Stereoselective synthesis of (S)-(+)-lycoperdic acid through an endo selective hydroxylation of the chiral bicyclic lactam enolate with MoOPH

Article abstract of DOI:10.1016/S0040-4020(02)01254-1

Efficient synthesis of (S)-(+)-lycoperdic acid has been achieved by use of the stereoselective hydroxylation of the enolate derived from the bicyclic lactam 3 with the molybdenum oxidizing reagent, MoOPH (MoO₅·Py·HMPA, oxodiperoxymolybdenum(pyr

Full text of DOI:10.1016/S0040-4020(02)01254-1

Tetrahedron 58 (2002) 9737–9740
Stereoselective synthesis of (S)-(1)-lycoperdic acid through an
endo selective hydroxylation of the chiral bicyclic lactam enolate
with MoOPH
Kazuishi Makino,a Kensuke Shintani,a Takahiro Yamatake,a Osamu Hara,a
Keiichiro Hatanob and Yasumasa Hamadaa
,
*
aGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bGraduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 4 September 2002; accepted 30 September 2002
Abstract—Efficient synthesis of (S)-(þ)-lycoperdic acid has been achieved by use of the stereoselective hydroxylation of the enolate derived
from the bicyclic lactam 3 with the molybdenum oxidizing reagent, MoOPH (MoO5·Py·HMPA, oxodiperoxymolybdenum(pyridine)(hex-
amethylphosphoric triamide)), as a key step. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(S)-(þ)-Lycoperdic acid (1), was isolated as an unusual
a-amino acid from the mushroom Lycoperdon perlatum by
R-Banga et al. in 1978.1 From the structural similarity of
this compound with (S)-glutamic acid, (S)-(þ)-lycoperdic
acid is expected to have antagonistic or agonistic activity for
glutamate receptor in the mammalian central nervous
system. In our continuous efforts2 directed towards the
development of stereocontrolled transformations of the
chiral bicyclic lactam 2, we have disclosed a highly
stereoselective hydroxylation reaction of the chiral bicyclic
lactam enolate with endo selectivity using MoOPH (MoO5·
Py·HMPA) and MoOPD (MoO5·Py·DMPU).2c The syn-
thesis of 1 has been already reported by Yoshifuji’s3a,b and
Hatakeyama’s3c groups independently. As an application of
our developed method, we wish to report here an efficient
synthesis of (S)-(þ)-lycoperdic acid featuring stereoselec-
tive construction of the quaternary carbon by this endo
selective hydroxylation as a key step (Fig. 1).
The synthesis of (S)-(þ)-lycoperdic acid (Scheme 1)
commenced with the allylation of the chiral bicyclic lactam
2,4 a versatile synthon in the synthesis of a variety of natural
products,5 to afford a 1:1 mixture of diastereomeric isomers
3 in 95% yield. This mixture 3 was directly treated with
2 equiv. of LDA at 2788C for 2 h followed by addition of
2 equiv. of freshly prepared MoOPH6 to give the
a-hydroxylated lactam 4 as a single diastereomer in 77%
yield (95% conversion yield). Alternatively, the use of
molecular oxygen7 as an oxidizing reagent showed low
diastereoselectivity (endo/exo¼2.8:1) in 65% yield. The
stereostructure of the endo product 4 was unambiguously
confirmed by NOE experiment of 4 and X-ray crystal-
lographic analysis of the latent 6. Catalyzed hydroboration
of 4 using catecholborane in the presence of a catalytic
amount of N,N-dimethylacetamide8 or Rh(PPh3)3Cl9 gave
no product and the starting material was recovered. The use
of a borane–dimethylsulfide complex afforded the desired
alcohol in moderate yield (55%). The treatment of 4 with a
borane–tetrahydrofuran complex followed by alkaline
hydrogen peroxide work-up, however, provided the desired
alcohol 5 in 85% yield along with small amounts of the
regioisomer (5%). Oxidation of the alcohol 5 with Jones
reagent directly afforded the g-lactone 6 in 67% yield. The
crystalline 6 was subjected to X-ray crystallographic
analysis of which the oxygen in the lactone ring at the
endo position clearly supports the NOE-assigned stereo-
structure of 4 as shown in Fig. 2. In subsequent conversion
of 6 to 1, we encountered unexpected epimerization during
Jones oxidation. Thus, after removal of the N,O-benzylidene
acetal with trifluoroacetic acid, the lactam alcohol was
Figure 1.
