Studies on the total synthesis of lactonamycin: Synthesis of the fused pentacyclic B-F ring unit

Article abstract of DOI:10.1002/ejoc.201101317

This paper describes an approach towards the total synthesis of lactonamycin with the elaboration of a key pentacyclic unit. Key steps include the synthesis of benzyl bromide 8 in eight steps and 23 % overall yield starting from 4-methoxyphenol; a high-yi

Full text of DOI:10.1002/ejoc.201101317

FULL PAPER
DOI: 10.1002/ejoc.201101317
Studies on the Total Synthesis of Lactonamycin: Synthesis of the Fused
Pentacyclic B–F Ring Unit
Sylvain A. Jacques,[a] Simon Michaelis,[a] Björn Gebhardt,[a] Andreas Blum,[a]
Nathalie Lebrasseur,[a] Igor Larrosa,[a] Andrew J. P. White,[a] and Anthony G. M. Barrett*[a]
Keywords: Natural products / Total synthesis / Cross-coupling / Fused-ring systems / Oxidation
This paper describes an approach towards the total synthesis
of lactonamycin with the elaboration of a key pentacyclic
unit. Key steps include the synthesis of benzyl bromide 8 in
eight steps and 23% overall yield starting from 4-meth-
oxyphenol; a high-yielding Suzuki coupling between boronic
ester 9 and benzyl bromide 8; and a Lewis acid mediated,
intramolecular Friedel–Crafts acylation to obtain the fused
BCDEF ring core.
Introduction
Lactonamycin (1)[1] and the more recently isolated lac-
tonamycin-Z (2)[2] possess unique structural architectures
and intriguing biological activities. The novel, highly func-
tionalized hexacyclic aglycon core, known as lactonamyci-
none (3), contains, in the western half, a highly oxygenated
fused perhydrofuranfuranone ring functionalized by a labile
tertiary methoxy group, and in the eastern half, a naph-
tha[e]isoindole ring system. Both natural products contain
a 2-deoxysugar unit (1, α-l-rhodinopyranose; 2, α-l-2,6-di-
deoxyribopyranose) attached through a tertiary α-keto gly-
cosidic linkage (Figure 1). Biological evaluation of lactona-
mycin (1) against Gram-positive bacteria showed significant
levels of antimicrobial activity.[3] Remarkably, it was espe-
cially active against clinically isolated methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus (VRE). In addition, lactonamycin (1) showed
significant levels of cytotoxicity against various tumor cell
lines.[3]
The interesting biological properties combined with the
challenging structure of lactonamycin (1) have generated
considerable interest in the total synthesis of this complex
and fascinating molecule. So far, six groups have reported
synthetic studies directed towards the total synthesis of lac-
tonamycin (1). Danishefsky and Cox were the first to report
two routes towards the construction of the model ABCD
ring system by using an oxidative dearomatization reac-
tion[4] and a diastereoselective dihydroxylation reaction.[5]
Danishefsky et al. also completed the diastereoselective syn-
thesis of aglycon core 3 by using a Diels–Alder cycload-
Figure 1. Structures of lactonamycin (1), lactonamycin-Z (2), and
lactonamycinone (3).
dition reaction.[6] Deville and Behar reported the synthesis
of the model ABCD ring system by using a tandem conju-
gate cyanide addition/Dieckmann condensation.[7] Kelly et
al. reported a short synthesis of the model CDEF ring sys-
tem by using a Diels–Alder reaction and an asymmetric
synthesis of the model AB ring system.[8a,8b] Parsons et al.
reported the synthesis of the model CDEF ring system by
using an elegant cascade cyclization reaction.[9] Recently,
Saikawa and Nakata published the synthesis of the model
BCDEF ring system by using a palladium-catalyzed cycliza-
tion/methoxy carbonylation.[10] In 2010, Tastuta et al. re-
ported the first total synthesis of lactonamycin (1) by using
a sequential intramolecular conjugate addition reaction, a
stereoselective glycosidation, and a Michael–Dieckmann-
type cyclization as key steps.[11] We reported the model
studies on the synthesis of the ABCD rings by using several
iterative Michael addition reactions and oxidations to con-
struct the oxygenated lactone entity.[12a] Of particular rele-
vance to the work presented here, two syntheses of the
CDEF ring system have also been reported. The first ap-
proach to such units was based on a Lewis acid mediated
[a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, England
Fax: +44-207-594-5805
E-mail: agm.barrett@imperial.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101317.
Eur. J. Org. Chem. 2012, 107–113
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A. G. M. Barrett et al.
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Scheme 1. Retrosynthetic approach to lactonamycin (1).
intramolecular Friedel–Crafts acylation and Negishi cou- stannane 13[15] in the presence of a Pd0 catalyst and copper
pling reaction,[12b] whereas the second approach was based iodide to yield alkene 14 (94%).[16] We first focused our
on benzyne–furan and maleimide–furan cycloaddition reac- attention on a one-step approach to construct the B ring.
tions, Suzuki coupling, and electrophilic aromatic substitu- Treatment of silyl ether 14 with tetrabutylammonium fluo-
tions.[12c] Herein, we wish to report more recent studies ride at 0 °C followed by additional heating at 60 °C resulted
towards the synthesis of lactonamycin (1) by using a Suzuki in cleavage of both silyl ethers, and the desired intramolecu-
coupling reaction and Friedel–Crafts acylation as key steps. lar Michael addition reaction occurred at the same time.
