Toward the total synthesis of citreamicin η: Synthesis of the pentacyclic core and GAB-ring annelation model studies

Article abstract of DOI:10.1016/j.tet.2018.04.049

A short 11-step synthesis of the pentacyclic core of the polycyclic xanthone antibiotic citreamicin η has been completed. Although the basic approach was inspired by our previous explorations of polycyclic xanthone chemistry, the present report features some new insights into the Moore rearrangement and offers some improvements to our original methodology that include additions of aryllithiums to squarate esters, additions of cerium acetylides to hindered ketones utilizing PDA as an internal indicator, and the use of cyclic di-tert-butylsilyl (DTBS) ethers to protect electron-rich benzyl alcohols toward ionization under acidic conditions. We also developed an improved protocol for selective o-bromination of phenols utilizing N-bromosuccinimide (NBS) and tetramethylguanidine (TMG) that promises to be generally useful. Finally, we developed a modular approach for the synthesis of isoquinolones and dihydro-5H-oxazolo[3,2-b]isoquinoline-2,5(3H)-diones that features a novel sequence of alkoxycarbonylation, acetone arylation, transamidation.

Full text of DOI:10.1016/j.tet.2018.04.049

Accepted Manuscript
Toward the total synthesis of citreamicin: Synthesis of the pentacyclic core and GAB-
ring annelation model studies
Shawn Blumberg, Stephen F. Martin
PII:
S0040-4020(18)30438-1
10.1016/j.tet.2018.04.049
TET 29464
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 March 2018
Revised Date: 14 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Blumberg S, Martin SF, Toward the total synthesis of citreamicin: Synthesis
of the pentacyclic core and GAB-ring annelation model studies, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.04.049.
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Toward the Total Synthesis of Citreamicin
η: Synthesis of the Pentacyclic Core and
GAB-Ring Annelation Model Studies
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Shawn Blumberg and Stephen F. Martin*
*Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States

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1
Tetrahedron
journal homepage: www.elsevier.com
Toward the Total Synthesis of Citreamicin: Synthesis of the Pentacyclic Core and GAB-
Ring Annelation Model Studies
Shawn Blumberg‡ and Stephen F. Martin
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A short 11-step synthesis of the pentacyclic core of the polycyclic xanthone antibiotic
citreamicin η has been completed. Although the basic approach was inspired by our previous
explorations of polycyclic xanthone chemistry, the present report features some new insights
into the Moore rearrangement and offers some improvements to our original methodology that
include additions of aryllithiums to squarate esters, additions of cerium acetylides to hindered
ketones utilizing PDA as an internal indicator, and the use of cyclic di-tert-butylsilyl (DTBS)
ethers to protect electron-rich benzyl alcohols toward ionization under acidic conditions. We
also developed an improved protocol for selective o-bromination of phenols utilizing N-
bromosuccinimide (NBS) and tetramethylguanidine (TMG) that promises to be generally useful.
Finally, we developed a modular approach for the synthesis of isoquinolones and dihydro-5H-
Available online
Keywords:
Polycyclic xanthone
Moore rearrangement
Acetylide addition
Selective bromination
Alkoxycarbonylation
Transamidation
oxazolo[3,2-b]isoquinoline-2,5(3H)-diones
that
features
a
novel
sequence
of
alkoxycarbonylation, acetone arylation, transamidation.
2017 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: sfmartin@mail.utexas.edu

ACCEPTED MANUSCRIPT
2
Tetrahedron
xanthones have also been described.11 We now disclose the details
1. Introduction
of our recent efforts to synthesize citreamicin η, including the
preparation of the pentacyclic core as well as exploratory studies to
annelate the G and A rings.12
The first member of the citreamicin family of antibiotics,1 which
constitutes a novel subclass of polycyclic xanthone natural
products, was isolated by Lechevalier in 1989 from a culture of
Micromonospora citrea that was taken from lake Manyara in
Tanzania.1a Shortly after this initial discovery, additional members
of this family were isolated and characterized by Carter1b and
others.1c,d The citreamicins generally display potent inhibitory
activity against a broad spectrum of Gram-positive aerobic and
anaerobic bacteria, but given the current problems of increasing
antibiotic resistance, it is especially notable that the citreamicins are
2. Retrosynthetic analysis
Naturally-occurring polycyclic xanthones captured our attention
several years ago because of their complex molecular architectures
coupled with their potent biological activities. The unique
challenges associated with the synthesis of the citreamicins
appealed to us, so we initiated efforts toward the total synthesis of
citreamicin η (1). Drawing upon our successful invention of a novel
approach to 1,4-dioxygenated xanthones and its application to the
synthesis of IB-00208 aglycone,7,13 we initially formulated the plan
for the synthesis of citreamicin η (1) that is outlined in Scheme 1.
We envisioned final assembly of 1 by annelating the G and A rings
active
against
multidrug-resistant
vancomycin-resistant
Enterococcus faecalis (VRE) and Staphylococcus aureus
(MDRSA).1c With a minimum inhibitory concentration (MIC) of 26
nM against several Gram-positive strains, citreamicin η (1) is one
of the most potent members of this family (Figure 1).1b Coupled
with their impressive antibiotic activity, several members of the
citreamicin family exhibit cytotoxic activity against HeLa and
Hep62 cells.1e The feature that differentiates the citreamicins from
other polycyclic xanthones natural products such as cervinomycin
A2 (2),2 IB-00208 (3),3 kibdelone C (4),4 kigamicin (5),5 xantholipin
onto the hexacyclic precursor
7 via a thermodynamically-
controlled, diastereoselective condensation of
7 with (S)-α-
methylserine.14 Formation of 7 from 8 requires a cross-coupling to
OH
O
(6),6 and others,7 is
a dihydrooxazolo-[3,2-b]-isoquinolinone
Late-Stage
Annelation
27
28
29
G
26
O
tricyclic subunit that comprises the GAB rings (Figure 1). In view
of the potent biological activities of the citreamicin antibiotics, it is
surprising that no member of this family has succumbed to
synthesis. On the other hand, the total syntheses of representative
cervinomycins8 and kibdelones9 have been reported, and we
recently disclosed the synthesis of the aglycone of IB-00208 (3).10
Synthetic efforts directed toward a number of other polycyclic
1
N
O
25
A
23
2
24
OH
3
4
O
O
B
10
8
6
OMe
OMe
5
7
9
11
22
21
C
F
D
E
O
20
18
16
14
12
19
17
13
15
O
citreamicin (1)
1
OH
O
CO2Me
OPMB
2
OMOM
OMOM
25
23
O
O
O
O
O
O
O
N
O
N
O
O
OMe
OMe
OMe
OH
OH
O
O
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
O
O
8
7
OPMB
O
O
OMOM
OMe
citreamicin (1)
cervinomycin A2 (2)
OPMB
5
6
OMOM
OMe
OH
O
6
OH OPG
O
O
Me
18
8
9
N
O
16
OH
O
O
O
O
OMe
OH
OMe
8
Cl
OH
O
O
OH
OH
O
OMe
OMe
O
OMe
O
HO
OH
HO
Moore
PMBO
OMe
Rearrangement
OMe
OMe
MeO
O
9
10
OMe
16
OMe
MeO
IBꢀ00208 (3)
kibdelone C (4)
7
MOMO
PMBO
6
O
8
17
4
OMe
OMe
HO
N
O
N
O
O
+
21
20
PMBO
OH
RCM
OH
O
O
OH
OH
OH
O
11
OMe
12
O
H
OMOM
MeO
O
O
Cl
4
PMBO
Br
5
6
OMe
O
O
HO
O
O
OMe
O
+
17
20
19
O
xantholipin (6)
kigamicin (5)
OMe
13
14
Scheme 1. Retrosynthetic analysis.
Figure 1. Polycyclic xanthone natural products.

ACCEPTED MANUSCRIPT
3
introduce the ester and the acetonyl groups. Compound 8 might
then be accessible from the quinone 9 via sequential oxidation and
cyclization, whereas generation of 9 features a variant of the Moore
rearrangement of 10,15 which would be formed by the union of an
acetylide anion derived from 11 and the naphthocyclobutenone 12.
There are no general methods for the syntheses of substituted
naphthocyclobutenones like 12, but we reasoned that 12 might be
prepared by coupling of bromostyrene 14 with the vinyl squarate 13
followed by a ring closing metathesis (RCM) to create the arene
ring.16
Table 1. Effect of amines on regioselectivity of bromination of
18.
Entry
Amine
Ratio of 16:17a
3. Synthesis of BCD ring precursor
1
2
3
4
tert-BuNH218a
(i-Bu)2NH18b
DBU
1:3.75
1:11.5
1:13.5
1:>20
In our first approach to the napthocyclobutenone fragment 12,
which was required for the acetylide stitching step, the C4 phenolic
moiety of 3,4-dihydroxybenzaldehyde (15) was selectively
protected as its p-methoxybenzyl (PMB) ether (Equation 1).17 To
our surprise, however, the amine-mediated, regioselective
bromination of the intermediate phenol did not proceed at the 2-
position to give 17 as expected,18 but rather at C5 to furnish 16
exclusively (Equation 1). To our knowledge, this is the first
example of selective bromination of an isovanillin derivative at the
5-position.19 Conversely, the corresponding benzyl ether analog
TMG
a) Ratios determined by NMR.
Although the conditions identified in Table 1 for brominating 18
to give 17 worked well on a small scale, it was necessary to change
the stoichiometry of NBS to TMG from 1:1 to 1:2 in order to
selectively produce 17 on a multigram scale because increased
quantities of 16 were observed when a 1:1 ratio was employed
(Scheme 2). Protection of the phenolic hydroxy group in 18 as a
methoxymethyl (MOM) ether followed by a Wittig olefination in a
mixture (1:1) of THF and DMSO provided bromostyrene 14 in
85% overall yield. Unfortunately, initial attempts to couple the
aryllithium reagent derived from 14 by metal-halogen exchange
with the vinyl squarate 13 led to the isolation of the debrominated
product 20, and an unexpected side-product that was tentatively
identified as 21 (Scheme 2).
underwent regioselective bromination to give
a C2-bromo
derivative in 55% yield. Apparently the PMB-protecting group
influences the regiochemistry in this bromination, but the origin of
this effect remains unknown.
OH
OH
1) MOMCl, DIPEA,
CH2Cl2
NBS/TMG (1:2),
CH2Cl2, –78 °C
PMBO
PMBO
Br
O
2) Ph3PMeBr,
n-BuLi,
THF/DMSO (1:1)
85%
83%
O
18
17
OMe
MeO
MOMO
O
tert-BuLi, Et2O, –78 °C; 13
OMOM
Br
Our overall plan suggested that the O-PMB protecting group
would likely be better than a benzyl group. Hence, we had to solve
the problem and develop a procedure that enabled regioselective
bromination ortho to the phenolic hydroxyl group in 18 at the 2-
position. Accordingly, we explored other conditions for the amine-
mediated bromination. We hypothesized that more basic amines
would favor the desired pathway to form 17, so we selected four
amines with varying basicity to evaluate their effect on the
regioselectivity in the bromination of 15 (Table 1).20 Consistent
with expectations, we found that the selectivity of ortho-
bromination of the phenol increased with basicity of the amine,
with tetramethylguanidine (TMG) providing 17 with >20:1
selectivity (Table 1, entry 4) using a solvent mixture (2:3) of
toluene and CH2Cl2; use of toluene as a cosolvent proved critical to
this success.
PMBO
then
PMBO
–78 °C
→
0 °C; TFAA
14
19
OMOM
MOMO
O
OMe
O
PMBO
PMBO
OMe
20
21
26-78%
10-20%
Scheme 2. Synthesis of bromostyrene 14 and attempted
coupling with squarate 13.
Debrominated starting material 20 formed even in the presence
of NaH, suggesting that the something in the reaction mixture, not
an adventitious protic impurity such as water, served as the proton
source. Some exploratory studies implicated the benzylic protons
on the PMB group as a probable proton source. We surmise that the
aryllithium 22 is transformed by proton transfer into the benzyl

