THF (10 mL) (cooled to –78 °C) was
added a soln of 2.6 M BuLi in hexanes (2.22 mL, 5.77 mmol, 1.2
equiv) and the mixture was stirred for 30 min. The soln was then
warmed to 0 °C for 5 min and recooled to –78 °C. 3-(4-Methoxy-
benzyloxy)oct-4-ynal (1.25 g, 4.81 mmol) dissolved in THF (5 mL)
was added slowly to the mixture. The mixture was stirred for 4 h at
0 °C. After TLC analysis showed the reaction was complete, it was
quenched with the addition of sat. NH4Cl (5 mL) and separated. The
aqueous layers were extracted with EtOAc (3 ×) and the combined
organic layers were washed with brine and H2O, concentrated, and
dried (MgSO4). The crude yellow oil was then subjected to careful
purification via column chromatography (silica gel) to give the de-
sired syn-product (0.78 g) and its anti-diastereomer (0.45 g) (71%
overall yield).
J = 7.21 Hz,
3
H, CCCH2CH2CH3), 0.93 [s,
9
H,
OSi(C(CH3)3)Me2], 0.1 [s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3): d = 159.4, 130.6, 129.9, 114.0, 86.6,
79.5, 70.3, 65.9, 59.6, 55.5, 39.5, 26.2, 22.5, 21.0, 13.8, –5.1.
HRMS-FAB: m/z [M – H]+ calcd for C22H35O3Si: 375.2333; found:
375.2355.
3-(4-Methoxybenzyloxy)oct-4-yn-1-ol
To a soln of 1-(tert-butyldimethylsiloxy)-3-(4-methoxybenzyl-
oxy)oct-4-yne (6.3 g, 0.017 mol) in THF (25 mL) was added 1 M
TBAF in THF (25.1 mL, 0.025 mol, 1.5 equiv) and the mixture was
stirred for 3 h. After completion of the reaction, the reaction was
quenched with sat. NaHCO3 (10 mL) and separated. The aqueous
layer was extracted with EtOAc; the recombined organic layers
were washed with brine and subsequently dried and concentrated.
Purification by chromatography (silica gel) gave a pale-yellow oil
(4.30 g, 96%).
syn-Diastereomer
IR (thin film): 3432, 2962, 2935, 2871, 2837, 2173, 1613, 1586,
1514, 1249, 1174, 1089, 1072, 1036, 844, 760 cm–1.
IR (thin film): 3422 (bs), 2961, 2933, 2871, 2837, 2232, 1612, 1514,
1248, 1036, 822, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.29 (d, J = 8.8 Hz, 2 H,
C6H4OMe), 6.92–6.89 (d, J = 8.8 Hz, 2 H, C6H4OMe), 4.79–4.75
1H NMR (300 MHz, CDCl3): d = 7.28 (d, J = 8 Hz, 2 H, C6H4OMe),
6.84 (d, J = 8 Hz, 2 H, C6H4OMe), 4.73 (d, J = 11.1 Hz, 1 H,
OCH2C6H4OMe), 4.62 [td, J = 8.55, 4.57 Hz, 1 H, CH(OPMB)],
4.46 (d, J = 11.3 Hz, 1 H, OCH2C6H4OMe), 4.27 [ddd, J = 7.33,
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

2392
J. C. Tung et al.
PAPER
3.97, 2.14 Hz, 1 H, CH(OH)], 3.81 (s, 3 H, C6H4OCH3), 2.75 (d,
J = 4.27 Hz, 1 H, CHOH), 2.30–2.22 [m, 3 H, CH2CH(OPMB),
C≡CCHaHbCH2CH3], 2.05–1.91 (m, 1 H, C≡CCHaHbCH2CH3),
1.59 (sextet, J = 7 Hz, 2 H, C≡CCH2CH2CH3), 1.0 (t, J = 7 Hz, 3 H,
C≡CCH2CH2CH3), 0.1 [s, 9 H, OSiC(CH3)3].
13C NMR (75 MHz, CDCl3): d = 159.6, 130.0, 129.9, 114.1, 105.9,
89.7, 87.7, 78.4, 70.4, 67.0, 61.4, 55.5, 43.9, 22.3, 21.0, 13.8, 0.1.
1-(tert-Butyldimethylsiloxy)-3-butylidene-4-(4-methoxybenzyl-
oxy)-2-methylenecyclopentane (4)
To a soln of benzene (6 mL, degassed for 10 min) at r.t. was added
Pd2(dba)3 (42 mg, 0.041 mmol, 0.025 equiv) and tri-o-tolylphos-
phine (50 mg, 0.164 mmol, 0.1 equiv) and the mixture was stirred
for 5 min. After 5 min, glacial AcOH (0.188 mL, 3.28 mmol, 2
equiv) and Et3SiH (2.62 mL, 16.4 mmol, 10 equiv) was added and
the mixture was stirred for 5 min. After 5 min, a soln of diyne 8
(0.657 g, 1.64 mmol) dissolved in benzene (5 mL) was added and
the mixture was stirred for exactly 1 h. The mixture was then con-
centrated to a thick black slurry and loaded onto a chromatography
column (silica gel) for immediate purification; elution gave 4 as a
pale yellow oil (0.651 g, 99%).
HRMS-FAB: m/z [M – 1]+ calcd for C21H29O3Si: 357.1886; found:
357.1860.
anti-Diastereomer
IR (thin film): 3449, 2962, 29334, 2872, 2837, 2172, 1617, 1587,
1514, 1249, 1174, 1070, 1036, 843, 760 cm–1.
IR (thin film): 3309, 2959, 2953, 2858, 2225, 1613, 1587, 1514,
1464, 1250, 1094, 1039, 839, 779, 657 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29 (d, J = 8 Hz, 2 H, C6H4OMe),
6.85 (d, J = 8 Hz, 2 H, C6H4OMe), 4.76 (d, J = 11.2 Hz, 1 H,
OCH2C6H4OMe), 4.62 [ddd, J = 12.67, 6.63, 2.19 Hz, 1 H, CH(OP-
MB)], 4.54 (ddd, J = 8.56, 3.85, 1.93 Hz, 1 H, CHOH), 4.44 (d,
J = 10.9 Hz, 1 H, OCH2C6H4OMe), 3.81 (s, 3 H, C6H4OCH3), 2.75
(d, J = 6.85 Hz, 1 H, CHOH), 2.33–2.06 [m, 4 H, CH2CH(OPMB),
C≡CCH2CH2CH3], 1.59 (sextet, J = 7 Hz, 2 H, C≡CCH2CH2CH3),
1.03 (t, J = 7 Hz, 3 H, C≡CCH2CH2CH3), 0.1 [s, 9 H, OSiC(CH3)3].
