Samarium diiodide-mediated intramolecular cyclodimerisation of bis-α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.03.031

Samarium(II) diiodide-mediated intramolecular cyclodimerisation of simple bis-enones and -enoates in THF/MeOH has been investigated. Spirocyclic and elaborated polycyclic products, including stereodefined cis-bicyclo[3.3.0]octane and trans-bicyclo[4.3.0]n

Full text of DOI:10.1016/j.tetlet.2009.03.031

Tetrahedron Letters 50 (2009) 3564–3567
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Samarium diiodide-mediated intramolecular cyclodimerisation
of bis-a,b-unsaturated carbonyl compounds
*
Jonathan R. Powell, Sally Dixon, Mark E. Light, Jeremy D. Kilburn
School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Samarium(II) diiodide-mediated intramolecular cyclodimerisation of simple bis-enones and -enoates in
THF/MeOH has been investigated. Spirocyclic and elaborated polycyclic products, including stereodefined
cis-bicyclo[3.3.0]octane and trans-bicyclo[4.3.0]nonanes, are obtained in synthetically useful yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 January 2009
Revised 19 February 2009
Accepted 6 March 2009
Available online 13 March 2009
Samarium(II) diiodide-mediated homodimerisation of
a
,b-
cyclisation of 8a–c upon treatment with SmI2 in THF/MeOH are
presented in Table 1.
unsaturated carbonyl compounds1 involves initial formation of a
delocalised ketyl radical, for example, 2, arising from single elec-
tron transfer to the enone, which may either couple with an iden-
tical radical, or undergo conjugate addition to another enone
molecule, directly or following further reduction to the corre-
sponding delocalised organosamarium anion. Cabrera1b,c and oth-
ers1e have reported that acyclic enones, upon treatment with
SmI2 in the presence of HMPA, undergo homodimerisation fol-
lowed by intramolecular aldol condensation to give b-hydroxyke-
tone products, whilst cyclic enones only participate in the first
homodimerisation step, without subsequent aldol reaction, yield-
ing simple 1,6-dicarbonyl products.
Pleasingly, intramolecular cyclisation of diketone 8a took place
in good overall yield (Table 1, entry 1). trans-Bicyclo[4.3.0]nonane
9 was isolated as the major product, and its stereochemistry was
confirmed by X-ray analysis, alongside two minor, diastereomeric
cis-bicyclo[3.3.0]octanes, 10 and 11, the stereochemistry of each
of which was also confirmed by X-ray analysis.11 Substrate 8b gave
rise to a ꢀ1:1 separable mixture of products, 12 and 13, again in a
good combined yield (Table 1, entry 2). Cyclodecane 12 arises from
tandem inter- then intramolecular enoate homodimerisation, and
13 arises from intramolecular conjugate addition followed by Dieck-
mann condensation. In the case of mixed keto-ester substrate 8c,
intermolecular enone homodimerisation predominates, followed
by intramolecular aldol reaction and 1,4-reduction of the enoate
moieties, giving diastereomeric cyclopentanes 14 (Table 1, entry 3).
Treatment of enones with SmI2 in the presence of added HMPA
and a proton source (stoichiometric tBuOH or MeOH) results in 1,4-
reduction of the enone.2 However, the complexity of the role of
additives in Sm(II)-mediated reactions is well known3,4 and a strik-
ing example is our report of SmI2-mediated reduction of an a-allyl-
oxy-substituted cyclopentenone, 1 (Scheme 1). Homodimerisation
was shown to be an efficient process in a mixed THF/MeOH solvent
system and subsequent intramolecular aldol condensation took
place. Stereodefined tetracycle 3 was obtained without 1,4-reduc-
tion of the enone.5
HO
O
SmI2 (4 equiv)
OH
O
O
O
THF/MeOH
(4:1)
To explore this reaction further, we have now examined the
intramolecular cyclodimerisation of various bis-enones and -eno-
ates,6 of general structure 4, in THF/MeOH solvent mixture. Trap-
ping of the first formed radical, 5, with a tethered enone or
enoate as Michael acceptor, could be followed by intramolecular
aldol or Dieckmann condensation, providing a novel cyclisation
pathway for one-pot access to [3.3.0]bicyclooctane skeletons 6
and 7, respectively (Scheme 2).
3
1
(67%)
O-
-O
O
O
O
O
O-
O
Cyclisation substrates, diketone 8a,6a diester 8b7 and keto-ester
8c8 were each prepared from glutaraldehyde (Fig. 1). The results of
O
O
2
* Corresponding author. Tel.: +44 23 80 593 596; fax: +44 23 80 596 805.
