Two approaches to the aromatic core of the aminonaphthoquinone antibiotics

Article abstract of DOI:10.1021/jo400737f

Two complementary approaches are presented for the synthesis of the quinone chromophores of the naphthoquinone ansamycins and related natural products. The first involves the use of an improved protocol for the manganese(III) acetate mediated cyclization of 5-aryl-1,3-dicarbonyl compounds to β-naphthols, leading to the simple, scalable preparation of building blocks suitable for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves the Diels-Alder reaction of a series of new, ester-containing Danishefsky-type dienes with N-protected aminobenzoquinones to allow more expeditious access to similar intermediates.

Full text of DOI:10.1021/jo400737f

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Article
Two Approaches to the Aromatic Core
of the Aminonaphthoquinone Antibiotics
Christopher C. Nawrat, Leoni I. Palmer, Alexander J. Blake, and Christopher J. Moody
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400737f • Publication Date (Web): 09 May 2013
Downloaded from http://pubs.acs.org on May 10, 2013
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Two Approaches to the Aromatic Core of the
Aminonaphthoquinone Antibiotics
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Christopher C. Nawrat, Leoni I. Palmer, Alexander J. Blake, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
c.j.moody@nottingham.ac.uk
Graphical Abstract
Abstract
Two complementary approaches are presented for the synthesis of the quinone chromophores of
the naphthoquinone ansamycins and related natural products. The first involves the use of an
improved protocol for the manganese(III) acetate mediated cyclization of 5ꢀarylꢀ1,3ꢀdicarbonyl
compounds to βꢀnaphthols, leading to the simple, scalable preparation of building blocks suitable
for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves
the DielsꢀAlder reaction of a series of new, esterꢀcontaining Danishefskyꢀtype dienes with Nꢀ
protected aminobenzoquinones to allow more expeditious access to similar intermediates.
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Introduction
Aminonaphthoquinones are found at the core of a number of commercially and medicinally
1
important natural products and their derivatives (Figure 1). For example, rifabutin 2, a semiꢀ
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synthetic derivative of rifamycin S 1 is a current frontline antibiotic used for the treatment of
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,3
multiꢀdrug resistant tuberculosis, and other members of the rifamycin family exhibit various
useful biological activities. In addition to these wellꢀknown examples, new members of this class
of compounds continue to be reported in the literature, for example the recently isolated natural
products hygrocin A 3 and salinisporamycin 4 exhibit anticancer and antibiotic activity
4,5
respectively. Given the historic importance of compounds of this type, chemistry that
facilitates rapid access to these natural products is desirable. For this reason, a number of
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ꢀ14
methods for the synthesis of the ansa chains of various ansamycins have been reported,
and
new methods for the synthesis of polyketide and polypropionate subunits frequently appear in
1
5,16
the literature.
However, the synthesis of the aminonaphthoquinone cores of these compounds
still tends to use lengthy sequences of classical aromatic chemistry that has changed very little
over the past 40 years. For example, Kishi’s synthesis of the aromatic core of rifamycin S 1
required 16 linear steps from commercial starting materials, and a more recent approach towards
the core of the Divergolides by Rasapalli took over 12 steps — relatively lengthy routes to reach
1
7ꢀ19
fairly simple substituted naphthalenes.
We now report two complementary approaches
suitable for more rapid access to the naphthoquinone chromophores of this important class of
molecules.
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Figure 1. Some naturally occurring aminonaphthoquinones and their derivatives.
Results and Discussion
Recently, during our studies on various ansamycin antibiotics, we required a rapid route to the
quinone chromophores of these compounds. Depending on the method used for the attachment of
the ansa chain, two similar precursors to these core structures could be imagined (Scheme 1). A
naphthoquinone ester such as 5 would be a versatile precursor to the naphthoquinone ansamycins
allowing the ansa chain to either be attached first at the ester position, or by amide formation at
the aminonaphthoquinone, giving a number of options for the order of bond formation in
construction of the macrolactam ring. Initially, it was decided to approach ester 5 using the
biomimetic oxidative radical cyclization developed by Rickards and Citterio, on a βꢀketoester
2
0,21
such as 6 or 7.
A second, complementary, approach to this same target can also be
envisioned, based on a DielsꢀAlder reaction between a suitable diene 8 and an
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aminobenzoquinone dienophile 9.
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O
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aminonaphthoquinone
ansamycins
O
Me
NHPg
PgO
MeO C
O
2
5
amino-
oxidative
radical
cyclization
benzoquinone
Diels-Alder
O
OPg
Me
NHPg
Me
X
PgO
MeO C
O
O
MeO C
2
2
6
7
X = NHAc
X = OMe
8
9
Scheme 1. Disconnections for the aminonaphthoquinone chromophore of the ansamycins (Pg =
protecting group).
It has been shown that ansamycins are derived in Nature from 3ꢀaminoꢀ5ꢀhydroxybenzoic acid
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3,24
1
0 (AHB),
and labelling studies have been used to determine the biosynthetic precursors to
2
5,26
the entire carbon skeleton of rifamycin S 1 (Scheme 2A).
A biosynthetic proposal put
forward by Rickards suggested that the rifamycin polyketide chain is attached first at the AHB
carboxylic acid to give diketone 11, and that amide formation occurs later to give macrolactam
1
2 (Scheme 2B). The naphthoquinone nucleus is then formed by oxidation of phenol 12 to the
27
quinone, followed by Michael addition of the readily enolized diketone and reꢀoxidation to 13.
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O-methyl
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A
Me Me Me
AcO
MeO
OH
Me
MeO
lost as
CO2
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OH
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O
Me
N
Me
NH
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O
methylmalonate
O
O
Me
[O]
acetate
malonate
1
rifamycin S
NH2
B
H
N
O
O
HO C
Me
NH2
SEnz
Me
O
O
H
2
Me
HO
N
O
O
OH
O
OH
OH
O
O
O
1
0 AHB
11
12
13
Scheme 2. A, The results of labelling studies carried out on rifamycin S; B, Rickards’
biosynthetic proposal for the naphthoquinone ansamycins.
