Enantiospecific synthesis of the proposed structure of the antitubercular marine diterpenoid pseudopteroxazole: Revision of stereochemistry

Article abstract of DOI:10.1021/ja010221k

An enantiospecific synthesis of structure 1, previously assigned to the antitubercular marine natural product pseudopteroxazole, has been accomplished as outlined in Scheme 1. Coupling of diene acid 3 and amino phenol 4 produced the amide 5, which was sub

Full text of DOI:10.1021/ja010221k

J. Am. Chem. Soc. 2001, 123, 4475-4479
4475
Enantiospecific Synthesis of the Proposed Structure of the
Antitubercular Marine Diterpenoid Pseudopteroxazole: Revision of
Stereochemistry
Ted W. Johnson and E. J. Corey*
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts, 02138
ReceiVed January 25, 2001
Abstract: An enantiospecific synthesis of structure 1, previously assigned to the antitubercular marine natural
product pseudopteroxazole, has been accomplished as outlined in Scheme 1. Coupling of diene acid 3 and
amino phenol 4 produced the amide 5, which was subjected to a novel oxidative intramolecular Diels-Alder
reaction to generate the tricyclic lactam 6a stereoselectively. This product was transformed via intermediates
7-11 into the diene 13. Cationic cyclization of 13 afforded two diastereomeric tricyclic amphilectanes which
were separated and transformed by parallel four-step sequences into 1 and 2, respectively. Neither 1 nor 2
were identical with pseudopteroxazole, indicating a need for revision of the structure, probably to 16.
Since the pioneering work of W. Fenical and his group on
the isolation, structure, and bioactivity of the pseudopterosins,1,2
a number of other members of this family of marine natural
products, the amphilectane group, have been discovered,3
including pseudopteroxazole (assigned structure 1), which was
found to be a potent inhibitor of Mycobacterium tuberculosis
H37Rv.4 The unexpected antitubercular activity of pseudopterox-
azole and its novel structure prompted us to undertake a total
synthesis using a stereocontrolled, biomimetic cyclization
process that was previously developed for the total synthesis
of pseudopterosins.5,6 Because this synthetic approach also
allows variation of configuration at C(1) in the final stages of
synthesis, it also offered a route to 2, the C(1)-diastereomer of
The synthetic pathway to 1 and 2 is outlined in Scheme 1.
Coupling of the (R)-carboxylic acid 38 with the amino phenol
4 (Aldrich) using dicyclohexylcarbodiimide and 1-hydroxyben-
zotriazole as reagents provided diene amide 5 cleanly. Treatment
of 5 with 2 equiv of lead tetraacetate in ethyl acetate at room
temperature generated the corresponding quinone monoimide9
that underwent internal Diels-Alder addition as it was formed
to give the endo adduct 6a in 69% isolated yield along with a
small amount of the diastereomeric adduct 6b (ratio 6a: 6b )
8:1) after silica gel chromatography with a flash column. The
(6) For other synthetic routes to the pseudopterosin family, see: (a)
Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584. (b)
Corey, E. J.; Carpino, P. J. Am. Chem. Soc. 1989, 111, 5472. (c) Corey, E.
J.; Carpino, P. Tetrahedron Lett. 1990, 31, 3857. (d) McCombie, S. W.;
Cox, B.; Lin, S.-I.; Ganguly, A. K.; McPhail, A. T. Tetrahedron Lett. 1991,
32, 2083. (e) McCombie, S. W.; Ortiz, C.; Cox, B.; Ganguly, A. K. Synlett
1993, 541. (f) Buszek, K. R. Tetrahedron Lett. 1995, 36, 9125. (g) Buszek,
K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129. (h) Gill, S.; Kocienski,
P.; Kohler, A.; Pontiroli, A.; Qun, L. J. Chem. Soc., Chem. Commun. 1996,
1743. (i) Majdalani, A.; Schmalz, H.-G. Tetrahedron Lett. 1997, 38, 4545.
(j) Majdalani, A.; Schmalz, H.-G. Synlett 1997, 1303. (k) Kato, N.; Zhang,
C.-S.; Matsui, T.; Iwabachi, H.; Mori, A.; Ballio, A.; Sassa, T. J. Chem.
Soc., Perkin Trans. 1 1998, 2475.