E-mail address: jdk1@soton.ac.uk (J.D. Kilburn).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.031

J. R. Powell et al. / Tetrahedron Letters 50 (2009) 3564–3567
3565
-
O
O
SmI2
O
O
SmI2
O-
R
R
R
R
R
R
R
8a/b
THF/MeOH
OR
-O
H
H
SmI2
R
SmI2
4
H
H
5
O
O
R = Me, OEt
I
R = Me, OEt
MeOH
O
R = Me
HO
R = Me
-
O
O
R
10, 11
6
R
Aldol,
O
R
R
SmI2
then SmI2 reduction
OR
H
H
O
H
R
O
H
O
OEt
I2Sm
13
O
O
R
R = OEt
Dieckmann
II R = Me, OEt
R = OEt
Scheme 3.
7
Scheme 2.
The formation of 10, 11 and 13 is readily rationalised. SmI2-
mediated reduction of 8a or 8b and 5-exo-trig cyclisation lead to
Sm(III)-chelated12 cis-intermediate I and partial protonation then
gives an enolate intermediate, II. Aldol condensation (R = Me) leads
to diastereomeric b-hydroxy ketones, further SmI2-mediated
reduction of which accounts for the observed diol products 10
and 11. Similarly, Dieckmann condensation of II (R = OEt) gives rise
to 13 (Scheme 3).
O
O
R
R1
8a R = R1= Me
8b R = R1 = OEt
8c R = Me, R1 = OEt
Diastereoselective formation of 9 as the major product from
diketone 8a can be explained by assuming that initial cyclisation
of 8a proceeds via a conformation in which one enone group
occupies a pseudo axial position. Reduction and conjugate addition
lead to a trans-intermediate III. Following protonation, aldol
condensation does not occur since a highly strained trans-bicy-
Figure 1.
Table 1
SmI2-mediated cyclisation of enone–enoate, bis-enone and bis-enoate substratesa
clo[3.3.0]octane would result; instead
a second protonation,
Entry
Substrate
Product(s) [yield%]b
reduction of the resulting bis-ketone to a (bis)-ketyl radical IV
and pinacol coupling, then leads to cis-diol 9 (Scheme 4).
H
OH
H
H
OH
We now sought to extend this method to the preparation of
polycyclic systems. b-Substituted cyclic enones 17a and 17b,13
respectively, functionalised with remote enone or enoate function-
ality, were readily prepared from 1,3-cyclohexandione via conver-
sion to aldehyde 1514–16 and Wittig olefination. Similarly a mixed
enone–enoate 18, tethered via an ether linkage, was also pre-
pared13 (Scheme 5). The results of cyclisation of 17a/b and 18,
upon treatment with SmI2 in THF/MeOH, are presented in Table 2.
Intramolecular coupling to the pendant enone was observed for
17a, followed by tandem pinacol coupling or aldol condensation, to
give tricyclic products 19 and 20a/b, respectively (Table 2, entry 1),
and we rationalise the formation of each according to the analo-
gous acyclic system 8a. Thus, reduction of one enone moiety and
intramolecular coupling to the other enone lead to diastereomeric,
spirocyclic intermediates V and VI. This is followed either by intra-
molecular aldol condensation to give 20a and 20b with an embed-
ded cis-fused bicyclo[3.3.0]octane, or by a pinacol coupling to give
19. As with the acyclic system, the aldol reaction appears to be fa-
voured over pinacol when it is not precluded by ring strain
(Scheme 6).
1
8a
OH
H
HO
H
HO
H
OH
9 [53]c
H
H
10 [12]c
11 [6]c
CO2Et
O
EtO2C
EtO2C
CO2Et
CO2Et
H
2
3
8b
12 [38]d
H
13 [35]
HO
7
8c
HO
CO2Et
CO2Et
14a [23],e 14b [33]e
Diols 21a/b, obtained from mixed enone/enoate 17b, demon-
strate that intramolecular coupling with a pendant enoate appears
to proceed more slowly than with an enone since intermolecular
homodimerisation of the enone predominates (Table 2, entry 2).
Once again, intramolecular aldol condensation follows the dimeri-
sation and further reduction then occurs to give the product diols.
The result is consistent with that observed in the acyclic series (Ta-
ble 1, entry 3). Interestingly, intramolecular conjugate addition of
b-alkoxy tethered analogue, 18, does take place in high yield. Sub-
a
Reactions were conducted on 1.60–1.94 mmol scale, in 4:1 THF/MeOH at
À78 °C.9
b
c
Isolated yield.
