Unified route to the palmarumycin and preussomerin natural products. Enantioselective synthesis of (-)-preussomerin G

Article abstract of DOI:10.1021/jo0110247

The total syntheses of eight members of the palmarumycin family have been achieved, with identification of the absolute stereochemistry for three of these natural products. In addition, the ras-farnesyl transferase inhibitor (-)-preussomerin G has been synthesized, achieving the first enantioselective route for accessing this family of natural products. Highlights of the synthetic work include an asymmetric epoxidation of a cyclic enone in excellent yield and enantiomeric excess and a potentially biomimetic oxidative spirocyclization for the introduction of the bis-spiroketal array unique to the preussomerin natural products.

Full text of DOI:10.1021/jo0110247

VOLUME 67, NUMBER 9
MAY 3, 2002
© Copyright 2002 by the American Chemical Society
Articles
Un ified Rou te to th e P a lm a r u m ycin a n d P r eu ssom er in Na tu r a l
P r od u cts. En a n tioselective Syn th esis of (-)-P r eu ssom er in G
Anthony G. M. Barrett,*,† Frank Blaney,‡ Andrew D. Campbell,† Dieter Hamprecht,†,‡
Thorsten Meyer,† Andrew J . P. White,† David Witty,‡ and David J . Williams†
Department of Chemistry, Imperial College of Science, Technology and Medicine,
South Kensington, London SW7 2AY, U.K., and GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex CM19 5AW, U.K.
agmb@ic.ac.uk
Received October 24, 2001
The total syntheses of eight members of the palmarumycin family have been achieved, with
identification of the absolute stereochemistry for three of these natural products. In addition, the
ras-farnesyl transferase inhibitor (-)-preussomerin G has been synthesized, achieving the first
enantioselective route for accessing this family of natural products. Highlights of the synthetic
work include an asymmetric epoxidation of a cyclic enone in excellent yield and enantiomeric excess
and a potentially biomimetic oxidative spirocyclization for the introduction of the bis-spiroketal
array unique to the preussomerin natural products.
In tr od u ction
ne, but at rich and varied oxidation levels. All three
classes of fungal metabolites are undoubtedly closely
interrelated biosynthetically and may well be derived
from a 1,8-naphthalenediol spiroketal with late introduc-
tion of the unusual oxygenation patterns. The palmaru-
mycins are exemplified by palmarumycin CP1 (1), C1 (2),
C2 (3), and C11 (4) among greater than 15 other members
that show diverse biological effects including antifungal
and antibacterial activity.1 Since our original publica-
tion,5 other routes for the synthesis of several racemic
palmarumycins and analogues have been published.6
The palmarumycins,1 diepoxins,2 preussomerins,3 and
related compounds4 are a structurally remarkable class
of natural products isolated from various fungal cultures.
They are all graced with a spiro-ketal entity formally
derived from 1,8-naphthalenediol and 1,4-naphthoquino-
† Imperial College of Science, Technology and Medicine.
‡ GlaxoSmithKline.
(1) (a) Krohn, K.; Michel, A.; Flo¨rke, U.; Aust, H.-J .; Draeger, S.;
Schulz, B. Liebigs Ann. Chem. 1994, 1093. (b) Krohn, K.; Michel, A.;
Flo¨rke, U.; Aust, H.-J .; Draeger, S.; Schulz, B. Liebigs Ann. Chem.
1994, 1099. (c) Krohn, K.; Beckmann, K.; Flo¨rke, U.; Aust, H.-J .;
Draeger, S.; Schulz, B.; Busemann, S.; Bringmann, G. Tetrahedron
1997, 53, 3101. (d) Bringmann, G.; Busemann, S.; Krohn, K.; Beck-
mann, K. Tetrahedron 1997, 53, 1655. (e) Chu, M.; Patel, G.; Pai, J .-
K.; Das, R.; Puar, S. Bioorg. Med. Chem. Lett. 1996, 6, 579. (e) Krohn,
K.; Steingro¨ver, K.; Zsila, F. Tetrahedron: Asymmetry 2001, 12, 1961.
(f) Krohn, K. Natural Products Derived from Naphthalenoid Precursors
by Oxidative Dimerization. In Prog. Chem. Org. Nat. Prod. (Herz, W.,
Falk, H., Kirby, G. W., Moore, R. E., Tamm, Ch., Eds.) 2001, 85, in
press.
(3) (a) Weber, H. A.; Baezinger, N. C.; Gloer, J . B. J . Am. Chem.
Soc. 1990, 112, 6718. (b) Weber, H. A.; Gloer, J . B. J . Org. Chem. 1991,
56, 4355. (c) Soman, A. G.; Gloer, J . B.; Koster, B.; Malloch, D. J . Nat.
Prod. 1999, 62, 659. (d) Polishook, J . D.; Dombrowski, A. W.; Tsou, N.
N.; Salituro, G. M.; Curotto, J . E. Mycologia 1993, 85, 62. (e) Singh, S.
B.; Zink, D. L.; Liesch, J . M.; Ball, R. G.; Goetz, M. A.; Bolessa, E. A.;
Giacobbe, R. A.; Silverman, K. C.; Bills, G. F.; Pelaez, F.; Cascales, C.;
Gibbs, J . B.; Lingham, R. B. J . Org. Chem. 1994, 59, 6296. (f) Krohn,
K.; Flo¨rke, U.; J ohn, M.; Root, N.; Steingro¨ver, K.; Aust, H.-J .; Draeger,
S.; Schulz, B.; Antus, S.; Simonyi, M.; Zsila, F. Tetrahedron 2001, 57,
4343.
(2) (a) Schlingmann, G.; West, R.; Milne, L.; Pearce, C. J .; Carter,
G. T. Tetrahedron Lett. 1993, 34, 7225. (b) Schlingmann, G.; Matile,
S.; Berova, N.; Nakanishi, K.; Carter, G. T. Tetrahedron 1996, 52, 435.
10.1021/jo0110247 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/03/2002

2736 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
The diepoxins were first reported in 1993 by Schling-
mann and co-workers and are characterized by the bis-
epoxide functionality on the northern fused decalin
rings.2 Subsequent publications of related products4
expanded this growing class to greater than 10 members
at present. The structures are exemplified by diepoxin
æ, also named palmarumycin C10 (5); diepoxin ú (6), also
named Sch 53516, palmarumycin C14, and cladispirone
bisepoxide; diepoxin η (7), also named Sch 53514 and
palmarumycin C13; and diepoxin σ (8), also named Sch
49209. The antitumor activity of diepoxin σ (8) was first
revealed by Chu and co-workers in 1994, with an IC50 of
0.75 µm against the invasion of HT 1080 human fibro-
sarcoma cells.4e Wipf et al. have recently reported an
elegant formal enantioselective synthesis of diepoxin
σ (8) using a key enantioselective asymmetric Diels-
Alder reaction of O-methyl naphthazarin and cyclopen-
tadiene.7
ketal functionality. Later work by Polishook and co-
workers led to the isolation of preussomerins from the
endophytic fungus Harmonerna demtioides.3d Singh et al.
isolated preussomerins G (11), H, and I (12) along with
preussomerin D (10) from the fermentation broth of an
unidentified ceolomycetes fungus.3e From the same broth,
the deoxypreussomerins B (3) and A (13), also respec-
tively known as palmarumycins C2 and CP2, were also
isolated. These were assumed to be biosynthetic pre-
cursors of the preussomerins. Singh et al. also showed
that preussomerins D (10) and G (11) had pronounced
ras-farnesyl transferase activity and are thus of potential
interest in cancer chemotherapy.3e Later, Krohn and
co-workers isolated a further three-members of the
preussomerin family, preussomerins J , K, and L (14),
and confirmed their absolute configuration by compar-
ison of experimentally determined and calculated CD
spectra.3f
The preussomerin family of natural products including
preussomerin A (9) and D (10) were originally isolated
from Preussia isomera in 1990 by Gloer and co-workers3a-c
during an investigation into interspecies competition
among coprophilous (dung-colonizing) fungi. These un-
usual natural products are characterized by a unique bis-
In 1999, Chi and Heathcock published an elegant
synthesis of racemic preussomerin G (11) and I (12) using
a potentially biomimetic construction of the unusual
diketal ring system (Scheme 1).8 Thus, trichloroacetate
15 was hydrolyzed to intermediate 16, subsequent tau-
tomerization formed bisketal 17 after protonation. The
authors depicted the reaction as a two-electron process
but did not discuss the mechanism further. The energy
difference, determined through ab initio calculations, was
found to be in favor of isomer 17 over quinone 16. The
syntheses of preussomerin I (12) and G (11) were
completed from diketal 17 in eight and nine steps,
respectively. Later work by Taylor and co-workers de-
scribed an alternative way of generating the preussom-
erin nucleus via 2-arylacetal anions.9
(4) (a) Thiergardt, R.; Hug, P.; Rihs, G.; Peter, H. H. Tetrahedron
Lett. 1994, 35, 1043. (b) Thiergardt, R.; Hug, P.; Rihs, G.; Peter, H. H.
Tetrahedron 1995, 51, 733. (c) Chu, M.; Truumees, I.; Patel, M. G.;
Gullo, V. P.; Blood, C.; King, I.; Pai, J .-K.; Puar, M. S. Tetrahedron
Lett. 1994, 35, 1343. (d) Petersen, F.; Moerker, T.; Vanzanella, F.; Peter,
H. H. J . Antibiot. 1994, 47, 1098. (e) Chu, M.; Truumees, I.; Patel, M.
G.; Gullo, V. P.; Puar, M. S. J . Org. Chem. 1994, 59, 1222. (f) Chu, M.;
Truumees, I.; Patel, M. G.; Blood, C.; Das, P. P.; Puar, M. S. J . Antibiot.
1995, 48, 329. (g) Sakemi, S.; Inagaki, T.; Kaned, K.; Hirai, H.; Iwata,
E.; Sakakibara, T.; Yamauchi, Y.; Norcia, M.; Wondrack, L. M.;
Sutcliffe, J . A.; Kojima, N. J . Antibiot. 1995, 48, 134. (h) Ogishi, H.;
Chiba, N.; Mikawa, T.; Sakaki, T.; Miyaji, S.; Sezaki, M. J pn Pat. J P
01294686 A2, Nov 28, 1989; Chem. Abstr. 1990, 113, 38906q. (i)
McDonald, L. A.; Abbanat, D. R.; Barbieri, L. R.; Bernan, V. S.;
Discafani, C. M.; Greenstein, M.; J anota, K.; Korshalla, J . D.; Lassota,
P.; Tischler, M.; Carter, G. T. Tetrahedron Lett. 1999, 40, 2489.
(5) Barrett, A. G. M.; Hamprecht, D.; Meyer, T. Chem. Commun.
1998, 809.
(6) (a) Wipf, P.; J ung, J .-K. J . Org. Chem. 1998, 63, 3530. (b) Ragot,
J . P.; Alcaraz, M.-L.; Taylor, R. J . K. Tetrahedron Lett. 1998, 39, 4921.
(c) Ragot, J . P.; Steeneck, C.; Alcaraz, M.-L.; Taylor, R. J . K. J . Chem.
Soc., Perkin Trans. 1 1999, 1073. (d) Coutts, I. G. C.; Allcock, R. W.;
Scheeren, H. W. Tetrahedron Lett. 2000, 41, 9105. (e) Wipf, P.; J ung,
J .-K.; Rodr´ıguez, S.; Lazo, J . S. Tetrahedron 2001, 57, 283. (f) see also
Krohn, K.; Beckmann, K.; Aust, H.-J .; Draeger, S.; Schulz, B.; Buse-
mann, S.; Bringmann, G. Liebigs Ann./ Recueil 1997, 2531.
(7) Wipf, P.; J ung, J .-K. J . Org. Chem. 2000, 65, 6319 and references
therein.
Resu lts a n d Discu ssion
Our initial retrosynthetic plan (Scheme 2) was to
proceed via a route that may enable the synthesis of
members of the palmarumycin, diepoxin, and laterally
the unique preussomerin natural products in enantiopure
form all from the same start point, drawing support from
the proposed biosynthetic pathway. Thus, acid-catalyzed
ketalization of 1,8-naphthalenediol 21 and 5-methoxyte-
(8) Chi, S. C.; Heathcock, C. H. Org. Lett. 1999, 1, 3.
(9) Ragot, J . P.; Prime, M. E.; Archibald, S. J .; Taylor, R. J . K. Org.
Lett. 2000, 2, 1613.

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2737
Sch em e 2
tetralone 20 with 1,8-naphthalenediol 21 under acid
catalysis. The reaction proceeded smoothly on a 1 mmol
scale under Dean-Stark conditions to give 86% yield of
the desired product 22. Unfortunately, this yield was
lowered to 53% on a 125 mmol scale, but was nonetheless
reproducible. The structure of spiroketal 22 was con-
firmed by X-ray crystallography. At this point, we decided
to carry out extensive model studies to ascertain a
reactivity chart for the palmarumycin core. Interestingly,
it turned out that the naphthalene moiety is the preferred
site of reaction for a wide range of reagents as exemplified
in Scheme 3.
Friedel-Crafts acylation of arene 22 using the condi-
tions of Kobayashi10 resulted in the smooth conversion
to ketone 24. Reaction of arene 22 with N-bromosuccin-
imide in acetonitrile also proceeded with substitution
para to the alkoxy substituent to provide bromide 25.
Acetoxylation of arene 22 using lead tetraacetate in acetic
acid and dichloromethane proceeded with similar selec-
tivity to reveal ester 26.11 Alternatively ortho-lithiation
and trapping with trimethyl borate gave, on oxidative
workup, the phenol 23 thereby underscoring the Lewis
basic nature of the spiroketal oxygens. However, the
northern anisole entity in spiroketal 22 could be selec-
tively oxidized to the corresponding quinone 28 by
demethylation to produce phenol 27 followed by hyper-
valent iodine-mediated oxidation (Scheme 4). Thus,
treatment of spiroketal 22 with sodium ethanethiolate
(2 equiv) in DMF at reflux gave phenol 27 in an excellent
97% yield. Oxidation using bis-trifluoroacetoxyiodoben-
zene (2 equiv) in THF and water (9:1) resulted in clean
tralone 20 followed by judicious choice of oxidation could
form palmarumycin CP1 (1) which could be enantiose-
lectively epoxidized to give palmarumycin C2 (3) before
further oxidation to keto-quinone 19. This intermediate
has the potential to undergo selective epoxidation to
furnish the diepoxins. Alternatively, quinone 19 could be
reduced and further functionalized on the southern
naphthalene ring (with creation of a remote ketal chiral
center) to give triol 18, which could be oxidized followed
by tautomerization to give preussomerin G (11).
The starting point for our synthesis was the prepara-
tion of spiroketal 22 by the condensation of 5-methoxy-
Sch em e 1
(10) Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545.
(11) Norman, R. O. C.; Thomas, C. B.; Willson, J . S. J . Chem. Soc.
B 1971, 518 and references therein.

