A novel approach to erythrinan alkaloids by utilizing substituted biphenyl as building block

Article abstract of DOI:10.1055/s-2004-817753

Aryl ortho-quinone monoacetal 6 possessing a carbamate group on the side chain was synthesized from the appropriate biphenyl precursor via selective oxidation of one of the aromatic rings. Under Lewis acidic conditions, the carbamate group underwent internal attack at the quinone acetal moiety to give the spiro tricycle 9 corresponding to the A-, C-, and D-rings of erythrinan alkaloids, from which O-methylerysodienone was synthesized via the B ring formation in an efficient manner.

Full text of DOI:10.1055/s-2004-817753

LETTER
615
A Novel Approach to Erythrinan Alkaloids by Utilizing Substituted Biphenyl
as Building Block
A
Novel
A
pproach
o
to Erythrina
s
n Alkaloi
h
ds izumi Yasui, Yukiko Koga, Keisuke Suzuki, Takashi Matsumoto*
Department of Chemistry, Tokyo Institute of Technology and CREST-JST Agency, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551,
Japan
Fax +81(3)5734-3531; E-mail: tmatsumo@chem.titech.ac.jp
Received 28 December 2003
attractive in light of the biosynthesis of erythrinan alka-
Abstract: Aryl ortho-quinone monoacetal 6 possessing a carbam-
loids in which the C(5)–N bond forms via oxidative cy-
ate group on the side chain was synthesized from the appropriate bi-
phenyl precursor via selective oxidation of one of the aromatic
rings. Under Lewis acidic conditions, the carbamate group under-
clization of the intermediary dibenz[d,f]azonine IV.4
Moreover, since various synthetic methods are now avail-
went internal attack at the quinone acetal moiety to give the spiro able for the substituted biphenyl compounds,5 this ap-
tricycle 9 corresponding to the A-, C-, and D-rings of erythrinan
alkaloids, from which O-methylerysodienone was synthesized via
the B ring formation in an efficient manner.
proach would offer a useful access to natural and
unnatural erythrinan-type compounds.
In this communication, we wish to describe the prelimi-
nary but quite promising results of the feasibility study on
this new approach.
Key words: erythrinan alkaloid, biphenyl compound, spirocycliza-
tion, ortho-quinone acetal, O-methylerysodienone
Isolated from many species of Erythrina (Leguminosae)
and also from some plants of Menispermaceae, the alka-
D
selective
oxidation
C(5)–N bond
formation
loids sharing indolo[7a,1-a]isoquinoline skeleton (eryth-
rinan skeleton), constitute a large group of natural
products and are designated as erythrinan alkaloids
(Figure 1).1,2 Because of their unique spirocyclic amine
structure and physiological activities, these alkaloids have
been synthetic targets for a long time.1,3 Synthetic chal-
lenges are posed by stereocontrolled construction of the
chiral spiro center and appropriate functionalization in the
rings A and B.
NHR
Y
NHR
Y
A
MeO
MeO
O
I
II
formation
of ring B
D
13C
NH
6
erythrinan
skeleton
Y
N-H
5
A
MeO
O
dibenz[d,f]azonine IV
III
HO
16
15
10
O
O
Scheme 1 Schematic drawing of the present approach to erythrinan
alkaloids.
D
C
8
N
N
N9
13
MeO
B
5
6
1
A
MeO
erysodienone
MeO
erythratinone
We set O-methylerysodienone as the initial synthetic goal
in this study (see compound 12 in Scheme 3).6 For this
purpose, ortho-quinone acetal 6 was synthesized as the
precursor of spirocyclization (Scheme 2).7 Suzuki–
Miyaura coupling8 of aryl bromide 1 and arylboronic acid
29 quickly proceeded in the presence of 5 mol% of
Pd(PPh3)4 and aqueous Ba(OH)2 to give biphenyl alde-
hyde 3 in high yield, which was then subjected to Wittig
methylenation and hydroboration followed by oxidative
workup. Alcohol 4, thus obtained, was further converted
to the Boc-protected biphenyl amine 5 via mesylation of
the hydroxy group, substitution with NaN3, reduction of
the resulting azide by PMe3, and protection.
2
O
O
erythrinan skeleton
Figure 1 Natural erythrinan alkaloids.
