Transmission of axial chirality to spiro center chirality, enabling enantio-specific access to erythrinan alkaloids

Article abstract of DOI:10.1055/s-2004-817754

Synthesis of O-methylerysodienone in enantiomerically pure form is described, where the axial chirality of the intermediate biphenyl is stereospecifically transmitted to the spiro center chirality of the erythrinan skeleton.

Full text of DOI:10.1055/s-2004-817754

LETTER
619
Transmission of Axial Chirality to Spiro Center Chirality, Enabling Enantio-
specific Access to Erythrinan Alkaloids
Transmission of
A
o
xial
C
hirality
s
to Spiro
h
Center
C
hira
i
lity zumi Yasui, 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
OMe
OMe
Abstract: Synthesis of O-methylerysodienone in enantiomerically
pure form is described, where the axial chirality of the intermediate
biphenyl is stereospecifically transmitted to the spiro center
chirality of the erythrinan skeleton.
MeO
MeO
MeO
MeO
NHBoc
NHBoc
OSi(i-Pr)3
OSi(i-Pr)3
Key words: erythrinan alkaloid, biphenyl compound, axial chirali-
ty, spiro center chirality
MeO
OH
O
I
II
MeO
MeO
MeO
MeO
The alkaloids, which share indolo[7a,1-a]isoquinoline
skeleton (erythrinan skeleton), constitute a large group of
plant metabolites called erythrinan alkaloids (Figure 1).1–3
N-Boc
N
OSi(i-Pr)3
MeO
MeO
HO
16
15
10
O
O
O
O
III
O-methylerysodienone (1)
D
C
8
N
N
N9
13
MeO
B
5
OMe
6
1
A
MeO
MeO
erysodienone
MeO
erythratinone
2
O
O
NHBoc
erythrinan skeleton
OSi(i-Pr)3
R
Figure 1 Natural erythrinan alkaloids.
MeO
OH
IV
In the preceding paper,4 we described a novel approach to
these alkaloids and its application to the total synthesis of
O-methylerysodienone (1) in racemic form (Scheme 1).
One of the key steps in this synthesis was the Lewis acid
promoted spirocyclization of ortho-quinone monoacetal
II, which was derived from appropriately substituted bi-
phenyl I. In our effort to develop the enantioselective vari-
ant of this approach, we were interested in possibility of
transmitting the axial chirality of the biphenyl intermedi-
ate to the spiro center chirality in the erythrinan product.
If viable, it would provide a new opportunity for the
enantioselective synthesis of erythrinan alkaloids,2i–k
since various methods are becoming more available for
the synthesis of axially chiral, non-racemic biphenyl
compounds.5 To test this possibility, we planned the
asymmetric synthesis of O-methylerysodienone (1)
starting from the non-racemic biphenyl IV possessing the
additional ortho substituent R, which is removable after
construction of the spiro center. Enantiospecific access to
1 would be possible if the substituent R could serve for
restricting the axial bond rotation of IV to make the
conformational isomers (enantiomers) isolable, and also
Scheme 1 Application of biphenyl with hindered rotation about the
axial bond.
for preventing racemization in the subsequent synthetic
process.
We hoped that trimethylsilyl group would be ideally suit-
ed for such purpose, and the trimethylsilylated biphenyl 9
was synthesized via bromobiphenyl 6 as shown in
Scheme 2.6
Starting from aryl bromide 2 and arylboronic acid 3,
biphenyl alcohol 4 was obtained in three steps including
Suzuki–Miyaura coupling,7 Wittig methylenation, and
hydroboration followed by oxidative workup in a similar
manner as previously reported.4 Alcohol 4 was further
converted to compound 5 via acetylation followed by acid
hydrolysis of the MOM group.8 Selective bromination at
the ortho position of the phenol in 5 was effected by pyri-
dine·HBr3 in pyridine in high yield. Other bromination
agents, such as NBS and N-bromoacetamide, were less ef-
fective due to the competing formation of the correspond-
ing ortho-quinone. The bromide, thus obtained, was
deacetylated with K2CO3 in MeOH to give diol 6.