2738 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
Sch em e 3
Sch em e 4
formation of the corresponding quinone 28. The choice
of solvent was shown to be crucial to the success of the
reaction with more polar solvents (e.g., acetonitrile)
favoring oxidation of the naphthalene moiety. We specu-
late that the polar solvent may facilitate stabilization of
a SET derived charge tranfer complex with the hyper-
valent iodine reagent. Switching to the less polar THF
as cosolvent may allow a two-electron oxidation process
to occur on the phenol ring.
In addition to the investigations of spiroketal oxidation
reactions, we decided to carry out model studies to access
the preussomerin core. In addition, it was hoped that our
studies might also shed some light on the mechanism of
the Heathcock cyclization8 originally tentatively drawn
as a two-electron phenolate tautomerization. Thus, phe-
nol 27 was protected as its benzyl ether which was
acetoxylated to provide acetate 29. Benzyl ether hydro-
genolysis followed by bis-trifluoroacetoxyiodobenzene
mediated oxidation afforded the quinone product 30 in
51% yield over two steps in approximately 90% purity.
We hoped that treatment of quinone 30 with aqueous
lithium hydroxide, according to the procedure of Chi and
Heathcock,8 would provide the preussomerin core. Un-
fortunately, none of the desired product was formed as
1
judged by analysis of the crude H NMR spectrum. The
reasons for this may simply be the lower rate of saponi-
fication of the acetate versus the trichloroacetate allowing
for competitive degradation. Despite this setback, we
considered an oxidative route to the preussomerin core
and thus quinone 30 was reduced with aqueous dithionite
to the unstable hydroquinone. Without further purifica-
tion, the acetate was subject to Zemplen methanolysis
to give triol 31. We were delighted to find that oxidative
cyclization of triol 31 with p-benzoquinone at -78 °C in

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2739
tones.14 CJ -12,371 (33)4g is a DNA-gyrase inhibitor
isolated from an unidentified fungus (N983-46). The
spectroscopic data of our synthetic material exactly
matched those published for the natural product 33.4g
Oxidation of CJ -12,371 (33) using bis-trifluoroacetoxy-
iodobenzene in aqueous THF followed by reduction with
sodium dithionite gave the corresponding hydroquinone
34 (56%). This substance showed spectroscopic data in
full agreement with that published for the natural
product CJ -12,372 (34).4g The synthetic material 34 was
found to have undergone racemization presumably
through a quinomethide pathway.
Sch em e 5
To obtain the R,â-unsaturated ketone moiety of pal-
marumycin CP1 (1), ketone 32 was dehydrogenated using
DDQ in benzene at reflux followed by O-demethylation
of ether 35 using B-bromocatecholborane to furnish
palmarumycin CP1 (1) in 36% yield over two steps.
Although successful on a small scale, the yield dropped
substantially on a larger scale. Additionally, the DDQ
oxidation reaction gave rise to a second minor product
37 (8%). The structure of this substance was established
as the furan 37 by an X-ray crystallographic study.
Presumably this product was formed by a SET cycload-
dition and subsequent retro-Diels Alder reaction mech-
anism. Accordingly these problems were circumvented
by formation of silyl-enol ether 36 from palmarumycin
CP2 (13) using trimethylsilyl trifluoromethanesulfonate
and 2,6-lutidine followed by Saegusa oxidation15 using
palladium acetate to form palmarumycin CP1 (1) in an
excellent 60-78% yield over a range of reaction scales
(Scheme 6). The spectroscopic data for palmarumycin CP1
(1) again accurately matched that published in the paper
describing its isolation.1a Additionally, the synthetic
compound 1 was identical with an authentic sample of
the natural product palmarumycin CP1 (1) kindly pro-
vided by Professor Karsten Krohn.
dry, degassed THF smoothly formed the preussomerin
17 in 75% yield after purification (Scheme 4). The exact
mechanism awaits further study but an SET mechanism
seems most likely to be operating.
With the early model studies proceeding well, we
undertook the syntheses of several palmarumycin natu-
ral products en route to the preussomerins. Thus, ben-
zylic oxidation of 22 using catalytic bipyridinium chlo-
rochromate, tert-butyl hydroperoxide, and Celite smoothly
formed ketone 32 in 60% yield.12 Many alternative
oxidants including the recently published periodinane
IBX-mediated oxidation by Nicolaou et al. were much less
efficient.13 Deprotection of the methyl ether was easily
achieved by treatment with freshly prepared magnesium
iodide in THF at room temperature for 24 h (with care
to exclude light) to give palmarumycin CP2 (13). The
spectroscopic data for this synthetic material exactly
matched that published1a and the compound was identi-
cal with an authentic sample of palmarumycin CP2 (13)
kindly provided by Professor Karsten Krohn. Ketone 13
was converted into CJ -12,371 (33) (60% yield, 93% ee)
by asymmetric reduction using (+)-B-chlorodiisopinocam-
pheylborane (Scheme 5).14 The enantiomeric excess of
alcohol 33 was determined by chiral HPLC while the
absolute stereochemistry was determined by comparison
With multigram quantities of synthetic palmarumycin
CP1 (1) now in hand, we focused our attention on
enantioselective epoxidation of the cyclic enone moiety,
a reaction that has been employed with little success
historically but for a few exceptions.16 Our attempts were
directed to the use of chiral phase transfer conditions
developed by Wynberg and co-workers16a and later used
by Taylor and co-workers for enantioselective epoxidation
of a quinone monoketal (32% yield, 89% ee) in their
synthesis of (+)-manumycin.16b Accordingly, the epoxi-
dation of palmarumycin CP1 (1) using N-benzylcincho-
ninium chloride 39 (10 mol %) as the chiral phase
transfer catalyst proceeded smoothly to provide the
desired epoxide 3 in an excellent 81% yield. Furthermore
the enantiomeric excess of the product 3 was greater than
95% as determined by chiral HPLC in comparison with
the racemic epoxide. The spectroscopic data for the
synthetic palmarumycin C2 (3) matched that published
for the natural product.1b Additionally, our synthetic
palmarumycin C2 (3) was identical with an authentic
sample of the natural product palmarumycin C2 (3), also
named deoxypreussomerin B, kindly provided by Dr.
Sheo B. Singh of Merck & Co., Inc. Finally, we have
confirmed the structure of our synthetic palmarumycin
of the optical rotation, [R]24 -42.2 (c 0.45, MeOH), with
D
that of the isolated natural product CJ -12,371 (33), [R]24
D
-46.8 (c 0.23, MeOH). It is germane to mention that
reduction presumably takes place via intramolecular
hydride delivery thereby reversing the absolute stereo-
chemistry of reaction seen with simple alkyl aryl ke-
(12) Rathore, R.; Saxena, N.; Chandrasekaran, S. Synth. Commun.
1986, 16, 1493.
(13) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L. J . Am. Chem. Soc.
2001, 123, 3183.
(14) Ramachandran, P. V.; Gong, B.; Brown, H. C. Tetrahedron Lett.
1994, 35, 2141.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(16) (a) Wynberg, H. Top. Stereochem. 1986, 16, 87. (b) Macdonald,
G.; Alcaraz, L.; Lewis, N. J .; Taylor, R. J . K. Tetrahedron Lett. 1998,
39, 5433 and references therein. (c) Arai, S.; Oku, M.; Miura, M.;
Shioiri, T. Synlett 1998, 1201.

2740 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
Sch em e 6
Sch em e 7
Sch em e 8
interaction is formed between the phenoxy-enone moiety
and the positively charged ammonium residue, thereby
activating the enone system from both ends. Due to the
shielding of the two aromatic sidearms, the preferred
direction of approach of the oxidant is to the si face of
the enone. On the other hand, in transition state 42, the
ammonium moiety is orientated away from the enone
system and no secondary interaction is possible. The cal-
culated energy difference of 3.9 kcal/mol for the two pre-
transition state complexes 41 and 42 are consistent with
a highly asymmetric addition of the hydroperoxide anion.
It is also noteworthy that epoxidation of palmarumycin
CP1 (1) with pseudo-enantiomeric N-benzylcinchonidin-
ium chloride proceeded with lower yield (69%) and much
lower enantioselecivity (14%). Similar findings were ob-
served by Taylor et al.,16b although in their system N-
benzylcinchonidinium chloride was successful (32% yield,
89% ee) while the pseudo enantiomer N-benzylcincho-
ninium chloride 39 was less effective (15%, 10% ee).
With the key epoxide intermediate, palmarumycin C2
(3), available in ample quantities, the next aim was
aromatic substitution of the naphthalene ring concurrent
with the creation of a chiral center at the spiro-ketal
carbon. Treatment of naphthalene 3 with acetyl nitrate18
resulted in aromatic substitution to form the nitroarenes
43 and 44 (1:1). Alternatively, bromination using N-
bromosuccinimide gave bromides 45 and 46 (1:1) (Scheme
9). Contrary to our hope that the epoxide entity in
palmarumycin C2 (3) would favor formation of isomers
C2 (3) by an X-ray structure determination. The optical
rotation of synthetic palmarumycin C2 (3), [R]20 -300
D
(c 1.00, CHCl3), was in reasonable agreement with the
value for the natural product, [R]20 -3411b (c 1.00,
D
CHCl3). Synthetic palmarumycin C2 (3) was coupled with
N-phenylsulfonyl proline to provide the crystalline ester
38 (Scheme 7) the structure of which was confirmed by
X-ray crystallography. This unequivocally verified the
absolute configuration of palmarumycin C2 (3) as 2(R),
3(S) and confirmed the stereochemical assignments for
palmarumycin C2 (3) by Bringmann et al. which were
based upon CD measurements.1d
It is also interesting to note that epoxidation of the
enone 35 under the same chiral phase transfer reaction
conditions resulted in a much slower and less efficient
reaction. The epoxide product 40 was isolated in only 61%
yield after 9 days reaction but in a much lower (23%)
enantiomeric excess (Scheme 8). This result clearly
underscores the key role of the phenol moiety in struc-
turing the transition state for the enantioselective hy-
droperoxide anion addition to the enone (Figure 1). On
the basis of these conformational and electronic analyses
of the catalyst, two diastereoisomeric pre-transition state
complexes 41 and 42 could be formulated through energy
minimization calculations.17 As can be seen for complex
41, the alcohol motif in the catalyst is hydrogen bonded
to one of the spiroketal oxygen atoms while a secondary
(17) The minimizations were performed using the Spartan applica-
tion employing AM1 semiempirical parameters.
(18) Fitzgerald, J . J .; Drysdale, N. E.; Olofson, R. A. Synth. Commun.
1992, 22, 1807.

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2741
Sch em e 9
Sch em e 10
F igu r e 1.
44 and 46 by reducing electron density at the anti-
spiroketal oxygen, both nitration and bromination reac-
tions proceeded without any significant diastereoselec-
tivities. In consequence, we attempted a kinetic resolution
approach to the naphthalene substitution problem. Thus,
palmarumycin CP1 (1) was allowed to react with acetyl
nitrate or N-bromosuccinimide to form the racemic are-
nes 47 and 48 respectively in good yield. These products
were subjected to the standard asymmetric epoxidation
conditions described earlier using only 50 mol % of tert-
butyl hydroperoxide in the hope that each enantiomer
would react at substantially different rates via diaste-
reoisomeric transition states. Unfortunately, although
both epoxidation reactions resulted in the required
conversions, the products 43/44 and 45/46 were both
isolated as a 1:1 mixture of diastereoisomers (Scheme 10).
At this point, it became apparent that a selective
substitution on the naphthalene ring would be difficult
without the aid of carefully designed chiral nitration or
bromination reagents. Therefore, to access the preus-
somerin natural products, we faced the necessity of a
separation of the diastereoisomers, but single enanti-
omers, at a late stage of the synthesis. We considered
that the extra conformational constriction imposed by the
second ketal unit of the preussomerins would allow an
easier separation of the two diastereoisomers. The pairs
of diastereoisomeric spiroketals 43/44 and 45/46 were

2742 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
Sch em e 11
configuration of palmarumycin C12 (49) is unequivocally
2(R),3(R),4(R)1f (Scheme 11).
Following hypervalent iodine-mediated oxidation of
palmarumycin C11 (4), the corresponding quinone was
further oxidized to the corresponding keto-quinone by
reaction with manganese dioxide. Subsequent reduction
of the quinone functionality with ascorbic acid gave
palmarumycin C3 (50) in 31% yield over three steps
(Scheme 11). The spectroscopic data for the synthetic
hydroquinone 50 matched that published for naturally
occurring palmarumycin C3 (50) although the optical
rotation value was found to be lower with the synthetic
sample ([R]20 -246 (c 1.00, CH2Cl2)) than the natural
D
product ([R]20D -300 (c 1.00, CH2Cl2)).1b Nonetheless, the
absolute configuration of palmarumycin C3 (50) is un-
equivocally 2(R),3(S).
Palmarumycin C3 (50) was converted into the corre-
sponding methoxyacetate 51 in excellent yield (92%), and
the product 51 was subjected to acetoxylation using lead
tetraacetate.11 The reaction was sluggish compared to
earlier studies possibly due to coordination of the lead
reagent to the methoxyacetate esters, however this lack
of reactivity was overcome by elevation of the reaction
temperature to 40 °C. Heating for 24-36 h smoothly
formed the desired products 52 as a 1:1 mixture of
diastereoisomers as expected. Unfortunately, the north-
ern methoxyacetate unit proved partially labile to silica
gel chromatography hampering clean isolation. There-
fore, the crude product 52 was simply treated with excess
lithium hydroxide in aqueous THF at 0 °C for 90 min to
furnish the desired triol 53 as a 1:1 mixture of diastere-
oisomers in 37% yield over two steps (Scheme 12).
With sufficient quantities of triol 53 in hand, we
examined the key oxidative cyclization reaction. We were
initially pleased to find that oxidation of triol 53 with
p-benzoquinone gave small quantities of the desired
preussomerin which was identified by analysis of the
crude 1H NMR spectrum. However, the yield was low,
and elevated temperatures were needed for reaction
compared with the model system (Scheme 4). The re-
maining material was largely recovered triol 53. Obvi-
ously the keto-moiety on the northern hydroquinone unit
decelerates the oxidation step consistent with this unit
being the site of oxidation and not the southern alkoxy-
hydroquinone moiety. A range of alternative oxidative
cyclization procedures were investigated and we were
delighted to find that treatment of triol 53 with lead
tetraacetate (1 equiv) at -78 °C for 10 min in dry
degassed dichloromethane smoothly formed (-)-preus-
somerin G (11) and (+)-epipreussomerin G (54) in an
excellent 55% yield as a 1:1 mixture of diastereoisomers
(Scheme 12). Furthermore, the conformational rigidity
conferred by the extra ring allowed the diastereoisomeric
products to be easily separated by chromatography.
Synthetic (-)-preussomerin G (11) showed spectroscopic
data fully matching that reported for the naturally
occurring preussomerin G (11).3e However, the optical
rotation for the synthetic material ([R]D -533 (c 0.05,
CH2Cl2)) was significantly lower than the value reported
for the natural product (lit.3e [R]D -688, (c 0.66, CH2-
Cl2)).3e Since we were concerned that our synthesis may
have proceeded with partial racemization, the conversion
of synthetic palmarumycin CP1 (1) into preussomerin G
(11) and epipreussomerin G (54) was repeated in the
racemic series. Thus epoxidation of palmarumycin CP1
(1) using the DBU-catalyzed addition of tert-butyl hy-
both chromatographically homogeneous. However frac-
tional crystallization of the nitroepoxide mixture of 43
and 44 from ethyl acetate and pentane gave crystals of
43 of sufficient quality to permit the determination of
an X-ray crystal structure. In addition, the mother liquor
was enhanced in the other diastereoisomer 44 as shown
1
by H NMR analysis.
We proceeded to synthesize more advanced members
of the palmarumycin family of natural products, and
accordingly, palmarumycin C2 (3) was reduced with
sodium borohydride in methanol to give palmarumycin
C11 (4) in good yield provided sonication was used prior
to hydride addition to aid solubilization of the starting
epoxy ketone (Scheme 11). The data for the synthetic
palmarumycin C11 (4) ([R]20 -155 (c 1.00, CH2Cl2))
D
closely matched that reported by Krohn1b for the natural
product ([R]20 -153 (c 0.24, CH2Cl2)). This implies that
D
the absolute configuration of palmarumycin C11 (4) is
unequivocally 2(R),3(R),4(R) and not 2(S),3(S),4(S) as
arbitarily drawn in the Krohn paper. Additionally, Chu
et al. have reported the isolation of Sch 53823, which was
stated to have structure 4.1e Since the reported physical
and spectroscopic data for Sch 53823 differ significantly
from palmarumycin C11 (4), this natural product has been
incorrectly identified.6c Possibly it is the epimeric second-
ary alcohol. Palmarumycin C11 (4) was subjected to the
standard phenol oxidation procedures to furnish the
unstable quinone alcohol, which was used without puri-
fication. Reduction with aqueous sodium dithionite fur-
nished palmarumycin C12 (49) in 30% yield over two steps
after purification. The authenticity of synthetic palmaru-
mycin C12 (49) was confirmed by comparison of the
spectral data with that published for the natural product.1b
In addition, the optical rotation ([R]20D -165 (c 0.26, CH2-
Cl2)) also correlated well with the reported value ([R]20
D
-179.6 (c 0.20, CH2Cl2)),1b implying that the absolute

