Stereoselective synthesis of medium-sized carbocycles using alkoxy radical fragmentation as a key methodology

Article abstract of DOI:10.1055/s-2007-973895

Stereoselective and regioselective synthesis of functionalized seven- and eight-membered carbocyclic systems was achieved by the ring expansion-cleavage of readily prepared [3.2.1] and [3.3.1] bicyclic alcohols using alkoxy radical fragmentation at room t

Full text of DOI:10.1055/s-2007-973895

LETTER
1071
Stereoselective Synthesis of Medium-Sized Carbocycles Using Alkoxy Radical
Fragmentation as a Key Methodology
Stereoselective
a
S
ynthesis
o
r
f
Mediu
u
m-Size
d
Car
n
bocycles K. Pradhan, Alfred Hassner*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax +972(3)7384053; E-mail: hassna@mail.biu.ac.il
Received 29 January 2007
HO
Abstract: Stereoselective and regioselective synthesis of function-
alized seven- and eight-membered carbocyclic systems was
achieved by the ring expansion–cleavage of readily prepared [3.2.1]
and [3.3.1] bicyclic alcohols using alkoxy radical fragmentation at
room temperature. Transannular migration in the cyclooctane
system explain formation of unusual products.
X
O
O
( )n
( )n
( )n
CO2Et
CO2Et
EtO2C
2
ARF
OHC
Key words: carbocycles, bicyclic compounds, radical reaction,
stereoselectivity, ring expansion
.
( )n
EtO2C
The skeleton of many natural products consists of medi-
um-sized carbocycles1–5 and their facile and simple syn-
thesis remains a challenge for synthetic organic chemists.
Among more important recently employed methods for
construction of functionalized medium-sized ring are
aldol, free radical and metathesis reactions.6–10
Scheme 1
4-hydroxy-8-oxobicyclo[3.2.1]octane-1-carboxylic acid
ethyl ester13a (3a), which we were able to separate into
exo-and endo-isomers in a 2:1 ratio (90% yield).
In continuation of our investigations11,12 towards the syn-
thesis of medium-sized rings we are constantly in search
of simple methods of stereoselective synthesis of such
functionalized carbocyclic systems. One attractive route
involves ring enlargement by cleavage of [m.n.1] bicyclic
systems. In fact base-catalyzed fission of [3.2.1] and
[3.3.1] bicyclic ketones leading to medium-sized rings has
been reported by several groups.13 Alkoxy radical
fragmentation14 (ARF), which we have used successfully
for other ring enlargements, provides an attractive alterna-
tive method. To achieve successful ARF, the presence of
a radical stabilizing group a to the OH-bearing carbon is
desirable, since it would control the regioselective cleav-
age of the bridgehead C–C bond, during the photochemi-
cal ARF reaction. We opted for the presence of a
carbethoxy function as shown in Scheme 1, since a-carbe-
thoxy cyclic ketones 2 are readily available simple com-
pounds, which also provide an opportunity to compare
base-induced cleavage13 to photochemical ARF. A ret-
rosynthetic analysis (see Scheme 1) indicates the advan-
tage of a b-keto ester precursor 2 in facilitating the
introduction of an appropriate side chain by a Michael
addition, which can be followed by aldol ring closure to a
bicyclic system.
After protection of the hydroxyl function of 3a by acetic
anhydride in pyridine under reflux, the bridgehead ketone
of 4a15 was reduced to the bridgehead hydroxyl func-
tion by sodium borohydride in 95% ethanol. The exo-iso-
mer of compound 4a underwent stereoselective
reduction to the exo-syn-alcohol, 4-acetoxy-8-hydroxybi-
cyclo[3.2.1]octane-1-carboxylic acid ethyl ester (1a)16
due to steric hindrance by the exo-OAc function. On the
other hand the ketone function of the endo-acetoxy isomer
of 4a was reduced to a mixture of both syn- and anti-alco-
hols at the 8-position (Scheme 2).
O
O
acrolein, Et3N
toluene, r.t.