As we had previously been unsuccessful in our attempts Unfortunately, alcohol 16 was formed in a low 50% yield.
to construct the B ring with the CDEF ring system already Therefore, a two-step procedure was considered to close the
in place, we thought to synthesize lactonamycin (1) by using B ring. Firstly, both silyl ethers were cleaved by using HCl
a precursor initially containing the BC ring system. Retro-
synthetically, we considered that 1 could be obtained from
aglycon core 4 after glycosidation and cleavage of the pro-
tecting groups (Scheme 1). On the basis of previous results,
which showed that the tertiary methoxy group was difficult
to introduce, we sought to install it through electrodecar-
boxylation of acid 5, which could in turn be obtained from
pentacycle 6 after dihydroxylation and lactonization. Penta-
cycle 6 could be obtained from carboxylic acid 7 by Frie-
del–Crafts acylation, protection of the resulting phenol, and
subsequent selective oxidation of the C ring. Finally, acid 7
should be available from boronic ester 9 and benzyl brom-
ide 8 through Suzuki coupling followed by selective saponi-
fication. We also considered that boronic ester 9 should be
available from known triflate 17, whereas benzyl bromide 8
should be available from 4-methoxyphenol.
Results and Discussion
Bromide 8 was synthesized on a multigram scale from
commercially available 4-methoxyphenol (10, Scheme 2).
Double hydroxymethylation with formaldehyde in the pres-
ence of calcium oxide[13] followed by selective phenolic
methylation gave diol 11 (70%). AgI-assisted monoiodin-
ation[14] and protection by tert-butyldimethylsilylation gave
iodide 12 (82%), which was coupled with freshly prepared Scheme 2. Synthesis of bromide 8.
108
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Studies on the Total Synthesis of Lactonamycin
at 0 °C to produce diol 15, which was converted into the In a similar manner, when methyl ester 20 was allowed to
corresponding benzofuran derivative 16 by reaction with react with an excess amount of Me3SnOH in 1,2-DCE at
NaH at high dilution. Finally, bromide 8 was obtained by 80 °C,[20] no conversion was observed even after prolonged
using a classical Appel reaction.[17] Starting from commer- reaction times. Reaction of methyl ester with Ba(OH)2 in
cially available 4-methoxyphenol, benzyl bromide 8 was an aqueous THF and MeOH resulted in no conversion,
successfully obtained on a multigram scale in eight steps whereas reaction in pure MeOH gave mostly highly polar
with an overall yield of 23%.
side products. Finally, we found that saponification with the
With known triflate 17[12b] in hand, we first thought to use of LiOH in aqueous MeOH gave required acid 7, which
obtain coupled product 20 from the corresponding or- was used without further purification in the next step. On
ganozinc compounds derived from bromide 8.[12c] Unfortu- the basis of previous results within the group,[12b] acid 7
nately, none of the conditions tested proved to be success- was allowed to react with the Ghosez reagent (1-chloro-
ful. Dissatisfied by these results, we decided to investigate N,N,2-trimethyl-1-propyleneamine)[21] and zinc chloride to
alternative Stille coupling reactions. At this stage, it was form pentacycle 13 in 75% yield after acetate protection.
planned to convert triflate 17 into the corresponding stan- The structure of pentacycle 22 (Scheme 4) was further con-
nane 18, which, with further Stille coupling with bromide firmed by X-ray crystallographic analysis.[22]
8, should lead to ester 20 (Scheme 3). Triflate 17 was sub-
jected to a variety of different stannylation reaction condi-
tions; however, none of these successfully afforded desired
stannane 18 and gave only an intractable mixture of alkyl-
ated and/or reduced products. Therefore, an alternative
strategy was investigated. It was envisaged that bromide 8
could be coupled with a boronic ester derived from triflate
17. Triflate 17 was smoothly converted into boronic ester
9 in one step by a Miyaura borylation reaction by using
pinacoldiborane (19, 86%).[18] It is of interest to note that
the success of this reaction was largely dependent on the
concentration of the reaction mixture (0.5 m). In contrast,
when the reaction was performed at lower concentration
the formation of the corresponding reduction product was
observed. With benzyl bromide 8 and boronic ester 9 in
hand, the Suzuki coupling was investigated. Extensive ex-
Scheme 4. Synthesis of pentacycle 22.
periments revealed that coupling product 20 could be iso-
lated in 76% yield on a gram-scale following reaction with
PdCl2(dppf) and K3PO4 at 80 °C in DME.
The synthesis was continued with an oxidative demethyl-
ation to afford quinone derivative 6 (Scheme 5). Previous
reported attempts for the oxidation on similar model sys-
tems showed that ceric ammonium nitrate (CAN) was an
excellent oxidation reagent for this transformation.[12b] As
a result, pentacycle 22 was allowed to react with an excess
amount of CAN at 0 °C. Surprisingly and contrary to Be-
gar’s studies,[23] an inseparable mixture of quinones 6/23
was obtained in a 1:5 ratio (Table 1, Entry 1). The ratio
could be reduced to 1:1.7 when the reaction was conducted
only at 0 °C, but undesirable quinone 23 was still obtained
as the major product (Table 1, Entry 2). Thus, this key oxi-
dative reaction was examined by using a variety of oxidative
agents (Table 1). Treatment of pentacycle 22 with iodo-
benzene bis-trifluoroacetate gave a complex mixture, and
quinones 6/23 could be isolated in a 1:10 ratio (Table 1, En-
try 3), whereas treatment with DDQ or silver(I) oxide
(Ag2O) resulted in little or no conversion after 12 h
(Table 1, Entries 4 and 5). Much to our delight, oxidation
of pentacycle 22 with an excess amount of silver(II) oxide
and concentrated nitric acid at room temperature favored
the formation of the desired quinone with quinones 6 and
Scheme 3. Synthesis of boronic ester 9 and Suzuki coupling with
bromide 8.
