A common synthetic route to homochiral tetracycles related to pillaromycinone and premithramycinone

Article abstract of DOI:10.1139/v11-119

Homochiral AB segments for (+)-and (-)-pillaromycinone were prepared in 11 steps from 2-acetylfuran. The synthesis featured an intramolecular Diels-Alder reaction of a 2,5-disubstituted furan and a hydroxyl-directed homogeneous hydrogenation of the tetrasubstituted alkene double bond of two enones. The CD segment was attached by a modified Staunton-Weinreb annulation to produce the desired homochiral tetracycle 21c related to (+)-pillaromycinone. An unusual acetonide migration enabled the synthesis of a tetracyclic model for premithramycinone.

Full text of DOI:10.1139/v11-119

1
457
A common synthetic route to homochiral
tetracycles related to pillaromycinone and
premithramycinone
Bryan Hill, Robert Jordan, Yang Qu, Abdeljalil Assoud, and Russell Rodrigo
Abstract: Homochiral AB segments for (+)- and (–)-pillaromycinone were prepared in 11 steps from 2-acetylfuran. The
synthesis featured an intramolecular Diels–Alder reaction of a 2,5-disubstituted furan and a hydroxyl-directed homogeneous
hydrogenation of the tetrasubstituted alkene double bond of two enones. The CD segment was attached by a modified
Staunton–Weinreb annulation to produce the desired homochiral tetracycle 21c related to (+)-pillaromycinone. An unusual
acetonide migration enabled the synthesis of a tetracyclic model for premithramycinone.
Key words: naphthacenone antibiotics, diastereoselective hydrogenation, Stauton–Weinreb annulation, furan Diels–Alder,
regioselective dehydrogenation.
Résumé : On a préparé les segments AB homochiraux des (+)- et (–)-pillromycinone en onze étapes à partir du 2-acétyl-
furane. La synthèse implique une réaction de Diels–Alder intramoléculaire d’un furane 2,5-disubstitué et une hydrogénation
homogène orientée par le groupe hydroxyle de la double liaison de l’alcène tétrasubstitué de deux énones. Le segment CD
a été fixé par une réaction d’annelation de Staunton–Weinreb modifiée pour conduire au dérivé tétracyclique 21c désiré, ap-
parenté à la (+)-pillromycinone. Une réaction inusitée de migration d’un acétonide a permis de réaliser la synthèse d’un mo-
dèle tétracyclique de la prémithramycinone.
Mots‐clés : antibiotiques de la naphtacénone, hydrogénation diastéréosélective, annelation de Stauton–Weinreb, réaction de
Diels–Alder avec le furane, déshydrogénation régiosélective.
[
Traduit par la Rédaction]
tion. Two serious problems remained to be solved if the work
was to be successfully adapted to a synthesis of any tetracycle
related to (+)-pillaromycinone. The configuration at C-4a,
established by heterogeneous hydrogenation of a tetrasubsti-
tuted double bond, was incorrect and no simple method
existed for its correction in (±)-4a or (±)-4b. The Staunton–
Weinreb annulation, although successful, needed four sepa-
rate steps4 to form a tetracycle in an unacceptable yield of
only 18% (Fig. 1).
Introduction
Pillaromycin A (1) was isolated from a culture of Strepto-
myces flavovirens 40 years ago. Its aglycone, (+)-pillaromy-
1
cinone 2, is a linear tetracycle with structural similarities to
both the tetracyclines and anthracyclinones. Although it has
attracted sporadic attention from the synthetic community,2
–4
no enantioselective route to (+)- or (–)-pillaromycinone has
a
been disclosed as yet. Premithramycinone (3), isolated in
1998 from a blocked mutant of Streptomyces argillaceus
We now report that the stereochemical deficiency has been
remedied, the annulation has been profitably modified, over-
all yields have been improved substantially, and our basic
plan4 has been adapted into a 14 step route to a homochiral
tetracycle closely related to (+)-pillaromycinone from 2-
acetylfuran. In addition, a serendipitous migration of an ace-
tonide in one tetracyclic intermediate was discovered. Its
possible application to the synthesis of premithramycinone
3 was briefly explored.
ATCC 12956 is a key intermediate in the biosynthesis of the
anticancer aureolic acids. No synthetic work towards this
5
compound has been recorded in the literature.
a
4a
Some years ago we tested the viability of a convergent
AB + CD plan, designed to provide rapid access to the tetra-
cyclic system of 2. Accordingly, the structurally appropriate
AB intermediates, bicyclic enones (±)-4a and (±)-4b, were
prepared in only 10 steps from furfural and incorporated into
tetracycles (±)-5a and (±)-5b by a Staunton–Weinreb annula-
Received 22 June 2011. Accepted 23 July 2011. Published at www.nrcresearchpress.com/cjc on 1 November 2011.
†
‡
B. Hill,* R. Jordan, Y. Qu, A. Assoud, and R. Rodrigo. Department of Chemistry, Unversity of Waterloo, ON N2L 3G1, Canada.
Corresponding author: Russell Rodrigo (e-mail: rrodrigo@uwaterloo.ca).
This article is part of a Special Issue to commemorate the International Year of Chemistry.
*
Present address: Department of Chemistry, Brandon University, Brandon, MN R7A 6A9, Canada.
†
Present address: Vibrant Pharma Inc., Brantford, ON N3P 1M1, Canada.
To whom enquiries about X-ray data should be addressed.
‡
Can. J. Chem. 89: 1457–1468 (2011)
doi:10.1139/V11-119
Published by NRC Research Press

1458
Can. J. Chem. Vol. 89, 2011
Fig. 1. Summary of previous synthetic work.4a
OH
A
H
O
A
OH
Me
H
H
O
D
C
B
B
OR
O
OTMS
OMe
OH OH
O
O
O
Me
HO
(
±) 4a or (±) 4b
1
2
.
.
R=
O
HO
OH
R= H
ref# 4a
OMe
A
O
H
6
H
HO
OH
O
4
D
C
B
O
12
9
OTMS
H
O 13 OMe
Me
OH
OH
Me
OMe OH
O
O
3
(
±) 5a or (±) 5b
Scheme 1. Preparation of diastereomeric Diels–Alder adducts.
n-BuLi
O
MeO
Me
N
RO
H
Br
Br
R
X
O
O
O
68%
H
OMe
Me
Me
NaI, NaHCO3
acetone, 93%
t-BuLi, Et O, 84%
8
9
1
(X = Br)
(X = I)
0 (X = Li)
6
(R = H)
(R = Me)
NaH, MeI
THF,80%
11
7
2
O
1
3 (X =
)
Me
O
O
H
OMe
H
Me
OMe
H
H
Me
4
OMe
R
O
9
12
1
O
Benzene
reflux
O
O
H
+
O
ZnI , CH Cl
2
2
2
6
[
13]
81%
(
-) 14a
2%
R =0.3
(+) 14b
39%
4
ca. 1:1
R =0.4
f
f
acrylamide; a necessity because the conjugated amide did
not react cleanly with 10, and the 2,5-disubstituted furanoid
core of these compounds was very sensitive to oxidizing
agents. The enone 13 was unmasked by a retro-Diels–Alder
reaction, effected by refluxing 12 in benzene overnight and
removing the solvent under reduced pressure. The residue
(13) was dissolved in dry methylene chloride and stirred at
ambient temperature with 50 mol % zinc iodide for 48 h.
The diastereomeric exo adducts7 14a and 14b resulting
thereby were formed in an ~1:1 ratio and a combined yield
of 81%. They were separated by flash column chromatogra-
phy as before4 (Scheme 1). The three new chiral centres
must have absolute configurations 2S,4aS,8aR and 2R,4aR,8aS
with the already established 9R centre common to both. In
our earlier work with racemates, X-ray crystallography of
acetonide (±)-15b prepared from the chromatographically
Results and discussion
The synthesis of homochiral AB units 18a–18d
The prochiral ketone 2-acetylfuran was reduced with bor-
ane in the presence of 5 mol % of the chiral ligand, diphenyl
6
prolinol. The resulting R(+) alcohol 6 (96% yield, >99%
enantioselectivity) was methylated (NaH/MeI) to provide
methyl ether (+)-7 (80% yield). Both reactions were routinely
conducted on 20 g scales and the product from each step iso-
lated by distillation. The iodopropyl side chain was attached
at the remaining furanoid a-carbon atom of 7 as before4 in
two steps, through the bromide 8 (68%) and the iodide 9
a
a
(
93%). Lithium–iodine exchange (t-BuLi, –78°) produced in-
termediate 10, which was quenched in situ with exo-amide
1 to form the desired ketone 12 in 84% yield. This circui-
tous protocol “masks” the double bond of N,O-dimethyl
1
Published by NRC Research Press