OR
O
OR
+
90–93%
CO2Et
EtO2C
EtO2C
2a
3a, exo, R = H
3a, endo, R = H
Ac2O, py
90–95%
4a, endo, R = Ac
4a, exo, R = Ac
NaBH4, EtOH
82%
NaBH4, EtOH
90%
HO
OH
OAc
OAc
This can indeed be achieved in one step by treating 2-carb-
ethoxycyclopentanone (2a) with acrolein in the presence
of triethylamine in toluene at room temperature to afford
EtO2C
1a, exo-syn
EtO2C
1a, endo-syn
endo-anti
SYNLETT 2007, No. 7, pp 1071–1074
Advanced online publication: 13.04.2007
2
4.
0
4.
2
0
0
7
Scheme 2
DOI: 10.1055/s-2007-973895; Art ID: G01107ST
© Georg Thieme Verlag Stuttgart · New York

1072
T. K. Pradhan, A. Hassner
LETTER
The same methodology was applied in the synthesis of
4-acetoxy-9-oxobicyclo[3.3.1] nonane-1-carboxylic acid
ethyl ester (1b) from 2-carbethoxycyclohexanone 2b
(Scheme 3). In this case after Michael addition to acrolein
in the polar solvent DMF, the reaction was stopped at the
intermediate stage of an aldehyde ketone17 which upon
aldol condensation (NaOEt) afforded the exo- and endo-
hydroxy ketones 3b13d as an inseparable mixture. Separa-
tion of exo- and endo-isomers became feasible after acety-
lation of the hydroxyl function of 3b to 4b. Similar to the
cyclopentanone case, sodium borohydride reduction of
the bridgehead ketone afforded stereoselectively the syn-
hydroxy product 1b from the exo-isomer of 4b and a
mixture of syn- and anti-isomeric 1b from the endo-iso-
mer of 4b (Scheme 3).
HO
OAc
OHC
OHC
DIB, I2,
CH2Cl2, hν
OAc
+
90–93%
EtO2C
I
CO2Et
I
CO2Et
6
5, β-OAc
7, α-OAc
1a, exo-syn
endo-syn
endo-anti
CH2Cl2, Et3N
92–95%
OHC
I
CO2Et
6
Scheme 4
O
OHC
O
acrolein, Et3N,
DMF, r.t.
i) NaOEt, EtOH,
0 °C
(Scheme 5). Most likely, after free-radical cleavage of the
bridgehead carbon in exo-syn-1b, the resulting COOEt-
stabilized radical, instead of trapping iodine, underwent a
transannular hydrogen transfer. However, because the
C-5 hydrogen geminal to the b-oriented aldehyde group is
not easily accessible, H-transfer occurs from C-6 to the
C-1 radical, ultimately affording compound 9. Trans
elimination of AcOH from 8 by means of Et3N led to
olefin 13.20
OR
O
ii) Ac2O, py
78%
CO2Et
CO2Et
EtO2C
overall 70%
2b
3b, R = H, exo:endo
4b, R = Ac, 2:1
exo
NaBH4,
EtOH, 90%
OH
NaBH4, EtOH
endo
OAc
85%
HO
EtO2C
1b, exo-syn
The formation of product 10 is interesting as it contains an
unexpected iodine substituent at the 3-position of the
cyclooctane ring. The dt (J = 12.5, 3.0 Hz) in 1H NMR of
H-3 places the iodine trans to the acetoxy function. For-
mation of 10 is best explained on conformational grounds.
In the exo-syn-isomer 1b, the chair–chair conformation
14a, which features a pseudoaxial acetoxy group, prefers
to equilibrate to a chair–boat conformer 14b in which the
OAc substituent becomes equatorial, thus making avail-
able an axial H at C-3 for abstraction by the initially
formed syn-alkoxy radical.19 Quenching of the newly
formed free radical at C-3 by iodine then leads to iodo
product 15. The latter, in the presence of DIB/I2, forms a
new alkoxy radical which undergoes fragmentation–ring
enlargement to 16a, followed by transannular H-abstrac-
tion from C-6 (see 16b) and ultimately formation of 10
(Scheme 6).