Unfortunately, selective monosaponification of the 23 being obtained in a 2.7:1 ratio (Table 1, Entry 6).[24]
methyl ester moiety in 20 proved to be problematic. Thus, Upon treatment under the same conditions at –10 °C, the
when methyl ester 20 was allowed to react with nPrSLi in ratio was further increased to 5:1 in favor of quinone 6
HMPA or DMF,[19] acid 7 was isolated in a poor 37% yield. (Table 1, Entry 7). Finally, the reaction was conducted at
Eur. J. Org. Chem. 2012, 107–113
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109

A. G. M. Barrett et al.
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–45 °C and only trace amounts of quinone 23 were de- Given the difficulties with the late-stage dihydroxylation re-
tected; pure quinone 6 was obtained in 60% yield (Table 1, action, alternative ABC ring coupling intermediates are
Entry 8).
currently being investigated.
Experimental Section
General Methods: All reactions were carried out in flame-dried or
oven-dried glassware under an atmosphere of dry N2 or Ar unless
otherwise stated. Prolonged periods of vessel cooling were attained
by the use of a CryoCool apparatus. All solvents and reagents were
obtained from commercial suppliers and used without further puri-
fication unless otherwise stated. The following reaction solvents
were distilled under an atmosphere of N2: Et2O and THF from Na/
benzophenone ketyl, PhMe from Na, CH2Cl2 and Et3N from
CaH2. MeOH was dried by heating at reflux over Mg turnings and
I2, followed by distillation from CaH2 under an atmosphere of N2.
Flash column chromatography was performed by using silica unless
otherwise stated. Melting points were measured with a Reichert-
Thermovar melting point apparatus. IR spectra were recorded with
a Mattson 5000 FTIR apparatus with automatic background sub-
traction. 1H NMR spectra were recorded at 400 MHz with a
Bruker DRX-300 or Bruker DRX-400 spectrometer or at 500 MHz
with a Bruker AM 500 spectrometer. 13C NMR spectra were re-
corded at 75 or 100 MHz with a Bruker DRX-300 or a Bruker
DRX-400 spectrometer, respectively, or at 125 MHz with a Bruker
AM 500 spectrometer.
Scheme 5. Selective oxidation of pentacycle 22.
Table 1. Selective oxidation of pentacycle 22.
Entry
Oxidant (equiv.)
T [°C]
Ratio 6/23
1
2
3
4
5
6
7
8
CAN (3.0)
CAN (3.0)
PhI(OCOCF3)2 (1.1)
DDQ (2.5)
0 to 23
0
0 to 23
23
–20
23
–20
–45
1:5
1:1.7
1:10
no reaction
no reaction
2.7:1
5:1
Ͼ99:1
Ag2O (3.0)
AgO (5.0), 4 n HNO3
AgO (5.0), 4 n HNO3
AgO (5.0), 4 n HNO3
Unfortunately, attempted dihydroxylation of quinone 6
under the conditions previously described by Danishefsky
(N-methylmorpholine N-oxide in the presence of 3.25 mol-
% OsO4)[5,6b] or by using stoichiometric quantities of OsO4
led to complete decomposition. Additionally, attempted di-
hydroxylation with ruthenium chloride and sodium per-
iodate[25] was also unsuccessful, despite being applied ear-
lier to other lactonamycin intermediates. Finally, attempted
dihydroxylation under Sharpless conditions[26] also failed
(Scheme 6). We suggest that the electron deficiency of the
double bond due to the enedione system in addition to the
possible steric hindrance of both tBu esters constitute a
challenge at the frontier of difficult dihydroxylations.
Synthesis of Benzyl Bromide 8 and Boronic Ester 9
(2,5-Dimethoxy-1,3-benzene)dimethanol (11): Finely ground p-
methoxyphenol (10; 31.0 g, 0.25 mol, 1.0 equiv.) was suspended in
H2O (200 mL), and the mixture was degassed by passing through
a stream of N2 for 30 min. Formalin (47 mL, 0.60 mol, 2.4 equiv.)
and CaO (7.0 g, 0.125 mol, 0.5 equiv.) were added at room tem-
perature, and the mixture was stirred for 5 d with the exclusion of
light. Glacial AcOH (20 mL) was added, and the mixture was
heated until most of the solid was dissolved. Charcoal (10 g) was
added, and the solution was filtered hot. The filtrate was cooled to
room temperature and placed in a freezer at –30 °C for 12 h. The
resulting mixture was warmed to room temperature and filtered to
give a white solid. The solid was subsequently washed with cold
water and dried under reduced pressure to give the triol (29.9 g,
65%) as a white solid. Rf = 0.32 (hexanes/EtOAc, 1:2). M.p. 126–
127 °C (EtOAc). IR (film): ν = 1731, 1611, 1483, 1314, 860,
˜
789 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.65 (s, 2 H,
Ar-H), 4.78 (s, 4 H, CH2), 3.75 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 153.0, 145.6, 136.2 (2 C), 111.6 (2
C), 63.6 (2 C), 55.8 ppm. MS (ESI): m/z = 184 [M]+. HRMS (ESI):
calcd. for C9H12O4 [M]+ 184.0732; found 184.0736. C9H12O4
(184.19): calcd. C 58.69, H 6.57; found C 58.63, H 6.52. The triol
(88.2 g, 0.479 mol, 1.0 equiv.) was dissolved in Me2CO (1.2 L) and
K2CO3 (79.4 g, 0.574 mol, 1.2 equiv.) and dimethyl sulfate
(49.8 mL, 0.527 mol, 1.1 equiv.) were added at room temperature,
and the mixture was heated to reflux for 4.5 h. The mixture was
allowed to cool to room temperature and was quenched by the
addition of a mixture of MeOH (200 mL) and saturated aqueous
NH3 (100 mL). The insoluble solid was filtered off and washed with
EtOAc (150 mL), and the filtrate was concentrated under reduced
pressure. The residue was dissolved in EtOAc (1 L) and saturated
aqueous NaHCO3 (300 mL) and H2O (100 mL) were added; the
aqueous layer was extracted with EtOAc (3ϫ150 mL). The com-
bined organic layers were washed with brine (200 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The
Scheme 6. Attempted dihydroxylation to form diol 24.