ACCEPTED MANUSCRIPT
4
Tetrahedron
4. Setting the stage for the Moore rearrangement
anion 23, which forms 20 upon aqueous workup (Scheme 3,
Pathway A). Alternatively, the reaction of vinyl squarate 13 with
aryllithium 22 produces the adduct 24, which is protonated to
furnish the desired 19 (Scheme 3, Pathway B). The side-product 21
likely originates from protonation of dienolate 25, which could be
generated via an oxy-anion accelerated electrocyclic ring opening
of 24 (Scheme 3, Pathway C).21
4.1. First generation approach to precursor of Moore
rearrangement
With the naphthocyclobutenone fragment 12 in hand, we turned
to the synthesis of a suitable substrate for the Moore rearrangement.
In our first approach, the salicylaldehyde 27, which was readily
prepared from 1,2,4-trimethoxybenzene (26) by
procedure,25 was O-protected with a PMB moiety to give 28 in
nearly quantitative yield (Scheme 5). Addition of
a
known
Pathway A
Disproportionation to benzyl anion
OMOM
Li
OMOM
ethynylmagnesium bromide to 28 then furnished the F-ring
fragment 11. Using conditions we previously developed during our
synthesis of IB-00208 aglycone,10 11 was treated with
tetramethylpiperidinomagnesium bromide (TMPMgBr) to form an
intermediate magnesium acetylide that was coupled with 12 to
provide 10, albeit in only 40% yield. We screened a number of
other bases and solvents to improve the yield of this reaction, but
these efforts were to no avail.
PMBO
Ar
O
tert-BuLi
H3O+
20
14
Li
22
23
13
MeO
LiO
OMe
OMe
PMBCl, DMF,
O
MOMO
PMBO
OLi OMe
MOMO
OMe
MeO
OMe
OMe
K2CO3
OMe
1) POCl3, DMF
PMBO
2) BBr3, CH2Cl2
OMe
99%
OMe
HO
See ref 25
26
27
24
25
21
O
OH
H3O+
H3O+
MgBr
OMe
OMe
OMe
THF, 0 °C
98%
19
Pathway B
Desired formation of 19
PMBO
PMBO
OMe
Pathway C
Ring-opening of squarate adduct
28
11
OPMB
2
Scheme 3. Putative pathways forming side-products.
OMOM
3
OMe
We postulated that the presence of non-polar co-solvents could
favor more aggregated forms of aryllithium 22 that might be less
prone to suffer proton transfers.22 After some experimentation, we
discovered that performing the metal-halogen exchange in a
mixture (5:1) of Et2O and toluene at –78 ºC, followed by addition
of 13 and warming the reaction mixture to 0 ºC led to the isolation
of 19 in 40% yield while suppressing the formation of 20.
However, the ring-opened side-product 21 was still isolated in
yields up to 20%. We reasoned that the oxy-anionic electrocyclic
ring-opening reaction of 24 would be suppressed at lower
temperatures and eventually found that raising the bath temperature
to –20 ºC after the addition of 13 enabled us to isolate 19 in 68%
yield with only traces of 21 being observed. Heating 19 in degassed
dichloroethane in the presence of Grubbs II catalyst led ring closing
metathesis and the formation of the naphthocyclobutenone 12 in
78% (91% BRSM) yield (Scheme 4).23,24
6
OMe
n-BuLi, PDA,
OH
17
CeCl3•2LiCl, 0 °C; 12
L.A., solvent/H2O
84% (91% brsm)
8
OMe
OMe
HO
14
PMBO
10
OMe
O
OH
6
OMOM
3
OMe
17
PMBO
2
8
14
OH OPMB
29
Scheme 5. Synthesis of F-ring fragment, acetylide coupling and
attempted hydrolysis.
Organocerium reagents may add more efficiently to ketones than
Grignard reagents.26 However, initial attempts to generate the
cerium reagent from 11 were complicated by adventitious proton
sources in the CeCl3•2LiCl solution.27 Because we wanted to
combine 11 and 12 in 1:1 stoichiometry, a suitable indicator was
needed so we could closely monitor formation of the cerium
acetylide anion from 11. Serendipitously, we had employed 4-
(phenylazo)diphenylamine (PDA)28 as an indicator to titrate the
solutions of TMPMgBr used to deprotonate 11 (vide supra). We
were impressed by the vivid endpoints, so we queried whether PDA
might be useful as an internal indicator to monitor generation of the
organocerium reagent from 11. Gratifingly, we found that adding n-
BuLi to a mixture of 11, CeCl3•2LiCl, and PDA produced a vivid
Scheme 4. Completion of the naphthocyclobutenone fragment.

ACCEPTED MANUSCRIPT
5
purple endpoint showing that complete deprotonation of the
benzylic alcohol moiety of 11 had occurred. Addition of another
equivalent of n-BuLi ensured quantitative formation of the
acetylide anion, whereupon 12 was added to deliver 10 in 84%
yield. Subsequent to these experiments, we demonstrated that PDA
is generally an excellent indicator for titrating a variety bases,
Lewis acids and reducing agents.29
With compound 10 in hand, it remained to selectively hydrolyze
the dimethyl ketal moiety to furnish 29, the requisite substrate for
the Moore rearrangement. However, all attempts to convert 10 into
29 using a variety of Lewis and Brønsted acid catalysts invariably
led to complex mixtures of compounds. This finding was surprising
because we had previously hydrolyzed a number of related
substrates without difficulty.10,13 We eventually found that 11 was
unstable to the acidic conditions, whereas 12 could be recovered
unscathed, suggesting that the benzyl alcohol moiety at C8 in 10
might be the offending functionality. This discovery signaled that
we needed a synthon for the F-ring subunit having a benzyl alcohol
that would be less prone to solvolysis under acidic conditions.
4.2. Second generation approach to precursor of Moore
rearrangement
A plausible explanation for the observed instability of 10 is that
the benzylic C–OH bond at C8 in the putatively preferred
conformation of 10 is aligned with the π-system of the arene as
shown in 10a (Figure 2). We reasoned that constraining this C–O
bond in approximately the plane of the aromatic ring might allow
selective hydrolysis of the dimethyl ketal without concomitant
solvolysis of the benzyl alcohol moiety. This goal might be
achieved through the agency of a cyclic protecting group that
incorporated both the benzylic hydroxyl group and the ortho
oxygen atom.
Scheme 6. Synthesis of 32
5. Moore rearrangement and synthesis of the pentacyclic core
When 32 was heated at 100 °C in DMSO according to the
protocol developed during our synthesis of IB-00208 aglycone,10
only trace amounts of the desired quinone 33 were observed
(Scheme 7). In previous studies of the Moore rearrangement, we
observed that solvent could influence the outcome. Accordingly,
we screened a number of solvents and discovered that heating 32 in
tert-amyl alcohol at 100 ºC gave a mixture (~1:1) of the desired 33
and the 5-exo cyclization product 34 (E/Z-ratio ca. 1.1:1) together
with smaller quantities of compounds that were tentatively
identified as the hydroquinone 35 and the C-H insertion adduct 36.
The formation of products as 34 from 5-exo-cyclizations in the
Moore reaction were known, but the isolation of 36 suggested the
possible intermediacy of compounds with carbene-like character at
C7. Although carbenoid mechanisms for the Moore rearrangement
have been predicted computationally,30 isolation of 36 offers some
experimental evidence for this mechanistic pathway.
R
R
OH
OPMB
OH
H
MeO
MeO
OPMB
MeO
OMe
10
10a
Figure 2. Putative origin of solvolytic instability of 10.
Based upon this hypothesis, we turned to the cyclic silylether
protecting group in 30, which was prepared in 82% yield by
addition of ethynylmagnesium bromide to 27 and reaction of the
unstable
intermediate
alcohol
with
di-tert-butylsilyl
bis(trifluoromethanesulfonate) DTBS(OTf)2 in analogy with our
previous work (Scheme 6).13 Application of the acetylide coupling
conditions developed previously furnished 31 in 90% yield on
multigram scale. Gratifyingly, hydrolysis of 31 with H3PO4-doped
hydrated silica gel provided 32 in virtually quantitative yield. The
stage was now set for the pivotal Moore rearrangement.