The relative stereochemistry of each of the products 9, 10 and 11 was deter-
mined by X-ray analysis.
d
Isolated as a 4:1 inseparable mixture of diastereomers with an unidentified side
product.
e
C7 epimers 14a/b were isolated, of which one (14a) was inseparable from a
further minor diastereomer (14a dr = 3.5:1).10 Stereochemical assignments are
based upon the known SmI2-mediated coupling of a
,b-unsaturated ketones.5

3566
J. R. Powell et al. / Tetrahedron Letters 50 (2009) 3564–3567
H
H
H
O-
SmIII
H
MeOH
SmI2
O-
SmI2
O
Pinacol
SmI2
OH
OH
O
O
H
-O
O-
H
H
O
SmI2
IV
III
9
8a
Scheme 4.
Table 2
O
SmI2-mediated cyclisation of cyclic enone–enoate, bis-enone and bis-enoate
substratesa
O
O
O
R
Product(s) [yield%]b
a) b) c)
e)
Entry
1
Substrate
HO
HO
HO
6
Ph3P=CHCOMe
or Ph3P=CHCO2Et
HO
17a R = Me
17b R = OEt
O
15
7
H
17a
H
5
O
O
20a [16],c 20b [9]c
O
OEt
19 [18]
O
O
e)
OH
OH
OH
OH
d) c)
H
H
Ph3P=CHCO2Et
O
O
6
6
7
7
18
16
2d
17b
Scheme 5. Reagents and conditions: (a) Catalytic p-TsOH, HC(OMe)3, MeOH, rt,
48 h (58%); (b) 5-bromo-1-pentene, Mg, Et2O, rt, then , 2 h (46%); (c) RuCl3, NaIO4,
CH3CN:H2O (6:1), rt, 4 h (15, 54%), (16, 21%); (d) 3-buten-1-ol, catalytic p-TsOH,
D
CO2Et
CO2Et
toluene,
toluene,
D
D
, 5 h, Dean–Stark conditions (79%); (e) Ph3P@CHCOMe or Ph3P@CHCO2Et,
, 3–16 h (17a, 61%), (17b, 71%), (18, 50%).
CO2Et
21a [14]e
CO2Et
21b [25]f
sequent protonation and further SmI2-mediated reduction lead to
spirocycles 22a/b (Table 2, entry 3).
OH
O
OEt
3
18
Finally, we also investigated the intramolecular (9-endo-trig)
cyclisation of dione 23.18 However, treatment of 23 under the same
reducing conditions resulted in a mixture of diastereomeric prod-
ucts, 24a and 24b, in modest yield, from which we were able to
separate one diastereomer (24a) and identify its structure by
X-ray analysis.11 Tricyclic tetraols 24 arise from a remarkable cas-
cade sequence involving reduction of 23 followed by intermolecu-
lar homodimerisation to give a samarium bis-enolate, double
intramolecular aldol condensation, further reduction of the resul-
tant ketone functionality and pinacol coupling (Scheme 7).
In conclusion, we have investigated the SmI2-mediated, intra-
O
22a [23],g 22b [48]g
a
Reactions were conducted on 1.18–1.29 mmol scale, in 4:1 THF/MeOH at
À78 °C.9
b
c
Isolated yield.
Single diastereoisomers 20a and 20b were separated by column chromatogra-
phy. Relative stereochemistry at C5 and C7 is rationalised according to the forma-
tion of 11.
d
A third product of unidentified structure was isolated in 10% yield.
A 3JH6–H7 = 10.0 Hz axial–axial coupling (1H NMR, 400 MHz, CDCl3) is diagnostic
e
of the exo-cis equatorial diastereomer.
molecular cyclodimerisation of several (bis)-a,b-unsaturated
We were unable to confirm the stereochemistry of this expected5 exo-cis axial
f
carbonyl compounds, which provide a rapid entry to cis-bicy-
clo[3.3.0]octane and trans-bicyclo[4.3.0]nonane products from
simple acyclic starting materials. Similarly, tricyclic products can
be obtained from cyclohexanone-containing precursors. In addi-
tion, ready access to other elaborate polycyclic and spirocyclic
products can be achieved, from simple starting materials and via
cascade sequences involving the iterative formation of multiple
carbon–carbon bonds and stereogenic centres.
diastereomer due to overlap of the H6 resonance in the 1H NMR spectrum
(400 MHz, CDCl3).
g
Two diastereomeric mixtures 22a and 22b were isolated by column chroma-
tography (22a dr = ꢀ2.5:1, 22b dr = ꢀ2:1).10,17
References and notes
1. (a) Cabrera, A.; Alper, H. Tetrahedron Lett. 1992, 33, 5007–5008; (b) Cabrera, A.;
Le Lagadec, R.; Sharma, P.; Arias, J. L.; Toscano, R. A.; Velasco, L.; Gavino, R.;
Alvarez, C.; Salmon, M. J. Chem. Soc., Perkin Trans. 1 1998, 3609–3617; (c)
Cabrera, A.; Rosas, N.; Sharma, P.; Le Lagadec, R.; Velasco, L.; Salmon, M. Synth.