13C NMR (75 MHz, CDCl3): d = 159.6, 130.0, 129.7, 114.1, 106.0,
89.7, 87.7, 78.1, 70.8, 67.2, 61.1, 55.5, 42.8, 22.3, 21.0, 13.8, 0.15.
HRMS-FAB: m/z [M – 1]+ calcd for C21H29O3Si: 357.1886; found:
357.1867.
1H NMR (300 MHz, CDCl3): d = 7.30 (d, J = 8 Hz, 2 H,
C6H4OMe), 6.90 (d, J = 8 Hz, 2 H, C6H4OMe), 6.1 (td, J = 6.1 Hz,
2.3 Hz, 1 H, =CHPr), 5.30 (d, J = 2.3 Hz, 1 H, C=CHaHb), 4.91 (d,
J = 2.3 Hz, 1 H, C=CHaHb), 4.52–4.44 [d, J = 11 Hz, 1 H,
OCHaHbC6H4OMe and m, 1 H, CH(OPMB)], 4.40–4.33 [d, J = 11
Hz, 1 H, OCHaHbC6H4OMe and m, 1 H, CH(OTBS)], 3.80 (s, 3 H,
C6H4OCH3), 2.49–2.38 [m, 1 H, CH(OTBS)CHaHbCH(OPMB)],
2.29–2.15
=CHCHaHbCH2CH3], 1.76–1.68 (m, 1 H, =CHCHaHbCH2CH3),
1.42–1.2 (m, H, =CHCH2CH2CH3), 0.8 [s, H,
[m,
2
H,
CH(OTBS)CHaHbCH(OPMB),
2
9
OSi(C(CH3)3)Me2], 0.7 (t, J = 7 Hz, 3 H, =CHCH2CH2CH3), 0.06 [2
s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3): d = 159.3, 151.6, 137.4, 129.8, 129.4,
129.3, 113.9, 102.7, 75.2, 72.6, 69.3, 55.5, 40.3, 30.9, 26.2, 22.9,
18.5, 14.3, –4.3, –4.5.
HRMS-FAB: m/z [M + H]+ calcd for C24H39O3Si: 403.2668; found:
403.2649.
3-(tert-Butyldimethylsiloxy)-5-(4-methoxybenzyloxy)deca-1,6-
diyne (8)
To a soln of 5-(4-methoxybenzyloxy)-1-(trimethylsilyl)deca-1,6-
diyn-3-ol (0.781 g, 2.18 mmol) dissolved in THF (25 mL) and add-
ed 1 M TBAF in THF (3.27 mL, 3.27 mmol, 1.5 equiv). The reac-
tion was stirred for 3 h. Upon completion of the reaction, it was
quenched with sat. NaHCO3. The aqueous layer was extracted with
EtOAc and the combined organic layers were washed with brine
and H2O, dried, and concentrated. The crude product was not puri-
fied but subjected immediately to the next reaction. The crude alco-
hol mixture was dissolved in DMF (10 mL), to which was added
TBSCl (0.656 g, 4.36 mmol, 2 equiv) and imidazole (0.445 g, 6.53
mmol, 3 equiv.) The mixture was stirred for 4 h; when TLC analysis
showed the reaction was complete, it was quenched with sat.
NaHCO3. The aqueous layer was extracted with EtOAc and the
combined organic layers were washed with brine and H2O, dried,
and concentrated. The crude oil was subjected to column chroma-
tography (silica gel) to give 8 as a clear yellow oil (0.657 g, 75%, 2
steps).
Dimethyl 1-(tert-Butyldimethylsiloxy)-3-(4-methoxybenzyl-
oxy)-4-propyl-2,3,4,7-tetrahydro-1H-indene-5,6-dicarboxylate
(3)
To a soln of cyclopentadiene 4 (0.651 g, 1.62 mmol) dissolved in
toluene (10 mL) was added DMAD (0.248 mL, 2.02 mmol, 1.25
equiv) and hydroquinone (cat.). The reaction was refluxed for 4 h
and then concentrated to a thick oil. The crude concentrate was sub-
jected to column chromatography (silica gel) and yielded 3 as a yel-
low solid (442 mg, 50%).
IR (thin film): 2954, 2932, 2857, 1726, 1612, 1514, 1251, 1055,
838, 776, 665 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30 (d, J = 8 Hz, 2 H,
C6H4OMe), 6.90 (d, J = 8 Hz, 2 H, C6H4OMe), 4.57 [t, J = 6 Hz, 1
H, CH(OTBS)], 4.52 (d, J = 11 Hz, 1 H, OCHaHbC6H4OMe), 4.40–
4.33 [d, J = 11 Hz, 1 H, OCHaHbC6H4OMe and m, 1 H, CH(OP-
MB)], 3.80–3.73 (3 s, 9 H, 2 CO2Me, C6H4OCH3), 3.62–3.54 (m, 1
H, CHPr), 3.19 [dd, J = 22, 7.7 Hz, 1 H, C=CRCHaHbC(CO2Me)],
2.94 [ddd, J = 22, 7.7, 2 Hz, 1 H, C=CRCHaHbC(CO2Me)], 2.72 [dt,
J = 13.8, 7 Hz, 1 H, CH(OTBS)CHaHbCH(OPMB)], 1.65 [dt,
J = 13.2, 5 Hz, 1 H, CH(OTBS)CHaHbCH(OPMB)], 1.54–1.44 [m,
2 H, CH(CH2CH2CH3)], 1.24–1.10 [m, 2 H, CH(CH2CH2CH3)], 0.8
IR (thin film): 3309, 2959, 2953, 2858, 2225, 1613, 1587, 1514,
1464, 1250, 1094, 1039, 839, 779, 657 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29 (d, J = 8 Hz, 2 H,
C6H4OMe), 6.88 (d, J = 8 Hz, 2 H, C6H4OMe), 4.72 (d, J = 11.1
Hz, 1 H, OCHaHbC6H4OMe), 4.62 [td, J = 5.86, 1.96 Hz, 1 H,
CH(OPMB)], 4.46 (d, J = 11.1 Hz, 1 H, OCHaHbC6H4OMe), 4.27
[t, J = 7.49 Hz, 1 H, CH(OTBS)], 3.80 (s, 3 H, C6H4OCH3), 2.38 (d,
J = 2 Hz, 1 H, C≡CH), 2.29–2.19 [m, 2 H, C≡CCH2CH2CH3, and m,
1 H, CHaHbCH(OPMB)], 2.05–1.91 [m, 1 H, CHaHbCH(OPMB)],
1.61 (sextet, J = 7 Hz, 2 H, C≡CCH2CH2CH3), 1.0 (t, J = 7 Hz, 3 H,
C≡CCH2CH2CH3), 0.8 [s, 9 H, OSi(C(CH3)3)Me2], 0.1 [2 s, 6 H,
OSi(t-Bu)(CH3)2].
