The samarium(II)-mediated intermolecular couplings of ketones and β-alkoxyacrylates: A short asymmetric synthesis of an antifungal γ-butyrolactone

Article abstract of DOI:10.1016/j.tetlet.2004.10.027

The samarium(II) iodide-mediated coupling of ketones with β-alkoxyacrylates gives β-hydroxy-γ-butyrolactones in moderate yield. The process has been applied to the asymmetric synthesis of an antifungal, γ-butyrolactone natural product.

Full text of DOI:10.1016/j.tetlet.2004.10.027

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9087–9090
The samarium(II)-mediated intermolecular couplings of
ketones and b-alkoxyacrylates: a short asymmetric synthesis
of an antifungal c-butyrolactone
Nessan J. Kerrigan, Tejas Upadhyay and David J. Procter*
Department of Chemistry, The Joseph Black Building, University of Glasgow, Scotland G128QQ, UK
Received 8 September 2004; revised 5 October 2004; accepted 5 October 2004
Abstract—The samarium(II) iodide-mediated coupling of ketones with b-alkoxyacrylates gives b-hydroxy-c-butyrolactones in mod-
erate yield. The process has been applied to the asymmetric synthesis of an antifungal, c-butyrolactone natural product.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Samarium(II) iodide (SmI2) continues to be used widely
throughout organic synthesis.1 This mild, single-electron
reductant has been used to mediate a broad range of
radical and anionic transformations ranging from func-
tional group interconversions to complex carbon–car-
bon bond-forming sequences.1 The reductive coupling
of carbonyl compounds with olefins represents one of
the most important classes of SmI2 carbon–carbon bond
forming reaction. In particular, the intermolecular cou-
pling of aldehydes or ketones with a,b-unsaturated
esters provides convenient access to substituted c-
butyrolactones (Fig. 1a).2 In 1997, Fukuzawa reported
an asymmetric approach to c-butyrolactones in which
aldehydes and ketones were coupled with ephedrinyl
acrylates and crotonates.3 The ephedrine auxiliary was
found to be effective in controlling the asymmetry of
the reaction producing c-butyrolactones in moderate
to high enantiomeric excess (Fig. 1b).4–7
lactone products. Although SmI2-mediated intramolecu-
lar carbonyl–olefin couplings with b-alkoxyacrylates
have been reported,9 to the best of our knowledge, no
intermolecular examples have been described.10
We began our studies by preparing four b-oxygenated
acrylates for use in our studies. 3-Benzoyloxy methyl
acrylate 1, 3-benzyloxy methyl acrylate 2a, 3-allyloxy
methyl acrylate 2b, and 3-(4-methoxybenzyloxy)methyl
acrylate 2c were prepared by the addition of benzoic
acid, benzyl, allyl or 4-methoxybenzyl alcohol, respec-
tively, to methylpropiolate (Scheme 1).
We next investigated the reaction of these substrates
with carbonyl compounds in the presence of SmI2. Inter-
estingly, treatment of a mixture of 1 and 2-hexanone
with SmI2 and t-BuOH as a proton source, gave tertiary
alcohol 5 in moderate yield with none of the desired c-
butyrolactone being formed (Scheme 2).
We have recently adapted FukuzawaÕs methodology in
the development of a solid phase asymmetric catch–re-
lease approach to c-butyrolactones using acrylates and
crotonates linked to resin through an ephedrine chiral
linker.8 Our interest in this transformation has led us
to investigate the use of b-oxygenated acrylates in the
coupling, thus allowing access to more diverse c-butyro-
A possible mechanism for the formation of 5 is shown in
Scheme 2. In an attempt to better intercept the samar-
ium(III) enolate 4, the use of more acidic proton sources
(CF3CH2OH and (CF3)2CHOH)11 was investigated but
this failed to lead to the formation of any c-butyrolac-
tone product.
We turned our attention to 3-benzyloxy methyl acrylate
2a, which although less electronically activated would be
less prone to elimination. We were pleased to find that
treatment of 2a with 2-hexanone and SmI2, with
t-BuOH as a proton source, gave lactone 7 in moderate
yield and as a 6:1 mixture of diastereoisomers, the
Keywords: Samarium(II) iodide; Intermolecular couplings; Antifungal;
Natural product.
*
Corresponding author at present address: The School of Chemistry,
Oxford Road, The University of Manchester, Manchester M13 9PL,
UK. Tel.: +44 161 275 1425; fax: +44 161 275 4939; e-mail:
david.j.procter@man.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.027

