Studies on the total synthesis of lactonamycin: Construction of model ABCD ring systems

Article abstract of DOI:10.1021/jo052637c

Model studies on the synthesis of the tetracyclic ABCD ring system of lactonamycin (1) are described. The key step involved the double Michael addition reaction of alcohol 8 to propynoate esters to produce the BCD units 13 and 14 of the target 1. Alternat

Full text of DOI:10.1021/jo052637c

Studies on the Total Synthesis of Lactonamycin: Construction of
Model ABCD Ring Systems
David A. Henderson,† Philip N. Collier,† Gregoire Pave´,† Paula Rzepa,†
Andrew J. P. White,† Jeremy N. Burrows,‡ and Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, England, and
AstraZeneca, Sodertalje S-151 85, Sweden
agm.barrett@imperial.ac.uk
ReceiVed December 23, 2005
Model studies on the synthesis of the tetracyclic ABCD ring system of lactonamycin (1) are described.
The key step involved the double Michael addition reaction of alcohol 8 to propynoate esters to produce
the BCD units 13 and 14 of the target 1. Alternatively, double Michael addition of alcohol 8 to di-tert-
butyl acetylenedcarboxylate gave the corresponding BCD ring systems 36 and 37. Acid-mediated hydrolysis
of the dihydroquinone monoketal units of 13 and 14 and 36 and 37 in the presence of air gave the
corresponding quinones 7 and 39. These were converted into the tetracyclic ABCD units 6, 26a, 40, and
42 of lactonamycin (1) by either dihydroxylation or epoxidation and acid-catalyzed lactonization.
Introduction
Lactonamycin(1)1 and the recently isolated derivative lac-
tonamycin-Z (2)2 have intriguing structural features that include
a naphtho[e]isoindole ring system on the east side (EF-rings)
and a densely oxygenated fused perhydrofuran-furanone ring
system containing a labile tertiary methoxy group on the west
side (AB-rings) (Figure 1). The natural products also each
contain a 2-deoxy sugar unit (1, R-L-rhodinopyranose; 2, R-L-
2,6-dideoxyribopyranose) attached through a tertiary R-keto-
glycosidic linkage. Lactonamycin (1) shows significant levels
of antimicrobial activity toward Gram-positive bacteria, being
especially active against methicillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).
In addition, lactonamycin (1) shows significant levels of
cytotoxicity against various tumor cell lines.3
FIGURE 1. Structures of lactonamycin (1), lactonamycin-Z (2), and
lactonamycinone (3).
Three groups have reported synthetic studies directed toward
the total synthesis of lactonamycin (1). Two different routes
for the construction of model ABCD ring systems were reported
by Danishefsky and Cox,4 and the Danishefsky group followed
* To whom correspondence should be addressed. Phone: 44-207-594-5766.
Fax: 44-207-594-5805.
† Imperial College London.
‡ AstraZeneca.
(1) Matsumoto, N.; Tsuchida, T.; Nakamura, H.; Sawa, R.; Takahashi,
Y.; Naganawa, H.; Iinuma, H.; Sawa, T.; Takeuchi, T.; Shiro, M. J. Antibiot.
1999, 52, 276 and references therein.
(2) Holtzel, A.; Dieter, A.; Schmid Dietmar, G.; Brown, R.; Goodfellow,
M.; Beil, W.; Jung, G.; Fiedler, H.-P. J. Antibiot. 2003, 56, 1058.
(3) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Kinoshita, N.; Homma,
Y.; Iinuma, H.; Sawa, T.; Hamada, M.; Takeuchi, T.; Heida, N.; Yoshioka,
T. J. Antibiot. 1999, 52, 269.
10.1021/jo052637c CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/16/2006
2434
J. Org. Chem. 2006, 71, 2434-2444

Studies on the Total Synthesis of Lactonamycin
SCHEME 1. Retrosynthetic Analysis of the Model ABCD
Tetracyclic Target
ester. The forward sequence from alcohol 8 to dihydrofuran 7
would involve a double Michael addition reaction to form the
B ring and subsequent deprotection and aerobic oxidation.
Finally, alcohol 8 should be available from quinone mono-
ketal 910 via the Michael addition of a methanol dianion
equivalent.
Results and Discussion
Synthesis of Quinone 7. Quinone monoketal 9 was synthe-
sized in multigram quantities from 4-methoxy-1-naphthol in a
modification of the Corey procedure11 using PhI(OCOCF3)2-
mediated oxidation of 4-methoxy-1-naphthol and 2,2-dimethyl-
1,3-propanediol. Since literature precedent indicated that the
Michael addition of cuprate reagents to quinone monoketals
could be problematic,12 the copper-mediated addition of a
suitably protected hydromethyl organometallic reagent was
not examined. Instead, nitromethane was employed as an
equivalent reagent. Thus, quinone monoketal 9 was converted
into nitroalkane 10 (83%) by the Michael addition of ni-
tromethane nitronate in a process catalyzed by triethylamine.
Subsequent oxidative Nef reaction using potassium hydroxide
and potassium permanganate in aqueous methanol13 gave
aldehyde 11, which was reduced to alcohol 8 using sodium
borohydride (Scheme 2). Three reactions in this sequence
required care in execution to prevent formation of the phenol
16, an acid-mediated rearrangement product derived from
ketal 9, carboxylic acid 17, an overoxidation product in the
Nef reaction, and diol 18 during formation of alcohol 8 (Figure
2).
up these initial studies with the total synthesis of the aglycon,
(()-lactonamycinone (3).5 Deville and Behar have published a
route to the CDEF ring system6 as have Kelly and co-workers,7
and more recently, the Kelly group has described a model
asymmetric synthesis of the AB ring system.8 Retrosynthetically,
we considered that the model ABCD ring system (4) should be
available using a sequence of Michael addition reactions
(Scheme 1). In this analysis, the tetracycle 4 was primarily
disconnected by the loss of the angular methoxy group (or
its equivalent) to reveal butenolide 5. Butenolide 5 could be
derived from the lactone 6 through direct oxidation with IBX
or an equivalent transformation.9 In turn, lactone 6 should
be available through oxidative lactonization of naphthoquinone
7 using a dihydroxylation or an epoxidation reaction. Quinone
7 could be disconnected to give alcohol 8 and a propynoate
Michael addition of alcohol 8 to methyl, ethyl, and tert-butyl
propynoate, catalyzed by N-methylmorpholine, successfully
furnished the vinyl ethers 12a-c (68-88%) all as single
geometric isomers. Early studies to close the B ring via enolate
formation and an intramolecular Michael addition were con-
ducted using lithium diisopropylamide (LDA) as a base and
SCHEME 2. Synthesis of Quinone 7a
a Key: (a) R ) Me (88%), Et (74%), t-Bu (68%); (b) LDA: R ) Me (41%), Et (45%), t-Bu (28%) or N-tert-butyl-N,N,N,N-tetramethylguanidine: R )
t-Bu (96%); (f) R ) Me (70%), t-Bu (57%).
J. Org. Chem, Vol. 71, No. 6, 2006 2435

Henderson et al.
Treatment of ketal 13a with aqueous acetic acid (3:7) at 60 °C
in the presence of air gave naphthoquinone 7a (70%). In
the same way, reaction of a mixture of 13c and 14c gave the
quinone 7c (57%) (Scheme 2). The constitution and stereo-
chemistry of the key intermediates 13 and 14 were con-
firmed by an X-ray crystallographic structure determination
of the oxime 1915 derived from ketone 13b (Figure 2). Again,
it is germane to comment on the isolation of side products
(Figure 2). The synthesis of enoate 12 was occasionally
accompanied by the formation of the double adduct 20 (12%).
In addition, a sample of the mixture of ketals 13c and 14c
underwent oxidative rearrangement on standing for several
months to provide the hydroxy ester 21, the structure of which
was established by X-ray crystallography.15
Construction of the A Ring. With quinone 7c in hand, the
synthesis of the A ring was investigated. Following the
Danishefsky precedent,4,5 dihydroxylation of 7c using catalytic
quantities of osmium tetraoxide in the presence of N-methyl-
morpholine N-oxide gave a mixture of diols 22 and 23 (dr )
7:3) in 70% yield. Separation of the diols was partially achieved
by chromatography and recrystallization to give pure 22, but
isolation of the pure minor diastereoisomer 23 was not possible.
Thus, the crude mixture of diols 22 and 23 was allowed to stand
with excess trifluoroacetic acid in dichloromethane to give
lactone 6 in 27% yield (Scheme 3). Presumably, only the minor
epimer 23 was able to undergo γ-lactonization. The major
isomer 22, contrary to wishful thinking, did not undergo
epimerization to 23 by a possible opening and reclosing of the
B ring through a retro-Michael Michael addition process and
reclosure. The mass balance of the reaction contained a highly
polar product, which was in all probability the corresponding
dihydroxy acid of 22.
The diastereoselectivity of the key dihydroxylation reaction
to provide diols 22 and 23 could not be improved in favor of
23 and therefore an alternative method of oxidizing quinone 7c
was investigated. Epoxidation using hydrogen peroxide and
sodium carbonate gave a mixture of epoxides 24 and 25 (dr )
6.3:3.7) in 93% yield. The structure and relative stereochemistry
of the major diastereoisomer 24 was confirmed by X-ray
crystallography.15 Treatment of 24 with trifluoroacetic acid in
dichloromethane led to γ-lactone 26a (97%), the epimer of
lactone 6. Treatment of epoxide 25 under identical acidic
conditions gave the epoxy acid 27 (Scheme 3). Attempted
epimerization of 26a to 6 under acidic or basic conditions
resulted in the recovery of starting material 26a or the formation
of intractable mixtures of polar products. Nevertheless, 26a
and subsequently trimethylsilyl ether 26b were obtained in
reasonable quantities and were used as model substrates to
investigate the introduction of the angular methoxy group.