As a novel approach to these alkaloids, we envisioned to
utilize a biphenyl framework as the progenitor of the A-
and D-rings (Scheme 1).2 The key transformations in-
clude (1) selective oxidation of one of the aromatic rings
in biphenyl amine derivative I to give ortho-quinone de-
rivative II, (2) spirocyclization by the internal attack of a
nitrogen function in a SN2¢ fashion (II→III), and (3) in-
tramolecular N-alkylation of the resulting spiroisoquino-
line III to form the ring B. We felt that this approach is
Having installed the nucleophilic nitrogen function in the
D-ring side chain, the A-ring was converted to the ortho-
quinone monoacetal as the acceptor counterpart for the
spirocyclization.10 In order to secure the C(2)-carbonyl
functionality and to avoid the cross-ring oxidation, the
SYNLETT 2004, No. 4, pp 0615–0618
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817753; Art ID: U29703ST
© Georg Thieme Verlag Stuttgart · New York
0
9.
0
3.
2
0
0
4

616
Y. Yasui et al.
LETTER
Table 1 Spirocyclization of Model Compound 7
OMe
Br
OMe
MeO
MeO
MeO
1) Pd(PPh3)4
Ba(OH)2
CHO
Lewis acid
NHBoc
OMe
N-Boc
OMe
CHO
1
CH2Cl2
OSi(i-Pr)3
93%
B(OH)2
molecular sieves 4A
MeO
MeO
MeO
OSi(i-Pr)3
O
O
7
8
OBn
MeO
3
OBn
2
Run Lewis acid
(Equiv)
(1.5)
(0.3)
(1.3)
(0.2)
(0.3)
(0.2)
(0.3)
Conditions
Yield (%)
OMe
1
2
3
4
5
6
7
BF3·OEt2
BF3·OEt2
Me3SiOTf
Me3SiOTf
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
–40 °C, 10 min
–20 °C, 45 min
–20 °C, 10 min
–20 °C, 20 min
25 °C, 4 h
48
90
82a
90
96
92
97
MeO
MeO
4) MsCl, pyridine
5) NaN3 (90%)
2) Ph3P=CH2
OH
OSi(i-Pr)3
3) (sia)2BH;
6) PMe3
7) (Boc)2O, Et3N
(91%)
H2O2, NaOH aq.
80% (2 steps)
OBn
4
OMe
OMe
25 °C, 1 h
MeO
MeO
25 °C, 15 h
8) H2, 5% Pd/C
(99%)
D
A
NHBoc
OSi(i-Pr)3
NHBoc
a Concomitant removal of the Boc group occurred in 10% yield.
OSi(i-Pr)3
9) (AcO)2IPh,
MeOH
(quant)
MeO
MeO
MeO
2
2
OBn
O
40 minutes to give the desired spiroisoquinoline 9 in 84%
yield (Scheme 3).13,14 The triisopropylsilyl group in 9 was
removed [Bu4NF, THF, 25 °C] and the resulting alcohol
10 was mesylated [MsCl, pyridine, 25 °C] to give mesy-
late 11, ready for the final B-ring cyclization. For cleavge
of the Boc group via the corresponding trimethylsilyl car-
bamate,15 compound 11 was treated with Me3SiOTf
[CH2Cl2, 0 °C]. Upon quenching the reaction by adding
pH 7 phosphate buffer (0.1 M), hydrolysis of the generat-
ed trimethylsilyl carbamate and the subsequent cycliza-
tion of the B-ring occurred in the resulting heterogeneous
mixture. Unfortunately, this protocol was not reproduc-
ible. After various attempts, we found that the cyclization
was able to be effected cleanly and reproducibly by add-
ing the phosphate buffer along with methanol for homog-
enizing the mixture. Thus, after confirming the
consumption of 11 by TLC [0 °C, 10 min], methanol and
the phosphate buffer (each 1/5 volume of CH2Cl2) were
added successively to the reaction mixture, and the result-
ing solution was stirred for 5 minutes at 0 °C. O-Methyl-
erysodienone (12)6 was obtained in 85% yield via
extractive workup (CHCl3) followed by chromatography
on alumina. Thus, the spirocyclization of the ortho-quino-
ne monoacetal was shown to be possible, offering a novel
and efficient route to erythrinan alkaloids.