Keywords: (S)-(þ)-lycoperdic acid; hydroxylation; MoOPH; bicyclic
lactam; endo selectivity.
*
Corresponding author. Tel./fax: þ81-43-290-2987;
e-mail: hamada@p.chiba-u.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01254-1

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K. Makino et al. / Tetrahedron 58 (2002) 9737–9740
Scheme 1.
3. Experimental
3.1. General
Melting points are uncorrected. Infrared spectra were
recorded on a JASCO FT/IR-230 spectrometer. Optical
rotations were determined on a JASCO DIP-140 polari-
meter. NMR spectra were recorded on JEOL JNM GSX
400A, JNM GSX500A and JNM ECP400 spectrometers.
Mass spectra were obtained on a JEOL HX-110A (LRFAB,
LREI) spectrometer. Column chromatography was per-
formed with silica gel BW-820MH (Fuji silysia).
Figure 2. X-Ray crystallographic structure of 6.
3.2. Experimental procedures
subjected to the Jones oxidation and the resulting carboxylic
acid was hydrolyzed with 6N hydrochloric acid to afford the
lycoperdic acid. The obtained lycoperdic acid, however,
showed minus value in specific rotation different from plus
one of the natural product, which seemed to suggest the
extensive epimerization at C2. After some experiments, we
found novel two-step conversion without epimerization.
Direct oxidation of 6 using sodium periodate and ruthenium
trichloride10 in acetonitrile–carbon tetrachloride–water at
room temperature for 38 h furnished the unexpected
anhydride 7 in 80% yield, which was derived from the
oxidation at C1 and N,O-acetal benzylic position. Finally,
hydrolysis of 7 in hydrochloric acid under refluxing
conditions for 18 h followed by purification using ion-
exchange chromatography (Dowex 1x8, eluted 2N acetic
acid) gave the crude product, which was recrystallized from
water to furnish (S)-(þ)-lycoperdic acid in 64% yield in
pure form, mp 200–2028C, [a]2D5¼þ14.4 (c 0.48, H2O) (lit.
[a]2D0¼þ14.9 (c 0.47, H2O),1 [a]D21¼þ14.2 (c 0.47, H2O),3a,
b [a]2D8¼þ12.7 (c 0.21, H2O)3c). The synthetic material was
found to be identical with natural lycoperdic acid through
spectral comparisons (1H and 13C NMR).
3.2.1. (2R,5S,7S) and (2R,5S,7R)-7-Allyl-2-phenyl-1-aza-
3-oxabicyclo[3.3.0]octan-8-one (3). To a stirred solution of
lithium diisopropylamide in THF at 2788C, prepared from
diisopropylamine (15.8 mL, 11.7 mmol) and n-BuLi
(1.57 M in n-hexane, 65.5 mL, 103 mmol) in THF
(150 mL) at 08C for 0.5 h, was added dropwise a solution
of bicyclic lactam 2 (20.8 g, 103 mmol) in THF (70 mL)
under an argon atmosphere. After stirring the mixture for
1 h, allylbromide (17.7 mL, 205 mmol) was added dropwise
at 2788C and the resulting mixture was stirred at the same
temperature for 4 h. The reaction was quenched with
saturated aqueous ammonium chloride and extracted three
times with ethyl acetate. The combined organic extracts
were washed with saturated brine, dried over sodium
sulfate, filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography (200 g, ethyl
acetate/n-hexane¼1:4) to afford 3 (23.7 g, 97.4 mmol, 95%)
as a yellow oil (endo-isomer/exo-isomer¼1:1). Analytical
samples of endo-3 and exo-3 were obtained through
separation using silica gel column chromatography.