[s,
9
H, OSi(C(CH3)3)Me2], 0.7 [t, J = 7 Hz,
3
H,
CH(CH2CH2CH3)], 0.06 [2 s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3): d = 169.5, 168.0, 159.4, 140.3, 138.3,
136.4, 130.9, 130.9, 129.6, 113.9, 78.8, 74.9, 69.8, 55.5, 52.5, 52.4,
41.3, 36.9, 32.6, 26.1, 26.1, 18.3, 18.0, 14.5, –4.2, –4.5.
13C NMR (75 MHz, CDCl3): d = 154.4, 130.3, 129.9, 114.0, 130.3,
129.9, 114.0, 87.3, 85.1, 78.6, 72.7, 70.3, 66.0, 60.3, 55.5, 44.8,
26.0, 22.4, 21.0, 18.4, 13.8, –4.3, –5.0.
HRMS-FAB: m/z [M – H]+ calcd for C30H43O7Si: 543.2778; found:
543.2797.
HRMS-FAB: m/z [M + H]+ calcd for C24H37O3Si: 401.2512; found:
401.2513.
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

PAPER
Towards the Total Synthesis of the Cornexistins
2393
Dimethyl 7-(tert-Butyldimethylsiloxy)-5-(4-methoxybenzyl-
oxy)-4,8-dioxo-3-propylcyclonon-1-ene-1,2-dicarboxylate
A soln of 3 (1.78 g, 3.29 mmol) and Sudan III dye (1.5 mL, 0.1
wt%) dissolved in CH2Cl2–MeOH (2:1, 40 mL) at –78 °C was sat-
urated with O2 gas for 10 min. The mixture was subjected to ozone
until the soln color had gone from a deep red to a light pink or or-
ange. The mixture was again saturated with O2 gas for 10 min; fol-
lowing this, thiourea (3 g) was added and the mixture was stirred at
r.t. for 4 h. The mixture was then filtered to remove solids, concen-
trated to a thick oil, redissolved in Et2O and then washed with brine
and H2O. The organic layer was then dried (MgSO4) and concen-
trated to give a viscous yellow oil. The oil was subjected to column
chromatography (silica gel) to give a pale, viscous yellow oil (1.57
g, 83%).
CH(CH2CH2CH3)], 0.93 [t, J = 7.36 Hz, 3 H, CH(CH2CH2CH3)],
0.8 [s, 9 H, OSi(C(CH3)3)Me2], 0.01 [2 s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3) d = 208.6, 168.4, 168.0, 159.4, 146.0,
138.4, 137.9, 130.6, 130.0, 115.6, 113.9, 78.9, 76.0, 72.9, 71.5,
55.5, 52.7, 52.4, 50.1, 44.8, 31.0, 29.4, 26.0, 20.7, 18.4, 14.4, –5.0.
HRMS-FAB: m/z [M – H]+ calcd for C31H45O8Si: 573.2884; found:
573.2892.
Dimethyl 7-(tert-Butyldimethylsiloxy)-4-hydroxy-5-(4-meth-
oxybenzyloxy)-8-methylene-3-propylcyclonon-1-ene-1,2-dicar-
boxylate (10)
To a soln of ketone 9 (0.048 g, 0.0836 mmol) dissolved in MeOH
(24 mL) at 0 °C was added NaBH4 (4.74 mg, 0.125 mmol, 1.5
equiv) and stirred for 3 h at 0 °C. After TLC analysis showed the
reaction was complete, the reaction was diluted with EtOAc and
washed with brine and H2O. The organic layer was then dried
(MgSO4) and concentrated. The crude product was purified via col-
umn chromatography (silica gel) and isolated to provide alcohol 10
as a clear oil (45 mg, 93%).
IR (thin film): 2955, 1726, 1613, 1514, 1465, 1436, 1252, 1106,
1076, 1038, 913, 837, 781 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 6.4 Hz, 2 H,
C6H4OMe), 6.82 (d, J = 6.4 Hz, 2 H, C6H4OMe), 4.59 [dd, J = 8.99,
4.50 Hz,
1 H, CH(OTBS)], 4.43 (d, J = 9.20 Hz, 1 H,
OCHaHbC6H4OMe), 4.40 (t, J = 4.71 Hz, 1 H, CHPr), 4.29 (d,
J = 10.7 Hz, 1 H, OCH2C6H4OMe), 4.20 [dd, J = 10.28, 5.14 Hz, 1
H, CH(OPMB)], 3.84–3.79 (2 s, 6 H, 2 CO2CH3), 3.75 (s, 3 H,
C6H4OCH3 and m, 1 H, C6 methylene), 3.40 (d, J = 12.62 Hz, 1 H,
C6 methylene), 2.41 [dt, J = 14.55, 4.72 Hz, 1 H, CH(OTBS)-
CHaHbCH(OPMB)], 2.15–2.02 [m, 1 H, CH(CHaHbCH2CH3)], 1.97
[ddd, J = 14.34, 10.2, 4.02 Hz, 1 H, CH(OTBS)CHaHbCH(OPMB)],
1.41–1.10 [m, 3 H, CH(CHaHbCH2CH3), CH(CH2CH2CH3)] 0.93 [t,
IR (thin film): 3438, 2954, 2854, 1725, 1612, 1513, 1460, 1434,
1252, 1065, 907, 837, 777 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 6.7 Hz, 2 H,
C6H4OMe), 6.88 (d, J = 6.7 Hz, 2 H, C6H4OMe), 4.94 (s, 1 H,
C=CHaHb), 4.80 (s, 1 H, C=CHaHb), 4.61 (d, J = 11.5 Hz, 1 H,
OCHaHbC6H4OMe),
4.51
(d,
J = 10.35
Hz,
1
H,
OCHaHbC6H4OMe), 4.22 [dd, J = 8.18, 5.88 Hz, 1 H, CH(OTBS)],
3.85–3.79 (2 s, 6 H, 2 CO2CH3), 3.74 (s, 3 H, C6H4OCH3), 3.58
(ddd, J = 9.15, 6.71, 2.93 Hz, 1 H, CHPr), 3.38–3.27 [m, 1 H,
CH(OPMB) and d, J = 14.3 Hz, 1 H, C6 methylene], 3.14 (dt,
J = 9.42, 4.88 Hz, 1 H, CHOH), 3.06 (d, J = 14.41 Hz, 1 H, C6
methylene), 2.03 [ddd, J = 15.62, 5.86, 4.27 Hz, 1 H,
CH(OTBS)CHaHbCH(OPMB)], 1.82–1.54 [m, 3 H, CH(OTBS)-
J = 7.36 Hz,
3
H, CH(CH2CH2CH3)], 0.8 [s,
9
H,
OSi(C(CH3)3)Me2], 0.01 [2 s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3), d = 208.6, 207.3, 167.6, 166.9, 159.5,
142.5, 131.6, 130.3, 130.0, 113.9, 78.0, 76.0, 71.7, 55.5, 53.2, 53.2,
52.7, 51.3, 41.3, 37.1, 29.3, 25.9, 20.7, 18.3, 14.5, –4.8, –5.1.
