Highly stereoselective synthesis of carbocycles via a radical addition reaction using 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) [V-70L]

Full text of DOI:10.1021/jo990777e

6
928
J . Org. Chem. 1999, 64, 6928-6930
High ly Ster eoselective Syn th esis of
Ca r bocycles via a Ra d ica l Ad d ition
Rea ction Usin g 2,2′-Azobis(2,4-
d im eth yl-4-m eth oxyva ler on itr ile) [V-70L]
†
†
†
Masato Matsugi, Kentoku Gotanda, Chiyo Ohira,
F igu r e 1.
Ta ble 1. Dia ster eoselective Ra d ica l Cycliza tion of
†
‡
,†
Miki Suemura, Atsunori Sano, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences,
Osaka University, 1-6, Yamada-oka, Suita,
Br om id es 1
Osaka 565-0871, J apan, and Tokyo Research Laboratories,
Wako Pure Chemical Industries, Ltd., 1633, Matoba,
Kawagoe, Saitama 350-1101, J apan
Received May 12, 1999
Carbocycles have widespread utility in organic syn-
thesis since many bioactive compounds contain these
structures. In this area, synthetic strategies of producing
carbocycles from carbohydrate compounds have been
developed over the past decade because of the easy
accessibility to enantiomerically pure carbocycles and
readily available starting materials.1,2 In particular, the
intramolecular radical cyclization reaction is one of the
most powerful methods for the construction of various
c
b
entry bromide
R
initiator yield (%)a,b ratio (anti:syn)
mono- and polycyclic compounds.3
-10
Furthermore, this
1
2
3
4
5
6
7
8
9
0
(Z)-1a
(Z)-1a
(Z)-1a
(Z)-1a
H
H
H
H
V-70L
AIBN
hν
85
80
86
69
98:2
6:1
94:6
99:1
99:1 (5:1)
99:1 (10:1)
30:70 (2:1)
26:74 (2:1)
33:67 (1:1)
24:76 (1:1.2)
strategy makes it possible to obtain high regio- and
d
e
f
stereochemistries.11
We have already reported that 2,2′-azobis(2,4-di-
methyl-4-methoxyvaleronitrile) [V-70] can easily generate
Et3B
(Z)-1b COMe V-70L
85 (80)
94 (89)
80 (80)
73 (80)
85 (82)
70 (87)
(Z)-1c
(E)-1a
(E)-1a
COPh
V-70L
V-70L
Et3B
radical species under mild conditions such as room
temperature (25 °C) or below.1
2,13
H
H
We then applied this
f
knowledge to the generation of anomeric radicals, and
achieved the stereoselective and efficient synthesis of
R-linked C-glycopyranosides.14 Furthermore, we revealed
that racemic V-70L (Figure 1) was a more active initiator
at room temperature compared with meso V-70H13 and
(E)-1b COMe V-70L
(E)-1c COPh V-70L
1
a
Total yields of stereoisomers. b Yields and ratios in parenthe-
The ratios were determined
by H NMR of crude products. Reported value, and the reaction
4
c
ses are reported values using AIBN.
1
d
4
e
established a practical synthetic method for pyrrolo[2,3-
was carried out under reflux using benzene as a solvent.
The
reaction was carried out under reflux. f These reactions were
d]pyrimidine antifolate TNP-351 using V-70L.15 We
carried out at -78 °C.
report here the highly stereoselective synthesis of poly-
hydroxylated carbocycles from carbohydrate derivatives4
during radical addition reactions which occurred using
V-70L as the initiator instead of AIBN.
We applied stereocontrol to the intramolecular radical
cycloaddition reactions of (Z)-1a using various initiators
Table 1, entries 1-4). As a result, the reaction using
V-70L gave the desired corresponding cyclized products
2 in higher yield and similar or higher diastereoselec-
tivity than when using other initiators. In the case of
*
To whom correspondence should be addressed. Phone: +81 6-879-
8
225. Fax: +81 6-879-8229. E-mail: kita@phs.osaka-u.ac.jp.
†
4
Osaka University.
Wako Pure Chemical Industries, Ltd.
‡
(
(
(
1) Review: Ferrier, R. J .; Middleton, S. Chem. Rev. 1993, 93, 2779.
2) Review: Marco-Contelles, J .; Alhambra, C.; Mart ´ı nez-Grau, A.