SYNLETT 2004, No. 4, pp 0619–0622
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817754; Art ID: U29803ST.pdf
© Georg Thieme Verlag Stuttgart · New York

620
Y. Yasui et al.
LETTER
OMe
OMe
OMe
MeO
MeO
HO
MeO
4) Ac2O, DMAP
5) TFA
1) Pd(PPh3)4
Ba(OH)2
6) pyr·HBr3, pyr
7) K2CO3, MeOH
CHO
OAc
OH
2
Br
OSi(i-Pr)3
OSi(i-Pr)3
B(OH)2
2) Ph3P=CH2
3) (sia)2BH;
H2O2,
90% (2 steps)
72% (2 steps)
OSi(i-Pr)3
MOMO
OBn
OBn
NaOH aq.
95% (3 steps)
MOMO
MeO
5
4
OBn
OMe
3
OMe
OMe
MeO
MeO
11) MsCl, pyr
8) (Me3Si)2NH
(92%)
N3
OH
OH
OSi(i-Pr)3
Me3Si
MeO
OSi(i-Pr)3
Br
OSi(i-Pr)3
Me3Si
HO
4
4
9) BuLi
10) 0.1 M HCl aq.
12) NaN3
13) NaH, MeI
(89%, 2 steps)
HO
82% (3 steps)
OMe
OBn
OBn
OBn
8
6
7
MeO
14) PMe3
NHBoc
Me3Si
MeO
OSi(i-Pr)3
15) (Boc)2O, Et3N
(84%, 2 steps)
16) H2, 5% Pd/C
(98%)
OH
9
Scheme 29 Conditions: (1) DME, H2O, 50 °C, 1 h; (2) THF, 25 °C, 1 h; (3) THF, 25 °C, 1 h; then 25 °C, 2 h; (4) pyridine, 25 °C, 15 min; (5)
CH2Cl2, 25 °C, 1.5 h; (6) 0 °C, 10 min; (7) THF, 50 °C, 2.5 h; (8) THF, reflux, 3 h; (9) THF, –78 °C, 15 min; (10) THF, 0 °C, 10 min; (11)
25 °C, 30 min; (12) DMF, 60 °C, 5 h; (13) DMF, 0 °C, 10 min; (14) MeCN, H2O, 25 °C, 5 h; (15) THF, 25 °C, 1 h; (16) EtOAc, MeOH, 25 °C,
1 h.
The axial bond rotation being hindered by three ortho lateral trimethylsilyl group rapidly proceeded at this tem-
substituents, diol 6 could be easily resolved by HPLC with perature to give the C(4)-trimethylsilylated biphenyl.3
chiral stationary phase [CHIRALPAK AD-H, hexane: Acid hydrolysis of the remaining trimethylsilyl ether gave
i-PrOH = 85:15] into the enantiomers, which proved to be biphenyl 7. This compound 7 was further converted to
stable to racemization at room temperature.9 The bromide phenol 9, the precursor of ortho-quinone acetal, in six
in each isomer of 6 was substituted by a trimethylsilyl as steps including selective mesylation of the alkanol, substi-
in the following. Both of the two hydroxy groups in 6 tution by NaN3, methylation of the phenol to give azide 8,
were trimethylsilylated and the resulting bis(trimethyl- reduction of the azide, protection with a Boc group fol-
silyl) ether was treated with BuLi in THF at –78 °C. lowed by cleavage of the benzyl group.
