Conversion of marcfortine A to paraherquamide A via paraherquamide B. The first formal synthesis of paraherquamide A

Article abstract of DOI:10.1021/jo9622791

The paraherquamides and marcfortines represent a novel class of anthelmintics. The sole structural difference between paraherquamide A and marcfortine A occurs in ring G. We synthesized paraherquamide B from marcfortine A in six steps. Paraherquamide A was then prepared from paraherquamide B in seven steps. This represents the first formal synthesis of paraherquamide A.

Full text of DOI:10.1021/jo9622791

J . Org. Chem. 1997, 62, 1795-1798
1795
Con ver sion of Ma r cfor tin e A to P a r a h er qu a m id e A via
P a r a h er qu a m id e B. Th e F ir st F or m a l Syn th esis of
P a r a h er qu a m id e A
Byung H. Lee* and Michael F. Clothier
Pharmacia and Upjohn Inc., Animal Health Discovery Research, Kalamazoo, Michigan 49001
Received December 6, 1996X
The paraherquamides and marcfortines represent a novel class of anthelmintics. The sole structural
difference between paraherquamide A and marcfortine A occurs in ring G. We synthesized
paraherquamide B from marcfortine A in six steps. Paraherquamide A was then prepared from
paraherquamide B in seven steps. This represents the first formal synthesis of paraherquamide
A.
Helminths, especially parasitic nematodes, cause sub-
stantial health problems in humans and domestic ani-
mals. Currently, three distinct chemical classes are used
for broad spectrum control of gastrointestinal nematodes
in veterinary medicine: benzimidazoles, imidazothiazoles,
and macrocyclic lactones.1 None of these drugs is ideally
suited for all therapeutic situations, and each class has
been challenged by the development of drug-resistant
nematode strains.2 Expansion of the anthelmintic arse-
nal is thus an urgent goal. Marcfortine A, paraherqua-
mide A, and their analogs have potent antiparasitic
activity.3 Because the marcfortines and paraherqua-
mides are unique both structurally and in their mode of
action, they represent a promising new class of anthel-
mintics.
The paraherquamides were isolated from Penicillium
sp.4 A total synthesis of the enantiomer of paraherqua-
mide B, which is the simplest member of the paraher-
quamide family, and synthetic studies of paraherquamide
A were described by Williams et al.5 We have utilized
paraherquamide B for the first formal synthesis of
paraherquamide A. A ready supply of paraherquamide
B was generated by conversion of the more easily
obtained marcfortine A which has the same absolute
configuration as the paraherquamides.6a Marcfortine A,
reported by Polonsky et al.,6b is a fungal metabolite of
Penicillium roqueforti and is structurally related to
paraherquamide B, the sole difference occurring in ring
G: paraherquamide B contains a five-membered G-ring
whereas the G-ring of marcfortine A is six-membered.
Opening the G-ring of marcfortine A, oxidatively remov-
ing one carbon atom, and reclosing was expected to give
paraherquamide B. This we accomplished in six steps
(Scheme 1). Treatment of marcfortine A with cyanogen
bromide7 opened the G-ring and gave bromo derivative
1. We were unable to form the terminal methylene 3 in
a single step from 1 through base-catalyzed elimination
t
of HBr using either DBU/CH3CN, KOH/MeOH, or BuOK/
DMSO. We overcame this resistance to elimination by
first converting 1 to selenide 2 which was accomplished
by treating 1 with diphenyl diselenide in the presence of
sodium borohydride. Oxidation of 2 with NaIO4 followed
by elimination of the resulting selenol in refluxing
benzene gave terminal alkene 3 in 80% yield. Hydrolysis
of the cyano group with NaOH in ethylene glycol8
produced 4 (50% yield) which under standard osmylating
conditions gave diol 5 (70%). Cleavage of the diol with
NaIO4 to an intermediate aldehyde followed by an
intramolecular reductive amination with sodium boro-
hydride formed the five-membered ring of paraherqua-
mide B (50%) whose 300-MHz 1H NMR and HRMS
spectra were identical with those reported for the natural
material.4c
We converted paraherquamide B to paraherquamide
A in seven steps (Scheme 2). Oxidation of paraherqua-
mide B with I2/NaHCO3 in THF/H2O gave lactam 6
X Abstract published in Advance ACS Abstracts, February 15, 1997.