These studies should be relevant to the possible methoxyla-
tion of epimer 6. The long-term strategy with intermediates
such as 26a may require the use of a nontraditional glycosida-
tion reaction to introduce the R-L-rhodinopyranosyl residue
with inversion of stereochemistry.16 Prior to carrying out
such studies, the ketone 26a was converted into the crystalline
oxime 28 and the silyl oxime mesylate 29. The structure
FIGURE 2. Structures of minor side products formed in Scheme 2
and oxime 19.
gave the corresponding tetrahydrofuran acetate esters 13a-c
albeit in poor yields (28-45%). In marked contrast, cyclization
of the tert-butyl ester 12c using the Barton base N-tert-butyl-
N,N,N,N-tetramethylguanidine14 proceeded in excellent yield
(96%) to provide both diastereoisomers 13c and 14c (4:6).
(4) Cox, C.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493. Cox, C.;
Danishefsky, S. J. Org. Lett. 2001, 3, 2899.
(5) Cox, C. D.; Siu, T.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003,
42, 5625. Siu, T.; Cox, C. D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2003, 42, 5629.
(6) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403.
(7) Kelly, T. R.; Xu, D.; Martinez, G.; Wang, H. Org. Lett. 2002, 4,
1527.
(8) Kelly, T. R.; Xiaolu, C.; Tu, B.; Elliott, E. L.; Grossmann, G.; Laurent,
P. Org. Lett. 2004, 6, 4953.
(9) For examples of the synthesis of unsaturated carbonyl compounds
by oxidation using IBX, see: Nicolaou, K. C.; Montagon, T.; Baran, P. S.
Angew. Chem., Int. Ed. 2002, 41, 993. Nicolaou, K. C.; Gray, D. L. F.;
Montagon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996.
(10) Breuning, M.; Corey, E. J. Org. Lett. 2001, 3, 1559.
(11) Sudini, R. R.; Khire, U. R.; Pandey, R. K.; Kumar, P. Ind. J. Chem.
Sect. B. 2000, 39, 738.
(12) Semmelhack, M. F.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W. J.
Org. Chem. 1985, 50, 5566.
(13) Deardorff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.;
Sheppeck, J. E., II.; Hager, D. C.; Aydin, N. J. Org. Chem. 1996, 61,
3616.
(14) Barton, D. H. R.; Elliott, J. D.; Gero, S. D. J. Chem. Soc., Perkin
Trans. 1 1982, 2085.
(15) See the Supporting Information for details of the X-ray crystal
structure.
(16) It was hoped that unconventional glycosidation methodology, a
Michael addition of the anomeric metal alkoxide of a L-rhodinose sugar
unit to a transient nitroso-alkene derived from 4, may be used. See: Barrett,
A. G. M.; Trewartha, G. Tetrahedron Lett. 2005, 46, 3553.
2436 J. Org. Chem., Vol. 71, No. 6, 2006

Studies on the Total Synthesis of Lactonamycin
SCHEME 3. Dihydroxylation and Epoxidation of 7
SCHEME 4. Synthesis of Epoxide 31
of oxime 28 was confirmed by an X-ray crystallographic
study.15
hydrogen peroxide and sodium carbonate gave epoxide 31
(Scheme 4). Unfortunately, attempted lactonization of this rather
sensitive compound 31 under acidic conditions (TFA-CH2Cl2
or camphorsulfonic acid-MeOH) gave only intractable mixtures
of polar products.
Synthesis of Carboxylic Acid 33: Masking the Methoxy
Group. In light of the difficulties in the attempted oxidations
of 26 and 7c, we considered that it should be possible to mask
the methoxy group as a carboxylic acid (see 33). In this design,
the methoxy group would be revealed via late halodecarboxy-
lation,23 decarboxylative acetoxylation,24 or through the inter-
mediacy of a methyl perester. In consequence, the retrosynthetic
disconnections were slightly modified as in Scheme 5 with the
use of di-tert-butyl acetylenedicarboxylate as the initial Michael
acceptor for reaction with alcohol 8.
Attempted oxidations of γ-lactones 26a or 26b using either
IBX-NMO or IBX-MPO17 to produce the corresponding buteno-
lide, in order to introduce the angular methoxyl group, were
unsuccessful. Attempted oxidations with Fenton’s reagent,18
ruthenium chloride and sodium periodate, iodosobenzene diac-
etate,19 lead tetracetate and iodine, chromium trioxide and
tetrabutyl periodate,20 ozone and silica,21 or dimethyldioxirane
(DMDO) oxidation22 were all unsuccessful. For example,
attempted Fenton oxidation of the lactone 26a gave the diol
ester 30 (74%). All other attempted oxidations either resulted
in starting material being recovered or in the formation of
intractable mixtures of products. As a consequence of these
failings, we sought to examine introduction of the angular
methoxy group at an earlier stage. Oxidation of ester 7c using
Michael addition of alcohol 8 to di-tert-butylacetylene
dicarboxylate was optimally catalyzed using 4-(dimethylamino)-
pyridine to provide adduct 35 (86%). Cyclization, via a second
Michael addition reaction using the Barton base, gave both
(17) IBX was prepared according to the method of: Frigerio, M.;
Santagostino, S.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
(18) Walling, C. Acc. Chem. Res. 1975, 8, 125.
(19) Francisco, C. G.; Herrera, A. J.; Suarez, E. J. Org. Chem. 2002,
67, 7439.
(20) Lee, S.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124, 13978.
(21) Keinan, E.; Mazur, Y. Synthesis 1976, 524.
(22) Bovicelli, P.; Lupattelli, P.; Fracassi, D. Tetrahedron Lett. 1994,
35, 935. Yu, B.; Liao, J.; Zhang, J.; Hui, Y. Tetrahedron Lett. 2001, 42,
77.
(23) Bolster, M. G.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2001,
57, 5657. Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron
2000, 56, 2703. Roy, S. C.; Guin, C.; Maiti, G. Tetrahedron Lett. 2001,
42, 9253.
(24) Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279. Thominiaux,
C.; Chiaroni, A.; Desmaele, D. Tetrahedron Lett. 2002, 43, 4107.
J. Org. Chem, Vol. 71, No. 6, 2006 2437

Henderson et al.
SCHEME 5. Proposed Disconnection of Acid 33 and Its
Conversion to the Western Entity 4
aerobic conditions provided quinone 39 (70%). Subsequent
epoxidation under basic conditions led to an inseparable 1:1
mixture of diastereoisomeric epoxides, which were directly
cyclized using TFA to give trans-lactone 40 (42% from 39)
(Scheme 6). Although the quinone 39 failed to react with
osmium tetraoxide in stoichiometric quantities, ruthenium(III)
chloride catalyzed dihydroxylation25 of quinone 39 gave diol
41. Finally, addition of trifluoroacetic acid in dichloromethane
gave cis-lactone 42 (26%). Again, it is germane to comment
on the isolation of side products in this sequence. The synthesis
of enoate 35 was accompanied by the formation of the
dihydrophenanthrene 43 (8%), the constitution of which was
established by spectroscopic data and an X-ray crystallo-
graphic structure determination.15 As an alternative to trans-
esterification, the ketals 36 and 37 were hydrolyzed using
70% aqueous acetic acid in air to give the quinone 44 (52%)
and this was further hydrolyzed in trifluoroacetic acid to pro-
vide a polar compound tentatively assigned as the diacid 45
(91%).
The selective diester 37 monohydrolysis, carboxylate alky-
lation, and ketal hydrolysis-oxidation were generalized with
the preparation of acid 47, diesters 46 and 48, and quinone 49.
At this stage, we had not unequivocally established the
regioselectivity of the initial monosaponification of the diester
36. In fact, we had naively assumed that the less hindered CH2-
CO2-t-Bu unit would undergo saponification faster. Indeed,
TFA-mediated hydrolysis of quinone 49 gave the corresponding
carboxylic acid 50, and this was directly converted into iodide
1
51 (35% unoptimized). Both the H and 13C NMR spectra of
this compound were consistent with the presence of an iodom-
ethyl substituent rather than a tertiary iodide. This confirmed
that the saponification of diester 36 took place selectively at
the more hindered ester. This was confirmed by an X-ray crystal
structure of diester 38.15 Presumably, the origin of the highly
selective saponification of diester 36 was the result of 1,2-
tetrahydrofurans 36 (65%) and 37 (11%). Much to our delight,
the diester 36 underwent highly selective monosaponification
using potassium hydroxide (vide infra). Subsequent benzylation
of the potassium carboxylate using benzyl bromide gave diester
38 (78%). Hydrolysis of ketal 38 by treatment with TFA under
SCHEME 6. Synthesis of Model Aglycons 40 and 42 Using a Carboxylate as a Masked Methoxy Group
2438 J. Org. Chem., Vol. 71, No. 6, 2006

Studies on the Total Synthesis of Lactonamycin
hydroxide addition to the ketone and the intermediacy of the
lactone alkoxide 52.
synthetic sequence was briefly explored. Thus, hydrogenolysis
of benzyl ester 39 occurred with concomitant quinone reduction
giving hydroquinone 55. Attempted reoxidation of hydroquinone
55 to the quinone oxidation level using excess manganese
dioxide was accompanied by oxidative decarboxylation giving
the furan 56.
Conclusion
The use of iterative Michael additions and quinone dihy-
droxylation or epoxidation reactions has been shown to be useful
for the concise synthesis of model ring ABCD units of
lactonamycin (1). Of particular note are the double Michael
addition reactions of alcohol 8 to propynoate and acetylenedi-
carboxylate esters to produce the lactonamycin BCD ring
systems 13, 14, 36, and 37. In addition, the use of the Barton
base (N-tert-butyl-N′,N′,N′′,N′′-tetramethylguanidine) for the
intramolecular Michael addition of ketone enolates to â-alkoxy-
acrylates should be of general synthetic importance.