Sequential halogen–metal exchange and migration of the
Phenol 9, thus obtained, was subjected to oxidation with
(AcO)2IPh in MeOH [25 °C, 15 min] to give ortho-quin-
one acetal 10 in high yield.10 Notably, each enantiomer of
OMe
OMe
10 proved to be enantiomerically pure and stable to race-
mization at room temperature, showing the full stereo-
chemical integrity during all these transformations.11,12
MeO
MeO
(AcO)2IPh
MeOH
NHBoc
NHBoc
13
5
Me3Si
MeO
OSi(i-Pr)3
Me3Si
MeO
OSi(i-Pr)3
99%
BF3·OEt2 was an efficient catalyst for the spirocyclization
of 10.4 With the catalyst load in 0.2 equivalents, the reac-
tion completed in 30 minutes at –20 °C to give spiroiso-
quinoline 11 in 90% yield. To our delight, both isomers of
11 proved to be enantiomerically pure,11 clearly showing
that the reaction process was completely free from racem-
ization.12 Upon treatment of 11 with Bu4NF (THF, 25 °C,
1.5 h), cleavage of trimethylsilyl and triisopropylsilyl
groups proceeded at once to give 12.
MeO
OH
O
9
10
MeO
MeO
MeO
MeO
BF3·OEt2
MS4A
ref 4
N-Boc
N
OR
X
90%
MeO
MeO
O
O
Finally, O-methylerysodienone (1)13,14 was obtained from
alcohol 12 in enantiomerically pure form in a same man-
ner as previously reported for the racemate.4 Thus, it was
demonstrated that the axial chirality of biphenyl 6 could
11: R = (i-Pr)3Si, X = Me3Si
12: R = H, X = H
1
Bu4NF (73%)
Scheme 39 Formation of ortho-quinone acetal 10 and its spirocycli-
zation.
Synlett 2004, No. 4, 619–622 © Thieme Stuttgart · New York

LETTER
Transmission of Axial Chirality to Spiro Center Chirality
2865, 1605, 1515, 1490, 1465, 1255, 1215, 1165, 1110,
621
be stereospecifically transmitted to the spiro center chiral-
1045, 755 cm–1. Anal. Calcd for C34H47BrO6Si: C, 61.90; H,
7.18. Found: C, 61.98; H, 7.45. HPLC (Daicel CHIRAL-
PAK AD-H, f0.46 × 250 mm × 2, hexane:i-PrOH = 85:15,
1.0 mL/min) retention time: 10.9 min for (+)-6, 12.8 min for
(–)-6. Compound 9: Colorless needles (hexane), mp 194.0–
194.5 °C; [a]D24 +16 (c 1.1, CHCl3)*. 1H NMR (CDCl3): d =
6.95 (s, 1 H), 6.78 (s, 1 H), 6.55 (s, 1 H), 5.48 (s, 1 H), 4.45
(s, 1 H), 3.92 (s, 3 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.60 (t, 2
H, J = 6.8 Hz), 3.30–3.18 (m, 2 H), 2.50–2.39 (m, 3 H), 2.34
(ddd, 1 H, J1 = J2 = 6.8 Hz, J3 = 13.2 Hz), 1.42 (s, 9 H), 0.95
(s, 21 H), –0.1 (s, 9 H). 13C NMR (CDCl3): d = 155.8, 151.1,
148.2, 147.1, 146.6, 138.5, 134.1, 133.5, 132.0, 129.5,
119.1, 114.3, 111.4, 79.2, 64.1, 61.3, 55.9, 55.7, 40.1, 36.9,
33.1, 28.4, 17.9, 11.9, 1.7. IR (KBr): 3325, 2940, 2865,
1685, 1515, 1465, 1245, 1170, 1110, 880 cm–1. Anal. Calcd
for C36H61NO7Si2: C, 63.96; H, 9.09; N, 2.07. Found: C,
64.26; H, 9.38; N, 2.06. HPLC (Daicel CHIRALCEL OD-H,
f0.46 × 250 mm × 2, hexane:i-PrOH = 98:2, 1.0 mL/min)
retention time: 20.5 min for (+)-9, 25.6 min for (–)-9.