(1) Lynn, R. C. Georgis’ Parasitology for Veterinarians; W. B.
Saunders Co.: Philadelphia, 1995; p 247.
9
(2) Prichard, R. Vet. Parasitol. 1994, 54, 259.
(40%) and 12-oxoparaherquamide B (25%). Treatment
of 6 with LDA and phenylselenenyl chloride followed by
oxidation of the resulting selenide with H2O2 gave the
R,â-unsaturated lactam 7 (58%). Our initial attempts to
epoxidize 7 were unsuccessful: H2O2/NaOH, m-CPBA,
isovaleraldehyde/VO(acac)2, and n-BuLi/H2O2 all failed
to give the epoxide 8. However, treatment of 7 in THF
with triton B10a and tert-butyl hydroperoxide10b gave
(3) (a) Blizzard, T. A.; Mrozik, H.; Fisher, M. H.; Schaeffer, S. M. J .
Org. Chem. 1990, 55, 2256. (b) Blizzard, T. A.; Margiatto, G.; Mrozik,
H.; Schaeffer, S. M.; Fisher, M. H. Tetrahedron Lett. 1991, 32, 2441.
(c) Shoop, W. L.; Egerton, J . R.; Eary, C. H.; Suhayda, D. J . Parasitol-
ogy 1990, 76, 349. (d) Ostlind, D. A.; Mickle, W. G.; Ewanciw, D. V.;
Andriuli, F. J .; Campbell, W. C.; Hernandez, S.; Mochale, S.; Munguira,
E. Res. Vet. Sci. 1990, 48, 260. (e) Blizzard, T. A.; Marino, G.; Sinclair,
P. J .; Mrozik, H. European Pat. Appl. EP 0 354 615 A1, 1990. (f)
Schaeffer, J . M.; Blizzard, T. A.; Ondeyka, J .; Goegelman, R.; Sinclair,
P. J .; Mrozik, H. Biochem. Pharmacol. 1992, 43, 679. (g) Mrozik, H.
U.S. Pat. Appl. US 4,866,060, 1989; (h) Blizzard, T. A.; Mrozik, H. U.S.
Pat. Appl. US 4,923,867, 1990.
(4) (a) Yamazaki, M.; Okuyama, E.; Kobayashi, M.; Inoue, H.
Tetrahedron Lett. 1981, 22, 135. (b) Ondeyka, J . G.; Goegelman, R. T.;
Schaeffer, J . M.; Kelemen, L.; Zitano, L. J . Antibiot. 1990, 43, 1375.
(c) Liesch, J .; Wichmann, C. J . Antibiot. 1990, 43, 1380. (d) Blanch-
flower, S. E.; Banks, R. M.; Everett, J . R.; Manger, B. R.; Reading, C.
J . Antibiot. 1991, 44, 492. (e) Blanchflower, S. E.; Banks, R. M.;
Everett, J . R.; Reading, C. J . Antibiot. 1993, 46, 1355.
1
epoxide 8 (58%), the H NMR spectrum of which showed
a single stereoisomer. The stereochemistry was assigned
to 8 based on the stereochemistry of alcohol 10 (vide
(7) von Braun, J . ; Engelbertz, P. Chem. Ber. 1923, 56, 1573.
(8) Misner, J . W. J . Org. Chem. 1987, 52, 3166.
(9) Bartlett, M. F.; Dickel, D. F.; Taylor, W. I. J . Am. Chem. Soc.
1958, 80, 126.
(10) (a) Methanol-free triton B (N-benzyltrimethylammonium hy-
droxide) was prepared by evaporating the MeOH from a commercially
available solution (Aldrich, 40 wt % triton B in MeOH). The reaction
failed when MeOH was present. (b) Grieco, P. A.; Nishizawa, M.; Oguri,
T.; Burke, S. D.; Marinovic, N. J . Am. Chem. Soc. 1977, 99, 5773.
(5) (a) Cushing, T. D.; Sanz-Cervera, J . F.; Williams, R. M. J . Am.
Chem. Soc. 1996, 118, 557. (b) Williams, R. M.; J ianhua, C. Tetrahe-
dron Lett. 1996, 37, 5441.