Experimental Section
4,4-(2,2-Dimethyl-1,3-propylenedioxy)naphthalen-1(4H)-
one (9). (1) 4-Methoxy-1-naphthol (25.0 g, 144.0 mmol) in CH2-
Cl2 (350 mL) and THF (25 mL) was added dropwise with stirring
over 45 min to 2,2-dimethyl-1,3-propanediol (85.0 g, 720 mmol)
and PhI(O2CCF3)2 (79.9 g, 173.0 mmol) in CH2Cl2 (600 mL) at 0
°C. Stirring was continued for a further 45 min, and the mixture
allowed to warm to ambient temperature. Saturated aqueous Na2-
CO3 (500 mL) was slowly added over 20 min when precipitation
occurred. The solid was filtered off and the filtrate rotary evaporated
to ca. half its total volume, washed with saturated aqueous Na2-
CO3 (500 mL), H2O (250 mL), brine (250 mL), dried (MgSO4),
and rotary evaporated. Recrystallization (4:1 hexanes/EtOAc) and
drying in vacuo at 50 °C gave enone 9 (14.9 g, 43%) as off-white
crystals: mp 139-141 °C (EtOAc/hexanes) (lit.10 mp 138-142
°C); Rf 0.46 (1:1 hexanes/EtOAc); IR (film) 1672, 1620, 1600, 1470,
Smooth conversion of ester 40 into carboxylic acid 53 (91%)
was achieved by transfer hydrogenation. Alternatively, trim-
ethylsilylation of alcohol 40 gave the silyl ether 54 (51%)
(Scheme 7). Selective debenzylation at an earlier stage in the
1
1329 cm-1; H NMR (CDCl3, 300 MHz) δ 0.93 (s, 3H), 1.52 (s,
3H), 3.65 (d, J ) 11.0 Hz, 2H), 4.06 (d, J ) 11.0 Hz, 2H), 6.47
(d, J ) 11 Hz, 1H), 7.52 (t, J ) 7.5 Hz, 1H), 7.70 (t, J ) 7.5 Hz,
1H), 7.80 (d, J ) 11 Hz, 1H), 8.01 (d, J ) 7.5 Hz, 1H), 8.07 (d,
J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.5, 23.6, 30.1,
71.9, 90.5, 126.0, 126.9, 129.3, 129.4, 129.8, 133.6, 137.3, 142.2,
183.8; MS (CI, NH3) m/z 245 (M + H)+; HRMS (CI) m/z calcd
for C15H17O3 (M + H)+ 245.1177, found (M + H)+ 245.1174. (2)
4-Methoxy-1-naphthol (25.8 g, 148 mmol) in dry CH2Cl2 (450 mL)
was added with stirring over 20 min at 0 °C to 2,2-dimethyl-1,3-
propanediol (80.0 g, 768 mmol) and PhI(O2CCF3)2 (82.8 g, 224
mmol) in dry CH2Cl2 (800 mL) under N2. After 10 min at 0 °C
and a further 45 min at room temperature, saturated aqueous Na2-
CO3 (300 mL) was carefully added. The excess diol precipitated
and was filtered and washed with CH2Cl2 (300 mL). The organic
phase from the mother liquors was separated and the aqueous phase
re-extracted with CH2Cl2 (150 mL). The combined organic solutions
were washed with brine (300 mL), dried (MgSO4), filtered, and
rotary evaporated. Recrystallization twice (1:1 cyclohexene/EtOAc)
gave spiroketal 9 (23.9 g, 66%) as a white amorphous solid. In
this experiment, further recrystallization of the mother liquor gave
phenol 16 (8.32 g, 23%) as an off-white solid: mp 207 °C (1:1
cyclohexane/EtOAc); Rf 0.30 (5:1 cyclohexane/EtOAc); IR (film)
SCHEME 7. Studies on Debenzylation Reactions
1
3369, 1734, 1664, 1601, 1470, 1396 cm-1; H NMR (400 MHz,
CDCl3) δ 0.93 (s, 3H), 1.52 (s, 3H), 3.68 (d, J ) 12.0 Hz, 2H),
4.15 (d, J ) 12.0 Hz, 2H), 7.53 (td, J ) 1.0, 8.0 Hz, 1H), 7.71 (td,
J ) 1.5, 8.0 Hz, 1H), 7.95 (s, 1H), 8.04 (dd, J ) 1.0, 8.0 Hz, 1H),
(25) Plietker, B.; Niggemann, M.; Pollrich, A. Org. Biomol. Chem. 2004,
2, 1116.
J. Org. Chem, Vol. 71, No. 6, 2006 2439

Henderson et al.
8.11 (dd, J ) 1.5, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
22.4, 23.6, 30.2, 71.9, 90.3, 126.7 (2C), 129.4, 129.8, 132.8, 133.8,
138.0, 138.1, 144.8, 182.2; MS (CI, NH3) m/z 245 (M + H)+;
HRMS (CI) m/z calcd for C15H17O3 (M + H)+ 245.1178, found
(M + H)+ 245.1177.
4.29 (d, J ) 11.5, 1H), 4.48-4.50 (m, 1H), 7.71 (td, J ) 1.5, 8.0
Hz, 1H), 7.48-7.52 (m, 1H), 7.65-7.69 (m, 1H), 7.87-7.92 (m,
2H); 13C NMR (75 MHz, CD3OD) δ 20.9, 22.3, 29.3, 37.1, 70.6,
71.1, 95.8, 125.0, 125.5, 126.6, 128.7, 131.9, 133.5, 173.3, 196.5;
MS (CI, NH3) m/z 308 (M + NH4)+, 292 (M + NH4 - H2O)+;
HRMS (CI) m/z calcd for C16H22NO5 (M + NH4)+ 308.1498, found
(M + NH4)+ 308.1501.
(3RS)-4,4-(2,2-Dimethyl-1,3-propylenedioxy)-3-nitromethyl-
2,3-dihydronaphthalen-1(2H)-one (10). MeNO2 (23.0 mL, 418.6
mmol) followed by Et3N (8.74 mL, 62.8 mmol) were added with
stirring to enone 9 (14.6 g, 59.8 mmol) in MeOH (45 mL). After
12 h, the product crystallized directly from the reaction mixture
and was filtered off, air-dried, and recrystallized from MeOH to
give nitroalkane 10 (15.3 g, 83%) as off-white crystals: mp 146-
147 °C (MeOH); Rf 0.5 (1:1 hexanes/EtOAc); IR (film) 1693, 1599,
1532, 1470, 1347, 1285, 1096 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.94 (s, 3H), 1.28 (s, 3H), 2.74 (dd, J ) 2.5, 18.0 Hz, 1H), 3.08
(dd, J ) 4.5, 18.0 Hz, 1H), 3.61 (app-t, J ) 11.5 Hz, 2H), 3.81
(app-t, J ) 11.5 Hz, 2H), 4.08 (app-br s, 1H), 4.11 (app-t, J ) 9.0
Hz, 1H), 4.51 (d, J ) 9.0 Hz, 1H), 7.52 (td, J ) 1.0, 7.5 Hz, 1H),
7.68 (td, J ) 1.0, 7.5 Hz, 1H), 7.88 (dd, J ) 1.0, 7.5 Hz, 1H), 8.01
(dd, J ) 1.0, 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.4,
23.1, 30.1, 34.6, 37.6, 70.6, 71.6, 75.9, 95.7, 125.7, 127.1, 129.8,
131.1, 134.5, 140.7, 194.3; MS (CI, NH3) m/z 323 (M + NH4)+
306 (M + H)+; HRMS (CI) m/z calcd for C16H20NO5 (M + H)+
306.1341, found (M + H)+ 306.1342. Anal. Calcd for C16H19NO5:
C, 62.94; H, 6.27; N, 4.59. Found: C, 62.85; H, 6.16; N, 4.67.
(3RS)-4,4-(2,2-Dimethyl-1,3-propylenedioxy)-3-(oxomethyl)-
2,3-dihydronaphthalen-1(2H)-one (11). (1) KOH in MeOH (1 M;
55.10 mL, 55.1 mmol) was added dropwise over 15 min to
nitroalkane 10 (15.20 g, 50.1 mmol) in MeOH (325 mL) at 0 °C.
The resulting mixture was stirred for 15 min, and KMnO4 (8.71 g,
55.1 mmol) and MgSO4 (5.41 g, 45.10 mmol) in H2O (425 mL)
were added dropwise over 15 min. The mixture was allowed to
warm to ambient temperature over 1 h and quenched by filtration
though Celite eluting with Et2O (100 mL). The filtrate was rotary
evaporated, and the resulting aqueous residue was extracted with a
mixture of Et2O and EtOAc (1:1; 3 × 250 mL). The organic extracts
were combined, dried (MgSO4), and rotary evaporated. The resultant
yellow solid was recrystallized (EtOAc/hexanes) to give two batches
of aldehyde 11 (7.56 g, 55%) as fine white needles: mp 143-145
°C (EtOAc/hexanes); Rf 0.32 (1:1 EtOAc/hexanes); IR (film) 1713,
1694, 1598, 1470, 1398 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.94
(s, 3H), 1.36 (s, 3H), 2.84 (dd, J ) 5.0, 18.0 Hz, 1H), 3.06 (dd, J
) 2.5, 18.0 Hz, 1H), 3.60 (dd, J ) 2.5, 11.5 Hz, 1H), 3.79-3.82
(m, 2H), 4.09 (d, J ) 11.5 Hz, 1H), 4.19 (dd, J ) 2.0, 5.0 Hz,
1H), 7.49 (td, J ) 1.0, 7.5 Hz, 1H), 7.65 (td, J ) 1.0, 7.5 Hz, 1H),
7.90 (dd, J ) 1.0, 7.5 Hz, 1H), 7.98 (dd, J ) 1.0, 7.5 Hz, 1H),
9.66 (d, J ) 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3,
23.1, 30.2, 34.5, 46.6, 71.0, 71.7, 95.6, 125.2, 126.9, 129.8, 131.2,
134.2, 140.6, 194.4, 200.3; MS (CI, NH3) m/z 292 (M + NH4)+
275 (M + H)+; HRMS (CI) m/z calcd for C16H19O4 (M + H)+
275.1283, found (M + H)+ 275.1277. Anal. Calcd for C16H18O4:
C, 70.06; H, 6.61. Found: C, 69.92; H, 6.57. (2) KOH in MeOH
(0.1 M; 271 mL, 27.1 mmol) was added dropwise over 20 min to
nitroalkane 10 (7.42 g, 24.6 mmol) in MeOH (174 mL) at 0 °C.