Compound 10: [a]D24 –24 (c 0.99, CHCl3)*. 1H NMR
(CDCl3): d = 6.81 (s, 1 H), 6.61 (s, 1 H), 6.10 (s, 1 H), 4.59
(br, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.72–3.61 (m, 2 H),
3.42–3.33 (m, 2 H), 3.35 (s, 3 H), 3.24 (s, 3 H), 2.61 (t, 2 H,
J = 7.7 Hz), 2.16 (ddd, 1 H, J1 = J2 = 7.2 Hz, J3 = 14.5 Hz),
2.03 (ddd, 1 H, J1 = J2 = 5.6 Hz, J3 = 14.5 Hz), 1.43 (s, 9 H),
0.99 (s, 21 H), –0.11 (s, 9 H). 13C NMR (CDCl3): d = 196.7,
155.7, 153.9, 153.2, 148.8, 148.3, 146.8, 130.1, 129.3,
125.2, 113.3, 111.3, 94.5, 79.3, 61.3, 55.9, 55.8, 50.3, 50.2,
39.8, 37.4, 33.2, 28.3, 17.9, 11.8, 1.6. IR (NaCl): 3385,
2945, 2865, 1715, 1665, 1510, 1465, 1250, 1165, 1090, 1070
cm–1. Anal. Calcd for C37H63NO8Si2: C, 62.94; H, 8.99; N,
1.98. Found: C, 62.65; H, 9.18; N, 1.94. HPLC (Daicel
CHIRALCEL OD-H, f0.46 × 250 mm, hexane:i-PrOH =
98:2, 1.0 mL/min) retention time: 7.4 min for (–)-10, 12.6
min for (+)-10. Compound 11: [a]D27 +52.0 (c 1.73,
CHCl3)*. 1H NMR (CDCl3): d = 6.56 (s, 1 H), 6.49 (s, 1 H),
6.05 (s, 1 H), 4.15 (ddd, 1 H, J1 = J2 = 5.1 Hz, J3 = 13.2 Hz),
3.85 (s, 6 H), 3.76 (ddd, 1 H, J1 = 5.1 Hz, J2 = 8.9 Hz,
J3 = 13.2 Hz), 3.66 (s, 3 H), 3.63 (ddd, 1 H, J1 = 6.2 Hz,
J2 = 8.1 Hz, J3 = 9.7 Hz), 3.49 (ddd, 1 H, J1 = 6.2 Hz,
J2 = 8.1 Hz, J3 = 9.7 Hz), 3.03 (ddd, 1 H, J1 = 5.1 Hz,
J2 = 8.9 Hz, J3 = 16.1 Hz), 2.93 (ddd, 1 H, J1 = J2 = 5.1 Hz,
J3 = 16.1 Hz), 2.31 (ddd, 1 H, J1 = J2 = 6.2 Hz, J3 = 12.3
Hz), 2.11 (ddd, 1 H, J1 = J2 = 8.1 Hz, J3 = 12.3 Hz), 1.37 (s,
9 H), 0.94 (s, 21 H), 0.0 (s, 9 H). 13C NMR (CDCl3): d =
181.6, 167.4, 157.1, 154.9, 148.7, 148.5, 147.7, 126.3,
124.3, 123.5, 111.0, 109.8, 81.1, 66.3, 61.3, 59.8, 55.8, 55.7,
40.1, 34.7, 28.3, 27.9, 17.9, 11.7, 1.4. IR (NaCl): 2940, 2865,
1695, 1660, 1515, 1365, 1260, 1225, 1165, 1090, 860 cm–1.
Anal. Calcd for C36H59NO7Si2: C, 64.15; H, 8.82; N, 2.08.
Found: C, 64.01; H, 9.02; N, 1.93. HPLC (Daicel CHIRAL-
CEL OD-H, f0.46 × 250 mm, hexane:i-PrOH = 99:1, 0.5
mL/min) retention time: 14.3 min for (+)-11, 17.1 min for
(–)-11. Compound 1: Pale yellow needles (CHCl3), mp
90.5–91.0 °C; [a]D24 +46 (c 0.86, CHCl3)*. HPLC (Daicel
CHIRALPAK AD-H, f0.46 × 250 mm, hexane:i-PrOH =
80:20, 1.0 mL/min) retention time: 31.6 min for (+)-1, 25.3
min for (–)-1.
ity in the erythrinan product 1.