(6) (a) Lee, B. H.; Han, F. Tetrahedron Lett. 1994, 35, 1135. (b)
Polonsky, J .; Merrien, M. A.; Prange, T.; Pascard, C.; Moreau, S. J .
Chem. Soc., Chem. Commun. 1980, 13, 601.
S0022-3263(96)02279-7 CCC: $14.00 © 1997 American Chemical Society

1796 J . Org. Chem., Vol. 62, No. 6, 1997
Lee and Clothier
F igu r e 1.
Sch em e 1
electron transfer reagent has been shown to cleave epoxy-
ketones, to our knowledge this is the first instance of its
application to amides. Reduction of 9 with LAH/AlCl3
gave 10 in only modest yield (24%), because the A-ring
was partially cleaved by the reducing agent. The ster-
eochemistry of 10 was established by comparison of its
1H NMR spectrum with that reported by Blizzard et al.
in their synthesis of 10 by an alternate synthetic route.3a
This also confirmed the stereochemical assignment of its
precursor, epoxide 8. Swern oxidation of 10 produced
ketone 11 (71%). Reaction of 11 with methyl magnesium
bromide in tetrahydrofuran gave paraherquamide A in
50% yield (based on recovered starting material) with
formation of only a trace of the related R-methyl epimer.
A similar transformation was reported by Blizzard et
al.,3a in which 5-bromo-14-oxo-17-norparaherquamide A
was treated with methyl magnesium iodide in predomi-
nantly methylene chloride giving rise to a 2:1 ratio of the
R-methyl to â-methyl epimers. The reason for the
differing facial selectivities is unclear. We suspect that
in our case the higher polarity of tetrahydrofuran pro-
duces less aggregation of the Grignard reagent, permit-
ting the magnesium ion to coordinate with both the target
carbonyl of 11 and the adjacent amide carbonyl thereby
directing attack to the â-face. The lower solvent polarity
of methylene chloride used by Blizzard favors a higher
degree of aggregation of the methyl magnesium bromide
and lower reactivity which in turn favors attack from the
less sterically hindered R-face. As the Grignard reagent
becomes bulkier, the degree of aggregation falls off which
may explain in part the mixed results Blizzard obtained
with ethyl- and vinylmagnesium bromide. The product
distribution observed by Blizzard in the case of very
bulky benzylmagnesium chloride is consistent with this
hypothesis. Semisynthetic paraherquamide A proved to
be identical to the natural product obtained from Profes-
sor Yamazaki by comparison of the 1H NMR, mobility
on TLC, and HRMS spectra.
Sch em e 2
Exp er im en ta l Section
infra). Presumably, the double bond of 7 was attacked
by peroxide from behind giving the R-epoxide, since the
back side is less hindered. In any case, the stereochem-
istry of these chiral centers is of little consequence since
they are removed at a later stage of the synthesis. While
standard methods utilizing NaBH4, BH3-THF, and super
hydride (Et3BHLi) failed to open the epoxide ring, sa-
marium iodide11 provided the required 14R-hydroxy
compound 9 in good yield (85%). Although this single
Gen er a l In for m a tion . 1H and 13C NMR spectra were
recorded on either a 300 MHz or a 400 MHz NMR spectrom-
eter. Column chromatography and flash column chromatog-
raphy were performed with silica gel grade 60 (230-400 mesh).
Preparatory thin layer chromatography (PTLC) was carried
out with Kieselgel 60 F254 precoated glass plates; visualization
was carried out with ultraviolet light and/or heating with a
(11) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 2596.

Conversion of Marcfortine A to Paraherquamide A
J . Org. Chem., Vol. 62, No. 6, 1997 1797
solution of 5-7% phosphomolybdic acid; or staining with I2.
All solvents were commercial grade and were distilled and
dried as follows: tertrahydrofuran (THF) from potassium
benzophenone ketyl; acetonitrile from P2O5. All other reagents
were commercial grade and used without further purification.