HRMS-FAB: m/z [M – 1]+ calcd for C30H44O9Si: 575.2797; found:
CHaHbCH(OPMB), CH(CH2CH2CH3)], 1.42–1.30 [m, 2 H,
575.2676.
CH(CH2CH2CH3)], 0.93 [t, J = 7.36 Hz, 3 H, CH(CH2CH2CH3)],
0.8 [s, 9 H, OSi(C(CH3)3)Me2], 0.01 [2 s, 6 H, OSi(t-Bu)(CH3)2].
Dimethyl 7-(tert-Butyldimethylsiloxy)-5-(4-methoxybenzyl-
oxy)-8-methylene-4-oxo-3-propylcyclonon-1-ene-1,2-dicarbox-
ylate (9)
13C NMR (75 MHz, CDCl3): d = 171.1, 168.9, 159.5, 147.8, 140.5,
136.5, 131.0, 116.7, 114.0, 78.9, 77.7, 75.7, 72.9, 55.5, 52.7, 52.6,
41.6, 41.4, 32.4, 28.7, 26.0, 21.1, 18.3, 14.4, –4.5, –4.6.
Diketone (0.150 g, 0.260 mmol) was dissolved in THF (4.7 mL)
with pyridine (0.147 mL, 1.82 mmol, 7 equiv) and cooled to –15 °C
to –22 °C. A 0.5 M soln of the Tebbe reagent in toluene (0.520 mL,
0.260 mmol, 1 equiv) was then added dropwise to the mixture,
which was carefully maintained at a constant temperature. TLC
analysis was used to monitor the progress of the reaction; typically,
after 2 h, the reaction was complete. An equivalent amount of THF
was syringed into the mixture, followed by the dropwise addition of
15% aq NaOH soln (4 mL). Stirring at low temperatures for ~20
min produced a dark blue soln, which announced the final destruc-
tion of the Tebbe reagent and formation of the aluminoxane byprod-
uct. After the addition of MgSO4, the mixture was filtered and
concentrated to give a dark yellow oil that was immediately subject-
ed to column chromatography. Chromatography gave 9 as a pale
yellow oil (80 mg, 54%).
HRMS-FAB: m/z [M + H]+ calcd for C31H49O8Si: 577.3197; found:
577.3194.
Dimethyl 4-Acetoxy-7-(tert-butyldimethylsiloxy)-5-(4-methoxy-
benzyloxy)-8-methylene-3-propylcyclonon-1-ene-1,2-dicarbox-
ylate (11)
To a soln of alcohol 10 (31 mg, 0.0538 mmol) in pyridine (3 mL)
was added Ac2O (0.75 mL, 7.91 mmol) and DMAP (cat.) at r.t.; the
mixture was stirred overnight. After dilution with EtOAc, the or-
ganic layer was washed sat. NH4Cl (2 ×) and brine (1 ×). The organ-
ic layer was then dried (MgSO4) and concentrated. Column
chromatography (silica gel) yielded acetate 11 as a clear oil (23 mg,
70%).
IR (thin film): 2954, 2858, 1741, 1612, 1514, 1464, 1433, 1371,
1250, 1104, 1039, 907, 837, 776 cm–1.
IR (thin film): 2955, 2931.4, 2858, 2360, 1727, 1613, 1586, 1514,
1463, 1435, 1390, 1362, 1174, 1042, 953, 916, 838, 779, 671 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.20 (d, J = 8.67 Hz, 2 H,
C6H4OMe), 6.83 (d, J = 8.67 Hz, 2 H, C6H4OMe), 5.21 (s, 1 H,
C=CHaHb), 5.08 (dd, J = 10.14, 2.32 Hz, 1 H, CHOAc), 4.91 (s, 1
H, C=CHaHb), 4.41 (AB q, J = 11.7 Hz, 2 H, OCH2C6H4OMe), 4.32
[t, J = 6.73 Hz, 1 H, CH(OTBS)], 3.79–3.76 (2 s, 6 H, 2 CO2CH3),
3.68 (s, 3 H, C6H4OCH3), 3.65–3.59 (m, 1 H, CHPr), 3.40 [ddd,
J = 10.62, 7.93, 3.05 Hz, 1 H, CH(OPMB)], 3.28 (d, J = 15.02 Hz,
1 H, C6 methylene), 3.21 (d, J = 14.89 Hz, 1 H, C6 methylene), 2.18
[ddd, J = 16.61, 5.25, 3.17 Hz, 1 H, CH(OTBS)CHaHbCH(O-
PMB)], 2.00 (s, 3 H, OCOCH3), 1.90 [ddd, J = 15.26, 9.04, 7.57 Hz,
1H NMR (500 MHz, CDCl3): d = 7.27 (d, J = 8.6 Hz, 2 H,
C6H4OMe), 6.81 (d, 2 H, 8.6 Hz, 2 H, C6H4OMe), 4.96 (2 s, 2 H,
C=CH2), 4.52 (d, J = 11 Hz, 1 H, OCHaHbC6H4OMe), 4.46–4.38
[m, 2 H, CH(OTBS), CHPr], 4.32 [dd, J = 9.16, 6.23 Hz, 1 H,
CH(OPMB)], 4.26 (d, J = 11 Hz, 1 H, OCHaHbC6H4OMe), 3.79–
3.78 (2 s, 6 H, 2 CO2CH3), 3.73 (s, 3 H, C6H4OCH3), 3.44 (d,
J = 13.55 Hz, 1 H, C6 methylene), 3.28 (d, J = 14.28 Hz, 1 H, C6
methylene), 2.16–1.94 [m, 3 H, CH(OTBS)CH2CH(OPMB),
CH(CHaHbCH2CH3)], 1.41–1.10 [m, 3 H, CH(CHaHbCH2CH3),
1
H, CH(OTBS)CHaHbCH(OPMB)], 1.80–1.65 [m, 1 H,
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