Synlett 1998, 693.
(
(
(
(
(
3) Wilcox, C. S.; Gaudino, J . J . J . Am. Chem. Soc. 1986, 108, 3102.
4) Wilcox, C. S.; Thomasco, L. M. J . Org. Chem. 1985, 50, 546.
5) RajanBabu, T. V. J . Am. Chem. Soc. 1987, 109, 609.
6) RajanBabu, T. V. J . Org. Chem. 1988, 53, 4522.
using Et
slightly low, probably due to decomposition of the starting
material 1 by the acidic Et B (entries 4 and 8). Addition-
3
B as an initiator, the yields of the products were
7) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J . Am. Chem. Soc.
3
1
989, 111, 1759.
8) Rondot, B.; Durand, T.; Girard, J . P.; Rossi, J . C.; Schio, L.;
Khanapure, S. P.; Rokach, J . Tetrahedron Lett. 1993, 34, 8245.
9) Rokach, J .; Khanapure, S. P.; Hwang, S.-W.; Adiyaman, M.;
Schio, L.; FitzGerald, G. A. Synthesis 1998, 569.
10) Bennett, S. M.; Biboutou, R. K.; Zhou, Z.; Pion, R. Tetrahedron
998, 54, 4761.
11) Review; Giese, B.; Kopping, B.; G o¨ bel, T.; Dickhaut, J .; Thoma,
G.; Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301.
12) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. Tetrahedron Lett. 1997, 38, 3549.
13) Kita, Y.; Gotanda, K.; Murata, K.; Suemura, M.; Sano, A.;
Yamaguchi, T.; Oka, M.; Matsugi, M. Org. Process Res. Dev. 1998, 2,
50.
14) Kita, Y.; Gotanda, K.; Sano, A.; Oka, M.; Murata, K.; Suemura,
M.; Matsugi, M. Tetrahedron Lett. 1997, 38, 8345.
15) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. J . Org. Chem. 1999, 64, 675.
ally, other (Z)- and (E)-bromides were examined. It is
noteworthy that the stereochemistries of the cycloaddi-
tion products were almost completely controlled using
V-70L, regardless of the structure of the R group in the
substrate (Z)-isomers (entries 1, 5, and 6). By using
AIBN, similar complete stereocontrol was not possible
(
(
(
1
(
4
(
as shown in the parentheses. Furthermore, in the case
of the (E)-isomers, we found that V-70L could reverse the
stereoselectivity during the cycloaddition process. Thus,
using V-70L, (E)-isomers gave syn-2 as the major product,
while AIBN gave an equivalent amount of anti-2 and
syn-2 or a slightly predominant anti-2 (entries 7, 9, and
10).
(
2
(
(
1
0.1021/jo990777e CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/19/1999

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6929
F igu r e 2. Transition state structures of the reaction of (Z)- and (E)-1.
Sch em e 1
were recorded as a KBr pellet. E. Merck silica gel 60 (70-230
mesh ASTM) for column chromatography was used. V-70 is
commercially available from Wako Pure Chemical Industries,
Ltd., J apan. Bromides 1a -c and 3 were prepared by the general
4
procedure of Wilcox. Unless otherwise noted, all experiments
were carried out under an atmosphere of dry nitrogen using
anhydrous solvents which were distilled and dried according to
standard procedure.
Sep a r a tion of th e Dia ster eom er s of V-70. V-70 (5.00 g)
2
in Et O (25 mL) was stirred at 10 °C for 30 min to precipitate
1
only V-70H (2.46 g; content of 100% from H NMR). On the other
hand, the filtrate, upon cooling to -10 °C for 2 days, gave
1
crystallized V-70L (1.05 g; content of 100% from H NMR).
1
V-70L: mp 58 °C dec; H NMR (CDCl
3
) δ 1.29 (s, 6 H), 1.64 (s,
6
(
H), 2.26 (d, 2 H, J ) 11.0 Hz), 2.42 (d, 2 H, J ) 11.0 Hz), 3.21
1
3
s, 6 H). V-70H: mp 100 °C dec; H NMR (CDCl ) δ 1.20 (s, 6
H), 1.27 (s, 6 H), 1.69 (s, 6 H), 2.19 (d, 2 H, J ) 11.0 Hz), 2.59
(
d, 2 H, J ) 11.0 Hz), 3.19 (s, 6 H).