12a-Cyan o-17-br om o-17,N-seco-m ar cfor tin e A (1). Marc-
fortine A (477 mg, 1 mmol) was dissolved in chloroform (15
mL) and treated with CNBr (1.5 g, 14 mmol) at room
temperature. The mixture was heated to reflux for 24 h. It
was cooled, diluted with methylene chloride (50 mL), and
washed with 10% aqueous K2CO3 solution (2 × 30 mL). After
the mixture was dried (MgSO4) and concentrated, the residue
was purified by silica gel chromatography (15% acetone in
methylene chloride) to give 1 as a white solid (467 mg, 80%).
1H NMR (300 MHz, CDCl3) δ 0.80 (s, 3H), 1.06 (s, 3H), 1.37
and 1.40 (2s, 6H), 1.4-2.0 (m, 9H), 2.71 (d, J ) 15.8 Hz, 1H),
3.05 (s, 3H), 3.14 (t, 1H), 3.32 and 3.85 (d, J ) 10.5 Hz, 2H),
3.41 (t, 2H, J ) 6.7 Hz), 4.84 and 6.25 (d, J ) 7.7 Hz, 2H),
6.64 and 6.75 (d, J ) 8.2 Hz, 2H), 7.67 (s, 1H). 13C NMR (75
MHz, CDCl3) δ 20.3, 21.7, 23.3, 26.9, 27.3, 29.7, 29.8, 30.8,
32.6, 33.4, 36.2, 46.4, 52.6, 55.8, 62.1, 62.7, 62.8, 79.8, 114.5,
117.5, 120.1, 138.4, 146.3, 171.6, 183.2. MS (FAB): m/ e 583
and 585 (M + H+).
12a -Cya n o-17-(p h en ylselen yl)-17,N-seco-m a r cfor tin e A
(2). Diphenyl diselenide (225 mg, 0.72 mmol, 1.5 equiv) was
suspended in methanol (15 mL) and solid sodium borohydride
added in small amounts until the yellow color disappeared.
Compound 1 (280 mg, 0.48 mmol) was added to the mixture
at room temperature, and the mixture was stirred for 0.5 h.
After the volatile components were removed, the residue was
taken up in methylene chloride (50 mL) and washed with 10%
aqueous K2CO3 solution (2 × 30 mL). The organic layer was
dried (MgSO4) and concentrated and the residue purified by
silica gel chromatography (4% methanol in methylene chloride)
to give 2 as a yellow solid (254 mg, 80%). 1H NMR (300 MHz,
CDCl3) δ 0.86 (s, 3H), 1.11 (s, 3H), 1.44 and 1.47 (2s, 6H), 1.5-
2.0 (m, 9H), 2.76 (d, J ) 15.8 Hz, 1H), 2.97 (t, 2H, J ) 6.7
Hz), 3.10 (s, 3H), 3.18 (t, 1H), 3.42 and 3.90 (d, J ) 10.54 Hz,
2H) , 4.91 and 6.32 (d, J ) 7.7 Hz, 2H), 6.71 and 6.80 (d, J )
8.2 Hz, 2H), 7.1-7.5 (m, 5H), 7.59 (s, 1H).
12a -Cya n o-16,17-a n h yd r o-17,N-seco-m a r cfor tin e A (3).
Compound 2 (1.6 g, 2.42 mmol) was dissolved in ethanol/
methylene chloride (30 mL/5 mL). The solution was treated
with an aqueous solution of sodium periodate (1.2 g in 10 mL
of water) at room temperature and stirred for 0.5 h. The
mixture was diluted with methylene chloride (50 mL) and
washed with 10% aqueous K2CO3 solution (2 × 30 mL). The
organic layer was dried (MgSO4) and concentrated and the
residue redissolved in benzene (50 mL). After the solution had
been heated to reflux for 15 min, the mixture was diluted with
ether (50 mL) and washed with 10% aqueous K2CO3 solution
(2 × 30 mL). The organic layer was dried (MgSO4) and
concentrated and the residue purified by silica gel chroma-
tography (0-30% acetone in methylene chloride) to give 3 as
a white solid (973 mg, 80%). 1H NMR (300 MHz, CDCl3) δ
0.87 (s, 3H), 1.13 (s, 3H), 1.44 (s, 6H), 1.7-2.4 (m, 9H), 2.77
(d, J ) 15.8 Hz, 1H), 3.13 (s, 3H), 3.22 (t, J ) 10.5 Hz, 1H),
3.42 and 3.92 (d, J ) 10.6 Hz, 2H), 4.94 and 6.39 (d, J ) 7.7
Hz, 2H), 5.10-5.20 and 5.7-5.9 (m, 3H), 6.71 and 6.82 (d, J
) 8.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 20.2, 23.3, 27.0,
27.1, 27.3, 29.7, 29.8, 31.0, 36.1, 46.4, 52.7, 55.8, 62.1, 62.8,
79.8, 114.8, 114.9, 115.2, 117.5, 120.1, 123.6, 132.6, 135.1,
137.4, 138.9, 146.3, 170.8, 182.5. MS (FAB): m/ e 503 (M +
H+).