1. We report herein the total synthesis of 1 and 2 and the
demonstration that each of these structures is different from
natural pseudopteroxazole, thus necessitating structural revision
of the latter. These results and previous studies leading to the
revision of the stereochemistry of pseudopterosins G-J and
helioporin E7 have allowed a reassignment of structure to
pseudopteroxazole.
(7) Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org. Lett. 2000, 2,
2389.
(1) (a) Look, S. A.; Fenical, W.; Matsumoto, G.; Clardy, J. J. Org. Chem.
1986, 51, 5140. (b) Fenical, W. J. Nat. Prod. 1987, 50, 1001. (c) Look, S.
A.; Fenical, W. Tetrahedron 1987, 43, 3363.
(2) Look, S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl. Acad.
Sci. U.S.A. 1986, 83, 6238.
(3) (a) Tanaka, J.-i.; Ogawa, N.; Liang, J.; Higa, T.; Gravalos, D. G.
Tetrahedron 1993, 49, 811. (b) Geller, T.; Schmalz, H.-G.; Bats, J. W.
Tetrahedron Lett. 1998, 39, 1537. (c) Ho¨rstermann, D.; Schmalz, H.-G.;
Kociok-Ko¨hn, G. Tetrahedron 1999, 55, 6905. (d) Rodr´ıguez, A. D.;
Gonza´lez, E.; Huang, S. D. J. Org. Chem. 1998, 63, 7083.
(4) Rodr´ıguez, A. D.; Ram´ırez, C.; Rodr´ıguez, I. I.; Gonza´lez, E. Org.
Lett. 1999, 1, 527.
(8) The (R)-acid 3 was synthesized starting with (R)-2-methyl-3-tert-
butylsilyloxypropionaldehyde (see: Burke, S. D.; Cobb, J. E.; Takeuchi,
K. J. Org. Chem. 1990, 55, 2138) by the following sequence: (1) Wittig
coupling with lithio (E)-2-butenyldiphenylphosphine oxide (Binns, M. R.;
Haynes, R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C. J. Am.
Chem. Soc. 1988, 110, 5411) by the method of Lythgoe et al. (Lythgoe,
B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston, S. J. Chem. Soc., Perkin
Trans. 1 1976, 2386) to form the (E,E)-diene; (2) TBS cleavage with
Bu4N+F- in THF at 23 °C; and (3) Jones oxidation with chromic acid and
sulfuric acid in acetone.
(9) Fernando, C. R.; Calder, I. C.; Ham, K. N. J. Med. Chem. 1980, 23,
1153.
(5) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777.
10.1021/ja010221k CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/14/2001

4476 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Johnson and Corey
Scheme 1
relative stereochemistry of the diastereomers 6a and 6b at the
carbons R and â to the lactam carbonyl was apparent from the
1H NMR spectra. The trans diaxial arrangement of HR and Hâ
in 6a was indicated by a 14 Hz coupling constant as compared
to a value JRâ ) ca. 5 Hz for diastereomer 6b. Sequential hydro-
genation of 6a at 1 atm of H2 in MeOH at 23 °C and benzylation
(K2CO3 and BnBr in acetone at reflux) produced benzyl ether
7 in 63% overall yield. Conversion of 7 to the N-tert-butoxy-
carbonyl derivative 8 and methanolysis of the resulting δ-lactam
subunit afforded the methyl ester 9 in high yield. Reduction of
the ester function of 9 with diisobutylaluminum hydride in
dichloromethane and subsequent cleavage of the tert-butoxy-
carbonyl group provided the amino alcohol 10 in good yield.
Replacement of the amino group in 10 by hydrogen, the next
synthetic objective of the plan summarized in Scheme 1, proved
to be problematic using conventional methodology. However,
it was discovered that conversion of 10 to the corresponding
diazonium salt followed by reduction with sodium cyanoboro-
hydride at 0 °C effected the required reductive deamination in
very good yield. Sodium cyanoborohydride can be recom-
mended for such deaminations. Oxidation of the resulting
primary alcohol with the Dess-Martin periodinane reagent
afforded aldehyde 11 quantitatively. Wittig coupling of 11 with
phosphonium ylide 1210,11 was stereospecific and gave the (E)-
conjugated diene 13 in 96% yield. Cationic cyclization of 13
was effected using methanesulfonic acid as catalyst in CH2Cl2
at -40 °C, a process applied earlier to the synthesis of
pseudopterosins.5 From previous results it had been expected
that the cyclization of the allylic cation from 13 would proceed
by the Ar-1,6 pathway to form the (1R)-diastereomer 14a.5 In
fact, although the cyclization proceeded quantitatively, the
product was a mixture of diastereomers 14a and 14b in a ratio
of about 1:2 (for discussion, see below). The mixture was
separated chromatographically on a Chiralcel OD column and
the individual diastereomers were converted by parallel pro-
cesses to the isomeric pseudopteroxazole structures 1 and 2.