Conclusions
A zinc chloride mediated, intramolecular Friedel–Crafts
acylation of carboxylic acid 7 has been successfully used to
synthesize the lactonamycin BCDEF pentacycle 22.
Whereas CAN oxidation afforded an inseparable mixture
of quinones 6/23, the use of silver(II) oxide and concen-
trated nitric acid successfully provided desired quinone 6.
Of particular importance is the multigram synthesis of
benzyl bromide 8, which was coupled with boronic ester 9
in a high-yielding Suzuki coupling to form precursor 20. yellow residue was purified by crystallization (EtOAc/Et2O, 2:1) to
110 Eur. J. Org. Chem. 2012, 107–113
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Studies on the Total Synthesis of Lactonamycin
give diol 11 (66.8 g, 70%) as a white solid. Rf = 0.40 (EtOAc/hex-
7.4 Hz, 9 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 172.1,
anes, 4:1). M.p. 106–108 °C (EtOAc/hexane, 1:1). IR (film): ν = 166.6, 161.5, 135.0, 81.3, 81.0, 28.9 (3 C), 28.2 (3 C), 27.9 (3 C),
˜
3261, 3165, 1607, 1473, 1362, 1317, 1234, 1208, 1146, 1052, 997,
27.3 (3 C), 13.7 (3 C), 12.0 (3 C) ppm. MS (CI): m/z = 519 [M +
H]+, 536 [M + NH4]+. HRMS (CI): calcd. for C24H50NO4Sn [M +
NH4]+ 536.2762; found 536.2781. C24H46O4Sn (517.32): calcd. C
1
949, 850 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 6.87 (s, 2
H, Ar-H), 4.70 (s, 4 H, CH2), 3.79 (s, 3 H, OMe), 3.78 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 156.2, 149.4, 55.72, H 8.96; found C 55.63, H 8.86.
134.9 (2 C), 113.5 (2 C), 62.2, 60.9 (2 C), 55.6 ppm. MS (ESI): m/z
Di-tert-butyl 2-{2,4-Bis[(tert-butyldimethylsilyloxy)methyl]-3,6-di-
= 198 [M]+. HRMS (ESI): calcd. for C10H14O4 [M]+ 198.0892;
found 198. 0894. C10H14O4 (198.22): calcd. C 60.59, H 7.12; found
C 60.57, H 7.00.
methoxyphenyl}fumarate (14): Stannane 13 (85.5 g, 165 mmol,
1.2 equiv.), CuI (10.5 g, 55 mmol, 0.4 equiv.), and Pd(PPh3)4 (6.3 g,
5.4 mmol, 4 mol-%) were sequentially added to iodide 12 (76.0 g,
137.6 mmol, 1.0 equiv.) in PhMe (500 mL), and the mixture was
heated at 120 °C for 12 h. Because the crude 1H NMR spectrum
showed incomplete conversion, additional CuI (2.6 g, 13.8 mmol,
0.1 equiv.) and Pd(PPh3)4 (3.1 g, 2.7 mmol, 2 mol-%) were added,
and the reaction mixture was stirred for 12 h at 120 °C. Rotary
evaporation and double chromatography (hexanes/EtOAc, 50:1,
25:1, 10:1, followed by hexanes/EtOAc, 100:1, 50:1, 25:1, 10:1) gave
alkene 14 (84.1 g, 94%) as a yellow oil. Rf = 0.69 (hexanes/EtOAc,
(1,3-Di-tert-butyldimethylsilyloxymethyl)-4-iodo-2,5-dimethoxybenz-
ene (12): Diol 11 (9.9 g, 50 mmol, 1.0 equiv.) was dissolved in
CHCl3 (150 mL), and the resulting mixture was cooled to 0 °C.
Ag(O2CCF3) (19.9 g, 90 mmol, 1.8 equiv.) was added followed by
the immediate dropwise addition of I2 (13.9 g, 55 mmol, 1.1 equiv.)
in CHCl3 (300 mL). The mixture was stirred for 1 h at 0 °C. Be-
cause TLC showed incomplete conversion, additional Ag(O2CCF3)
(1.1 g, 49.7 mmol, 0.1 equiv.) and I2 (1.3 g, 5.1 mmol, 0.1 equiv.) in
CHCl3 (100 mL) were added, and the reaction mixture was stirred
at 0 °C for 1 h. The mixture was filtered through cotton and SiO2
and washed with CH2Cl2 and MeOH (25:1). The crude product
was purified by recrystallization (pentane/EtOAc, 1:1) to give 1,3-
bis(hydroxymethyl)-4-iodo-2,5-dimethoxybenzene (13.4 g, 82%) as
a white solid. Rf = 0.41 (CH2Cl2/MeOH, 10:1). M.p. 126–127 °C
10:1). IR (film): ν = 1711, 1462, 1368, 1252, 1155, 837, 777 cm–1.
˜
1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.01 (s, 1 H, Ar-H), 6.90
(s, 1 H, C=CH), 4.83 (d, J = 13.6 Hz, 1 H, CH2), 4.78 (d, J =
13.6 Hz, 1 H, CH2), 4.57 (d, J = 10.8 Hz, 1 H, CH2), 4.47 (d, J =
10.8 Hz, 1 H, CH2), 3.75 (s, 3 H, OMe), 3.74 (s, 3 H, OMe), 1.44
[s, 9 H, C(CH3)3], 1.17 [s, 9 H, C(CH3)3], 0.95 [s, 9 H, Si-C-
(CH3)3], 0.88 [s, 9 H, Si-C(CH3)3], 0.11 (s, 6 H, SiMe2), 0.05 (s, 6
H, Me2) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 165.2,
164.8, 152.9, 149.0, 140.5, 134.6, 131.7, 131.1, 124.8, 109.2, 81.4,
80.7, 62.7, 60.0, 57.6, 55.8, 27.9 (3 C), 27.6 (3 C), 26.1 (3 C), 25.9
(3 C), 18.6, 18.4, –5.3 (2 C), –5.5 (2 C) ppm. MS (CI): m/z = 653
[M + H]+. HRMS (CI): calcd. for C34H61O8Si2 [M + H]+ 653.3905;
found 653.3921. C34H60O8Si2 (653.02): calcd. C 62.54, H 9.26;
found C 62.47, H 9.18.