16,17-An h yd r o-17,N-seco-m a r cfor tin e A (4). Compound
3 (120 mg, 0.24 mmol) was suspended in ethylene glycol (1
mL). The mixture was treated with NaOH (38 mg, 0.95 mmol,
4 equiv) and heated to 130 °C for 15 min. It was diluted with
methylene chloride (50 mL) and washed with 10% aqueous
K2CO3 solution (2 × 30 mL). The organic layer was dried
(MgSO4) and concentrated and the residue purified by silica
gel chromatography (5% methanol in methylene chloride) to
give 4 as a solid (57 mg, 50%). 1H NMR (300 MHz, CDCl3) δ
0.85 (s, 3H), 1.13 (s, 3H), 1.44 and 1.45 (2s, 6H), 1.6-2.4 (m,
9H), 2.72 (d, J ) 15.6 Hz, 1H), 2.94 and 3.44 (d, J ) 11.6 Hz,
2H), 3.08 (t, 1H), 3.11 (s, 3H), 4.91 and 6.35 (d, J ) 7.7 Hz,
2H), 4.9-5.2 and 5.8-6.0 (m, 3H), 6.68 and 6.82 (d, J ) 8.2
Hz, 2H), 8.27 (s, 1H). MS (FAB): m/ e 478 (M + H+).
16,17-Dih yd r oxy-17,N-seco-m a r cfor tin e A (5). Com-
pound 4 (24 mg, 0.05 mmol) and 4-methylmorpholine N-oxide
(20 mg, 0.17 mmol) were dissolved in acetone/water (9:1, 6 mL).
The mixture was treated with OsO4 (24 µL, 2.5% wt in tert-
butyl alcohol, obtained from Aldrich) and stirred at room
temperature for 16 h. It was diluted with in methylene
chloride (50 mL) and washed with 10% aqueous K2CO3 solution
(2 × 30 mL). The organic layer was dried (MgSO4) and
concentrated and the residue purified by preparative layer
chromatography (10% methanol in methylene chloride) to give
5 (mixture of diastereomer) as a solid (17 mg, 70%). 1H NMR
(300 MHz, CDCl3) δ 0.85 (s, 3H), 1.12 (s, 3H), 1.44 and 1.45
(2s, 6H), 1.6-3.9 (m, 20H), 4.91 and 6.35 (d, J ) 7.7 Hz, 2H),
6.68 and 6.82 (d, J ) 8.2 Hz, 2H), 8.36 and 8.39 (2s, 1H). MS
(FAB): m/ e 512 (M + H+).
P a r a h er qu a m id e B. Compound 5 (10 mg, 0.02 mmol) was
dissolved in ethanol (3 mL) and treated with sodium periodate
(0.4 mL of 20 mg/mL aqueous solution) and stirred at 0 °C for
20 min. Sodium borohydride (5 mg) was added to the mixture,
which was stirred for an additional 10 min at 0 °C. The
mixture was taken up in methylene chloride (20 mL) and
washed with 10% aqueous K2CO3 solution (2 × 10 mL). The
organic layer was dried (MgSO4) and concentrated and the
residue purified by preparative layer chromatography (7%
methanol in methylene chloride) to give paraherquamide B
as a solid (5 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 0.85 (s,
3H), 1.13 (s, 3H), 1.44 and 1.45 (2s, 6H), 1.4-2.8 (m, 10H),
2.65 and 3.65 (d, J ) 10.9 Hz, 2H), 3.0-3.2 (m, 4H), 4.89 and
6.32 (d, J ) 7.7 Hz, 2H), 6.68 and 6.82 (d, J ) 8.2 Hz, 2H),
7.69 (s, 1H). MS (FAB): m/ e 464 (M + H+). HRMS (FAB):
m/ e, 464.2577 (C27H33N3O4 + H+ requires 464.2549).