9088
N. J. Kerrigan et al. / Tetrahedron Letters 45 (2004) 9087–9090
O
O
O
a. Fukuzawa 1986
b. Fukuzawa 1997
1
R = alkyl, Ph
1
2
4
R
R
R
3
2
R
OEt
R = H, Me, Et, Ph
O
17-82% yield
3
4
SmI THF
2
R = H, Me
R
4
t-BuOH
1
2
3
R = H, Me
R
R R
O
O
O
Ph
1
R = alkyl, Ph
1
2
R
R
N
O
43-99%ee
43-88% GC yield
2
3
R = H, Me, Et
R
O
3
SmI THF
2
R = H, Me
1
2
3
t-BuOH -78 ˚C
R
R R
Figure 1. SmI2-mediated reductive couplings to give c-butyrolactones.
O
O
O
a
b
OMe
RO
OMe
BzO
OMe
1
2a R= Bn
2b R= Allyl
2c R= PMB
Scheme 1. Reagents and conditions: (a) PhCO2H (1equiv), N-methylmorpholine (1equiv), CH2Cl2, rt, 88%; (b) benzyl, allyl or p-methoxybenzyl
alcohol (1equiv), PBu3 (0.15 equiv), CH2Cl2, 97% (2a), 95% (2b), and 98% (2c), respectively.
O
O
1
OMe
SmI THF t-BuOH
2
HO
-15 ˚C 30%
5
III
Sm
OBz O
OBz O
SmI
2
OMe
OMe
III
III
Sm O
Sm O
3
4
Scheme 2.
cis-isomer being the major product12 (Table 1, entry 1).
To assess the generality of the reaction, we carried out
the ketone–olefin reductive coupling with a range of
ketones and the acceptors 2a–c (Table 1).13
In order to illustrate the utility of this new coupling, we
have carried out a short asymmetric synthesis of the
antifungal furanone 14 isolated from Mutisia friesiana.14
Our synthesis began with the preparation of ketone 16
by Swern oxidation of 1,4-pentanediol to give ketoalde-
hyde 15, followed by Wittig reaction (Scheme 3).
2-Hexanone was also found to undergo reductive cou-
pling with the allyl-protected acceptor 2b, to give 8 as
a 4:1 mixture of diastereoisomers (entry 2). The more
bulky 3-methylbutan-2-one underwent reductive cou-
pling with 2a and 2c to give 9 and 10, respectively, with
complete selectivity for the cis-diastereoisomers (entries
3 and 4),12 while benzylacetone underwent coupling with
2c to give 11 as a mixture of diastereoisomers (entry 5).
Finally, cycloheptanone reacted with acceptors 2a and
2c to give spirocyclic lactones 12 and 13, respectively
(entries 6 and 7). Although products were obtained in
moderate isolated yields (40–52%), the coupling proto-
col represents a reliable, one-step, stereoselective proto-
col for the assembly of functionalised c-butyrolactones.
(By-products resulting from ketone reduction and pina-
col coupling were sometimes observed in addition to
some recovered starting materials. These could be sepa-
rated from the desired products by chromatography.)
In order to carry out an asymmetric, Fukuzawa reduc-
tive coupling, 3-benzyloxy ephedrinyl acrylate 18 and
3-(4-methoxybenzyloxy) ephedrinyl acrylate 21 were
prepared for reaction with ketone 16. Hydrolysis of 2a
and 2c, acid chloride formation and coupling with
(1R,2S)-N-methyl ephedrine gave 18 and 21, respec-
tively. Satisfying, treatment of ketone 16 and benzyloxy
substrate 18 gave the desired product 19 in moderate
yield and as a 6:1 mixture of diastereoisomers12
that were readily separated by chromatography (silica
gel, 20% EtOAc/hexane as eluant). Attempts to
remove the benzyl protecting group from 19 were
unsuccessful.
Fortunately, coupling of PMB substrate 21 with ketone
16 also proceeded satisfactorily to give 22 as a separable