OAc
EtO2C
1b, endo-syn
endo-anti
Scheme 3
The photochemical ARF reaction of the exo-syn-isomer of
bicyclo[3.2.1]alcohol 1a, in the presence of diacetoxy io-
dobenzene (DIB) and iodine in dichloromethane under ir-
radiation with a 100 W tungsten filament lamp afforded
the seven-membered ring carbocycles 5 and 6.18 In a sim-
ilar reaction, the mixture of endo-syn- and endo-anti-iso-
mers of compound 1a afforded the endo-acetoxy
compound 7 as well as olefin 6.18 Elimination of acetic
acid from b- and a-acetoxy derivatives 5 and 7 occurred
on treatment with triethylamine, affording olefin 6
(Scheme 4). Ultimately, the above sequence of events
provided selectively a single seven-membered ring car-
bocyclic compound 6 possessing aldehyde, ester, iodine
and olefin functions, in a very good yield, a ring enlarge-
ment of the original cyclopentane by two carbons.
On the other hand the mixture of endo-syn- and endo-anti-
isomers of compound 1b provided a diastereomeric mix-
ture of eight-membered ring carbocycles 11 and 12, each
as two diastereomers, in very good yield. As in the case of
8, the diastereomeric mixture of acetates 11 was convert-
ed into olefin 13 by treatment with triethylamine
(Scheme 7). The formation of minor product 12 contain-
ing an additional iodine substituent at the 3-position is ap-
parently again (similar as in the formation of 10) due to an
equilibration to conformation 17 of the endo-syn-isomer
of 1b, in which the pseudoaxial C-3 hydrogen becomes
available for abstraction by the syn-alkoxy radical. In this
case, however, the free radical analogous to 16a is trapped
by iodine to afford 12.
The radical cleavage of the cyclohexanone-derived bicy-
cle 1b proceeded in a slightly different manner. In the
event, the exo-syn-isomer of the bicyclic [3.3.1] alcohol
derivative 1b afforded three eight-membered ring alde-
hydes 8, 9 and 10 in a total yield of 80%, among which the
ethyl syn-4-acetoxy-5-formyl-1-iodocyclooctanecarbox-
ylate (8) was the major product and 9 was devoid of iodine
Synlett 2007, No. 7, 1071–1074 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Medium-Sized Carbocycles
1073
OH
OHC
OAc
OHC
OAc
OHC
OAc
DIB, I2,
CH2Cl2, hν
OAc
I
+
+
EtO2C
CO2Et
8, 40%
Et3N, CH2Cl2, 90%
1b, exo-syn
CO2Et
10, 15%
CO2Et
I
9, 25%
OHC
CO2Et
I
13
Scheme 5
compound 9 is a singlet and its dC is 190 ppm indicating
bonding to the quaternary carbon of an a,b unsaturated
system.
O
O
OH
H
3
OAc
OAc
I
I2
OAc
In conclusion, a facile stereo- and regioselective synthesis
of functionalized seven- and eight-membered carbocycles
by ring expansion of bicyclic compounds synthesized
from simple ketones was developed. Trivalent iodine was
used as the radical generating agent. The free-radical frag-
mentation led to transannular migrations in the cyclo-
octanes with formation of unusual products.
EtO2C
EtO2C
EtO2C
14a
14b
15
DIB
OAc
OHC
OAc
OHC
I
I
10
Acknowledgment
H
16b
CO2Et
CO2Et
16a
Support of this research by the Marcus Center for Medicinal and
Pharmaceutical Chemistry at Bar-Ilan University is gratefully
acknowledged. We are grateful to Dr. H. E. Gottlieb for valuable
help with NMR spectra.
