Efficient conversion of aucubin into 6-epi-aucubin

Article abstract of DOI:10.1021/np9804583

Selective deprotection of peracetylaucubin (3) by use of KCN led to 6- O-acetylaucubin (4), which was readily converted into 2',3',4',6',10-penta- O-benzoylaucubin (7). Configuration inversion performed on 7, using a modified Mitsunobu reaction, followed by deprotection, afforded 6-epi- aucubin (2).

Full text of DOI:10.1021/np9804583

400
J . Nat. Prod. 1999, 62, 400-402
Efficien t Con ver sion of Au cu bin in to 6-epi-Au cu bin
Xavier Cachet, Brigitte Deguin, Michel Koch, Kader Makhlouf, and Franc¸ois Tillequin*
Laboratoire de Pharmacognosie de l'Universite´ Rene´ Descartes-URA/ CNRS 1310, Faculte´ des Sciences Pharmaceutiques et
Biologiques, 4 avenue de l’Observatoire 75006 Paris, France
Received October 16, 1998
Selective deprotection of peracetylaucubin (3) by use of KCN led to 6-O-acetylaucubin (4), which was
readily converted into 2′,3′,4′,6′,10-penta-O-benzoylaucubin (7). Configuration inversion performed on 7,
using a modified Mitsunobu reaction, followed by deprotection, afforded 6-epi-aucubin (2).
Sch em e 1a
Iridoids represent a large group of natural monoterpe-
noids, which can be advantageously used as starting
material for the chiral pool synthesis of various bioactive
compounds.1-5 For instance, the synthesis of chiral pros-
tanoids from iridoid glycosides is well documented.5-15
Aucubin (1) is often used as starting material in these
syntheses, because it can be readily extracted in large
amounts from the fruits or leaves of Aucuba japonica
Thunb.16 (Cornaceae). Very often an inversion of the
configuration of the carbon derived from C-6 of aucubin
has to take place during the synthesis, to obtain the desired
final compound. This reaction, performed in the course of
a complex synthesis, generally involves oxidation of the
secondary alcohol into a ketone, followed by nonstereo-
specific hydride reduction, with the double disadvantage
of a moderate yield and a tedious separation of isomers.7-8
There is, therefore, a need for a readily available source of
6-epi-aucubin (2), as the natural occurrence of 2 appears
very limited.17,18 Consequently, an efficient conversion of
aucubin (1) into 6-epi-aucubin (2) appeared highly desir-
able, inasmuch as the only route previously described17
involves a multistep process and results only in a 3%
overall yield, starting from peracetylaucubin (3).
a
(i) KCN, CH2Cl2-MeOH, room temperature; (ii) (PhCO)2O, 4-DMAP,
Pyr, 0 °C-room temperature; (iii) Mg(OCH3)2, CH2Cl2-MeOH, room tem-
perature; (iv) PPh3, DEAD, ClCH2COOH, THF, 0 °C-room temperature;
(v) MeONa, CH2Cl2-MeOH, room temperature.
was employed as a base. In contrast, the use of magnesium
methoxide,22 which had been previously shown to hydrolyze
O-acetyl groups more rapidly than O-benzoyl groups,
smoothly afforded the required deprotected compound 7 in
60% yield. Finally, the configuration inversion at C-6 was
achieved in 80% yield by a modified Mitsunobu reaction.23
Monochloroacetic acid, a low pKa carboxylic acid partner,
was chosen to take into account the steric hindrance of the
alcoholic function at C-6. Classical Zemplen24 transesteri-
fication of 8 finally afforded 6-epi-aucubin (2).
In conclusion, we report here an efficient conversion of
aucubin into its 6-epimer with a 20% overall yield, which
can be increased to 35% by recycling. This route can easily
be performed on a gram scale.