N. J. Kerrigan et al. / Tetrahedron Letters 45 (2004) 9087–9090
Table 1. SmI2-mediated reductive couplings of ketones and b-alkoxy acrylates
9089
Entry
Ketone substrate
Acceptor
Product (racemic)
cis/trans ratioa
Yield (%)
O
O
1
2
2a
2b
7 R=Bn
8 R=Allyl
6:1
4:1
52
42
O
OR
O
O
O
3
4
2a
2c
9 R=Bn
10 R=PMB
1:0
1:0
52
42
OR
O
O
O
5
2c
11
5:1
42
OPMB
Ph
O
O
O
6
7
2a
2c
12 R=Bn
13 R=PMB
41
40
OR
a Diastereoisomeric ratios determined from the crude 1H NMR. The stereochemistry of the major product was confirmed by NOE studies for selected
examples and inferred for the remainder (Ref. 12).
O
OH
O
O
a
b
O
OH
O
OH
15
16
14
Scheme 3. Reagents and conditions: (a) DMSO, oxalyl chloride, NEt3, CH2Cl2, À78ꢁC, 66%; (b) (CH3)2CHPPh3I, n-BuLi, THF, À78ꢁC to rt, 40%.
O
O
O
Ph
c
a,b
N
RO
OMe
RO
Cl
RO
O
17 R= Bn
20 R= PMB
2a R= Bn
2c R= PMB
18 R= Bn
21 R= PMB
d
O
O
e
14
R= PMB
OR
19 R= Bn
22 R= PMB
Scheme 4. Reagents and conditions: (a) NaOH, dioxane, recrystallisation 43% R = Bn, 62% R = PMB; (b) SOCl2, R = Bn = PMB, 100%; (c) (1R,
2S)-N-methylephedrine, NEt3, CH2Cl2, rt, R = Bn 88%, R = PMB 89%; (d) SmI2, t-BuOH, THF, rt, R = Bn 39%, R = PMB 37%; (e) DDQ, CH2Cl2,
H2O, 68%.
5:1 mixture of diastereoisomers. Removal of the PMB
protection15 then completed the synthesis and provided
14 in 97% ee (Scheme 4).16
In conclusion, we have described the reductive, intermo-
lecular coupling of carbonyl compounds with b-alk-
oxyacrylates mediated by SmI2. We have applied our