KMnO4 (3.89 g, 24.63 mmol) and MgSO4 (2.37 g, 19.7 mmol) in
H2O (454 mL) were added dropwise over 20 min. The mixture
was allowed to warm to room temperature over 45 min, filtered
through Celite, washed with Et2O (200 mL) and the filtrate rotary
evaporated. The residue was dissolved in EtOAc (300 mL), filtered,
and concentrated by rotary evaporation. The crystalline aldehyde
11 (3.81 g) was filtered off, the mother liquor rotary evaporated,
and the residue chromatographed (2:1 to 1:2 cyclohexane/EtOAc)
to give additional aldehyde 11 (total yield: 4.61 g, 68%, 77% based
on recovered nitroalkane 10) as a white amorphous solid. Further
chromatography gave carboxylic acid 17 (712 mg, 10%) as a white
amorphous solid: mp 153 °C (EtOAc); Rf 0.25 (EtOAc); IR (film)
3276 (br), 1730, 1695, 1599, 1556 cm-1; 1H NMR (300 MHz, CD3-
OD) δ 0.88 (s, 3H), 1.35 (s, 3H), 2.78-2.92 (m, 2H), 3.50 (d, J )
10.0 Hz, 1H), 3.65 (d, J ) 10.0, 1H), 3.97 (d, J ) 11.5 Hz, 1H),
(3RS)-4,4-(2,2-Dimethyl-1,3-propylenedioxy)-3-hydroxymethyl-
2,3-dihydronaphthalen-1(2H)-one (8). (1) Sodium borohydride
(0.97 g, 25.5 mmol) was added in small portions, over 15 min, to
aldehyde 11 (6.36 g, 23.2 mmol) in MeOH (360 mL) at -5 °C.
Stirring was continued for a further 30 min, and the reaction was
quenched by careful addition of AcOH (5.70 mL). The mixture
was rotary evaporated and the resulting residue slurried in EtOAc
(150 mL), stirred for 30 min at 40 °C, and filtered though Celite to
remove insoluble material. Rotary evaporation and chromatography
(1:1 EtOAc/hexanes) gave alcohol 8 (4.94 g, 77%) as a clear oil:
Rf 0.18 (1:1 EtOAc/hexanes); IR (film) 3464 (br), 1686, 1599 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.90 (s, 3H), 1.30 (s, 3H), 2.19
(br-s, 1H), 2.71 (dd, J ) 2.5, 17.5 Hz, 1H), 2.97 (dd, J ) 5.0, 17.5
Hz, 1H), 3.44-3.52 (m, 2H), 3.53-3.64 (m, 2H), 3.65-3.71 (m,
1H), 3.84 (d, J ) 11.5 Hz, 1H), 3.96 (d, J ) 11.5 Hz, 1H), 7.48
(td, J ) 1.0, 7.5 Hz, 1H), 7.66 (td, J ) 1.0, 7.5 Hz, 1H), 7.92 (dd,
J ) 1.0, 7.5 Hz, 1H), 7.97 (dd, J ) 1.0, 7.5 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 22.4, 23.3, 30.1, 36.3, 37.5, 62.9, 70.8, 71.4,
97.4, 125.6, 126.5, 129.3, 131.5, 133.9, 141.4, 196.3; MS (CI, NH3)
m/z 294 (M + NH4)+, 277 (M + H)+; HRMS (CI) m/z calcd for
C16H21O4 (M + H)+ 277.1439, found (M + H)+ 277.1445. (2)
NaBH4 (313 mg, 8.28 mmol) was added over 10 min to aldehyde
11 (2.39 g, 8.72 mmol) in dry MeOH (130 mL) at -5 °C under
N2. After 15 min, the reaction was quenched by careful addition
of HOAc (2.6 g) and the mixture allowed to warm to room
temperature and rotary evaporated. Chromatography (2:1 cyclo-
hexane/EtOAc) gave alcohol 8 (1.48 g, 61%) and subsequently (1:2
cyclohexane/EtOAc) diol 18 (752 mg, 31%): mp 158 °C (EtOAc);
Rf 0.31 (EtOAc); IR (film) 3290 (br), 1734, 1716, 1653, 1558, 1508
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.95 (s, 3H), 1.26 (s, 3H),
2.05-2.25 (m, 4H), 3.12-3.20 (m, 1H), 3.51-3.61 (m, 4H), 3.79
(d, J ) 11.5 Hz, 1H), 3.90 (d, J ) 11.5 Hz, 1H), 4.80 (q, J ) 8.0
Hz, 1H), 7.39-7.44 (m, 2H), 7.53-7.55 (m, 1H), 7.80-7.83 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 21.1, 22.4, 29.2, 29.6, 34.6,
59.1, 64.4, 69.9, 70.6, 97.4, 126.1, 126.3, 126.9, 128.3, 136.8, 139.9;
MS (CI, NH3) m/z 279 (M + H)+, 261 (M + H - H2O)+; HRMS
(CI) m/z calcd for C16H23O4 (M + H)+ 279.1596, found (M + H)+
279.1600. Activated MnO2 (1.17 g, 13.5 mmol) was added in four
portions over 30 min to diol 18 (752 mg, 2.70 mmol) in CH2Cl2
(30 mL) at room temperature. Additional activated MnO2 (704 mg,
8.10 mmol) was added after 3 h, and the mixture was stirred
overnight, filtered through Celite, and rotary evaporated to give
alcohol 8 (739 mg, 99%; total yield of alcohol 8 from aldehyde 11
2.219 g, 91%).
(3RS)-tert-Butyl 3-((E)-(4,4-(2,2-Dimethyl-1,3-propylenedioxy)-
2,3-dihydro-1-oxonaphthalen-3-yl)methoxy)acrylate (12c). tert-
Butyl propynoate (3.20 mL, 23.3 mmol) was added with stirring
to N-methylmorpholine (2.36 mL, 21.5 mmol) in Et2O (10 mL).
After 30 min, alcohol 8 (4.94 g, 17.9 mmol) in Et2O (12 mL) was
added and stirring continued for 12 h. The mixture was diluted
with Et2O (100 mL) and H2O (100 mL), shaken vigorously, and
the layers were allowed to separate. The aqueous layer was extracted
with Et2O (100 mL), and the organic layers were combined and
washed with brine (100 mL), dried (MgSO4), and rotary evaporated.
Chromatography (1:4 EtOAc/hexanes) gave the double adduct
20 (370 mg, 12%) as a clear oil: Rf 0.73 (1:3 EtOAc/hexanes);
IR (film) 2976, 2931, 2871, 1711, 1642, 1624, 1367, 1125 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.86 (s, 3H), 1.24 (s, 3H), 1.42
(s, 9H), 1.47 (s, 9H), 3.40-3.88 (m, 7H), 4.98 (d, J ) 12.5 Hz,
1H), 5.51 (d, 1H, J ) 7.0 Hz), 5.57 (d, 1H, J ) 12.0 Hz), 7.40
(d, 1H, J ) 12.5 Hz), 7.37-7.45 (m, 3H), 7.62 (d, 1H, J ) 12.0
Hz), 7.76-7.78 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.8,
2440 J. Org. Chem., Vol. 71, No. 6, 2006

Studies on the Total Synthesis of Lactonamycin
22.5, 23.3, 28.2, 30.54, 70.4, 70.6, 71.2, 76.7, 77.0, 77.4, 79.7, 80.2,
96.5, 98.4, 104.6, 105.3, 122.3, 125.0, 128.7, 129.1, 129.3, 135.5,
150.6, 161.3, 166.4, 166.9; MS (CI, NH3) m/z 546 (M + NH4)+,
529 (M + H)+; HRMS (CI) m/z calcd for C30H40O8 (M + NH4)+
529.2801, found (M + NH4)+ 529.2799. Anal. Calcd for
C30H40O8: C, 68.16; H, 7.63. Found: C, 68.25; H 7.70. Further
elution gave enoate 12c (6.37 g, 68%) as a clear oil: Rf 0.32 (1:3
EtOAc/hexanes); IR (film) 1694, 1686, 1642, 1626 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.85 (s, 3H), 1.26 (s, 3H), 1.38 (s, 9H), 2.79
(dd, J ) 2.5, 18.0 Hz, 1H), 2.90 (dd, J ) 5.0, 18.0 Hz, 1H), 3.45-
3.59 (m, 2H), 3.62-3.67 (m, 2H), 3.82 (app-t, J ) 10.0 Hz, 2H)
3.89 (dd, J ) 5.0, 10.0 Hz, 1H), 4.87 (d, J ) 12.5 Hz, 1H), 7.32
(d, J ) 12.5 Hz, 1H), 7.41 (t, J ) 1.0, 7.5 Hz, 1H), 7.61 (t, J )
1.0, 7.5 Hz, 1H), 7.82 (td, J ) 1.0, 7.5 Hz, 1H), 7.91 (td, J ) 1.0,
7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.3, 23.3, 28.3, 30.1,
34.1, 36.9, 69.5, 70.5, 71.5, 79.9, 95.9, 98.6, 125.7, 126.6, 129.4,
131.4, 134.4, 141.1, 161.0, 166.8, 195.5; MS (CI, NH3) m/z 403
(M + H)+; HRMS (CI) m/z calcd for C23H31O6 (M + H)+ 403.2121,
found (M + H)+ 403.2131.