Aucubin was first converted to its peracetyl derivative 3
in almost quantitative yield. Selective deacetylation of 3
could be ensured by use of a catalytic amount of potassium
cyanide (Scheme 1), previously shown to permit selective
deacetylation reactions in the field of sugar chemistry.19
This reaction led, within 7 h at 20 °C, to 6-O-acetylaucubin
(4) in 45% yield, accompanied by fully deprotected aucubin,
which could be readily separated and recycled. Longer
reaction time resulted in the formation of significant
amounts of 10-O-acetylaucubin (5),20,21 most probably aris-
ing from 4 by a transesterification process. Benzoylation
of 4 to 6 was successfully achieved in almost quantitative
yield by use of benzoic anhydride in the presence of
4-(dimethylamino)pyridine (4-DMAP). Selective deprotec-
tion of the O-acetyl group of 6 was not observed when DBU
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Spectra were re-
corded on the following apparatus: MS, Nermag R10-10C
(DCIMS using NH3 as reagent gas), Analytica source (elec-
trospray); IR, Perkin-Elmer FT-IR 1600; NMR, Bruker AC
300, 1H NMR (300 MHz) and 13C NMR (75 MHz). Chemical
* To whom correspondence should be adressed. Tel.: 0033153739803.
Fax: 0033140469658. E-mail: tillequin@pharmacie.univ-paris5.fr.
10.1021/np9804583 CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/21/1999

Notes
J ournal of Natural Products, 1999, Vol. 62, No. 2 401
shifts are given in parts per million ppm, using the solvent
peaks as internal standards (MeOH-d4: δ 3.40, CDCl3: δ 7.27);
J values are given in Hertz. The signals of 1H and 13C spectra
were unambiguously assigned by use of 1D homonuclear
decoupling experiments and carbon-proton shift correlation
spectra. Elemental analyses were performed at the I. C. S. N.
(CNRS, Gif-sur-Yvette, France). Optical rotations were mea-
sured on a Perkin-Elmer 241 polarimeter (c in g/100 mL).
Melting points are not corrected. TLC were performed on
Merck Si gel 60F254 aluminum sheets using sulfuric vanillin
as spray reagent. Column chromatographies were conducted
using flash Si gel 60 Merck (35-70 µm). Compound 1 was
isolated from Aucuba japonica using a previously reported
procedure.12 Compound 3 was obtained according to the classic
acetylation method.1 The analytical and spectral data of
compounds 217,21,25-29 and 31,30 were identical to those previ-
ously published.
6-O-Acetyla u cu bin (4). To a solution of 3 (2.0 g, 3.34
mmol) in a 2:1 mixture of anhydrous MeOH and anhydrous
CH2Cl2 (15 mL), anhydrous KCN (22 mg, 0.33 mmol) was
added under argon. The reaction mixture, monitored by TLC,
was stirred 7 h at room temperature and then stopped by
filtration on Si gel. The solvent was removed in a rotary
evaporator, and the residue (1.5 g) was chromatographed on
Si gel by eluting with CH2Cl2-MeOH 9:1 to afford 432 as an
amorphous powder (585 mg, 1.50 mmol, yield 45%) and also
aucubin 1 (519 mg, 1.50 mmol).