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Some studies towards this end have already been carried out by Rickards, Citterio and others,
but the yields remain low, and the precursors themselves often require lengthy synthetic routes
Scheme 3). Thus, although Rickards successfully demonstrated the pseudoꢀbiomimetic
(
oxidative cyclization of acetanilide 14 to naphthalene 15 in good yield (Scheme 3A), this
precursor took 9 steps to prepare from 3,5ꢀdihydroxybenzoic acid and was obtained in low
overall yield (<15%). The catechol derivative 16 (Scheme 3B) is more readily available, being
preparable from oꢀvanillin in 5 steps, but the overall yield for the key cyclization and
aromatization steps to give naphthalene 18 via tetralone 17 is considerably lower (16 vs 74%).
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A
1. Mn(OAc)3,
AcOH,
Me
NHAc
Me
HO
NHAc
93%
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. SiO2,
O
CH Cl ,
2
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OBn
OBn
O
Et
80%
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Et
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Mn(OAc)3
AcOH,
81%
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OEt
16
OEt
17
SiO2,
CH Cl ,
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0%
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OBn
Me
HO
OMe
O
OEt
18
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Scheme 3. Rickards' biomimetic approach to the core of the naphthoquinone ansamycins.
We began our studies towards naphthoquinone ester 5 by synthesizing a range of new βꢀ
ketoesters precursors for the oxidative cyclization reaction, in the hope of finding a more readily
accessible substrate for this reaction than those previously reported by Rickards (Scheme 4). This
involved reaction of the dianion of methyl propionylacetate with the known benzyl bromides
2
1
28,29
21
19, 21,
and 23 to give the βꢀketoesters 20, 22 and 24 in generally high yields (see
Experimental Section for details of improved routes to benzyl bromides 19 and 21). The structure
of βꢀketoester 20 was confirmed by Xꢀray crystallography (see Supporting Information).
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Scheme 4. Preparation of 5ꢀarylꢀ3ꢀoxopentanoate oxidative cyclization precursors.
First, cyclization of the βꢀketoesters was attempted using Fremy’s salt in acetone/phosphate
buffer under the conditions previously described by Rickards for the corresponding 1,3ꢀ
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diketones. Surprisingly, given the generally high yields reported for this reaction on various
1,3ꢀdiketones in the literature, and our own studies, only a trace of naphthoquinones were
obtained for the βꢀketoesters. This is presumably due to the lower acidity of the methylene group
in this compound and hence the greater difficulty associated with formation of the enol required
for cyclization to occur. In light of the apparent failure of this cyclization method when applied
to βꢀketoesters, we turned to the use of manganese(III) acetate as the oxidant, as this does not
rely on enolization for cyclization to occur, and is well precedented in this context (Scheme
2
7
3
B). Next, acetanilide 20, containing a βꢀketoester, was investigated, so that its reactivity could
be compared to the corresponding 1,3ꢀdiketone 14 reported by Rickards. This change in
functionality did not significantly affect the reactivity and, after cyclization and aromatization,
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we obtained βꢀnaphthol 25 in essentially the same yield as had been reported for diketone 14.
Protected resorcinol 22 was then prepared so its reactivity could be compared to the protected
catechol 16 used by Rickards. Surprisingly, altering the position of the benzyloxy group had a
dramatic effect on the reactivity of these substrates, and while 16 reportedly cyclized in an
excellent yield of 81% when treated with manganese(III) acetate, our substrate 22 gave a
markedly lower yield of 40% yield under the same conditions. Our yield for the aromatization of
the initial cyclization product of 22 (19%) was comparable to that obtained by Rickards for the
aromatization of 17 into 18 (20%). However, we had been using the aromatization conditions
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reported by Citterio (i.e. heating with silica under reflux in benzene), whereas Rickards had
employed basic silica (pH 10) in dichloromethane in his studies. Both steps for the conversion of
22 into naphthalene 26 were poor (Table 1) but sufficient material could be produced to confirm
the structure of 26 by Xꢀray crystallography (see Supporting Information). In view of this, we reꢀ
examined the possibility of using the known naphthoate ester 18 instead. Rickards has previously
shown that βꢀketoester 16 cyclizes efficiently into 17, but the low overall yield was due to the
difficulty in aromatization of initial adduct 17 to naphthoate ester 18. If this second step in the
synthesis of 18 could be improved, then 18 could become accessible enough to enable its use in
these studies. Remarkably, when we applied Citterio’s conditions to the aromatization of the
cyclization product obtained from βꢀketoester 24 (the corresponding methyl ester of 16), we were
delighted to find that aromatization occurred in a greatly improved yield of 93%. Using this new
protocol, naphthoate ester 27 (the corresponding methyl ester of 18) could now be prepared in
8
3% yield over two steps from βꢀketoester 24, and is therefore a viable building block for use in
total synthesis.
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Substrate
Product
Yield/%
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8
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%
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3%
Table 1. Preparation of ester precursors. Oxidative cyclization was performed by treatment with
Mn(OAc) and AcOH followed by aromatization by reflux with silica in benzene (yields over 2
3
steps).
Reviewing the above results, we decided that although both βꢀketoesters 20 and 24 underwent
conversion into the corresponding naphthoates in similar yields, 24 would be a better choice with
which to continue the synthesis. Although βꢀketoester 20 might appear to be a more advanced
and useful intermediate as it already contains a protected amino group, the much greater
difficulty in preparing this material offset this advantage. Indeed, under the improved conditions
described above, naphthoate 27 can now be prepared in 53% over 6 steps from inexpensive oꢀ
vanillin, whereas even after careful optimization, 25 can only be prepared in 14% over 9 steps; a
significant difference in number of steps and overall yield.