Scheme 6
All new compounds were identified by chemical shift and
coupling constant of 1H NMR, 13C NMR and COSY anal-
ysis as well as mass spectra. For example the chemical
shift of axial H-4 proton in endo-isomer of 3a appears at
d = 4.93 ppm with a coupling pattern of ddd, whereas in
the exo-isomer the chemical shift of equatorial H-4 is at
d = 5.15 ppm as a broad singlet. The aldehyde peak of
References and Notes
(1) (a) Molander, G. A. Acc. Chem. Res. 1998, 31, 603.
(b) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881.
(2) Fillion, E.; Beingessner, R. L. J. Org. Chem. 2003, 68, 9485.
(3) Nakamura, H.; Aoyagi, K.; Shim, J.-G.; Yamamoto, Y. J.
Am. Chem. Soc. 2001, 123, 372.
(4) Lopez, L.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc.
2002, 124, 4218.
(5) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124,
2102.
(6) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.;
Battistini, L.; Gaetani, E.; Curti, C.; Casiraghi, G. J. Org.
Chem. 2003, 68, 5881.
(7) Molander, G. A.; Brown, G. A.; De Gracia, I. S. J. Org.
Chem. 2002, 67, 3459.
HO
OHC
OAc
OHC
OAc
DIB, I2,
CH2Cl2, hν
I
OAc
+
EtO2C
CO2Et
CO2Et
12, 15%
11, 63%
Et3N, CH2Cl2, 93%
I
I
1b, endo-syn
endo-anti
(8) Marco-Contelles, J.; De Opazo, E. J. Org. Chem. 2002, 67,
3705.
O
H
(9) Posner, G. H.; Hatcher, M. A.; Maio, W. A. Org. Lett. 2005,
7, 4301.
OHC
(10) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions: Concepts, Guidelines and Synthetic
Applications; VCH: Weinheim, 1996.
(11) (a) Ramesh, N. G.; Hassner, A. Synlett 2004, 975.
(b) Ramesh, N. G.; Hassner, A. Eur. J. Org. Chem. 2005,
1892.
OAc
EtO2C
CO2Et
17
I
13
Scheme 7
Synlett 2007, No. 7, 1071–1074 © Thieme Stuttgart · New York

1074
T. K. Pradhan, A. Hassner
LETTER
(12) Hassner, A.; Pradhan, T. K. Tetrahedron Lett. 2006, 47,
5511.
(18) ARF Reaction of exo-syn-Isomer of 1a
A solution of exo-syn-isomer of compound 1a (0.512 g, 20
mmol), diacetoxy iodobenzene (1.28 g, 40 mmol) and iodine
(1.52 g, 60 mmol) in CH2Cl2 (60 mL) taking in a round-
bottomed flask was irradiated under one 100 W tungsten
filament lamp for 2 h at r.t. The mixture was washed with
NaHSO3 solution (3 × 30 mL), brine (2 × 30 mL) and dried
(Na2SO4). Solvent was removed under reduced pressure and
the residue was chromatographed to obtain the colorless oily
compound 5 as a mixture of diastereomers in an almost 1:1
ratio, and compound 6 [eluant: EtOAc–n-hexane (1:4)].
Compound 5 (diastereomeric mixture): 1H NMR (300 MHz,
CDCl3): d = 9.63 (d, J = 1.2 Hz, 1 H, CHO), 9.59 (d, J = 1.2
Hz, 1 H, CHO), 5.28–5.22 (m, 2 H, CHO), 4.28–4.19 (m, 4
H, CH2O), 2.80 (dd, J = 8.0, 15.0 Hz, 1 H), 2.66–2.56 (m, 3
H), 2.48–2.33 (m, 6 H), 2.04–1.97 (m, 5 H), 1.92–1.60 (m, 8
H), 1.47–1.32 (m, 1 H), 1.25–1.20 (m, 6 H). 13C NMR:
d = 200.7, 200.5 (CHO), 172.3 (O–C=O), 170.2 (O–C=O),
71.8, 71.2 (CHO), 62.3 (OCH2), 56.8, 56.3 (CHCHO), 44.7
(C–I), 42.1, 40.9, 37.1, 37.0, 30.4, 29.5, 23.0, 21.7, 21.2
(COCH3), 13.8. (CH3CH2). HRMS (CI, CH4): m/z (%) calcd
for C13H19IO5: 382.028; found: 383.033 (5) [MH]+, 355.013
(25) [MH – CO]+, 339.010 (40) [M – CH3CO]+.