Typ ica l P r oced u r e for th e Ra d ica l Ad d ition Rea ction
of (Z)- a n d (E)-Br om id es Usin g V-70L. To a stirred solution
of bromide 1 (0.122 mmol) and V-70L (0.037 mmol) in dry CH Cl
SnH (0.367 mmol) in one portion at 25
C. A 1 mL sample of 15% aqueous KF was added, and the
2
2
We next examined the reaction of the (Z),(E)-bromides
(Z),(E)-3), in which the 1,2-diol was protected by cyclo-
(
°
1.2 mL) was added Bu
3
(
hexylidene using V-70L and obtained cyclized products
in good yields and with high diastereoselectivity under
mixture was vigorously stirred at room temperature for 2 h. The
organic layer was separated and extracted with CH Cl , dried
4
2
2
mild conditions (Scheme 1). In these cases, the reaction
of (Z)-3 gave the anti-4 and the (E)-isomer predominantly
gave syn-4 similar to the reaction of the bromides 1.
The stereoselectivity during these cyclization processes
can be considered by the transition states in the reactions
4
over MgSO , and concentrated in vacuo, and the residue was
chromatographed on silica gel (hexane-AcOEt) to give 2.
Eth yl 2-[(3aS,4S,6R,6aR)-6-Hydr oxy-2,2-dim eth yltetr ah y-
4
,16
d r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl]a ceta te (a n ti-2a )
a n d Eth yl 2-[(3a S,4R,6R,6a R)-6-Hyd r oxy-2,2-d im eth yltet-
r a h yd r o-3a H -cyclop en t a [d ][1,3]d ioxol-4-yl]a cet a t e (syn -
2a ).4 These products were isolated as a diastereo mixture. anti-
,16
(Figure 2). In the case of the (Z)-bromides, the reaction
1
proceeded through a favorable transition state A, since
B was disfavored because of the steric interaction be-
tween the ester carbonyl oxygen and isopropylidene
methyl, and afforded anti-products with extremely high
selectivity. On the other hand, in the case of the (E)-
bromides, it was considered that the reaction using V-70L
was more kinetically controlled since it enabled the
generation of radical species under mild conditions such
as room temperature compared with AIBN, which re-
quires elevated temperatures for the generation of the
radicals. Thus, the reaction proceeded through D and
gave predominantly syn-2 (Figure 2).
2a : H NMR (CDCl
1
1
3
) δ 1.26 (3H, t, J ) 7.2 Hz), 1.34 (3H, s),
.51 (3H, s), 1.71 (1H, dt, J ) 13.2, 4.8 Hz), 1.96 (1H, ddd, J )
3.2, 8.1, 7.2 Hz), 2.23 (1H, dd, J ) 15.3, 8.1 Hz), 2.30 (1H, dd,
J ) 15.3, 7.8 Hz), 2.45 (1H, d, J ) 7.8 Hz), 2.53 (1H, m), 4.03-
.18 (1H, m), 4.14 (2H, q, J ) 7.2 Hz), 4.40 (1H, dd, J ) 5.7, 1.7
4
13
Hz), 4.50 (1H, t, J ) 5.7 Hz); C NMR (CDCl
3
) δ 14.2, 24.5,
26.1, 36.8, 37.0, 38.1, 60.5, 71.5, 79.9, 83.8, 112.0, 172.5. syn-
1
2a : H NMR (CDCl
.47 (3H, s), 1.68-1.76 (1H, m), 1.90-2.08 (2H, m), 2.27 (1H, t,
J ) 7.5 Hz), 2.39 (1H, dd, J ) 16.5, 6.6 Hz), 2.59 (1H, dd, J )
6.5, 7.5 Hz), 3.88 (1H, ddd, J ) 16.2, 10.8, 6.0 Hz), 4.14 (2H, q,
J ) 7.2 Hz), 4.46 (1H, t, J ) 5.4 Hz), 4.59 (1H, t, J ) 4.8 Hz);
3
) δ 1.26 (3H, t, J ) 7.2 Hz), 1.33 (3H, s),
1
1
13
C NMR (CDCl
78.5, 80.2.