With large amounts of naphthoate 27 now available, manipulation of the ester and development
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of the latent quinone functionality was investigated. Thus naphthol 27 was protected as the
MOM ether 28 and, following debenzylation to naphthol 29, oxidized to the corresponding
naphthoquinone 30 using oxygen and a catalytic amount of the cobalt(II) salen complex
salcomine (Scheme 5). Initially, this reaction appeared to be quite capricious, but upon further
investigation it was discovered that the yield was highly dependent on the commercial source of
the salcomine used. With the methoxynaphthoquinone 30 in hand, only displacement of the
methoxy group with ammonia was required to complete the target naphthoquinone nucleus, and
this was accomplished by treatment with liquid ammonia in a pressure vessel at –78 ºC, followed
by warming to room temperature to give aminonaphthoquinone 31 in good yield. Unfortunately,
further manipulation of the ester in this substrate was complicated by the presence of the
sensitive aminonaphthoquinone ring system, indicating that introduction of the ansa chain might
be easier on a naphthalene system instead of a naphthoquinone. Therefore, naphthoate ester 28
was also converted into the corresponding naphthaldehyde 32, as it was anticipated that this
might be a more useful precursor for the carbonꢀcarbon bond forming reactions required to
introduce the ansa chain.
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Scheme 5. Conversion of 27 to building blocks for the synthesis of aminonaphthoquinones.
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Thus, two useful naphthalene building blocks 31 and 32 for the synthesis of the ansamycin
antiobiotics were now available in 8 and 9 steps respectively. However, although this route was
both straightforward and scalable, it did have the disadvantage of being quite linear, lengthy and
inflexible if a range of different aminonaphthoquinones needed to be rapidly prepared.
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Given our interest in the DielsꢀAlder reaction of aminobenzoquinones for the preparation of
2
2,30
building blocks for the synthesis of aminonaphthoquinoneꢀcontaining natural products,
we
speculated that a more direct approach to this type of system would be possible. However, this
would require the use of a Danishefskyꢀtype diene bearing an ester and, at the outset of these
studies, no diene in this class containing an electron withdrawing group had been reported.
Fortunately, Nazarovꢀtype ester 33 has already be described in the literature, and provided a
convenient starting point to launch an investigation into the synthesis of such dienes (Scheme 8).
Initially, ester 33 was synthesized by reaction of the dianion of ethyl hydrogen malonate, formed
using a slight excess of isopropylmagnesium chloride, with methacryloyl chloride, followed by
3
1
decarboxylation. However, upon scaleꢀup of this route, the slightly lower yielding procedure of
3
2
Miyata was employed, as this was more convenient and practical. With ester 33 in hand, a
range of three dienes bearing TMS, TBS and TIPS groups respectively was prepared so that their
reactivity could be compared. While this work was in progress, the related nitrileꢀcontaining
33
diene 37 was reported by Trauner, prepared in four steps from methyl methacrylate.
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7
8
9
0
Scheme 6. Preparation of ethyl 3ꢀsiloxypentaꢀ2,4ꢀdienoates 34, 35 and 36.
With a suitable range of dienes and protected aminobenzoquinones in hand, their union by Dielsꢀ
Alder reaction was now investigated. Initially, TIPS protected diene 34 was synthesized and
trialled, as several synthetic steps would have to be carried out after the DielsꢀAlder reaction and
a fairly robust protecting group would therefore be required. The results of reacting this diene
with the previously described protected aminobenzoquinones 38–40 are shown below (Scheme
7
). Due to the deactivating effect of the ester, and the steric barrier to adopting the reactive Sꢀcis
conformation imposed by the TIPS group, diene 34 proved to be quite unreactive, and the Dielsꢀ
Alder reaction therefore had to be carried out at elevated temperature. Thus, when diene 34 was
heated with benzoquinones 39 and 40 to 150 ºC in 1,2ꢀdichlorobenzene, the expected
naphthoquinone products 42 and 43 were obtained, albeit in low yield. The use of excess diene
or quinone did not improve the yields obtained, and no other byꢀproducts were isolated.
Although the reaction was successful with benzoylꢀ and acetylꢀprotected aminobenzoquinones
39 and 40, only traces of product were observed when Bocꢀprotected aminobenzoquinone 38 was
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employed, possibly due to the known thermal instability of this protecting group.
Next, the corresponding TBSꢀprotected diene 35 was studied, and found to undergo the Dielsꢀ
Alder reaction at a slightly lower temperature (130 ºC), although the yields of the reaction
remained moderate (Scheme 7). At this lower temperature, the Bocꢀprotected
aminobenzoquinone 38 could be used, and was found to perform considerably better than the
acetylꢀ and benzoylꢀprotected compounds, although this yield was not maintained upon scaleꢀup.
Thus, although the reaction gave the desired naphthoquinone in a reasonable 67% yield when
conducted on 70 mg (0.3 mmol) scale, when the reaction was run on gramꢀscale (4.5 mmol) the
yield decreased dramatically to 16%.
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45
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48
49
50
51
52
53
54
55
56
57
58
59
60
Finally, the TMSꢀprotected diene 36, readily synthesized by treatment of ester 33 with TMSCl
and LDA, was found to be very unstable, and difficult to even isolate and characterize. No Dielsꢀ
Alder products were observed from reactions of this diene with the above dienophiles at ambient
or elevated temperatures and the unreacted benzoquinones 38ꢀ40 could be recovered from the
reaction mixture.
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0
1
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3
4
5
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7
8
9
0
1
2
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7
8
9
0
Scheme 7. Initial DielsꢀAlder reactions of ethyl 3ꢀsiloxypentaꢀ2,4ꢀdienoates with
aminobenzoquinones.