1
endo-3: [a]2D4¼þ219 (c 1.11, EtOH); H NMR (400 MHz,
CDCl3) d 1.58 (ddd, J¼7.0, 10.9, 12.9 Hz, 1H), 2.20 (ddd,
J¼7.4, 8.8, 14.6 Hz, 1H), 2.50 (ddd, J¼7.1, 8.8, 12.9 Hz,
1H), 2.62–2.67 (m, 1H), 2.98–3.01 (m, 1H), 3.49 (t,
J¼8.0 Hz, 1H), 4.06 (quintet, J¼7.1 Hz, 1H), 4.22 (dd,
J¼6.3, 8.1 Hz, 1H), 5.07–5.14 (m, 2H), 5.74–5.83 (m, 1H),
6.33 (s, 1H), 7.32–7.46 (m, 5H); 13C NMR (400 MHz,
In conclusion, we have achieved the synthesis of (S)-(þ)-
lycoperdic acid in six steps from the chiral bicyclic
lactam 2 with an overall yield of 21% based on the
highly endo selective hydroxylation using MoOPH as a key
step.

K. Makino et al. / Tetrahedron 58 (2002) 9737–9740
9739
CDCl3) d 29.6, 31.2, 34.7, 44.5, 56.5, 72.3, 86.7, 117.1,
125.9, 128.4, 135.2, 138.6, 177.7; IR (neat) 2924, 1705,
1452, 1377, 1169, 918 cm21; HRMS (FAB) calcd for
C15H18NO2: 244.1338 (MþHþ). Found 244.1352.
desired diol 5 (119 mg, 0.429 mmol, 86%) and its
regioisomer (7.4 mg, 0.029 mmol, 5%) as a colorless oil.
[a]2D4¼þ121 (c 1.17, CHCl3); 1H NMR (400 MHz, CDCl3)
d 1.73–1.76 (m, 2H), 1.84–1.88 (m, 1H), 1.97–2.09 (m,
2H), 2.51 (dd, J¼6.6, 12.9 Hz, 1H), 3.58–3.64 (m, 2H),
3.72–3.76 (m, 1H), 3.41 (quint, J¼6.8 Hz, 1H), 4.29 (dd,
J¼6.2, 8.2 Hz, 1H), 6.29 (s, 1H), 7.33–7.43 (m, 5H); 13C
NMR (400 MHz, CDCl3) d 27.0, 35.9, 39.6, 54.7, 62.5,
72.6, 80.6, 86.8, 126.0, 128.8, 138.1, 178.3; IR (neat) 3421,
2924, 1699, 1405, 1043 cm21; HRMS (FAB) calcd for
C15H20NO4 278.1392 (MþHþ). Found 278.1374.
3.2.4. (2R,5S,7S)-7-(20-Tetrahydrofuranyl-50-oxo)-2-phe-
nyl-1-aza-3-oxabicyclo[3.3.0]octan-8-one (6). To a stirred
solution of diol 5 (97.0 mg, 0.350 mmol) in acetone
(1.4 mL) at 2158C was added dropwise Jones reagent
(7.8 M in water, 180 mL, 1.40 mmol). After the mixture was
stirred at 2158C to 08C for 4 h, the reaction was quenched
with isopropanol (1 mL) and saturated aqueous sodium
hydrogen carbonate (1 mL). After the resulting mixture was
extracted with chloroform, the organic extracts were washed
with saturated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
recrystallization from ethyl acetate to afford the lactone 6
(63.7 mg, 0.233 mmol, 67%) as white solids. Mp 1718C;
[a]2D7¼þ122 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.26 (dt, J¼10.1, 13.4 Hz, 1H), 2.45 (dd, J¼5.9, 13.9 Hz,
1H), 2.56–2.64 (m, 3H), 2.89–2.98 (m, 1H), 3.58 (t,
J¼8.4 Hz, 1H), 4.02–4.09 (m, 1H), 4.37 (dd, J¼8.3, 5.9 Hz,
1H), 6.31 (s, 1H), 7.34–7.47 (m, 5H); 13C NMR (400 MHz,
CDCl3) d 28.1, 32.0, 36.4, 53.9, 71.9, 87.1, 87.7, 125.9,
128.5, 128.9, 137.7, 173.4, 175.3; IR (KBr) 1788, 1726,
1398, 1340, 1221, 1174, 1011, 918 cm21; HRMS (FAB)
calcd for C15H16NO4 (MþHþ) 274.1079. Found 274.1084.