eluting solvent. Compound 7 (81 mg, 66%) was obtained as a
crystalline powder. Recrystallization (cyclohexane-Me2CO 2:1)
gave colorless needles, mp 178-179 °C; [R]20 -34.7° (c 1.05,
D
CHCl3); IR (NaCl film) νmax 3495.1, 3060.4, 2918.2, 1726.4,
1654.3, 1601.9, 1451.4, 1266.5, 1109.1, 1069.7, 1026.4, 708.6
1
cm-1; H NMR (CDCl3) δ 8.10-7.70 (10H, m, Ph-CO), 7.60-
7.20 (15H, m, Ph-CO), 5.98 (1H, dd, J 3-4 ) 6.5 Hz, J 3-5 ) 1.5
Hz, H-3), 5.95 (1H, t, J 3′-2′ ) J 3′-4′ ) 9.5 Hz, H-3′), 5.88 (1H,
dd, J 7-6 ) J 7-9 ) 1.5 Hz, H-7), 5.70 (1H, t, J 4′-3′ ) J 4′-5′ ) 9.5
Hz, H-4′), 5.60 (1H, dd, J 2′-3′ ) 9.5 Hz, J 2′-1′ ) 8 Hz, H-2′),
5.27 (1H, d, J 1′-2′ ) 8 Hz, H-1′), 5.22 (1H, d, J 1-9 ) 5.5 Hz,
H-1), 5.07 (1H, d, J 10a-10b ) 14.5 Hz, H-10a), 4.95 (1H, d,
J 10b-10a ) 14.5 Hz, H-10b), 4.62 (1H, dd, J 4-3 ) 6.5 Hz, J 4-5
)
3.5 Hz, H-4), 4.58 (1H, dd, J 6′a-6′b ) 12.5 Hz, J 6′a-5′ ) 3.5 Hz,
H-6′a), 4.50 (1H, dd, J 6′b-6′a ) 12.5 Hz, J 6′b-5′ ) 5 Hz, H-6′b),
4.38 (1H, m, H-6), 4.18 (1H, ddd, J 5′-4′ ) 9.5 Hz, J 5′-6′b ) 5
Hz, J 5′-6′a ) 3.5 Hz, H-5′), 3.20 (1H, m, J 9-1 ) 5.5 Hz, H-9),
2.65 (1H, m, H-5); 13C NMR (CDCl3) δ 166.0, 165.7, 165.1, 164.9
(Ph-CO), 142.0 (C-8), 139.4 (C-3), 133.4, 133.0, 131.2, 129.7,
129.6, 129.3, 128.6, 128.3 (Ph-CO, C-7), 104.7 (C-4), 96.4 (C-
1′), 94.7 (C-1), 81.3 (C-6), 72.6 (C-3′), 72.4 (C-5′), 71.3 (C-2′),
69.6 (C-4′), 62.8 (C-6′), 62.0 (C-10), 46.7 (C-9), 43.1 (C-5); MS-
DIC (NH3) m/z 884 [M + NH4]+; anal. C 68.81%, H 4.98%, calcd
for C50H42O14, 0.6 H2O, C 68,41%, H 4,97%.
6-O-Ch lor oa cetyl-2′, 3′, 4′, 6′, 10-p en ta -O-ben zoyl-epi-
a u cu bin (8). To an anhydrous mixture of triphenylphosphine
(4 equiv, 0.71 mmol, 187 mg), 7 (154 mg, 0.17 mmol) and
monochloroacetic acid (3 equiv, 0.53 mmol, 50 mg), anhydrous
THF (5 mL) was added under argon. The solution was cooled
at 0 °C and diethylazodicarboxylate (4 equiv, 0.71 mmol, 0.1
mL) was added dropwise. The reaction mixture was allowed
to stand at room temperature and stirred over 2.5 h. The
solvent was removed in vacuo, and the residue was chromato-
graphed on Si gel by eluting with cyclohexane-EtOAC 9:1 to
6-O-Acetyl-2′, 3′, 4′, 6′, 10-p en ta -O-ben zoyla u cu bin (6).
Compound 4 (1.22 g, 3.14 mmol) was dissolved with stirring
in anhydrous pyridine (60 mL) and cooled at 0 °C with an ice
bath. After addition of benzoic anhydride (10 equiv, 7.11 g, 31
mmol) and 4-DMAP (0.1 equiv, 38 mg, 0.31 mmol), the reaction
mixture was allowed to stand at room temperature and stirred
over 24 h. Excess benzoic anhydride was quenched with ice.