(pentane/EtOAc, 1:1). IR (film): ν = 3338, 1582, 1424, 1395, 1314,
˜
1227, 1080, 1007 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
6.89 (s, 1 H, Ar-H), 4.87 (s, 2 H, CH2), 4.74 (s, 2 H, CH2), 3.88 (s,
3 H, OMe), 3.84 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 154.9, 150.4, 137.7, 135.1, 110.4, 91.7, 64.1, 63.3, 60.7,
56.9 ppm. MS (CI): m/z = 342 [M + NH4]+. HRMS (CI): calcd.
for C10H17NIO4 [M + NH4]+ 342.0202; found 342.0199. C10H13IO4
(324.11): calcd. C 37.06, H 4.04; found C 36.94, H 4.07. 1,3-Bis(hy-
droxymethyl)-4-iodo-2,5-dimethoxybenzene (73.3 g, 226 mmol,
1.0 equiv.) was dissolved in CH2Cl2 (250 mL) and cooled to 0 °C.
Imidazole (68.1 g, 678 mmol, 3.0 equiv.) and tBuMe2SiCl (85.2 g,
565 mmol, 2.5 equiv.) were added in CH2Cl2 (250 mL), and the re-
sulting mixture was stirred at 0 °C for 2 h. Aqueous HCl (0.2 m,
300 mL) was added, and the aqueous layer was extracted with
CH2Cl2 (4ϫ100 mL). The combined organic layers were dried
(MgSO4), filtered, concentrated, and chromatographed (hexanes/
EtOAc, 200:1, 100:1, 50:1, 25:1) to give iodide 12 (120.3 g, 96%)
as a white solid. Rf = 0.69 (CH2Cl2/MeOH, 10:1). M.p. 38–40 °C
Di-tert-butyl 2-[2,4-Bis(hydroxymethyl)-3,6-dimethoxyphenyl]fumar-
ate (15): Concentrated HCl (40 mL, 476 mmol, 4.0 equiv.) was
added with stirring to silyl ether 14 (77.9 g, 119 mmol, 1.0 equiv.)
in THF (1 L) at 0 °C. After 3 h, saturated aqueous NaHCO3
(500 mL) was added, and the aqueous layer was extracted with
CH2Cl2 (3ϫ100 mL). The combined organic layers were dried
(MgSO4), filtered, concentrated, and chromatographed (hexanes/
EtOAc, 1:1) to give diol 15 (36.6 g, 86%) as a colorless oil. Rf =
0.23 (hexanes/EtOAc, 1:1). IR (film): ν = 3442, 1708, 1641, 1602,
˜
1461, 1369, 1251, 1153, 1070, 1010, 850, 769 cm–1. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 6.98 (s, 1 H, Ar-H), 6.92 (s, 1 H,
C=CH), 4.77 (s, 2 H, CH2), 4.53 (d, J = 11.6 Hz, 1 H, CH2), 4.42
(d, J = 11.2 Hz, 1 H, CH2), 3.89 (s, 3 H, OMe), 3.75 (s, 3 H, OMe),
1.46 [s, 9 H, C(CH3)3], 1.25 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 165.7, 165.2, 152.6, 150.2, 139.7,
134.8, 133.3, 131.8, 124.4, 110.3, 82.5, 82.0, 63.1, 61.1, 58.1, 55.9,
27.8 (3 C), 27.7 (3 C) ppm. MS (CI): m/z = 447 [M + Na]+. HRMS
(CI): calcd. for C22H32O8Na [M + Na]+ 447.1995; found 447.2000.
C22H32O8 (424.49): calcd. C 62.25, H 7.60; found C 62.22, H 7.56.
(pentane/Et O, 1:1). IR (film): ν = 1583, 1460, 1424, 1368, 1255,
˜
2
1109, 1075, 1007, 837, 776 cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.02 (s, 1 H, Ar-H), 4.84 (s, 2 H, CH2), 4.77 (s, 2 H,
CH2), 3.86 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 0.95 [s, 9 H, Si-
C(CH3)3], 0.93 [s, 9 H, Si-C(CH3)3], 0.19 (s, 6 H, SiMe2), 0.12 (s, 6
H, SiMe2) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 154.9,
149.6, 137.0, 135.6, 109.4, 91.7, 64.1, 63.0, 59.8, 56.7, 26.0 (3 C),
25.8 (3 C), 18.5, 18.3, –5.1 (2 C), –5.3 (2 C) ppm. MS (CI): m/z =
570 [M + NH4]+. HRMS (CI): calcd. for C22H44NIO4Si2 [M +
NH4]+ 570.1932; found 570.1942. C22H41IO4Si2 (552.64): calcd. C
47.81, H 7.48; found C 47.85, H 7.53.
tert-Butyl 1-[2-(tert-Butoxy)-2-oxoethyl]-5-(hydroxymethyl)-4,7-di-
Bu3SnH methoxy-1,3-dihydroisobenzofuran-1-carboxylate (16): NaH (3.1 g,
Di-tert-butyl
(13.1 mL, 48.6 mmol, 1.1 equiv.) was added dropwise with stirring
to solution of di-tert-butyl acetylenedicarboxylate (10.0 g,
2-(Tributylstannyl)fumarate
(13):[15]
77.7 mmol, 3.0 equiv.) was added with stirring to diol 15 (11.0 g,
25.9 mmol, 1.0 equiv.) in THF (1 L) at 0 °C. After 1 h, the reaction
a
44.2 mmol, 1.0 equiv.) in benzene (170 mL). at room temperature. was quenched by addition of H2O (200 mL), and the aqueous layer
After 3 h, rotary evaporation and chromatography (hexanes/ was extracted with CH2Cl2 (3ϫ150 mL). The combined organic
EtOAc, 200:1, 100:1, 50:1, 25:1) gave stannane 13 (22.8 g, 99%) as layers were dried (Na2SO4), filtered, concentrated, and chromato-
a colorless oil. R = 0.46 (hexanes/EtOAc, 10:1). IR (film): ν = graphed (hexanes/EtOAc, 1:1) to give benzofuran derivative 16
1704, 1458, 1368, 1322, 1247, 1154 cm–1. 1H NMR (400 MHz, (10.3 g, 94%) as a yellow solid. Rf = 0.24 (hexanes/EtOAc, 1:1).
