First stereoselective total synthesis of macrocarpal C: Structure elucidation of macrocarpal G

Article abstract of DOI:10.1039/a705231f

The first stereoselective total synthesis of macrocarpal C is achieved via a coupling reaction of a silyl dienol ether with a novel hexasubstituted benzene chromium tricarbonyl complex as an optically active benzyl cation equivalent, thereby clarifying the identity of macrocarpal C and G.

Full text of DOI:10.1039/a705231f

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First stereoselective total synthesis of macrocarpal C: structure elucidation of
macrocarpal G
Tetsuaki Tanaka,a Hidenori Mikamiyama,a Kimiya Maeda,a Toshimasa Ishida,b Yasuko Inb and
Chuzo Iwata*a
a Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565, Japan
b Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-11, Japan
MeO
OCOCH2Cl
Bui
The first stereoselective total synthesis of macrocarpal C is
achieved via a coupling reaction of a silyl dienol ether with a
novel hexasubstituted benzene chromium tricarbonyl com-
plex as an optically active benzyl cation equivalent, thereby
clarifying the identity of macrocarpal C and G.
3
MeO2C
MeO
Bui
OMe
Cr(CO)3
H
H
MeO2C
8
Ar′
11
11
Macrocarpals1,2 are structurally characterized by fusion of
isopentylphloroglucinol dialdehyde to various sesquiterpene
skeletons and are known to exhibit various interesting bio-
logical activities, such as antibacterial activity,2a,c,e,g inhibitory
activity of HIV reverse transcriptase,2b aldose reductase2d,e and
glucosyl transferase.2e,g Since the original isolation of macro-
carpal A 1 from Eucalyptus macrocarpa in 1990,2a a number of
macrocarpals have been isolated from Eucalyptus species.2b–g
Complete structures have been elucidated for macrocarpals A
(1), B (2) and C (3) using X-ray diffraction studies and spectral
and chemical investigations, and the absolute stereochemistries
of 1 and 3 have been determined by a modified Mosher’s
method.2b Macrocarpal G 4,2c however, has been assigned the
same planar structure as 3,† and quite a few macrocarpals have
not been designated relative stereochemistries. In this
communication, we report the first and highly stereoselective
total synthesis of macrocarpal C 3, thereby clarifying its identity
with respect to macrocarpal G 4.
O
OR
OR
9
OR
7
H
R = SiMe2But
11
O
5
OR
6
Scheme 1
which possesses the requisite functionalities and desired
stereochemistry for the subsequent manipulations toward
macrocarpal C 3, would be obtained selectively after com-
plexation.
Scheme 2 outlines the synthesis of the chiral chromium
complex 8 starting from commercially available 1,3,5-trimeth-
oxybenzene 10. Friedel–Crafts acylation of 10 with isovaleryl
chloride, followed by LAH reduction led to alcohol 12 via
ketone 11. After complexation of 12 with Cr(CO)6, stepwise
introduction of two methoxycarbonyl groups via direct nuclear
lithiation5 to the aromatic ring furnished diester rac-13. The
resolution of this racemic benzyl alcohol was then examined.
Diastereomeric carbamates derived from the CuCl assisted6
Bui
Bui
Bui
H
H
Ar
Ar
Ar
H
H
HO
Macrocarpal A 1 (β-Ar)
Macrocarpal B 2 (α-Ar)
Macrocarpal C 3
Macrocarpal G 4
Ar = 2,4,6-trihydroxy-3,5-diformylphenyl
OMe
MeO
R2
R1
MeO2C
MeO
As illustrated in the retrosynthetic analysis of macrocarpal C
3 (Scheme 1), our synthetic approach began from the previously
reported tricyclic enone 6,3 which we prepared from the
commercially available and inexpensive (+)-3-carene 5. The
coupling reaction of the sesquiterpene moiety 6 with the
isopentylphloroglucinol dialdehyde part is a crucial step
requiring high stereoselectivity at both the benzylic and C11
positions. To this end, we planned the Lewis acid mediated
coupling reaction of silyldienol ether 7 with a novel hexasub-
stituted benzene chromium tricarbonyl complex 8 as an
optically active benzyl cation equivalent. Our previous studies
suggested that an electrophile would be introduced stereo-
selectively at the C11 position from the less hindered b-side of
7.3 In connection with stereochemical control at the benzylic
position, it is known that, with some nucleophiles, SN1-type
carbon–carbon bond formation via the Cr(CO)3-stabilized
carbonium ion proceeds with stereochemical retention at the
benzylic position.4 Hence, the desired coupling product 9,
Bui
iii–v
MeO
OMe
OMe
Cr(CO)3
MeO2C
Me
10 R1 = H
rac-13 R2 = OH
14 R2 =
(S)-13 R2 = β-OH
8 R2 = β-O2CCH2Cl
vi
vii
i
11 R1 = C(O)Bui
12 R1 = CH(OH)Bui
β-O2CNH
1-naphthyl
ii
viii
Scheme 2 Reagents and conditions: i, isovaleryl chloride, AlCl3, CH2Cl2,
0 °C, 81%; ii, LAH, Et2O, 0 °C, 91%; iii, Cr(CO)6, Bun2O–1,4-dioxane–
n-heptane (5:5:1), 120 °C, 43% (92% based on conversion); iv, BunLi,
TMEDA, THF, 278 °C, then CO2, 278 °C, then TMSCHN2, C6H6–MeOH
(4:1); v, LDA, TMEDA, THF, 250 °C, then CO2, 278 °C, then
TMSCHN2,
C6H6–MeOH
(4:1),
75%
overall;
vi,
(R)-(2)-1-(1-naphthyl)ethyl isocyanate, CuCl, DMF, 99%, then separation;
vii, BF3·Et2O, wet MeCN, 0 °C, 81%; viii, (ClCH2CO)2O, pyridine,
CH2Cl2, 0 °C, 92%
Chem. Commun., 1997
2401

