A novel method for the stereoselective formation of trans bicyclic ketones by way of oxidative radical cyclization

Article abstract of DOI:10.1055/s-1999-2686

The stereoselective formation of cyanohydrin 4 was achieved by radical cyclization-oxygen trapping reaction of 5 into an intramolecular acrylic nitrile moiety. The cyanohydrin was used for ring closure reaction with a tosylate, providing the bicyclic systems 1 and 2 with a trans ring fusion.

Full text of DOI:10.1055/s-1999-2686

6
44
LETTER
A Novel Method for the Stereoselective Formation of Trans Bicyclic Ketones
by Way of Oxidative Radical Cyclization
Takashi Takahashi,* Satoshi Tomida, Takayuki Doi
Department of Chemical Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
Fax +81-3-5734-2884; E-mail: ttakashi@o.cc.titech.ac.jp
Received 2 March 1999
ports,7,8 by bubbling air into the reaction mixture instead
Abstract: The stereoselective formation of cyanohydrin 4 was
using oxygen itself. If successful, the method could be
achieved by radical cyclization-oxygen trapping reaction of 5 into
used in the synthesis of the CD fragment of vitamin D
an intramolecular acrylic nitrile moiety. The cyanohydrin was used
9
for ring closure reaction with a tosylate, providing the bicyclic sys- precursors (system 1a), and of the AB ring of castaster-
tems 1 and 2 with a trans ring fusion.
one (system 2b).10
Key words: bicyclo[4.3.0]nonan-1-one, bicyclo[4.4.0]decan-1-
one, oxidative radical cyclization, cyanohydrin, intramolecular
alkylation
We initially examined the synthesis of trans indanone 1a
via radical cyclization-oxygen trapping. MM2 models of
11
transition structures suggested that the radical cycliza-
tion of 5a could lead to the desired trans stereochemistry
between the angular positions in 1a. The precursor 11 was
prepared from geraniol (6) as shown in Scheme 1. Chlo-
ride formation from 6, followed by the substitution of the
resulting chloride by cyanide afforded 7 in 80% yield.
Treatment of 7 with t-butyllithium generated the lithium
enolate of 7, whose addition to crotonaldehyde provided
an 86:14 diastereomeric mixture of 1,2-adducts 8 in quan-
titative yield. Thermal oxy-Cope rearrangement of 8 pro-
ceeded at 200 °C in N-methylpyrrolidone (NMP)12 and
was followed by reduction of the resulting aldehyde to
provide a 93:7 diastereomeric mixture of 9 in 50% yield,
accompanied by 25% recovery of 8. Iodide formation
from 9, followed by oxidative-cleavage of the trisubstitut-
ed alkene, afforded aldehyde 10 in 79% overall yield. Re-
duction of aldehyde carbonyl of 10, followed by
tosylation, furnished 11 in 61% yield.
We wish to report an approach to the stereoselective syn-
thesis of bicyclo[4.3.0]nonan-1-one system 1 and bicyc-
lo[4.4.0]decan-1-one system 2, which leads to the trans
relationship of the angular methyl and hydrogen.
R1
R2
R1
R2
R1
R2
*
*
n
n
n
*
•
TsO
TsO
O2
H
H
O
CN
PO CN
1
2
(n = 1)
(n = 2)
5
3
4
: P = O•
: P = H
a : R1 = H; R2 = Me; n = 1
b : R1 = Me; R2 = H; n = 2
Figure 1
Stereocontrolled formation of a carbon-carbon bond next
to a carbonyl group has been a significant problem in or-
ganic synthesis, particularly to the a,b-substituted cyclic
ketones. As solutions to this problem, there have been re-
ported excellent methods, such as conjugate addition-
c
d, e
quant.
50%
OH
X
recovered 8
CN
25%
a, b
0%
6 : X = OH
7: X = CN
8
8
1
2
alkylation, bromoacetal tethered radical cyclization, an-
3
ionic allylic epoxide cyclization, and acid-catalyzed cy-
i, j
1%
4
clization of 5-alkenal acetal. We hoped that a
6
X
Y
TsO
I
stereoselective intramolecular addition of radical 5 to an
5
CN
CN
acrylic nitrile moiety (an electron-deficient olefin ) would
11
9
: X =Me2C, Y = OH
0: X = O, Y = I
be followed by trapping of the radical at the a-position of
the nitrile by oxygen. A peroxide intermediate 3 could be
reduced by an excess of radical inducing reagent, e.g.
f, g, h
1
Scheme 1. (a) MsCl, NEt3, THF, -78 °C then LiCl, 0 °C; (b) NaCN,
DMSO, 45 °C; (c) t-BuLi, THF, -78 °C then crotone aldehyde; (d)
NMP, 200 °C, 1h; (e) NaBH , EtOH; (f) I , PPh , imidazole, benzene
85%); (g) mCPBA, Na2HPO4, CH2Cl2; (h) 7% HClO4, THF / H2O, 0
C then NaIO4 (79% for 2 steps); (i) NaBH4, EtOH, 0 °C; (j) TsCl, Py,
CHCl3
Bu SnH to generate cyanohydrin 4, with the stereochem-
3
4
2
3
(
°
istry shown in Figure 1. Protected cyanohydrins such as 4
would be good precursors of 1 and 2 by intramolecular
alkylation, followed by simple deprotection under mild
conditions, without epimerizing the a-position to the car-
6
bonyl group. This process would require that the initial
radical 5 should cyclize faster than it gets trapped by oxy-
gen. This should be feasible, according to previous re-
Synlett 1999, No. 5, 644–646 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Method for the Stereoselective Formation of Trans Bicyclic Ketones
645
Radical cyclization-oxygen trapping reaction of 11 was
carried out after separation of the diastereomers by col-
umn chromatography. Treatment of 11 with tributyltin hy-
dride (3 equiv.) in the presence of AIBN (1 equiv.) in
a, b, c
67%
d, e, f
58%
9
O
OTs
OTs
7,8
refluxing benzene, while bubbling in air (O / N = 1 / 4)
CN
Z
CN
13: Z = OH
4: Z = I
2
2
12
g