The assignment of configuration to the C(1)-diastereomers 14a
1
and 14b was made from the H NMR spectra by comparison
with the corresponding C(1)-diastereomers of the pseudopterosins5
and using the detailed analysis recently published.7 In the case
of 14a, the vinyl proton attached to C(14) appeared at δ 5.13
as a broadened doublet, J ) 9.2 Hz. In the case of 14b, the
vinyl proton attached to C(14) appeared further upfield at δ
5.00 as a broadened doublet, J ) 9.2 Hz. For 14a, the allylic
proton attached to C(1) appeared at δ 3.64 as a broadened
doublet, J ) 9.2 Hz, due to coupling with the vicinal vinyl
proton and broadening from small couplings to the C(2)
(10) Cristau, H.-J.; Ribeill, Y. Synthesis 1988, 911.
(11) Vedejs, E.; Fang, H. W. J. Org. Chem. 1984, 49, 210.

Antitubercular Marine Diterpenoid Pseudopteroxazole
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4477
methylene protons. For 14b the C(1) allylic proton showed up
at δ 3.79 as a doublet of doublets of doublets, J ) 9.2, 9.2, 9.2
Hz, from coupling to the vicinal vinyl proton (J ) 9.2 Hz) and
the vicinal protons at C(2). These data for 14a and 14b are
remarkably similar to those for A type pseudopterosin structures
on one hand and their C(1)-diastereomers on the other.5,7
The transformation of 14a into 1 was then accomplished by
a sequence of four steps, as shown in Scheme 1. The tricyclic
benzyl ether 14a was subjected to benzyl ether cleavage (BBr3
in CH2Cl2 at 0 °C) and then nitrated (HNO3 in hexanes12) to
form the nitro phenol 15a. Treatment of 15a with Zn dust and
NH4Cl in CH3OH at 23 °C for 1 h13 effected conversion to the
corresponding amino phenol which upon reaction with methyl
orthoformate and a catalytic amount of 4-toluenesulfonic acid
at 23 °C for 1 h14 gave the desired tetracyclic oxazole 1 in 92%
yield over the two steps. In a parallel series of experiments
starting with benzyl ether 14b the tetracylic oxazole 2 was
produced (see Supporting Information).
Figure 1. (A) Pre-transition state assembly (endo) leading to 6a. (B)
Pre-transition state assembly (endo) leading to 6b.
Comparison of the spectral data for pseudopteroxazole4,15 with
those for synthetic 1 and 2 showed that all these compounds
differ. It is clear that the stereochemistry of pseudopteroxazole
must be revised from that assigned 1,4 as we had previously
surmised.7 It now seems that pseudopteroxazole probably is best
represented by structure 16, in common with other synthetic5
Figure 2. Steric repulsion involving the C(7)-methyl substituent
disfavoring formation of 14a relative to 14b during the cationic
cyclization of 13.
(because of secondary orbital interactions), and since there do
not appear to be any special steric factors favoring an exo
transition state,16 the endo transition states in Figure 1 seem
probable for the reaction 5 f 6.
and naturally occurring amphilectanes.7 The synthesis of 16 is
now in progress in our laboratories. If pseudopteroxazole is
found to have structure 16, it would then reside in the same
stereochemical family with pseudopterosins G-J and helioporin
E. Further, all the pseudopterosins, e.g. A-E type and G-J
type, would be unified biosynthetically as originating from
serrulatane (seco pseudopterosin) precursors by ring closure,
which connects C(1) to the benzenoid ring.
Two aspects of the above-described synthesis of 1 and 2
deserve comment: (1) the diastereoselective intramolecular
Diels-Alder reaction to form 6a and 6b in a ratio of 8:1 and
(2) the cationic ring closure 13 f 14a + 14b. With regard to
the former, it should be noted that the cyclization 5 f 6 appears
to be the first example of this type of internal cycloaddition
involving an in situ generated quinone imide. The diastereose-
lectivity favoring 6a over 6b is readily understood in terms of
an endo transition state for the internal Diels-Alder process,
even though the structures of the reaction products 6a and 6b
provide no information with regard to endo vs exo pathways.