2394
J. C. Tung et al.
PAPER
CH(CHaHbCH2CH3)], 1.52–1.22 [m, 3 H, CH(CHaHbCH2CH3),
CH(CH2CH2CH3)], 0.93 [t, J = 7.36 Hz, 3 H, CH(CH2CH2CH3)],
0.90 [s, 9 H, OSi(C(CH3)3)Me2], 0.01 [2 s, 6 H, OSi(t-Bu)(CH3)2].
13C NMR (75 MHz, CDCl3): d = 205.0, 170.0, 168.2, 166.9, 159.5,
147.4, 143.1, 132.9, 130.1, 129.9, 120.0, 114.0, 76.8, 76.0, 71.9,
55.5, 52.8, 52.0, 45.9, 42.2, 32.8, 32.4, 21.0, 20.7, 14.1.
13C NMR (75 MHz, CDCl3): d = 170.4, 168.7, 168.3, 159.3, 148.5,
142.3, 134.6, 130.9, 129.5, 116.0, 113.9, 74.4, 72.5, 55.5, 52.6,
51.9, 43.7, 40.8, 32.6, 29.5, 26.0, 21.1, 20.9, 18.3, 14.5, –4.6, –4.5.
HRMS-FAB: m/z [M – 1]+ calcd for C27H33O9: 501.2124; found:
501.2125.
Dimethyl 4-Acetoxy-7-hydroxy-5-(4-methoxybenzyloxy)-
8-methylene-3-propylcyclonon-1-ene-1,2-dicarboxylate (15)
To a soln of ketone (10 mg, 0.020 mmol) in MeOH (2 mL) at 0 °C
was added NaBH4 (1.13 mg, 0.03 mmol, 1.5 equiv) and stirred for
2 h. Upon completion, the reaction was diluted with EtOAc and
washed with brine and H2O. The reaction was then dried (MgSO4),
concentrated to a pale oil and subjected to column chromatography
(silica gel). The reaction yielded desired alcohol 15 as a cloudy
white oil (6 mg, 60%); ratio 15/12 = 4:1.
HRMS-FAB: m/z [M – H]+ calcd for C33H49O9Si: 617.3146; found:
617.3177.
Dimethyl 4-Acetoxy-7-hydroxy-5-(4-methoxybenzyloxy)-
8-methylene-3-propylcyclonon-1-ene-1,2-dicarboxylate (12)
To a soln of acetate 11 (14 mg, 0.0226 mmol) in THF (1 mL) was
added 1 M TBAF in THF (45 mL, 0.045 mmol, 2 equiv) and stirred
for 2 h. After completion of the reaction, the reaction was quenched
with sat. NaHCO3 and separated. The aqueous layer was extracted
with EtOAc; the recombined organic layers were washed with brine
and subsequently dried and concentrated. Purification (silica gel)
gave product alcohol 12 as a pale yellow oil (10 mg, 87%).
IR (thin film): 3512, 2954, 2872, 1724, 1613, 1514, 1434, 1372,
1301, 1247, 1077, 1038, 971, 917, 851, 821, 734, 664 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.18 (d, J = 8.5 Hz, 2 H,
C6H4OMe), 6.85 (d, J = 8.6 Hz, 2 H, C6H4OMe), 5.22 (s, 1 H,
C=CHaHb), 5.11 (s, 1 H, C=CHaHb), 5.08 (dd, J = 9.47, 2.44 Hz, 1
H, CHOAc), 4.60 (dd, J = 8.85, 3.35 Hz, 1 H, CHOH), 4.46 (d,
J = 11.6 Hz, 1 H, OCHaHbC6H4OMe), 4.40 (d, J = 11.3 Hz, 1 H,
OCHaHbC6H4OMe), 3.80–3.76 (2 s, 6 H, 2 CO2CH3), 3.72–3.64 (m,
1 H, CHPr), 3.70 (s, 3 H, C6H4OCH3), 3.58 (d, J = 15.87 Hz, 1 H,
C6 methylene), 3.28–3.22 [m, 1 H, CH(OPMB)], 2.88 (d, J = 16.18,
1 H, C6 methylene), 2.22 [ddd, J = 15, 8.85, 2.14 Hz, 1 H,
CH(OH)CHaHbCH(OPMB)], 2.04–1.92 [m, 1 H, CH(OH)CHaHb-
CH(OPMB)], 1.96 (s, 3 H, OCOCH3), 1.82–1.58 [m, 2 H,
CH(CH2CH2CH3)], 1.50–1.20 [m, 2 H, CH(CH2CH2CH3)], 0.88 [t,
J = 7.33 Hz, 3 H, CH(CH2CH2CH3)].