3
) δ 13.6, 24.5, 25.6, 33.2, 34.7, 35.7, 60.3, 71.7,
We clarified that the use of V-70L made it possible to
achieve the highly stereoselective radical addition reac-
tion, which could not be achieved by AIBN under mild
conditions. It is expected that the construction reaction
of the carbon-carbon bond using V-70L will be applicable
to various stereoselective reactions.
Eth yl 2-[(3a S,4S,6R,6a S)-6-(Acetyloxy)-2,2-d im eth yltet-
r a h yd r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl]a ceta te (a n ti-
4
19
-1
2
b): colorless oil; [R]
D
+58° (c 1.4, CHCl
) δ 1.26 (3H, t, J ) 6.7 Hz), 1.30 (3H, s), 1.48
3H, s), 1.76 (1H, ddd, J ) 12.8, 6.1, 3.0 Hz), 2.10 (3H, s), 2.19
1H, ddd, J ) 12.8, 9.8, 7.3 Hz), 2.25 (1H, dd, J ) 15.2, 7.9 Hz),
3
); IR 1738, 1732 cm ;
1
H NMR (CDCl
3
(
(
2.34 (1H, dd, J ) 15.2, 7.3 Hz), 2.55 (1H, m), 4.15 (2H, q, J )
6
(
.7 Hz), 4.38 (1H, d, J ) 6.1 Hz), 4.68 (1H, t, J ) 5.5 Hz), 4.92
1H, dd, J ) 9.8, 5.5 Hz); 13C NMR (CDCl
) δ 14.1, 20.8, 24.5,
3
Exp er im en ta l Section
2
6.1, 32.6, 36.9, 37.7, 60.6, 73.0, 78.1, 84.0, 111.7, 170.6, 171.6.
All melting points are uncorrected. 1H NMR spectra were
measured in CDCl
3
on 300 and 500 MHz spectrometers with
(16) J ones, M. F.; Roberts, S. M. J . Chem. Soc., Perkin Trans. 1 1988,
SiMe as the internal standard. Infrared (IR) absorption spectra
4
2927.

6
930 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Eth yl 2-[(3a S,4R,6R,6a S)-6-(Acetyloxy)-2,2-d im eth yltet-
J ) 16.5, 7.9 Hz), 4.16 (2H, dq, J ) 3.1, 7.3 Hz), 4.64 (1H, t, J
) 4.9 Hz), 4.80 (1H, t, J ) 5.5 Hz), 4.93 (1H, ddd, J ) 11.6, 6.1,
5.5 Hz), 7.43 (2H, m), 7.55 (1H, m), 8.07 (2H, dd, J ) 7.9, 1.2
r a h yd r o-3a H -cyclop en t a [d ][1,3]d ioxol-4-yl]a cet a t e (syn -
4
19
-1 1
2
b): colorless oil; [R]
NMR (CDCl ) δ 1.26 (3H, t, J ) 7.2 Hz), 1.30 (3H, s), 1.46 (3H,
s), 1.64 (1H, t, J ) 6.6 Hz), 1.69 (1H, dd, J ) 12.9, 10.8 Hz),
D
+35° (c 1.7, CHCl
3
); IR 1738 cm ; H
Hz); 13C NMR (CDCl ) δ 14.2, 24.4, 25.8, 31.9, 33.4, 34.5, 60.4,
3
3
7
3.9, 77.8, 80.1, 102.0, 128.3, 129.8, 132.9, 172.6.
1
2
4
(
7
.93-2.00 (1H, m), 2.10 (3H, s), 2.41 (1H, dd, J ) 16.5, 6.6 Hz),
.62 (1H, dd, J ) 16.5, 7.7 Hz), 4.14 (2H, dq, J ) 1.2, 7.2 Hz),
.58 (1H, dd, J ) 5.1, 4.6 Hz), 4.65-4.73 (2H, m); 13C NMR
Eth yl 2-[(3a S,4S,6R,6a R)-6-Hyd r oxy-2-1′-cycloh exa n etet-
r a h yd r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl]a ceta te (a n ti-
) a n d Eth yl 2-[(3a S,4R,6R,6a R)-6-Hyd r oxy-2-1′-cycloh ex-
a n etetr a h yd r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl]a ceta te
syn -4). These products were isolated as a diastereo mixture.