ACCEPTED MANUSCRIPT
6
Tetrahedron
OPMB
OMOM
double bond in the central ring of phenanthrenes are known to
undergo facile reduction by catalytic hydrogenation.37 This result
has interesting implications for the synthesis of other polycyclic
xanthones, such as kibdelone C (4), which lacks the double bond in
the C ring.
O
6
OH
17
16
tert-amylOH, 100 °C
7
OPMB
OMOM
60%
8
OMe
OMe
9
O
t-Bu
O
OPMB
OMOM
Si
t-Bu
t-Bu
14
O
15
Si
t-Bu
O
O
8
O
OH
20
32
19
MTBE, 60 °C
41%
OMe
OPMB
OMOM
OPMB
OMOM
t-Bu
Si O
t-Bu
t-Bu
t-Bu
20
8
15
OMe
Si
19
14
O
O
O
8
O
14
O
O
O
OMe
t-Bu
6
8
9
6
Si
7
9
OMe
OMe
16
7
O
OMe
t-Bu
15
+
33
17
16
OMe
32
17
O
O
OMe
OPMB
33 (30%)
34 (30%)
15
OMOM
O
OH OH
8
also isolated:
MnO2, CH2Cl2/pyr (10:1)
44%
HF•pyridine
OPMB
OPMB
OH
20
pyridine, THF
73%
t-Bu
OMe
t-Bu
19
OMOM
OH
Si
O
OMe
O
O
O
t-Bu
6
Si
37
16
O
O
OPMB
17
OMe
8
OMOM
O
O
OH
35 (6%)
OMe
O
8
OMe
OMe
OMe
H2 balloon, Pd/C
MeO
36 (5%)
20
PhMe/MeOH
53%
O
19
15
O
Scheme 7. Initial studies of Moore rearrangement.
8
Recent studies of the Moore rearrangement reveal that protic
solvents can affect the course of the reaction. For example, when
1% H2O is present, mixtures (1:1) of 5-endo and 6-exo products are
formed, rather than products expected from a radical cyclization.31
We thus surmised that use of tert-amyl alcohol as solvent might
have a similar effect, so we queried whether improved ratios of 33
to 34 might be obtained in an aprotic solvent. We eventually
discovered that the Moore rearrangement of 32 in methyl-tert-
butylether (MTBE) proceeds at 60 ºC to give a mixture (1.4:1, 70%
combined yield) of 33 and 34, the latter of which was isolated as a
single diastereomer (Scheme 8); only trace amounts of 36 were
detected. With a reliable procedure for forming 33 in hand, the
cyclic silyl ether protecting group was removed with HF•pyridine
to furnish 37 in 73% yield. Compound 37 proved to be sensitive to
acids, bases and a variety of oxidants, so options to selectively
OH
OMOM
OH
O
8
OMe
OMe
20
O
15
19
OH
38
Scheme 8. Synthesis of pentacyclic core of citreamicin η
6. GAB ring model studies
The polycyclic xanthone natural products, which are
exemplified in Figure 1, bear one or two additional rings fused to
the pentacyclic BCDEF core. Accordingly, we wanted to develop a
unified and modular strategy that could be used to append these
different heterocyclic rings at a late stage in the synthesis of these
natural products. We envisioned that the dihydrooxazolo-[3,2-b]-
isoquinolinone 43, the isoquinolinone 42, and the isocoumarin 44
could all be accessed from the keto ester 41 (Scheme 9). Although
there are a number of routes to keto-esters such as 41 from o-halo,38
methyl,39 or alkynyl benzoate derivatives,40 there was no general
methodology that enabled the elaboration of substituted phenols
such as 39 into the pivotal intermediate 41. We thus sought to
develop a reliable approach to 41 and the derived annelated ring
systems 42–44 from phenols 39 by sequential palladium-catalyzed
alkoxycarbonylation and ketone arylation of the differentially
functionalized arene 40, which could be prepared with our new
procedure for selective o-bromination of phenols (see Table 1).
oxidize the benzylic alcohol were limited. Following
a
comprehensive examination of numerous oxidants, MnO2 emerged
as the oxidant of choice,32 although some experimentation with
Lewis basic additives was necessary.33 We eventually discovered
that the combination of pyridine and MnO2 furnished 8, which
comprises the pentacyclic core of citreamicin η, in reproducible
44% yield.34
We then turned to the task of removing the PMB group.
However, exposure of 8 to several oxidative conditions known to
remove PMB groups resulted in rapid decomposition of 8,35
whereas use of Lewis acids selectively removed the MOM group,
perhaps owing to its close spatial proximity to the quinone carbonyl
oxygen atom.36 Although we were able to selectively remove the
PMB group from 8 by hydrogenolysis, the quinone and the C19-
C20 double bond were also unavoidably reduced to provide 38 in
53% yield. This was unexpected, but not unprecedented as the

ACCEPTED MANUSCRIPT
7
OMe
OMe
O
OR1
OMe
HO
R5
O
HO
Br
TfO
Br
Tf2O, 2,6-lut
NBS, TMG
N
X
CH2Cl2
95%
CH2Cl2, –78 °C
84%
R2
45
46
47
43: X = H2 or O
X
Condition A
OH
O
n-BuO
Br
OMe
H2N
O
Pd(OAc)2, dppp, n-BuOH, (CO balloon)
n-Bu4NOAc, K2CO3, PhMe, 3 Å MS, 70 °C
R5
R4
N
Condition B
R2
Base
O
O
R3O
R2
O
48
Pd(OAc)2, dppp, n-BuOH, (CO balloon)
n-Bu4NOAc, DMSO, 3 Å MS, 70 °C
OR1
R2
OR1
OR1
R4NH2
Condition A: 76%
Condition B: 69%
O
also isolated:
42
41
44
OMe
O
O
OMe
O
CO
R3OH
HO
n-BuO
R2
n-BuO
Br
OH
OTf
46
Condition A: 0%
Condition B: 10%
49
Br
OR1
[Br+]
Tf2O
OR1
11-19%
0%
Scheme 10. Synthesis of model system and
39
40
alkoxycarbonylation.
Scheme 9. A unified methodology strategy for the GAB rings.
There are several methods for coupling aryl halides with
acetone,43 but we eventually adopted a procedure reported by
Buchwald.43a ,In the event, 48 was coupled with acetone using
JohnPhos and Pd2(dba)3•CHCl3 in the presence of n-Bu4NOAc and
4-methoxyphenol, and the putative keto ester intermediate cyclized
spontaneously to furnish the known isocoumarin 50,in 65% yield
(Scheme 11). 44,45
We initiated a model study by brominating guaiacol (45) using
NBS and TMG to furnish 46 in 84% yield, (Scheme 10), and
subsequent reaction with triflic anhydride provided 47 in 95%
yield. In preliminary experiments to convert 47 into 48, hydrolysis
to return 46 was problematic. Toward addressing this issue, we
modified conditions that had been originally reported by
Buchwald41 and found that use of molecular sieves, 1,3-
bis(diphenylphosphino)propane (dppp), and dry n-Bu4NOAc in
toluene gave 48 in 76% yield together; however, the phthalate 49
was also isolated (11–19%) (Scheme 10, condition A). Because
polar aprotic solvents can favor palladium-catalyzed reactions of a
triflate moiety versus a halide,42 we screened several polar aprotic
solvents and discovered that use of DMSO gave only trace amounts
of 49, although 46 was also formed in about 10% yield.
O
1
OMe
O
1
OMe
Pd2(dba)3•CHCl3, JohnPhos
4-methoxyphenol, n-Bu4NOAc
n-BuO
O
K3PO4, acetone, PhMe, 50 °C
65%
Br
24
48
50
neat
~20% (100% brsm)
OH
O
O
Condition A
Bn
Bn
O
AlMe3, L-phenylalanine
DCE, reflux
1
1
N
O
N
O
+
OMe
OMe
24
24
Condition B
LiAlMe4, L-phenylalanine
THF/PhMe reflux
51
Condition A: 10%
52
29%
85%
Condition B:
0%
also isolated:
OMe
O
53
Condition A: 32%
Condition B: 0%
Scheme 11. Acetone arylation and amino acid coupling.
Although we had hoped to isolate the intermediate keto ester
instead of 50, the reaction of amino alcohols with isocoumarins

ACCEPTED MANUSCRIPT
8
Tetrahedron
related to 50 was known to form dihydrooxazolo-[3,2-b]-
isoquinolinones or isoquinolinones.8a,d Toward inducing this
condensation, we turned to a method we had previously developed i
which for AlMe3 was used to couple amino acids with amino esters
pressure using a Buchi rotary evaporator. Solutions of n-BuLi, and
tert-BuLi were titrated according to our published procedure.29
Reaction mixtures were degassed by putting the reaction vessel
under vacuum until the solvent effervesced, and backfilling with
nitrogen (3 x). Infrared (IR) spectra were obtained using a FT IR
1600 spectrophotometer using sodium chloride plates and reported
as wave numbers. Low resolution chemical ionization mass spectra
to form peptides.46 When 50 was allowed to react with
L-
phenylalanine in the presence of AlMe3, a mixture of 51–53 was in
about 70% combined yield (Condition A, Scheme 11). The
formation of 53 was unexpected, and we reasoned that a less Lewis
acidic promoter might suppress methylation of the coumarin
were obtained with
a
TSQ-70 instrument. High resolution
VG Analytical ZAB2-E
measurements were made with
a
carbonyl group. Accordingly, we first combined
L
-phenylalanine
instrument. Thin layer chromatography (TLC) was performed on
glass-backed precoated silica gel plates (0.25 mm thick with 60
F254) and were visualized using one or both of the following
manners: UV light (254 nm) and staining with basic aqueous
KMnO4 or Cerium ammonium molybdate (CAM). Flash
chromatography was performed according to Still’s procedure
using ICN Silitech 32-67 D 60A silica gel.49 1H nuclear magnetic
resonance (NMR) spectra were obtained at either 600, 500, or 400
MHz as indicated as solutions in CDCl3 with 0.05% v/v
tetramethylsilane (TMS) unless indicated otherwise. 13C-NMR was
obtained at either 125, 100 or 75 MHz as shown in the indicated
deuterated solvent. Chemical shifts are reported in parts per million
(ppm, δ), and referenced to TMS, and coupling constants are
reported in Hertz (Hz). Spectral splitting patterns are designated as
s, singlet; d, doublet; t, triplet; q, quartet; quint, quintuplet; sex,
sextet; sept, septuplet; m, multiplet; comp, overlapping multiplets
of magnetically nonequivalent protons; br, broad; and app,
apparent.
and LiAlMe4, which was generated in situ from AlMe3 and MeLi,
in a mixture of THF and toluene under reflux.47 After adding
isocoumarin 50, the isoquinolone 52 was isolated in 85% yield
(Condition B, Scheme 11); neither 51 nor 53 was observed. We
attempted to convert 52 into 51 using Brønsted and Lewis acids,
but these efforts were unavailing. Serendipitously, we discovered
that merely storing the isoquinolone 52 at room temperature for
several days gave the dihydro-5H-oxazolo[3,2-b]isoquinoline-
2,5(3H)-dione 51 as a single diastereomer with a conversion of
about 20%. Further studies on the cyclization of isoquinolones to
dihydro-5H-oxazolo[3,2-b]isoquinoline-2,5(3H)-diones
underway.
are
7. Summary
In summary, we completed a short 11-step synthesis of the
pentacyclic core of citreamicin η by an approach that exploits a
novel variant of the Moore rearrangement inspired by our previous
methodological work13 and our synthesis of the aglycone of IB-
00208.10 In order to solve a problem involving the regioselective
bromination of a vanillin derivative, we discovered a way to induce
selective ortho bromination of phenols using TMG and NBS. The
use of TMG as an alternative to other amines as a means of
promoting such brominations may be generally useful. In another
key step, we exemplified the utility of a new route to angular aryl
cyclobutendiones that exploits a RCM reaction. We also showed
that PDA can be exploited as an internal indicator to enable the
quantitative generation of cerium acetylides uncontaminated with
excess nucleophilic bases. Finally, our exploratory studies to
develop tactics for the annelation of the G and A rings of
citreamicin η led to the discovery of a potentially general, four step
approach to the synthesis of isocoumarins and isoquinolones from
phenols.
8.2. Synthetic procedures
3-Hydroxy-4-((4-methoxybenzyl)oxy)
benzaldehyde
(18).
Prepared according to a modified procedure used by Plourde,17
A
mixture of 3,4-dihydroxybenzaldehyde (15) (10.0 g, 65.6 mmol),
NaHCO3 (8.2 g, 98.4 mmol) and sodium iodide (NaI) (3.0 g, 19.6
mmol) in anhydrous DMF (40 mL) was heated at 40 °C for 2 h. p-
Methoxybenzyl chloride (PMBCl) (20.6 g, 17.8 mL, 131.2 mmol),
prepared according to Sosa’s procedure,50 was added, and the
reaction was stirred at 40 °C for 24 h, whereupon the reaction was
cooled to room temperature and H2O (80 mL) was added. The
mixture was extracted with EtOAc (3 x 30 mL), and the combined
organic extracts were washed with 13% aqueous brine solution (4 x
10 mL) and dried (Na2SO4). Hexanes (50 mL) were added, and the
combined organic extracts were filtered through a silica plug and
eluted with EtOAc/Hexanes (2:1; 1 x 300 mL), and the combined
organic layers were concentrated under reduced pressure. The crude
material was crystallized from toluene (40 mL) to yield 13.4 g
(79%) pure 18 as a white solid: mp 117-120 °C.
8. Experimental section
8.1. General
Unless otherwise noted, solvents and reagents were used without
purification. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
dried by passage through two columns of activated neutral alumina.
Methanol (CH3OH), acetonitrile (CH3CN), and N,N-
dimethylformamide (DMF) were dried by passage through two
columns of activated molecular sieves.48 Toluene was dried by
sequential passage through a column of activated neutral alumina
followed by a column of Q5 reactant. Methylene chloride (CH2Cl2),
benzene, triethylamine (Et3N), and diisopropylethylamine (DIPEA)
were distilled from calcium hydride prior to use. Dimethyl
sulfoxide (DMSO), and tert-amyl alcohol were stored over 4Å
molecular sieves for 48 h prior to use. All solvents were determined
to contain less than 50 ppm H2O by Karl Fischer coulometric
moisture analysis, unless otherwise noted. All reactions were
performed in flame-dried glassware under argon or nitrogen unless
otherwise indicated. Volatile solvents were removed under reduced
The mother liquors were washed with 5% aqueous NaOH
solution (3 x 60 mL), the combined aqueous extracts were
neutralized with saturated aqueous NH4Cl (ca. 32 mL) until the pH
was 5-7 (pH paper), and the mixture was extracted with EtOAc (3 x
20 mL). The combined organic extracts were washed with a
saturated aqueous NaHCO3 solution (5 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The solids were
purified by flash chromatography eluting with a gradient of
EtOAc/hexanes (1:4 → 1:2) to provide 3.4 g (20%) more 18 as an
1
off-white solid (99% total): H-NMR (400 MHz) δ 9.83 (s, 1 H),
7.52 (d, J = 2.0 Hz, 1 H), 7.44 (dd, J = 2.0, 8.0 Hz, 1 H), 7.36 (d, J
= 8.8, 2 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 2 H), 5.10
(s, 2 H), 3.84 (s, 3 H); 13C-NMR (100 MHz) δ 191.0, 160.0, 151.1,
146.3, 130.7, 129.8, 127.2, 124.3, 114.3, 114.2, 111.5, 71.1, 55.3;
IR (film) 3213, 1668, 1612, 1504, 1274, 1128 cm-1; HRMS (ESI)
–
m/z calc for C15H14O4 , 257.0819; found, 257.0826.