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2743
Sch em e 12
(230-400 mesh) (eluants are given in parentheses). All reac-
tions were carried out in oven-dried glassware under N2
atmosphere unless stated otherwise. All reagents were used
as supplied. Solvents were distilled prior to use when anhy-
drous conditions were required: Et3N, pyridine, DMF, PhH,
MeCN, and CH2Cl2 were distilled from calcium hydride under
nitrogen; THF and Et2O were distilled from sodium wire and
benzophenone while DBU was filtered through a short column
of basic alumina. Ac2O was distilled from phosphorus pentox-
ide, B(OMe)3 from LiCl. Solutions of tert-butyl hydroperoxide
in PhMe or PhH were dried by azeotropic removal of the H2O,
and the concentrations were determined by 1H NMR spectros-
copy.
droperoxide gave the racemic epoxide (()-palmarumycin
C2 (3) (83%). Subsequent redox manipulations using
exactly the same methods as described in Schemes 11
and 12 gave racemic preussomerin G (()-(11) and
epipreussomerin G (()-54. Chiral HPLC confirmed that
the synthetic preussomerin G (11) was indeed a single
enantiomer (tR 9 min 55 s) and not contaminated by the
enantiomer (tR 9 min). Finally, the synthetic preussom-
erin G (11) was identical with an authentic sample3f
kindly provided by Professor Karsten Krohn. In our
hands this sample of natural preussomerin G (11) showed
an optical rotation value of [R]D -567 (c 0.68, CH2Cl2).
Na p h th a len e-1,8-d iol 21. 1,8-Naphthosultone (24.62 g, 120
mmol), KOH pellets (105.5 g, 1.884 mol), and H2O (35 mL)
were heated to 225 °C under a stream of N2. A green melt
obtained initially was converted into a black tar, and heating
was continued for 30 min until the mixture solidified. After
cooling to room temperature, the black residue was dissolved
in H2O (1.75 L) and Et2O (600 mL) and the mixture was
acidified with 13% w/w hydrochloric acid (560 mL). The organic
layer was separated and the aqueous layer was extracted with
Et2O (2 × 500 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Chromatography
(EtOAc/hexanes, 1:2 to 1:1) gave diol 21 (15.87 g, 83%) as a
white solid: mp 140-141 °C (EtOAc/hexanes) (lit.19 mp 141-
142 °C).
(2H)-5-Meth oxy-2,3-dih ydr ospir o[n aph th alen e-1(4H),2′-
n a p h th o[1,8-d e][1,3]d ioxin e] 22. 5-Methoxytetralone 20
(8.80 g, 50 mmol), TsOH‚H2O (1.90 g, 10.0 mmol), and diol 21
(10.0 g, 62.5 mmol) in PhMe (125 mL) were heated to reflux
under N2 (Dean-Stark with 4 Å molecular sieves). The brown
mixture was heated under reflux for 72 h, cooled to room
temperature, and rotary evaporated to dryness. The residue
was dissolved in Et2O (500 mL) and saturated aqueous
NaHCO3 (200 mL), and the organic layer was dried (MgSO4),
filtered, and rotary evaporated. The resulting yellow solid was
chromatographed (Et2O/hexanes, 1:5) to provide spiroketal 2220
(8.37 g, 53%) as a slightly yellow solid: mp 155 °C (hexanes/
Et2O); Rf 0.40 (EtOAc/hexanes 1:9); IR (KBr disk) 1604, 1272
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.95 (m, 2H), 2.16 (m, 2H),
2.82 (t, J ) 6.6 Hz, 2H), 3.90 (s, 3H), 6.94 (m, 3H), 7.35 (app-
t, J ) 8.0 Hz, 1H), 7.44-7.58 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 18.8, 23.1, 30.4, 55.6, 110.6, 109.3, 110.4, 111.3, 119.2,
120.2, 127.1, 127.4, 127.5, 134.2, 136.3, 148.3, 156.7; MS (CI)
Con clu sion s
In conclusion, we have developed a unified approach
to the palmarumycin and preussomerin natural products
culminating in the synthesis of two achiral, one racemic,
and five enantiomerically pure members of the palmaru-
mycin family and establishing the absolute configuration
in three cases for the first time. In addition we have
achieved an enantioselective synthesis of (-)-preussom-
erin G (11), this being the first enantioselective synthesis
of the preussomerin class of natural products. These
natural products were synthesized utilizing a chiral
phase transfer catalyzed epoxidation procedure and a
potentially biomimetic oxidative cyclization as the key
synthetic steps. We are currently applying the same
methodology to the synthesis of additional preussomerins
and diepoxins.
Exp er im en ta l Section
Gen er a l P r oced u r es. Normal phase HPLC separations
were carried out with Unicam Crystal 200 or Alliance Waters
2690 machines using Chiracel OD-H or Chiralpak AD (250 mm
× 4.6 mm) columns. The following methods were applied:
method A, EtOH/hexane (3:17), flow 0.7 mL/min, 212 nm;
method B, EtOH/hexane (1:19), flow 1 mL/min, 224 nm;
method C: EtOH/hexane (1:19), flow 0.7 mL/min., 224 nm;
method D: EtOH/hexane (1:1), flow 1 mL/min, 215 nm.
Analytical and preparative thin-layer chromatography (TLC)
was performed on silica gel TLC plates. Visualization was
accomplished using UV light or by staining with potassium
permanganate or vanillin solutions. Column chromatography
was performed under medium pressure using silica gel 60
(19) Erdmann, H. Liebigs Ann. 1888, 247, 306.
(20) For the initial report of this compound see ref 5; for subsequent
publications see refs 6b and 6c.

2744 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
m/z 319 (M + H)+ m/z (CI) calcd for C21H19O3 319.1334, found
319.1344. Anal. Calcd for C21H18O3: C, 79.21; H, 5.70. Found:
C, 78.97; H, 5.71. Crystal data for 22: C21H18O3, M ) 318.4,
monoclinic, P21 (no. 4), a ) 8.890(1) Å, b ) 8.478(1) Å, c )
11.474(1) Å, â ) 109.27(1)°, V ) 816.3(1) Å3, Z ) 2, Dc ) 1.295
g cm-3, µ(Cu KR) ) 0.69 mm-1, T ) 293 K, colorless prisms;
(s, 1H), 3.85 (s, 3H), 6.87 (d, J ) 7.4 Hz, 1H), 6.93 (d, J ) 7.7
Hz, 1H), 7.21-7.49 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 19.2,
23.0, 30.5, 55.6, 100.9, 109.8, 110.5, 114.1, 118.1, 119.4, 120.5,
120.8, 124.7, 127.0, 127.6, 128.7, 131.9, 136.0, 138.9, 146.9,
156.7; MS (CI) m/z 335 (M + H)+, 177; m/z (CI) calcd for
C
21H19O4 335.1283, found 335.1291.
1293 independent measured reflections, F2 refinement, R1
)
(2H)-4′-Acetoxy-5-m eth oxy-2,3-d ih yd r osp ir o[n a p h th a -
0.049, wR2 ) 0.136, 1130 independent observed reflections [|Fo|
> 4σ(|Fo|), 2θ e 120°], 218 parameters. The absolute structure
of 22 could not be determined. CCDC 182476.
len e-1(4H),2′-n a p h th o[1,8-d e][1,3]d ioxin e] 26. CH2Cl2 (2
mL) and AcOH (4 mL) were added to spiroketal 22 (80 mg,
0.25 mmol) and Pb(OAc)4 (216 mg, 0.50 mmol), and the
mixture was stirred under N2 for 16 h. The mixture was
diluted with EtOAc (20 mL) and saturated aqueous NH4Cl (10
mL), and the organic layer was separated, dried (MgSO4), and
filtered. Chromatography (EtOAc/hexanes, 1:4) gave 26 (61
mg, 65%) as a white solid: mp 144-146 °C (Et2O); Rf 0.20
(EtOAc/hexanes 1:4); IR (thin film) 1763, 1608, 1201 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.88-1.98 (m, 2H), 2.11-2.17 (m,
2H), 2.46 (s, 3H), 2.81 (t, J ) 6.3 Hz, 2H), 3.88 (s, 3H), 6.85-
7.00 (m, 3H), 7.19 (d, J ) 8.1 Hz, 1H), 7.35 (app-t, J ) 8.1 Hz,
1H), 7.42-7.50 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 19.1,
21.3, 23.4, 30.8, 55.9, 101.3, 109.1, 110.5, 110.8, 114.5, 114.7,
119.5, 119.9, 127.4, 127.7, 127.9, 128.5, 136.5, 140.8, 146.4,
148.9, 157.1, 170.1; MS (CI) m/z 377 (M + H)+. Anal. Calcd
for C23H20O5: C, 73.39; H, 5.36. Found: C, 73.36; H, 5.24.
(2H)-5-Hydr oxy-2,3-dih ydr ospir o[n aph th alen e-1(4H),2′-
n a p h th o[1,8-d e][1,3]d ioxin e] 27. DMF (5 mL) was added to
anisole 22 (318 mg, 1.0 mmol, 1.0 equiv) and NaSEt (168 mg,
2.0 mmol, 2.0 equiv), and the resulting red solution was heated
to reflux for 90 min under N2. After the mixture was cooled to
room temperature, H2O (5 mL) was added, and the reaction
mixture was acidified with 1.0 M aqueous HCl. A white solid
precipitated out of the orange organic layer. Et2O (20 mL) was
added, the layers were separated, and the aqueous phase was
extracted with Et2O (10 mL). The combined organic layers
were washed with brine (10 mL), dried (MgSO4), and rotary
evaporated to give a yellow solid that was adsorbed on silica
gel (1.5 g). Chromatography (Et2O/hexanes, 2:1) gave phenol
27 (291 mg, 97%) as a white solid: mp 158 °C (Et2O/hexane);
Rf 0.43 (Et2O/hexanes, 3:2); IR (KBr disk) 3317, 1632, 1608,
(2H )-4′-Br om o-5-m et h oxy-2,3-d ih yd r osp ir o[n a p h t h a -
len e-1(4H),2′-n a p h th o[1,8-d e][1,3]d ioxin e] 25. Freshly re-
crystallized NBS (3.91 g, 22 mmol) was added in portions over
a period of 30 min to anisole 22 (6.37 g, 20 mmol) in dry MeCN
(100 mL). The dark blue solution was maintained at room
temperature for 1 h while it turned cloudy. Silica gel (30 g)
was added, the mixture was rotary evaporated, and the
resulting solid chromatographed (Et2O/hexanes, 1:1). A dark
liquid was collected and then stirred over activated charcoal
(5 g) for 30 min. After filtration and evaporation of the solvent,
bromide 25 (7.43 g, 94%) was obtained as a white foam: Rf
0.43 (Et2O/hexanes 3:2); IR (KBr disk) 1605, 1472, 1262 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.90-1.97 (m, 2H), 2.12-2.16
(m, 2H), 2.81-2.85 (m, 2H), 3.90 (s, 3H), 6.84 (d, J ) 8.1 Hz,
1H), 6.95 (d, J ) 7.9 Hz, 1H), 7.02 (d, J ) 7.5 Hz, 1H), 7.39
(app-t, J ) 8.0 Hz, 1H), 7.50 (d, J ) 8.0 Hz, 1H), 7.57 (dd, J )
8.3, 7.9 Hz, 1H), 7.72 (d, J ) 8.0 Hz, 1H), 7.81 (d, J ) 8.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 18.7, 23.0, 30.3, 55.6, 100.9,
110.2, 110.4, 113.3, 114.5, 119.1, 119.2, 120.0, 127.1, 127.6,
128.8, 130.9, 133.7, 135.9, 148.0, 148.4, 156.7; MS (EI) m/z 398,
396 (M•+), 381, 379, 300; m/z (EI) calcd for C21H1781BrO3
398.0341, found 398.0342. Anal. Calcd for C21H17BrO3: 63.49;
H, 4.31. Found: C, 63.38; H, 4.27.
(2H)-4′-Acetyl-5-m eth oxy-2,3-dih ydr ospir o[n aph th alen e-
1(4H),2′-n a p h th o[1,8-d e][1,3]d ioxin e] 24. Anisole 22 (159
mg, 0.5 mmol) in MeNO2 (2 mL) was added to Ac2O (229 µL,
2.5 mmol) followed by scandium triflate (49 mg, 0.1 mmol).
The color of the reaction mixture changed to brown im-
mediately, and stirring was continued for 10 h. The reaction
was terminated by the addition of solid NaHCO3 followed by
H2O (2 mL) and CHCl3 (5 mL). The aqueous layer was
separated, extracted with CHCl3 (2 × 5 mL), the extract
washed with brine (5 mL) and dried (MgSO4). Chromatography
of the brown residue (Et2O/hexanes, 1:3) gave ketone 24 (104
mg, 58%) as a white solid: mp 195 °C (hexane/EtOH); Rf 0.41
1
1272 cm-1; H NMR (300 MHz, CDCl3) δ 2.00 (m, 2H), 2.17
(m, 2H), 2.82 (t, J ) 6.6 Hz, 2H), 4.84 (s, 1H), 6.87 (d, J ) 7.3
Hz, 1H), 6.95 (dd, J ) 6.7, 0.5 Hz, 2H), 7.35 (app-t, J ) 8.0
Hz, 1H), 7.41-7.58 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 18.7,
22.8, 30.4, 100.5, 109.3 113.7, 115.5, 119.8, 120.3, 125.1, 127.2,
127.4, 134.2, 136.8, 148.2, 152.8; MS (CI) m/z 305 (M + H)+;
m/z (CI) calcd for C20H17O3 305.1178, found 305.1179. Anal.
Calcd for C20H16O3: C, 78.93; H, 5.30. Found: C, 78.73; H,
5.04.
1
(Et2O/hexanes 1:1); IR (KBr disk) 1669, 1603 cm-1; H NMR
(300 MHz, CDCl3) δ 1.96-1.98 (m, 2H), 2.15-2.18 (m, 2H),
2.75 (s, 3H), 2.83 (t, J ) 6.4 Hz, 2H), 3.90 (s, 3H), 6.94 (d, J )
8.1 Hz, 1H), 6.95 (dd, J ) 8.1, 1.0 Hz, 1H), 7.03 (dd, J ) 7.6,
1.0 Hz, 1H), 7.37 (t, J ) 8.1 Hz, 1H), 7.50 (dd, J ) 8.0, 1.0 Hz,
1H), 7.62 (dd, J ) 7.6, 7.6 Hz, 1H), 8.10 (d, J ) 7.6 Hz, 1H),
8.72 (dd, J ) 8.9, 8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
18.7, 23.0, 29.2, 30.4, 55.6, 101.1, 108.1, 110.6, 111.6, 113.8,
119.0, 120.0, 127.1, 127.5, 127.6, 130.2, 132.0, 132.9, 135.7,
148.0, 152.6, 156.7, 199.7; MS (CI) m/z 361 (M + H)+; m/z (CI)
calcd for C23H21O4 361.1439, found 361.1437. Anal. Calcd for
(2H)-2,3-Dih yd r osp ir o[n a p h th a len e-1(4H),2′-n a p h th o-
[1,8-d e][1,3]-d ioxin e]-5,8-d ion e 28. Phenol 27 (61 mg, 0.2
mmol) was added in small portions over a period of 30 min to
PhI(OCOCF3)2 (181 mg, 0.42 mmol) in THF and H2O (9:1; 2
mL) at room temperature. After the addition was complete,
stirring was continued for a further 20 min, and H2O (1 mL)
and Et2O (4 mL) were added. The organic layer was separated,
washed with brine (1 mL), dried (MgSO4), and concentrated.
Chromatography (Et2O/hexanes, 1:2) gave quinone 28 (42 mg,
66%) as a red solid: mp 85 °C (hexanes); Rf 0.51 (Et2O/hexanes,
C
23H20O4: C, 76.65; H, 5.59. Found: C, 76.69; H, 5.50.
(2H)-2′-Hyd r oxy-5-m eth oxy-2,3-d ih yd r osp ir o[n a p h th a -
len e-1(4H),2′-n a p h th o[1,8-d e][1,3]d ioxin e] 23. s-BuLi in
hexane (1.3 M; 0.26 mL, 0.33 mmol) was added to anisole 22
(95 mg, 0.30 mmol) in THF (1.2 mL) at -78 °C over 5 min.
The resulting brown solution was stirred at this temperature
for 1.5 h when B(OMe)3 (54 µL, 0.48 mmol) was added. After
being stirred for 1.5 h, the reaction mixture was allowed to
warm to room temperature over a period of 30 min. After the
mixture was cooled back to -78 °C, aqueous NaOH (2.5 M;
144 µL) and aqueous H2O2 (27%; 76 µL) were added, and the
mixture was allowed to warm to room temperature and stirred
for 90 min. Neutralization with 1 M HCl followed by extraction
with Et2O (3 × 10 mL) gave a yellow organic layer that was
dried (MgSO4), filtered, and concentrated. Chromatography
(Et2O/hexanes, 1:3) gave alcohol 23 (72 mg, 72%) as a white
solid: mp 164 °C (hexanes); Rf 0.60 (Et2O/hexanes 1:1); IR
1:1); IR (KBr disk) 1659, 1605 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 1.83-1.90 (m, 2H), 2.10-2.12 (m, 2H), 2.62 (t, J )
6.0 Hz, 2H), 6.72-6.95 (m, 4H), 7.40-7.58 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 17.7, 23.6, 31.8, 98.9, 109.2, 113.0, 120.5,
127.3, 134.3, 135.1, 135.6, 137.9, 146.8, 146.9, 183.5, 187.4;
MS (EI) m/z 318 (M•+), 115; m/z (EI) calcd for C20H15O4
318.0892, found 318.0906. Anal. Calcd for C20H14O4: C, 75.46;
H, 4.43. Found: C, 75.58; H, 4.54.
(2H )-5-B e n zy lo x y -2,3-d ih y d r o s p ir o [n a p h t h a le n e -
1(4H),2′-n a p h th o[1,8-d e][1,3]-d ioxin e]. MeCN (5 mL) fol-
lowed by PhCH2Br (59 µL, 0.05 mmol) were added to phenol
27 (150 mg, 0.50 mmol), K2CO3 (137 mg, 0.99 mmol), and NaI
(10 mg), and the reaction mixture was heated at reflux for 4
h. After rotary evaporation, the residue was dissolved in EtOAc
(20 mL) and saturated aqueous NaHCO3 (10 mL), and the
organic layer was separated, dried (MgSO4), and filtered.
Chromatography (EtOAc/hexanes, 1:15 to 1:9 to 1:4) gave the
(KBr disk) 3349 cm-1
1.93 (m, 2H), 2.07-2.11 (m, 2H), 2.80 (t, J ) 6.3 Hz, 2H), 3.87
;
1H NMR (300 MHz, CDCl3) δ 1.83-