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N. J. Kerrigan et al. / Tetrahedron Letters 45 (2004) 9087–9090
mediated by chiral Lewis acids: Sibi, M. P.; Zimmerman,
J.; Rheault, T. Angew. Chem., Int. Ed. 2003, 42, 4521–4523.
11. Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem.
2003, 68, 3190–3198.
methodology in an asymmetric synthesis of the anti-
fungal furanone 14.
12. The cis-relative stereochemistry of lactones 7,9,and 19 was
determined by NOE studies (no corresponding NOE was
observed for the minor diastereoisomer of 19):
Acknowledgements
We thank the Engineering and Physical Research Coun-
cil (EPSRC) (GR/R72242/01, N.J.K.), AstraZeneca for
the award of a Strategic Research Grant (D.J.P.) and
Pfizer for unrestricted funding (D.J.P.).
O
O
O
O
19
7
9
O
O
O
O
OBn
nOe
OBn
nOe
OBn
nOe
OBn
nOe
Me H
Me H
Me H
Me H
References and notes
X
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13. All new compounds were characterised by 1H and 13C
NMR, IR and HRMS. Typical procedure: To a solution of
SmI2 (11.2mL, 0.1M in THF, 1.12mmol, 5.5 equiv) at
0ꢁC was added a solution of 2-hexanone (77.0lL,
0.61mmol, 3equiv), 3-benzyloxy methyl acrylate
(39.2mg, 0.21mmol, 1equiv) and t-BuOH (38.4lL,
0.41mmol, 2equiv) in THF (1mL). After 24h, aqueous
saturated NaCl was added and the aqueous layer extracted
with ethyl acetate (3 · 5mL). The combined organic layers
were then dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography (silica gel, 30%
ethyl acetate/petroleum ether (40–60)) gave trans-7 (4mg,
0.02mmol, 8%) as a colourless oil. Further elution then
gave cis-7 (24mg, 0.09mmol, 44%) as a colourless oil. For
cis-7: mmax (thin film) 2863s, 1772s (C@O), 1458m, 1090m:
2. (a) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S.
Chem. Commun. 1986, 624–625; (b) Otsubo, K.; Inanaga,
J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 5763–5764;
(c) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S.
J. Chem. Soc., Perkin Trans. 1 1988, 1669–1675.
d
H (400MHz, CDCl3) 7.39–7.30 (5H m, ArH), 4.59 (1H, d,
3. Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am.
Chem. Soc. 1997, 119, 1482–1483.
AB system, J 11.8Hz, 1H from PhCH2O), 4.45 (1H, d, AB
system, J 11.8Hz, 1H from PhCH2O), 3.92(1H, dd, J 6.4,
4.0Hz, CHOBn), 2.81 (1H, dd, J 17.8, 6.4Hz, 1H from
CH2CHOBn), 2.65 (1H, dd, J 17.8, 4.0Hz, 1H from
CH2CHOBn), 1.84–1.79 (2H, m, CH2), 1.42–1.33 (4H, m,
CH2 · 2), 1.33 (3H, s, CH3) and 1.03 (3H, t, J 8.2Hz,
CH3CH2): dC (100MHz, CDCl3) 175.1 (C@O), 138.0
(ArC), 129.3 (ArCH · 2), 128.8 (ArCH), 128.4
(ArCH · 2), 89.9 (C(O)), 81.1 (CHO), 72.6 (ArCH2O),
36.1 (CH2C(O)), 34.9 (CH2), 26.5 (CH2), 24.9 (CH3), 24.0
(CH2) and 14.8 (CH2CH3): m/z (CI mode, isobutane)
263.2 ((M + H)+, 25%), 155 (100), 91 (10), 71 (12) (Found
(M + H)+ 263.1647. C16H23O3 requires 263.1647).
14. Viturro, C. I.; Maier, M. S.; Stortz, C. A.; de la Fuente, J.
R. Tetrahedron: Asymmetry 2001, 12, 991–998.
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Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59,
6900–6901; (b) Matsuda, F.; Kawatsura, M.; Dekura, F.;
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Fukuzawa, S.; Miura, M.; Saitoh, T. J. Org. Chem. 2003,
68, 2042–2044; (e) Taniguchi, N.; Uemura, M. Tetrahe-
dron Lett. 1997, 38, 7199–7202; (f) Merlic, C. A.; Walsh, J.
C. Tetrahedron Lett. 1998, 39, 2083–2086; (g) Merlic, C.
A.; Walsh, J. C. J. Org. Chem. 2001, 66, 2265–2274.
5. For other auxiliary-controlled couplings: (a) Xu, M.-H.;
Wang, W.; Lin, G. Org. Lett. 2000, 2, 2229–2232; (b) Xu,
M.-H.; Wang, W.; Xia, L.-J.; Lin, G. J. Org. Chem. 2001,
66, 3953–3962; (c) Wang, W.; Zhong, Y.; Lin, G.
Tetrahedron Lett. 2003, 44, 4613–4616.
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G. A.; Sono, M. Tetrahedron 1998, 54, 9289–9302.
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Kerrigan, N. J.; Hutchison, P. C.; Heightman, T. D.;
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148–149, and references cited therein.
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5125–5128.
16. The enantiomeric excess of 14 was determined by chiral
GC (Supelco b-Dex 120 column) and by comparison with
a racemic sample (prepared by the coupling of 16 with 2c).
The absolute stereochemistry of synthetic 14 was assigned
based on the optical rotation and comparison with
the literature value.14
Spectroscopic data was identical to that in the literature.14
For example: dH (400MHz, CDCl3) 5.17 (1H, app. t, J
7.2Hz), 4.20 (1H, br s, CHOH), 2.96 (1H, dd, J 18.0,
6.0Hz, 1H from CH2C(O)), 2.52 (1H, dd, J 18.0, 2.4Hz,
1H from CH2C(O)), 2.05–2.18 (2H, m, CH2), 1.97 (1H, d,
J 4.0Hz, OH), 1.76–1.90 (2H, m, CH2), 1.72(3H, s,
CH3C@), 1.65 (3H, s, CH3C@) and 1.36 (3H, s, CH3).
10. Sibi has recently reported the enantioselective intermo-
lecular addition of alkyl radicals to b-acyloxyenoates