(1SR,3aSR,9aRS)-tert-Butyl 4,4-(2,2-Dimethyl-1,3-propylene-
dioxy)-9-oxo-(1,3,3a,4,9,9a-hexahydronaphtho[2,3-c]furan-1-yl)-
acetate (13c) and (1RS,3aSR,9aRS)-tert-Butyl 4,4-(2,2-Dimethyl-
1,3-propylenedioxy)-9-oxo-(1,3,3a,4,9,9a-hexahydronaphtho[2,3-
c]furan-1-yl)acetate (14c). (1) Reaction of acrylate 12c (0.101 g,
0.25 mmol) with LiN(i-Pr)2 as for 12a and chromatography (4:1
hexanes/EtOAc) gave 13c (30 mg, 28%) as a clear oil. (2) 2-tert-
Butyl-1,1,3,3-tetramethylguanidine (2.5 mL, 12.26 mmol) was
added with stirring to acrylate 12c (4.48 g, 11.2 mmol) in CH2Cl2
(50 mL) at 0 °C. After 10 min, the mixture was stirred at ambient
temperature for 8 h, diluted with CH2Cl2 (150 mL) and H2O (100
mL), shaken vigorously, and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (100 mL), and the organic layers
were combined, washed with H2O (100 mL) and brine (100 mL),
dried (MgSO4), and rotary evaporated. Chromatography (1:5
EtOAc/hexanes) gave tetrahydrofurans 13c and 14c (4.30 g, 96%),
a 4:6 mixture of diastereoisomers, as a clear oil: Rf 0.32 (1:3
EtOAc/hexanes); IR (film) 1731, 1685, 1367, 1153 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.95 (s, 3H), 1.15 (s, 1.8H), 1.18 (s, 1.2H),
1.48 (s, 9H), 2.33 (dd, J ) 8.0, 17.0 Hz, 0.6H), 2.59-2.78 (m,
1.4H), 3.07 (dd, J ) 4.5, 9.0 Hz, 0.4H), 3.28 (app-t, J ) 5.5 Hz,
0.6H), 3.30-4.95 (m, 6H), 4.05-4.20 (m, 1H), 4.33 (dt, J ) 4.5,
8.0 Hz, 0.4H), 4.41 (dt, J ) 5.5, 8.0 Hz, 0.6H), 7.50 (app-q, J )
7.5 Hz, 1H), 7.59-7.69 (m, 1H), 7.77 (d, J ) 8.0 Hz, 0.4H), 7.87
(m, 1.6H); 13C NMR (CDCl3, 75 MHz) both isomers δ 22.5, 23.1,
28.1, 30.2, 37.3, 39.7, 40.2, 41.4, 51.4, 52.9, 68.1, 69.2, 71.0, 71.1,
71.3, 79.4, 80.4, 80.9, 81.0, 95.5, 96.3, 125.3, 125.4, 126.2, 127.3,
129.3, 132.2, 133.2, 134.3, 141.1, 141.4, 169.8, 170.3, 197.0, 197.4;
MS (CI, NH3) m/z 403 (M + H)+; HRMS (CI) m/z calcd for
C23H31O6 (M + H)+ 403.2121, found (M + H)+ 403.2116. A
sample of the crude mixed esters 13c and 14c was found to deposit
crystals on standing at room temperature over several months. These
were assigned as hydroxy ester 21 by an X-ray crystallographic
study.15
5.65 (m, 1H), 7.74-7.78 (m, 2H), 8.08-8.18 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 28.0, 40.2, 72.6, 81.1, 82.0, 126.4, 126.5,
132.8, 132.9, 133.9, 134.0, 146.6, 146.7, 169.3, 181.4, 181.6; MS
(CI, NH3) m/z 315 (M + H)+; HRMS (CI) m/z calcd for C18H19O5
(M + H)+ 315.1232, found (M + H)+ 315.1218. Anal. Calcd for
C18H18O5: C, 68.78; H, 5.77. Found: C, 68.82; H, 5.86. (2) TsOH‚
H2O (72 mg, 0.379 mmol) was added with stirring to ketals 13c
and 14c (102 mg, 0.253 mmol) in Me2CO (10 mL). After the
mixture was stirred overnight, saturated aqueous NaHCO3 (15 mL)
was added and the mixture extracted with EtOAc (2 × 20 mL).
The combined organic extracts were dried (MgSO4), filtered, rotary
evaporated, and chromatographed (3:1 cyclohexane/EtOAc) to give
quinone 7c (61 mg, 77%) as a yellow solid.
(1RS,3aSR,9aRS)-tert-Butyl (3a,9a-Dihydroxy-4,9-dioxo-1,3,-
3a,4,9,9a-hexahydronaphtho[2,3-c]furan-1-yl)acetate (22) and
(1SR,3aSR,9aRS)-tert-Butyl (3a,9a-Dihydroxy-4,9-dioxo-1,3,-
3a,4,9,9a-hexahydronaphtho[2,3-c]furan-1-yl)acetate (23). N-
Methylmorpholine N-oxide (0.66 g, 5.55 mmol) followed by OsO4
in t-BuOH (2.5 wt %; 1.50 mL, 0.25 mmol) were added to quinone
7c (1.58 g, 5.03 mmol) in Me2CO and H2O (1:1; 30 mL) at 0 °C.
The mixture was stirred at ambient temperature for 12 h, after which
saturated aqueous Na2SO3 (10 mL) was added and the mixture
stirred for a further 15 min and diluted with H2O (10 mL). The
aqueous portion was extracted with EtOAc (3 × 50 mL), and the
organic layers were combined, washed with brine (20 mL), dried
(MgSO4), rotary evaporated, and chromatographed (2:3 EtOAc/
hexanes) to give diols 22 and 23 (1.23 g, 70%), a 7:3 mixture of
diastereoisomers, as a white solid. A small sample of the major
diastereoisomer 22 (15 mg) was isolated by further chromatography
(3:7 EtOAc/hexanes) as a white solid: mp 138-140 °C (CH2Cl2);
Rf 0.38 (1:1 EtOAc/hexanes); IR (film) 3383 (br), 1723, 1696, 1270
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9H), 2.63 (dd, J )
7.0, 14.5 Hz, 1H), 2.69 (dd, J ) 7.0, 14.5 Hz, 1H), 3.50 (s, 1H),
3.87 (d, J ) 9.0 Hz, 1H), 4.53 (d, J ) 9.0 Hz, 1H), 4.57 (t, J ) 7.0
Hz, 1H), 4.60 (s, 1H), 7.83-7.88 (m, 2H), 8.08-8.11 (m, 1H),
8.18-8.21 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 27.9, 35.7,
72.9, 80.6, 81.6, 84.0, 84.7, 127.7, 128.2, 132.7, 132.8, 135.5, 135.6,
169.8, 192.4, 195.3; MS (CI, NH3) m/z 366 (M + NH4)+; HRMS
(CI) m/z calcd for C18H24NO7 (M + NH4)+ 366.1545, found (M +
NH4)+ 366.1553. Anal. Calcd for C18H20O7: C, 62.06; H, 5.79.
Found: C, 62.29: H, 5.60. The data reported for diol 23 refers to
a chromatographed white solid containing both 23 and 22 (68:22):
Rf 0.37 (1:1 EtOAc/hexanes); IR (film) 3383 (br), 1723, 1696, 1270
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 2.51 (dd, J )
7.5, 17.0 Hz, 1H), 2.85 (dd, J ) 6.5, 17.0 Hz, 1H), 4.00 (d, J )
10.5 Hz, 1H), 4.15 (br-s, 1H), 4.27 (d, J ) 10.5 Hz, 1H), 4.43 (dd,
J ) 6.5, 7.5 Hz, 1H), 5.10 (br-s, 1H), 7.82-7.84 (m, 2H), 8.04-
8.06 (m, 2H); MS (CI, NH3) m/z 366 (M + NH4)+; HRMS (CI)
m/z calcd for C18H24NO7 (M + NH4)+ 366.1545, found (M +
NH4)+ 366.1553. Anal. Calcd for C18H20O7: C, 62.06; H, 5.79.
Found: C, 62.29; H 5.60.
(3aSR,5aSR,11aRS)-5a-Hydroxy-3,3a,5,5a-tetrahydrofuro[3,2-
b]naphtho[2,3-c]furan-2,6,11-trione (6). Diols 22 and 23 (1.51
g, 4.34 mmol) were dissolved in CH2Cl2 (25 mL) and cooled to 0
°C, and a mixture of TFA and H2O (9:1; 3 mL) was added. After
10 min at 0 °C and a further 12 h at room temperature, the mixture
was rotary evaporated, the residue was partitioned between EtOAc
(50 mL) and saturated aqueous NaHCO3 (20 mL), shaken vigor-
ously, and the layers were allowed to separate. The aqueous layer
was extracted with EtOAc (2 × 20 mL), and the organic layers
were combined, washed with H2O (10 mL) and brine (10 mL),
dried (MgSO4), and rotary evaporated. Chromatography (1:2-1:1
EtOAc/hexanes) and recrystallization from EtOAc/hexanes gave
hydroxy ketone 6 (0.321 g, 27%) as a white crystalline solid: mp
174-175 °C (EtOAc/hexanes) (lit.4 mp 173 °C dec); Rf 0.26 (1:1
EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz) δ 2.78 (dd, J ) 2.0,
19.0 Hz, 1H), 2.92 (dd, J ) 7.0, 19.0 Hz, 1H), 3.52 (s, 1H), 3.94
(d, J ) 10.0 Hz, 1H), 4.35 (d, J ) 10.0 Hz, 1H), 4.75 (dd, J ) 2.0,
7.0 Hz, 1H), 7.89-7.94 (m, 2H), 8.15 (m, 2H); 13C NMR (CDCl3,
(1SR)-tert-Butyl (4,9-Dioxo-1,3,4,9-tetrahydronaphtho[2,3-c]-
furan-1-yl)acetate (7c). (1) AcOH in H2O (7:3; 20 mL) was added
to ketals 13c and 14c (3.61 g, 8.98 mmol) and the mixture heated
at 60 °C under an atmosphere of air for 12 h. After being cooled
to ambient temperature, the orange solution was rotary evaporated,
the residue was partitioned between H2O (150 mL) and Et2O (150
mL), shaken vigorously, and the layers were allowed to separate.