Hill et al.
1459
Scheme 2. Synthesis of hydroxy enones 16a and 16b.
Scheme 3. Synthesis of cis-decalones 17a–17b.
16a
1
4a
14b
1. OsO , K Fe(CN)
6
16b
H2, 1 atm
Cat B, 66%
Cat A = [Ir(COD)py(PCy3)] [PF6]-
+
1
8
2
. OsO , K Fe(CN)
6
1%
. p-TsOH
H2, 1 atm
4
3
4
3
+
-
Cat A, 87% Cat B = [Ir(COD)py(PCy )] [BAr ]
8
2
4%
. p-TsOH
3
F
MeO OMe
MeO OMe
O
O
H
H
H
O
O
9
1%
O
98%
4
6
Me
H
Me
H
2
8
O
O
O
OH OMe
H
OH OMe
O
O
O
1
7b
17a
O
Me
H
Me
H
for a similar hydrogenation, also left these enones intact. The
cationic iridium catalysts were evaluated next. A structural re-
quirement for the successful hydrogenation of 3-cyclohexenols
was that the hydroxyl group of the substrate be axially dis-
posed. This ensures that both the hydroxyl group and the
double bond are within reach of the metal in the putative
H
H
O
15a OMe
O
15b OMe
Na
MeOH
Na
MeOH
73%
80%
3+
octahedral Ir complex resulting from oxidative addition of
O
O
8
hydrogen to the precatalyst. Our substrates did meet this
O
O
criterion admirably, but they were seriously crowded around
the reaction site. The homogenous hydrogenation with the
Crabtree catalyst11 was initially conducted in methylene
chloride with the “slower” enone 16a at various pressures
of hydrogen, catalyst loadings, and reaction times. In gen-
eral, the reaction was slow and incomplete. This was not
surprising: tetrasubstituted double bonds are not easily hy-
drogenated. However, the desired product (the cis-decalone
Me
H
Me
H
OMe
OH OMe
6a
OH
O
O
1
16b
faster adduct (Scheme 2), indicated that its relative configu-
ration was 2S*,4aS*,8aR*,9S*. It therefore follows that the
absolute configuration of the faster adduct (14b) is
R,4aR,8aS,9R (R = 0.4, [a]D = +32.2) and the slower
14a) is 2S,4aS,8aR,9R (R = 0.3, [a]D = –37.5). These as-
1
1
7a) was obtained in 87% yield after 48 h at a pressure of
atm of hydrogen (Scheme 3).
2
f
(
f
Surprisingly, and for reasons unknown, no conditions
signments are also recorded in Scheme 1.
could be found that would hydrogenate the double bond of
6b with the Crabtree catalyst. It has been reported that this
The 9R centre must be destroyed at a subsequent stage to
generate the C-2 acetyl group of pillaromycinone, thereby
converting the two diastereomers into enantiomers each of
which can relate to (+)- or (–)-pillaromycinone. The chiral
1
catalyst can suffer deactivation over time by the formation of
trimeric hydrogen-bridged iridium species, and this would be
especially likely in slow reactions such as this. However, it is
also known12 that exchanging the PF6 counterion for the
9
R substituent thus serves as a traditional resolving agent,
–
but one that is also an integral part of the target molecule.
4
a
more lipophilic tetrakis[3,5-bis(trifluoromethyl)phenyl] borate
Proceeding as before, the C-3, C-4 double bond of each
adduct was dihydroxylated and converted to the respective
acetonides 15a and 15b. Each acetonide was then subjected
to cleavage of the oxygen bridge by brief treatment with so-
dium in refluxing methanol. The resulting hydroxy enones
–
(
BArF) improved catalyst performance and resistance to
deactivation. We decided to prepare this catalyst by reaction
+
–
of the Crabtree catalyst with Na (BAr ) in a two-phase
methylene chloride – water system.
F
13,14
Column chromatogra-
phy of the product (methylene chloride / silica) followed by
crystallization from ethanol/ether gave the desired catalyst
1
6a and 16b (higher R ) were obtained in 10% and 9.3%
f
overall yields, respectively, from 2-acetylfuran after nine
steps (Scheme 2). We were able to separate (±)-16a on a
chiralcell-OD column and show that our sample of 16a
was >99% enantiomerically pure (Fig. 1 of the Supplemen-
tary data).
+
–
[Ir(cod)py(PCy3)] [BArF] , whose structure was confirmed
by X-ray crystallography (Supplementary data). Hydrogena-
tion of the other diastereomeric enone (16b) with 10 mol %
of this catalyst overnight, at a pressure of 1 atm of hydro-
gen produced the decalone 17b in 66% yield. These reac-
tions were also performed with the racemates (±)-16a and
(±)-16b and the products (±)-17a and (±)-17b analysed by
X-ray crystallography to establish their structures and rela-
tive stereochemistry (Supplementary data). It was gratifying
indeed to observe that the difficulty with the configuration
at C-4a had finally been resolved and the desired hydroxyl-
directed hydrogenation had been achieved. At this stage we
decided to also investigate the possibility of epimerising
17a and 17b at C-8a to obtain the trans-decalones 17c and
17d (Scheme 4). This was achieved in 80% yield by treat-
ment with LiHMDS in THF (–78° → 0°), but the reactions
could not be taken to completion and the products contained
It was now necessary to face the difficult problem of hy-
drogenation of the tetrasubstituted C-4a, C-8a double bond
of each enone with delivery of hydrogen syn to the C-7 hy-
droxyl group and C –C acetonide. Indeed, this was the step
5
6
that had failed to produce the desired AB ring fusion in our
earlier work.4 Some promising precedents employing
homogeneous hydrogenation techniques are available in the
literature. A cationic rhodium catalyst had efficiently hydro-
genated a tetrasubstituted double bond syn to a homoallylic
a
8
9
hydroxyl group, but our substrates 16a and 16b were unaf-
+
–
fected by 5 or 10 mol % of [Rh(nbd)(diphos-4)] BF4 at
pressures of 1–50 atm (1 atm = 101.325 kPa) of hydrogen,
at room temperature, after 24 or 36 h. Diimide, used earlier10
Published by NRC Research Press

1460
Can. J. Chem. Vol. 89, 2011
Scheme 4. Synthesis of cis- and trans-enones 17a–17d.
O
O
H
H
H
O
LiHMDS
THF, 80%
O
LiHMDS
THF, 80%
Me
H
Me
H
17a
17b
H
OH OMe
OH OMe
O
O
LDA, TMSCl
Pd(OAc) , O
LDA, TMSCl
17d
1
7c
2
2
Pd(OAc) , O2
2
LDA, TMSCl
LDA, TMSCl
Pd(OAc) , O 56%
2
6
3%
63%
Pd(OAc) , O2 72%
2
2
O
O
O
O
H
H
H
H
O
O
O
O
Me
H
Me
H
Me
H
Me
H
H
OR OMe
H
OR OMe
H
OR OMe
H
OR OMe
O
O
O
O
1
8a
R = TMS
18c
R = TMS
18b
R = TMS
18d R = TMS
~
20% of the starting cis-decalones 17a and 17b, which
undergo the Michael addition – Dieckmann condensation se-
quence to afford polycyclic ketones in satisfactory yields.
Both diastereomers 18a and 18c reacted with the stannane
19 after tin–lithium exchange to form ABCD tetracycles 20a
(62%) and 20c (71%), respectively.
These homochiral tetracycles were then dehydrogenated
with dicyanodichloroquinone (DDQ) in benzene. The AB cis
fused heterocycle 20a was unexpectedly resistant to the aro-
matisation of ring C and the reactions were difficult to com-
plete, with product (21a) yields around 30%. Using other
dehydrogenating agents (e.g., Pd/C or chloranil) did not im-
prove matters.
This unfortunate setback was alleviated somewhat by test-
ing the trans-enone 18c instead, in the two-step annulation.
As it happened, the AB trans tetracycle 20c produced (71%
yield) in the first step was quantitatively dehydrogenated by
DDQ to (+)-21c ([a]D = +32.4). This florescent yellow-
green compound bearing the requisite substitution and
absolute stereochemistry at C-3, C-4, and C-4a suitable for
progressing to (+)-pillaromycinone was obtained in 14 steps
and 3.95% overall yield from 2-acetylfuran (Scheme 5).
However, the configuration at the enolisable C-12a centre
will have to be inverted in a subsequent hydroxylation step.
We began our effort to approach (+)-pillaromycinone by
examining the possibility of O-desilylation and subsequent
elimination of the tertiary hydroxyl group at C-2. Initially,
treatment with TBAF in wet THF resulted in a complex mix-
ture of products (see later), but PPTS in methanol at 0° did
accomplish the desired desilylation in excellent yield. Many
attempts were made to dehydrate the resulting C-2 tertiary
hydroxyl group of 22. With milder reagents like DCC, thio-
carbonyl diimidazole, and mesyl chloride / DMAP, the start-
ing material was recovered. Other reagents like thionyl
chloride or triphenyl phosphine / iodine caused extensive de-
composition. Acid-catalyzed dehydration with p-TsOH in
moist THF was examined at temperatures between 0° and
were separated by column chromatography. In Fig. 2 of the
Supplementary data, the H NMR spectra (500 MHz) of
1
1
7a–17d are displayed. Particularly noteworthy is the small,
but measureable W-coupling (found only in 17a) between
H-8a and the C-7 hydroxyl proton. This coupling is greatly
reduced upon D O exchange. The other diagnostic feature
in the figure is the lack of any signals between 2.5 and
2
3
.2 ppm in the spectra of 17c and 17d. This region con-
tains the cis-ring junction protons H-4a and H-8a in 17a
and 17b and their absence reflects the trans-ring fusion in
the former compounds.
2,3
Unlike the previous reports that employed the Diels–Alder
reaction to create the AB cis-ring fusion, our hydrogenation/
epimerization sequence produces two pairs of AB inter-
mediates cis and trans fused at will, each with a rigorously
predetermined absolute configuration. The first pair (17a
and 17c) had stereochemistry at C-4a, C-5, and C-6 identi-
cal with that of (+)-pillaromycinone, whereas the second
(
17b and 17d) related to the (–)-enantiomer in a similar
manner. With each pair, a choice of configuration at the
enolisable C-8a centre was available. We soon found that
this versatility was a valuable asset in a subsequent step of
the synthesis. Dehydrogenation of each decalone (17a–17d)
at C-2, C-3 was achieved by the two-step Saegusa
method.15 The kinetic enolates were quenched with excess
TMSCl and the resulting enol silanes were each oxidized
16
with Pd(OAc) in DMSO under an atmosphere of oxygen.
2
The enones (18a–18d) were isolated in 56%–72% yields. At
this stage a final check on structure and stereochemistry of
these AB segments was secured by a X-ray crystal structure
of one of them, (±)-18b. We decided to continue the syn-
thesis with the 18a, 18c pair only, because their configura-
tions related to the natural antibiotic and they were
produced in the highest overall yields from 2-acetylfuran
(5.5% and 4.3%, respectively).
2
5° with regular monitoring by TLC. After reaction under
Synthesis of homochiral tetracycles
such conditions overnight at room temperature, the starting
material 22 was consumed and two products were detected.
One was the deprotected acetonide, a tetrahydroxy compound
that could be eluted from a column only with neat ethyl ace-
tate. The other, slightly slower on TLC than the starting
The next obstacle, the unacceptable yield of the Staunton–
Weinreb annulation, was overcome by our “stannane modifi-
4
b
cation” of the process. No less than seven cyclic enones,
with and without17 enolisable hydrogen atoms, were found to
Published by NRC Research Press