Unfortunately, although 2D NMR experiments and previous studies on DielsꢀAlder reactions of
22,34
this type appeared to support the regiochemical assignments made above,
unambiguous proof
by Xꢀray crystallographic analysis was not possible, due to the oily/amorphous nature of the
naphthoquinone products. Therefore it was decided to access the previously described
napthoquinone 31 from the oxidative cyclization route described above (Scheme 5) using this
DielsꢀAlder methodology, in order to allow the regiochemistry of the DielsꢀAlder reaction to be
confirmed. In order to minimize the number of steps required to achieve this, diene 48, bearing a
MOMꢀprotecting group in place of the silyl protecting group previously employed, was
synthesized (Scheme 8). As far as we are aware this is only the second example of a MOMꢀ
35
protected Danishefskyꢀtype diene synthesized to date, and this protecting group appears to offer
an excellent, more atom efficient alternative to the silyl protecting groups commonly employed
in this role. The stability of MOMꢀprotected diene 48 appears to be similar to that of the TBS
protected diene 35 described above, and it could be purified by column chromatography and
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stored for several weeks after preparation. Again, a relatively high temperature (160 ºC) was
required for the DielsꢀAlder reaction with Bocꢀprotected aminobenzoquinone 38, and the yield
obtained was somewhat lower than that obtained for TBSꢀprotected diene 35. However, despite
this success, it was clear that removal of the Bocꢀprotecting group in 51 would not be possible
without disturbing the more sensitive MOM ether. Thus, two new aminobenzoquinones bearing
alloc and Cbz protecting groups (49 and 50 respectively; see Experimental Section for details)
were prepared, in the hope that these groups would prove to be orthogonal to the MOM ether.
Although the Cbzꢀprotected aminobenzoquinone 49 only gave traces of the desired
aminonaphthoquinone product 52 in the DielsꢀAlder reaction, accompanied by extensive
degradation of both starting materials, the allocꢀprotected quinone 50 fared better, giving
naphthoquinone 52 in 47% yield.
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35
36
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38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Interception of a previous intermediate.
Cleavage of the allyloxycarbamate to reveal the aminonaphthoquinone 31 without affecting the
sensitive MOM ether was carried out by stirring with a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) and excess dimedone at room temperature in THF
(
Scheme 9). Comparison of spectroscopic data for material prepared via this DielsꢀAlder route
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with that recorded for 31 prepared by the unambiguous route above (Scheme 5) allowed us to
conclude that we had been correct in our assignment of the structures of the DielsꢀAlder adducts.
Furthermore, we have demonstrated that the use of an allocꢀprotected aminobenzoquinone 50 in
the DielsꢀAlder reaction is useful in the preparation of aminonaphthoquinone systems where the
amine must be unmasked without disturbing acid and base sensitive functional groups, and the
use of such orthogonally protected naphthoquinones could find future use in natural products
synthesis.
0
1
2
3
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9
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 9. Deprotection of naphthoquinone 54 and completion of 31 by DielsꢀAlder route.
With esters such as 44ꢀ46 now in hand, attempts were made to convert the ester into the
corresponding aldehyde, as this would provide a more suitable handle for attachment of the ansa
chain. Although the presence of the naphthoquinone moiety precluded reduction directly to the
aldehyde, it was hoped that the use of excess reducing agent (e.g. lithium borohydride or lithium
aluminum hydride) would allow reduction of the quinone and the ester. It was anticipated that the
hydroquinone would reoxidize rapidly upon workꢀup and then a simple oxidation of the benzylic
alcohol would be required to obtain the desired aldehyde. Unfortunately, manipulation of the
ester could not be carried out without a separate step to reduce and protect the quinone. In
addition, amide formation at aminonaphthoquinones has been shown to be challenging, due to
the comparatively low reactivity of the amino group stemming from delocalization of the
nitrogen lone pair into the quinone system. Hence, temporary reduction of the
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aminonaphthoquinone to facilitate coupling at this position is a common sight in the total
synthesis of natural products containing this core, and thus performing this step early, to enable
manipulation of the ester, would likely not lengthen the overall synthetic sequence.
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48
49
50
51
52
53
54
55
56
57
58
59
60
From these initial studies it became apparent that the inclusion of an electronꢀwithdrawing group
in Danishefskyꢀtype dienes has a deleterious effect on their reactivity and restricts their use in
synthesis due to the low yields and poor scalability of the reactions. All efforts to include an
additional activating group such as the second alkoxy group in Trauner’s diene 37 were met with
failure, and so a different approach was taken. A number of alternative dienes were considered,
containing a latent carbonyl group in place of the esters used above and a new diene 57,
containing an allyl group, was synthesized (Scheme 10). The route began from known ester 55,
readily prepared in a twoꢀstep oneꢀpot transformation from butanone, and the required allyl
group was introduced by alkylation with LDA and allyl iodide in the presence of DMPU.
Treatment of the allylated product with LDA and TESCl as before gave triene 57 whose
reactivity in the DielsꢀAlder reaction was then investigated. Gratifyingly, 57 was far more
reactive than the dienes described above, undergoing a DielsꢀAlder reaction with
aminobenzoquinone 38 at room temperature in just two hours. Aromatization by stirring with
silica gel was also rapid, and aminonaphthoquinone 58 was obtained in almost quantitative yield.
Unfortunately, the major product from the DielsꢀAlder reaction lacked the TES protecting group,
which was invariably lost during the aromatization step. Surprisingly, when the corresponding
TBS protected diene was prepared and subjected to the DielsꢀAlder reaction, the unprotected
naphthol 58 was again the major product. Despite the loss of the protecting group during
aromatization, an efficient route to allylnaphthoquinone 58 had been developed which could
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easily be used to produce gramꢀquantities of this material, and methods were now investigated
for functionalization of the allyl chain.
0
1
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9
0
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0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 10. DielsꢀAlder reaction of triene 57.
Unexpectedly, isomerization of the allyl group to the corresponding propꢀ1ꢀenyl group proved
challenging under a range of rutheniumꢀ and rhodiumꢀmediated conditions. A possible reason for
the failure of these methods could be the presence of the quinone in 58, which may serve to
intercept the metal hydride intermediates through which such transformations are believed to
3
6
proceed. Indeed, the addition of small amount of benzoquinone to metathesis reactions using
3
7
Grubbs’ ruthenium based catalysts is a wellꢀknown tactic to avoid unwanted isomerization.