ACCEPTED MANUSCRIPT
9
2-Bromo-3-hydroxy-4-((4-methoxybenzyl)oxy)
benzaldehyde
NMR (100 MHz) δ 159.8, 151.8, 143.7, 135.7, 131.7, 129.3,
(17). A suspension of aldehyde 18 (3.73 g, 14.44 mmol) in CH2Cl2
(144 mL) was cooled to – 78 °C. In a separate flask, TMG (3.32 g,
3.62 mL, 28.88 mmol) was added to a slurry of NBS (2.57 g, 14.44
mmol) in CH2Cl2 (43 mL) at 0 °C. The mixture was stirred until it
became homogenous (ca. 5 min), whereupon it was added in one
portion to the slurry of 18 at – 78 °C. The reaction mixture was
stirred for 30 min at – 78 °C, whereupon AcOH (0.87 g, 0.83 mL,
28.88 mmol) was added, and the reaction was warmed to room
temperature. The mixture was filtered through a silica plug (300
mL) eluting with EtOAc/Hexane (1:1, 1 x 1.5 L). The eluent was
concentrated under reduced pressure to provide 4.05 g (83%) 17 as
a pale yellow solid: mp 154-156 °C (IPA). The crude material can
be purified by flash chromatography eluting with a gradient of
acetone/hexanes with 1% Et3N (1:7 → 3:7), but the material was
128.3, 121.9, 119.6, 115.2, 114.0, 113.2, 98.7, 71.0, 58.1, 55.3; IR
(film) 2934, 2835, 1614, 1587, 1515, 1484, 1465, 1382, 1287,
1251, 1214, 1174, 1159, 1033, 985 cm-1; HRMS (CI) m/z calc for
+
C18H1979BrO4 , 377.0388; found, 377.0391.
4,4-Dimethoxy-3-(3-((4-methoxybenzyl)oxy)-2-
(methoxymethoxy)-6-vinylphenyl)-2-vinylcyclobut-2-en-1-one (19).
Compound 14 (500 mg, 1.32 mmol) was dried by dissolving in
toluene (2 mL) and concentrating under reduced pressure (2 x),
whereupon it was stored under vacuum for 2 h. 3,4,4-Trimethoxy-
2-vinylcyclobut-2-en-1-one (13), prepared according to Moore’s
procedure,15b was freshly purified via flash chromatography eluting
with a gradient of EtOAc/hexanes (1:10 → 1:2), and the oil thus
obtained was stored under vacuum for 2 h. Toluene (9 mL), Et2O
(44 mL) and NaH (60 % dispersion in mineral oil, 16 mg, 0.26
mmol) were added to the flask containing 14, and the mixture was
stirred for 10 min before cooling to – 78 °C. This mixture was
degassed, and a solution of tert-BuLi in pentanes (1.85 M, 1.64 mL,
3.03 mmol) was added dropwise at – 78 °C. Stirring was continued
for an additional 5 min, whereupon a solution of 13 in Et2O (2 mL)
that had been slurried over NaH (60 % dispersion in mineral oil, 8
mg, 0.13 mmol) for at least 5 min was added. The reaction mixture
was warmed to –20 °C and stirring continued for 15 min,
whereupon a solution of saturated aqueous NaHCO3 (10 mL) was
added. The mixture was extracted with EtOAc (3 x 10 mL), and the
combined organic extracts were dried (Na2SO4) and concentrated
under reduced pressure. The crude oil was purified by flash
chromatography eluting with a gradient of EtOAc/hexanes (1:10 →
1:4) to provide 364 mg (61%) of 19 as a yellow oil that slowly
1
sufficiently pure for use in the next step; H-NMR (400 MHz) δ
10.26 (s, 1 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 2 H),
6.99 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 2 H), 6.13 (s, 1 H),
5.17 (s, 2 H), 3.84 (s, 3 H); 13C-NMR (100 MHz) δ 190.9, 160.1,
143.5, 137.9, 129.8, 127.3, 126.8, 122.5, 114.3, 113.0, 110.6, 71.5,
55.4; IR (film) 3388, 2927, 1680, 1588, 1516, 1487, 1464, 1282,
+
1251, 1176, 1130 cm-1; HRMS (ESI) m/z calc for NaC15H1379BrO4
(M+Na), 358.9889; found, 358.9010.
2-Bromo-4-((4-methoxybenzyl)oxy)-3-(methoxymethoxy)
benzaldehyde A solution of the crude aldehyde 17 (6.76 g, 20.05
mmol) and diisopropylethylamine (DIPEA) (3.89 g, 5.25 mL, 30.07
mmol) in CH2Cl2 (140 mL) was cooled to 0 °C. Chloromethyl
methyl ether (MOMCl) (1.18 M, 25.5 mL, 30.07 mmol), prepared
according to Chong’s procedure,51 was added, and the cooling bath
was removed. The solution was stirred at room temperature for 3 h,
whereupon a solution of saturated aqueous NaHCO3 (20 mL) was
added. The mixture was extracted with CH2Cl2 (3 x 20 mL), and the
combined organic extracts were dried (Na2SO4), filtered, and
concentrated under reduced pressure to provide crude material as a
white solid: mp 88-90 °C. The crude material can be purified by
flash chromatography eluting with a gradient of EtOAc/hexanes
(1:20 → 1:3), but the material was sufficiently pure for use in the
next step; 1H-NMR (400 MHz) δ 10.27 (s, 1 H), 7.72 (d, J = 8.6 Hz,
1 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 1 H), 6.92 (d, J
= 8.6 Hz, 2 H), 5.19 (s, 2 H), 5.11 (s, 2 H), 3.82 (s, 3 H), 3.58 (s, 3
H); 13C-NMR (100 MHz) δ 191.0, 159.8, 157.4, 143.6, 129.4,
127.5, 127.2, 126.4, 123.2, 114.1, 112.2, 98.8, 71.0, 58.1, 55.3; IR
(film) 2968, 1674, 1515, 1382, 1250, 931 cm-1; HRMS (ESI) m/z
calc for NaC17H1779BrO5+ (M+Na), 403.0152; found, 403.0147.
1
turns solid upon standing: mp 75-77 °C; H-NMR (600 MHz) δ
7.37 (d, J = 8.6 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 2 H), 7.02 (d, J = 8.6
Hz, 1 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.77 (dd, J = 10.8, 17.6 Hz, 1
H), 6.16 (dd, J = 2.8, 17.6 Hz, 1 H), 6.08 (dd, J = 10.4, 18.0 Hz, 1
H) 5.60 (dd, J = 1.2, 17.6 Hz, 1 H), 5.56 (dd, J = 2.8, 10.4 Hz, 1 H),
5.18 (dd, J = 1.2, 10.8 Hz, 1 H), 5.06 (s, 2 H), 5.04 (s, 2 H) 3.81 (s,
3 H), 3.47 (s, 6 H), 3.38 (s, 3 H); 13C-NMR (150 MHz) δ 191.1,
170.9, 159.6, 152.8, 151.1, 142.5, 134.2, 129.3, 129.3, 128.4,
126.0, 125.8, 124.1, 121.3, 116.7, 115.1, 114.5, 114.0, 99.0, 70.7,
57.3, 55.3, 52.7; IR (film) 2945, 1765, 1515, 1465, 1251, 1028, 992
+
cm-1; HRMS (CI) m/z calc for C26H28O7 (M+), 452.1835; found,
452.1837.
1,1-Dimethoxy-7-((4-methoxybenzyl)oxy)-8-
(methoxymethoxy)cyclobuta[a]naphthalen-2(1H)-one
(12).
A
solution of 19 (1.14 g, 2.513 mmol), Grubbs II (149 mg, 0.176
mmol) and butylated hydroxytoluene (BHT) (111 mg, 0.502 mmol)
in dichloroethylene (DCE) was degassed and then heated under
reflux for 8 h. The reaction mixture was cooled to room
temperature, whereupon DMSO (0.564 g, 0.62 mL, 8.795 mmol)
was added, and the mixture was stirred for 16 h. The solvent was
removed under reduced pressure, and the crude material was
purified by flash chromatography eluting with a gradient of
EtOAc/hexanes (1:10 → 1:2) to provide 836 mg (78%) of 12 as a
brownish green solid: mp 83-85 °C and 214 mg (13%) 19 (91%
brsm); 1H-NMR (500 MHz) δ 7.90 (d, J = 8.4 Hz, 1 H), 7.70 (d, J =
8.8 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 2 H),
7.36 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.35 (s, 2 H),
5.20 (s, 2 H), 3.82 (s, 3 H), 3.57 (comp, 9 H); 13C-NMR (125 MHz)
δ 193.2, 160.3, 159.6, 150.4, 147.5, 140.6, 133.8, 132.7, 129.4,
128.4, 125.8, 125.2, 120.1, 118.2, 114.7, 114.0, 99.6, 71.7, 57.7,
55.3, 53.7; IR (film) 2942, 2836, 1760, 1614, 1584, 1515, 1462,
1334, 1251, 1174, 1108, 1033, 937 cm-1; HRMS (CI) m/z calc for
C24H25O7+ (M+), 425.1600; found, 425.1596.
2-Bromo-4-((4-methoxybenzyl)oxy)-3-(methoxymethoxy)-1-
vinylbenzene (14).
A slurry of methyltriphenylphosphonium
bromide (Ph3PMeBr) (14.12 g, 40.10 mmol) in THF (35 mL) was
cooled to 0 °C and degassed. A solution of n-BuLi in hexanes (1.61
M, 25 mL, 40.10 mmol) was slowly added over 10 min. The
mixture was stirred for an additional 5 min, whereupon DMSO (70
mL) was added followed by a solution of crude aldehyde 17 in THF
(35 mL). The reaction was stirred for 10 min, whereupon a solution
of saturated aqueous NaHCO3 (50 mL) and water (100 mL) was
added. The mixture was extracted with EtOAc (3 x 100 mL), and
the combined extracts were dried (Na2SO4) and concentrated under
reduced pressure. The crude oil was purified by flash
chromatography eluting with a gradient of EtOAc/hexanes (1:20 →
1:4) to provide 6.51 g (86% from 17) of 14 as a white waxy solid:
mp 41-43 °C; 1H-NMR (400 MHz) δ 7.34 (d, J = 8.8 Hz, 2 H), 7.26
(d, J = 8.8 Hz, 1 H), 7.02 (dd, J = 11.2, 17.2 Hz, 1 H), 6.90 (comp,
3 H), 5.56 (dd, J = 1.2, 17.2 Hz, 1 H), 5.25 (dd, J = 1.2, 11.2 Hz, 1
H), 5.17 (s, 2 H), 5.03 (s, 2 H) 3.82 (s, 3 H), 3.59 (s, 3 H); 13C-