Hill et al.
1461
Scheme 5. Synthesis of homochiral tetracycles.
1
3
SnBu3
CO Et
R = MeCHOMe
2
OMe
19
O
O
O
H
H
6
H
H
1
9
DDQ
O
1
8a
4
1
ref
# 4b
OTMS
30%
12
O
9
OTMS
R
R
OMe OH
O
OMe OH
2
0a
2
1a
O
O
H
H
O
O
1
9
DDQ
OTMS
1
8c
OTMS
ref
#
4b
100%
H
R
R
H
OMe OH
O
OMe OH
O
2
0c
2
1c
Fig. 2. Progress made towards pillaromycinone and premithramycinone.
O
OR
4
OMe
H
6
H
H
H
H
O
OH
O
4
a
OH
1
2a
Me
9
12
O
OH
Me
H
O
1
H
MeO H
OMe OH
Me
OMe OH
OMe OH
O
MeO H
O
MeO
2
2
25
23 (R = H)
24 (R = Me)
OMe
O
O
O
H
H
H
H
O
O
OH
Me
Me
MeO H
OH
Me
OH
MeO H
OMe OH
OMe OH
O
OMe OH
O
O
MeO H
26
27
28
material 22, had the same molecular formula (HRMS), but a
alcohol to generate the C-1, C-2 double bond as we had in-
tended to do in our synthetic planning. Therefore, we de-
cided to examine the complex mixture produced by the
TBAF treatment of 21c more carefully. Purification by chro-
matography provided a crystalline reddish yellow compound
in an optimized yield of 60%. It had a molecular formula of
C H O (HRMS) in contrast to the starting material 21c
1
different H NMR spectrum, particularly in the signals of the
protons on ring A (H-1, H-3, H-4, and H-4a, Table 1).18 We
were able to crystallize this product and establish its structure
as 23 by X-ray crystallography. This isomeric acetonide was
also formed from the silyl ether 21c under identical condi-
tions. Although these results were frustrating, we did not
lose sight of the fact that the formation of 23 from 21c or 22
represents the selective deprotection of the C-3, C-4 aceto-
nide at C-4. This finding could be of much significance for
a future attempt to synthesize premithramycinone 3. To illus-
trate, methylation (NaH/MeI) of the now unprotected C-4 hy-
droxyl group afforded methyl ether 24 quantitatively.
Hydrolysis of the acetonide (THF / aq HCl) left the C-2, C-3
diol 25, which was oxidized (IBX, acetonitrile, 80°)19 to pro-
vide the C-3 ketone 26. These simple transformations pro-
duced a tetracycle with structure and stereochemistry not far
removed from the A ring of 3 (Fig. 2).
2
5
28
7
(C H O Si). Therefore, it must have been desilylated
2
8
38
7
(–C H Si), but in addition had a deficiency of two hydro-
3
8
gen atoms. These features were confirmed by comparison
1
13
of its H and C NMR spectra with those of 21c.
1
In particular, the H NMR signals assigned to the C-1 pro-
tons (d 1.68, 2.67) and the C-12a proton (d 2.95) of the start-
ing material were absent in the spectrum of the product, but a
13
new signal was evident as a singlet at 7.13 ppm. The
C
spectrum confirmed the presence of a trisubstituted alkene
with the appearance of two new signals at 135.3 and
136.5 ppm (protonated and nonprotonated, respectively).
Based on these and other NMR comparisons (Table 1) we as-
signed the structure 27 to this compound and confirmed it by
single-crystal X-ray analysis. We found that 27 was also
Even though these were interesting and potentially useful
reactions, they represented no advance towards pillaromycin-
one. In particular, we had no success in dehydrating the C-2
Published by NRC Research Press

1
Table 1. H NMR data (500 MHz, d (in ppm), J (in Hz)) for tetracycles 21c, 22, 23, 27, and 28 in CDCl .
3
Compound
21c
22
23
27
28
O
O
OH
O
H
H
H
H
H
H
O
R
O
O
O
O
OH
OH
OH
R
R
R
OMe OH
O
Proton
H-1
OMe OH
O
OMe OH
O
OMe OH
O
ax. 1.68(t), J=12.8, 12.8
eq. 2.68 overlapped by H-5
4.02(d), J=4.8
4.15(dd), J=8.6, 4.7
1.98(m), J=12.5, 12.5, 8.6, 3.6
ax. 2.68 overlapped by H-leq
ax. 2.07(dd), J=15, 8.7
eq. 2.33(dd), J=15, 7.5
4.33(d), J=7.0
ax. 1.43(t), J=13.5, 13.5
eq. 2.85(dd), J=14.3, 3.6
4.19(d), J=3.8
3.86(td), J=10.5, 10.5, 3.8
2.2 (complex m)
7.13(d), J=2.9
6.9(s)
H-3
H-4
H-4a
H-5
4.30(d), J=6.6
4.19(t), J=6.2, 6.2
3.0 (complex m)
4.72(d), J=6.3
4.49(dd), J=10.2, 6.3
2.16(m)
4.11(dd), J=9.0, 7.0
2.5(m), overlapped by C-2 OH
ax. 2.68, partially overlapped by
H-4a, and H-12a
ax. 2.7(m) overlapped with H-12a
ax. 2.79(t), J=14, 14
ax. and eq. 3.2–3.25 complex
multiplet
eq. 3.3 overlapped by H-13 and
eq. 3.3 overlapped by H-13 and
C13–OMe
2.63(dt), J=13, 8.2, 8.0 partially
eq. 3.49(dd), J=16, 3.6
eq. 3.30(dd), J=14.8, 5.4
—
C13–OMe
H-12a
H-13
2.95(td), J=12.6, 12.6, 2.9
2.7 (complex m) overlapped with
H-5ax
3.45(q), J=6.2
—
overlapped by H-5
3.32(q), J=6.3
ax
3.3, overlapped by H-5 and
eq
3.34(q), J=6.3
4.02–4.06 overlapped by
C
13–OMe
1.29(d), J=6.3
4.03, C 3.31
C –OMe
10
1.44(d), J=6.4
4.05, C 3.4
C
OMe
-Me
3
1.29(d), J=6.3
1.34(d), J=6.2
1.29(d). J=6.3
1
C
C
4.03, C 3.37
13
C
4.04, C 3.33
C
4.01, C 3.36
13
C
1
0
13
10
1.53, 1.45
10
1.47, 1.37
13
10
1.50, 1.43
10
1.49, 1.38
13
O
Me
Me
1.5, 1.43
O
OH
C
11–OH, 15.2
C
2.46, C 15.1
11
C
2.13(d), J=10.3, C 15.56
11
C
2.9, C 15.45
11
C
2.21, C 14.66
2
4
2
12a 11
Note: Aromatic H signals appeared in a narrow range in all compounds as follows: H-8(t) 7.47–7.53, H-7(d) 7.20–7.25, H-6(s) 6.90–7.01, and H-9(d) 6.80–6.84, with coupling constants J = 7.80–8.0 Hz.
1
R = MeCHOMe
3
.