After some experimentation it was found that bis(acetonitrile)dichloropalladium(II) in boiling
dichloromethane did effect isomerization to the desired naphthoquinone 59, although the yield
was modest (Scheme 13). To our surprise, isomerization on protected derivatives of 58 under
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these conditions failed completely. Oxidative cleavage using both ozone and LemieuxꢀJohnsonꢀ
type conditions on 59 was unsuccessful, and reaction mixtures subjected to these conditions
rapidly decolorized, suggesting that oxidation was instead occurring at the quinone olefin.
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48
49
50
51
52
53
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57
58
59
60
O
O
Me
HO
NHBoc
Me
HO
NHBoc
PdCl (MeCN) ,
2
2
CH Cl , , 63%
2
2
O
O
Me
59
58
THF-H O
2
NaBH4,
CeCl •H O
then KOH,
3
2
Me SO , 93%
2
4
OMe
OMe
OMe
Me
NHBoc
Me
NHBoc
KOt-Bu,
THF, 84%
MeO
MeO
OMe
Me
60
6
1
OsO , NMO, then NaIO ,
acetone-H O THF-H O,
4
4
2
2
58%
OMe
Me
NHBoc
MeO
OHC
OMe
6
2
Scheme 11. Isomerization of allylnaphthoquinone 58.
In light of these difficulties, it was finally decided that in order to manipulate the allyl group and
thence connect the ansa chain, that reduction of the quinone would be required. Thus,
allylnaphthoquinone 58 was reduced and trimethylated by exposure to Luche conditions,
followed by treatment with potassium hydroxide and dimethyl sulfate to give naphthalene 60 in
3
3
excellent yield. Surprisingly, the isomerization step remained challenging, as allyl naphthalene
60 was now completely unreactive towards the palladiumꢀbased conditions described above,
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6
presumably due to the decreased acidity of the benzylic protons. However, it was found that
isomerization of 60 to 61 could be carried out in excellent yield by simply heating with four
equivalents of potassium tertꢀbutoxide in THF. The use of fewer equivalents resulted in poor
conversion and inseparable mixtures of product and starting materials. Ozonolysis of 61 resulted
in a complex mixture of aldehydes that was difficult to purify, but a twoꢀstep protocol consisting
of Upjohn dihydroxylation followed by oxidative cleavage of the resulting crude diol with
sodium periodate did provide the desired aldehyde 62 in reasonable yield.
0
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0
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0
Conclusion
In conclusion, two routes suitable for the preparation of building blocks applicable to the
synthesis of the aminonaphthoquinone antibiotics have been described. The first, based on the
oxidative radical cyclization methodology developed by Rickards, is highly scalable and allows
for manipulation of the naphthoate ester (to introduce the ansa chain) before oxidation to the
quinone has been carried out, obviating the need for a reduction and protection sequence later on.
Second, a number of DielsꢀAlder approaches were investigated, leading to the development of a
more concise route to a naphthaldehyde precursor, ready for the attachment of the ansa chain.
Additionally, the synthesis of two new aminobenzoquinone dienophiles, bearing Cbz and alloc
protecting groups, and their use in DielsꢀAlder reactions was described. The ability to remove
these amine protecting groups under mild and specific conditions without unmasking other
functionality in the rest of the molecule may prove useful in the syntheses of these compounds.
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Experimental
Commercially available reagents were used throughout without purification unless otherwise
stated. Anhydrous solvents were used as supplied unless otherwise stated. Tetrahydrofuran was
distilled from sodium benzophenone ketyl under a nitrogen atmosphere. Toluene was dried by
passage through activated alumina. Dichloromethane was distilled from calcium hydride under a
nitrogen atmosphere. Light petroleum refers to the fraction with bp 40 – 60 °C. Ether refers to
diethyl ether. Reactions were routinely carried out under a nitrogen or argon atmosphere.
Analytical thin layer chromatography was carried out on aluminum backed plates coated with
silica gel, and visualized under UV light at 254 and/or 360 nm and/or potassium permanganate or
ethanolic vanillin dip. Chromatography was carried out on silica gel. Fully characterized
compounds were chromatographically homogeneous. Infrared spectra were recorded in the range
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29
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33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1
4
000 – 600 cm as solutions in chloroform, as Nujol mulls or as a solid in attenuated total
reflectance (ATR) mode. NMR spectra were recorded NMR spectra were recorded at the
frequencies stated. Chemical shifts are quoted in ppm and J values in Hz. Chemical shift values
1
3
are referenced against residual proton in the deuterated solvents. In the C NMR spectra, signals
corresponding to CH, CH , or CH are assigned from DEPT spectra; all others are quaternary C.
2
3
High resolution mass spectra were recorded on an ESI timeꢀofꢀflight spectrometer wit
electrospray ionization.
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2
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Methyl 3-amino-5-hydroxybenzoate
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9
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0
3,5ꢀDihydroxybenzoic acid (6.0 g, 39.0 mmol), ammonium chloride (5.1 g, 97.0 mmol) and
aqueous ammonia solution (28%; 18.0 mL) were heated in a steel bomb at 180 °C for 40 h. The
reaction mixture was allowed to cool to rt, taken up in methanol and evaporated to dryness. The
dry residue was then taken up in methanol (300 mL), treated dropwise with concentrated sulfuric
acid (9.0 mL) and heated at reflux for 36 h. The reaction mixture was cooled to rt, concentrated,
and the residue taken up in cold water (150 mL). The aqueous phase was then extracted with
ether (3 × 100 mL) and the combined organic layers washed with sulfuric acid (1 M; 200 mL),
brine (200 mL), dried (MgSO ) and concentrated to give the byꢀproduct methyl 3,5ꢀ
4
dihydroxybenzoate. The acidic aqueous washings were combined and adjusted to pH 7 by
addition of solid NaHCO , then extracted with ethyl acetate (6 × 200 mL). The combined organic
3
extracts were washed with brine (200 mL), dried (MgSO ) and concentrated in vacuo. The
4
residual red oil was purified by flash column chromatography on silica gel, eluting with ethyl
acetate – dichloromethane (1:4 – 2:3) to give the title compound as a pale yellow oil that
3
8
crystallized on standing (3.81 g, 59%); mp 123 – 125 °C (lit., mp 125–127 °C); (Found: [M –
+
–
ꢀ1
H ], 166.0509. C H NO requires 166.0499); ν
(ATR)/cm 3402, 3319, 1706, 1600, 1362,
max
8
8
3
1
346, 1302, 1253, 1183, 1004, 766; δ (400 MHz; CD OD) 6.89 (1H, t, J 2.0), 6.79 (1H, t, J
H
3
2
.0), 6.41 (1H, t, J 2.0), 3.84 (3H, s); δ (100 MHz; CD OD) 169.2 (C), 159.4 (C), 150.5 (C),
C
3
132.9 (C), 109.2 (CH), 107.8 (CH), 107.1 (CH), 52.5 (Me).