16-Oxop a r a h er qu a m id e B (6). To paraherquamide B (4
mg, 0.0086 mmol) and sodium bicarbonate (10 mg, 0.12 mmol)
in tetrahydrofuran (THF, 1.5 mL) and H2O (0.5 mL) was added
I2 (16 mg, 0.06 mmol) dropwise in THF (1 mL) at ambient
temperature. After 1 h of stirring, the reaction was quenched
with a saturated aqueous solution of sodium thiosulfate (Na2
S2O3, 10 mL) and extracted into methylene chloride (CH2Cl2,
25 mL). The organic layer was dried (MgSO4), filtered, and
concentrated to give residue that was purified on silica gel
(40% acetone/hexane) to give 6 (1.6 mg, 40%) and 12-oxopara-
herquamide B (1 mg, 25%) both as white solids. Compound
6: 1H NMR (300 MHz, CDCl3) δ 0.87 (s, 3H), 1.10 (s, 3H), 1.43
and 1.46 (2s, 6H), 1.75-2.10 (m, 3H), 2.0 and 2.85 (d, 2H),
2.48-2.55 (m, 1H), 2.88-3.0 (m, 1H), 3.08 (s, 3H), 3.28 (t, 1H),
3.48 and 3.74 (d, 2H), 4.90 and 6.30 (d, J ) 7.7 Hz, 2H), 6.60
and 6.80 (d, 2H), 7.27 (brs, 1H). 13C NMR (75 MHz, CDCl3) δ
20.6, 23.5, 23.7, 27.2, 29.8, 29.9, 30.0, 31.1, 36.7, 46.2, 49.0,
53.4, 63.1, 64.9, 65.0, 79.9, 115.2, 117.7, 120.3, 124.3, 132.4,
135.4, 138.9, 146.3, 171.3, 173.4, 182.4. HRMS (FAB): m/ e
478.2384 (C27H31N3O5 + H requires 478.2342).
12-Oxop a r a h er qu a m id e B: 1H NMR (400 MHz, CDCl3) δ
0.87 and 0.83 (s, 6H), 1.46 and 1.44 (s, 6H), 1.95-1.60 (m, 2H),
2.11-1.95 (m, 2H), 2.87 (m, 1H), 3.02 (s, 3H), 3.11 (d, 1H),
3.27 and 2.53 (d, J ) 15.2 Hz, 2H), 3.70-3.39 (m, 3H), 4.89
and 6.31 (d, J ) 7.7 Hz, 2H), 6.70 and 7.03 (d, J ) 8.2 Hz,
2H), 7.35 (s, 1H). HRMS (FAB): m/ e 478.2356 (C27 H31N3O5
+ H requires 478.2342).
14,15-Deh yd r o-16-oxop a r a h er qu a m id e B (7). A solu-
tion of lithium diisopropylamide prepared from n-butyllithium
(1.6 M, 0.6 mL, 0.98 mmol) and diisopropylamine (0.14 mL,
1.0 mmol), in THF (8 mL), was cooled to -78 °C and treated
dropwise with 6 (0.12 g, 0.25 mmol) in THF (4 mL). The
reaction slowly warmed to -5 °C over a 0.5 h period and was
then recooled to -78 °C and treated dropwise with phenylse-
lenyl chloride (0.06 g, 0.3 mmol) in THF (3 mL). This caused
the turbid solution to clear. The reaction mixture was
quenched 5 min later with saturated NaHCO3 (10 mL) and
extracted into CH2Cl2 (25 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to give residue that was
diluted with THF (15 mL) and treated with H2O2 (30%, 0.1
mL). The reaction mixture was stirred for 0.5 h at ambient
temperature and then quenched with NaOH (1 N, 15 mL) and
extracted into CH2Cl2 (25 mL). The organic layer was dried

1798 J . Org. Chem., Vol. 62, No. 6, 1997
Lee and Clothier
(MgSO4), filtered, and concentrated to give residue that was
subjected to silica gel chromatography to yield 7 (0.07 g, 58%)
as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.90 and 1.07
(2s, 6H), 1.45 and 1.47 (2s, 6H), 1.56 and 2.36 (dd, 2H), 2.09
and 2.85 (d, J ) 15.7 Hz, 2H), 3.09 (s, 3H), 3.36 (t, 1H), 3.60
and 3.95 (d, J ) 11.9 Hz, 2H), 4.91 and 6.32 (d, 2H), 6.25 and
7.36 (d, 2H, J ) 9.1 Hz), 6.71 and 6.81 (d, 2H), 7.78 (brs, NH).