afforded cyanohydrins 4a in 82% yield (Figure 1). It is no-
ticeable that the reaction appeared to give only products of
radical cyclization-oxygen trapping, and neither uncyc-
lized product nor reductive cyclization product was ob-
1
72%
Scheme 2. (a) TsCl, Py, CHCl3; (b) mCPBA, Na2HPO4, CH2Cl2; (c)
% HClO4, THF/H2O, 0 °C then NaIO4; (d) [MeOCH2PPh3]Cl, KHMDS,
THF, -78 to 0 °C; (e) 1M HCl, THF; (f) NaBH4, EtOH, 0 °C; (g) I2, PPh3,
imidazole, benzene.
7
7
served. The stereoselection in the cyclization was 80:20
in favor of the trans bicyclic product, as determined after
conversion to 1a. After protection of cyanohydrin 4a as its
ethoxyethyl ether, intramolecular alkylation was per- In conclusion, we have demonstrated that the bicyclic sys-
formed by addition to a benzene solution of NaN(TMS)2 tems 1a and 2b with an angular methyl group and a carbo-
6
at 80 °C (80%). Acid treatment (CSA/MeOH), followed nyl adjacent to a trans bicyclic junction can be
by aqueous base (2% NaOHaq/Et O) afforded ketone 1a synthesized by a novel radical cyclization process which
2
1
3,14
and its cis isomer in 94% combined yield.
should be useful for the synthesis of a number of naturally
occurring bicyclic systems.
Next, we examined whether the method could be applied
to the construction of the decalin skeleton of castasterone
AB-ring system 2b (Figure 1). The 6-exo-trig closure is
known to be a slower radical cyclization than a 5-exo-trig
closure. Then, if the 6-exo-trig cyclization of 5b is slower
than the oxygen trapping reaction, the desired cyclization
will not be observed. However, if the cyclization occurs,
Acknowledgement
This work was supported by a Grant-in-Aid for JSPS Fellows (S.T.,
No. 5167) from the Ministry of Education, Science, Sports and Cul-
ture, Japan.
1
1
the MM2 transition structure model suggested that radi-
cal cyclization of 5b should give the desired trans stereo-
chemistry at the angular positions. The radical cyclization
precursor 14 was prepared from 9 as shown in Scheme 2.
After tosylation of 9, selective epoxidation of the trisub-
stituted alkene and two step cleavage of the resulting ep-
oxide afforded aldehyde 12 in 67% overall yield. Wittig
References and Notes
(
1) Stork, G. Pure & Appl. Chem. 1968, 17, 383-401.
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1
1
1
992, 64, 1809-1812; Stork, G. Bull. Soc. Chim. Fr. 1990,
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54.
reaction of the aldehyde 12 by MeOCH = PPh , followed
3
(
(
3) Stork, G.; Kobayashi, Y.; Suzuki, T.; Zhao, K. J. Am. Chem.
Soc. 1990, 112, 1661-1663.
4) Johnson, W. S.; Elliott, J. D.; Hanson, G. J. J. Am. Chem. Soc.
1984, 106, 1138-1139.
by hydrolysis provided the aldehyde, which was reduced
to alcohol 13 in 58% overall yield. Iodide formation from
alcohol 13 gave the 14 in 72% yield. Radical cyclization-
oxygen trapping reaction of 14 was examined in the same
manner as described above, to provide the cyanohydrins
(5) Giese, B. Angew. Chem. Int. Ed. Engl. 1985, 24, 553-565;
Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford,
4
b in 54% yield (Figure 1). In this reaction, the alcohol 13
1
991; Vol. 4, p 779.
6) Stork, G.; Depezay, J. C.; d'Angelo, J. Tetrahedron Lett. 1975,
89-392; Takahashi, T.; Nagashima, T.; Tsuji, J. Tetrahedron
formed by the oxidation of the primary radical 5b without
cyclization, was also obtained in 14% yield. This result
suggested that the 6-exo-trig closure is somewhat faster
than the oxygen trapping reaction of the primary radical
(
3
Lett. 1981, 22, 1359-1362; Takahashi, T.; Nemoto, H.; Tsuji,
J. Tetrahedron Lett. 1983, 24, 2005-2008.
(7) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii D. J. Am. Chem.
Soc. 1991, 113, 8980-8982.
5
b under aerobic reaction conditions. The recovered 13
can be racquired by repeating the iodide formation and the
cyclization. The bicyclic system 2b was then constructed
by intramolecular alkylation. After protection of the cy-
anohydrin 4b (EVE/PPTS), the ring closure was carried
(
(
8) Mayer S.; Prandi, J. Tetrahedron Lett. 1996, 37, 3117-3120.
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(
10) Yokota, T.; Arima, M.; Takahashi, N. Tetrahedron Lett. 1982,
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2
out using NaN(TMS) in benzene at 80 °C (67% yield).
2
(11) Takahashi, T.; Katouda, W.; Sakamoto, Y.; Tomida, S.;
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Treatment with acid (CSA/MeOH) and then base (2%
NaOHaq./Et O) afforded decalin derivative 2b in 95%
2
yield. It is noteworthy that the stereoselectivity in this rad-
ical cyclization to a decalin system is more than 95%, and
(
12) Fujita, Y.; Onishi, T.; Nishida, T. J. Chem. Soc., Chem.
Commun. 1978, 972-973; Tomooka, K.; Nagasawa, A.; Wei,
S.-Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8899-8900.
13) The stereoselectivity (80:20) was determined by HPLC
analysis. The major isomer was determined as trans because
1
5
the trans bicyclic system 2b is the only product.
(
1
the chemical shifts of H NMR of an angular methyl group in
the major isomer was shielded (d 0.52) relative to the
analogous protons in the minor isomer (d 0.92). This
Synlett 1999, No. 5, 644–646 ISSN 0936-5214 © Thieme Stuttgart · New York