3
8
Data were consistent with those found in the literature.
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Methyl 3-acetylamino-5-hydroxybenzoate
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50
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58
59
60
Acetic anhydride (1.41 mL, 15.0 mmol) was added dropwise to methyl 3ꢀaminoꢀ5ꢀ
hydroxybenzoate (2.50 g, 15.0 mmol) in dry pyridine (6.0 mL) at 0 °C. The reaction mixture was
warmed to rt and poured into hydrochloric acid (1 M; 50 mL). The layers were separated, the
aqueous phase was extracted with ethyl acetate (3 × 50 mL) and the combined organic phases
were washed with saturated aqueous NaHCO (50 mL) and brine (50 mL), dried (MgSO ), and
3
4
concentrated. The resultant cream solid was heated in ethyl acetate (50 mL) and methanol (10
mL) and the solution was cooled and filtered to give the title compound as a colorless powder
3
9
+
(2.936 g, 76 %); mp 227 – 229 °C; (lit., mp 230 – 232 °C); (Found: [M – H ], 208.0611.
–
4
ꢀ1
C H NO requires 208.0604); ν
(ATR)/cm 3364, 3112, 1712, 1653, 1599, 1478, 1433,
max
10
10
1320, 1244, 1020, 873, 766; δ (400 MHz; CD OD) 8.27 (1H, s), 8.07 (1H, s), 7.81 (1H, s), 4.53
H
3
(
3H, s), 2.77 (3H, s); δ (100 MHz; CD OD) 171.8 (C), 168.3 (C), 159.2 (C), 141.3 (C), 132.7
C
3
(C), 113.2 (CH), 112.8 (CH), 112.7 (CH), 52.7 (Me), 23.9 (Me).
3
9
The data obtained matched those previously reported.
Methyl 3-acetylamino-5-benzyloxybenzoate
Benzyl bromide (301 ꢀL, 2.53 mmol) was added to methyl 3ꢀacetylaminoꢀ5ꢀhydroxybenzoate
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
530 mg, 2.53 mmol) and K CO (699 mg, 5.06 mmol) in acetone (50 mL) and the reaction
2 3
mixture was heated to reflux and stirred for 16 h. The resulting solution was cooled to rt,
concentrated, and the residue was taken up in water (30 mL) and ethyl acetate (30 mL). The
aqueous phase was extracted with ethyl acetate (3 × 25 mL) and the combined organic extracts
were washed with water (50 mL), dried (Na SO ) and concentrated in vacuo. The residue was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
purified by flash column chromatography on silica gel, eluting with ethyl acetate –
dichloromethane (1:4) to give the title compound as a colorless oil that solidified on standing
+
+
(
614 mg, 81%); mp 121 – 123 °C; (Found: [M + H ], 300.1226. C H NO requires 300.1230);
1
7
18
4
ꢀ1
νmax (ATR)/cm 3272, 2997, 1714, 1652, 1531, 1348, 1304, 1232, 1171, 764; δ (400 MHz;
H
CDCl ) 7.75 (1H, s), 7.57 (1H, s), 7.43 – 7.32 (6H, m), 5.06 (2H, s), 3.88 (3H, s), 2.16 (3H, s);
3
δ (100 MHz; CDCl ) 169.2 (C), 166.9 (C), 159.2 (C), 139.5 (C), 136.4 (C), 131.4 (C), 128.6
C
3
(CH), 128.1 (CH), 127.6 (CH), 113.3 (CH), 111.3 (CH), 111.1 (CH), 70.2 (CH ), 52.3 (Me), 24.3
2
(Me).
3
-Benzyloxy-5-hydroxymethylacetanilide
Lithium aluminum hydride (38 mg, 1.00 mmol) in THF (1.0 mL) was added to methyl 3ꢀ
acetylaminoꢀ5ꢀbenzyloxybenzoate (300 mg, 1.00 mmol) in THF (2.5 mL) at 0 ºC. The reaction
mixture was stirred at 0 °C for 20 min, warmed to rt, diluted with THF (10 mL) and quenched by
®
careful addition of water (0.3 mL). The reaction mixture was filtered through a pad of Celite ,
washing with ethyl acetate (3 × 30 mL). The filtrate was concentrated in vacuo to give the title
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9
compound as a colorless oil that solidified on standing and did not require further purification
+
+
(269 mg, 99%); mp 146 – 147 °C; (Found: [M + H ], 272.1282. C H NO requires 272.1281);
1
6
18
3
ꢀ1
νmax (ATR)/cm 3298, 3116, 2858, 1665, 1612, 1564, 1438, 1283, 1164, 1031, 741; δ (400
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz; CD OD) 7.45 – 7.44 (2H, m), 7.40 – 7.38 (2H, m), 7.33 – 7.29 (1H, m), 7.27 (1H, t, J 2.0),
3
7
.10 (1H, s), 6.78 (1H, s), 5.08 (2H, s), 4.56 (2H, s), 2.12 (3H, s); δ (100 MHz; CD OD) 171.7
C
3
(C), 160.7 (C), 144.8 (C), 141.0 (C), 138.7 (C), 129.5 (CH), 128.9 (CH), 128.6 (CH), 112.0
(CH), 110.0 (CH), 106.8 (CH), 71.0 (CH ), 65.0 (CH ), 23.9 (Me).