HRMS (FAB): m/ e 476.2195 (C27 H29N3O5 + H requires
476.2185).
14r,15r-Ep oxy-16-oxop a r a h er qu a m id e B (8). Triton B
(benzyltrimethylammonium hydroxide, 40 wt % in methanol,
0.7 mL, 1.6 mmol) was evaporated to dryness under vacuum
to remove all MeOH. It was then diluted with THF (10 mL)
and treated with tert-butyl hydroperoxide (anhydrous, 5-6 M
in decane, 0.4 mL, 2.4 mmol) followed by addition of 7 (0.17 g,
0.3 mmol) in THF (3 mL) 5 min later. The reaction mixture
was stirred for 2 h at room temperature and then quenched
with water (25 mL) and extracted into EtOAc (50 mL). The
organic layer was dried (MgSO4), filtered, and concentrated
to give a residue that was subjected to silica gel chromatog-
raphy to yield 8 (0.1 g, 58%) as a white solid. 1H NMR (400
MHz, CDCl3) δ 0.89 and 1.06 (2s, 6H), 1.44 and 1.46 (2s, 6H),
1.91 and 2.18 (dd, 2H), 2.00 and 2.83 (d, J ) 15.7 Hz, 2H),
3.08 (s, 3H), 3.34 (t, 1H), 3.52 and 3.66 (d, 2H), 3.70 and 4.41
(d, J ) 2.9 Hz, 2H), 4.91 and 6.31 (d, J ) 7.7 Hz, 2H), 6.71
and 6.78 (d, J ) 8.2 Hz, 2H), 7.52 (s, NH). HRMS (FAB): m/ e
492.2145 (C27 H29N3O6 + H requires 492.2134).
14r-Hyd r oxy-16-oxop a r a h er qu a m id e B (9). To a solu-
tion of 8 (20 mg, 0.04 mmol) in THF (3 mL) and MeOH (0.5
mL) at 0 °C under N2 was added samarium(II) iodide (0.1 M
in THF, 2 mL, 0.24 mmol) dropwise until a green color
persisted in the reaction mixture. The reaction was then
quenched with saturated K2CO3 (15 mL) and extracted into
CH2Cl2 (25 mL). The organic layer was dried (MgSO4), filtered,
and concentrated to give 9 (18 mg, 85%) as a white solid
without further purification. 1H NMR (400 MHz, CDCl3) δ
0.89 and 1.06 (2s, 6H), 1.45 and 1.47 (2s, 6H), 1.90-2.11 (m,
2H), 2.49-2.61 (m, 2H), 2.04 and 2.80 (d, J ) 15.7 Hz, 2H),
2.91 (dd, 1H), 3.08 (s, 3H), 3.30 (t, 1H), 3.50 and 3.80 (d, J )
12.0 Hz, 2H), 4.91 and 6.32 (d, J ) 7.7 Hz, 2H), 5.10 (m, 1H),
6.72 and 6.81 (d, J ) 8.2 Hz, 2H), 7.78 (s, NH).