The aqueous layer was extracted with Et2O (2 × 100 mL), the
organic layers combined, washed with saturated aqueous NaHCO3
(2 × 100 mL), H2O (100 mL), and brine (100 mL), dried (MgSO4),
and rotary evaporated. Chromatography (1:9 EtOAc/hexanes) gave
quinone 7c (1.61 g, 57%) as an orange oil that slowly solidified
upon standing: Rf 0.4 (1:3 EtOAc/hexanes); IR (film) 1731, 1667,
1
1621, 1152 cm-1; H NMR (CDCl3, 400 MHz) δ 1.19 (s, 9H),
2.80 (dd, J ) 6.5, 16.0 Hz, 1H), 3.04 (dd, J ) 4.0, 16.0 Hz, 1H),
5.06 (dd, J ) 4.5, 16.0 Hz, 1H), 5.14 (dd, J ) 6.0, 16.0 Hz, 1H),
J. Org. Chem, Vol. 71, No. 6, 2006 2441

Henderson et al.
100 MHz) δ 35.9, 75.2, 80.9, 83.6, 91.9, 128.1, 128.3, 132.2, 133.2,
135.8, 136.3, 173.4, 189.2, 191.7; MS (CI, NH3) m/z 292 (M +
NH4)+; HRMS (CI) m/z calcd for C14H14NO6 (M + NH4)+
292.0821, found (M + NH4)+ 292.0815. Anal. Calcd for
C14H10O6: C, 61.32; H, 3.68. Found: C, 61.31; H 3.58.
boxylate 32 (716 mg, 3.17 mmol) in dry CH2Cl2 (10 mL) at room
temperature under N2. After being stirred overnight, the mixture
was diluted with brine (40 mL) and CH2Cl2 (30 mL). The layers
were separated, and the aqueous layer was re-extracted with CH2-
Cl2 (20 mL). The combined organic extracts were dried (MgSO4),
filtered, rotary evaporated, and chromatographed (5:1 cyclohexane/
EtOAc) to give dihydrophenanthrene 43 (183 mg, 8%) as a white
solid: mp 198 °C dec (5:1 hexanes/EtOAc); Rf 0.24 (5:1 hexanes/
(1SR,3aRS,9aSR)-tert-Butyl (3a,9a-Epoxy-4,9-dioxo-1,3,3a,4,9,-
9a-hexahydronaphtho[2,3-c]furan-1-yl)acetate (24) and (1RS,-
3aRS,9aSR)-tert-Butyl (3a,9a-Epoxy-4,9-dioxo-1,3,3a,4,9,9a-
hexahydronaphtho[2,3-c]furan-1-yl)acetate (25). Aqueous H2O2
(30 wt %; 13 mL) was added with stirring to quinone 7c (1.30 g,
4.14 mmol) in THF (45 mL) at ambient temperature. Na2CO3 (0.44
g, 4.55 mmol) in H2O (4.4 mL) was added dropwise over 2 min,
with the orange solution quickly turning colorless. Stirring was
continued at ambient temperature for 1 h, and the mixture was
poured into ice-cold saturated aqueous Na2SO3 (150 mL) and stirred
vigorously for 30 min. The product was extracted with Et2O (2 ×
100 mL), and the organic layers were combined, washed with brine
(50 mL), dried (MgSO4), and rotary evaporated. The crude mixture
of epoxides (6.3:3.7, 24:25) was chromatographed (1:5 EtOAc/
hexanes) to give epoxide 24 (0.83 g, 60%) as a white solid: mp
116-117 °C (CHCl3); Rf 0.47 (1:3 EtOAc/hexanes); IR (film) 1720,
1
EtOAc); IR (film) 1722 (br), 1633, 1478, 1459 cm-1; H NMR
(300 MHz, CDCl3) δ 0.82 (s, 3H), 1.24 (s, 12H), 1.40 (s, 18H),
1.62 (s, 18H), 1.71 (s, 9H), 3.23 (d, J ) 11.5 Hz, 1H), 3.50-3.58
(m, 2H), 3.65 (t, J ) 8.0 Hz, 1H), 4.08-4.11 (m, 1H), 4.21 (d, J
) 12.0 Hz, 1H), 4.38-4.41 (m, 1H), 5.75 (s, 1H), 7.28 (d, J ) 7.5
Hz, 1H), 7.40 (d, J ) 7.5 Hz, 1H), 7.55 (d, J ) 7.5 Hz, 1H), 7.88
(d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.6, 23.6,
27.7 (2C), 27.9 (2C), 28.2 (2C), 30.0, 39.3, 70.7, 71.8, 72.4, 80.5,
82.6, 83.5, 83.7 (x3), 84.0 (2C), 97.6, 104.6, 125.3, 127.9, 128.4,
129.2, 130.2, 131.4, 131.9, 133.5, 134.1, 134.8, 135.4, 137.1, 153.3,
161.9, 163.8, 165.8, 166.2, 166.6, 167.8, 171.2; MS (FAB) m/z
936 (M+•); HRMS (FAB) m/z calc for C52H72O15 M+• 936.4871,
found M+• 936.4828. Further elution gave ester 35 (1.06 g, 86%)
as a colorless oil: Rf 0.21 (5:1 cyclohexene/EtOAc); IR (film) 1719,
1
1698, 1247, 906 cm-1; H NMR (CDCl3, 300 MHz) δ 1.33 (s,
1
1690, 1476 cm-1; H NMR (300 MHz, CDCl3) δ 0.81 (s, 3H),
9H), 2.88 (dd, J ) 4.0, 16.5 Hz, 1H), 3.15 (dd, J ) 4.0, 16.5 Hz,
1H), 4.30 (d, J ) 14.0 Hz, 1H), 4.39 (d, J ) 14.0 Hz, 1H), 4.75 (t,
J ) 4.0 Hz, 1H), 7.79 (m, 2H), 8.03-8.07 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 27.9, 37.7, 65.9, 68.9, 69.3, 74.2, 81.6, 127.4,
127.6, 132.8, 132.9, 134.6, 134.7, 170.4, 188.4, 189.5; MS (CI,
NH3) m/z 348 (M + NH4)+; HRMS (CI) m/z calcd for C18H22NO6
(M + NH4)+ 348.1447, found (M + NH4)+ 348.1447. Anal. Calcd
for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.59; H, 5.61. Further
elution gave epoxide 25 (0.46 g, 33%) as a white amorphous
solid: Rf 0.38 (1:3 EtOAc/hexanes); IR (film) 1730, 1699, 1300
1.26 (s, 3H), 1.36 (s, 9H), 1.39 (s, 9H), 2.86 (dd, J ) 2.5, 18.0 Hz,
1H), 3.10 (d, J ) 18.0 Hz, 1H), 3.43-3.56 (m, 3H), 3.74-3.80
(m, 1H), 3.82 (d, J ) 11.5 Hz, 1H), 3.97 (d, J ) 11.5 Hz, 1H),
4.08-4.11 (m, 1H), 5.97 (s, 1H), 7.39 (t, J ) 7.5 Hz, 1H), 7.57 (t,
J ) 7.5 Hz, 1H), 7.84 (d, J ) 7.5 Hz, 1H), 7.92 (d, J ) 7.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 22.1, 23.3, 27.8, 28.0, 29.8,
34.6, 36.4, 70.2, 71.4, 72.3, 81.1, 82.9, 95.8, 111.0, 125.5, 126.4,
129.2, 131.5, 134.0, 141.6, 153.8, 161.8, 163.6, 195.8; MS (CI,
NH3) m/z 503 (M + H)+, 464 (M - C4H8 + NH4)+; HRMS (CI)
m/z calcd for C28H39O8 (M + H)+ 503.2645, found (M + H)+
503.2665.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.51 (s, 9H), 2.66 (dd, J )
10.0, 16.0 Hz, 1H), 3.03 (dd, J ) 2.5, 16.0 Hz, 1H), 4.27 (d, J )
11.0 Hz, 1H), 4.43 (d, J ) 11.0 Hz, 1H), 4.84 (dd, J ) 2.5, 10.0
Hz, 1H), 7.79-7.82 (m, 2H), 8.02-8.05 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 28.1, 37.0, 64.9, 67.7 (2-C), 72.7, 81.3, 127.4, 127.5,
132.9 (2-C), 134.8, 134.9, 169.4, 189.1 (2-C); MS (CI, NH3) m/z
348 (M + NH4)+; HRMS (CI) m/z calcd for C18H22NO6 (M +
NH4)+ 348.1447, found (M + NH4)+ 348.1447. Anal. Calcd for
C18H18O6: C, 65.45; H, 5.49. Found: C, 65.59; H, 5.61.