2
2
Methyl 5-(3-acetylamino-5-benzyloxy-phenyl)-4-methyl-3-oxopentanoate 20
Phosphorus tribromide (77 ꢀL, 0.82 mmol) was added dropwise to a stirred solution of 3ꢀ
benzyloxyꢀ5ꢀhydroxymethylacetanilide (200 mg, 0.74 mmol) in dry 1,4ꢀdioxane (2.5 mL) at 40
°C. The reaction mixture was stirred at 40 °C for 1 h, cooled to rt and poured into saturated
aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was extracted with
ethyl acetate (3 × 10 mL) and the combined organic phases were dried (MgSO ), and
4
concentrated. The residue was purified by flash column chromatography on silica gel, eluting
with ethyl acetate – dichloromethane (1:19) to give 3ꢀbenzyloxyꢀ5ꢀbromomethylacetanilide 19 as
a pale yellow foam (188 mg, 76%) that was used directly without full characterization; (Found:
+
79
+
[
M + H ], 334.0430. C H BrNO2 requires 334.0437); δ (400 MHz; CDCl ) 7.46 – 7.43
16
17
H
3
(6H, m), 7.20 (1H, br. s), 7.10 (1H, s), 6.79 (1H, s), 5.08 (2H, s), 4.43 (2H, s), 2.19 (3H, s). 3ꢀ
Benzyloxyꢀ5ꢀbromomethylacetanilide 19 (156 mg, 0.47 mmol) in THF (2 mL) was treated with
sodium hydride (19 mg, 0.47 mmol) at 0 °C, stirred for 10 min at this temperature then added via
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1
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1
1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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4
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5
5
5
5
5
5
5
5
5
5
6
cannula to a freshly prepared solution of the dianion of methyl 3ꢀoxopentanoate at 0 °C. [The
dianion was prepared by the dropwise addition of methyl 3ꢀoxopentanoate (83 ꢁL, 0.66 mmol) to
a suspension of sodium hydride (26 mg, 0.66 mmol) in THF (1.5 mL) at 0 °C. The resulting
solution was warmed to rt, stirred for 10 min then reꢀcooled to 0 ºC. nꢀButyllithium (2.5 M
solution in hexanes; 264 ꢀL, 0.66 mmol) was added over 15 min and the yellow solution was
stirred at 0 °C for 45 min before use.] The reaction mixture was warmed to rt over 1.5 h and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
quenched with aqueous NaH PO solution (20%; 10 mL). The aqueous phase was extracted with
2
4
ethyl acetate (3 × 20 mL) and the combined organic extracts were washed with saturated aqueous
ammonium chloride solution (50 mL), dried (Na SO ) and concentrated. The residue was
2
4
purified by flash column chromatography on silica gel, eluting with ethyl acetate –
dichloromethane (1:4) to give title compound as a colorless oil (112 mg, 62%); (Found: [M +
+
+
ꢀ1
H ], 384.1805. C H NO requires 384.1806); νmax (CHCl )/cm 3436, 2929, 1746, 1713,
2
2
26
5
3
1
616, 1594, 1456, 1313, 1155, 1060, 868; δ (400 MHz; CDCl ) 7.46 – 7.32 (5H, m), 7.19 (1H,
H
3
s), 6.78 (1H, s), 6.55 (1H, s), 5.06 (2H, s), 3.71 (3H, s), 3.43 (1H, d, J 15.6), 3.37 (1H, d, J 15.6),
3.00 – 2.91 (2H, m), 2.59 – 2.52 (1H, m), 2.17 (3H, s), 1.13 (3H, d, J 6.4); δ (100 MHz; CDCl )
C
3
1
68.3 (C), 167.9 (C), 159.4 (C), 141.1 (C), 139.1 (C), 138.2 (C), 136.7 (C), 128.6 (CH), 128.0
(CH), 127.6 (CH), 112.6 (CH), 111.8 (CH), 104.4 (CH), 70.0 (CH ), 52.3 (Me), 48.4 (CH ), 48.1
2
2
(
CH), 38.9 (CH ), 24.8 (Me), 16.3 (Me).
2
Methyl 3-hydroxy-5-methoxybenzoate
Iodomethane (1.86 mL, 30.0 mmol) was added to methyl 3,5ꢀdihydroxybenzoate (5.04 g, 30.0
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mmol) and K CO (4.55 g, 33.0 mmol) in acetone (150 mL) at 0 °C. The reaction mixture was
2
3
warmed to rt, stirred for 15 h and filtered, washing with ethyl acetate (100 mL). The filtrate was
concentrated and the residue was purified by flash column chromatography on silica gel, eluting
with ethyl acetate – light petroleum (1:39 – 1:7) to give the title compound as a colorless
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
0
+
crystalline solid (2.11 g, 39%); mp 94 – 96 °C (lit., mp 93 – 95 °C); (Found: M , 182.0575.
+
ꢀ1
C H O requires 182.0574); νmax (CHCl )/cm 3593, 2952, 1720, 1602, 1493, 1456, 1347,
9
10
4
3
1323, 1277, 1147, 1104, 1057, 1005; δ (400 MHz; CDCl ) 7.22 (1H, d, J 1.2), 7.16 (1H, dd, J
H
3
2
.1, 1.2), 6.66 (1H, t, J 2.1), 3.93 (3H, s), 3.82 (3H, s); δ (100 MHz; CDCl ) 167.1 (C), 160.9
C
3
(C), 156.9 (C), 132.0 (C), 109.3 (CH), 107.1 (CH), 106.7 (CH), 55.6 (Me), 52.4 (Me).
40
The data obtained matched those found in the literature.