1
exo-3: [a]2D4¼þ145 (c 1.15, EtOH); H NMR (400 MHz,
CDCl3) d 2.08–2.12 (m, 2H), 2.36–2.41 (m, 1H), 2.57–
2.63 (m, 1H), 2.77–2.80 (m, 1H), 3.40 (dd, J¼8.1, 8.8 Hz,
1H), 4.04–4.07 (m, 1H), 4.21 (dd, J¼6.2, 8.1 Hz, 1H),
5.10–5.16 (m, 2H), 5.77–5.84 (m, 1H), 6.33 (s, 1H), 7.30–
7.46 (m, 5H); 13C NMR (400 MHz, CDCl3) d 27.0, 36.1,
44.2, 57.1, 71.1, 87.1, 117.5, 125.7, 128.3, 134.5, 138.8,
180.0; IR (neat) 2945, 1705, 1379, 1354, 1159, 1026,
918 cm21; HRMS (FAB) calcd for C15H18NO2: 244.1338
(MþHþ). Found 244.1319.
3.2.2. (2R,5S,7S)-7-Allyl-7-hydroxy-2-phenyl-1-aza-3-
oxabicyclo[3.3.0]octan-8-one (4). To a stirred solution of
lithium diisopropylamide in THF at 2788C, prepared from
diisopropylamine (6.3 mL, 45.2 mmol) and n-BuLi (1.57 M
in n-hexane, 26.2 mL, 41.1 mmol) in THF (10 mL) at 08C
for 1.5 h, was added dropwise a solution of bicyclic lactams
3 (5.00 g, 20.6 mmol) in THF (20 mL) under an argon
atmosphere. After stirring the mixture for 1.5 h, freshly
prepared MoOPH (17.8 g, 41.1 mmol) was added portion-
wise at 2788C and the resulting mixture was stirred at the
same temperature for 2 h. The reaction was quenched with
saturated aqueous sodium sulfite (150 mL) and extracted
three times with ethyl acetate. The combined organic
extracts were washed with 5% aqueous ammonium chloride
and saturated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (200 g, ethyl acetate/n-hexane¼1:2) to
afford 4 (4.13 g, 15.9 mmol, 77%) as a colorless oil along
with the starting material 3 (1.05 g, 4.3 mmol, 21%) as a
yellow oil.
3.2.5. Benzoic (5S,8S)-2,6-dioxo-1-oxa-7-aza-spiro[4.4]-
nonane-8-carboxylic anhydride (7). To a stirred solution
of 6 (20.0 mg, 0.0732 mmol) in CH3CN (1.2 mL) and CCl4
(0.8 mL) at 08C was added a solution of sodium periodate
(62.5 mg, 0.292 mmol) in water (1.2 mL) and ruthenium
trichloride (1.5 mg, 0.00723 mmol). After stirring the
mixture for 72 h at rt, the reaction was quenched with
isopropanol (0.1 mL). The resulting mixture was filtered
through a pad of Celite, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel chromato-
graphy (10 g, chloroform/methanol¼9:1) to afford 7
[a]2D5¼þ125 (c 1.13, CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.01 (dd, J¼7.1, 13.0 Hz, 1H), 2.47 (dd, J¼7.9, 13.8 Hz),
2.55–2.62 (m, 2H), 2.92 (brs, 1H), 3.56 (t, J¼8.2 Hz, 1H),
3.95 (m, 1H), 4.29 (dd, J¼6.1, 8.3 Hz, 1H), 5.19–5.24 (m,
2H), 5.82–5.92 (m, 1H), 6.31 (s, 1H), 7.34–7.44 (m, 5H);
13C NMR (400 MHz, CDCl3) d 38.1, 43.0, 54.5, 72.4, 80.4,
86.7, 119.8, 125.9, 128.4, 128.7, 131.5, 138.0, 177.7; IR
(neat) 3380, 2920, 1700, 1450, 1360, 1280, 1220, 1170,
1070, 1020, 920 cm21; HRMS (FAB) calcd for C15H18NO3
260.1287 (MþHþ). Found 260.1295.
(17.8 mg, 0.0587 mmol, 80%) as
a
colorless oil.