The endo transition state leading to 6a involves no adverse steric
factors, whereas that leading to 6b involves a significant
repulsion between the methyl substituent on the C(3) stereo-
center and the olefinic hydrogen at C(5) (pseudopterosin
numbering, see Figure 1). Since the endo pathway is normally
preferred for Diels-Alder reactions with quinoid dienophiles
The cationic ring closure 13 f 14a + 14b is far less
diastereoselective than the corresponding Ar-1,6 ring closure
in the pseudopterosin A series.5 One obvious explanation for
this difference is the orientation of the methyl group attached
to C(7). In the cationic cyclization of 13, that methyl substituent
disfavors formation of 14a relative to 14b because of steric
interference with the E-methyl part of the isopropylidene group
during ring closure to form 14a. Such repulsions are clearly
absent for the Ar-1,6 cyclization of the C(7) diastereomeric
series. The two Ar-1,6-pathways leading to 14a and 14b are
shown in Figure 2.
The oxidative intramolecular Diels-Alder reaction utilized
for the construction of 6a (Scheme 1) is potentially widely
useful. We have demonstrated the prototype reaction for the
synthesis of 18 from 17. The oxidative cyclization occurs rapidly
and cleanly with Pb(OAc)4 in THF at 23 °C to give in good
yield after acetylation the bicyclic acetate 18. The oxidant Pb-
(OAc)4 is superior to C6H5I(OAc)2. A number of other oxidants
were found to be unsatisfactory, including Ag2CO3, Ag2O,
MnO2, and chloranil.
(12) Wiedenau, P.; Monse, B.; Blechert, S. Tetrahedron 1995, 51, 1167.
(13) Evans, D.; Smith, C. E.; Williamson, W. R. N. J. Med. Chem. 1977,
20, 169.
(14) (a) Katritzky, A. R.; Musgrave, R. P.; Rachwal, B.; Zaklika, C.
Heterocycles 1995, 41, 345. (b) Nakahara, Y.; Fujita, A.; Beppu, K.; Ogawa,
T. Tetrahedron 1986, 42, 6465.
(15) We are grateful to Prof. A. D. Rodr´ıguez for data on pseudopterox-
azole.
(16) See: Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927.

4478 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Johnson and Corey
(0.642 mL, 0.642 mmol, 1.0 M solution in THF) and the mixture was
stirred at 0 °C for 0.5 h. The solution was cooled to -20 °C and a
solution of the aldehyde 11 (0.069 g, 0.214 mmol) in DME (1 mL)
was added dropwise. The solution was stirred at -20 °C for 0.5 h and
then quenched with saturated ammonium chloride solution and extracted
with ether (3 × 5 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated under reduced pressure.
The crude material was taken up in 20:1 hexanes-ethyl acetate and
passed through a short plug of silica gel, eluting with 20:1 hexanes-
ether to provide the pure diene 13 (0.077 g, 96%) as a clear glass.
None of the cis diene was detectable in the proton NMR spectrum. 1H
NMR (CDCl3, 400 MHz) δ 7.60-7.30 (5H, m), 6.85 (1H, s), 6.62
(1H, s), 6.37 (1H, dd, J ) 15.2, 10.8 Hz), 5.90 (1H, d, J ) 10.4 Hz),
5.77 (1H, dd, J ) 15.6, 7.2 Hz), 5.13 (1H, d, J ) 11.6 Hz), 5.05 (1H,
d, J ) 11.6 Hz), 3.29 (1H, m), 3.21 (1H, m), 2.97 (1H, m), 2.36 (3H,
m), 1.90-1.50 (4H, m), 1.82 (6H, s), 1.26 (3H, d, J ) 6.8 Hz), 0.87
(3H, d, J ) 6.4 Hz). 13C NMR (CDCl3, 100 MHz) δ 156.35, 139.93,
137.97, 137.03, 135.70, 133.31, 130.01, 128.66, 127.77, 127.18, 125.62,
125.44, 120.41, 109.37, 69.86, 43.34, 39.92, 29.41, 26.92, 26.32, 22.08,
In summary, the structure previously assigned to pseudopterox-
azole has been synthesized, compelling revision of structure and
consideration of the alternative formulation 16.