Methyl 3-benzyloxy-5-methoxybenzoate
Benzyl bromide (3.75 mL, 31.5 mmol) was added to methyl 3ꢀhydroxyꢀ5ꢀmethoxybenzoate
(
5.74 g, 31.5 mmol) and K CO (8.71 g, 63.0 mmol) in acetone (500 mL). The reaction mixture
2 3
was heated to reflux and stirred for 12 h then cooled and filtered, washing with ethyl acetate (100
mL). The filtrate was concentrated and the residue was purified by flash column chromatography
on silica gel, eluting with ethyl acetate – light petroleum (1:7) to give the title compound as a
+
+
4
colorless oil (8.50 g, 99%); (Found: [M + H ], 273.1137. C H O requires 273.1121); ν
16
17
max
ꢀ1
(
CHCl )/cm 2953, 1718, 1597, 1456, 1439, 1380, 1350, 1325, 1303, 1156, 1106, 1061; δ (400
3
H
MHz; CDCl ) 7.48 – 7.36 (5H, m), 7.33 (1H, dd, J 2.0, 1.2), 7.25 (1H, dd, J 2.0, 1.2), 6.76 (1H, t,
3
J 2.4), 5.10 (2H, s), 3.93 (3H, s), 3.83 (3H, s); δ (100 MHz; CDCl ) 166.8 (C), 160.7 (C), 159.8
C
3
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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4
4
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5
5
5
5
5
5
5
5
5
6
(
C), 136.6 (C), 132.1 (C), 128.7 (CH), 128.1 (CH), 127.6 (CH), 108.0 (CH), 107.5 (CH), 106.5
CH), 70.3 (CH ), 55.6 (Me), 52.3 (Me).
(
2
3
-Benzyloxy-5-methoxybenzyl alcohol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
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8
9
0
1
2
3
4
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6
7
8
9
0
Lithium aluminum hydride (1.14 g, 30.0 mmol) in THF (40 mL) was added to methyl 3ꢀ
benzyloxyꢀ5ꢀmethoxybenzoate (8.17 g, 30.0 mmol) in THF (120 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 20 min, rt for 1 h and then diluted with THF (50 mL). Water (2.0
mL) was carefully added, and the colorless suspension was stirred for 10 min then filtered
®
through Celite , washing with ethyl acetate (2 × 150 mL). The filtrate was concentrated to give
the title compound as a colorless oil that did not require further purification (7.0 g, 96%);
+
+
ꢀ1
(
Found: [M + Na ], 267.0999. C H NaO requires 267.0992); ν (CHCl )/cm 3607, 2941,
15
16
3
max
3
1597, 1456, 1381, 1349, 1321, 1296, 1156, 1066; δ (400 MHz; CDCl ) 7.46 – 7.35 (5H, m),
H
3
6
.63 (1H, s), 6.56 (1H, s), 6.50 (1H, t, J 2.2), 5.06 (2H, s), 4.64 (2H, d, J 5.2), 3.80 (3H, s); δC
(100 MHz; CDCl ) 161.0 (C), 160.2 (C), 143.5 (C), 136.9 (C), 128.6 (CH), 128.0 (CH), 127.6
3
(CH), 105.4 (CH), 104.9 (CH), 100.5 (CH), 70.1 (CH ), 65.3 (CH ), 55.4 (Me).
2 2
2
8
Data obtained matched those previously reported.
3
-Benzyloxy-5-methoxybenzyl bromide 21
Phosphorus tribromide (1.28 mL, 13.6 mmol) was added to 3ꢀbenzyloxyꢀ5ꢀmethoxybenzyl
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alcohol (3.0 g, 12.3 mmol) in 1,4ꢀdioxane (30 mL) and the resulting solution was stirred at 40 °C
for 1 h, cooled to rt and poured into saturated aqueous sodium hydrogen carbonate solution (100
mL). Solid NaHCO was added until the mixture was neutralized, and the aqueous phase was
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were dried (Na SO )
2
4
and concentrated to give the title compound as a colorless oil that solidified on standing and did
+
not require further purification (3.04 g, 81%); mp 52 – 53 °C; (Found: M , 306.0255.
79
+
ꢀ1
C H BrO requires 306.0250); ν (CHCl )/cm 1597, 1456, 1381, 1348, 1324, 1297, 1155,
15
15
2
max
3
1
5
1
062; δ (400 MHz; CDCl ) 7.47 – 7.37 (5H, m), 6.66 (1H, s), 6.59 (1H, s), 6.51 (1H, t, J 2.2),
H
3
.07 (2H, s), 4.45 (2H, s), 3.81 (3H, s); δ (100 MHz; CDCl ) 160.9 (C), 160.1 (C), 139.8 (C),
C
3
36.7 (C), 128.4 (CH), 128.1 (CH), 127.6 (CH), 107.8 (CH), 107.4 (CH), 101.4 (CH), 70.2
(
CH ), 55.4 (Me), 33.6 (CH ).
2 2
1
13
29
H and C NMR data obtained matched those previously reported.
Methyl 5-(3-benzyloxy-5-methoxyphenyl)-4-methyl-3-oxopentanoate 22
3ꢀBenzyloxyꢀ5ꢀmethoxybenzyl bromide 21 (1.45 g, 4.72 mmol) in THF (25 mL) was added via
cannula to a freshly prepared solution of the dianion of methyl 3ꢀoxopentanoate at 0 °C. [The
dianion was prepared by the dropwise addition of methyl 3ꢀoxopentanoate (830 ꢁL, 6.61 mmol)
to a suspension of sodium hydride (264 mg, 6.61 mmol) in THF (40 mL) at 0 °C. The resulting
solution was warmed to rt, stirred for 10 min then reꢀcooled to 0 ºC. nꢀButyllithium (2.1 M
solution in hexanes; 3.15 mL, 6.61 mmol) was added over 15 min and the yellow solution was
stirred at 0 °C for 45 min before use.] The reaction mixture was warmed to rt over 1.5 h and
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