CDCl3, 25 °C): δ = 6.66 (s, 1 H), 1.51–1.44 (m, 6 H), 1.49 (s, 9 H), M.p. 74–76 °C (Et O). IR (film): ν = 3442, 1735, 1637, 1486, 1465,
1.47 (s, 9 H), 1.34–1.25 (m, 6 H), 1.03–0.99 (m, 6 H), 0.87 (t, J = 1367, 1249, 1160, 1049, 846 cm–1. 1H NMR (400 MHz, CDCl3,
˜
f
˜
2
Eur. J. Org. Chem. 2012, 107–113
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
111

A. G. M. Barrett et al.
FULL PAPER
25 °C): δ = 6.78 (s, 1 H, Ar-H), 5.39 (d, J = 11.6 Hz, 1 H, CH2O),
5.25 (d, J = 12.0 Hz, 1 H, CH2O), 4.68 (s, 2 H, CH2), 3.80 (s, 3 H,
with stirring at 80 °C for 38 h. After cooling to room temperature,
the mixture was quenched with H2O (20 mL), and the aqueous
OMe), 3.75 (s, 3 H, OMe), 3.47 (d, J = 16 Hz, 1 H, CH2CO2tBu), layer was extracted with CH2Cl2 (4ϫ25 mL). The combined or-
2.94 (d, J = 16 Hz, 1 H, CH2CO2tBu), 1.38 [s, 9 H, C(CH3)3], 1.33 ganic layers were dried (MgSO4), filtered, concentrated, and chro-
[s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
170.1, 169.3, 150.2, 145.4, 134.0, 132.3, 128.1, 110.7, 88.6, 81.3,
80.2, 72.4, 61.1, 60.0, 55.6, 41.1, 27.9 (3 C), 27.7 (3 C) ppm. MS
matographed (EtOAc/MeOH, 100:1) to give methyl ester 20 (1.4 g,
76%) as a pale brown solid. Rf = 0.36 (EtOAc/MeOH, 10:1). M.p.
78–80 °C (Et O). IR (film): ν = 1686, 1596, 1487, 1366, 1249, 1154,
˜
2
(CI): m/z = 447 [M + Na]+. HRMS (CI): calcd. for C22H32O8Na 1054, 845 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.70 (s, 1
[M + Na]+ 447.1995; found 447.2003. C22H32O8 (424.49): calcd. C
62.25, H 7.60; found C 62.26, H 7.75.
H), 6.41 (s, 1 H), 5.37 (d, J = 12.0 Hz, 1 H), 5.21 (d, J = 12.0 Hz,
1 H), 4.51 (s, 2 H), 4.39 (s, 2 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.64
(s, 3 H), 3.63 (s, 3 H), 3.41 (d, J = 15.9 Hz, 1 H), 3.10 (s, 3 H),
2.91 (d, J = 15.9 Hz, 1 H), 1.34 (s, 9 H), 1.27 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 170.0, 169.2 (2 C), 166.3,
158.7, 150.1, 148.6, 146.5, 145.6, 133.7, 132.5, 126.9, 119.0, 117.2,
113.4, 111.9, 88.5, 81.1, 80.0, 72.4, 59.7, 55.9, 55.5, 53.3, 51.5, 40.9,
34.4, 28.9, 27.7 (3 C), 27.6 (3 C) ppm. MS (ESI): m/z = 641 [M]+,
642 [M + H]+. HRMS (ESI): calcd. for C34H44NO11 [M + H]+
642.2914; found 642.2913. C34H43NO11 (641.71): calcd. C 63.64, H
6.75, N 2.18; found C 63.63, H 6.73, N 2.19.