Hill et al.
1463
Scheme 6. Proposed mechanism for the formation of 27 from 21c or 22.
OH
O
O
O
A
O
H
H
H
O
O
O
O
B
OH
OH
OH
R
R
OMe OH
O
OMe OH
O
2
7
22
H O
2
R = MeCHOMe
O
H
O
O
OH
H
O
OH
R
H
H
HO O
H
O
H
R
O
H O
2
HO OH
OH
+
H2
R
HO
H
OH
H OH
1
produced from the desilylated tetracycle 22 in similar yield
under identical conditions. This remarkably selective dehy-
drogenation probably occurs by means of a radical chain
component. The H spectrum of the green fluorescent prod-
uct, when compared with the starting enone, showed many
changes in the chemical shifts of protons associated with
ring A. The alkene proton remained as a singlet, now at
6.9 ppm, and the signals assigned to H-3, H-4, and H-13
showed significant downfield shifts, whereas H-4a, no longer
allylic, was shifted upfield considerably (Table 1). These
changes taken together suggested that an allylic rearrange-
ment22 had occurred in ring A. The structure 28 is proposed
for the fluorescent product with the double bond now at C-1,
C-2 and the hydroxyl group at C-12a. The evident lack of a
C-12a proton and the presence of a broad OH signal at
2.21 ppm supported the structural assignment. The configura-
tion of the hydroxyl substituent at C-12a is still uncertain,
however, and the difficulties experienced with purification of
the product implies that it is an epimeric mixture of two C-
12a alcohols. We have tried very hard to obtain suitable crys-
tals of 28 for X-ray analysis without success so far, but these
attempts are continuing.
2
0
process initiated by THF peroxide and propagated by hy-
droxyl radicals. We propose a mechanism (Scheme 6) that
accounts for the regioselectivity by assigning a crucial role
to the carbonyl group at C-12 and avoids the intermediacy
of an enolate radical at C-12a. The collapse of such a radical
would result in the aromatization of ring B. The absolute
configurations at every other chiral centre besides C-12a
were unaffected in the transformation, and we had recognized
earlier that the existing configuration at that centre would
have to be corrected eventually. Consequently, we saw this
g-hydroxy enone 27 as an opportune substrate either for in-
troducing the required hydroxyl group at C-12a in the correct
orientation or for generating the desired C-2 acetyl group by
dehydration at C-2, C-13.
We attempted the dehydration first by applying a simple
2
1
procedure recommended specifically for tertiary alcohols
and illustrated with many examples of success with sensitive
substrates. Under the conditions cited (mesyl chloride, tri-
ethylamine, DMAP in dry dichloromethane 0° → rt, 30 min)
we obtained a green fluorescent compound that was sepa-
rated from the reaction mixture by column chromatography
on silica gel, first in ethyl acetate / hexane and then in
dichloromethane/ether (85:15). However, even after careful
chromatography, this material (a single spot on the TLC
analysis) could not be obtained pure. The base peak at m/z
Conclusion
If the configuration of 28 can be conclusively settled it
would mean that we have succeeded in developing a synthe-
sis of a very advanced intermediate for (+)-pillaromycinone
requiring only minor structural adjustments for completion.
It incorporates the correct absolute configuration at C-3, C-
4, and C-4a and the double bond at C-1, C-2. Its synthesis
required only 16 steps from 2-acetylfuran and features novel
protocols for (i) stereochemical control at C-4a, C-4, and C-
3; (ii) the Staunton–Weinreb annulation; (iii) regioselective
dehydrogenation of a tetracyclic ketone at C-1, C-12a; and
(iv) introduction of the hydroxyl group at C-12a. In addition,
an interesting possibility of modifying ring A for the synthe-
sis of premithramycinone has been created.
4
40 in its mass spectrum corresponded to a molecular for-
mula C H O (by HRMS) making it isomeric with the
25
28
7
starting enone. In addition, the spectrum did not display an
ion of significant intensity at m/z 422, thereby implying that
1
13
the projected dehydration had not occurred. The H and
C
NMR spectra indicated the presence of about 10% of an im-
purity that appeared to be structurally similar to the major
Published by NRC Research Press

1464
Can. J. Chem. Vol. 89, 2011
quenched with solid NaHSO3 and stirred for a further
Experimental
Experimental procedures and spectroscopic data for race-
0
.5 h. It was extracted with ethyl acetate (3×) and the re-
maining aqueous layer continuously extracted with ethyl
acetate for a further 48 h. The ethyl acetate extracts were
mic compounds 6–15, stannane 19, and chiral tetracycles
4
20a and 20c have been published previously. Experimental
combined, dried (MgSO ), and then evaporated. The residue
4
protocols have been modified in some instances and yields
improved. In such cases, the new conditions and yields are
provided. See the Supplementary data for notes on general
experimental methods.
was purified by chromatography to obtain a white solid in
each case.
Dihydroxylation of 14a
1
3a (2.87 g, 12.9 mmol), OsO (0.0714 mol/L) in water
4
R-(+)-1-Furylethanol (6)
(
3
2
36 mL), K Fe(CN) (12.73 g, 38.7 mmol), K CO (5.35 g,
3 6 2 3
To a stirred solution of S-diphenylprolinol (2.3 g,
8.7 mmol), t-BuOH (50 mL), and water (14 mL). Yield:
.63 g (81%). [a] = –4.73 (c 0.676, CHCl ).
9
.08 mmol) in THF (650 mL) was added 2.0 mol/L BH –
3
D
3
SMe (64 mL, 128 mmol). The mixture was stirred overnight
2
at room temperature (rt). A solution of 2-acetylfuran (20 g,
Dihydroxylation of 14b
3b (2.0 g, 9.0 mmol), OsO4 (0.098 mol/L) in water
18 mL), K Fe(CN) (8.89 g, 27 mmol), K CO (3.73 g,
1
81.6 mmol) in THF (30 mL) was added slowly via a syringe
1
pump and the mixture was stirred overnight at rt. The reac-
tion was quenched with methanol and the solvents removed
in vacuo at rt. Distillation (water aspirator) gave 6 (19.5 g,
(
2
1
3
6
2
3
7 mmol), t-BuOH (35 mL), and water (17 mL). Yield:
.934 g (84%). [a] = +4.44 (c 0.608, CHCl ).
9
6%) as a clear colourless liquid, bp 64°–70°. [a] = +21.1
D
3
D
(
c 1.06, CHCl ). Optical rotation suggests >99% enantiose-
3
2
3
lectivity for the reduction.
2H-2-(1′-Methoxyethyl)-3b,4b-di-O-isopropylidene-2,4a-
epoxy-octahydronaphthalen-8-one (15a and 15b)4
To a refluxing solution of the diol (1.0 equiv) in 2,2-dimeth-
oxypropane and dichloromethane was added a few crystals
of TsOH. Refluxing was continued for a further 0.5 h, the
mixture cooled, neutralized with solid K2CO3, and the sol-
vents removed in vacuo. Flash column chromatography
3:1, hexanes / ethyl acetate) gave the pure acetonides. 15a:
Diol (5.817 g, 22.7 mmol), 2,2-dimethoxy propane (66.2 g,
36 mmol), CH Cl2 (360 mL), TsOH (a few crystals).
a
4
a
R(+)-2-(1′-Methoxy)ethylfuran (7)
a] = +109.9 (c 1.006, CHCl ), 80% yield.
[
D
3
4a
R(+)-2-(3-Bromopropyl)-5-(1′-methoxy)ethylfuran (8)
a] = +67.0 (c 1.216, CHCl ), 68% yield.
[
D
3
(
4a
R(+)-2-(3-Iodopropyl)-5-(1′-methoxy)ethylfuran (9)
a] = +59.1 (c 1.482, CHCl ), 93% yield.
6
[
2
D
3
Yield: 6.09 g (91%). [a]D = –26.8 (c 0.954, CHCl ). 15b:
Diol (1.774 g, 6.92 mmol), 2,2-dimethoxypropane (20 g,
194 mmol), CH Cl2 (150 mL), TsOH (a few crystals).
Yield: 2.0 g (98%). [a] = +33.2 (c 1.05, CHCl ).
3
2
b-(N-Methyl-N-methoxyamido)-7-oxabicyclo[2.2.1]hept-5-
4a
ene (11) and R(+)4-[5-(1-methoxyethyl)furan-2-yl]-1-(7-
2
oxabicyclo[2.2.1]hept-5-ene-2-yl)butan-1-one (12)4a
D
3
[
a] = +61.0 (c 1.184, CHCl ), 84% yield.
D 3
7
-(1′-Methoxyethyl)-7b-hydroxy-5b,6b-di-O-
isopropylidene-4a,8a-dehydro-1-decalone (16a and 16b)
To a solution of sodium (5 equiv) in methanol was added
the ketone 15a or 15b (1 equiv) in methanol. After 20–
2
H-2-(1′-Methoxyethyl)-2,4a-epoxy-1,8a,5,6,7,8-
hexahydronaphthalen-8-one (14a and 14b)
A solution of ketone 12 (10.98 g, 37.8 mmol) in benzene
100 mL) was heated at reflux for 48 h. The liquids were
evaporated and the residue dissolved in dichloromethane
100 mL) and zinc iodide (4.82 g, 15.1 mmol) was added.
3
0 min the solution was cooled and poured onto dry ice. It
(
was diluted with ether and filtered. The filtrate was evapo-
rated to dryness and purified by flash chromatography (hex-
anes / ethyl acetate, 2:1). 16a: ketone 15a (2.0 g, 6.75 mmol),
MeOH (55 mL), sodium (0.775 g, 33.7 mmol) in MeOH
(
The suspension was stirred for 48 h at rt and quenched with
aqueous sodium bicarbonate. The mixture was extracted with
dichloromethane (3 × 50 mL), the organic extracts combined
(
–
1
55 mL), refluxed for 20 min. Yield: 1.595 g (79.8%). [a] =
102.7 (c = 0.736, CHCl ). H NMR (300 MHz, CDCl ) d:
D
1
and washed with brine, then dried (MgSO ) and concen-
3
3
4
.17 (3H, d, J = 6.3 Hz), 1.42, 1.46 (3H each, s), 1.99 (2H,
trated. Flash chromatography (30% ethyl acetate – hexanes)
gave 6.7 g (81%) of a mixture of 14a and 14b and 0.23 g of
unchanged starting material. The diastereomeric adducts 14a
m), 2.2, 2.42 (4H, m), 2.68 (2H, m), 3.25 (1H, qt), 3.31 (3H,
s), 4.42 (1H, d, J = 7.2 Hz), 4.53 (1H, d, J = 7.2 Hz). 13
C
4
a
NMR (75 MHz, CDCl ) d: 12.2, 22.1, 24.7, 24.8, 26.6, 26.9,
37.7, 57.1, 71.3, 74.6, 75.2, 78.6, 109.0, 130.1, 150.6, 198.6.
and 14b were separated as before by chromatography. 14b
R ≈ 0.4; [a] = +32.2 (c 1.006, CHCl ); 39% yield. 14a:
R ≈ 0.3; [a] = –37.5 (c 1.004, CHCl ); 42% yield.
3
f
D
3
+
EI HRMS (M – CH3) found: 281.1387; C15H21O5 calcd:
f
D
3
2
81.1367. 16b: ketone 15b (0.485 g, 1.63 mmol) in MeOH
Dihydroxylation of 14a and 14b: 2H-2-(1′-methoxyethyl)-
b,4b-dihydroxy-2,4a-epoxy-octahydronaphthalen-8-one4a
(11 mL), sodium (0.188 g, 8.18 mmol) in MeOH (11 mL)
1
3
refluxed for 30 min. Yield: 0.353 g (73%). H NMR
(
300 MHz, CDCl ) d: 1.13 (3H, d, J = 6.3 Hz), 1.35, 1.36
3
Modified procedure
(3H each, s), 1.99 (2H, m), 2.2, 2.42, 2.64 (6H, m), 3.09
A mixture of 14a or 14b (1 equiv), OsO (0.2 equiv),
(1H, qt), 3.29 (3H, s), 4.42 (1H, d, J = 7.2 Hz), 4.48 (1H,
4
d, J = 7.2 Hz). 13C NMR (75 MHz, CDCl ) d: 12.7, 22.2,
K Fe(CN) (3.0 equiv), K CO (3.0 equiv), H O, and tert-
3
6
2
3
2
3
butyl alcohol were stirred at rt for 48 h. The reaction was
25.3, 26.6, 27.1, 27.4, 37.6, 57.1, 72.8, 75.4, 76.1, 79.9,
Published by NRC Research Press