Experimental Section
Diels-Alder Reaction of 5. To a stirred solution of the amide 5
(0.320 g, 1.304 mmol) in ethyl acetate (10 mL) at 25 °C was added
lead tetraacetate (1.157 g, 2.609 mmol) and the reaction was stirred
vigorously for 5 min. Sodium bicarbonate (5%) was added and the
solution was extracted with ethyl acetate (2 × 10 mL). The combined
organic layers were washed again with 5% sodium bicarbonate, dried
over sodium sulfate, and filtered. Nitrogen was bubbled through the
solution for 5 min, and the flask was capped and left to sit for 18 h.
The solution was concentrated and proton NMR spectroscopy showed
an approximate 8:1 mixture of the cycloadducts 6a and 6b, respectively.
Flash column chromatography (silica gel, 2:1:1 hexanes-ethyl acetate-
chloroform then 1:1:1 hexanes-ethyl acetate-chloroform) provided
the major Diels-Alder product 6a (0.218 g, 69%), which showed a
large (14.0 Hz) coupling between the protons R and â to the lactam
carbonyl and the diastereomeric minor cycloadduct 6b, which displayed
only a small coupling (J e 5 Hz) between the protons R and â to the
lactam carbonyl. Data for 6a: 1H NMR (CDCl3, 400 MHz) δ 7.44
(1H, bs, N-H), 6.52 (1H, s), 5.90 (1H, m), 5.84 (1H, m), 5.19 (1H,
bs, O-H), 3.52 (1H, m), 3.18 (1H, bd, J ) 14.0 Hz), 2.29 (1H, sextet,
J ) 7.2 Hz), 2.15 (3H, s), 1.41 (3H, d, J ) 5.6 Hz), 1.34 (3H, d, J )
5.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 174.11, 148.84, 132.72, 127.62,
123.27, 122.59, 121.20, 120.53, 115.65, 40.67, 37.43, 29.38, 22.82,
16.43, 11.62. Data for 6b: 1H NMR (CDCl3, 400 MHz) δ 7.24 (1H,
bs), 6.51 (1H, s), 5.98 (1H, m), 5.59 (1H, m), 3.77 (1H, m), 3.57 (1H,
m, J e 5 Hz), 2.77 (1H, m), 2.18 (3H, s), 1.34 (1H, d, J ) 5.6 Hz),
0.96 (3H, d, J ) 6.0 Hz).
20.92, 18.67, 18.00, 13.67. IR (thin film) 2961, 2870, 1611, 1578 cm-1
.
High-resolution MS (EI, m/z) 374.2599, calcd for [C27H34O]+ 374.2610.
[R]20 +1.6 (c 0.70, CHCl3).
D
Cationic Cyclization of 13 to 14a and 14b. To a stirred solution
of the diene 13 (0.032 g, 0.085 mmol) in dichloromethane (8 mL) at
-78 °C was added a 1.0 M solution of methanesulfonic acid in
dichloromethane (85 µL, 0.085 mmol). The mixture was warmed to
-40 °C and stirred for 10 h. The solution was quenched with
triethylamine (118 µL, 0.850 mmol) and passed through a plug of silica
gel, eluting with 20:1 hexanes-ether. Concentration under reduced
pressure gave the tricyclic product 14a and the diastereomeric tricycle
14b (0.032 g, approximate 1:2 ratio), which could be separated by
preparative HPLC (Chiralcel OD column, 100% hexanes, elution
times: 15 min for 14b and 20 min for 14a). Data for 14a: 1H NMR
(CDCl3, 400 MHz) δ 7.60-7.30 (5H, m), 6.62 (1H, s), 5.13 (1H, bd,
J ) 9.2 Hz), 5.06 (1H, d, J ) 11.6 Hz), 5.02 (1H, d, J ) 11.6 Hz),
3.64 (1H, bd, J ) 9.2 Hz), 3.35 (1H, quintet, J ) 6.4 Hz), 2.13 (3H,
s), 2.10 (1H, m), 1.98 (1H, m), 1.94-1.60 (5H, m), 1.74 (3H, s), 1.66
(3H, s), 1.50 (1H, m), 1.22 (3H, d, J ) 7.2 Hz), 1.03 (3H, d, J ) 4.8
Hz). 13C NMR (CDCl3, 100 MHz) δ 154.07, 137.89, 136.33, 134.56,
130.71, 130.27, 128.87, 128.35, 128.16, 127.43, 126.88, 111.52, 69.61,
46.51, 40.82, 35.41, 30.79, 29.60, 27.49, 25.69, 22.83, 22.43, 20.86,
Reductive Deamination of 10. To a stirred solution of the aniline
10 (0.058 g, 0.171 mmol) in THF (5 mL) at 0 °C was added 1.0 M
aqueous HCl (0.531 mL, 0.531 mmol) followed by 1.0 M aqueous
NaNO2 (0.342 mL, 0.342 mmol) and the mixture was stirred at 0 °C
for 40 min. A freshly prepared 1.0 M solution of sodium cyanoboro-
hydride in water (1.709 mL, 1.709 mmol) was added dropwise and the
solution was stirred for 1 h at 0 °C and then overnight at 25 °C. Water
was added and the mixture was extracted with ether (3 × 5 mL). The
combined organic extracts were dried over magnesium sulfate, filtered,
and concentrated under reduced pressure to give the crude reduced
aromatic. Flash column chromatography (silica gel, 5:1 hexanes-ethyl
acetate) provided the deamination product (0.050 g, 91%) as a clear
19.79, 17.72. IR (thin film) 2948, 2844, 2922, 2863, 1455, 1322 cm-1
.