(13) (a) Buchanan, G. L.; Mc Lay, G. W. Tetrahedron 1966, 25,
1521. (b) Buchanan, G. L.; Mc Killop, A.; Raphael, R. A. J.
Chem. Soc. 1965, 833. (c) Kraus, W.; Patzelt, H.; Sawitzki,
G. Tetrahedron Lett. 1978, 445. (d) Simon, C.; Peyronel, J.-
F.; Clerc, F.; Rodriguez, J. Eur. J. Org. Chem. 2002, 19,
3359.
(14) (a) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron
Lett. 1994, 35, 1003. (b) Gonzalez, C. C.; Leon, E. I.;
Riesco-Fagundo, C.; Suarez, E. Tetrahedron Lett. 2003, 44,
6347. (c) Gonzalez, C. C.; Kennedy, A. R.; Leon, E. I.;
Riesco-Fagundo, C.; Suarez, E. Angew. Chem. Int. Ed. 2001,
40, 2326.
(15) Synthesis of 4-Acetoxy-8-oxobicyclo[3.3.1]octane-1-
carboxylic Acid Ethyl Ester(4a) – Analytical Data
endo-Isomer: 1H NMR (300 MHz, CDCl3): d = 4.93 (ddd,
J = 9, 6, 3 Hz, 1 H, CHO), 4.13 (q, J = 7 Hz, 2 H, CH2O),
2.65–2.62 (m, 1 H), 2.59–2.45 (m, 1 H), 2.07–1.82 (m, 9 H),
1.78–1.59 (m, 1 H), 1.19 (t, J = 7 Hz, 3 H, CH2CH3). 13
C
NMR: d = 208.9 (C=O), 170.8 (O–C=O), 169.6 (O–C=O),
74.2 (C4HO), 61.2 (OCH2), 56.8 (C1), 50.6 (C5H), 30.8, 26.8,
23.6, 21.0 (COCH3), 17.0, 14.1 (CH3CH2). HRMS (CI,
CH4): m/z (%) calcd for C13H18O5: 254.115; found: 254.123
(27) [M]+, 255.119 (45) [MH]+.
Compound 6 (oil): 1H NMR (300 MHz, CDCl3): d = 9.33 (s,
1 H, CHO), 6.85 (m, 1 H, CH=C), 4.28 (q, J = 7 Hz, 2 H,
exo-Isomer: 1H NMR (300 MHz, CDCl3): d = 5.15 (br s, 1 H,
CHO), 4.19–4.15 (m, 2 H, CH2O), 2.61–2.42 (m, 3 H), 2.08–
1.92 (m, 7 H), 1.78–1.61 (m, 2 H), 1.19 (t, J = 7 Hz, 3 H,
CH2CH3). 13C NMR: d = 209.9 (C=O), 170.9 (O–C=O),
170.2 (O–C=O), 78.7 (C4HO), 61.3 (OCH2), 57.0 (C1), 48.6
(C5H), 33.8, 25.8, 23.3, 21.1 (COCH3), 19.2, 14.2
(CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H18O5:
254.115; found: 255.120 (33) [MH]+.
CH2O), 2.70–2.28 (m, 8 H), 1.30 (t, J = 7 Hz, 3 H, CH3). 13
NMR: d = 193.4 (CHO), 172.4 (O–C=O), 154.2 (CH=),
C
146.0 (C=), 62.2 (OCH2), 48.3 (C–I), 39.5, 39.3, 27.6, 21.9,
13.8. (CH3). HRMS (CI, CH4): m/z (%) calcd for C11H15IO3:
322.007; found: 320.999 (23) [M – H]+, 194.076 (27) [M –
HI]+, 193.068 (45) [M – H – HI]+.