ACCEPTED MANUSCRIPT
10
Tetrahedron
2-Hydroxy-4,5-dimethoxy benzaldehyde (27). A solution of
(methoxymethoxy)-1,2-dihydrocyclobuta[a]naphthalen-2-ol (10). A
solution of 12 (143 mg, 0.337 mmol) in toluene (2 mL) was
concentrated under reduced pressure (3 x), put under vacuum for 2
h and dissolved in THF (2.7 mL). A separate round-bottomed flask
containing 11 (221 mg, 0.674 mmol) was dissolved in toluene (2
mL), concentrated under reduced pressure (3 x) and put under
vacuum for 2 h. 4-(Phenylazo)diphenylamine (PDA) (5 mg, 0.017
mmol) was added to the flask containing 11, followed by a solution
of CeCl3•2LiCl in THF (0.33 M, 4.1 mL, 1.35 mmol), prepared by
Knochel’s method,27 and the reaction mixture was cooled to – 78
°C and degassed. The cooling bath was removed, and the mixture
was warmed to 0 °C, whereupon a solution of n-BuLi (1.21 M, 1.5
mL, 1.81 mmol) in hexanes was added until the reaction mixture
turned a persistent purple color. After the purple endpoint had been
seen, an additional amount of n-BuLi in hexanes (1.21 M, 0.56 mL,
0.67 mmol) was added, and the reaction mixture was stirred for 10
min at 0 °C. The solution of 12 in THF (1 mL) was slurried over
NaH (60 % dispersion in mineral oil, ca. 6 mg, 0.150 mmol) before
adding to the reaction mixture containing 11, and stirring was
continued for 1 h at 0 °C. A solution of saturated aqueous NaHCO3
(5 mL) was then added and the mixture was extracted with EtOAc
(3 x 10 mL). The combined organic extracts were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude oil
was purified by flash chromatography eluting with a gradient of
EtOAc/hexanes (1:2 → 3:4) to provide 212 mg (84%) of 10 and 10
mg (7%) of 12 (91% brsm): 1H-NMR (600 MHz) δ 7.81 (d, J = 8.6
Hz, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 6.9 Hz, 1 H), 7.58
(d, J = 6.9 Hz, 1 H), 7.40-7.35 (Comp, 6 H), 7.30 (d, J = 9.0 Hz, 2
H), 7.27 (d, J = 8.8 Hz, 2 H), 7.24 (d, J = 8.8 Hz, 2 H), 7.084 (s, 1
H), 7.07 (s, 1 H), 6.55 (s, 1 H), 6.53 (s, 1 H) 5.74 (app. d, 2 H), 5.29
(d, J = 5.3 Hz, 1 H), 5.25 (d, J = 5.3 Hz, 1 H), 5.16 (app qd, 4 H),
5.09 (d, J = 5.3 Hz, 1 H), 5.04 (d, J = 5.3 Hz, 1 H), 4.96 (app qd, 4
H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.80 (s, 6 H), 3.74 (s, 3 H), 3.73 (s,
3 H), 3.72 (s, 3 H), 3.67 (s, 3 H), 3.64 (s, 3 H), 3.63 (s, 3 H), 3.58
(s, 3 H), 3.53 (s, 3 H), 3.52 (app. d, 6 H); 13C-NMR (150 MHz) δ
159.5, 159.4, 150.3, 150.1, 150.0, 149.5, 149.4, 146.3, 143.4,
138.7, 136.7, 132.6, 131.0, 129.4, 129.2, 128.8, 128.7, 126.3,
126.2, 121.4, 117.2, 117.1, 116.6, 114.0, 113.9, 111.8, 111.6,
107.6, 99.8, 99.7, 87.1, 83.9, 83.7, 77.6, 71.8, 71.6, 60.9, 60.6,
57.6, 56.3, 56.2, 56.1, 55.3, 55.2, 53.2, 51.9, 51.8; IR (film) 3466
(O-H), 2939 (C-H), 2838 (C-H), 2251 (C≡C), 1728, 1613, 1515,
1463, 1405, 1382, 1303, 1251, 1209, 1113, 1032, 912 cm-1; HRMS
2,4,5-trimethoxybenzaldehyde (26) (3.3 g, 16.78 mmol),25a in
CH2Cl2 (84 mL) was cooled to 0 °C, whereupon BBr3 (freshly
distilled from CaH2, 4.59 g, 1.74 mL, 18.45 mmol) was added, and
the mixture was warmed to room temperature and stirred for 24 h.
H2O (20 mL) was added, and stirring was continued for an
additional 10 min. The mixture was extracted with CH2Cl2 (2 x 20
mL), and the combined organic extracts were dried (Na2SO4),
filtered, and concentrated under reduced pressure to provide 2.60 g
(85%) crude 27 as a dark green solid: mp 104-106 °C (MeOH). The
crude material can be purified by flash chromatography eluting
with a gradient of acetone/hexanes (1:3 → 1:1), but in most cases
the material is sufficiently pure for the next step; 1H-NMR (400
MHz) δ 11.41 (s, 1 H), 9.71 (s, 1 H), 6.91 (s, 1 H), 6.48 (s, 1 H),
3.94 (s, 3 H), 3.89 (s, 3 H); 13C-NMR (100 MHz) δ 194.0, 159.3,
152.2, 142.9, 113.1, 112.8, 100.1, 56.4, 56.3; IR (film) 2838 (C-H),
1625 (C=O), 1506, 1475, 1443, 1369, 1339, 1280, 1251, 1198,
1147, 998 cm-1; LRMS (CI) m/z found, 183.0.
4,5-Dimethoxy-2-((4-methoxybenzyl)oxy)benzaldehyde (28). A
mixture of crude aldehyde 27 (0.50 g, 2.74 mmol), K2CO3 (0.76 g,
5.48 mmol) and NaI (0.12 g, 0.82 mmol) in DMF (1.7 mL) was
heated at 40 °C for 2 h.Paramethoxybenzyl chloride (PMBCl)50
(0.64 g, 0.56 mL, 4.12 mmol) was added, and the mixture was
stirred at 40 °C for 24 h. H2O (10 mL) was added, and the reaction
mixture was cooled to room temperature. The mixture was
extracted with CH2Cl2 (3 x 5 mL), and the combined organic
extracts were washed with 5% NaOH solution (1 x 10 mL), 13%
aqueous brine solution (4 x 3 mL), dried (Na2SO4) and concentrated
under reduced pressure. The crude material was purified by flash
chromatography eluting with a gradient of EtOAc/hexanes (1:4 →
1:2) to provide 820 mg (99%) 28 as a white solid: mp (IPA) 98-99
°C; 1H-NMR (500 MHz) δ 10.34 (s, 1 H), 7.35 (d, J = 8.8 Hz, 2 H),
7.32 (s, 1 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.56 (s, 1 H), 5.10 (s, 2 H),
3.93 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H); 13C-NMR (125 MHz) δ
188.1, 159.8, 157.8, 155.6, 144.0, 129.2, 128.1, 118.2, 114.2,
108.8, 98.1, 71.7, 56.2, 55.3; IR (film) 2958 (C-H), 2937 (C-H),
2837, 1655 (C=O), 1606, 1468, 1454, 1276, 1216, 1127, 1037,
+
1021, 915 cm-1; HRMS (CI) m/z calc for C17H18O5 (M+),
302.1154; found, 302.1159.
1-(4,5-Dimethoxy-2-((4-methoxybenzyl)oxy)phenyl)prop-2-yn-1-
ol (11). A solution of aldehyde 28 (354 mg, 1.17 mmol) in THF (7
mL) was degassed. A solution of ethynyl magnesium bromide (0.5
M, 5.8 mL, 2.93 mmol) in THF was added and the reaction mixture
was stirred for 2 h at 5 °C, whereupon a solution of saturated
aqueous NaHCO3 (1 mL) was added. The mixture was extracted
with EtOAc (3 x 2 mL), and the combined organic extracts were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude oil was purified by flash chromatography eluting with
EtOAc/hexanes (1:2) to provide 375 mg (98%) of 11 as a waxy
+
(ESI) m/z calc for NaC43H44O12 (M+Na), 775.2725; found,
775.2722.
2,2-Di-tert-butyl-4-ethynyl-6,7-dimethoxy-4H-
benzo[d][1,3,2]dioxasiline (30). A solution of aldehyde 27 (1.56
mg, 8.57 mmol),25 in THF (16 mL) was cooled to – 78 °C, and the
reaction vessel was degassed. A solution of ethynyl magnesium
bromide (0.5 M, 42.8 mL, 21.41 mmol) was then added at – 78 °C.
The cooling bath was removed, and the reaction mixture was
warmed to room temperature and stirred for 1 h, whereupon a
solution of dilute NH4Cl (10 mL) was added. The mixture was
extracted with EtOAc (3 x 10 mL), and the combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The crude oil was purified by silica plug eluting with 1:1
mixture acetone/hexanes (500 mL) to provide 1.44 g of the
acetylide adduct as a brown solid that used directly in the next step.
1
solid: H-NMR (600 MHz) δ 7.36 (d, J = 8.8 Hz, 2 H), 7.13 (s, 1
H), 6.92 (d, J = 8.8 Hz, 2 H), 6.60 (s, 1 H), 5.68 (dd, J = 2.4, 6 Hz,
1 H), 5.05 (dd, J = 4, 10.6 Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H),
3.82 (s, 3 H), 2.79 (d, J = 6 Hz, 1 H), 2.62 (d, J = 2.4 Hz, 1 H); 13C-
NMR (150 MHz) δ 159.6, 150.1, 149.7, 143.5, 129.1, 128.7, 120.8,
114.1, 111.5, 99.5, 83.6, 73.9, 71.7, 66.3, 56.5, 56.2, 55.3; IR (film)
3469 (O-H), 3282, 3001, 2936 (C-H), 2836 (C-H), 1612, 1515,
1464, 1405, 1383, 1304, 1249, 1209, 1175, 1114, 1019, 941 cm-1;
+
HRMS (ESI) m/z calc for NaC19H20O5 (M+Na), 351.1203; found,
A solution the acetylide adduct (1.44 g, 6.92 mmol) and 2,6-
lutidine (1.85 g, 2.0 mL, 17.3 mmol) in CH2Cl2 (18 mL) was cooled
to – 40 °C, (tert-Bu)2Si(OTf)2 (3.65 g, 2.7 mL, 8.30 mmol) was
added, and the reaction mixture was warmed to 0 °C by replacing
the cooling bath with an ice/water bath. The mixture was stirred for
351.1200.
2-(3-(4,5-Dimethoxy-2-((4-methoxybenzyl)oxy)phenyl)-3-
hydroxyprop-1-yn-1-yl)-1,1-dimethoxy-7-((4-methoxybenzyl)oxy)-8-