Hill et al.
1465
1
2
09.3, 129.8, 151.4, 198.6. EI HRMS (M – Me)+ found:
CDCl ) d: 1.15 (3H, d, J = 6.3 Hz), 1.23–1.30 (1H, m),
3
81.1386; C H O calcd: 281.1356.
1.35 (3H, s), 1.46 (3H, s), 1.66 (1H, br.q, J = 14.0 Hz),
15
21
5
1
.81 (1H, q, J = 9.1 Hz), 1.98 (1H, br.q, J = 11.0 Hz),
7
-(1′-Methoxyethyl)-7-hydroxy-5,6-di-O-isopropylidene-
2.06–2.12 (3H, m), 2.21–2.31 (2H, m), 2.42 (1H, br.d, J =
14.0 Hz), 2.5–2.7 (1H, br), 3.14 (1H, q, J = 6.0 Hz), 3.33
(3H, s), 3.90 (1H, dd, J = 8.4, 6.5 Hz), 4.24 (1H, d, J =
6.5 Hz). 13C NMR (125 MHz) d: 12.5, 25.2, 25.9, 27.5,
27.9, 29.8, 41.5, 43.6, 47.0, 57.3, 73.4, 74.8, 80.2, 81.8,
decal-1-ones (17a and 17b)
A solution of the enone 16a or 16b (1 equiv) with iridium
catalyst (0.1 equiv) in dichloromethane was flushed with hy-
drogen (3×) and stirred under an atmosphere of hydrogen for
+
2
4–48 h at rt. Brine was added and the layers separated. The
108.7, 209.7. EI HRMS (M ) found: 298.1788; C16H26O5
aqueous layer was extracted with dichloromethane (3×) and
calcd: 298.1780
1
the organic layers were combined, dried (MgSO ), and con-
The H NMR (500 MHz) spectra of 17a–17d are displayed
4
centrated. Flash column chromatography (hexanes / ethyl ace-
in Fig. 2 of the Supplementary data.
tate, 2:1) yielded pure products as white solids. 17a: enone
+
–
1
6a (0.332 g, 1.12 mmol), [Ir(COD)py(PCy )] [PF ]
7-(1′-Methoxyethyl)-7-trimethylsilyloxy-5,6-di-O-
3
6
(
0.09 g, 0.112 mmol) in CH Cl (80 mL), stirred under H
isopropylidene-2,3-dehydrodecal-1-ones (18a–18d)
Diisopropylamine (12 equiv) in THF at 0° was stirred with
n-BuLi (12 equiv) for 15 min. The solution was cooled to –78°
and the ketone 17 (1 equiv) in THF was added slowly by a
syringe. After stirring for a further 1 h at –78°, TMSCl
2
2
2
for 48 h. Yield: 0.291 g (87%). [a]D = +9.63 (c 0.114,
CHCl ). H NMR (500 MHz, CDCl ) d: 1.10 (3H, d, J =
1
3
3
6
1
.3 Hz), 1.28 (3H, s), 1.62 (1H, dd, J = 15.0, 8.0 Hz), 1.8–
.9 (4H, m), 2.08 (1H, ddd, J = 15.0, 6.5, 2.1 Hz), 2.31 (2H,
m), 2.45 (1H, d, J = 2.1 Hz), 2.81 (2H, m), 3.08 (1H, q, J =
.3 Hz), 3.28 (3H, s), 3.89 (1H, dd, J = 8.0, 7.6 Hz), 4.16
(
20 equiv) was added and the stirring was continued for a
6
further 1.25 h. The solution was allowed to warm to 0°
and was stirred for a further 15 min and then quenched
1
3
(
1H, d, J = 7.6 Hz). C NMR (75 MHz, CDCl ) d: 12.1,
3
2
7
6
2.5, 23.0, 24.6, 25.6, 26.7, 39.0, 40.7, 44.4, 57.3, 73.1,
with aq NH Cl, extracted with ether (3×), washed with
4
3.3, 74.4, 80.4, 108.0, 212.7. Anal calcd for C H O : C
1
6
26
5
brine, dried (MgSO ), and concentrated. The crude bis-silylether
4
4.41, H 8.78; found: C 64.60, H 8.87. 17b: enone 16b
0.125 g, 0.421 mmol), [Ir(COD)py(PCy )] [BAr ]
was taken up in DMSO and Pd(OAc)2 (0.5 equiv) was
+
–
(
3 F
added and flushed with O (3×). It was then stirred under
2
(
0.064 g, 0.042 mmol) in CH Cl (30 mL) under H for
2 2 2
an atmosphere of oxygen for 48 h at rt. The reaction was
quenched with brine and extracted with EtOAc (5×) and
the extracts washed with water and then brine, and then
1
2
1
4 h. Yield: 0.0835 g (66%). H NMR (500 MHz, CDCl ) d:
3
.20 (3H, d, J = 6.3 Hz), 1.36 (3H, s), 1.51 (3H, s), 1.63
(1H, dd, J = 15.0, 8.0 Hz), 1.89 (4H, m), 2.27 (1H, ddd,
dried (MgSO ). The solvents were removed and the residue
4
J = 15.0, 9.4, 1.5 Hz), 2.40 (2H, m), 2.84 (1H, m), 2.91–
.93 (2H, m), 3.09 (1H, q, J = 6.3 Hz), 3.34 (3H, s), 3.86
1H, dd, J = 9.2, 7.5 Hz), 4.11 (1H, d, J = 7.5 Hz). 13
purified by flash chromatography (hexanes / ethyl acetate,
2
(
8
2
:1). 18a: 17a (0.336 g, 1.13 mmol in THF 12 mL),
C
.0 mol/L n-BuLi (6.75 mL, 13.5 mmol), i-Pr NH
2
NMR (125 MHz, CDCl ) d: 13.0, 22.5, 25.0, 25.3, 26.3,
3
(
2
2.0 mL, 14.0 mmol), THF (12 mL); TMSCl (2.9 mL,
2.5 mmol), Pd(OAc)2 (0.126 g, 0.563 mmol), DMSO
2
7.0, 38.5, 40.7, 44.2, 57.5, 73.2, 73.5, 75.1, 83.0, 108.4,
+
2
13.0. EI HRMS (M – Me) found: 283.1548; C H O
15
23
5
(
+
12 mL) yielded 18a as an oil. Yield: 0.264 g, (63%). [a] =
D
calcd: 283.1546.
1
13.4 (c 0.298, CHCl ). H NMR (300 MHz, CDCl ) d:
3
3
0
(
1
(
.13 (9H, s) 1.16 (3H, d, J = 6.3 Hz), 1.30 (3H, s), 1.48
3H, s), 1.89 (1H, dd, J = 14.7, 7.1 Hz), 2.08 (1H, dd, J =
4.7, 6.0 Hz), 2.42–2.48 (2H, m), 2.59–2.69 (2H, m), 3.12
1H, q, J = 6.3 Hz), 3.16 (3H, s), 3.87 (1H, d, J =
4
ab,8aa-Decal-1-one (17c)
cis-Decalone 17a prepared above was dissolved in dry
THF (0.25 mol/L solution) and cooled to –78°. LiHMDS
1.5 equiv) was added and the mixture stirred at –78° for
0 min. It was allowed to warm to 0° and stirred at that tem-
perature for a further 30 min. The reaction was quenched at
(
1
6
.0 Hz), 4.01 (1H, dd, J = 7.5, 6.2 Hz), 5.99 (1H, dt, J =
1
0.0, 1.9 Hz), 6.76 (1H, dd, J = 10.0, 4.3 Hz). 13C NMR
(75 MHz, CDCl ) d: 2.8 (3C), 12.0, 25.6, 26.5, 27.2, 27.5,
3
0
° with methanol and allowed to reach rt. The solvents were
3
1
5.3, 41.9, 55.7, 76.1, 76.9, 77.5, 82.5, 107.6, 130.1, 146.3,
removed and the crude product purified by chromatography
+
99.0. EI HRMS [M –Me] found: 353.1785; C H O Si
18
29
5
to leave a thick oil. Yield: 80%. [a]D = –10.6 (c 0.46,
CHCl ). H NMR (500 MHz, CDCl ) d: 1.17 (3H, d, J =
calcd: 353.1785. 18b: 17b (0.171 g, 0.572 mmol in THF
1
3
3
(6 mL)), 2.0 mol/L BuLi (3.43 mL, 6.86 mmol), i-Pr NH
2
6
.3 Hz), 1.29–1.34 (1H, m), 1.36 (3H, s), 1.45 (3H, s), 1.63
(1.0 mL, 7.16 mmol) in THF (6 mL), TMSCl (1.5 mL,
(
1H, qt, J = 13.6, 4.0 Hz), 1.77 (1H, dd, J = 15.0, 7.1 Hz),
.96–2.06 (3H, m), 2.38–2.41 (1H, m), 3.21 (1H, m), 3.21
1H, q, J = 6.3 Hz), 3.29 (3H, s), 3.99 (1H, dd, J = 9.0,
1
1.44 mmol); Pd(OAc) (64 mg, 0.286 mmol) in DMSO
2
1
(
6 mL). Yield: 0.133 g (63%) of 18b as a pale yellow oil.
(
1
1
3
H NMR (300 MHz, CDCl3) d: 0.12 (9H, s), 1.16 (3H, d, J =
7
.1 Hz), 4.18 (1H, d, J = 7.1 Hz). C NMR (125 MHz,
6
.3 Hz), 1.25 (3H, s), 1.45 (3H, s), 1.65 (1H, dd, J = 14.9,
.8 Hz), 2.22 (1H, dd, J = 14.9, 7.0 Hz), 2.41–2.46, (2H,
CDCl ) d: 12.1, 24.2, 24.9, 25.8, 27.2, 30.3, 41.6, 43.5,
4
3
6
6.3, 57.0, 73.4, 76.2, 80.3, 80.7, 108.3, 210.1. EI HRMS
+
m), 2.76–2.85 (2H, m), 3.19 (3H, s), 3.15–3.21 (1H, m),
3
M found: 298.1780; C H O calcd: 298.1779.
1
6
26
5
.91 (1H, d, J = 6.6 Hz), 4.0 (1H, t, J = 6.3 Hz), 5.99
(
1H, d, J = 10.0 Hz), 6.80 (1H, dt, J = 10.0, 4.0, 4.0 Hz).
4
ab,8aa-Decal-1-one (17d)
Prepared from 17b as above. The product was obtained in
13C NMR (75 MHz, CDCl3) d: 2.6 (3C), 13.6, 25.8, 26.7,
27.2, 28.2, 35.1, 40.8, 56.0, 74.3, 75.7, 77.1, 81.7, 108.3,
129.7, 147.3, 199.8. 18c: ketone 17c (0.463 g, 1.56 mmol)
a similar yield as a 7:1 mixture of 17d:17b and purified by
column chromatography as before. H NMR (500 MHz,
1
Published by NRC Research Press