6
46
T. Takahashi et al.
LETTER
1
difference in the chemical shift has previously been observed
in a similar compound; Cicero, B. L.; Weisbuch, F.; Dana, G.
(15) The H NMR spectrum of 2 is identical with the reported one;
Piers, E.; Hall, T.-W. Can. J. Chem. 1980, 58, 2613-2623.
J. Org. Chem. 1981, 46, 914-919.
1
(
14) Spectrum data of 1a : H NMR (270 MHz, CDCl ): d = 2.42
3
(
dd, J = 10.9, 7.6 Hz, 1H), 2.26 (br d, J = 6.9 Hz, 1H), 2.19
ddd, J = 14.2, 6.9, 1.2 Hz, 1H), 2.09-1.23 (m, 9H), 0.88 (d,
J = 6.3 Hz, 3H), 0.52 (s, 3H); C NMR (67.8 MHz, CDCl ):
Article Identifier:
1437-2096,E;1999,0,05,0644,0646,ftx,en;Y02299ST.pdf
(
1
3
3
d = 212.1, 61.3, 49.6, 45.6, 40.9, 36.6, 29.3, 23.9, 19.6, 13.8,
-1
1
2.3; IR (neat):2952, 1710, 1452, 1380, 1226 cm .
Synlett 1999, No. 5, 644–646 ISSN 0936-5214 © Thieme Stuttgart · New York