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We thank Professor Mugio Nishizawa (Tokushima Bunri
University) for provision of natural macrocarpal C 3 and copies
of its spectra. We also thank Professor Seiichi Homma
(Ochanomizu University) for copies of the spectra for natural
macrocarpal G 4. This research was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture of Japan (No.
08672425).
i
ii, iii
6
7
9
Scheme 3 Reagents and conditions: i, ButMe2SiOTf, Et3N, Et2O–CH2Cl2
(1:1), 98%; ii, 8, ZnCl2, CH2Cl2; iii, CAN, MeOH, 0 °C, 61% from 8
reaction of rac-13 with (R)-(2)-1-(1-naphthyl)ethyl isocya-
nate7 were separated by simple chromatography on silica gel.
Hydrolysis of the polar carbamate 14 was achieved by treatment
with BF3·Et2O in hydrous MeCN to provide the alcohol (S)-13,
[a]2D6 221.9 ( > 98% ee) without racemization.‡ Finally, (S)-13
was converted to the chloroacetate 8, which was expected to
have the required reactivity.8
With the desired chiral complex 8 as an aromatic side-chain
unit in hand, we subjected 8 to the coupling reaction (Scheme
3). For this purpose, the enone 6 was converted to the tert-
butyldimethylsilyl dienol ether 7. A 1.5-fold excess of this
intermediate was then coupled with the chiral complex 8 in the
Footnotes and References
* E-mail: iwata@phs.osaka-u.ac.jp
† The 1H and 13C NMR spectra of macrocarpals C 3 and G 4 were measured
in different solvents, which made comparison difficult. In ref. 1, however,
it has been considered that these were diastereomers due to the difference
between their physicochemical properties.
‡ Enantiomeric purity was determined by 1H NMR analysis of Mosher ester
derivatives.11 Absolute stereochemistry was assigned by Mosher’s
method.12
§ A small amount (2%) of the benzylic epimer of 9 was obtained, but neither
the C11 epimer nor the regioisomer was isolated.
9
presence of ZnCl2 to afford 9 stereoselectively§ after decom-
plexation with ceric ammonium nitrate (CAN).
¶ The structural assignment of 17 was confirmed by X-ray crystallographic
analysis of its C10 carbonylimidazolide derivative 22. Crystal data for 22:
Since the stereoselective route to the promising precursor of
macrocarpal C 9 had already been developed, we further
pursued the total synthesis (Scheme 4). Catalytic hydrogenation
of the enone 9 afforded desilylated ketone 15 with the desired
stereochemistry.3 NaBH4 reduction of 15 followed by acetyla-
tion of the primary hydroxy group led to monoacetate 17¶ via
diol 16. The application of modified Grieco’s protocol10
allowed dehydration of the C10 secondary hydroxy group of 17.
Deacetylation of the resulting product followed by catalytic
hydrogenation afforded alcohol 18, which was subjected to
dehydration again, furnishing exo-olefin 19. DIBAL-H reduc-
tion of diester 19 followed by oxidation afforded trimethyl
macrocarpal C 21 via diol 20. Finally, the cleavage of all three
methyl ethers was fully achieved by our original method (10
equiv. of 4-MeC6H4SLi, 50 equiv. of HMPA, toluene, reflux)∑
to furnish macrocarpal C 3, which was identical to a natural
authentic sample (1H and 13C NMR).** Moreover, the synthetic
sample was found to be identical to natural macrocarpal G
4.††
C39H54N2O11
, M = 726.86, orthorhombic, space group P212121,
a = 16.723(2), b = 19.979(2), c = 11.547(2) Å, V = 3858.0(9) Å3, Z = 4,
Dc = 1.251 g cm23, m(Cu-Ka) = 7.13 cm21, F(000) = 1560, T = 293 K.