tert-Butyl 5-(Bromomethyl)-1-(2-tert-butyloxycarbonylmethyl)-4,7-
dimethoxy-1,3-dihydroisobenzofuran-1-carboxylate
(8):
PPh3
(12.4 g, 47.4 mmol, 2.0 equiv.) and CBr4 (15.7 g, 47.4 mmol,
2.0 equiv.) were added with stirring to alcohol 16 (10.1 g,
23.7 mmol, 1.0 equiv.) in DMF (100 mL) at room temperature. Af-
ter 4 h, the reaction was quenched by addition of H2O (200 mL)
followed by hexanes/EtOAc (1:1, 200 mL). The aqueous layer was
extracted with hexanes/EtOAc (1:1, 5ϫ50 mL), and the combined
organic layers were washed with H2O (3ϫ50 mL), dried (MgSO4),
filtered, concentrated, and chromatographed (hexanes/EtOAc, 5:1)
to give bromide 8 (9.8 g, 85%) as a white solid. Rf = 0.85 (CH2Cl2/
tert-Butyl 12-Acetoxy-10-(tert-butyloxycarbonylmethyl)-4,7,11-tri-
methoxy-2-methyl-3-oxo-2,3,8,10-tetrahydro-1H-furo[3Ј,4Ј:6,7]naph-
tho[2,3-e]isoindole-10-carboxylate (22): LiOH (689 mg, 28.8 mmol,
10.0 equiv.) was added with stirring to methyl ester 20 (1.8 g,
2.88 mmol, 1.0 equiv.) in MeOH/H2O (1:1, 100 mL) at room tem-
perature. After 48 h, the reaction was quenched with saturated
aqueous NH4Cl (100 mL), and the aqueous layer was acidified with
conc. HCl to pH 3 and extracted with CH2Cl2 (4ϫ150 mL). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated to give crude acid 7, which was used without any further
purification. Me2C=C(Cl)NMe2 (21; 1.52 mL, 11.4 mmol,
5.0 equiv.) was added with stirring to crude acid 7 (1.4 g, 2.3 mmol,
1.0 equiv.) in CH2Cl2 (25 mL) at room temperature. After 2 h, the
mixture was cooled to 0 °C and ZnCl2 (3.9 mL, 3.9 mmol,
1.7 equiv.) was added. After stirring for 2 h at 0 °C, DMAP
(13.9 mg, 114 μmol, 0.05 equiv.) was added followed by pyridine
(50 mL) and Ac2O (35 mL), and the resulting mixture was stirred
for 12 h. The reaction was quenched with saturated aqueous
NH4Cl (100 mL), and the aqueous layer was extracted with CH2Cl2
(3ϫ200 mL). The combined organic layers were dried (MgSO4),
filtered, concentrated, and chromatographed (hexanes/EtOAc, 5:1
to EtOAc/MeOH, 100:1, 50:1, 20:1). Recrystallization (EtOAc)
gave the lactonamycin BCDEF pentacycle 22 (1.4 g, 75% over two
steps) as bright yellow crystals. Rf = 0.47 (CH2Cl2/MeOH, 10:1).
MeOH, 10:1). M.p. 98–102 °C (pentane/Et O, 1:1). IR (film): ν =
˜
2
1734, 1491, 1416, 1367, 1249, 1160, 1056, 847, 757 cm–1. H NMR
1
(400 MHz, CDCl3, 25 °C): δ = 6.74 (s, 1 H, Ar-H), 5.38 (d, J =
12 Hz, 1 H, CH2O), 5.24 (d, J = 12 Hz, 1 H, CH2O), 4.56 (d, J =
10 Hz, 1 H, CH2Br), 4.51 (d, J = 9.6 Hz, 1 H, CH2Br), 3.82 (s, 3
H, OMe), 3.81 (s, 3 H, OMe), 3.40 (d, J = 16 Hz, 1 H,
CH2CO2tBu), 2.98 (d, J = 15.6 Hz, 1 H, CH2CO2tBu), 1.39 [s, 9
H, C(CH3)3], 1.31 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 169.8, 169.2, 150.2, 146.0, 133.0, 131.2, 129.7,
112.3, 88.8, 81.5, 80.3, 72.5, 60.1, 55.7, 41.1, 28.2, 27.9 (3 C), 27.8
(3 C) ppm. MS (EI): m/z = 509 [M{79Br} + Na]+, 511 [M{81Br} +
Na]+. HRMS (EI): calcd. for C22H3179BrO7Na, C22H3181BrO7Na
[M
+
Na]+ 509.1151, 511.1142; found 509.1151, 511.1142.
C22H31BrO7 (487.39): calcd. C 54.22, H 6.41; found C 54.29, H
6.46.
Methyl 7-Methoxy-2-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)isoindoline-4-carboxylate (9): Triflate 17 (6.4 g,
16.7 mmol, 1.0 equiv.), bis(pinacolato)diboron 19 (6.4 g,
25.0 mmol, 1.5 equiv.), Pd(dppf)Cl2 (341 mg, 418 μmol, 2.5 mol-
%), and NaOAc (4.1 g, 50.1 mmol, 3.0 equiv.) were added to freshly
degassed PhH (35 mL), and the reaction mixture was stirred for
13 h at 80 °C. After cooling to room temperature, the mixture was
filtered through silica (CH2Cl2/MeOH, 10:1). The filtrate was con-
centrated, and the residue was chromatographed (CH2Cl2/MeOH,
20:1, 10:1) to give boronic ester 9 (4.9 g, 86%) as an off-white solid.
Rf = 0.47 (CH2Cl2/MeOH, 10:1). M.p. 166–170 °C (pentane/Et2O,
M.p. 216–218 °C (EtOAc). IR (film): ν = 1773, 1729, 1687, 1620,
˜
1
1453, 1362, 1154, 1038 cm–1. H NMR (400 MHz, CDCl3, 25 °C):
δ = 8.58 (s, 1 H), 7.25 (s, 1 H), 5.61 (d, J = 12.4 Hz, 0.6 H, rot-
amer 2), 5.53 (d, J = 12.6 Hz, 0.4 H, rotamer 1), 5.48 (d, J =
12.6 Hz, 0.4 H, rotamer 1), 5.40 (d, J = 12.4 Hz, 0.6 H, rotamer 2),
5.03 (d, J = 18.4 Hz, 1 H), 4.61 (d, J = 18.7 Hz, 1 H), 4.07 (s, 3
H), 4.05 (s, 3 H), 3.88 (s, 1 H, rotamer 1), 3.79 (d, J = 16.2 Hz, 0.6
H, rotamer 2), 3.78 (s, 2 H, rotamer 2), 3.58 (d, J = 16.2 Hz, 0.4
H, rotamer 1), 3.26 (s, 3 H), 3.15 (d, J = 16.0 Hz, 0.4 H, rotamer 1),
3.05 (d, J = 16.0 Hz, 0.6 H, rotamer 2), 2.52 (br. s, 3 H), 1.45 (s, 6
H, rotamer 1), 1.37 (s, 3 H, rotamer 1), 1.34 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 170.9, 169.5, 169.1, 169.0,
168.3, 168.0, 166.8, 154.5, 144.8, 144.7, 144.4, 142.2, 141.8, 141.2,
1:1). IR (film): ν = 1681, 1580, 1442, 1361, 1300, 1247, 1143, 1051,
˜
845 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.93 (s, 1 H),
4.53 (s, 2 H), 4.02 (s, 3 H), 3.93 (s, 3 H), 3.15 (s, 3 H), 1.44 (s, 12
H) ppm.13C NMR (100 MHz, CDCl3, 25 °C): δ = 167.2, 166.5,
159.9, 145.3 (2 C), 121.3, 119.9, 113.6, 84.2 (2 C), 56.0, 52.9, 52.2,
29.1, 24.9 (4 C) ppm. MS (ESI): m/z = 362 [M + H]+. HRMS
(ESI): calcd. for C18H25BNO6 [M + H]+ 362.1758; found 362.1775.