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2745
title benzyl ether (140 mg, 72%) as a white solid: mp 163-
164 °C (Et2O); Rf 0.60 (EtOAc/hexanes 1:4); IR (thin film) 1606,
1589, 1272 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.89-2.00 (m,
2H), 2.12-2.20 (m, 2H), 2.92 (t, J ) 6.3 Hz, 2H), 5.16 (s, 2H),
6.90-7.00 (m, 3H), 7.31-7.55 (m, 11H). 13C NMR (75 MHz,
CDCl3) δ 18.3, 22.8, 29.9, 69.6, 100.1, 108.8, 111.3, 113.2, 119.0,
119.8, 126.5, 126.7, 126.7, 126.9, 127.4, 127.4, 128.1, 133.7,
136.8, 147.8, 155.3; MS (CI) m/z 395 (M + H)+. Anal. Calcd
for C27H22O3: C, 82.21; H, 5.62. Found: C, 82.17; H, 5.69.
(2H )-4′-Acet oxy-5-b en zyloxy-2,3-d ih yd r osp ir o[n a p h -
th a len e-1(4H),2′-n a p h th o[1,8-d e][1,3]-d ioxin e] 29. CH2Cl2
(2 mL) and AcOH (4 mL) were added to the preceding benzyl
ether (140 mg, 0.36 mmol) and Pb(OAc)4 (307 mg, 0.71 mmol),
and the mixture was stirred under N2 for 16 h. The mixture
was diluted with EtOAc (20 mL) and saturated aqueous NH4-
Cl (10 mL), and the organic layer was separated, dried
(MgSO4), and filtered. Chromatography (EtOAc/hexanes, 1:2)
gave acetate 29 (100 mg, 62%) as a white solid: mp 193-194
°C (Et2O); Rf 0.30 (EtOAc/hexanes 1:4); IR (thin film) 1763,
1608, 1201 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.86-1.99 (m,
2H), 2.10-2.17 (m, 2H), 2.45 (s, 3H), 2.88 (t, J ) 6.3 Hz, 2H),
5.12 (s, 2H), 6.86-6.97 (m, 3H), 7.17-7.49 (m, 10H); 13C NMR
(75 MHz, CDCl3) δ 18.8, 21.0, 23.3, 30.4, 70.1, 101.0, 108.8,
110.1, 111.9, 114.1, 114.4, 119.3, 119.6, 127.1, 127.1, 127.3,
127.9, 128.0, 128.2, 128.6, 136.2, 137.2, 140.4, 146.1, 148.5,
155.8, 169.8; MS (CI) m/z 453 (M + H)+. Anal. Calcd for
evaporated. Chromatography (EtOAc/hexanes, 1:2) gave triol
31 (61 mg, 46%) as a white solid: mp 228-230 °C dec (Et2O);
Rf 0.15 (EtOAc/hexanes, 1:2); IR (thin film) 3400, 1610, 1265
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.85-1.95 (m, 2H), 2.05-
2.18 (m, 2H), 2.75-2.81 (m, 2H), 5.07 (br s, 1H), 5.98 (br s,
1H), 6.79 (app-d, J ) 8.5 Hz, 2H), 6.83 (app-d, J ) 8.5 Hz,
2H), 7.03 (d, J ) 7.6 Hz, 1H), 7.20 (s, 1H), 7.46 (t, J ) 8.3 Hz,
1H), 7.81 (d, J ) 8.5 Hz, 1H); 13C NMR (75 MHz, acetone-d6)
δ 19.0, 23.9, 31.1, 103.2, 109.4, 110.4, 110.7, 114.8, 115.1, 116.1,
117.0, 121.1, 125.5, 126.4, 126.5, 140.0, 147.6, 147.8, 148.4,
150.2; MS (CI) m/z 337 (M + H)+; m/z (CI) calcd for C20H17O5
337.1076, found 337.1090. Anal. Calcd for C20H16O5: C, 71.42;
H, 4.79. Found: C, 71.51; H, 4.82.
Did eoxyp r essom er in G 17. p-Benzoquinone (2.2 mg, 0.020
mmol) in THF (0.3 mL) was added to triol 31 (5.7 mg, 0.016
mmol) in dry, degassed THF (1.0 mL) at -78 °C under N2.
Following stirring at the same temperature for 30 min, more
p-benzoquinone (2.2 mg, 0.020 mmol) in THF (0.3 mL) was
added and stirring continued for 10 min. Reaction was
quenched by addition of 1 M HCl (1 mL), and the mixture was
diluted with Et2O (10 mL). The organic layer was separated,
dried (MgSO4), filtered, and rotary evaporated. Preparative
TLC (EtOAc/hexanes, 1:2) gave dideoxypressomerin G 17 (4.0
mg, 75%) as a yellow solid: mp 220-223 °C (Et2O); Rf 0.40
(EtOAc/hexanes 1:2); IR (thin film) 3399, 1677, 1292 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.97-2.24 (m, 2H), 2.40-2.62 (m,
2H), 2.64-2.79 (m, 1H), 2.88-2.99 (m, 1H), 4.42 (br. s, 1H),
6.53 (d, J ) 10.2 Hz, 1H), 6.54 (d, J ) 8.9 Hz, 1H), 6.69 (d, J
) 8.6 Hz, 1H), 7.02 (dd, J ) 8.3, 1.0 Hz, 1H), 7.15 (d, J ) 9.9
Hz, 1H), 7.35 (app-t, J ) 9.9 Hz, 1H), 7.56 (dd, J ) 7.6, 1.0
Hz, 1H); MS (CI) m/z 335 (M + H)+, 179; m/z (CI) calcd for
C
29H24O5: C, 76.98; H, 5.35. Found: C, 76.95; H, 5.29.
(2H)-4′-Acetoxy-5-h yd r oxy-2,3-d ih yd r osp ir o[n a p h th a -
len e-1(4H),2′-n a p h th o[1,8-d e][1,3]d ioxin e]. Benzyl ether 29
(100 mg, 0.22 mmol) in EtOAc (5 mL) and 10% Pd/C (20 mg)
were hydrogenated at atmospheric pressure for 6 h. The
mixture was filtered through Celite and chromatographed
(EtOAc/hexanes, 1:4) to give the title phenol (85 mg, 100%) as
a white solid: mp 193-194 °C (Et2O); Rf 0.30 (EtOAc/hexanes
1:2); IR (thin film) 3454, 1744, 1668, 1271 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.82-1.93 (m, 2H), 2.03-2.10 (m, 2H), 2.41 (s,
3H), 2.72 (t, J ) 6.3 Hz, 2H), 5.16 (br. s, 1H), 6.71 (d, J ) 7.6,
0.9 Hz, 1H), 6.83 (d, J ) 8.3 Hz, 1H), 6.90 (dd, J ) 6.9, 1.3 Hz,
1H), 7.12-7.19 (m, 2H), 7.34-7.44 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 18.6, 21.0, 22.8, 30.3, 100.8, 108.8, 110.2, 114.1, 114.4,
115.5, 119.6, 119.6, 125.1, 127.2, 128.2, 136.5, 140.4, 146.0,
148.5, 152.9, 152.9, 169.9; MS (CI) m/z 363 (M + H)+ 233; m/z
(CI) calcd for C22H19O5 363.1232, found 363.1249. Anal. Calcd
for C20H18O5: C, 72.92; H, 5.01. Found: C, 72.90; H, 4.94.
(2H)-4′-Acetoxy-2,3-dih ydr ospir o[n aph th alen e-1(4H),2′-
n a p h th o[1,8-d e][1,3]d ioxin e]-5,8-d ion e 30. PhI(OCOCF3)2
(42.4 mg) in THF and H2O (9:1; 0.5 mL) was added to the
preceding benzyl ether (17 mg, 0.047 mmol) in THF and H2O
(9:1; 1 mL) portionwise over 25 min under N2, and the red
mixture was stirred for 30 min. The mixture was diluted with
Et2O (15 mL) and H2O (5 mL), and the organic layer was dried
(MgSO4), filtered, and rotary evaporated. Chromatography
(EtOAc/hexanes, 1:2) gave the quinone 30 (9 mg, 51%) as an
orange solid: mp 123-127 °C (Et2O); Rf 0.30 (EtOAc/hexanes
1:2); IR (thin film) 1764, 1661, 1609, 1202 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.82-1.94 (m, 2H), 2.04-2.16 (m, 2H), 2.46 (s,
3H), 2.63 (t, J ) 6.3 Hz, 2H), 6.76-6.88 (m, 3H), 6.93 (d, J )
6.6 Hz, 1H), 7.19 (d, J ) 8.2 Hz, 1H), 7.42-7.54 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 17.5, 20.9, 23.5, 31.7, 99.2, 108.6,
109.9, 113.3, 114.5, 115.2, 119.4, 119.7, 128.0, 128.1, 135.0,
137.9, 140.5, 144.6, 147.0, 169.7, 183.3, 187.3; MS (EI) m/z 376
(M•+), 334, 43; m/z (CI) calcd for C20H16O6 376.0947, found
376.0938.
C
20H15O5 335.0920, found 335.0919. The spectroscopic data
matched those reported by Chi and Heathcock.8
5-Meth oxy-2,3-dih ydr ospir o[n aph th alen e-1(4H),2′-n aph -
th o[1,8-d e][1,3]d ioxin ]-4-on e 32. Spiroketal 22 (5.67 g, 18
mmol, 1.0 equiv), bipyridinium chlorochromate (525 mg, 1.8
mmol, 0.1 equiv), and Celite (2.9 g) were suspended in PhH
(70 mL). tert-Butyl hydroperoxide in PhH (3 M; 60 mL, 287
mmol, 16 equiv) was added over 5.25 h (syringe pump) under
N2, and the dark mixture was stirred for 16 h and filtered
through Celite. HCl (1 M, 50 mL) was added, the layers were
shaken vigorously, and the separated organic layer was
washed with brine (80 mL) and dried (MgSO4). Silica gel (50
g) was added, and the residue, after rotary evaporation, was
chromatographed (EtOAc/hexanes, 2:1) to afford ketone 3220
(3.56 g, 60%) as an orange solid: mp 154-156 °C (hexane); Rf
0.28 (Et2O/hexanes, 4:1); IR (KBr disk) 1681, 1634, 1272 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.49 (t, J ) 6.8 Hz, 2H), 2.78 (t,
J ) 6.8 Hz, 2H), 3.99 (s, 3H), 6.98 (d, J ) 7.3 Hz, 2H), 7.14 (d,
J ) 8.0 Hz, 1H), 7.43-7.68 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 29.4, 35.4, 56.4, 98.9, 109.4, 113.5, 113.6, 117.8, 120.8, 121.0,
127.5, 134.2, 134.9, 142.7, 147.6, 156.7, 195.3; MS (CI) m/z 333
(M + H)+; m/z (CI) calcd for C21H19O4 333.1126, found
333.1125. Anal. Calcd for C21H18O4: C, 75.89, H, 4.85. Found:
C, 75.98; H, 4.88.
P a lm a r u m ycin CP 2 13. Et2O (12.5 mL) and PhH (25 mL)
were added to iodine (10.0 g, 39.4 mmol) and Mg turnings (2
g, 83 mmol) under N2 at 0 °C (caution: exothermic), and the
mixture was stirred for 20 min. The mixture was warmed to
room temperature and stirred for a further 1.5 h in the dark,
after which time the initially brown color had faded. An aliquot
of this freshly prepared MgI2 solution (30.6 mL, 32 mmol, 2.5
equiv) was added to a solution of ketone 3220 (4.27 g, 12.7
mmol) in THF (120 mL), and the resulting solution was stirred
for 24 h in the dark. The reaction mixture was diluted with 1
M HCl (50 mL) and Et2O (200 mL). The aqueous layer was
separated and extracted with Et2O (50 mL), and the combined
organic layers were dried (MgSO4), filtered, and evaporated
to dryness. Chromatography (EtOAc/hexanes, 1:9-1:4) gave
palmarumycin CP2 (13) (3.37 g, 83%) as a white solid: mp 171
°C (hexane); Rf 0.40 (EtOAc/hexanes 1:9); IR (KBr disk) 1643,
1608, 1271 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.51 (t, J ) 6.8
Hz, 2H), 2.87 (t, J ) 6.8 Hz, 2H), 6.98 (d, J ) 7.3 Hz, 2H),
7.11 (dd, J ) 8.0, 1.0 Hz, 1H), 7.45-7.50 (m, 4H), 7.56 (d, J )
(2H)-5,8,4′-Tr ih yd r oxy-2,3-d ih yd r osp ir o[n a p h th a len e-
1(4H),2′-n a p h th o[1,8-d e][1,3]-d ioxin e] 31. Quinone 30 (149
mg, 0.40 mmol) in Et2O (20 mL) was washed with Na2S2O4
(390 mg, 2.2 mmol) in H2O (2 mL) until decolorization was
complete. The organic layer was separated, dried (MgSO4),
filtered, and rotary evaporated. Chromatography (EtOAc/
hexanes, 1:2-1:1) gave an unstable colorless oil. This was
dissolved in degassed MeOH (9 mL), treated with NaOMe (33
mg, 6.1 mmol), and stirred for 1 h during which time the
mixture turned from yellow to light brown. The mixture was
quenched with EtOAc (30 mL) and 1 M HCl, and the organic
layer was separated, dried (MgSO4), filtered, and rotary
7.8 Hz, 1H), 7.64 (app-t, J ) 8.0, 7.8 Hz, 1H) 12.47 (s, 1H); 13
C