Compound 7: 1H NMR (300 MHz, CDCl3): d = 9.55 (br s, 1
H, CHO), 9.52 (br s, 1 H, CHO), 5.59–5.51 (m, 2 H, CHO),
4.28–4.16 (m, 4 H, CH2O), 2.94 (dd, J = 7, 15 Hz, 1 H),
2.75–2.09 (m, 10 H), 2.01–1.78 (m, 11 H), 1.74–1.45 (m, 2
H), 1.27–1.22 (m, 6 H). 13C NMR: d = 200.1, 200.1 (CHO),
172.7, 172.3, 170.0, 169.9, 70.3, 70.2, 62.1, 62.1 (OCH2),
55.8, 55.5 (CHCHO), 46.0, 45.0 (C–I), 41.9, 40.9, 36.3,
36.3, 30.0, 29.0, 21.0, 20.9, 20.9, 19.3, 13.6, 13.6.
(16) Synthesis of 4-Acetoxy-8-hydroxybicyclo[3.2.1]octane-1-
carboxylic Acid Ethyl Ester(1a) by NaBH4/EtOH
Reduction of 4a – Analytical Data
exo-syn-Isomer of 1a: 1H NMR (300 MHz, CDCl3): d = 4.90
(br s, 1 H, CHO), 4.22 (d, J = 4.5 Hz, 1 H, HOCH), 4.12 (q,
J = 7.0 Hz, 2 H, CH2O), 2.98 (br s, 1 H, OH), 2.43–2.38 (m,
1 H), 2.22–2.11 (m, 1 H), 2.04–1.95 (m, 4 H), 1.90–1.58 (m,
5 H), 1.32–1.26 (m, 1 H), 1.20 (t, J = 7.0 Hz, 3 H, CH2CH3).
13C NMR: d = 176.7 (O–C=O), 170.5 (O–C=O), 75.8
(CHO), 70.1 (CHO), 60.7 (OCH2), 50.1 (C1), 42.3 (C5H),
29.1, 25.9, 23.6, 21.4 (COCH3), 19.2, 14.2 (CH3CH2).
HRMS (CI, CH4): m/z (%) calcd for C13H20O5: 256.131;
found: 257.142 (11) [MH]+, 197.117 (34) [MH – HOAc]+,
196.110 (43) [M – HOAc]+, 150.070 (51) [M – HOAc –
EtOH]+.
(CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H19IO5:
382.028; found: 382.029 (17) [M]+, 383.033 (23) [MH]+.
(19) In the seven-membered-ring analogue 1a the C-3 hydrogen
is less readily accessible for radical abstraction.
(20) Compound 13: 1H NMR (300 MHz, CDCl3): d = 9.39 (s, 1
H, CHO), 6.69 (dd, J = 2.1, 3.3 Hz, 1 H, CH=CH2), 4.20–
4.10 (m, 2 H, CH2O), 2.68 (dt, J = 16.0, 5.0 Hz, 1 H), 2.54–
2.46 (m, 1 H), 2.34–2.28 (m, 1 H), 2.18–2.07 (m, 1 H), 2.95–
1.85 (m, 1 H), 1.66 (dd, J = 10.0, 4.0 Hz, 1 H), 1.40–1.21 (m,
6 H), 0.82 (dd, J = 4.0, 6.6 Hz, 1 H). 13C NMR: d = 194.6
(CHO), 174.0 (O–C=O), 149.8 (CH=), 143.1 (C=), 60.9
(OCH2), 29.7 (C–I), 28.3, 25.4, 23.3, 22.7, 20.1, 14.2 (CH3).
HRMS (CI, CH4): m/z (%) calcd for C12H17IO3: 336.022;
found: 336.023 (24) [M]+, 337.025 (47) [MH]+.
(17) Aspinall, H. C.; Greeves, N.; Valla, C. Org. Lett. 2005, 7,
1919.
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