IR (thin film): 3504, 2954, 2873, 1724, 1612, 1586, 1514, 1458,
1433, 1373, 1248, 1174, 1078, 1036, 906, 850, 821, 756 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.17 (d, J = 8.42 Hz, 2 H,
C6H4OMe), 6.84 (d, J = 8.6 Hz, 2 H, C6H4OMe), 5.15 (s, 2 H,
C=CH2), 5.10 (dd, J = 7.33, 2.56 Hz, 1 H, CHOAc), 4.41 (d,
J = 11.7 Hz, 1 H, OCHaHbC6H4OMe), 4.39 (d, J = 11 Hz, 1 H,
OCHaHbC6H4OMe), 4.16 (dd, J = 8.79, 4.03 Hz, 1 H, CHOH),
3.79–3.76 (2 s, 6 H, 2 CO2CH3), 3.68 (s, 3 H, C6H4OCH3), 3.52–
3.42 (m, 1 H, CHPr and d, J = 15.39 Hz, 1 H, C6 methylene), 3.38–
3.30 [m, 1 H, CH(OPMB)], 3.12 (d, J = 15.74 Hz, 1 H, C6 methyl-
ene), 2.18 [ddd, J = 15.75, 3.66, 2.93 Hz, 1 H, CH(OH)CHaHb-
CH(OPMB)], 2.04–1.88 [m, 1 H, CH(OH)CHaHbCH(OPMB)],
1.98 (s, 3 H, OCOCH3), 1.73–1.56 [m, 2 H, CH(CH2CH2CH3)],
1.48–1.20 [m, 2 H, CH(CH2CH2CH3)], 0.88 [t, J = 6.96 Hz, 3 H,
CH(CH2CH2CH3)].
13C NMR (75 MHz, CDCl3) d = 170.3, 168.5, 168.5, 159.3, 150.4,
141.1, 134.0, 130.9, 129.6, 115.2, 113.9, 77.5, 74.8, 72.4, 72.1,
55.5, 52.8, 52.0, 42.4, 41.1, 34.4, 32.5, 21.1, 20.8, 14.4.
13C NMR (75 MHz, CDCl3): d = 170.3, 168.4, 168.1, 159.4, 150.4,
142.7, 133.5, 130.7, 129.6, 115.7, 113.9, 77.9, 77.1, 74.0, 71.9,
55.6, 52.8, 52.0, 41.1, 40.7, 32.4, 31.7, 21.1, 20.7, 14.2.
HRMS-FAB: m/z [M – H]+ calcd for C27H35O9: 503.2281; found:
503.2271.
Dimethyl 4-Acetoxy-7-(allyldimethylsiloxy)-5-(4-methoxyben-
zyloxy)-8-methylene-3-propylcyclonon-1-ene-1,2-dicarboxy-
late (16)
HRMS (FAB) m/z [M+] calcd for C27H36O9: 504.2359; found:
504.2333.
To a soln of alcohol 15 (0.005 g, 0.01 mmol) was added allyldi-
methylsilyl chloride (7 mL, 0.05 mmol, 5 equiv) and Et3N (25 mL,
0.177 mmol, 35 equiv). The mixture was stirred overnight at r.t. and
subsequently quenched with sat. NaHCO3. The aqueous layer was
extracted with EtOAc and the combined organic layers were
washed with brine and H2O. The organic layers were then dried
(MgSO4) and concentrated. The compound was then subjected to
column chromatography (silica gel), which yielded silyl ether 16 as
a pale yellow oil (3 mg, 50%, 63% based on recovered 15).
Dimethyl 4-Acetoxy-5-(4-methoxybenzyloxy)-8-methylene-
7-oxo-3-propylcyclonon-1-ene-1,2-dicarboxylate
To a soln of 12 (39 mg, 0.077 mmol) in CH2Cl2 (2 mL) was added
Dess–Martin periodinane (66 mg, 0.155 mmol, 2 equiv). The mix-
ture was stirred for 1 h and monitored by TLC. When the reaction
was complete, it was diluted with EtOAc, washed with sat.
Na2S2O3, brine and H2O. The organic layer was then dried
(MgSO4), concentrated to give crude product (38 mg, 98%) that was
used immediately for the following reaction.
IR (thin film): 3074, 2954, 2872, 1736, 1630, 1613, 1514, 1458,
1369, 1301, 1248, 1142, 1110, 1091, 1039, 992, 954, 931, 900 cm–1.
IR (thin film): 2956, 1735, 1689, 1612, 1514, 1433, 1371, 1234,
1032 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.18 (d, J = Hz,
2 H,
1H NMR (300 MHz, CDCl3): d = 7.20 (d, J = 6.63 Hz, 2 H,
C6H4OMe), 6.85 (d, J = 6.63 Hz, 2 H, C6H4OMe), 5.51 (s, 1 H,
C=CHaHb), 5.39 (s, 1 H, C=CHaHb), 5.15 (dd, J = 9.84, 2.99 Hz, 1
H, CHOAc), 4.54 (d, J = 11.77 Hz, 1 H, OCH2C6H4OMe), 4.46 (d,
J = 11 Hz, 1 H, OCH2C6H4OMe), 3.82–3.72 (2 s, 6 H, 2 CO2CH3
and m, 1 H, CHPr), 3.64 (s, 3 H, C6H4OCH3), 3.56 (d, J = 15.20, 1
H, C6 methylene), 3.24 (d, J = 14.98 Hz, 1 H, C6 methylene), 2.98
[ddd, J = 8.78, 4.30, 3.00 Hz, 1 H, CH(OPMB)], 2.90 [d, J = 13.48
Hz, 1 H, C(O)CHaHbCH(OPMB)], 2.84 [dd, J = 13.27, 2.56 Hz, 1
H, C(O)CHaHbCH(OPMB)], 1.94 (s, 3 H, OCOCH3), 1.79–1.60
OCH2C6H4OMe), 6.84 (d, J = Hz, 2 H, OCH2C6H4OMe), 5.80
[ddd, J = 8.43, 10.41, 16.86 Hz, 1 H, OSiMe2(CH2CH=CH2)], 5.09
(s, 1 H, C=CHaHb), 5.08 (dd, J = 9.47, 2.44 Hz, 1 H, CHOAc), 5.02
(s,
1
H, C=CHaHb), 4.92 [d, J = 17.35 Hz,
1
1
H,
H,
OSiMe2(CH2CH=CHaHb)], 4.86 [d, J = 9.92 Hz,
OSiMe2(CH2CH=CHaHb)], 4.70 [d, J = 6.94 Hz, 1 H, CH(OSiR3)],
4.48 (d, J = 11.6 Hz, 1 H, OCHaHbC6H4OMe), 4.30 (d, J = 11.3 Hz,
1 H, OCHaHbC6H4OMe), 3.82 (t, J = 8.92 Hz, 1 H, CHPr), 3.79–
3.75 (2 s, 6 H, 2 CO2CH3), 3.73–3.68 (s, 3 H, C6H4OCH3 and d,
J = 17.85 Hz, 1 H, C6 methylene), 3.48 [ddd, J = 2.48, 4.96, 8.92
Hz, 1 H, CH(OPMB)], 2.84 (d, J = 17.35, 1 H, C6 methylene), 2.27
[ddd, J = 15.37, 7.93, 1.48 Hz, 1 H, CH(OSiR3)CHaHbCH(O-
PMB)], 1.93 (s, 3 H, OCOCH3), 1.88 [ddd, J = 15.37, 8.93, 2.48 Hz,
[m,
1
H, CH(CHaHbCH2CH3)], 1.52–1.33 [m,
1
H,
CH(CHaHbCH2CH3)], 1.33–1.18 [m, 2 H, CH(CH2CH2CH3)], 0.87
[t, J = 6.96 Hz, 3 H, CH(CH2CH2CH3)].