ACCEPTED MANUSCRIPT
11
4 h, whereupon a solution of saturated aqueous NaHCO3 (5 mL)
methoxybenzyl)oxy)-8-
was added, and the mixture was extracted with EtOAc (3 x 10 mL).
The combined organic extracts were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude oil was purified by
flash chromatography eluting with a gradient of EtOAc/hexanes
(1:20 → 1:10) to provide 1.98 g (82% from 27) of 30 as a waxy
(methoxymethoxy)cyclobuta[a]naphthalen-1(2H)-one (32). H3PO4
(85%, 7 mg, 4 µL, 0.0697 mmol) and H2O (28 mg, 28 µL, 1.2546
mmol) was added to a slurry of silica (280 mg) in CH2Cl2 (2.1 mL).
The mixture was stirred vigorously for 1 h, whereupon 31 (54 mg,
0.0697 mmol) and CH2Cl2 (1 mL) were added, and the mixture was
stirred for 1 h. Et3N (35 mg, 49 µL, 0.3485 mmol) was added, and
the mixture was filtered through a silica plug (~10 mL). The plug
was eluted with EtOAc/hexanes (1:1, 1 x 100 mL) and the eluant
was concentrated under reduced pressure (bath temp 30 °C) to
provide 48 mg (95%) of 32 as an orange oil. The material was
unstable, so it was used directly in the next step without further
purification; 1H-NMR (600 MHz) δ 8.04 (d, J = 8.3 Hz, 1 H), 8.03
(d, J = 8.5 Hz, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.65 (d, J = 9.0 Hz, 1
H), 7.63 (d, J = 8.2 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.41-7.37
(comp, 6 H), 6.91 (d, J = 8.7 Hz, 4 H), 6.72 (s, 1 H), 6.68 (s, 1 H),
6.46 (s, 1 H), 6.44 (s, 1 H), 5.90 (d, J = 0.7 Hz, 1 H), 5.87 (d, J =
0.7 Hz, 1 H), 5.40-5.36 (m, 4 H), 5.20 (d, J = 3.2 Hz, 4 H), 3.84 (s,
3 H), 3.82 (s, 3 H), 3.81 (s, 6 H), 3.75 (s, 3 H), 3.73 (s, 3 H), 3.54
(s, 3 H), 3.52 (s, 3 H), 1.04 (s, 9 H), 1.03 (s, 9 H), 0.99 (s, 9 H),
0.97 (s, 9 H); 13C-NMR (150 MHz) δ 182.9, 160.4, 160.3, 159.6,
151.6, 149.8, 149.7, 147.0, 146.9, 143.2, 142.1, 140.4, 138.6,
130.9, 129.3, 128.3, 126.1, 124.1, 118.1, 116.6, 116.4, 116.3,
114.0, 109.5, 103.6, 103.5, 99.6, 99.5, 90.0, 89.9, 85.5, 82.2, 82.1,
71.5, 64.7, 57.7, 56.3, 56.2, 56.0, 55.9, 55.3, 27.0, 26.9, 26.8, 21.5,
20.8; IR (neat) 3435, 2935, 2860, 1765, 1615, 1587, 1512, 1465,
1406, 1336, 1251, 1216, 1200, 1175, 1120, 1080, 1034, 941 cm-1;
HRMS (ESI) m/z calc for NaC41H46O10Si+ (M+Na), 749.2752;
found, 749.2739.
1
white solid: mp 78-80 °C; H-NMR (500 MHz) δ 6.82 (s, 1 H),
6.49 (s, 1 H), 5.84 (dd, J = 0.7, 2.3 Hz, 1 H), 3.85 (s, 1 H), 3.83 (s,
3 H), 2.66 (d, J = 2.3 Hz, 1 H), 1.06 (s, 9 H), 1.03 (s, 9 H); 13C-
NMR (125 MHz) δ 149.8, 147.1, 143.2, 116.5, 109.8, 103.6, 83.1,
74.1, 64.5, 56.4, 55.9, 26.9, 26.9, 21.5, 20.9; IR (film) 3287, 2936,
2896, 2860, 2120, 1616, 1512, 1471, 1471, 1450, 1405, 1364,
1326, 1291, 1264, 1218, 1200, 1195, 1175, 1126, 1084, 1012, 940
cm-1; HRMS (ESI) m/z calc for NaC19H28O4Si+ (M+Na), 371.1649;
found, 371.1652.
2-((2,2-Di-tert-butyl-6,7-dimethoxy-4H-
benzo[d][1,3,2]dioxasilin-4-yl)ethynyl)-1,1-dimethoxy-7-((4-
methoxybenzyl)oxy)-8-(methoxymethoxy)-1,2-
dihydrocyclobuta[a]naphthalen-2-ol (31). A solution of 12 (1 g,
2.36 mmol) in toluene (5 mL) was concentrated under reduced
pressure (1 X), put under vacuum for 2 h, and dissolved in THF (5
mL). A separate round-bottomed flask containing 30 (1.64 mg, 4.72
mmol) was dissolved in toluene (5 mL), concentrated under
reduced pressure (1 X), and put under vacuum for 2 h. 4-
(Phenylazo)diphenylamine (PDA) (32 mg, 0.12 mmol), THF (24
mL) and a solution of CeCl3•2LiCl in THF (0.33 M, 17.8 mL, 5.89
mmol)27 was added to the flask containing 30 and the mixture was
cooled to – 78 °C and the reaction vessel was degassed, whereupon
a solution of n-BuLi in hexanes was added until the reaction
mixture turned a persistent purple color. After the purple endpoint
had been seen, an additional amount of n-BuLi in hexanes (2.47 M,
1.91 mL, 4.72 mmol) was added, the cooling bath was removed,
and the reaction mixture was warmed to 0 °C. The solution of 12 in
THF was slurried over NaH (60 % dispersion in mineral oil, ca. 60
mg, 1.5 mmol) before adding to the reaction mixture containing 9,
and stirring continued for an additional 1 h.The reaction was
quenched with neat AcOH (7.07 mL, 1.36 g, 23.6 mmol) followed
by de-ionized H2O (50 mL), and the mixture was extracted with
EtOAc (3 x 50 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude oil was purified by flash chromatography eluting with a
gradient of EtOAc/hexanes (1:4 → 1:2) to provide 1.64 g (90%) of
3-(2,2-Di-tert-butyl-6,7-dimethoxy-4H-
benzo[d][1,3,2]dioxasilin-4-yl)-6-((4-methoxybenzyl)oxy)-5-
(methoxymethoxy)phenanthrene-1,4-dione (33). A solution of crude
32 (35 mg, 0.0472 mmol) in degassed MTBE (14 mL) was heated
to 60 °C for 1 h. The reaction mixture was cooled to room
temperature, the solvent was removed under reduced pressure, and
the crude oil was purified by flash chromatography eluting with a
gradient of acetone/hexanes (1:10 → 3:10) to provide 61 mg (37%)
of 33 as an amorphous red solid and 48 mg (29%) of 34 as a yellow
solid: 1H-NMR (600 MHz) δ 8.00 (d, J = 8.5 Hz, 1 H), 7.97 (d, J =
8.5 Hz, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), 7.48 (d, J = 8.9 Hz, 1 H),
7.40 (d, J = 8.7 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.73 (s, 1 H),
6.56 (s, 1 H), 6.47 (s, 1 H), 6.37 (s, 1 H), 5.29-5.16 (comp, 4 H),
3.87 (s, 3 H), 3.81 (s, 3 H), 3.66 (s, 3 H), 3.31 (s, 3 H), 1.09 (s, 9
H), 1.02 (s, 9 H); 13C-NMR (150 MHz) δ 186.9, 185.4, 159.6,
154.8, 150.9, 149.8, 148.3, 143.3, 142.8, 133.6, 133.1, 133.0,
132.9, 132.0, 129.4, 128.5, 125.3, 125.0, 120.1, 119.6, 117.8,
114.0, 110.6, 103.7, 98.9, 71.9, 69.4, 57.6, 56.5, 56.0, 55.3, 27.1,
27.1, 21.9, 20.8; IR (film) 2934, 2859, 1662, 1614, 1588, 1513,
1448, 1407, 1336, 1299, 1251, 1199, 1135, 1058, 919 cm-1; HRMS
(ESI) m/z calc for NaC41H46O10Si+ (M+Na), 749.2752; found,
749.2747.
1
31 as a golden foam; H-NMR (600 MHz) δ 7.81 (d, J = 8.3 Hz, 2
H), 7.60 (d, J = 8.9 Hz, 2 H), 7.41 (d, J = 8.3 Hz, 1 H), 7.40 (d, J =
8.3 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 4 H), 7.31 (d, J = 9.0 Hz, 2 H),
6.90 (d, J = 9.7 Hz, 4 H), 6.78 (s, 1 H), 6.69 (s, 1 H), 6.44 (s, 1 H),
6.43 (s, 1 H), 5.89 (d, J = 6.4 Hz, 2 H), 5.31 (dd, J = 5.3, 6.8 Hz, 2
H), 5.18 (dq, J = 2.4, 11.4 Hz, 4 H), 5.10 (dd, J = 5.3, 8.3 Hz, 2 H),
3.82 (s, 3 H), 3.81 (s, 6 H), 3.67 (s, 3 H), 3.66 (s, 3 H), 3.65 (s, 3
H), 3.61 (s, 3 H), 3.56 (s, 3 H), 3.53 (s, 3 H), 3.52 (s, 3 H), 3.51 (s,
3 H), 3.50 (s, 3 H), 1.51 (s, 9 H), 1.03 (s, 9 H), 0.96 (s, 9 H), 0.90
(s, 9 H); 13C-NMR (150 MHz) δ 159.5, 150.1, 150.0, 149.5, 149.4,
147.0, 146.3, 143.0, 142.9, 138.7, 136.8, 136.7, 132.5, 131.0,
129.4, 128.8, 128.7, 126.3, 126.2, 117.1, 117.0, 116.6, 113.9,
109.9, 109.8, 107.6, 107.5, 103.4, 99.8, 86.7, 83.8, 77.5, 71.6, 64.8,
57.6, 56.1, 55.9, 55.3, 53.2, 51.9, 51.8, 26.9, 21.5, 21.0, 20.8; IR
(film) 3498, 2937, 2860, 2353, 1732, 1615, 1594, 1513, 1464,
1405, 1337, 1252, 1200, 1175, 1121, 1080, 1035, 1012, 938 cm-1;
HRMS (ESI) m/z calc for NaC19H28O4Si+ (M+Na), 795.3171;
found, 795.3163.
3-(Hydroxy(2-hydroxy-4,5-dimethoxyphenyl)methyl)-6-((4-
methoxybenzyl)oxy)-5-(methoxymethoxy)phenanthrene-1,4-dione
(37). One drop of HF•Pyridine was added to a solution of 33 (41
mg, 0.0565 mmol) and pyridine (49 mg, 50 µL, 0.6210 mmol) in
THF (2 mL), and the reaction was stirred for 30 min at room
temperature. The mixture was diluted with EtOAc (5 mL), and the
solution was washed with NH4Cl (1 x 2 mL) and de-ionized H2O (1
x 2 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure, and the crude oil was purified by flash
chromatography eluting with a gradient of EtOAc/hexanes (1:2 →
2-((2,2-Di-tert-butyl-6,7-dimethoxy-4H-
benzo[d][1,3,2]dioxasilin-4-yl)ethynyl)-2-hydroxy-7-((4-
1
3:4) to provide 24 mg (72%) of 37 as an amorphous red solid: H-