Commun. 1998, 28, 1103–1108; (d) Inanaga, J.; Handa, Y.; Tabuchi, T.; Otsubo,
K.; Yamaguchi, M.; Hanamoto, T. Tetrahedron Lett. 1991, 32, 6557–6558; (e)
Zhou, L. H.; Zhang, Y. M. Synth. Commun. 2000, 30, 597–607.
Acknowledgement
We thank the EPSRC for a studentship (J.R.P.).
2. Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38, 2121–2124.
3. For detailed mechanistic studies of the role of additives, see: (a) Flowers, R. A.
Synlett 2008, 1427–1439; (b) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.;
Flowers, R. A. J. Am. Chem. Soc. 2008, 130, 7228–7229.
4. For an elegant example of the use of alcohol proton donors in directing the
reaction pathway, see: Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5,
4811–4814.
Supplementary data
X-ray crystallographic data for compounds 9, 10 and 11 and 24a
are provided in cif. format. Spectroscopic characterisation of com-
pounds 9–11, 13, 14b, 17a/b, 18, 19, 20a/b and 21a/b. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.03.031.
5. Howells, D. M.; Barker, S. M.; Watson, F. C.; Light, M. E.; Hursthouse, M. B.;
Kilburn, J. D. Org. Lett. 2004, 6, 1943–1945.

J. R. Powell et al. / Tetrahedron Letters 50 (2009) 3564–3567
3567
8. Pandey, G.; Hajra, S.; Ghorai, M. K.; Kumar, K. R. J. Am. Chem. Soc. 1997, 119,
8777–8787.
O-
SmI2
O-
SmI2
SmI2
9. Typical procedure: MeOH (19 mL) was added to a stirring solution of SmI2 in dry
THF (0.1 M, 78 mL) and the resultant purple mixture was cooled to À78 °C. A
solution of diketone 8a (350 mg, 1.94 mmol) in dry THF (5 mL) was then added
dropwise over a period of 10 min, and the mixture was stirred at À78 °C for a
further 2 h. Brine (40 mL), followed by citric acid (489 mg, 2.33 mmol) was
then added before stirring for 20 min. EtOAc (80 mL) was added to the stirring
solution and, after 10 min, the organic phase was separated. This process was
then repeated (5 Â 80 mL EtOAc in total). The aqueous phase was further
extracted with EtOAc (80 mL), before the combined organic extracts were
washed with brine (2 Â 50 mL) and dried over MgSO4 before concentration in
vacuo. Purification by flash column chromatography (SiO2 eluted with
10%?20% EtOAc in petrol) gave 9 (190 mg, 1.03 mmol, 53%) as a white
crystalline solid, Rf = 0.36 (40% EtOAc in petrol), 10 (43 mg, 0.23 mmol, 12%) as
a pale yellow solid, Rf = 0.22 (40% EtOAc in petrol) and 11 (21 mg, 0.11 mmol,
O
+
17a
H
H
O
VI
V
MeOH
SmI2
MeOH
SmI2
-
O
O
SmI2
6%) as
a yellow solid, Rf = 0.17 (40% EtOAc in petrol). Spectroscopic
O
characterisation of compounds 9–11, 13, 14b, 19, 20a/b and 21a/b is
provided as Supplementary data.
SmIII
H
-O
10. Diastereomeric product mixtures 14a, 22a and 22b were satisfactorily
characterised by 1H and 13C NMR spectroscopy, IR and high resolution mass
spectrometry.
11. Crystallographic data (excluding structure factors) for structures 9, 10 and 11
in this Letter have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 715426, 715427 and
715428. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 lEZ, UK [fax: +44(0)-1223-336033 or e-
Aldol,
Pinacol
SmI2 reduction
19
20a/b
mail: deposit@ccdc.cam.ac.uk]. Data were collected on
a Bruker Nonius
Scheme 6.