The mixture was extracted with CH2Cl2 (3 × 150 mL). The
organic layers were washed with aqueous 10% HCl until
neutral, water, and brine. The combined extracts were dried
over Na2SO4. Filtration and evaporation of the solvent gave a
residue (8.5 g) that was chromatographed on a Si gel column
(cyclohexane-Me2CO 85:15) to afford 6 (2.80 g, 98%) as a
crystalline compound. Recrystallization (n-hexane-Me2CO 8:2)
afford 8 (167 mg, 82%) as an amorphous powder: [R]19.5
D
-31.4° (c 2.4, CHCl3); IR (NaCl film) νmax 3064.2, 2957.7,
1731.4, 1652.0, 1601.6, 1584.0, 1491.9, 1451.5, 1370.2, 1273.9,
1177.3, 1110.2, 1069.9, 1026.3, 970.8, 853.6, 801.8, 708.7 cm-1
;
1H NMR (CDCl3) δ 8.10-7.80 (10H, m, Ph-CO), 7.60-7.20
(15H, m, Ph-CO), 6.25 (1H, dd, J 3-4 ) 6.5 Hz, J 3-5 ) 2 Hz,
H-3), 5.98 (1H, t, J 3′-2′ ) J 3′-4′ ) 9.5 Hz, H-3′), 5.95 (1H, m,
H-7), 5.75 (1H, t, J 4′-3′ ) J 4′-5′ ) 9.5 Hz, H-4′), 5.70 (1H, m,
H-6), 5.62 (1H, dd, J 2′-3′ ) 9.5 Hz, J 2′-1′ ) 8 Hz, H-2′), 5.30
(1H, d, J 1′-2′ ) 8 Hz, H-1′), 5.20 (1H, d, J 10a-10b ) 15 Hz, H-10a),
5.05 (1H, d, J 10b-10a ) 15 Hz, H-10b), 4.98 (1H, d, J 1-9 ) 7.5
Hz, H-1),4.65 (1H, m, H-4), 4.65 (1H, m, J 6′a-6′b ) 12 Hz, H-6′a),
4.50 (dd, J 6′b-6′a ) 12 Hz, J 6′b-5′ ) 5 Hz, H-6′b), 4.20 (1H, m,
gave colorless needles, mp 116-117 °C; [R]20 -79.7 (c 1.2,
D
CHCl3); IR (NaCl film) νmax 3064.4, 2928.4, 1731.2, 1712.5,
1661.7, 1602.0, 1584.5, 1492.2, 1452.8, 1372.2, 1269.9, 1177.6,
1111.9, 1026.1, 969.0, 854.1, 803.1, 708.1 cm-1 1H NMR
;
(CDCl3) δ 8.10-7.70 (10H, m, Ph-CO), 7.60-7.20 (15H, m, Ph-
CO), 5.95 (1H, t, J 3′-2′ ) J 3′-4′ ) 9.5 Hz, H-3′), 5.90 (1H, dd,
J 3-4 ) 6 Hz, J 3-5 ) 2 Hz, H-3), 5.88 (1H, dd, J 7-6 ) J 7-9 ) 1.5
Hz, H-7), 5.72 (1H, t, J 4′-3′ ) J 4′-5′ ) 9.5 Hz, H-4′), 5.58 (1H,
dd, J 2′-3′ ) 9.5 Hz, J 2′-1′ ) 8 Hz, H-2′), 5.32 (1H, d, J 1-9 ) 4.5
Hz, H-1), 5.25 (1H, d, J 1′-2′ ) 8 Hz, H-1′), 5.22 (1H, m, H-6),
5.05 (1H, d, J 10a-10b ) 15 Hz, H-10a), 4.95 (1H, d, J 10b-10a ) 15
Hz, H-10b), 4.68 (1H, dd, J 6′a-6′b ) 12 Hz, J 6′a-5′ ) 3.5 Hz,
H-6′a), 4.55 (1H, dd, J 4-3 ) 6 Hz, J 4-5 ) 2.5 Hz, H-4), 4.48
(1H, dd, J 6′b-6′a ) 12 Hz, J 6′b-5′ ) 5 Hz, H-6′b), 4.18 (1H, ddd,
J 5′-4′ ) 9.5 Hz, J 5′-6′b ) 5 Hz, J 5′-6′a ) 3.5 Hz, H-5′), 3.28 (1H,
m, J 9-1 ) 4.5 Hz, H-9), 2.78 (1H, m, H-5), 2.05 (3H, s, CH3-
CO); 13C NMR (CDCl3) δ 170.7 (CH3CO), 165.9, 165.7, 165.0,