5
6
Scheme 2 Conditions: (1) DME, H2O, 50 °C, 1 h; (2) THF, 25 °C,
15 min; (3) THF, –15 °C then 25 °C, 1 h; (4) 25 °C, 30 min; (5) DMF,
60 °C, 3 h; (6) MeCN, H2O, 25 °C, 5 h; (7) THF, 25 °C, 2 h; (8)
EtOAc, MeOH, 25 °C, 15 min; (9) 25 °C, 10 min.
C(2) phenol was first liberated. The resulting phenol
was cleanly oxidized upon treatment with (AcO)2IPh in
methanol at 25 °C,11 thereby giving the desired ortho-
quinone monoacetal 6 in quantitative yield.
Concerning the crucial spirocyclization, model studies
were carried out for screening the conditions by using the
simple ortho-quinone acetal 7 (Table 1).12 It was found
that various Lewis acids, including BF3·OEt2, Me3SiOTf
and some other metal triflates, were able to effect the de-
sired reaction in high yield. CH2Cl2 was the solvent of
choice and the presence of 4 Å molecular sieves improved
the yield. Selected results are shown in Table 1. It should
be noted that the Lewis acid is better employed as catalyst
(0.2–0.3 equiv), since the stoichiometric use considerably
lowered the yield. For example, with 1.5 equivalents of
BF3·OEt2, the starting material 7 was consumed in 10 min-
utes at –40 °C to give spirocycle 8 in 48% yield along with
many unidentified side products (run 1), while the reac-
tion proceeded more cleanly by reducing the catalyst load
to 0.3 equivalents to give 8 in 90% yield (run 2). When
Me3SiOTf was employed stoichiometrically, cleavage of
the Boc group accompanied (run 3).
In summary, a novel approach to erythrinan alkaloids by
utilizing the substituted biphenyl compound as the build-
ing block was developed, and was successfully applied to
the synthesis of O-methylerysodienone. Attempts to de-
velop the enantioselective variant of this approach are cur-
rently underway in our laboratories, and the preliminary
results will be described in the following paper.16
Having these data in hand, the reaction of quinone acetal
6 was attempted with BF3·OEt2 (0.2 equiv), which gratify-
ingly proceeded cleanly at –20 °C and were complete in
Synlett 2004, No. 4, 615–618 © Thieme Stuttgart · New York

LETTER
A Novel Approach to Erythrinan Alkaloids
617
1 H, J1 = J2 = 7.4 Hz), 6.90 (s, 1 H), 6.79 (s, 1 H), 6.66 (s, 1
H), 6.63 (s, 1 H), 5.17 (s, 2 H), 4.39 (br s, 1 H), 3.92 (s, 3 H),
3.85 (s, 3 H), 3.82 (s, 3 H), 3.61–3.50 (m, 2 H), 3.26–3.09
(m, 2 H), 2.59–2.40 (m, 4 H), 1.40 (s, 9 H), 0.95 (s, 21 H).
13C NMR (CDCl3): d = 155.7, 148.1, 147.5, 147.1, 146.9,
137.1, 133.5, 132.9, 129.0, 128.9, 128.5, 127.8, 127.4,
115.7, 113.7, 113.2, 112.1, 79.1, 71.0, 64.0, 56.1, 55.9, 55.8,
41.4, 36.6, 33.0, 28.3, 17.9, 11.8. IR (KBr): 3330, 2940,
2865, 1700, 1685, 1510, 1465, 1250, 1160, 1115 cm–1. Anal.
Calcd for C40H59NO7Si: C, 69.23; H, 8.57; N, 2.02. Found:
C, 69.39; H, 8.87; N, 1.93. Compound 6: 1H NMR (CDCl3):
d = 6.77 (s, 1 H), 6.62 (s, 1 H), 6.21 (s, 1 H), 6.05 (s, 1 H),
4.59 (br, 1 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.68–3.58 (m, 2
H), 3.41 (s, 3 H), 3.40 (s, 3 H), 3.40–3.19 (m, 2 H), 2.71
(ddd, 1 H, J1 = J2 = 6.4 Hz, J3 = 12.8 Hz), 2.50 (ddd, 1 H,
J1 = J2 = 6.4 Hz, J3 = 12.8 Hz), 2.27 (ddd, 1 H, J1 = J2 = 7.2
Hz, J3 = 14.5 Hz), 2.19 (ddd, 1H, J1 = J2 = 7.2 Hz, J3 = 14.5
Hz), 1.42 (s, 9 H), 0.97 (s, 21 H). 13C NMR (CDCl3): d =
193.9, 155.7, 152.6, 148.8, 147.4, 139.7, 133.4, 129.3,
129.0, 124.3, 112.2, 112.1, 91.1, 79.3, 61.1, 55.9, 55.8, 49.9,
49.8, 41.3, 37.3, 33.4, 28.4, 17.9, 11.8. IR (NaCl): 3380,
2940, 2870, 1710, 1680, 1515, 1465, 1365, 1250, 1230,
1170, 1100, 755 cm–1. Anal. Calcd for C34H55NO8Si: C,
64.42; H, 8.75; N, 2.21. Found: C, 64.24; H, 8.98; N, 2.01.