2746 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
NMR (75 MHz, CDCl3) δ 29.4, 34.1, 98.4, 109.5, 113.4, 115.4,
116.7, 119.6, 120.9, 127.6, 134.2, 137.2, 141.0, 147.4, 162.5,
203.3; MS (CI) m/z 319 (M + H)+, 161; m/z (EI) calcd for
MS (CI) m/z 331 (M + H)+, 115; m/z (CI) calcd for C21H15O4
331.0970, found 331.0965. Anal. Calcd for C21H14O4: C, 76.36;
H, 4.27. Found: C, 76.54; H, 4.24. The minor, less polar furan
37 (32 mg, 8%) was also isolated by chromatography as a
crystalline solid: mp 238 °C (Me2CO/H2O); Rf 0.52 (Et2O/
hexanes, 2:1); IR (NaCl disk) 2224, 1610, 1411, 1378, 1269,
1055, 752 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 2H), 4.03
(s, 3H), 6.91 (d, J ) 7.6 Hz, 2H), 7.13 (dd, J ) 8.3, 0.8 Hz,
1H), 7.47 (dd, J ) 8.3, 7.6 Hz, 2H), 7.52 (app t, J ) 8.2, 7.9
Hz, 1H), 7.56 (d, J ) 8.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 28.9, 56.2, 99.1, 108.4, 109.4, 109.7, 112.9, 113.2, 113.3, 117.5,
118.8, 121.3, 127.6, 129.0, 132,2, 134.2, 135.9, 146.4, 153.4,
155.4; m/z (EI) 407 (M + H)+, 406 (M•+), 391, 374, 363, 345,
159; m/z (EI) calcd for C25H14O4N2 406.0953, found 406.0945.
Anal. Calcd for C25H14O4N2: C, 73.89; H, 3.47; N, 6.89.
Found: C, 73.70; H, 3.54; N, 6.78. Crystal data for 37:
C
20H15O4 319.0970, found 319.0976. Anal. Calcd for C20H14O4:
C, 75.46; H, 4.43. Found: C, 75.76; H, 4.61. The sample of
synthetic palmarumycin CP2 (13) was identical in all respects
with an authentic sample of the natural product kindly
provided by Professor Karsten Krohn.1a
CJ -12,371 33. Palmarumycin CP2 (13) (160 mg, 0.50 mmol)
in THF (1.5 mL) at -78 °C was added to (+)-B-chlorodiisopi-
nocampheylborane (288 mg, 0.90 mmol) in THF (1.5 mL). The
red solution was maintained at this temperature for 30 min,
allowed to warm to room temperature, and left standing for
18 h. The reaction was terminated by the addition of aqueous
hydrogen peroxide (27%; 1.5 mL) and 2 M NaOH (1 mL). After
being stirred for 1 h, the reaction mixture was neutralized with
1 M HCl and the aqueous layer separated and extracted with
Et2O (2 × 5 mL). The combined organic layers were washed
with brine (2 mL), dried (MgSO4), and rotary evaporated.
Chromatography (Et2O/hexanes, 2:1) gave CJ -12,371 (33)5,21
C
25H14N2O4, M ) 406.4, triclinic, P1 (no. 1), a ) 5.170(1) Å, b
) 8.290(1) Å, c ) 12.177(1) Å, R ) 108.26(1)°, â ) 94.11(1)°, γ
) 102.12(1)°, V ) 479.2(1) Å3, Z ) 1, Dc ) 1.408 g cm-3, µ(Cu
KR) ) 0.80 mm-1, T ) 293 K, colorless blocks; 1620 indepen-
(96 mg, 60%) as a colorless solid: [R]24 -42.2 (c 0.46, MeOH)
dent measured reflections, F2 refinement, R1 ) 0.038, wR2
)
D
(lit.4g [R]24D -46.8 (c 0.23, MeOH)); mp 186 °C (CH2Cl2); Rf 0.44
0.102, 1552 independent observed reflections [|Fo| > 4σ(|Fo|),
2θ e 128°], 281 parameters. The absolute structure of 37 could
not be determined. CCDC 182477.
1
(Et2O/hexanes, 2:1); IR (KBr disk) 3441, 1606, 1257 cm-1; H
NMR (300 MHz, CDCl3) δ 1.95-2.17 (m, 2H), 2.24-2.33 (m,
1H), 2.39-2.48 (m, 2H), 5.18 (dd, J ) 5.9, 8.1 Hz, 1H), 6.94 (2
d, J ) 7.1, 6.8 Hz, 2H), 7.04 (dd, J ) 7.8, 1.2 Hz, 1H), 7.36-
7.63 (m, 6H), 7.97 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ
25.9, 28.2, 61.5, 100.5, 109.6 (×2), 113.5, 116.6, 117.9, 120.7
(×2), 126.9, 128.2 (×2), 129.0, 134.3, 136.1, 148.0, 148.3, 155.9;
MS (FAB) m/z 320 (M+.), 303; m/z (FAB) calcd for C20H16O4
320.1049, found 320.1049. Anal. Calcd for C20H16O4: C, 74.99;
H, 5.03. Found: C, 75.17; H, 5.01. Chiral HPLC (method A):
tR ) 8 min 20 s (CJ -12,371 (33)) and tR ) 11 min 22 s ((+)-
CJ -12,371); 92% ee. Synthetic CJ -12,371 (33) showed spectro-
scopic data in agreement with that published for the natural
product.4g Reduction of palmarumycin CP2 (13) (63 mg, 0.0
mmol) in MeOH (1.5 mL) using NaBH4 (23 mg, 0.6 mmol, 3.0
equiv) at 0 °C for 1 h, and workup as above gave racemic CJ -
12,371 ((()-33) (60 mg, 94%).
P a lm a r u m ycin CP 1 1. Meth od 1. 2,6-Lutidine (3.21 mL,
27.5 mmol) was added to palmarumycin CP2 13 (2.50 g, 7.9
mmol) in dry CH2Cl2 (30 mL) at 0 °C followed by the
portionwise addition of trimethylsilyl triflate (4.28 mL, 23.6
mmol) every 8 min over 1 h. The mixture was stirred at 0 °C
for 1 h and quenched by addition of saturated aqueous
NaHCO3 (20 mL). The mixture was diluted with CH2Cl2 (30
mL); the organic layer was separated, dried (Na2SO4) and
evaporated under high vacuum with azeotropic removal of 2,6-
lutidine with PhMe (3 × 20 mL); and the residue enol silane
36 was used without further purification. MeCN (80 mL) was
added followed by Pd(OAc)2 (1.77 g, 7.86 mmol), and the
mixture was stirred under N2 for 16 h. The mixture was
filtered through Celite, which was washed with CH2Cl2 (2 ×
20 mL), and the combined organic phases were evaporated to
dryness. The residue was dissolved in CH2Cl2 (120 mL) and
washed with saturated aqueous NH4Cl (30 mL), and the
organic layer was dried (MgSO4) and rotary evaporated.
Chromatography (CH2Cl2/hexanes, 2:1 to CH2Cl2) gave pal-
marumycin CP1 (1)20 (1.94 g, 78% over both steps) as a yellow
solid: mp 172-173 °C (Et2O); Rf 0.69 (Et2O/hexanes, 2:1); IR
(KBr disk) 1661, 1610, 1268, cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.38 (d, J ) 10.6 Hz, 1H), 6.99 (d, J ) 7.6 Hz, 2H), 7.04 (d,
J ) 10.6 Hz, 1H), 7.16 (d, J ) 8.4 Hz, 1H), 7.47-7.52 (m, 3H),
7.59 (dd, J ) 9.0, 0.5 Hz, 2H), 7.68 (app-t, J ) 8.0 Hz, 1H),
12.19 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 92.9, 109.9, 113.0,
113.8, 119.4, 119.7, 121.4, 127.6, 129.8, 134.2, 136.6, 138.8,
139.7, 147.2, 161.9, 188.8; MS (EI) m/z 317 (M + H)+, 130,
114, 88; m/z (EI) calcd for C20H13O4 317.0814, found 317.0821.
Anal. Calcd for C20H12O4: C, 75.94; H, 3.82. Found: C, 75.94;
H, 3.71. The spectroscopic data was identical to that reported
previously1a and the synthetic palmarumycin CP1 (1) was
identical with an authentic sample provided by Professor
Karsten Krohn. Meth od 2. B-Bromocatecholborane (571 mg,
2.9 mmol) in CH2Cl2 (1.0 mL) was added to an ice-cooled
solution of ketone 35 (190 mg, 0.58 mmol) and DBU (175 µL,
1.15 mmol) in CH2Cl2 (1.4 mL) over a period of 5 min. After
the mixture was stirred for 2 min at this temperature,
saturated aqueous NaHCO3 (2 mL) was added to the brown
reaction mixture, and stirring was continued for another 10
min. Hydrochloric acid (1.0 M) was added to pH 2, and the
aqueous layer was extracted with CH2Cl2 (3 × 8 mL). The
combined organic layers were washed with brine (10 mL),
dried (MgSO4), and rotary evaporated. The resulting orange
residue was adsorbed on silica gel (250 mg) and chromato-
graphed (Et2O/hexanes, 1:4) to yield palmarumycin CP1 (1)
(101 mg, 56%) as a yellow solid.
Ra cem ic CJ -12,372 ((()-34). CJ -12,371 (33) (32 mg, 0.1
mmol, 1.0 equiv) in THF and H2O (9:1, 1 mL) was added
dropwise over 30 min to PhI(OCOCF3)2 (95 mg, 0.22 mmol,
2.2 equiv) in THF and H2O (9:1, 1 mL) at room temperature.
The orange reaction mixture was allowed to stir for 1 h, and
then H2O (2 mL) and Et2O (4 mL) were added. The red organic
layer was separated and washed with a solution of sodium
dithionite (87 mg), H2O (2 mL), and brine (2 mL) and dried
(MgSO4). Chromatography (Et2O/hexanes, 2:1) gave unreacted
CJ -12,371 (33) (2 mg, 6%) followed by racemic CJ -12,372 ((()-
34 (19 mg, 56%) as a white solid: mp 178 °C (CHCl3); Rf 0.25
(Et2O/hexanes 3:1); IR (KBr disk) 3418, 3361, 1605, 1466, 1408,
1
1266 cm-1; H NMR (300 MHz, CDCl3) δ 1.70-2.01 (m, 3H),
2.23-2.34 (m, 1H), 4.93 (s, 1H), 5.08 (br s, 1H), 6.69 (d, J )
8.6, 2.3 Hz, 1H), 6.78 (dd, J ) 8.6, 2.3 Hz, 1H), 6.86 (dd, J )
7.6, 1.0 Hz, 1H), 6.91 (dd, J ) 7.6, 1.0 Hz, 1H), 7.42-7.55 (m,
4H), 8.41 (d, J ) 2.3 Hz, 1H) 9.01 (d, J ) 2.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 27.3, 28.0, 61.9, 101.5, 109.2, 113.1,-
117.2, 117.8, 120.2, 120.9, 127.7, 128.1, 134.3, 148.1, 148.3,
149.7; m/z (EI) 318 (M - H2O)•+, 301, 160, 84; m/z (EI) calcd
for C20H14O4, found 318.0892, found 318.0885.
5-Meth oxysp ir o[n a p h th a len e-1(4H),2′-n a p h th o[1,8-d e]-
[1,3]d ioxin ]-4-on e 35. PhH (5 mL) was added to ketone 32
(332 mg, 1.0 mmol) and DDQ (272 mg, 1.2 mmol) under N2.
The resulting dark reaction mixture was heated to reflux for
10 h during which time a yellow solid precipitated. After the
mixture was cooled to room temperature, silica gel (3 g) was
added and the mixture rotary evaporated. Chromatography
(Et2O/hexanes, 2:1) gave enone 3520 (213 mg, 65%) as a yellow
solid: mp 204 °C (hexane); Rf 0.38 (Et2O/hexanes, 4:1); IR (KBr
disk) 1673, 1642, 1271 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.03
(s, 3H), 6.30 (d, J ) 10.5 Hz, 1H), 6.86 (d, J ) 10.5 Hz, 1H),
6.99 (d, J ) 7.5 Hz, 2H), 7.18 (d, J ) 8.0 Hz, 1H), 7.42-7.62
(m, 5H), 7.71 (app-t, J ) 8.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 56.5, 93.4, 109.8, 113.2, 113.9, 119.0, 120.2, 121.2,
127.6, 132.2, 134.2, 134.9, 135.2, 141.1, 147.4, 160.0, 183.0;
P a lm a r u m ycin C2 3. Sm a ll-Sca le P r ep a r a tion . N-Ben-
zylcinchoninium chloride 39 (8 mg, 0.02 mmol), H2O (0.1 mL),
and tert-butyl hydroperoxide in PhMe (3.17 M; 0.12 mL, 0.38
mmol) were added to palmarumycin CP1 (1) (60 mg, 0.19