1
H, CH(OSiR3)CHaHbCH(OPMB)], 1.74–1.61 [m, 2 H,
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

PAPER
Towards the Total Synthesis of the Cornexistins
2395
CH(CH2CH2CH3)], 1.64 [dd, J = 7.94, 13.89 Hz,
2
H,
H,
[dd, J = 14.87, 9.92 Hz, 1 H, C(OH)CHaHbCH(OPMB)], 1.98 (s, 3
H, OCOCH3), 1.99–1.90 [ddd, J = 14.87, 9.42, 2.97 Hz, 1 H,
OSiMe2(CH2CH=CHaHb)],
1.46–1.38
[m,
1
CH(CH2CHaHbCH3)], 1.32–1.22 [m, 1 H, CH(CH2CHaHbCH3)],
0.88 [t, J = 7.33 Hz, 3 H, CH(CH2CH2CH3)], 0.13 [s, 6 H,
OSi(CH3)2(CH2CH=CH2)].
13C NMR (75 MHz, CDCl3): d = 170.4, 168.9, 167.9, 151.2, 141.8,
134.2, 133.4, 131.2, 129.2, 114.1, 113.9, 113.3, 77.6, 74.8, 72.1,
71.5, 55.5, 52.6, 51.8, 44.2, 39.9, 34.6, 32.5, 24.7, 21.1, 20.8, 14.4,
–2.0, –2.2.
CH(OH)CHaHbCH(OPMB)],
1.90–1.78
[m,
1
H,
CH(CHaHbCH2CH3)], 1.51–1.39 [m, 2 H, CH(CHaHbCH2CH3) and
CH(CH2CHaHbCH3)], 1.37–1.25 [m, 1 H, CH(CH2CHaHbCH3)],
0.88 [t, J = 7.44 Hz, 3 H, CH(CH2CH2CH3)].
13C NMR (75 MHz, CDCl3): d = 170.2, 168.9, 168.4, 159.4, 143.3,
141.6, 134.1, 130.7, 129.7, 129.6, 113.9, 74.6, 72.0, 69.1, 58.8,
55.5, 52.9, 52.0, 40.5, 36.5, 32.8, 30.0, 21.1, 20.9, 14.3.
HRMS-FAB: m/z [M – H]+ calcd for C32H45O9Si: 601.2833; found:
HRMS-FAB: m/z [M + H]+ calcd for C28H39O10: 535.2543; found:
601.2856.
535.2513.
Dimethyl 9-Acetoxy-10-(4-methoxybenzyloxy)-2,2-dimethyl-
8-propyl-3,8,9,10,11,11a-hexahydro-2H,5H-1-oxa-2-silabenzo-
cyclononene-6,7-dicarboxylate (17)
Silyl ether 16 (6 mg, 0.01 mmol) was dissolved in CH2Cl2 (10 mL)
and heated to reflux for 10 min. Grubbs 2nd generation RCM cata-
lyst 14 (cat.) was added and the mixture was heated to reflux for 3
h. The mixture was then concentrated to dryness, redissolved in
hexanes and subjected to column chromatography (silica gel),
which yielded a quantitative amount of silacycle 17 as a brown oil.
Acknowledgment
R.E.T. gratefully acknowledges Paul A. Wender for his continual
mentorship, inspiration, and support. We would like to acknow-
ledge the progressive views of Professor Anthony K. Hyder (Uni-
versity of Notre Dame) and the Embedded Center Research Fund
for support of this work. J.C.T. acknowledges Dow Agrosciences
for a research fellowship. We would like to thank Jaroslav Zajicek
for assistance with detailed NMR analysis and Chris Nicholson for
computer modeling experiments.
IR (thin film): 2923, 2852, 1740, 1612, 1514, 1458, 1373, 1250,
1043, 855 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.20 (d, J = 9 Hz, 2 H, C6H4OMe),
6.83 (d, J = 8 Hz, 2 H, C6H4OMe), 6.10 (dd, J = 8.55, 3.67 Hz, 1 H,
C=CHCH2SiMe2OR), 5.12 (dd, J = 10.07, 2.44 Hz, 1 H, CHOAc),
4.34 [dd, J = 8.85, 3.35 Hz, 1 H, CH(OSiMe2R)], 4.46 (d, J = 11.6
Hz, 1 H, OCHaHbC6H4OMe), 4.42 (d, J = 11.3 Hz, 1 H,
OCHaHbC6H4OMe), 3.80–3.76 (2 s, 6 H, 2 CO2CH3), 3.70 (s, 3 H,
C6H4OCH3), 3.42–3.34 (m, 1 H, CHPr), 3.38 (d, J = 14.34 Hz, 1 H,
C6 methylene), 2.88–2.84 [m, 1 H, CH(OPMB)], 2.68 (d, J = 14.35
Hz, 1 H, C6 methylene), 2.12–2.04 [m, 1 H, CH(OSiR3)CHaHb-
CH(OPMB)], 1.98 (s, 3 H, OCOCH3), 1.99–1.90 [m, 1 H,
References
(1) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Sato, S.; Furukawa,
Y.; Furuya, K.; Honma, T.; Kadotani, J.; Kozasa, M.;
Haneishi, T. J. Antibiot. 1991, 44, 1065.
(2) Fields, S. C.; Mireles-Lo, L.; Gerwick, B. C. J. Nat. Prod.
1996, 59, 698.
(3) Barton, D. H. R.; Sutherland, J. K. J. Chem. Soc. 1965, 1769.
(4) (a) Spiegel, D. A.; Njardarson, J. T.; McDonald, I. M. Chem.