4
CDCl
3
) δ 14.2, 20.9, 24.2, 25.7, 31.5, 33.2, 34.4, 60.4, 73.4, 77.7,
9.7, 110.7, 170.7, 172.6.
3a S,4R,6S,6a S)-6-(2-Eth oxy-2-oxoeth yl)-2,2-d im eth yltet-
r a h yd r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl Ben zoa te (a n ti-
(
(
1
anti-4: H NMR (CDCl ) δ 1.26 (3H, t, J ) 7.0 Hz), 1.40 (2H, br
3
4
19
d, J ) 4.9 Hz), 1.53-1.72 (9H, m), 1.95 (1H, dt, J ) 13.1, 7.6
Hz), 2.22 (1H, dd, J ) 15.2, 7.9 Hz), 2.31 (1H, dd, J ) 15.2, 7.6
Hz), 2.48-2.57 (2H, m), 4.05 (1H, br m), 4.14 (2H, q, J ) 7.0
2
(
c): colorless crystal; mp 42-44 °C (hexanes-Et
2
O); [R]
); IR 1732, 1728 cm ; H NMR (CDCl ) δ 1.28 (3H,
t, J ) 7.8 Hz), 1.29 (3H, s), 1.40 (3H, s), 1.88 (1H, ddd, J ) 14.7,
D
+49°
-1 1
c 0.7, CHCl
3
3
1
3
6
7
5
.6, 4.2 Hz), 2.27-2.43 (3H, m), 2.67 (1H, m), 4.17 (2H, q, J )
.8 Hz), 4.45 (1H, dd, J ) 6.3, 1.2 Hz), 4.80 (1H, t, J ) 5.6 Hz),
.18 (1H, dt, J ) 8.6, 5.6 Hz), 7.44 (2H, t, J ) 8.1 Hz), 7.56 (1H,
Hz), 4.39 (1H, dd, J ) 5.8, 1.5 Hz), 4.50 (1H, t, J ) 5.8 Hz);
NMR (CDCl ) δ 14.1, 23.5, 23.9, 25.0, 33.7, 35.8, 36.6, 36.8, 38.1,
60.5, 71.0, 78.6, 83.7, 112.5, 171.8. syn-4: H NMR (CDCl
C
3
1
3
) δ
1
3
t, J ) 8.1 Hz), 8.08 (2H, d, J ) 8.1 Hz); C NMR (CDCl
3
) δ
4.2, 24.6, 26.1, 33.2, 36.9, 37.9, 60.6, 73.5, 78.4, 84.2, 112.1,
28.3, 129.8, 130.1, 132.9, 166.1, 171.7.
3aS,4R,6R,6aS)-6-(2-Eth oxy-2-oxoeth yl)-2,2-dim eth yltet-
r a h yd r o-3a H-cyclop en ta [d ][1,3]d ioxol-4-yl Ben zoa te (syn -
1.26 (3H, t, J ) 7.0 Hz), 1.35-1.43 (2H, m), 1.52-1.73 (9H, m),
1.96-2.08 (2H, m), 2.40 (1H, dd, J ) 16.5, 6.6 Hz), 2.47 (1H, br
d, J ) 9.9 Hz), 2.60 (1H, dd, J ) 16.5, 7.2 Hz), 3.87 (1H, ddd, J
1
1
(
) 16.2, 10.8, 5.7 Hz), 4.14 (2H, q, J ) 7.0 Hz), 4.44 (1H, t, J )
13
5
2
1
3
.5 Hz), 4.56 (1H, dd, J ) 5.2, 4.6 Hz); C NMR (CDCl ) δ 14.1,
4
19
-1 1
2
c): colorless oil; [R]
D
+26° (c 0.2, CHCl
3
); IR 1732 cm ; H
) δ 1.27 (3H, t, J ) 7.3 Hz), 1.30 (3H, s), 1.45 (3H,
s), 1.86 (1H, br q, J ) 11.6 Hz), 2.09 (1H, ddd, J ) 11.6, 6.1, 5.5
Hz), 2.19 (1H, m), 2.47 (1H, dd, J ) 16.5, 6.7 Hz), 2.67 (1H, dd,
3.5, 24.9, 33.1, 33.6, 34.6, 35.3, 35.6, 60.2, 71.9, 78.3, 79.5, 111.0,
72.8.
NMR (CDCl
3
J O990777E