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2747
mmol) in PhMe (1.9 mL) at room temperature followed by the
addition of aqueous NaOH (0.11 M; 0.85 mL, 50 mol %). After
8 h, additional oxidant (30 µL, 0.6 equiv) was added, and
stirring was continued for 2 h. HCl (1 M, 0.3 mL), CH2Cl2 (8
mL), and H2O (4 mL) were added and both layers shaken
vigorously. The separated aqueous layer was extracted with
CH2Cl2 (2 × 10 mL), and the combined organic extracts were
dried (MgSO4). After filtration, silica gel (300 mg) was added
and the mixture rotary evaporated and chromatographed
(EtOAc/hexanes, 1:4) to give palmarumycin C2 (3) (51 mg, 81%)
as a white solid: mp 225 °C (Me2CO/H2O); Rf 0.47 (Et2O/
hexane 1:2); [R]D -300 (c 1.00, CH2Cl2) (lit.1b [R]D -341 (c 1.00,
CH2Cl2)); IR (KBr disk) 1650, 1611, 1269 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.69 (d, J ) 4.0 Hz, 1H), 4.11 (d, J ) 4.0 Hz,
1H), 6.94 (d, J ) 7.5 Hz, 1H), 7.14 (d, J ) 8.2 Hz, 1H), 7.20 (d,
J ) 7.3 Hz, 1H), 7.43-7.70 (m, 6H), 11.38 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 53.3, 95.9, 109.3, 110.1, 112.3, 112.8, 119.1,
120.0, 121.3, 121.4, 127.6, 127.8 (2), 134.2, 136.9, 137.6, 146.7,
146.9, 161.9, 196.5; MS (EI) m/z 332 (M+.), 287, 145; m/z (EI)
calcd for C20H12O5 332.0684, found 332.0685. Anal. Calcd for
mL), and tert-butyl hydroperoxide in PhMe (3.07 M; 65 µL)
were added to enone 35 (33 mg, 0.10 mmol) in PhMe (2 mL).
Aqueous NaOH (0.11 M; 0.43 mL) was added while the color
of the organic layer changed to orange immediately. After
being stirred at room temperature for 9 days, 5% aqueous
Na2S2O5 (0.5 mL) was added, and the resulting mixture was
dissolved in CH2Cl2 (10 mL) and H2O (2 mL). After separation
of the layers, the organic extract was washed with brine (3
mL), dried (MgSO4), and filtered. Silica (200 mg) was added
and the residue, after rotary evaporation, chromatographed
(Et2O/hexane, 2:1) to provide epoxyketone 40 (102 mg, 61%),
which was obtained as a white solid, as well as starting enone
35 (9 mg, 27%). Epoxyenone 40: [R]D -67 (c 0.28, CH2Cl2);
mp 187 °C (Et2O/hexanes); Rf 0.53 (EtOAc/hexane, 1:2); IR
(KBr disk) 1670, 1637, 1274 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.72 (d, J ) 4.4 Hz, 1H), 3.97 (s, 3H), 4.09 (d, J ) 4.4 Hz,
1H), 6.89 (dd, J ) 7.1, 1.0 Hz, 1H), 7.14 (d, J ) 8.1 Hz, 1H),
7.20 (dd, J ) 7.1, 1.0 Hz, 1H), 7.43 (dd, J ) 8.2, 7.6 Hz, 1H),
7.48-7.58 (m, 4H), 7.63 (dd, J ) 8.1, 6.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 53.0, 54.1, 56.4, 97.1, 109.3, 109.9, 112.8,
113.9, 118.1, 118.8, 121.1, 121.3, 127.7 (x 2), 134.1, 134.9,
138.1, 146.7, 147.0, 158.9, 191.7; MS (EI) m/z 347 (M + H)+,
55; m/z (CI) calcd for C21H14O5 347.0919, found 347.0934. Anal.
Calcd for C21H14O5: C, 72.83; H, 4.07. Found: C, 72.97; H,
4.18; chiral HPLC (method C) tR ) 25 min 11 s and tR ) 27
min 4 s, (23% ee).
C
20H12O5: C, 72.29; H, 3.64. Found: C, 72.45; H, 3.61. Chiral
HPLC (method B): tR ) 8 min 12 s (palmarumycin C2 (3)) and
tR ) 9 min 56 s ((+)-palmarumycin C2). The spectroscopic data
were identical to that reported in the literature,1b and in
addition, the synthetic palmarumycin C2 (3) was identical in
all respects with an authentic sample of the natural product,
also named deoxypreussomerin A (3), kindly provided by Dr.
Sheo B. Singh (Merck and Co., Inc.).3e La r ger Sca le P r oce-
d u r e. N-Benzylcinchoninium chloride 39 (48 mg, 0.12 mmol),
H2O (0.6 mL), and tert-butyl hydroperoxide in PhMe (3.17 M;
0.75 mL, 2.3 mmol) were added to palmarumycin CP1 (1) (363
mg, 1.15 mmol) in PhMe (11.4 mL) at room temperature.
Aqueous NaOH (0.11 M; 5.1 mL, 50 mol %) was added while
the color of the organic layer changed from yellow to orange
immediately and the mixture was stirred for 8 h. HCl (1 M)
was added (2 mL), and a color change back to yellow was
observed. CH2Cl2 (50 mL) and H2O (20 mL) were added, and
both layers shaken together vigorously. The separated aqueous
layer was extracted with CH2Cl2 (2 × 10 mL) and the combined
organic extracts were dried (MgSO4), filtered, and rotary
evaporated. The crude mixture was triturated with refluxing
EtOAc (6 mL) and allowed to cool to room temperature. The
mixture was filtered to give palmarumycin C2 (3) (286 mg,
75%) as a yellow solid. The spectroscopic data matched those
reported above including optical rotation: [R]D -302 (c 1.00,
CH2Cl2). Crystal data for 3: C20H12O5, M ) 332.3, orthorhom-
bic, P212121 (no. 19), a ) 5.245(1) Å, b ) 13.895(1) Å, c )
20.182(1) Å, V ) 1470.9(3) Å3, Z ) 4, Dc ) 1.501 g cm-3, µ(Cu
KR) ) 0.90 mm-1, T ) 293 K, yellow needles; 1452 independent
measured reflections, F2 refinement, R1 ) 0.046, wR2 ) 0.108,
1216 independent observed reflections [|Fo| > 4σ(|Fo|), 2θ e
128°], 231 parameters. The absolute structure of 3 could not
be determined from the X-ray analysis, but was assigned by
reference to that of 38. CCDC 182478.
(()-P a lm a r u m ycin C2. tert-Butyl hydroperoxide in PhMe
(3 M; 98 µL, 0.30 mmol,) was added to ice-cooled enone 1 (63
mg, 0.2 mmol) in CH2Cl2 (1 mL). After the mixture was stirred
for 5 min, DBU in CH2Cl2 (0.4 M; 50 µL, 0.02 mmol) was added
while the color of the clear solution changed from yellow to
orange. The mixture was stirred under ice cooling for 8 h when
the reaction was terminated by the addition of a 5% aqueous
Na2S2O5 (1 mL). After dilution with CH2Cl2 (2 mL) and H2O
(2 mL), the layers were separated and the aqueous layer was
extracted with CH2Cl2 (1 × 5 mL). The combined organic
extracts were dried (MgSO4), rotary evaporated, and chro-
matographed (Et2O/hexanes, 1:8) to give racemic palmarumy-
cin C2 ((()-3)21 (55 mg, 83%) as a yellow solid. The spectro-
scopic data matched that reported above for the natural
enantiomer.
(2R,3S)-7′,7′a -Dih yd r o-7′-oxosp ir o[n a p h th o[1,8-d e]-1,3-
d ioxin -2,2′(1′a H)-n a p h th [2,3-b]oxir en ]-6′-yl 1-(Ben zen e-
su lfon yl)p yr r olid in e-2(S)-ca r boxyla te 38. L-N-Phenylsul-
fonylproline (81 mg, 0.36 mmol) was added to freshly distilled
oxalyl chloride (78 µL, 0.9 mmol, 5.0 equiv) in dry PhH (2 mL)
under N2. After the mixture was stirred for 5 min, DMF
(microsyringe, 1 drop) was added, resulting in a fierce gas
evolution. The clear solution was maintained at room temper-
ature for 30 min and rotary evaporated. PhH (1 mL) was
added, and after rotary evaporation, an orange oil was
obtained. This was dissolved in CH2Cl2 (2 mL) and stirred with
pyridine (43 µL, 0.54 mmol) and N,N-(dimethylamino)pyridine
(2 mg). Palmarumycin C2 (3) (63 mg, 0.18 mmol, 1.0 equiv) in
CH2Cl2 (0.5 mL) was added, and after standing at room
temperature for 1 h, the mixture was diluted with CH2Cl2 (2
mL) and H2O (2 mL). The organic phase was successively
washed with saturated aqueous CuSO4 (1 mL), H2O (1 mL),
and brine (1 mL) and dried (MgSO4). Filtration, rotary
evaporation, and chromatography (Et2O/hexanes, 2:1) gave
ester 38 (62 mg, 59%) as a white solid: mp 171-174 °C
(acetone/H2O); Rf 0.35 (Et2O/hexanes, 2:1); [R]D -276 (c 0.19,
CH2Cl2); IR (KBr disk) 1770, 1700, 1447, 1268, cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.84-1.95 (m, 1H), 2.13-2.31 (m, 2H),
2.60-2.71 (m, 1H), 3.38 (dd, J ) 7.3, 7.2 Hz, 1H), 3.61-3.65
(m, 2H), 3.65 (d, J ) 4.3 Hz, 1H), 4.55 (d, J ) 4.3 Hz, 1H),
6.91 (d, J ) 7.5 Hz, 1H), 7.21 (d, J ) 7.3 Hz, 1H), 7.41 (d, J )
8.2 Hz, 1H), 7.80 (d, J ) 7.8 Hz, 1H), 7.52-7.66 (m, 7H), 7.76
(t, J ) 8.0 Hz, 1H), 7.88 (d, J ) 8.1 Hz, 1H), 7.96 (d, J ) 7.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9, 30.3, 48.8, 53.1,
53.8, 60.8, 96.4, 109.4, 110.1, 112.7, 121.3, 121.5, 125.4, 126.2,
127.5, 127.6, 127.7, 129.2 (x 2), 132.9, 134.2, 134.9, 137.7,
138.1, 146.6, 146.9, 149.2, 170.1, 190.9; MS (EI) m/z 569 (M +
H)+, 332, 220; m/z (EI) calcd for C31H24NO8S 569.1144, found
569.1134. Crystal data for 38: C31H23NO8S‚Me2CO, M ) 627.6,
monoclinic, P21 (no. 4), a ) 11.942(2) Å, b ) 8.049(1) Å, c )
16.425(2) Å, â ) 109.84(1)°, V ) 1485.1(4) Å3, Z ) 2, Dc ) 1.404
g cm-3, µ(Cu KR) ) 1.48 mm-1, T ) 173 K, colorless platy
needles; 2660 independent measured reflections, F2 refine-
ment, R1 ) 0.047, wR2 ) 0.116, 2388 independent observed
reflections [|Fo| > 4σ(|Fo|), 2θ e 128°], 395 parameters. The
absolute structure of 38 was determined by a both an R-factor
+
-
test [R1 ) 0.0466, R1 ) 0.0475] and by use of the Flack
parameter [x+ ) +0.19(8), x- ) +0.81(8)]. CCDC 182479.
4′-Nitr op a lm a r u m ycin CP 1 47. AcONO2 in Ac2O20 (0.20
mL, 3.16 M, 0.63 mmol, 2.0 equiv) was added to palmarumycin
CP1 (1) (100 mg, 0.32 mmol) in MeCN (3 mL) in three portions
over 20 min at 0 °C. The mixture was allowed to warm to room
temperature, stirred for 14 h, and diluted with Et2O (20 mL)
and saturated aqueous NH4Cl (10 mL), and the organic layer
(2R,3S)-1′a ,7′a -Dih yd r o-6′-m eth oxysp ir o[n a p h th o[1,8-
d e]-1,3-d ioxin -2,2′(7′H)-n a p h th [2,3-b]oxir en ]-7′-on e 40. N-
Benzylcinchoninium chloride 39 (42 mg, 0.10 mmol), H2O (1
(21) This compound has previously been reported as a racemic
modification; see ref 6c.