Rev. 2003, 103, 2691. (b) Hayashi, Y.; Itoh, T.; Fukuyama,
T. Org. Lett. 2003, 5, 2235.
CH(OSiR3)CHaHbCH(OPMB)],
1.90–1.80
(m,
2
H,
C=CHCH2SiMe2OR), 1.58–1.38 [m, 2 H, CH(CH2CH2CH3)], 1.38–
1.20 [m, 2 H, CH(CH2CH2CH3)], 0.88 [t, J = 7.33 Hz, 3 H,
CH(CH2CH2CH3)], 0.13 (s, 3 H, OSi(CH3)(CH3)(CH2CH=CH2)],
0.07 (s, 3 H, OSi(CH3)(CH3)(CH2CH=CH2)].
13C NMR (75 MHz, CDCl3): d = 178.7, 170.0, 159.1, 140.9, 138.5,
130.7, 129.4, 129.2, 129.8, 113.7, 75.4, 75.4, 74.9, 72.8, 55.3, 52.3,
51.8, 46.0, 42.4, 41.0, 35.4, 32.0, 20.8, 14.1, 13.1, 1.04.
(5) Stork, G.; Tabak, J. M.; Blount, J. F. J. Am. Chem. Soc. 1972,
94, 4735.
(6) (a) White, J. D.; Kim, J.; Drapela, N. E. J. Am. Chem. Soc.
2000, 122, 8665. (b) White, J. D.; Dillon, M. P.; Butlin, R. J.
J. Am. Chem. Soc. 1992, 114, 9673.
(7) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003,
5, 89.
(8) Wender, P. A.; Lechleiter, J. C. J. Am. Chem. Soc. 1977, 99,
267.
(9) Aldehyde 5 was derived from the monoprotection of
propane-1,3-diol (BuLi, TBSCl, THF, –78 °C to reflux) and
TEMPO/bleach oxidation.
(10) The syn-relationship of 8 was determined by removal of the
protecting groups, formation of the acetonide and
Rychnovsky 13C analysis: Rychnovsky, S. D.; Ryan, B. N.;
Richardson, T. I. Acc. Chem. Res. 1998, 31, 9.
(11) Mitsunobu, O. Synthesis 1981, 1.
(12) Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255.
(13) Crystal data, selected bond lengths and angles for 3:
Formula: C30H44O7Si, MW = 544.74, a = 10.3090(4) Å,
b = 12.2193(5) Å, c = 13.9422(5) Å, a = 70.593(2)°,
b = 78.609(2)°, g = 74.217(2)°, P1, V = 1582.90(11) Å3,
Z = 2, R1 = 0.0588, wR2 = 0.1815. Data collection: 0.5° f
and w scans, CCD area detector. Solved by direct methods
and refined by full-matrix least-squares refinement against
F2. Selected bond lengths (Å): O2–C1: 1.429(4), C2–C3:
1.497(4), C8–C9: 1.525(5), C1–C2: 1.499(4), C3–C28:
1.542(4). Selected bond angles (°): C1–O2–C16: 112.5(3),
O2–C1–C2: 111.2(3), O2–C1–C9: 113.5(3), C2–C1–C9:
102.5(3), C2–C3–C4: 110.5(2), C2–C3–C28: 112.6(2), C4–
C3–C28: 112.6(2). Details of the crystal structure
determination have been deposited with the Cambridge
HRMS-FAB: m/z [M + H]+ calcd for C30H43O9Si: 575.2676; found:
575.2665.
Dimethyl 4-Acetoxy-7-hydroxy-8-(2-hydroxyethylidene)-5-(4-
methoxybenzyloxy)-3-propylcyclonon-1-ene-1,2-dicarboxylate
(18)
To a soln of silacycle 17 (2 mg, 0.003 mmol) in THF–MeOH (1:1,
1 mL) at r.t. was added KHCO3 (5 mg, 0.05 mmol, 15 equiv), KF (5
mg, 0.086 mmol, 25 equiv), and H2O2 (10 mL, 0.28 mmol, 80 equiv)
and the mixture was stirred for 4 h. The solvent was removed and
the crude product was redissolved in EtOAc, washed with brine and
dried (MgSO4) to give diol 18 as a clear oil (1.9 mg, quantitative).
IR (thin film): 3450, 2923, 2852, 1721, 1613, 1514, 1463, 1373,
1248, 1037, 914, 820, 733 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.20 (d, J = 6.45 Hz, 2 H,
C6H4OMe), 6.83 (d, J = 6.45 Hz, 2 H, C6H4OMe), 5.72 (t, J = 6.94
Hz, 1 H, =CHCH2OH), 5.06 (dd, J = 8.93, 1.99 Hz, 1 H, CHOAc),
4.86 (d, J = 6.45 Hz, 1 H, CHOH), 4.45 (d, J = 11.41 Hz, 1 H,
OCHaHbC6H4OMe),
4.41
(d,
J = 11.41
Hz,
1
H,
OCHaHbC6H4OMe), 4.13 (m, 2 H, =CHCH2OH), 3.76 (2 s, 6 H, 2
CO2CH3), 3.74 (t, J = 8.46 Hz, 1 H, CHPr), 3.70 (s, 3 H,
C6H4OCH3), 3.62 (d, J = 16.86 Hz, 1 H, C6 methylene), 3.44–3.39
[m, 1 H, CH(OPMB)], 2.94 (d, J = 16.86, 1 H, C6 methylene), 2.34
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York

2396
J. C. Tung et al.
PAPER
crystallographic Data Centre and may be retrieved at
www.ccdc.cam.ac.uk by citing CCDC 642483.
(14) (a) Pine, S. H.; Kim, G.; Lee, V. Org. Synth. 1990, 69, 72.
(b) Renneberg, D.; Pfander, H.; Leumann, C. J. J. Org.
Chem. 2000, 65, 9069.
(15) (a) Gauthier, D. R. Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron
1998, 54, 2289. For an elegant example of the use of a
temporary tether to control olefin geometry, see: (b)Evans,
D. A.; Carreira, E. M. Tetrahedron Lett. 1990, 31, 4703.
Inspired by our initial results, this strategy has recently been
successfully applied to total synthesis, see, (c) Li, F.;
Miller, M. J. J. Org. Chem. 2006, 71, 5221.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(17) Tamao, K.; Ishida, N.; Kumada, M. Org. Synth. 1990, 69, 96.
Synthesis 2007, No. 15, 2388–2396 © Thieme Stuttgart · New York