Compound 9: 1H NMR (CDCl3): d = 6.61 (s, 1 H), 6.45 (s, 1
H), 6.19 (s, 1 H), 5.79 (s, 1 H), 4.34 (ddd, 1 H, J1 = J2 = 4.1
Hz, J3 = 12.9 Hz), 3.86 (s, 3 H), 3.70–3.63 (m, 1 H), 3.67 (s,
3 H), 3.65 (s, 3 H), 3.47 (ddd, 1 H, J1 = 6.2 Hz, J2 = 8.5 Hz,
J3 = 10.9 Hz), 3.36 (ddd, 1 H, J1 = 5.8 Hz, J2 = 8.7 Hz,
J3 = 10.9 Hz), 3.01 (ddd, 1 H, J1 = 4.1 Hz, J2 = 10.9 Hz,
J3 = 15.3 Hz), 2.80 (ddd, 1 H, J1 = 3.1 Hz, J2 = 4.1 Hz,
J3 = 15.3 Hz), 2.40 (ddd, 1 H, J1 = 5.8 Hz, J2 = 8.5 Hz,
J3 = 11.6 Hz), 2.08 (ddd, 1 H, J1 = 6.2 Hz, J2 = 8.7 Hz,
J3 = 11.6 Hz), 1.35 (s, 9 H), 0.96 (s, 21 H). 13C NMR
(CDCl3): d = 181.7, 165.8, 155.0, 149.7, 148.5, 147.9, 128.5,
123.9, 123.5, 118.3, 111.2, 109.7, 81.6, 63.9, 61.3, 55.9,
55.8, 55.0, 40.2, 34.0, 29.2, 28.1, 17.8, 11.7. IR (NaCl):
2940, 2865, 1695, 1670, 1645, 1620, 1515, 1465, 1365,
1260, 1220, 1160, 1090, 755 cm–1. Anal. Calcd for
C33H51NO7Si: C, 65.86; H, 8.54; N, 2.33. Found: C, 65.59;
H, 8.58; N, 2.05. Compound 12: Pale yellow needles
(CHCl3), mp 157.5–158.0 °C. 1H NMR (CDCl3): d = 6.57 (s,
1 H), 6.38 (s, 1 H), 6.31 (s, 1 H), 5.99 (s, 1 H), 3.85 (s, 3 H),
3.70 (s, 3 H), 3.62 (s, 3 H), 3.53 (ddd, 1 H, J1 = 5.7 Hz,
J2 = 12.3 Hz, J3 = 14.4 Hz), 3.32 (ddd, 1 H, J1 = J2 = 7.0 Hz,
J3 = 14.4 Hz), 3.31–3.14 (m, 3 H), 2.71–2.59 (m, 2 H), 2.54
(dd, 1 H, J1 = 5.7 Hz, J2 = 17.3 Hz). 13C NMR (CDCl3):
d = 181.7, 167.3, 149.7, 148.5, 148.0, 125.9, 124.1, 122.4,
115.7, 112.1, 108.3, 64.8, 55.83, 55.82, 55.0, 47.0, 40.9,
27.9, 20.2. IR (KBr): 2940, 2845, 1675, 1655, 1620, 1510,
1465, 1250, 1210, 1175, 1105, 1010 cm–1. Anal. Calcd for
C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.41; H,
6.76; N, 4.04.
OMe
MeO
BF3·OEt2,
MS4A, CH2Cl2,
–20 °C
NHBoc
OSi(i-Pr)3
84%
MeO
MeO
O
6
MeO
MeO
MeO
MeO
TMSOTf, CH2Cl2;
N-Boc
N
OR
then MeOH,
pH 7 phosphate
buffer
MeO
MeO
O
O
85%
12
9: R = (i-Pr)3Si
10: R = H
11: R = Ms
Bu4NF (80%)
MsCl, pyridine (83%)
Scheme 3 Spirocyclization of ortho-quinone acetal 6 and synthesis
of O-methylerysodienone (12).