2748 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
was dried (MgSO4), filtered, and rotary evaporated. Chroma-
tography (EtOAc/hexanes, 1:9-1:4) gave nitroarene 47 (60 mg,
53%) as a yellow solid: mp 195-197 °C dec (Et2O); Rf 0.20
δ 6.39 (d, J ) 10.2 Hz, 1H), 6.89 (d, J ) 7.9 Hz, 1H), 7.00 (d,
J ) 10.5 Hz, 1H), 7.08 (d, J ) 7.6 Hz, 1H), 7.17 (d, J ) 8.3 Hz,
1H), 7.45 (d, J ) 7.6 Hz, 1H), 7.62 (t, J ) 8.6 Hz, 1H), 7.69 (t,
J ) 8.3 Hz, 1H), 7.77 (d, J ) 8.3 Hz, 1H), 7.89 (d, J ) 8.6 Hz,
1H), 12.15 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 93.1, 110.8,
111.1, 113.8, 114.7, 119.4, 119.9, 121.2, 121.4, 129.0, 130.1,
131.1, 132.6, 136.7, 138.4, 139.1, 146.8, 147.3, 161.9, 188.6;
(EtOAc/hexanes, 1:9); IR (thin film) 1662, 1607, 1273 cm-1
;
1H NMR (300 MHz, CDCl3) δ 6.45 (d, J ) 10.2 Hz, 1H), 6.99
(d, J ) 10.5 Hz, 1H), 7.05 (d, J ) 8.6 Hz, 1H), 7.18 (d, J ) 7.6
Hz, 1H), 7.20 (d, J ) 6.6 Hz, 1H), 7.47 (d, J ) 6.6 Hz, 1H),
7.71 (app-t, J ) 7.9 Hz, 1H), 7.78 (t, J ) 8.3 Hz, 1H), 8.53 (d,
J ) 8.5 Hz, 1H), 8.58 (d, J ) 8.9 Hz, 1H), 12.13 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 93.7, 108.9, 112.1, 112.9, 113.7, 118.6,
119.3, 120.3, 126.9, 128.2, 130.8, 131.9, 136.8, 137.6, 138.1,
139.8, 147.3, 152.6, 162.0, 188.2; MS (CI) m/z 379 (M + 18+,
20), 362 (M + H)+, 317, 49; m/z (CI) calcd for C20H15N2O6
379.0930, found 379.0937. Anal. Calcd for C26H11NO6: C,
66.49; H, 3.07, N, 3.88. Found: C, 66.52; H, 2.99; N, 3.82.
4′-Nitr op a lm a r u m ycin C2 43 a n d 44. Meth od 1. N-
Benzylcinchoninium chloride 39 (64 mg, 0.15 mmol), H2O (0.05
mL), and tert-butyl hydroperoxide in PhMe (3.16 M; 0.024 mL,
0.076 mmol) was added to enone 47 (53 mg, 0.15 mmol) in
PhMe (1.6 mL), followed by aqueous NaOH (0.12 M; 0.34 mL).
The mixture was stirred for 14 h at room temperature,
quenched with aqueous HCl (1 M; 0.5 mL), and diluted with
EtOAc (20 mL) and saturated aqueous NH4Cl (10 mL). The
organic layer was dried (MgSO4), filtered, and rotary evapo-
rated. Chromatography (EtOAc/hexanes, 1:9-1:4) gave recov-
ered enone 47 (30 mg, 55%) followed by a mixture of epoxides
43 and 44 (20 mg, 35%) as a yellow solid as a 1:1 mixture of
diastereoisomers: mp 135-137 °C and 172-175 °C dec
(EtOAc/hexanes); Rf 0.20 (EtOAc/hexanes, 1:9); [R]D -245 (c
MS (EI) m/z 396, 394 (M•+), 287; m/z (EI) calcd for C20H11
79BrO4 393.9841, found 393.9837. Anal. Calcd for C20H11
Br1O4: C, 60.78; H, 2.81. Found: C, 60.86; H, 2.75.
-
-
4′-Br om op a lm a r u m ycin C2 45 a n d 46. Meth od 1. N-
Bromosuccinimide (11 mg) in MeCN (0.5 mL) was added to
palmarumycin C2 (3) (17 mg, 0.051 mmol) in dry MeCN (1.0
mL) over 1 h at 0 °C. The mixture was stirred for 14 h, silica
(50 mg) was added, and the mixture was rotary evaporated.
Chromatography (EtOAc/hexanes, 1:9) gave a mixture of the
bromides 45 and 46 (10 mg, 48%) as a white solid: mp 173-
175 °C and 201-205 °C (Et2O); Rf 0.50 (EtOAc/hexanes, 1:9);
[R]D -238 (c 1.00, CHCl3); IR (thin film) 1657, 1608, 1264 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.71 (app-d, J ) 3.9 Hz, 1H),
4.08 (d, J ) 4.0 Hz, 0.5H), 4.08 (d, J ) 4.0 Hz, 0.5H), 6.83 (d,
J ) 8.2 Hz, 0.5H), 7.02 (d, J ) 7.6 Hz, 0.5H), 7.10 (d, J ) 7.9
Hz, 0.5H), 7.17 (d, J ) 8.3 Hz, 1H), 7.29 (d, J ) 7.5 Hz, 0.5H),
7.34 (d, J ) 1.9 Hz, 0.5H), 7.42 (app-d, J ) 7.6 Hz, 1H), 7.57-
7.70 (m, 2H), 7.82 (d, J ) 7.9 Hz, 0.5H), 7.90 (app-t, J ) 8.6
Hz, 1H) 11.37 (app-s, 1H); 13C NMR (75 MHz, CDCl3) δ 54.2,
54.3, 97.4, 110.4, 111.3, 111.3, 111.6, 112.1, 112.4, 113.4, 114.6,
115.7, 115.9, 120.1, 120.2, 121.2, 121.4, 122.3, 122.4, 122.6,
128.8, 128.9, 130.1, 130.2, 132.2, 132.4, 133.7, 137.6, 138.8,
147.4, 147.7, 147.8, 148.2, 163.0, 197.4; MS (EI) m/z 412, 410
(M+.), 145; m/z (EI) calcd for C20H1179BrO5 409.9790, found
409.9797. Anal. Calcd for C20H11BrO5: C, 58.42; H, 2.70.
Found: C, 58.36; H, 2.80. Meth od 2. N-Benzylcinchoninium
chloride 39 (2 mg) and tert-butyl hydroperoxide in PhMe (3.19
M; 12 µL, 0.038 mmol) were added to bromoketone 48 (30 mg,
0.076 mmol) in PhMe (0.8 mL), followed by aqueous NaOH
(0.11 M; 0.17 mL, 0.5 equiv). The mixture stirred for 14 h at
room temperature, quenched by the addition of aqueous HCl
(1 M; 0.5 mL). The mixture was diluted with EtOAc (20 mL)
and saturated aqueous NH4Cl (10 mL). The organic layer was
dried (MgSO4), filtered, and rotary evaporated. Chromatog-
raphy (EtOAc/hexanes, 1:20 to 1:9) gave bromides 45 and 46
(10 mg, 32%) as a yellow solid as a 1:1 mixture of diastereoi-
somers along with recovered 48 (18 mg, 60%). The spectro-
scopic data for this sample matched those in method 1: [R]D
-235 (c 1.00, CHCl3).
0.47, CHCl3); IR (thin film) 1659, 1608, 1516, 1414, cm-1 13C
;
NMR (1:1 mixture of diastereoisomers) (75 MHz, CDCl3) δ
52.9, 53.0, 53.0, 96.9, 108.3, 109.0, 111.5, 112.2, 112.6, 112.7,
118.5, 118.7, 118.8, 120.6, 120.6, 126.9, 128.2, 128.2, 131.9,
132.0, 135.6, 135.6, 137.6, 137.6, 139.8, 140.0, 146.7, 147.1,
151.8, 152.2, 162.0, 195.8, 195.9; MS (CI) m/z 395 (M + NH4)+,
378 (M + H)+, 52; m/z (CI) calcd for C20H15N2O7 395.0879,
found 395.0882. Vapor-phase recrystallization using EtOAc
and pentane (1:1) over 7 days gave separated diastereoisomer
43 (8 mg, 0.022 mmol, 14%) as yellow crystals. Evaporation
of the mother liquor gave a mixture of diastereoisomers 44
and 43 (4:1). Diastereoisomer 43: 1H NMR (300 MHz, CDCl3)
δ 3.76 (d, J ) 3.9 Hz, 1H), 4.10 (d, J ) 3.9 Hz, 1H), 6.99 (d, J
) 8.6 Hz, 1H), 7.19 (d, J ) 8.5 Hz, 1H), 7.39 (d, J ) 8.1 Hz,
1H), 7.41 (d, J ) 8.0 Hz, 1H), 7.68 (t, J ) 8.1 Hz, 1H), 7.84
(dd, J ) 8.8, 7.9 Hz, 1H), 8.51 (d, J ) 8.6 Hz, 1H), 8.60 (d, J
) 8.9 Hz, 1H), 11.35 (s, 1H); [R]D -181.7 (c 0.60 CHCl3).
Crystal data for 43: C20H11NO7, M ) 377.3, monoclinic, P21
(no. 4), a ) 5.066(1) Å, b ) 12.601(1) Å, c ) 12.298(1) Å, â )
92.55(1)°, V ) 784.4(1) Å3, Z ) 2, Dc ) 1.598 g cm-3, µ(Cu KR)
) 1.05 mm-1, T ) 293 K, yellow plates; 1263 independent
measured reflections, F2 refinement, R1 ) 0.039, wR2 ) 0.098,
1144 independent observed reflections [|Fo| > 4σ(|Fo|), 2θ e
128°], 258 parameters. The absolute structure of 43 could not
be determined from the X-ray analysis, but was assigned by
reference to those of 38 and 3. CCDC 182480. Diastereoisomer
44: 1H NMR (300 MHz, CDCl3) δ 3.76 (d, J ) 3.9 Hz, 1H),
4.10 (d, J ) 3.9 Hz, 1H), 7.11 (d, J ) 7.8 Hz, 1H), 7.18 (d, J )
8.5 Hz, 1H), 7.26 (d, J ) 8.6 Hz, 1H), 7.36 (d, J ) 6.7 Hz, 1H),
7.67 (t, J ) 8.1 Hz, 1H), 7.75 (dd, J ) 8.8, 7.8 Hz, 1H), 8.55 (d,
J ) 7.4 Hz, 1H), 8.59 (d, J ) 7.1 Hz, 1H), 11.36 (s, 1H).
Meth od 2. AcONO2 in Ac2O20 (3.16 M; 0.023 mL, 1.2 equiv)
was added to palmarumycin C2 (3) (20 mg, 0.060 mmol) in CH2-
Cl2 (1 mL) at 0 °C, and the mixture was stirred for 14 h and
rotary evaporated. Chromatography (EtOAc/hexanes, 1:9-1:
4) gave 43 and 44 (8 mg, 35%) as a 1:1 mixture of diastereoi-
somers. Spectroscopic data for this sample matched those
reported in method 1: [R]D -240 (c 1.00, CHCl3).
P a lm a r u m ycin C11 4. Palmarumycin C2 (3) (504 mg, 1.52
mmol) in dry MeOH (31 mL) under N2 was sonicated for 2
min followed by the addition of NaBH4 (57 mg, 1.52 mmol) at
0 °C. After being stirred for 10 min at this temperature, the
clear colorless solution was quenched by addition of saturated
aqueous NH4Cl (10 mL) and EtOAc (10 mL), and the mixture
was warmed to room temperature. HCl (1 M, 5 mL) was added
to dissolve the precipitate, and EtOAc (10 mL) was added. The
organic layer was separated and was again washed with 1 M
HCl (10 mL) followed by drying (MgSO4), filtration, and
evaporation. Chromatography (preadsorbed on silica with CH2-
Cl2) (EtOAc/hexanes, 1:2) gave palmarumycin C11 (4) (386 mg,
76%) as a white solid: mp 220-225 °C (CHCl3); Rf 0.25
(EtOAc/hexanes, 1:2); [R]D -155 (c 1.00, CH2Cl2), (lit.1b [R]D
-153 (c 0.24, CH2Cl2)); IR (KBr disk) 3491, 1670, 1270 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.02 (br d, J ) 11.5 Hz, 1H),
3.76 (dd, J ) 4.4, 2.7 Hz, 1H), 3.89 (d, J ) 4.3 Hz, 1H), 5.46
(dd, J ) 11.4, 2.6 Hz, 1H), 6.93 (d, J ) 7.3 Hz, 1H), 7.07 (dd,
J ) 6.8, 2.4 Hz, 1H), 7.15 (d, J ) 7.3 Hz, 1H), 7.35 (app-t, J )
7.9, 7.7 Hz, 1H), 7.39 (dd, J ) 7.6, 2.4 Hz, 1H), 7.43 (app-t, J
) 8.3, 7.6 Hz, 1H), 7.50 (app-t, J ) 8.3, 7.4 Hz, 1H), 7.51-
7.63 (m, 2H), 8.26 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 52.8,
54.2, 66.2, 96.6, 109.0, 109.9, 112.8, 118.5, 118.9, 119.3, 120.9,
121.0, 127.4, 127.7, 130.5, 132.0, 134.1, 147.2, 147.3, 156.5;
MS (CI) m/z 334 (M + H)+, 316, 287, 114; m/z (CI) calcd for
4′-Br om op a lm a r u m ycin CP 1 48. N-Bromosuccinimide (93
mg, 0.52 mmol, 1.1 equiv) in MeCN (3 mL) was added to
palmarumycin CP1 (1) (150 mg, 0.48 mmol) in MeCN (6 mL)
in five portions over 40 min. The mixture was stirred for 14 h
and evaporated to dryness. Chromatography (EtOAc/hexanes,
1:9-1:4) gave bromide (48) (162 mg, 86%) as a yellow solid:
mp 180-182 °C dec (Et2O); Rf 0.55 (EtOAc/hexanes 1:9); IR
(thin film) 1661, 1606, 1413 cm-1; 1H NMR (300 MHz, CDCl3)
C
20H15O5 335.0919, found 335.0932. Anal. Calcd for C20H14O5:
C, 71.85; H, 4.22. Found: C, 71.62; H, 4.27. The spectroscopic
data for synthetic palmarumycin C11 (4) closely matched those
reported by Krohn for the natural product.1b Reduction of

