Zinc-Mediated Allylation Followed by Lactonization of Dialkyl 2-(3-Oxo-1,3-diarylpropyl)malonates: Construction of δ-Lactones with Multiple Stereocenters

Article abstract of DOI:10.1055/s-0035-1560052

A variety of polysubstituted δ-lactones containing three or four stereocenters were prepared from various dialkyl 2-(3-oxo-1,3-diarylpropyl)malonates by a Barbier-type zinc-mediated allylation or cyclohexenylation of the keto group, followed by intramolec

Full text of DOI:10.1055/s-0035-1560052

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2121–2126
letter
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C. Reddy, S. A. Babu
Letter
Synlett
Zinc-Mediated Allylation Followed by Lactonization of Dialkyl
2-(3-Oxo-1,3-diarylpropyl)malonates: Construction of δ-Lactones
with Multiple Stereocenters
Chennakesava Reddy
Srinivasarao Arulananda Babu*
Indian Institute of Science Education and Research (IISER)
Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali,
Manauli P.O., Punjab, 140306, India
sababu@iisermohali.ac.in
Received: 29.05.2015
Accepted after revision: 02.07.2015
Published online: 20.08.2015
Barbier-type allylation7 of ketones, followed by lactoni-
zation of the resulting metal alkoxide with one of the ester
functional groups of the substrates 1 (Scheme 1). In this let-
ter, we report our preliminary investigations on the synthe-
sis of various polysubstituted δ-lactones by using a zinc-
mediated Barbier-type allylation7 and subsequent lactoni-
zation of dialkyl 2-(3-oxo-1,3-diarylpropyl)malonates 1.
At the outset, we performed optimization studies on the
synthesis of δ-lactones by Barbier-type allylation/lactoniza-
tion sequences from substrates 1a and 1b (Table 1). Ini-
tially, we performed the Barbier reaction on substrate 1a
with allyl bromide in the presence of indium powder in an-
hydrous tetrahydrofuran; the allylation and subsequent
transesterification promoted lactonization to afford the
δ-lactone 3a in 86% yield. Allylation followed by lactoniza-
tion of substrate 1a generated three stereocenters in δ-lac-
tone 3a and, therefore, four diastereomers were expected to
be formed in this reaction. However, we observed the for-
mation of only two diastereomers of 3a in a diastereomeric
ratio of 75:25 (Table 1, entry 1). Allylation of the substrate
1a with allyl bromide in the presence of indium powder in
anhydrous N,N-dimethylformamide gave product 3a in 78%
yield with moderate diastereoselectivity (dr = 65:35; entry
2).
The indium-mediated allylation of the substrate 1a with
allyl bromide in other solvents, such as ethanol, methanol,
dimethyl sulfoxide, 1,4-dioxane, or 1,2-dichloroethane gave
product 3a in low yield (5–28%) (Table 1, entries 3–7). The
indium-mediated allylation of the substrate 1a in water or
aqueous tetrahydrofuran did not afford 3a (entries 8 and 9).
Allylation of substrate 1a with allyl bromide in the presence
of zinc powder instead of indium powder in anhydrous tet-
rahydrofuran gave product 3a in high yield (98%) (entry 10)
and with a comparable diastereoselectivity (dr 75:25) to
that of the indium-mediated reaction (entry 1).
DOI: 10.1055/s-0035-1560052; Art ID: st-2015-d0405-l
Abstract A variety of polysubstituted δ-lactones containing three or
four stereocenters were prepared from various dialkyl 2-(3-oxo-1,3-dia-
rylpropyl)malonates by a Barbier-type zinc-mediated allylation or cyclo-
hexenylation of the keto group, followed by intramolecular lactoniza-
tion/transesterification. The stereochemistry of the major isomers was
confirmed by X-ray crystal structure analysis of representative com-
pounds.
Key words allylation, diastereoselectivity, lactones, stereoselective
synthesis, zinc
δ-Lactones are present as core units in numerous natu-
ral products, and they are considered as very important or-
ganic molecules in the areas of medicinal and organic
chemistry and flavor components.1,2 Numerous δ-lactone
derivatives have been found to exhibit a wide range of bio-
logical activities, and δ-lactones are also important syn-