1466
Can. J. Chem. Vol. 89, 2011
in THF (17 mL), 1.6 mol/L BuLi (12.5 mL, 20 mmol), i-Pr NH
was extracted into Et O and washed sequentially with satu-
2
2
(
2.8 mL, 20 mmol) in THF (17 mL), TMSCl (4 mL,
0 mmol), Pd(OAc)2 (0.179 g, 0.79 mmol) in DMSO
17 mL) yielded 18c (0.415 g, 1.13 mmol, 72%). A small
amount (0.03 g) of the cis fused enone 18a was also isolated.
rated NaHCO3 and brine. The organic layer was dried
(Na SO ), filtered, and concentrated to dryness under re-
3
(
2
4
duced pressure. The crude product was purified by silica gel
chromatography (EtOAc/hexanes, 1.9) to afford the desired
product 21c (282 mg, 0.515 mmol, 100%) as a bright green
amorphous solid. [a] = +32.4 (CHCl ). R 0.36 (EtOAc/
1
[
a] = +45.5 (c 1.156, CHCl ). H NMR (300 MHz, CDCl )
D 3 3
d: 0.08 (9H, s), 1.16 (3H, d), 1.34 (3H, s), 1.45 (3H, s), 1.50
1H, t, J = 13.4 Hz), 1.79–1.85 (1H, m), 1.98–2.08 (1H,
m), 2.38 (1H, dd, J = 13.9, 2.5 Hz), 2.56 (1H, td, J =
D
3
f
(
1
hexanes, 1:4). H NMR (CDCl , 500 MHz): data are shown
in Table 1. C NMR (CDCl , 125 MHz) d: 2.7 (3C), 12.5,
3
13
3
1
3
4
1
2.0, 12.0, 3.0 Hz) 2.67 (1H, dt, J ≈ 18.0, 5.0, 5.0 Hz),
,
26.4, 28.6 (2C), 33.9, 41.4, 44.7, 56.1, 57.2, 77.5, 80.4,
.20 (1H, q., J = 6.3 Hz), 3.23 (3H, s), 3.9 (1H, d, J =
.5 Hz), 4.04 (1H, dd, J = 8.7, 4.7 Hz), 5.94 (1H, dd, J =
8
1
1.3, 85.1, 105.4, 107.8, 111.1, 115.1, 116.6, 119.7, 130.8,
37.8, 140.1, 159.8, 165.7, 204.9. EI HRMS calcd for
0.0, 2.4 Hz), 6.90 (1H, ddd, J = 10.0, 5.9, 1.9 Hz). 13
C
C H O Si m/z: 514.2387; found: 514.2380.
28
38
7
NMR (125 MHz, CDCl ) d: 2.7 (3C), 12.4, 26.4, 28.2,
3
2
1
3
8.6, 30.5, 41.8, 43.9, 57.1, 77.4, 80.5, 81.3, 85.0, 107.8,
+
2,11-Dihydroxy-10-methoxy-2-(1′-methoxyethyl)-3,4-di-O-
29.4, 148.5, 200.2. EI HRMS (M – Me) found:
isopropylidene-1,2,3,4,4a,5,12,12a-octahydronaphthacen-
53.1779; C H O Si calcd: 353.1774. 18d: ketone 17d
18
29
5
1
2-one (22)
(
(
(
0.204 g, 0.68 mmol) in THF (6 mL), 1.6 mol/L BuLi
To ensure complete dissolution, THF (0.60 mL) was added
to a solution containing silyl ether 20c (95.7 mg,
0.186 mmol) partially dissolved in HPLC grade MeOH
(6.0 mL). The solution was cooled to 0 °C prior to adding
pyridinium p-toluenesulfonate (52.8 mg, 0.210 mmol) as a
solid in one portion. The reaction mixture was stirred in the
dark under an Ar atmosphere at 0 °C for 4 h. The reaction
6.6 mL, 10.6 mmol), i-Pr NH (1.2 mL, 8.6 mmol) in THF
2
6 mL), TMSCl (1.8 mL, 13.73 mmol), Pd(OAc) (82.4 mg,
2
0
2
.37 mmol) in DMSO (8 mL). Yield: 98.3 mg (47%) and
7.4 mg of recovered starting material (17d). H NMR
1
(
300 MHz, CDCl ) d: 0.08 (9H, s), 1.15 (3H, d, J =
3
6
1
6
.2 Hz), 1.45 (3H, s), 1.78 (1H, dd, J = 14.2, 11.4 Hz),
.94–2.22 (4H, m), 2.65–2.75 (1H, m), 3.2 (1H, q, J =
.2 Hz), 3.27 (3H, s), 3.90 (1H, dd, J = 8.0, 5.0 Hz), 4.27
mixture was quenched with saturated NaHCO (0.5 mL) at
3
(1H, d, J = 5.0 Hz), 5.98 (1H, dd, J = 10.0, 1.8 Hz), 6.92
0 °C and the organic solvent removed in vacuo. The crude
mixture was redissolved in CH Cl and washed with satu-
+
(
1H, m). EI LRMS m/z: 353 [M – Me] (10), 309 [M –
2
2
+
MeCHOMe] (90), 251 (100), 73 (30).
rated NaHCO and saturated NaCl. The organic layer was
3
dried over MgSO , filtered, and evaporated to dryness. The
crude product was purified by flash column chromatography
(EtOAc/hexanes, 2:3) to give the tetracyclic diol 22
4
1
1-Hydroxy-10-methoxy-2-trimethylsilyloxy-2-(1′-
methoxyethyl)-3,4-di-O-isopropylidene-1,2,3,4,4a,5,12,12a-
octahydronaphthacen-12-one (21a)
(
82.5 mg, 0.186 mmol, 100%) as a fluorescent green, amor-
4
b
1
A solution of tetracycle 20a (120 mg, 0.232 mmol) and
DDQ (79 mg, 0.348 mmol) in benzene (18 mL) was refluxed
for 4 h. The solution was cooled, diluted with ether and
water, and extracted with ether (3 × 20 mL). The organic ex-
tracts were combined, washed with water and then with
brine, and dried over MgSO . The solvents were removed
and the residue chromatographed (hexanes / ethyl acetate,
phous solid. R 0.29 (EtOAc/hexanes, 3:7). H NMR (CDCl ,
500 MHz): data are shown in Table 1. C NMR (CDCl3,
f
3
13
125 MHz) d: 12.2, 25.1, 25.6, 27.3, 34.9, 39.2, 43.9, 56.1,
5
1
7.0, 73.7, 76.2, 79.9, 80.9, 105.5, 108.6, 111.2, 115.1,
16.6, 119.7, 130.9, 137.4, 140.1, 159.8, 165.7, 204.6. EI
4
HRMS calcd for C H O m/z: 442.1992; found: 442.1990.
25 30 7
8
:1) and the bright fluorescent band (R = 0.38) was sepa-
f
4
,11-Dihydroxy-10-methoxy-2-[1′-methoxyethyl]-2b,3b,-di-
rated from the starting material (R = 0.26), which did not
fluoresce. Yield: 25.1 mg (21%); starting material recovered:
f
O-isopropylidene-1,2,3,4,5,12,12a-octahydronaphthacen-
1
12-one (23)
4
8.8 mg (41%). H NMR (500 MHz, CDCl ) d: 1.20 (3H, d,
3
To a vial containing a solution of 21c (16.6 mg,
J = 6.3 Hz), 1.31 (3H, s), 1.54 (3H, s), 1.98 (dd, J = 14.7,
0
.032 mmol) in THF (0.40 mL) was added H O (0.10 mL)
7
2
3
3
.4 Hz), 2.45 (1H, dd, J = 14.5, 4 Hz), 2.49–2.54 (1H, m),
.80 (3H, s), 2.94 (1H, m), 3.02 (1H, dd, J = 15.8, 3.8 Hz),
.05 (1H, q, J = 6.3 Hz), 3.08 (1H, dd, J =15.8, 3.8 Hz),
.83 (1H, d, J = 5.3 Hz), 3.92 (1H, dd, J = 9, 5.3 Hz), 3.99
2
as a co-solvent. To the vial was then added a catalytic
amount of p-toluenesulfonic acid monohydrate (2.0 mg,
0
.011 mmol) and the reaction stirred at 25 °C for 48 h. The
(3H, s), 6.76 (1H, d, J = 7.9 Hz), 6.97 (1H, s), 7.17 (1H, d, J =
reaction was terminated by removal of the solvent in vacuo.
The crude reaction was applied directly to silica gel and puri-
fied by flash column chromatography (EtOAc/hexanes, 2:3)
to afford 23 (6.0 mg, 0.014 mmol, 42%) as a fluorescent yellow-
green amorphous solid, recrystallized from CH2Cl2/hexane.
7
5
.9 Hz), 7.42 (1H, t, J = 8 Hz). EI HRMS M+ found:
14.2380; C H O Si calcd: 514.2374.
28
38
7
1
1-Hydroxy-10-methoxy-2-trimethylsilyloxy-2-(1′-
1
methoxyethyl)-3,4-di-O-isopropylidene-1,2,3,4,4a,5,12,12a-
octahydronaphthacen-12-one (21c)
[a]D = –26.3 (CHCl3). Rf 0.51 (EtOAc/hexanes, 1:1). H
13
NMR (CDCl , 500 MHz): data are shown in Table 1.
C
3
Silyl ether 20c4b (286 mg, 0.55 mmol) was dissolved in
benzene (55 mL) under argon. The solution was then treated
with 2,3-dichloro-5,6-dicyanobenzoquinone (197 mg,
NMR (CDCl3, 125 MHz) d: 13.6, 26.9, 28.4, 28.9, 33.0,
40.3, 46.3, 56.1, 56.7, 74.2, 81.5, 82.4, 83.3, 105.4, 108.8,
111.2, 115.1, 116.6, 119.8, 130.9, 137.6, 140.2, 159.8,
165.8, 204.5. EI HRMS calcd for C H O m/z: 442.1992;
0
.87 mmol) in one portion at 25 °C. The reaction was stirred
25
30
7
for 5 h at 25 °C and then quenched with water. The product
found: 442.1988.
Published by NRC Research Press