High-resolution MS (EI, m/z) 392.2946, calcd for [C27H34O + NH4]+
392.2952. [R]20 -116.6 (c 0.63, CHCl3). Data for 14b: 1H NMR
D
1
syrup. H NMR (CDCl3, 400 MHz) δ 7.60-7.30 (5H, m), 6.80 (1H,
(CDCl3, 400 MHz) δ 7.60-7.30 (5H, m), 6.63 (1H, s), 5.07 (1H, d, J
) 12.0 Hz), 5.02 (1H, d, J ) 12.0 Hz), 5.00 (1H, bd, J ) 9.2 Hz),
3.79 (1H, ddd, J ) 9.2, 9.2, 9.2 Hz), 3.31 (1H, quintet, J ) 6.4 Hz),
2.30-2.10 (2H, m), 2.17 (3H, s), 1.98 (1H, m), 1.90-1.70 (2H, m),
1.73 (3H, s), 1.66 (3H, s), 1.50-1.30 (2H, m), 1.30-1.20 (1H, m),
1.25 (3H, d, J ) 6.4 Hz), 1.04 (3H, d, J ) 6.4 Hz). 13C NMR (CDCl3,
100 MHz) δ 154.00, 138.32, 137.88, 134.64, 130.84, 130.67, 128.34,
128.26, 127.57, 127.42, 126.87, 111.57, 69.58, 43.46, 39.98, 35.35,
34.84, 29.57, 27.17, 25.56, 22.88, 21.51, 20.48, 20.16, 17.67. IR (thin
film) 2950, 2921, 2862, 1594, 1454 cm-1. High-resolution MS (EI,
s), 6.63 (1H, s), 5.12 (1H, d, J ) 11.6 Hz), 5.05 (1H, d, J ) 11.6 Hz),
3.75 (1H, dd, J ) 10.8, 7.2 Hz), 3.66 (1H, dd, J ) 10.0, 7.2 Hz), 3.30
(1H, m), 3.09 (1H, m), 2.51 (1H, m), 2.34 (3H, s), 1.90-1.50 (4H, m),
1.27 (3H, d, J ) 7.2 Hz), 0.76 (3H, d, J ) 6.8 Hz). 13C NMR (CDCl3,
100 MHz) δ 155.93, 139.68, 137.53, 135.39, 129.47, 128.28, 127.41,
126.81, 120.03, 109.00, 69.51, 66.65, 39.08, 38.44, 28.76, 26.44, 21.78,
20.77, 17.38, 11.44. IR (thin film) 3363, 2923, 2870, 1578, 1454, 1272
cm-1. High-resolution MS (EI, m/z) 324.2090, calcd for [C22H28O2]+
324.2094. [R]20 +39.0 (c 0.6, CHCl3).