In summary, synthesis of O-methylerysodienone in enan-
tiomerically pure form was described. Considering the in-
creasing availability of axially chiral, non-racemic
biphenyl compounds, the present conception, i.e. the
transmission of axial chirality to spiro center chirality,
will render a totally efficient and enantioselecive access to
erythrinan alkaloids. The research in this direction is
currently in progress and will be reported in due course.
References
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(3) Throughout this work, the commonly accepted erythrinan
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1.
(4) Yasui, Y.; Koga, Y.; Suzuki, K.; Matsumoto, T. Synlett
2004, DOI: 10.1055/s-2004-817753.
(5) For reviews, see: (a) Bringmann, G.; Breuning, M.; Tasler,
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(6) All new compounds were fully characterized by 1H and 13
NMR, IR and combustion analysis. Data for the selected
C
compounds follow. [*The specific rotation is shown for (+)-
6 and for each isomer derived from (+)-6. See ref. 9 and ref.
14] Compound 6: [a]D28 +20.5 (c 1.12, CHCl3)*. 1H NMR
(CDCl3): d = 7.46–7.36 (m, 5 H), 6.97 (s, 1 H), 6.86 (s, 1 H),
6.54 (s, 1 H), 6.01 (s, 1 H), 5.15 (s, 2 H), 3.93 (s, 3 H), 3.82
(s, 3 H), 3.73–3.55 (m, 4 H), 2.60–2.45 (m, 4 H), 1.35 (br, 1
H), 0.97 (s, 21 H). 13C NMR (CDCl3): d = 148.4, 147.3,
145.2, 141.8, 135.9, 134.2, 131.8, 130.0, 128.8, 128.5,
128.4, 127.9, 113.5, 113.2, 112.4, 111.5, 71.4, 63.8, 62.6,
55.8, 55.7, 37.6, 36.2, 17.9, 11.8. IR (NaCl): 3515, 2940,
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(8) Attempts to remove the MOM group from alcohol 4 led to
concomitant desilylation.
(9) We converted both isomers of 6 to O-methyleryso-
dienone(1). The absolute configuration of each intermediate
Synlett 2004, No. 4, 619–622 © Thieme Stuttgart · New York

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Y. Yasui et al.
LETTER
was not determined. In Scheme 2 and Scheme 3, one of the
enantiomers was tentatively drawn for convenience.
(10) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org.
Chem. 1987, 52, 3927. (b) Lewis, N.; Wallbank, P.
(12) We were afraid of racemization in the oxidation of 9 and in
the cyclization of 10. If the reaction process involved
dienone i as a transient intermediate, generated by the
intermolecular attack of a nucleophile at the C(5), the change
in the C(5) hybridization into sp3 might have caused
racemization due to the lowered rotational barrier about the
C(5)-C(13) bond (Figure 2).
Synthesis 1987, 1103. (c) For reviews on phenolic oxidation
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Org. React. 2001, 57, 327. (e) For a review on synthetic
uses of ortho-quinone monoacetals, see: Quideau, S.;
Pouységu, L. Org. Prep. Proced. Int. 1999, 31, 617.
MeO
NHBoc
Nu
(11) The enantiomeric purity was determined by HPLC analysis.
For the analytical conditions and retention times, see ref. 6.
13
MeO
(i-Pr)3SiO
SiMe3
5
OMe
O
i
Figure 2
(13) (a) Ghosal, S.; Majumdar, S. K.; Chakraborti, A. Aust.
J. Chem. 1971, 24, 2733. (b) Chou, C.-T.; Swenton, J. S.
J. Am. Chem. Soc. 1987, 109, 6898.
(14) The specific rotation of O-methylerysodienone has not been
reported.
Synlett 2004, No. 4, 619–622 © Thieme Stuttgart · New York