Hill et al.
1467
+
1
1-Hydroxy-4,10-dimethoxy-2b,3b-di-O-isopropylidene-2a-
7.47 (1H, t, J = 8 Hz), 14.99 (1H, s). EI HRMS M found:
(
1′-methoxyethyl)-1,2,3,4,4a,5,12,12a-
414.1687; C H O calcd: 414.1679.
23
26
7
octahydronaphthacen-12-one (24)
Tetracyclic ketone 23 (6.0 mg, 0.014 mmol) dissolved in
dry THF (1 mL) was treated with excess sodium hydride
that had been previously rinsed with dry THF. Iodomethane
2,11-Dihydroxy-10-methoxy-2-hydroxy-2-(1′-
methoxyethyl)-3,4-di-O-isopropylidene-2,3,4,5,12-
hexahydronaphthacene-12-one (27)
(
0.2 mL) was added and the mixture stirred at rt with
To an oven-dried vial containing 21c (10.4 mg,
0.020 mmol) dissolved in anhydrous THF (0.40 mL) was
added a THF solution of TBAF (1 mol/L, 0.40 mL,
0.040 mmol) at 0 °C. The reaction mixture was stirred in
darkness for 4.5 h at 0 °C and then at 25 °C for 18 h. The
reaction was quenched by the addition of H2O (0.30 mL)
and purified directly by flash column chromatography using
silica gel. The desired product was eluted using EtOAc/hex-
anes (2:3) to afford intermediate 27 (6.0 mg, 0.014 mmol,
70%) as a yellow-orange solid and crystallized from methyl-
ene chloride / hexane. [a]D = –345 (CHCl3). Rf 0.49 (EtOAc/
occasional monitoring by TLC. After 1.5 h the starting mate-
rial was completely consumed. The THF solution was poured
into saturated aqueous ammonium chloride and extracted with
dichloromethane (3 × 10 mL). The combined organic extracts
were dried (Na SO ) and evaporated. The residue was puri-
2
4
fied by chromatography (ethyl acetate / hexanes, 5:7). Yield:
1
6
6
2
2
mg (94%) H NMR (500 MHz, CDCl ) d: 1.31 (3H, d, J =
3
.2 Hz), 1.35 (3H, s), 1.43 (1H, t, J ≈ 1.34 Hz), 1.45 (3H, s),
.33 (1H, qd, J ≈ 12.4, 12.4, 3.5 Hz), 2.59–2.69 (2H, m),
.80 (1H, dd, J ≈ 14, 3.6 Hz), 3.31 (3H, s), 3.39–3.47 (3H,
1
m), 3.56 (3H, s), 4.0 (3H, s), 4.27 (1H, d, J = 3.25 Hz), 6.77
hexanes, 2:3). H NMR (CDCl3, 500 MHz): data are shown
in Table 1. 13C NMR (CDCl3, 125 MHz) d: 12.7, 25.4, 27.4,
34.5, 39.0, 56.2, 56.8, 72.6, 76.8, 79.8, 80.6, 105.8, 109.3,
111.7, 115.2, 116.5, 119.9, 131.4, 135.3, 136.5, 138.1,
(1H, d, J = 7.9 Hz), 6.97 (1H, s), 7.19 (1H, d, J = 8 Hz),
+
7
4
.44 (1H, t, J ≈ 8 Hz), 15.17 (1H, s). EI HRMS M found:
56.2155; C H O calcd: 456.2148.
26
32
7
1
4
40.4, 159.9, 167.2, 189.7. EI HRMS calcd for C H O m/z:
25 28 7
40.1835; found: 440.1837.
1,12a-Dihydroxy-10-methoxy-3,4-di-O-isopropylidene-2-
2
b,3b,11-Trihydroxy-4b,10-dimethoxy-2a-[1′-
methoxyethyl]-1,2,3,4,4a,5,12,12a-octahydronaphthacen-
1
1
2-one (25)
(
1
1′-methoxyethyl)-3,4,4a,5,11,12a-hexahydronaphthacen-
Tetracycle 24 (6.0 mg, 0.013 mmol) dissolved in THF
2-one (28)
(
1 mL) was treated with 1 N aq HCl (0.4 mL) and stirred at
The enone 27 (16 mg, 0.036 mmol) dissolved in dry di-
chloromethane (5 mL) was treated with methylamine
rt with monitoring by TLC. After 36 h, the solution was
poured into saturated aq NaHCO and extracted with di-
chloromethane (4 × 10 mL). The extracts were combined,
dried (Na SO ), and the solvents removed. The residue was
chromatographed (ethyl acetate / hexanes, 3:1) to obtain the
triol 25. Yield: 5 mg (91%). H NMR (500 MHz, CDCl ) d:
1
3
(
0.2 mL) and DMAP (4 mg). The solution was cooled to 0 °C
and methanesulfoxyl chloride (0.5 mL) was added. The
mixture was stirred at 0 °C for 0.5 h and monitored by
TLC for the disappearance of the starting material. It was
poured into cold aqueous sodium bicarbonate and the solu-
tion was extracted with dichloromethane (3 × 10 mL). The
combined organic extracts were dried (Na SO ) and the res-
2
4
1
3
.26 (3H, d, J = 6.2 Hz), 1.54 (1H, s), 1.60 (1H, t, J ≈
3 Hz), 2.25 (1H, qd, J ≈ 12.6, 12.6, 3.4 Hz), 2.57–2.65
1
2
4
(2H, m), 2.69 (1H, dd, J ≈ 13.6, 3.55 Hz), 2.79 (1H, s),
idue chromatographed on silica (ethyl acetate / hexanes, 1:2).
The greenish yellow fluorescent fraction, slightly slower on
the TLC than 22 or 27, was collected and evaporated. Fur-
ther purification by column chromatography (dichlorometh-
ane/hexane, 85:15) resulted in the collection of a product
that showed a single spot on the TLC, but still appeared to
3
.31 (1H, dd, J = 10.3, 2.7 Hz), 3.34 (3H, s), 3.37 (1H, q,
J = 6.3 Hz), 3.49 (3H, s), 3.97 (1H, d, J = 2 Hz), 4.0 (3H,
s), 6.78 (1H, d, J ≈ 7.9 Hz), 6.96 (1H, s), 7.18 (1H, d, J =
Hz), 7.45 (1H, t, J = 8 Hz), 15.07 (1H, s). 1 C NMR
3
8
(CDCl , 125 MHz) d: 12.5, 28.3, 33.4, 37.3, 45.7, 56.2,
3
5
1
7.0, 57.3, 69.7, 75.2, 79.7, 83.3, 105.5, 111.3, 115.1,
1
13
be contaminated by ~10% of an impurity ( H and
C
16.8, 119.8, 130.9, 137.7, 140.2, 159.8, 165.7, 204.3. EI
1
+
NMR). H NMR (CDCl3, 500 MHz): data are shown in Ta-
HRMS M found: 416.1832; C H O calcd: 416.1835.
2
3
28
7
ble 1. 13C NMR (125 MHz, CDCl ) d: 12.2, 19.2, 25.7,
3
2
1
1
7.1, 28.1, 41.8, 56.2, 56.5, 70.8, 71.7, 75.5, 77.4, 105.7,
05.9, 109.6, 109.7, 115.0, 117.2, 119.8, 124.9, 131.5,
37.3, 159.8, 163.7, 199. EI HRMS M+ found: 440.1832;
2
b,11-Dihydroxy-4b,10-dimethoxy-2a-[1′-methoxyethyl]-
,2,3,4,4a,5,12,12-octahydronaphthacene-3,12-dione (26)
Triol 25 (5 mg, 0.012 mmol) in acetonitrile (1 mL) was
1
C H O calcd: 440.1835.
25
28
7
heated to 70° with o-iodobenzoic acid and the progress of
the reaction monitored by TLC. After 18 h, almost all the
starting material had been consumed. The solvents were re-
moved and the residue was chromatographed (ethyl acetate /
hexanes, 4:1). The product 26 was isolated, but a small
Supplementary data
Supplementary data (general experimental methods; copies
1
of H NMR spectra for compounds 16a, 16b, 17a–17d, 18a–
13
amount of starting material 25 also remained. Yield: 3.5 mg
18d, 21c, and 22–28; C or JMOD spectra for compounds
16a, 16b, 17a–17d, 18a, 18c, 21c, 22, 23, 25, 27, and 28;
H–H COSY spectrum for compound 28; EIMS for compound
28; and HPLC traces of compound 16a) are available for this
article through the journal Web site at http://nrcresearchpress.
com/doi/suppl/10.1139/v11-119. CCDC 814893–814898
contain the X-ray data (17a, 17b, 18b, 23, 27, and catalyst
1
(70%). H NMR (500 MHz, CDCl ) d: 1.27 (3H, d, J =
3
6
3
.2 Hz), 2.27–2.35 (2H, m), 2.86 (1H, td, J = 13, 13, 1 Hz),
.17 (1H, td, J = 12.5, 12.5, 3.7 Hz), 3.35 (3H, s), 3.41 (1H,
q, J = 6.2 Hz), 3.44 (1H, dd, J = 15.8, 3.5 Hz), 3.56 (3H, s),
.88 (1H, s), 4.0 (3H, s), 4.11 (1H, d, J = 11.1 Hz), 6.80
1H, d, J = 8 Hz), 6.97 (1H, s), 7.19 (1H, d, J = 8.3 Hz),
3
(
Published by NRC Research Press