References
(1) (a) Dyke, S. F.; Quessy, S. N. In The Alkaloids, Vol. 18;
Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981,
1. (b) Tsuda, Y.; Sano, T. In The Alkaloids, Vol. 48; Cordell,
G. A., Ed.; Academic Press: San Diego, 1996, 249.
(2) Throughout this work, the commonly accepted erythrinan
numbering is used. See: Boekelheide, V.; Prelog, V. In
Progress in Organic Chemistry, Vol. 3; Cook, J. W., Ed.;
Butterworths Scientific: London, 1955, Chap. 5, see also ref.
1.
(3) For recent synthetic studies, see: (a) Fukumoto, H.; Esumi,
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Phytochemistry 1999, 52, 373.
(5) For a recent review on aryl–aryl bond formations, see:
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Tetrahedron Lett. 2003, 44, 7771. (d) Hamura, T.; Morita,
M.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2003, 44,
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(8) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
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Synlett 1992, 207. (c) For a review, see: Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457.
(9) Boronic acid 2 was prepared from isovanillin in six steps [(1)
BnBr, NaOH aq, Bu4NHSO4, CH2Cl2 (73%); (2) Ph3P=CH2,
THF (98%); (3) (sia)2BH, THF, then H2O2, NaOH aq (97%);
(i-Pr)3SiCl, imidazole, DMF (quant); (5) NBS, DMF (84%);
(6) BuLi, THF, –78 °C, then B(i-PrO)3, –78 °C to 0 °C, then
2 M HCl aq (75%)].
(6) (a) Ghosal, S.; Majumdar, S. K.; Chakraborti, A. Aust. J.
Chem. 1971, 24, 2733. (b) Chou, C.-T.; Swenton, J. S. J.
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(7) All new compounds were fully characterized by 1H and 13
NMR, IR and combustion analysis. Data for the selected
compounds follow. Compound 5: Colorless needles
C
(10) For a review on synthetic use of ortho-quinone monoacetals,
see: Quideau, S.; Pouységu, L. Org. Prep. Proced. Int. 1999,
31, 617.
(hexane), mp 99.5–100.0 °C. 1H NMR (CDCl3): d = 7.48 (d,
2 H, J = 7.4 Hz), 7.39 (dd, 2 H, J1 = J2 = 7.4 Hz), 7.32 (dd,
Synlett 2004, No. 4, 615–618 © Thieme Stuttgart · New York

618
Y. Yasui et al.
LETTER
(13) Experimental Procedure as Follows: To a mixture of
(11) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org.
Chem. 1987, 52, 3927. (b) Lewis, N.; Wallbank, P.
Synthesis 1987, 1103. (c) For reviews on phenolic oxidation
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Tetrahedron 2001, 57, 273. (d) Moriarty, R. M.; Prakash, O.
Org. React. 2001, 57, 327.
(12) Compound 7 was synthesized from aryl bromide i and
boronic acid ii in three steps [(1) 10 mol% Pd(PPh3)4,
Ba(OH)2, DME, H2O, reflux; (2) H2, 10% Pd/C, MeOH; (3)
(AcO)2IPh, MeOH] in 37% overall yield (Figure 2).
powdered molecular sieves 4 Å (40 mg) and BF3·OEt2 (2.6
mg, 18 mmol) in CH2Cl2 (0.5 mL) was added 6 (49.2 mg,
0.0776 mmol) in CH2Cl2 (1.5 mL) at –20 °C. After 40 min,
the reaction was quenched with sat. aq NaHCO3 and the
mixture was extracted with EtOAc (× 3). The combined
organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by
PTLC (hexane/EtOAc = 6:4) to give 9 (39.3 mg, 84%) as a
colorless oil.
(14) Cu(OTf)2, Sc(OTf)3, and Yb(OTf)3, though worked
satisfactorily, did not exceed BF3·OEt2 in the yield of 9.
(15) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870; and
references cited therein.
B(OH)2
OMe
NHBoc
MeO
(16) Yasui, Y.; Suzuki, K.; Matsumoto, T. Synlett 2004, DOI.
Br
OBn
i
ii
Figure 2
Synlett 2004, No. 4, 615–618 © Thieme Stuttgart · New York