Synthesis of Quinone 6
Methyl 5-[(1-tert-Butyloxycarbonylmethyl)-1-(tert-butoxycarbonyl)- 134.7, 131.2, 130.6, 130.5, 125.8, 124.4, 118.7, 118.5 118.4, 117.5,
4,7-dimethoxy-1,3-dihydroisobenzofuran-5-yl]methyl-7-methoxy-2-
methyl-1-oxoisoindoline-4-carboxylate (20): Boronic ester 9 (1.0 g,
2.76 mmol, 1.0 equiv.) and bromide 8 (1.5 g, 3.31 mmol, 1.2 equiv.)
were dissolved in DME (7 mL), and the solution was degassed with
Ar. Pd(dppf)Cl2 (56 mg, 69.0 μmol, 2.5 mol-%) and K3PO4 (1.8 g,
8.30 mmol, 3.0 equiv.) were added, and the mixture was heated
105.1, 87.9, 87.6, 82.2, 81.9, 80.9, 80.5, 71.6, 71.5, 63.3, 62.8, 60.1,
55.9, 53.6, 42.0, 41.2, 29.3, 27.9, 27.8, 27.6, 21.1 ppm (contains rot-
amers). MS (ESI): m/z = 652 [M + H]+. HRMS (ESI): calcd. for
C35H42NO11 [M + H]+ 652.2753; found 652.2748. C35H41NO11
(651.71): calcd. C 64.50, H 6.34, N 2.15; found C 64.59, H 6.39, N
2.23.
112
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 107–113

Studies on the Total Synthesis of Lactonamycin
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tert-Butyl 12-Acetoxy-10-(tert-butyloxycarbonylmethyl)-4-methoxy-
2-methyl-3,7,11-trioxo-2,3,7,8,10,11-hexahydro-1H-furo[3Ј,4Ј:6,7]-
naphtho[2,3-e]isoindole-10-carboxylate (6): Pentacycle 22 (150 mg,
0.23 mmol, 1.0 equiv.) was dissolved in PhMe (5 mL) and concen-
trated under reduced pressure. This process was repeated three
times. DME (10 mL) was added, and the reaction mixture was
cooled to –45 °C. AgO (85.5 mg, 0.69 mmol, 3.0 equiv.) was added,
and the resulting mixture was sonicated for 30 s, when aqueous
HNO3 (4 m; 600 μL) was added. The mixture was stirred for 10 min
at –45 °C. The mixture was poured into a separation funnel con-
taining precooled CH2Cl2 (5 mL) and H2O (5 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ20 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The crude product
was chromatographed (EtOAc/MeOH, 100:1, 50:1, 20:1) to give
quinone 6 (86.0 mg, 60%) as an orange solid. Rf = 0.47 (CH2Cl2/
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MeOH, 10:1). M.p. 108–110 °C (Et O). IR (film): ν = 1780, 1695,
˜
[12] a) D. A. Henderson, P. N. Collier, G. Pavé, P. Rzepa, A. J. P.
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2
1666, 1367, 1279, 1157, 1058 cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 8.53 (s, 1 H), 7.39 (s, 1 H), 5.23 (d, J = 16.0 Hz, 1 H),
5.16 (d, J = 15.4 Hz, 1 H), 4.89 (br. s, 1 H), 4.58 (br. s, 1 H), 4.14
(s, 3 H), 3.28 (d, J = 15.4 Hz, 1 H), 3.25 (s, 3 H), 3.23 (d, J =
16.0 Hz, 1 H), 2.63 (s, 3 H), 1.45 (s, 9 H), 1.36 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 180.2, 178.7, 168.4, 165.6,
157.8, 148.2, 147.1, 144.8, 142.6, 139.4, 131.5, 126.1, 125.4, 120.5,
117.9, 108.9, 91.6, 83.2, 81.1, 73.2, 56.3, 52.8, 40.6, 29.4, 27.9 (3
C), 27.7 (3 C), 21.8 ppm (2 carbonyl signals missing). MS (ESI):
m/z = 622 [M + H]+. HRMS (ESI): calcd. for C33H36NO11 [M +
H]+ 622.2288; found 622.2269. C33H35NO11 (621.64): calcd. C
63.76, H 5.68, N 2.25; found C 63.70, H 5.53, N 2.17.
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tween iodide 12 and di-tert-butyl fumarate proved to be unsuc-
cessful.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for the intermediates
for the synthesis of bromide 8, boronic ester 9, and diesters 20 and
22 and quinone 6; X-ray crystal structure of compound 22.
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Acknowledgments
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We thank the Engineering and Physical Sciences Research Council
(EPSRC) and the Deutsche Forschungsgemeinschaft (DFG) for
generous support of our research and GlaxoSmithKline for their
generous endowment. We additionally thank Dr. Andrew P. White
for X-ray crystal structure determination and Peter R. Haycock
and Richard N. Sheppard for high-resolution NMR spectroscopy
measurements.
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Received: September 9, 2011
Published Online: November 15, 2011
Eur. J. Org. Chem. 2012, 107–113
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
113