KappaCCD with a Mo rotating anode generator; standard procedures were
followed. All hydrogen atoms were identified from the difference map and
then positioned geometrically and refined using a riding model. Crystal data for
9: C11H20O2, Mr = 184.27, T = 120(2) K, triclinic, space group P-1, a = 9.8736(4),
HO
b = 10.5209(3), c = 11.2839(7) Å,
V = 1072.84(7) Å3, calc = 1.141 g cmÀ3
collected: 15537, independent reflections: 4887 (Rint = 0.0560), final R indices
[I > 2 I]: R1 = 0.0567, wR2 = 0.1439, indices (all data): R1 = 0.0924,
wR2 = 0.1642. Crystal data for 10: C11H20O2, Mr = 184.27, T = 120(2) K,
monoclinic, space group P21/c, a = 14.5734(19), b = 5.6030(7),
c = 14.6007(17) Å, b = 117.153(6)°, V = 1060.8(2) Å3, calc = 1.154 g cmÀ3
= 0.077 mmÀ1, Z = 4, reflections collected: 9485, independent reflections:
2418 (Rint = 0.1289), final indices [I > 2 I]: R1 = 0.0913, wR2 = 0.1550, R
a
= 89.986(2), b = 72.579(1),
c = 74.358(2)°,
O
HO
H
= 0.076 mmÀ1
,
Z = 4, reflections
SmI2
H
q
,
l
THF/MeOH
H
H
+
r
R
OH
-78 oC
OH
HO
HO
HO
HO
O
q
,
24b (35%)
23
24a (5%)
l
R
r
indices (all data): R1 = 0.1951, wR2 = 0.1877. Crystal data for 11: C11H20O2,
Mr = 184.27, T = 120(2) K, monoclinic, space group P21/c, a = 9.5216(2),
b = 7.0923(1),
calc = 1.195 g cm
independent reflections: 2355 (Rint = 0.0518), final
R1 = 0.0484, wR2 = 0.1269, indices (all data): R1 = 0.0805, wR2 = 0.1508.
Crystal data for 24a: C18H28O4, Mr = 308.4, T = 120(2) K, orthorhombic, space
group Pca21, a = 18.0495(8), b = 20.9129(7), c = 35.4953(16) Å,
V = 13398.3(10) Å3, calc = 1.070 g cmÀ3 = 0.074 mmÀ1, Z = 28. These data
c À=315.8780(3) Å,
b = 107.270(1)°,
Z = 4, reflections collected: 14420,
indices [I > 2 I]:
V = 1023.90(3) Å3,
q
,
l
= 0.080 mmÀ1
,
O
R
r
R
OSmI2
-O
-O
- O
- O
q
, l
are from an isotropic refinement of sub-publication quality. The coordinates
are available in CIF format as Supplementary data.
O
OSmI2
O
OSmI2
12. An oligomeric samarium species is probable, and expected from a radical-
radical 5-exo-trig homodimerisation. Only for the purpose of clarity,
monomeric samarium(III) chelation control is shown: Keck, G. E.; Wager, C.
A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64, 2172–2173.
13. Spectroscopic characterization of compounds 17a/b and 18 is provided as
Supplementary data.
OSmI2
O
Scheme 7.
14. Mattay, J.; Banning, A.; Bischof, E. W.; Heidbreder, A.; Runsink, J. Chem. Ber.
1992, 125, 2119–2127.
15. Takahashi, K.; Tanaka, T.; Suzuki, T.; Hirama, M. Tetrahedron 1994, 50, 1327–
1340.
16. Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814–4818.
17. Approximate diastereomeric ratios are reported based upon measurement of
the peak height and integral of resonances of paired diastereomeric carbons in
the 13C NMR spectrum (400 MHz, CDCl3).
6. For intramolecular cyclodimerisation of tethered bis-enone and enone/enoate
systems under Bu3 SnH/AIBN/ conditions, see: (a) Enholm, E. J.; Kinter, K. S. J.
Org. Chem. 1995, 60, 4850–4855; For -tethered bis-cyclohexenones, see: (b)
Handy, S. T.; Omune, D. Tetrahedron 2007, 63, 1366–1371; For an -tethered
mixed enone/enoate under strongly reducing conditions (Li/NH3) see: (c)
Wasnaire, P.; Wiaux, R. T.; Markó, I. E. Tetrahedron Lett. 2006, 47, 985–989.
7. Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P.
D.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 1284–1301.
D
a
a
18. Christoffers, J.; Oertling, H.; Onal, N. J. Prakt. Chem. 2000, 342, 546–553.