ACCEPTED MANUSCRIPT
12
Tetrahedron
NMR (600 MHz) δ 7.97 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1
H), 7.68 (bs, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 1
H), 7.39 (d, J = 8.7 Hz, 2 H), 6.93 (d, J = 8.7 Hz, 2 H), 6.67 (s, 1
H), 6.55 (s, 1 H), 6.47 (d, J = 1.6 Hz, 1 H), 6.17 (bs, 1 H), 5.19 (s, 2
H), 5.13 (d, J = 4.8 Hz, 1 H), 5.19 (d, J = 4.8 Hz, 1 H), 4.40 (bs, 1
H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.82 (s, 3 H), 3.19 (s, 3 H); 13C-
NMR (150 MHz) δ 188.8, 185.0, 159.7, 152.7, 150.9, 150.3, 150.0,
143.0, 141.4, 133.8, 133.2, 132.9, 132.7, 130.0, 129.4, 128.3,
125.3, 125.1, 119.6, 114.1, 114.0, 113.6, 111.2, 102.4, 98.2, 71.7,
70.3, 57.6, 56.6, 56.0, 55.3; IR (film) 3431, 2933, 2837, 1659,
1614, 1588, 1514, 1449, 1335, 1302, 1250, 1197, 1137, 1112,
it was added to the solution containing guiacol (45) at – 78 °C over
10 min. The reaction mixture was stirred for 30 min at – 78 °C
whereupon AcOH (1.1 mL, 1.15 g, 19.33 mmol) was added, and
the reaction was warmed to room temperature. The mixture was
washed with H2O (1 x 100 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude oil was purified by
flash chromatography eluting with a gradient of acetone/hexanes
(1:4 → 1:2) buffered with 1% Et3N to provide 2.74 g (84%) of 46
as a white solid: mp 49-53 °C; 1H-NMR (600 MHz) δ 7.09 (dd, J =
1.4, 8.1 Hz, 1 H), 6.81 (dd, J = 1.4, 8.1 Hz, 1 H), 6.74 (t, J = 8.1
Hz, 1 H), 3.90 (s, 3 H); 13C-NMR (150 MHz) δ 147.4, 143.2, 124.8,
120.7, 109.9, 108.4, 56.3; IR (film) 3409 (O-H), 2953 (C-H), 2848
(C-H), 1601, 1490, 1471, 1442, 1354, 1287, 1263, 1234, 1201,
1147, 1072, 1027 cm-1; HRMS (CI) m/z calc for C7H7O279Br+ (M+),
201.9629; found, 201.9632.
+
1055, 1035, 916 cm-1; HRMS (ESI) m/z calc for NaC33H39O10
(M+Na), 609.1731; found, 609.1722.
10,11-Dimethoxy-2-((4-methoxybenzyl)oxy)-1-
(methoxymethoxy)-13H-naphtho[1,2-b]xanthene-7,13,14-trione (8).
Activated manganese dioxide (MnO2) (667 mg, 7.670 mmol) was
added to a solution of 37 (30 mg, 0.051 mmol) in CH2Cl2 (6.1 mL)
and pyridine (0.3 mL) at room temperature and stirred for 4 h. The
mixture was then filtered through a silica plug, eluting with a
mixture (1:1) of acetone/hexanes (20 mL) and the combined
filtrates were concentrated under reduced pressure. The crude
material was then purified by flash chromatography eluting with a
gradient of acetone/hexanes (7:20 → 1:2) to provide 13 mg (44%)
of 8 as an amorphous orange solid: 1H-NMR (500 MHz) δ 8.04 (d,
J = 8.5 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.65 (s, 1 H), 7.61 (d, J
= 9.1 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2 H),
7.15 (s, 1 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.26 (s, 2 H), 5.23 (s, 2 H),
4.03 (s, 3 H), 4.01 (s, 3 H), 3.82 (s, 3 H), 3.44 (s, 3 H); 13C-NMR
(125 MHz) δ 182.1, 179.1, 172.6, 159.6, 155.6, 153.8, 151.2, 150.6,
148.8, 143.7, 135.2, 133.7, 133.3, 130.4, 129.4, 128.5, 125.2,
124.7, 121.6, 121.0, 119.8, 119.1, 114.0, 105.1, 100.6, 99.2, 77.1,
57.8, 56.8, 56.5, 55.3; IR (film) 2928, 1688, 1641, 1620, 1600,
1512, 1467, 1450, 1428, 1402, 1334, 1272, 1249, 1175, 1126,
2-Bromo-6-methoxyphenyl trifluoromethanesulfonate (47). A
solution of phenol 46 (4.38 g, 21.57 mmol) and pyridine (3.41 g,
3.47 mL, 43.14 mmol) in CH2Cl2 (120 mL) was cooled to 0 °C.
Neat triflic anhydride (Tf2O) (7.31 g, 4.35 mL, 25.88 mmol) was
added, and the reaction mixture was stirred for 1 h. H2O (100 mL)
was added, and the layers were separated. The organic layer was
washed with aqueous CuSO4 (1 M, 1 x 100 mL) dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude oil
was purified by flash chromatography eluting with EtOAc/hexanes
1
(1:10) to provide 6.83 g (94%) of 47 as a clear oil: H-NMR (600
MHz) δ 7.22 (dd, J = 1.5, 8.2 Hz, 1 H), 7.18 (t, J = 8.2 Hz, 1 H),
6.97 (dd, J = 2.5, 8.2 Hz, 1 H), 3.91 (s, 3 H); 13C-NMR (150 MHz)
δ 152.6, 137.0, 129.3, 125.3, 118.6 (q, J = 321 Hz), 116.9, 112.0,
56.4; IR (film) 1595, 1475, 1300, 1282, 1210, 1136, 1036, cm-1;
HRMS (ESI) m/z calc for NaC8H679BrF3O4S+ (M+Na), 356.9014;
found, 356.9026.
Butyl 2-bromo-6-methoxybenzoate (48).
+
1081, 1048, 992 cm-1; HRMS (ESI) m/z calc for NaC33H26O10
Using PhMe: Pd(OAc)2 (75 mg, 0.33 mmol), 1,3-
bis(diphenylphosphino)propane (DPPP) (270 mg, 0.65 mmol),
K2CO3 (1.81 g, 13.08 mmol) and tetrabutylammonium acetate
(TBAA) (1.97 g, 6.54 mmol) were weighed in a glove-box and
added to a flame dried round bottomed flask. Pulverized 3 Å
molecular sieves (1.1 g) were added, and the flask was put under
vacuum and backfilled with N2 (3 x). Toluene (20 mL) was added
and the reaction mixture was stirred for 10 min before adding 47
(2.19 g, 6.54 mmol) and n-BuOH (1.46 g, 1.80 mL, 19.61 mmol).
The reaction mixture was heated to 70 °C for 16 h. The mixture
was cooled to room temperature and filtered through a silica plug.
The plug was washed with 1:1 EtOAc/hexanes (200 mL), and the
combined eluant was concentrated and purified by flash
chromatography eluting with a gradient of CH2Cl2/hexanes (1:4 →
3:4) to provide 1.26 g (67%) of 48 as a clear oil.
(M+Na), 605.1418; found, 605.1410.
2,7,14-Trihydroxy-10,11-dimethoxy-1-(methoxymethoxy)-5,6-
dihydro-13H-naphtho[1,2-b]xanthen-13-one (38). Pd/C (ca. 1-2
mg) was added to a solution of 8 (7 mg, 0.12 mmol) in a mixture
(1:1) of MeOH/PhMe (1 mL). The reaction mixture was sparged
with a balloon of H2 for 5 min then stirred at room temperature for
24 h under a hydrogen atmosphere. The reaction mixture was
filtered through a silica plug, eluting with a mixture (1:1)
acetone/hexanes (5 mL). The solution was concentrated under
reduced pressure and the crude material was purified by flash
chromatography eluting with a gradient of acetone/hexanes (7:20
→ 1:2) to provide 3 mg (53%) of 38 as an amorphous yellow solid:
1H-NMR (500 MHz) δ 13.06 (s, 1 H), 8.25 (s, 1 H), 6.98 (d, J = 8.5
Hz, 1 H), 6.944 (s, 1 H), 6.941 (d, J = 8.0 Hz, 1 H), 5.39 (bs, 1 H),
5.29 (bs, 2 H), 4.07 (s, 3 H), 4.03 (s, 3 H), 3.62 (s, 3 H), 1.57 (bs, 4
H); 13C-NMR (125 MHz) δ 180.9, 156.1, 151.9, 151.3, 148.1,
147.2, 143.9, 142.9, 136.5, 131.9, 131.5, 124.6, 123.4, 115.8,
114.8, 113.4, 106.8, 104.7, 99.7, 99.3, 57.0, 56.6, 56.4, 29.2, 23.9;
IR (film) 3396 (O-H), 2955 (C-H), 1644 (C=O), 1615, 1588, 1509,
1479, 1453, 1434, 1382, 1361, 1299, 1277, 1237, 1211, 1175,
1147, 1115, 1073, 1030, 1003, 988 cm-1; HRMS (ESI) m/z calc for
NaC25H22O9+ (M+Na), 489.1156; found, 489.1154.
Using DMSO: Pd(OAc)2 (34 mg, 0.149 mmol), 1,3-
bis(diphenylphosphino)propane (DPPP) (123 mg, 0.298 mmol),
and tetrabutylammonium acetate (TBAA) (900 mg, 2.98 mmol)
were weighed in a glove-box, and added to a flame dried round
bottomed flask. Pulverized 3 Å molecular sieves (1.5 g) were added
and the flask was put under vacuum and backfilled with N2 (3 x).
Degassed DMSO (20 mL) was added, and the reaction mixture was
stirred for 10 min before adding 47 (500 mg, 1.49 mmol) and n-
BuOH (0.33 g, 0.41 mL, 4.47 mmol). The mixture was heated to 70
°C for 16 h. The mixture was cooled to room temperature and
filtered through a silica plug. The plug was washed with 1:1
EtOAc/hexanes (1 x 100 mL), and the combined eluant was washed
with H2O (1 x 50 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure and the crude oil was purified by flash
2-Bromo-6-methoxyphenol (46). Guiacol (45) (2.0 g, 16.11
mmol) was dissolved in CH2Cl2 (160 mL) and cooled to – 78 °C. In
a separate flask, TMG (4.45 g, 4.85 mL, 38.66 mmol) was added to
a slurry of NBS (3.44 g, 19.33 mmol) in CH2Cl2 (43 mL) at 0 °C.
The mixture was stirred until it became homogenous (~5 min), then