14r-Hyd r oxyp a r a h er qu a m id e B (10). To a solution of
LAH (1 M in THF, 0.36 mL, 0.36 mmol) in THF (6 mL) at
-60 °C under N2 was added AlCl3 (24 mg, 0.18 mmol) in three
portions. Compound 9 (30 mg, 0.06 mmol) was added 10 min
later at -45 °C dropwise in THF (3 mL). The reaction was
allowed to warm to -15 °C over a 20 min period and quenched
with dropwise addition of MeOH (1 mL). The mixture was
stirred at room temperature for 15 min and then treated with
NaCNBH3 (60 mg) and partitioned between water (25 mL) and
CH2Cl2 (30 mL). The organic layer was dried (MgSO4), filtered,
and concentrated to give a residue that was purified by silica
gel chromatography (5% MeOH/CH2Cl2) to give 10 (7 mg, 24%)
as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.87 and 1.13
(2s, 6H), 1.44 and 1.45 (2s, 6H), 1.6-2.3 (m, 7H), 2.48 (m, 1H),
2.64 (d, 1H), 2.70 (d, 1H), 3.09 (s, 3H), 3.21 (t, 1H), 3.65 (d,
1H), 4.75 (brs, 1H), 4.90 and 6.32 (d, J ) 7.7 Hz, 2H), 6.68
and 6.82 (d, J ) 8.2 Hz, 2H), 7.81 (s, NH). HRMS (FAB): m/ e
480.2512 (C27 H33N3O5 + H requires 480.2498).
14-Oxop a r a h er qu a m id e B (11). To oxalyl chloride (0.006
mL, 0.084 mmol) in CH2Cl2 (4 mL) at -78 °C under N2 was
added DMSO (0.25 mL, 3.5 mmol) dropwise in CH2Cl2 (4 mL).
The reaction was stirred for 10 min and then treated with a
solution of 10 (7 mg, 0.014 mmol) dropwise in CH2Cl2 (2 mL).
Following 10 min of stirring at -78 °C the reaction was
quenched with NEt3 (0.015 mL, 0.1 mmol) and then stirred
for 5 min at ambient temperature. The reaction was parti-
tioned between H2O (15 mL) and CH2Cl2 (20 mL). The organic
layer was dried (MgSO4), filtered, and concentrated to give a
residue that was purified by silica gel chromatography (5%
MeOH/CH2Cl2) to give 11 (5 mg, 71%) as a white solid. 1H
NMR (400 MHz, CDCl3) δ 0.87 and 0.89 (2s, 6H), 1.45 and
1.46 (2s, 6H), 1.90 (d, 1H), 2.21 (d, 1H), 2.42-2.75 (m, 5H),
3.09 (s, 3H), 3.18 (t, 1H), 3.38 (t, 1H), 3.75 (d, 1H), 4.90 and
6.32 (d, J ) 7.7 Hz, 2H), 6.69 and 6.82 (d, J ) 8.2 Hz, 2H),
7.56 (s, NH). HRMS (FAB): m/ e 478.2356 (C27 H31N3O5 + H
requires 478.2342).
P a r a h er qu a m id e A. To a solution of 11 (5 mg, 0.01 mmol)
in THF (4 mL) at -78 °C under a nitrogen atmosphere was
added MeMgBr (3 M in ether, 0.03 mL, 0.09 mmol). The
reaction mixture was allowed to slowly warm to -20 °C over
a 40 min period. The reaction was quenched with saturated
NH4Cl (15 mL) and extracted into CH2Cl2 (20 mL). The
organic layer was dried (MgSO4), filtered, and concentrated
to give residue that was purified by silica gel chromatography
(4% MeOH/CH2Cl2) to give paraherquamide A (2 mg, 50%
based on recovery of 11) as a white solid which was identical
to an authentic sample obtained by Professor Yamazaki on
TLC (Rf 0.23 in 4% MeOH/CH2Cl2, Rf 0.34 in 30% acetone/
1
CH2Cl2) and H NMR. 1H NMR (400 MHz, CDCl3) δ 0.89 and
1.11 (2s, 6H), 1.45 and 1.46 (2s, 6H), 1.66 (s, 3H), 1.78-1.95
(m, 4H), 2.15-2.41 (m, 2H), 2.57 (d, 1H), 2.70 (d, 1H), 3.00 (d,
1H), 3.06 (s, 3H), 3.21 (m, 1H), 3.61 (d, 1H), 4.89 and 6.31 (d,
J ) 7.6 Hz, 2H), 6.69 and 6.81 (d, J ) 8.2 Hz, 2H), 7.56 (s,
NH). HRMS (FAB): m/ e 494.2653 (C28 H35N3O5 + H requires
494.2655).
Ack n ow led gm en t. We are grateful to Professor
Yamazaki at Chiba University for furnishing a sample
of natural paraherquamide A.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds (14 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9622791