D
m/z) 392.2956, calcd for [C27H34O + NH4]+ 392.2952. [R]20 +59.3
Aldehyde 11. To a stirred solution of the reduced aromatic alcohol
(0.0125 g, 0.0385 mmol) in dichloromethane at 25 °C was added Dess-
Martin periodinane (0.020 g, 0.0462 mmol) and the mixture was stirred
for 0.5 h. The cloudy mixture suspension was concentrated under
reduced pressure and passed through a short plug of silica gel, eluting
with 10:1 hexanes-ethyl acetate to provide aldehyde 11 (0.0124 g,
D
(c 0.85, CHCl3). For a discussion of stereochemical assignments based
1
on the H NMR data, see ref 7.
Benzoxazole 1. To a stirred solution of the o-nitrophenol 15a (0.0040
g, 0.012 mmol) in 90% methanol (2 mL) at 25 °C was added solid
ammonium chloride (2 mg, 0.036 mmol) followed by zinc dust (8 mg,
0.121 mmol) and the solution was stirred for 1 h at room temperature.13
The mixture was filtered through Celite, rinsing with methanol. The
solution was concentrated under reduced pressure, water was added,
and the mixture was extracted with diethyl ether (3 × 2 mL). The
combined organic extracts were dried over sodium sulfate, filtered, and
concentrated under reduced pressure to yield the o-aminophenol (0.004
g), which was used directly in the next step without further purification.
The o-aminophenol from the previous step was dissolved in trimethyl
orthoformate and one drop of a toluenesulfonic acid monohydrate
solution in trimethyl orthoformate (4 mg/0.5 mL) was added and the
solution was stirred at 25 °C for 1 h.14 The solvent was removed under
1
100%) as a clear, thick oil. H NMR (CDCl3, 400 MHz) δ 9.87 (1H,
s), 7.60-7.30 (5H, m), 6.71 (1H, s), 6.62 (1H, s), 5.10 (1H, d, J )
12.0 Hz), 5.03 (1H, d, J ) 12.0 Hz), 3.51 (1H, m), 3.27 (1H, m), 3.14
(1H, m), 2.32 (3H, s), 1.90-1.60 (3H, m), 1.45 (1H, m), 1.23 (3H, d,
J ) 6.8 Hz), 0.96 (3H, d, J ) 7.2 Hz). 13C NMR (CDCl3, 100 MHz)
δ 205.08, 156.18, 137.37, 137.26, 135.82, 129.82, 128.36, 127.53,
126.85, 119.40, 109.59, 69.61, 50.18, 37.91, 28.80, 26.41, 21.81, 20.77,
18.83.
Diene 13. To a stirred solution of bis(3-methyl-2-butenyl)diphe-
nylphosphonium bromide9,10 (0.259 g, 0.642 mmol, azeotroped with
benzene) in DME (5 mL) at 0 °C was added potassium tert-butoxide

Antitubercular Marine Diterpenoid Pseudopteroxazole
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4479
reduced pressure and residual amounts of solvent were removed by
azeotroping with benzene. Flash column chromatography (silica gel,
5:1 hexanes-ether) provided the pure benzoxazole 1 (0.0034 g, 92%
1051 cm-1. High-resolution MS (EI, m/z) 310.2157, calcd for [C21H27-
NO + H]+ 310.2169. [R]20 -158.2 (c 0.17, CHCl3).
D
1
two steps) as a clear, thick oil. H NMR (CDCl3, 400 MHz) δ 7.97
Acknowledgment. We are grateful to the National Institutes
of Health for a postdoctoral fellowship to T.W.J.
(1H, s), 5.09 (1H, bd, J ) 9.2 Hz), 3.84 (1H, bd, J ) 9.2 Hz), 3.39
(1H, quintet, J ) 6.4 Hz), 2.40 (3H, s), 2.19 (1H, m), 2.10 (1H, m),
1.98 (1H, m), 1.79 (3H, d, J ) 1.6 Hz), 1.67 (3H, d, J ) 1.6 Hz), 1.49
(1H, m), 1.36 (3H, d, J ) 7.2 Hz), 1.07 (3H, d, J ) 5.6 Hz), 1.90-
1.58 (4H, m). 13C NMR (CDCl3, 100 MHz) δ 151.14, 146.82, 137.56,
134.41, 133.37, 130.14, 129.49, 126.12, 122.74, 46.03, 40.47, 35.70,
30.28, 29.51, 28.25, 25.61, 23.18, 22.47, 20.69, 17.68, 12.60. IR (thin
film) 2959, 2950, 2824, 2871, 2862, 1523, 1464, 1445, 1376, 1078,
Supporting Information Available: Experimental proce-
dure for the synthesis of 15b and 2 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA010221K