ACCEPTED MANUSCRIPT
13
chromatography eluting with a gradient of CH2Cl2/hexanes (1:4→
3:4) to provide 272 mg (69%) of 48 as a clear oil. 1H-NMR (500
MHz) d 7.18 (dd, J = 8.1, 8.0 Hz, 1 H), 7.13 (dd, J = 1.0, 8.3 Hz, 1
H), 6.85 (dd, J = 1.0, 8.0 Hz, 1 H), 4.36 (t, J = 6.6 Hz, 2 H), 3.81 (s,
3 H), 1.74 (quin, J = 6.6 Hz, 2 H), 1.47 (sex, J = 7.6 Hz, 2 H), 0.96
(t, J = 7.3 Hz, 3 H); 13C-NMR (125 MHz) d 166.3, 157.2, 131.1,
126.4, 124.5, 119.7, 110.0, 65.6, 56.1, 30.6, 19.1, 13.7; IR (film)
2960 (C-H), 2873 (CH), 1731 (C=O), 1591, 1573, 1464, 1433,
1267, 1187, 1157, 1107, 1066, 1035, 839 cm-1; HRMS (ESI) m/z
calc for NaC12H1579BrO3+ (M+Na), 309.0097; found, 309.0102.
(3S,10aS)-3-Benzyl-6-methoxy-10a-methyl-10,10a-dihydro-
5H-oxazolo[3,2-b]isoquinoline-2,5(3H)-dione (51). Isolated from a
sample of 52 which was left on the bench at room temperature for ~
1 week. Purified via preparative TLC (50% EtOAc/hexanes) to
1
provide 9 mg (20%) of 51 as an amorphous white solid: H-NMR
(600 MHz) δ 7.40 (dd, J = 7.5, 8.5 Hz, 1 H), 7.27-7.20 (comp, 5 H),
6.96 (d, J = 8.6 Hz, 1 H), 6.76 (d, J = 7.4 Hz, 1 H), 4.97 (dd, J =
2.6, 6.4 Hz, 1 H), 3.95 (s, 3 H), 3.52 (dd, J = 6.4, 13.9 Hz, 1 H),
3.42 (dd, J = 2.6, 13.9 Hz, 1 H), 3.16 (d, J = 14.6 Hz, 1 H), 3.05 (d,
J = 14.7 Hz, 1 H), 0.53 (d, J = 1.0 Hz, 3 H); 13C-NMR (150 MHz) δ
171.3, 161.0, 159.9, 136.3, 136.0, 133.7, 130.5, 128.6, 127.3,
120.2, 116.5, 111.9, 94.2, 69.6, 58.0, 56.3, 53.8, 24.6; IR (film)
3436, 1729 (C=O), 1666 (C=O), 1599, 1571, 1478, 1434, 1319,
1282, 1262, 1163, 1089, 1039, 980 cm-1; HRMS (CI) m/z calc for
C20H19NO4+ (M+), 337.1314; found, 337.1310.
8-Methoxy-3-methyl-1H-isochromen-1-one
(50).
Pd2(dba)3•HCCl3 (45 mg, 0.043 mmol), (2-biphenyl)di-tert-
butylphosphine (52 mg, 0.174 mmol), K3PO4 (923 mg, 4.35 mmol),
para-methoxyphenol
(43
mg,
0.348
mmol)
and
tetrabutylammonium acetate (TBAA) (525 mg, 1.74 mmol) were
weighed in a glove-box and added to a flame dried round bottomed
flask. Pulverized 3 Å molecular sieves (250 mg) was added and the
flask was put under vacuum and backfilled with N2 (3 x). Toluene
(5 mL) was added, and the reaction mixture was stirred for 10 min
before adding a degassed solution of 48 (2.19 g, 6.54 mmol) in
toluene (4 mL) and acetone (freshly distilled from CaH2, 0.61 g,
0.77 mL, 10.44 mmol) and the mixture was heated to 60 °C for 16
h. The mixture was then cooled to room temperature, and filtered
Acknowledgments
We thank the Robert A. Welch Foundation (F-0652) for support
and Dr. Richard Pederson (Materia, Inc.) for catalyst support. We
also thank Angela Spangenberg and Steve Sorey for technical
support.
through
a silica plug. The plug was washed with 3:1
References and notes
EtOAc/hexanes (100 mL) and the combined eluant was
concentrated and purified by flash chromatography eluting with a
gradient of EtOAc/hexanes (1:4 → 1:2) to provide 197 mg (59%)
of 50 as a brown amorphous solid: 1H-NMR (600 MHz) δ 7.57 (dd,
J = 7.77, 7.78 Hz, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 6.86 (d, J = 7.77
Hz, 1 H), 6.15 (app d, J = 1 Hz, 1 H), 3.99 (s, 3 H), 2.23 (d, J = 1
Hz, 3 H); 13C-NMR (150 MHz) δ 161.6, 159.8, 155.1, 140.7, 135.7,
117.0, 109.3, 108.0, 103.6, 56.3, 19.5; IR (film) 3436, 1729 (C=O),
1666, 1599, 1571, 1478, 1434, 1319, 1282, 1262, 1163, 1089,
‡
Current address: Southwest Research Institute, 6220 Culebra Rd, San
Antonio, Texas 78238, United States
1. (a) citreamicin
α (originally called LL-E19085α): Maiese, W. M.;
Lechevalier, M. P.; Lechevalier, H. A.; Korshalla, J.; Goodman, J.;
Wildey, M. J.; Kuck, N.; Greenstein, M. J. Antibiot. 1989, 42 , 846-851.
(b) Citreamicins β, γ , ζ and η: Carter, G.; Nietsche, J. A.; Williams, D. R.;
Borders, D. B. J. Antibiot. 1990, 43, 504-512. (c) citreamicins δ and ε:
Hopp, D. C.; Milanowski, D. J.; Rhea, J.; Jacobsen, D.; Rabenstein, J.;
Smith, C.; Romari, K.; Clarke, M.; Francis, L.; Irigoyen, M.; Luche, M.;
Carr, G. J.; Mocek, U. J. Nat. Prod. 2008, 71, 2032-2035. (d)
Neocitreamicins I and II: Peoples, A. J.; Zhang, Q.; Millett, W.; Rothfeder,
P. M. T.; Pescatore, B. C.; Madden, A. A.; Ling, L. L.; Moore, C. M. J.
Antibiot. 2008, 61, 457-463. (e) citreamicins ε and B: Liu, L.-L.; He, L.-S.;
Xu, Y.; Han, Z.; Li, Y.-X.; Zhong, J.-L.; Guo, X.-R.; Zhang, X.-X.; Ko, K.
M. Qian, P.-Y. Chem. Res. Toxicol. 2013, 26, 1055-1063.
+
1039, 980 cm-1; HRMS (ESI) m/z calc for NaC11H10O3 (M+Na),
213.0522; found, 213.0523.
(S)-2-(8-Methoxy-3-methyl-1-oxoisoquinolin-2(1H)-yl)-3-
phenylpropanoic acid (52). A solution of AlMe3 (2 M, 3.44 mL,
6.89 mmol) in toluene was added to THF (10 mL), followed by a
solution of MeLi (1.26 M, 5.5 mL, 6.89 mmol) in Et2O. The
mixture was stirred for 10 min before adding to a degassed flask
containing solid L-phenylalanine (487 mg, 2.95 mmol). The
mixture was stirred for 10 min before heating to 50 °C and heating
for an additional 30 min or until the mixture became homogeneous.
A solution of 50 (187 mg, 0.98 mmol) in toluene (10 mL) was then
added and the mixture was stirred for 1 h at 50 °C, whereupon the
reaction was cooled to room temperature and poured into cold 1 M
HCl (20 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 x 10 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude oil was purified by flash chromatography
eluting with a gradient of MeCN/HCCl3 (1:20 → 1:10) buffered
with 2% AcOH to provide 262 mg (79%) of 52 as a yellow oil: 1H-
NMR (600 MHz) δ 7.50 (m, 1 H), 7.16 (comp, 3 H), 7.01 (m, 2 H),
6.92 (m, 1 H), 6.85 (m, 1 H), 6.09 (app d, 1 H), 4.65 (m, 1 H), 3.98
(app d, 3 H), 3.67-3.60 (comp, 2 H), 2.64 (s, 3 H); 13C-NMR (150
MHz) δ 175.9, 161.8, 160.9, 140.1, 140.0, 138.3, 133.4, 129.5,
128.6, 126.7, 117.5, 113.8, 107.3, 106.6, 61.3, 56.0, 34.4, 20.8; IR
(film) 3443 (O-H), 2924 (C-H), 1730 (C=O), 1653 (C=O), 1602,
1561, 1481, 1455, 1399, 1335, 1296, 1267, 1212, 1180, 1154,
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1115, 1084, 1065 cm-1; HRMS (ESI) m/z calc for NaC20H19NO4
(M+Na), 360.1206; found, 360.1208.

14
Tetrahedron
ACCEPTED MANUSCRIPT
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