(1RS,3aSR,9aRS)-tert-Butyl ((1-tert-Butyloxycarbonyl)-4,4-
(2,2-dimethyl-1,3-propylenedioxy)-9-oxo-(1,3,3a,4,9,9a-hexahy-
dronaphtho[2,3-c]furan-1-yl))acetate (36) and (1SR,3aSR,9aRS)-
Di-tert-butyl ((1-tert-Butyloxycarbonyl)-4,4-(2,2-dimethyl-1,3-
propylenedioxy)-9-oxo-(1,3,3a,4,9,9a-hexahydronaphtho[2,3-
c]furan-1-yl))acetate (37). 2-tert-Butyl-1,1,3,3-tetramethylguanidine
(360 mg, 2.10 mmol) was added with stirring to ester 35 (1.056 g,
2.10 mmol) in dry CH2Cl2 (15 mL) at room temperature under N2.
After being stirred overnight, the mixture was diluted with brine
(40 mL) and CH2Cl2 (30 mL). The layers were separated, and the
aqueous layer was re-extracted with CH2Cl2 (20 mL). The combined
organic extracts were dried (MgSO4), filtered, rotary evaporated,
and chromatographed (5:1 cyclohexane/EtOAc) to give ester 37
(113 mg, 11%) as a colorless oil: Rf 0.22 (5:1 cyclohexene/EtOAc);
(3aSR,5aRS,11aRS)-5a-Hydroxy-3,3a,5,5a-tetrahydrofuro[3,2-
b]naphtho[2,3-c]furan-2,6,11-trione (26a). Epoxide 24 (0.53 g,
1.61 mmol) in CH2Cl2 (20 mL) was cooled to 0 °C, and TFA (2
mL) was added dropwise with stirring over 2 min. After 0.5 h, the
mixture was allowed to warm to room temperature and stirred for
a further 3 h. After rotary evaporation, the residue was partitioned
between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL).
The aqueous layer was extracted with EtOAc (2 × 50 mL), and
the organic layers were combined, washed with brine (50 mL), dried
(MgSO4), and rotary evaporated. The crude product was purified
by dilution with EtOAc (100 mL) and filtration though a short plug
of silica gel (1:1 EtOAc/hexanes) to give a beige solid, which was
recrystallized from EtOAc/hexanes to give lactone 26a (0.43 g,
97%) as a white crystalline solid: mp 192-194 °C (EtOAc/
IR (film) 1735, 1688, 1458, 1369 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.91 (s, 3H), 1.15 (s, 3H), 1.45 (s, 9H), 1.53 (s, 9H),
2.47 (d, J ) 17.5 Hz, 1H), 3.00 (d, J ) 17.5 Hz, 1H), 3.34 (d, J )
11.5 Hz, 1H), 3.42 (d, J ) 8.0 Hz, 1H), 3.58 (t, J ) 8.0 Hz, 1H),
3.68 (d, J ) 11.5 Hz, 2H), 3.86 (d, J ) 11.5 Hz, 1H), 4.11-4.21
(m, 1H), 4.34 (d, J ) 9.0 Hz, 1H), 7.50 (t, J ) 7.5 Hz, 1H), 7.62
(t, J ) 7.5 Hz, 1H), 7.77 (d, J ) 7.5 Hz, 1H), 7.84 (d, J ) 7.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 22.4, 23.1, 27.9, 28.1, 30.2,
39.1, 40.7, 54.1, 69.8, 71.1, 71.3, 81.1, 82.0, 87.4, 96.0, 125.2,
126.5, 129.4, 133.4, 133.6, 141.0, 169.0, 171.1, 196.3; MS (CI,
NH3) m/z 520 (M + NH4)+, 503 (M + H)+; HRMS (CI) m/z calcd
for C28H39O8 (M + H)+ 503.2645, found (M + H)+ 503.2665.
Further elution (3:1 cyclohexane/EtOAc) gave diastereoisomeric
ester 36 (687 mg, 65%) as a white solid: mp 170 °C (CH2Cl2/
Et2O); Rf 0.16 (5:1 cyclohexene/EtOAc); IR (film) 1736, 1687,
1
hexanes) (lit.4 mp 187 °C dec); Rf 0.34 (1:1 EtOAc/hexanes); H
NMR (CDCl3, 300 MHz) δ 2.87 (d, J ) 18.5 Hz, 1H), 2.99 (dd, J
) 4.5, 18.5 Hz, 1H), 3.68 (s, 1H), 4.24 (d, J ) 11.0 Hz, 1H), 4.50
(d, J ) 11.0 Hz, 1H), 5.34 (d, J ) 4.5 Hz, 1H), 7.83-7.85 (m,
2H), 8.12-8.15 (m, 2H); 13C NMR (CDCl3, 75 MHz) 35.9, 72.1,
80.4, 84.1, 92.5, 127.2, 127.4, 128.1, 132.1, 133.5, 135.1, 135.6,
173.8, 189.0, 191.7; MS (CI, NH3) m/z 292 (M + NH4)+; HRMS
(CI) m/z calcd for C14H14NO6 (M + NH4)+ 292.0821, found (M +
NH4)+ 292.0827. Anal. Calcd for C14H10O6: C, 61.32; H, 3.68.
Found: C, 61.19; H, 3.63.
(3RS)-tert-Butyl 3-((E)-(4,4-(2,2-Dimethyl-1,3-propylenedioxy)-
2,3-dihydro-1-oxonaphthalen-3-yl)methoxy)fumarate (35). 4-(Dim-
ethylamino)pyridine (60 mg, 82 µmol) was added with stirring to
alcohol 8 (673 mg, 2.44 mmol) and di-tert-butyl acetylenedicar-
1
1455, 1368 cm-1; H NMR (300 MHz, CDCl3) δ 0.87 (s, 3H),
1.19 (s, 3H), 1.34 (s, 9H), 1.47 (s, 9H), 2.81 (d, J ) 15.5 Hz, 1H),
3.10 (d, J ) 15.5 Hz, 1H), 3.38 (d, J ) 11.5 Hz, 1H), 3.53 (d, J )
8.0 Hz, 1H), 3.64-3.90 (m, 4H), 3.92-4.10 (m, 2H), 7.48 (t, J )
7.5 Hz, 1H), 7.62 (t, J ) 7.5 Hz, 1H), 7.81 (d, J ) 7.5 Hz, 1H),
7.86 (d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.4,
2442 J. Org. Chem., Vol. 71, No. 6, 2006

Studies on the Total Synthesis of Lactonamycin
23.2, 27.7, 28.1, 30.1, 39.0, 43.9, 55.3, 70.6, 71.0, 71.2, 80.9, 82.4,
88.2, 95.0, 124.9, 127.2, 129.3, 132.8, 133.7, 140.8, 169.1, 169.7,
195.3; MS (CI, NH3) m/z 520 (M + NH4)+, 503 (M + H)+; HRMS
(CI) m/z calcd for C28H39O8 503 (M + H)+ 503.2645, found 503
(M + H)+ 503.2656. Anal. Calcd for C28H38O8: C, 66.91; H, 7.62.
Found: C, 67.05; H, 7.79.
MHz, CDCl3) δ 37.8, 70.3, 75.4, 84.6, 86.9, 95.0, 127.8, 128.4,
128.9 (3C), 129.3, 133.6, 134.4, 135.3, 135.4, 169.8, 170.1, 187.3,
188.1; MS (CI, NH3) m/z 426 (M + NH4)+, 340; HRMS (CI) m/z
calcd for C22H20O8N (M + NH4)+ 426.1189, found (M + NH4)+
426.1178. Anal. Calcd for C22H16O8: C, 64.71; H, 3.95. Found:
C, 64.54; H, 3.81.
(1RS,3aSR,9aRS)-tert-Butyl ((1-Benzyloxycarbonyl)-4,4-(2,2-
dimethyl-1,3-propylenedioxy)-9-oxo-(1,3,3a,4,9,9a-hexahydronaph-
tho[2,3-c]furan-1-yl))acetate (38). Aqueous KOH (0.384 M; 3 mL,
1.153 mmol) was added with stirring to diester 36 (579 mg, 1.153
mmol) in dioxane (6 mL) at room temperature. After being allowed
to stand overnight, the mixture was rotary evaporated and azeo-
troped with PhMe (20 mL) to give an off-white solid. This was
suspended in DMF (10 mL), PhCH2Br (394 mg, 2.31 mmol) was
added, and the mixture was stirred overnight. Et2O (50 mL) and
H2O (50 mL) were added, the aqueous layer was further extracted
with Et2O (50 mL), and the combined organic extracts were dried
(MgSO4), filtered, rotary evaporated, and chromatographed (5:1
cyclohexane/EtOAc) to give ester 38 (484 mg, 78%) as a colorless
solid: mp 172 °C (2:1 cyclohexane/EtOAc); Rf 0.30 (2:1 cyclo-
Benzyl (1SR,3aSR,9aRS)-1-((tert-Butyloxycarbonyl)methyl)-
3a,9a-dihydroxy-4,9-dioxo-1,3,3a,4,9,9a-hexahydronaphtho[2,3-
c]furan-1-carboxylate (41). RuCl3 (2 mg 0.5%), NaIO4 (0.652 g,
3.05 mmol), and H2SO4 (0.023 mL, 0.4 mmol) were added to
quinone 39 (0.911 g, 2.03 mmol) in EtOAc, CH3CN, and H2O (6:
6:1, 26 mL) at 0 °C and the mixture stirred for 2 h. The solution
was quenched with saturated aqueous Na2S2O3 (20 mL), the aqueous
phase was separated and extracted with EtOAc (3 × 25 mL), and
the combined organic extracts were dried (MgSO4). Rotary
evaporation and chromatography (7:3 pentane/EtOAc) gave diol
41 as a white solid (0.624 g, 64%): IR (film) 3426, 1732, 1698,
1593, 1455, 1369, 1267 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.31
(s, 9H), 1.96 (d, J ) 15.5 Hz, 1H), 2.80 (d, J ) 15.5 Hz, 1H), 4.15
(d, J ) 9.0 Hz, 1H), 4.82 (d, J ) 9.0 Hz, 1H), 5.30 (s, 2H), 7.29-
7.48 (m, 5H), 7.89-7.94 (m, 2H), 8.14-8.18 (m, 1H), 8.25-8.27
(m, 1H); 13C (CDCl3, 75 MHz) δ 27.8, 42.1, 67.4, 72.8, 82.2, 82.4,
84.2, 89.9, 127.4, 128.4, 128.5 (3C), 128.7, 133.6, 133.9, 135.7,
136.4, 167.0, 168.7, 191.0, 194.1; MS (Cl, NH3) m/z 500 (M +
NH4)+; HRMS calcd for C26H26O9 (M + NH4)+ 500.1894, found
500.1907.