Enantioselective Synthesis of (-)-Preussomerin G
J . Org. Chem., Vol. 67, No. 9, 2002 2749
1
racemic palmarumycin C2 (()-2 in the same way gave racemic
palmarumycin C11 ((()-4)21 (74%).
CHCl3); IR (thin film) 1785, 1702, 1113 cm-1; H NMR (300
MHz, CDCl3) δ 3.08 (s, 3H), 3.60 (s, 3H), 3.63 (d, J ) 17.0 Hz,
1H), 3.63 (d, J ) 4.0 Hz, 1H), 3.81 (d, J ) 17.0 Hz, 1H), 3.99
(d, J ) 4.0 Hz, 1H), 4.41 (s, 2H), 7.00 (d, J ) 7.6 Hz, 1H), 7.11
(d, J ) 7.6 Hz, 1H), 7.36 (d, J ) 8.9 Hz, 1H), 7.40-7.61 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 53.2, 54.1, 59.2, 59.7, 69.0,
69.6, 95.7, 109.6, 109.8, 112.0, 121.5, 121.5, 122.9, 127.3, 127.8,
127.8, 129.3, 131.4, 134.2, 145.9, 145.9, 147.0, 147.1, 168.2,
168.9, 189.6; MS (CI) m/z 510, (M + NH4)+. Anal. Calcd for
P a lm a r u m ycin C12 49. PhI(OCOCF3)2 (76 mg, 0.18 mmol)
was added to palmarumycin C11 (4) (27 mg, 0.080 mmol) in
THF and H2O (9:1; 1.6 mL) under N2 over a period of 20 min.
The temperature of the mixture was maintained between 25
and 30 °C while the color of the reaction mixture changed to
orange. Two further aliquots of the oxidant (2 × 15 mg, 2 ×
0.32 mmol) were added after 2 and 3 h, and the reaction was
terminated 1 h after the last addition. H2O (1 mL) and Et2O
(3 mL) were added, and the separated organic layer washed
with aqueous sodium dithionite (2 mL of 70 mg Na2S2O4 in 4
mL H2O) followed by brine (2 mL) and drying (MgSO4).
Chromatography (EtOAc/hexanes, 1:2) gave palmarumycin C12
(49) (9 mg, 30%) as well as unreacted palmarumycin C11 (4)
(3 mg, 11%). Palmarumycin C12 (49): mp 199-201 °C (CH2-
Cl2); Rf 0.34 (Et2O/hexanes 2:1); [R]D -165 (c 0.26, CH2Cl2);
C
26H20O10: C, 63.42; H, 4.09. Found: C, 63.51; H, 4.08.
Protection of racemic palmarumycin C3 ((()-50) in the same
way gave racemic diester ((()-51) (96%).
4′-Hyd r oxyp a lm a r u m ycin C3 53. Dry CH2Cl2 (3.5 mL)
and AcOH (3.5 mL) were added to diester 51 (117 mg, 0.24
mmol) and Pb(OAc)4 (212 mg, 0.48 mmol) under N2. The
mixture was heated to 40 °C for 40 h and rotary evaporated,
and AcOH was removed by azeotrope with PhMe (2 × 5 mL).
The residue was dissolved in CH2Cl2 (20 mL) and saturated
aqueous NH4Cl (10 mL), and the organic layer was separated,
dried (MgSO4), filtered, and rotary evaporated. LiOH (100 mg,
2.38 mmol) in degassed H2O (2.34 mL) was added to the crude
product 52 in dry THF (11.7 mL) at 0 °C, and the mixture
was stirred for 1.5 h. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and EtOAc (20 mL), and
the organic layer was separated. The aqueous layer was re-
extracted with EtOAc (10 mL), and the combined organic
layers were dried (MgSO4), filtered, and rotary evaporated.
Chromatography (EtOAc/hexanes, 1:2) gave triol 53 (32 mg,
37% over two steps) as a yellow solid: mp 200-205 °C dec
(Et2O); Rf 0.20 (EtOAc/hexanes, 1:2); [R]D -230 (c 0.50, CHCl3);
IR (KBr disk) 3484, 3447, 1585, 1266, cm-1 1H NMR (300
;
MHz, CDCl3) δ 3.04 (d, J ) 11.5 Hz, 1H), 3.74 (dd, J ) 4.3,
4.2 Hz, 1H), 3.85 (d, J ) 4.4 Hz, 1H), 5.38 (dd, J ) 11.5, 2.9
Hz, 1H), 6.89 (s, 1H), 6.98 (d, J ) 8.9 Hz, 1H), 7.03 (d, J ) 8.9
Hz, 1H), 7.05 (d, J ) 7.3 Hz, 1H), 7.23 (d, J ) 7.5 Hz, 1H),
7.50 (dd, J ) 8.3, 7.6 Hz, 1H), 7.52 (d, J ) 8.2 Hz, 1H), 7.58
(d, J ) 8.3 Hz, 1H), 7.52-7.64 (dd, J ) 8.2, 6.9 Hz, 1H), 7.80
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 52.7, 54.2, 66.1, 99.0,
110.2, 110.9, 113.1, 115.2, 118.9, 120.1, 120.9, 121.5, 122.4,
127.6, 127.7, 134.1, 145.7, 146.9, 149.8, 150.0; MS (EI) m/z 350
(M+.), 332, 316, 160; m/z (EI) calcd for C20H14O6 350.0790,
found 350.0775. Spectroscopic data for synthetic palmarumy-
cin C12 (49) were in excellent agreement for those published
for the natural product 49.1b
IR (thin film) 3472, 1653, 1613 cm-1 1H NMR (300 MHz,
;
P a lm a r u m ycin C3 50. PhI(OCOCF3)2 (322 mg, 0.75 mmol)
in THF and water (9:1; 2.8 mL) was added to palmarumycin
C11 (4) (125 mg, 0.37 mmol) in THF and H2O (9:1; 5.5 mL)
over 1 min at 40 °C, and stirring was continued at the same
temperature for 4 h. The mixture was diluted with EtOAc (25
mL) and saturated aqueous NaHCO3 (10 mL). The organic
layer was separated, dried (MgSO4), filtered, and rotary
evaporated, and the residue was dissolved in MeCN (15 mL).
MnO2 (619 mg) was added followed by a second portion (311
mg) after a 30 min delay. Stirring was continued for a further
1 h when the mixture was filtered through Celite and washed
with MeCN (2 × 5 mL). Ascorbic acid (153 mg) was added to
the mixture with stirring until the red solution changed to pale
yellow. Rotary evaporation and chromatography (EtOAc/
hexanes, 1:4) gave palmarumycin C3 (50) (40 mg, 31% over
three steps) as a yellow solid: mp 210-215 °C (CHCl3/
hexanes); Rf 0.51 (Et2O/hexanes, 2:1); [R]D -246 (c 0.62, CHCl3)
(lit.1b [R]D -300 (c 1.0, CH2Cl2)); IR (KBr disk) 3479, 1655,
acetone-d6) δ 3.63 (app-d, J ) 4.0 Hz, 1H), 3.64 (d, J ) 4.0 Hz,
0.5H), 4.03 (app-d, J ) 4.0 Hz, 1H), 6.72-7.07 (m, 4H), 7.17-
7.26 (m, 1H), 7.34-7.45 (m, 1H), 7.74-7.80 (m, 1H), 7.92 (app-
d, J ) 8.3 Hz, 0.5H), 8.85 (s, 0.5H), 8.92 (s, 0.5H), 11.38 (s,
0.5H), 11.40 (s, 0.5H); 13C NMR (75 MHz, acetone-d6) δ 55.3,
54.5, 54.7, 98.9, 110.4, 110.6, 111.2, 111.5, 112.1, 112.9, 115.2,
117.6, 118.0, 119.4, 122.9, 123.0, 126.4, 127.6, 127.7, 130.9,
140.7, 147.7, 149.6, 150.9, 157.9, 198.1; MS (CI) m/z 365 (M +
H)+; m/z (CI) calcd for C20H13O7 365.0661, found 365.0665.
Anal. Calcd for C20H12O7: C, 65.94; H, 3.32. Found: C, 66.00;
H, 3.20. Reaction of racemic diester (()-51 in the same way
gave racemic triol (()-53 (35%).
P r eu ssom er in G 11 a n d Ep ip r eu ssom er in G 54. Pb-
(OAc)4 (12.2 mg, 0.028 mmol) in dry CH2Cl2 (1 mL) was added
to triol 53 (10.0 mg, 0.028 mmol) in dry CH2Cl2 (8 mL) at -78
°C under N2 and the mixture stirred for 10 min. The mixture
was quenched with saturated aqueous NH4Cl (10 mL) and
CH2Cl2 (20 mL), and the organic layer was separated. The
aqueous layer was re-extracted with CH2Cl2 (10 mL), and the
combined organic layers were dried (MgSO4), filtered, and
rotary evaporated. Chromatography (EtOAc/hexanes, 1:2) gave
preussomerin G (11) and epipreussomerin G (54) (5.5 mg,
0.015 mmol, 55%) as a yellow solid. Further chromatography
(EtOAc/hexanes, 1:4) gave (-)-preussomerin G (11) (2.5 mg,
25%) followed by epipreussomerin G (54) (2.5 mg, 25%) both
as yellow solids. P r eu ssom er in G (11). An analytical sample
was prepared by trituration of this sample with hot Et2O and
pentane (1:5; 1 mL): mp 210-213 °C (Et2O/pentane) (lit.3e mp
222-225 °C dec); Rf 0.20 (EtOAc/hexanes, 1:4); [R]D -533 (c
1
1611, 1266, cm-1; H NMR (300 MHz, CDCl3) δ 3.66 (d, J )
4.0 Hz, 1H), 4.06 (d, J ) 4.0 Hz, 1H), 7.06 (d, J ) 7.1 Hz, 1H),
7.14 (d, J ) 9.2 Hz, 1H), 7.28 (d, J ) 7.0 Hz, 1H), 7.32 (d, J )
9.2 Hz, 1H), 7.38 (s, 1H), 7.52 (app-t, J ) 8.3, 7.6 Hz, 1H),
7.57 (app-t, J ) 8.3, 7.6 Hz, 1H), 7.64 (d, J ) 8.0 Hz, 1H), 7.70
(d, J ) 8.1 Hz, 1H), 11.50 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 52.7, 53.2, 99.0, 110.4, 111.3 (×2), 113.1, 116.1, 121.8, 122.5,
122.9, 127.7, 128.0, 129.8, 134.2, 145.1, 146.6, 149.3, 157.2,
195.7; MS (EI) m/z 348 (M•+), 303, 215; m/z (EI) calcd for
C
20H12O6 348.0633, found 348.0631. The spectroscopic data for
synthetic palmarumycin C3 (50) matched that reported for the
natural product.1b Reaction of racemic palmarumycin C11 ((()-
4) in the same way gave racemic palmarumycin C3 ((()-50)
(30%).
0.05, CH2Cl2; IR (thin film) 3382, 3352, 1678, 1661, 1467 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.86 (d, J ) 4.0 Hz, 1H), 4.25 (d,
J ) 4.0 Hz, 1H), 6.59 (d, J ) 10.0 Hz, 1H), 6.96 (d, J ) 9.0 Hz,
1H), 7.04-7.08 (m, 2H), 7.24 (d, J ) 10 Hz, 1H), 7.43 (app-t,
J ) 8.0 Hz, 1H), 7.65 (d, J ) 7.6 Hz, 1H), 10.22 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 52.1, 53.6, 89.9, 93.8, 109.7, 115.1,
120.5, 120.6, 120.8, 121.2, 126.7, 129.8, 131.1, 133.5, 140.7,
143.3, 148.6, 156.0, 183.7, 195.4; UV λmax (CHCl3) 373 (ꢀ 3.3 ×
104), 272 (6.0 × 103), 241 (9.0 × 103) nm; MS (CI) m/z 363 (M
+ H)+, 191, 174, 52; m/z (CI) calcd for C20H11O7 363.0505, found
363.0516. Chiral HPLC (method D): tR ) 9 min and tR ) 11
min ((-)-preussomerin G (11); (>95% ee)). The spectroscopic
data for synthetic preussomerin G (11) matched that reported
for the natural product3e and the sample was identical with
authentic samples of preussomerin G (11) provided by Profes-
P a lm a r u m ycin C3 Di(2-m et h oxya cet a t e) 51. Pyridine
(189 µL) and 2-methoxyacetyl chloride (117 uL, 1.28 mmol)
were added to palmarumycin C3 (50) (90 mg, 0.26 mmol) and
4-N,N-(dimethylamino)pyridine (1 mg) in CH2Cl2 (5 mL) at
-78 °C under N2, and the mixture was stirred for 3 h. The
mixture was quenched with of 1 M HCl (5 mL) and CH2Cl2
(10 mL), and the organic layer was separated, dried (MgSO4),
filtered, and rotary evaporated. Excess 2-methoxyacetyl chlo-
ride was removed by azeotrope with PhMe (2 × 5 mL). The
residue was triturated with Et2O (1.5 mL) at reflux and filtered
to give diester 51 (117 mg, 92%) as a white solid: mp 170-
173 °C (Et2O); Rf 0.10 (EtOAc/hexanes, 1:2); [R]D -166 (c 0.57,

2750 J . Org. Chem., Vol. 67, No. 9, 2002
Barrett et al.
sor Karsten Krohn and Dr. Sheo B. Singh (Merck and Co. Inc.).
Oxidation of racemic triol (()-53 in the same way gave racemic
preussomerin G (()-11 (20%). Ep ip r eu ssom er in G (54). An
analytical sample was prepared by trituration of this sample
with hot Et2O (1 mL): mp 173-174 °C (Et2O); Rf 0.15 (EtOAc/
hexanes, 1:4); [R]D ) +285 (c 0.05, CH2Cl2); IR (thin film) 3644,
1680, 1650, 1473, cm-1; 1H NMR (300 MHz, CDCl3) δ 3.80 (d,
J ) 3.0 Hz, 1H), 4.12 (d, J ) 3.0 Hz, 1H), 6.60 (d, J ) 10.0 Hz,
1H), 6.95 (d, J ) 9.0 Hz, 1H), 7.04 (d, J ) 9.0 Hz, 1H), 7.14 (d,
J ) 10.0 Hz, 1H), 7.18 (d, J ) 8.5 Hz, 1H), 7.43 (app-d, J )
8.0 Hz, 1H), 7.62 (d, J ) 7.5 Hz, 1H), 11.02 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 53.0, 59.0, 89.8, 89.8, 112.0, 118.3, 120.3,
120.5, 121.2, 121.3, 127.3, 129.2, 131.0, 133.6, 140.0, 142.6,
148.4, 157.8, 183.5, 191.9; MS (CI) m/z 363 (M + H)+, 190,
174, 161, 52; m/z (CI) calcd for C20H11O7 363.0505, found
363.0509.
preussomerin G (()-11 kindly carried out by Gregory
D. J onas; the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medicinal
Science at Imperial College; Professor Karsten Krohn
for authentic samples of palmarumycins CP1 (1), CP2
(13), C12 (49), and preussomerin G (11); and Dr. Sheo
B. Singh and Merck and Co., Inc., for authentic samples
of palmarumycin C2 (deoxypreussomerin B (3)) and
preussomerin G (11).
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for 3, 22, 37, 38, and 43; 1H and 13C NMR spectra
for palmarumycin CP1 (1), palmarumycin C2 (3), palmarumy-
cin C11(4), palmarumycin CP2 (13), (-)-preussomerin G (11),
CJ ,12-371 (33), (()-CJ ,12-372 (34), palmarumycin C12 (49),
and palmarumycin C3 (50); and 1H NMR spectra for phenol
23, quinone 30, ester 38, nitro arenes 43/44, and epipreus-
somerin G (54). This material is available free of charge via
the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank GlaxoSmithKline for
most generous support of our research, for the Glaxo
endowment (to A.G.M.B.), and for the HPLC analysis
of synthetic preussomerin G (11) and synthetic racemic
J O0110247