164.9 (Ph-CO), 144.4 (C-8), 139.5 (C-3), 139.5, 133.3, 133.1,
133.0, 130.0, 129.7, 129.6, 129.3, 128.6, 128.2 (Ph-CO), 127.1
(C-7), 104.0 (C-4), 96.4 (C-1′), 93.9 (C-1), 82.3 (C-6), 72.6 (C-
3′), 72.4 (C-5′), 71.2 (C-2′), 69.4 (C-4′), 62.8 (C-6′), 61.7 (C-10),
47.0 (C-9), 39.2 (C-5), 21.0 (CH3CO); Electrospray m/z 931 [M
+ Na]+; anal. C 68.14%, H 4.93%, calcd for C52H44O15, 0.4 H2O,
C 68.16%, H 4.93%.
2′, 3′, 4′, 6′, 10-P en ta -O-ben zoyla u cu bin (7). Compound
6 (129 mg, 0.14 mmol) was dissolved in a 1:1 mixture of
anhydrous MeOH and anhydrous THF. A 10% magnesium
methoxide solution (73 mL; 0.6 equiv, 0.08 mmol) was added
dropwise under nitrogen. The reaction mixture was stirred for
6.5 h at room temperature and then quenched by addition of
HCl 0.4 N (1.5 mL). The suspension was filtered on Si gel and
the solvent evaporated in vacuo to give a residue that was
chromatographed on Si gel using cyclohexane-EtOAc 7:3 as
H-5′), 3.90 (2H, s, CH2), 2.98 (1H, m, H-5), 3.20 (1H, m, J 9-1
)
5.5 Hz, H-9); 13C NMR (CDCl3) δ 166.1-164.5 (Ph-CO), 147.9
(C-8), 142.5 (C-3), 133.5-128.0 (Ph-CO), 126.3 (C-7), 99.95 (C-
4), 97.6 (C-1′), 97.6 (C-1), 79.5 (C-6), 72.7 (C-3′), 72.5 (C-5′),
71.5 (C-2′), 69.6 (C-4′), 62.9 (C-6′), 62.4 (C-10), 46.7 (C-9), 40.4
(CH2), 39.1 (C-5); electrospray m/z 983 [M + K]+; HRFABMS
m/z 943.2388 (calcd for C52H44O15Cl, 942.2368).
Dep r otection of 8. Compound 8 (35 mg, 0.037 mmol) was
dissolved in a 1:1 mixture of anhydrous CH2Cl2 and anhydrous
MeOH (2 mL). The solution was cooled at 0 °C and sodium
methoxide (6.6 equiv, 0.24 mmol, 13 mg) was added. The ice-
bath was removed, and the reaction mixture was stirred under
argon for 3 h. Silica was added to neutralize the NaOMe
excess. The suspension was stirred for 15 min. Evaporation
of the solvent, followed by flash chromatography of the residue
on Si gel (eluted with 8:2 CH2Cl2-MeOH), gave 2 (11 mg, 85%)
as a colorless oil, whose spectral data were identical with those
previously published, [R]19.5D -59.3° (c 1.0, MeOH) [lit.17[R]25
-58.9° (c 0.7, MeOH)].
D
Ack n ow led gm en t. We thank Dr. Y. Rolland (Laboratoires
Servier, Neuilly, France) for helpful discussions on the chem-
istry of aucubin.
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A. W. Can. J . Chem. 1994, 72, 2137-2142.

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NP9804583