The structure was solved by direct methods and refined by full-matrix least-
squares to R = 0.052 and Rw = 0.067 using 2185 reflections with Fo
3s(Fo). CCDC 182/601.
>
∑ A preliminary study suggested that only bis-demethylation would occur by
the use of sodium salt (4-MeC6H4SNa), as previously reported.13
** Synthetic 3 displayed 1H and 13C NMR spectra that were indistinguish-
able from those of the natural isolate and showed the following optical
properties: [a]2D5 222.1 (c 0.150, EtOH). A small rotation, [a]2D4 23.0 (c
0.92, EtOH), was originally reported for 3 that had been isolated from E.
globulus.2b This rotation, however, is believed to be erroneous due to
contamination of the natural sample (M. Nishizawa, personal communica-
tion, April 15, 1997).
†† Synthetic 3 exhibited spectroscopic data (1H, 13C, IR) identical to those
for natural macrocarpal G 4. The rotation for synthetic 3, [a]2D5 224.7 (c
0.135, MeOH), corresponded closely to the rotation reported for 4, [a]D
227.1 (c 0.59, MeOH).2c
1 For a review of bioactive acylphloroglucinol derivatives from Euca-
lyptus species, see: E. L. Ghisalberti, Phytochemistry, 1996, 41, 7.
2 (a) M. Murata, Y. Yamakoshi, S. Homma, K. Aida, K. Hori and
Y. Ohashi, Agric. Biol. Chem., 1990, 54, 3221; (b) M. Nishizawa,
M. Emura, Y. Kan, H. Yamada, K. Ogawa and N. Hamanaka,
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A. Shimizu and S. Homma, Biosci. Biotech. Biochem., 1992, 56, 1570;
(d) M. Murata, Y. Yamakoshi, S. Homma, K. Arai and Y. Nakamura,
Biosci. Biotech.Biochem., 1992, 56, 2062; (e) K. Osawa, H. Yasuda,
H. Morita, K. Takeya and H. Itokawa, Phytochemistry, 1995, 40, 183; (f)
I. P. Singh and H. Etoh, Biosci. Biotech. Biochem., 1995, 59, 2330; (g)
K. Osawa, H. Yasuda, H. Morita, K. Takeya and H. Itokawa, J. Nat.
Prod., 1996, 59, 823.
3 T. Tanaka, K. Maeda, H. Mikamiyama, Y. Funakoshi, K. Uenaka and C.
Iwata, Tetrahedron, 1996, 52, 4257.
4 M. Uemura, T. Kobayashi, K. Isobe, T. Minami and Y. Hayashi, J. Org.
Chem., 1986, 51, 2859 S. G. Davies and T. J. Donohoe, Synlett, 1993,
323.
5 M. F. Semmelhack, J. Bisaha and M. Czarny, J. Am. Chem. Soc., 1979,
101, 768; H.-G. Schmalz, T. Volk, D. Bernicke and S. Huneck,
Tetrahedron, 1997, 53, 9219.
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8 W. R. Roush and C. K. Wada, Tetrahedron Lett., 1994, 35, 7347.
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10 P. A. Grieco, S. Gilman and M. Nishizawa, J. Org. Chem., 1976, 41,
1485.
Bui
Bui
H
H
iv–vi
i
Ar′
Ar′
9
X
H
H
OR1
OH
15 R1 = H, X = O
18
ii
16 R1 = H, X = β-OH, H
iii
vii
17 R1 = Ac, X = β-OH, H
Bui
OMe
H
R2
MeO
OMe
H
R2
19 R2 = CO2Me
20 R2 = CH2OH
21 R2 = CHO
viii
ix
x
Macrocarpal C 3
Ar′ = 2,4,6-trimethoxy-3,5-bis(methoxycarbonyl)phenyl
Scheme 4 Reagents and conditions: i, H2 (5 atm), 10% Pd–C, MeOH, 88%;
ii, NaBH4, MeOH, 96%; iii, Ac2O, DMAP, CH2Cl2, 100%; iv, 2-NO2C6H4-
SeCN, Bun3P, THF, sealed tube, 75 °C, then 30% aq. H2O2 0 °C; v, NaOMe,
MeOH, 64% from 17; vi, H2 (5 atm), 10% Pd–C, MeOH, 100%; vii,
2-NO2C6H4SeCN, Bun3P, THF, 50 °C, then 30% aq. H2O2, 0 °C, 77%; viii,
DIBAL-H, toluene, 278 °C, 100%; ix, Prn4NRuO4, 4-methylmorpholine
N-oxide, molecular sieves 4 Å, MeCN, 87%; x, 4-MeC6H4SLi, HMPA,
toluene, reflux, 58%
11 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543.
12 J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.
13 C. Hansson and B. Wickberg, Synthesis, 1976, 191.
Received in Cambridge, UK, 21st July 1997; 7/05231F
2402
Chem. Commun., 1997