1468
Can. J. Chem. Vol. 89, 2011
B) in CIF format for this manuscript. These data can be ob-
tained, free of charge, via http://www.ccdc.cam.ac.uk/cgi-bin/
catreq.cgi (Or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1Ez, UK; fax +44
(10) Butora, G.; Gum, A. G.; Hudlicky, T.; Abboud, K. A.
Synthesis 1998, 1998 (03), 275. doi:10.1055/s-1998-4529.
11) Crabtree, R. Acc. Chem. Res. 1979, 12 (9), 331. doi:10.1021/
ar50141a005.
12) Pfaltz, A.; Blankenstein, J.; Hilgoaf, R.; Hörmann, E.;
McIntyre, S.; Menges, F.; Schönleber, M.; Smidt, S. P.;
Wüstenberg, B.; Zimmerman, N. Adv. Synth. Catal. 2003, 345
(
(
1223 336033; or e-mail deposit@ccdc.cam.ac.uk).
Acknowledgement
(
1–2), 33. doi:10.1002/adsc.200390027.
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for support of this work and J.
Shikaze for invaluable administrative assistance.
(
(
13) Reger, D. L.; Wright, T. D.; Little, C. A.; Lamba, J. J. S.;
Smith, M. D. Inorg. Chem. 2001, 40 (15), 3810. doi:10.1021/
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