[a]2D7¼2126 (c 0.41, MeOH); 1H NMR (400 MHz,
CDCl3) d 2.18–2.26 (m, 2H), 2.54–2.72 (m, 4H), 2.79–
2.95 (m, 2H), 5.8 (dd, J¼4.8, 8.8 Hz), 7.46–7.73 (m, 5H);
13C NMR (100 MHz, CD3OD) d 28.1, 29.6, 34.1, 54.5, 85.1,
128.1, 129.3, 133.2, 170.0, 170.3, 172.7, 175.1; IR (neat)
3016, 1792, 1752, 1734, 1693, 1601, 1453, 1285,
1162 cm21; HRMS (FAB) calcd for C15H14NO6 (MþHþ)
304.0821. Found 304.0848. Anal. calcd for C15H15NO4: C,
65.92; H, 5.53; N, 5.13. Found: C, 66.07; H, 5.59; N, 5.12.
3.2.3. (2R,5S,7S)-7-Hydroxy-7-(1-ol-propyl)-2-phenyl-1-
aza-3-oxabicyclo[3.3.0] octan-8-one (5). To a stirred
solution of 4 (130 mg, 0.500 mmol) in THF (2.0 mL) at
08C was added dropwise borane–tetrahydrofuran complex
(1.0 M in THF, 1.0 mL, 1.0 mmol) under an argon
atmosphere. After the mixture was warmed to room
temperature over 4 h, the reaction was quenched with
sodium hydroxide (3N in water, 2 mL) and 30% aqueous
hydrogen peroxide (2 mL) at 08C. After the resulting
mixture was extracted with chloroform, the organic layer
was washed with saturated aqueous sodium thiosulfate,
saturated aqueous ammonium chloride and saturated brine,
dried over sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromato-
graphy (2 g, ethyl acetate/n-hexane¼2:1) to afford the
3.2.6. (1)-Lycoperdic acid (1). A suspension of 7
(80.2 mg, 0.265 mmol) in hydrochloric acid (6N, 5.0 mL)
was heated under reflux for 24 h. After the resulting mixture
was concentrated in vacuo, the residue was applied to a
column of Dowex 1£8 (200–400 mesh, acetate form), and
eluted with aqueous acetic acid (2N). Concentration of the

9740
K. Makino et al. / Tetrahedron 58 (2002) 9737–9740
7787–7790. (d) Okamoto, N.; Hara, O.; Makino, K.; Hamada,
Y. Tetrahedron: Asymmetry 2001, 12, 1353–1358.
eluate to dryness afforded the crude product as a white solid,
which was recrystallized from water to furnish (þ)-
lycoperdic acid 1 (33.1 mg, 0.153 mmol, 64%) as colorless
solids. Mp 200–2028C (lit 200–2018C,3a,b 200–2028C3c);
[a]D24¼þ14.4 (c 0.48, H2O) (lit [a]D20¼þ14.9 (c 0.47, H2O),1
[a]2D1¼þ14.2 (c 0.47, H2O)3a,b, [a]2D8¼þ12.7 (c 0.21,
3. (a) Kaname, M.; Yoshifuji, S. Tetrahedron Lett. 1992, 33,
8103–8104. (b) Yoshifuji, S.; Kaname, M. Chem. Pharm.
Bull. 1995, 43, 1617–1620. (c) Masaki, H.; Mizozoe, T.;
Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Tetrahedron Lett.
2000, 41, 4801–4804.
1
H2O)3c); H NMR (400 MHz, D2O) d 2.14–2.25 (m, 2H),
4. (a) Thottathil, J. K.; Przybyla, C.; Mally, M.; Gougoutas, J. Z.
Tetrahedron Lett. 1986, 27, 1533–1536. (b) Thottathil, J. K.;
Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P.
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2.44–2.50 (m, 1H), 2.55–2.60 (m, 2H), 2.74 (dd, J¼2.8,
15.2 Hz, 1H), 3.80 (dd, J¼3.2, 10.4 Hz, 1H); 13C NMR
(100 MHz, D2O) d 27.8, 32.3, 37.9, 52.0, 88.3, 172.5, 175.9,
179.9; IR (KBr) 3446, 3235, 2954, 2919, 2849, 2594, 1777,
1734, 1653, 1560, 1206, 1101 cm21; HRMS (FAB) calcd
for C8H11NO6 (MþHþ) 218.0665. Found 218.0660.
5. (a) Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am. Chem. Soc.
1994, 116, 2139–2140. (b) Herdeis, C.; Hubmann, H. P.;
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Acknowledgements
This work was partially supported by the Sasakawa
Scientific Research Grant from the Japan Science Society
(to K. M.).
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