1
hexane/EtOAc); IR (film) 1736, 1686 cm-1; H NMR (300 MHz,
CDCl3) δ 0.91 (s, 3H), 1.17 (s, 3H), 1.42 (s, 9H), 2.83 (d, J )
15.5 Hz, 1H), 3.27 (d, J ) 15.5 Hz, 1H), 3.36 (d, J ) 11.5 Hz,
1H), 3.49 (d, J ) 7.5 Hz, 1H), 3.67-3.89 (m, 4H), 4.07-4.15 (m,
2H), 5.02 (d, J ) 12.5 Hz, 1H), 5.10 (d, J ) 12.5 Hz, 1H), 7.29
(m, 5H), 7.38 (t, J ) 7.5 Hz, 1H), 7.57-7.66 (m, 2H), 7.84 (d, J
) 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 21.9, 22.6, 27.4,
29.6, 38.9, 43.3, 55.5, 66.7, 69.3, 71.0 (2C), 80.8, 88.0, 94.7, 124.4,
126.5, 127.6, 127.7, 127.8, 128.8, 132.3, 133.1, 134.7, 140.1, 167.8,
169.8, 195.0; MS (CI, NH3) m/z 554 (M + NH4)+, 537 (M + H)+,
481; HRMS (CI) m/z calcd for C31H37O8 (M + H)+ 537.2488, found
(M + H)+ 537.2484. Anal. Calcd for C31H36O8: C, 69.39; H, 6.76.
Found: C, 69.45; H, 6.70.
Benzyl (1SR,3aSR,9aRS)-5a-Hydroxy-2,6,11-trioxo-2,3,5,5a,6,-
11-hexahydrofuro[3,2-b]naphtho[2,3-c]furan-3a-carboxylate (42).
TFA (0.5 mL) was added to diol (0.1 g, 0.21 mmol) in CH2Cl2 (3
mL) and the solution allowed to stand for 18 h at room temperature.
The solvent and TFA were evaporated in vacuo and the residue
chromatographed (7:3 pentane/AcOEt) to furnish lactone 42 (0.023
g, 26%) as a white solid: IR (CH2Cl2) 3442, 1809, 1738, 1703,
(1SR)-tert-Butyl (1-(Benzyloxycarbonyl)-4,9-dioxo-1,3,4,9-tet-
rahydronaphtho[2,3-c]furan-1-yl)acetate (39). Diester 38 (2.58
g, 4.81 mmol) was heated to 55 °C in 70% aqueous HOAc (25
mL) for 13 h, rotary evaporated, and chromatographed (8:1
cyclohexane/EtOAc) to give quinone 39 (1.508 g, 70%) as a yellow
solid: mp 108 °C (EtOAc); Rf 0.46 (2:1 cyclohexane/EtOAc); IR
(film) 1735, 1669, 1594, 1456 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.32 (s, 9H), 3.33-3.37 (m, 2H), 5.17-5.23 (m, 4H), 7.29-
7.32 (m, 5H), 7.74-7.80 (m, 2H), 8.08-8.14 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 28.3, 41.1, 68.2, 73.9, 81.7, 91.2, 126.8, 127.1,
128.3, 128.8, 129.0, 133.2 (2C), 134.4, 134.6, 135.4, 145.1, 148.1,
168.6, 169.3, 180.8, 181.9; MS (CI, NH3) m/z 468 (M + NH4 +
H2)+, 466 (M + NH4)+; HRMS (CI) m/z calcd for C26H30NO7 (M
+ NH4 + H2)+ 468.2022, found (M + NH4 + H2)+ 468.2018. Anal.
Calcd for C26H28O7: C, 69.63; H, 5.39. Found: C, 69.80; H, 5.27.
(3aSR,5aRS,11aSR)-Benzyl 5a-Hydroxy-2,6,11-trioxo-3,3a,5,-
5a-tetrahydrofuro[3,2-b]naphtho[2,3-c]furan-3a-carboxylate (40).
K2CO3 (27 mg, 0.196 mmol) was added with stirring to quinone
39 (88 mg, 0.196 mmol) and 50% aqueous H2O2 (133 µL, 1.96
mmol) in THF (3 mL). After overnight stirring, saturated aqueous
sodium sulfite (3 mL) and Et2O (10 mL) were added, and the
aqueous phase was extracted with Et2O (5 mL). The combined
organic extracts were dried (MgSO4), filtered, and rotary evaporated.
The crude epoxide(s) was dissolved in CH2Cl2 (3 mL), and TFA
(0.5 mL) was added. After 4 h, the mixture was rotary evaporated
and the residue dissolved in EtOAc, filtered through silica, and
rotary evaporated. Half of the product was dissolved in PhMe (4
mL) and TFA (0.3 mL), heated at 110 °C for 3 h, rotary evaporated,
and chromatographed (2:1 cyclohexane/EtOAc) to give lactone 40
(17 mg, 42%) as a white solid: mp 155 °C (cyclohexene/EtOAc
5/1); Rf 0.28 (2:1 cyclohexane:EtOAc); IR (film) 3307, 1816, 1720,
1
1593, 1271 cm-1; H NMR (CDCl3, 300 MHz) δ 3.04 (d, J )
18.5 Hz, 1H), 3.67 (d, J ) 18.5 Hz, 1H), 4.15 (d, J ) 9.5 Hz, 1H),
4.78 (d, J ) 12.0 Hz, 1H), 4.85 (d, J ) 12.0 Hz, 1H), 4.89 (d, J )
9.5 Hz, 1H), 7.09-7.32 (m, 5H), 7.74-7.85 (m, 2H), 7.98 (d, J )
7.0 Hz, 1H), 8.02 (d, J ) 7.0 Hz, 1H); MS (Cl, NH3) m/z 426 (M
+ NH4)+; HRMS (CI) m/z calcd for C22H20NO8 (M + NH4)+
426.1189, found 426.1184.
(3aSR,5aRS,11aSR)-5a-Hydroxy-2,6,11-trioxo-3,3a,5,5a-tet-
rahydrofuro[3,2-b]naphtho[2,3-c]furan-3a-carboxylic Acid (53).
Ester 40 (20.0 mg, 49.0 µmol) and 10% Pd-C (2 mg) in EtOH (2
mL) and cyclohexene (0.3 mL) were heated at 80 °C for 50 min.
The mixture was filtered, rotary evaporated, and chromatographed
(THF) to give carboxylic acid 53 (14.2 mg, 91%) as a white solid:
161 °C dec (THF); Rf 0.30 (THF); IR (film) 3442, 1807, 1717,
1619, 1574 cm-1; 1H NMR (300 MHz, MeOH-d4) δ 2.17 (s, 1H),
2.92 (d, J ) 18.5 Hz, 1H), 3.57 (d, J ) 18.5 Hz, 1H), 4.36 (d, J )
10.0 Hz, 1H), 4.53 (d, J ) 10.0 Hz, 1H), 7.85-7.93 (m, 2H), 8.10-
8.13 (m, 2H); 13C NMR (75 MHz, MeOH-d4) δ 0.7, 39.8, 53.4,
68.4, 72.5, 86.0, 87.3, 127.7, 127.8, 127.9, 128.6 (3C), 134.3, 134.7,
134.9, 135.1, 166.2, 170.5, 185.8, 190.1; LR, HR or FAB MS failed
to provide usable data.
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Royal Society and the
Wolfson Foundation for a Royal Society Wolfson Research
Merit Award (to A.G.M.B.), the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry in
Medical Sciences at Imperial College, the Engineering and
Physical Sciences Research Council and AstraZeneca for
generous support of our studies, and the European Commission
for a Marie Curie Intra-European Fellowship. We additionally
thank Dr. Andrew P. White for X-ray crystal structure deter-
minations and Peter R. Haycock and Richard N. Sheppard for
high-resolution NMR spectroscopy.
1
1592 cm-1; H NMR (300 MHz, CDCl3) δ 3.05 (d, J ) 18.5 Hz,
1H), 3.62 (d, J ) 18.5 Hz, 1H), 4.55 (d, J ) 10.5 Hz, 1H), 4.66
(d, J ) 10.5 Hz, 1H), 5.38 (d, J ) 12.0 Hz, 1H), 5.44 (d, J ) 12.0
Hz, 1H), 6.03 (s, 1H), 7.46-7.50 (m, 5H), 7.77-7.88 (m, 2H),
8.10 (d, J ) 7.0 Hz, 1H), 8.16 (d, J ) 7.5 Hz, 1H); 13C NMR (75
J. Org. Chem, Vol. 71, No. 6, 2006 2443

Henderson et al.
Supporting Information Available: Additional experimental
procedures and structural data for all new compounds; crystal-
lographic data (including ORTEPs and CIFs) for compounds 19,
21, 24, 28, 38, and 43 (CCDC 292842-292847, respectively);
copies of 1H NMR and 13C NMR spectra for selected new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO052637C
2444 J. Org. Chem., Vol. 71, No. 6, 2006