thetic building blocks for the synthesis of various natural
products and biologically active synthetic molecules.1–4 For
example, ophiodilactone A (I) and ophiodilactone B (II)
(Scheme 1) have been found to exhibit cytotoxic activity
against P388 murine leukemia cells.3a,b Aryl-substituted
enol δ-lactones V and VI (Scheme 1) have been shown to
inhibit human neutrophil elastase and trypsin-like prote-
ases.3e
Numerous methods have been reported for synthesizing
multifunctionalized δ-lactones.1–6 Steglich’s group showed
the asymmetric synthesis of polysubstituted δ-lactone ca-
lopin (III).3c Kobayashi’s group reported a concise stereose-
lective synthetic route for the synthesis of polysubstituted
δ-lactone prelactone C (IV).3d In general, stereoselective
construction of polysubstituted δ-lactones is a relatively
difficult task.1–6 We have accomplished a zinc-mediated
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C. Reddy, S. A. Babu
Letter
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To corroborate the efficiency of the zinc-mediated al-
lylation process, we treated diester 1b with allyl bromide in
the presence of zinc powder in anhydrous tetrahydrofuran,
and we obtained the corresponding product 3b in good
yield (76%, dr 75:25) (Table 1, entry 11). We also carried out
the zinc-mediated allylation of substrate 1a in N,N-dimeth-
ylformamide and in 1,4-dioxane, which gave the product 3a
in 89 and 50% yield, respectively, but with low diastereose-
lectivities (entries 12 and 13). Allylation of the substrate 1b
with allyl bromide in the presence of aluminum powder in
anhydrous tetrahydrofuran gave product 3b in 40% yield
(entry 14), but no product was obtained in the presence of
tin powder (entry 15).
Next, the generality of this protocol was explored
through the use of the substrates 1c–n (Scheme 2). Zinc-
mediated Barbier-type allylation followed by the lactoniza-
tion of the substrates 1c–n gave the corresponding polysub-
stituted δ-lactones 3c–n, each containing three stereocen-
ters, in 60–98% yield. In all these cases, the allylation and
subsequent lactonization generated three stereocenters in
the δ-lactone product 3c–n; correspondingly, each reaction
was expected to provide four diastereomers. However, we
observed the formation of only two of the diastereomers of
3c–n with a diastereomeric ratio of up to 80:20 (Scheme 2).
In the cases of substrates 1g, 1h, 1j, and 1k, which con-
tained hetaryl groups, the zinc-mediated allylation reaction
gave the corresponding products 3g, 3h, 3j, and 3k with rel-
atively low diastereoselectivities.
We then performed a Barbier allylation/lactonization on
substrates 1a and 1d by treatment with prenyl bromide in
the presence of zinc powder and we successfully obtained
the corresponding polysubstituted δ-lactones 3o (64%, dr
80:20) and 3p (56%, dr 75:25) with good diastereoselectivi-
ties (Scheme 3). Allylation/lactonization of substrate 1b
with 2,3-dibromoprop-1-ene in the presence of zinc pow-
der in anhydrous tetrahydrofuran failed to give δ-lactone
3q. On the other hand, zinc-mediated allylation/lactoniza-
tion of substrate 1d with 3-bromo-2-methylprop-1-ene in
anhydrous tetrahydrofuran successfully gave the polysub-
stituted δ-lactone 3r in 91% yield with a diastereomeric ra-
tio of 70:30. Next, we explored the synthesis of polysubsti-
tuted γ-lactones by the allylation/lactonization protocol.
Accordingly, we carried out Barbier-type allylation/lactoni-
zation of substrates 1o–q with allyl bromide in the pres-
ence of zinc powder and we successfully obtained the cor-
responding polysubstituted γ-lactones 3s (70%, dr 76:24),
3t (75%, dr 88:12), and 3u (58%, dr 80:20) with good diaste-
reoselectivities (Scheme 3). In these cases, we once again
observed the formation of only two diastereomers of γ-lac-
tones 3s–u.
representative examples of naturally occurring polysubstituted δ-lactone molecules
O
OH
OH
OH
O
O
O
O
OH
O
O
O
O
Me
O
O
Me
Me
O
HO
Me
OH
IV
prelactone C
I
II
ophiodilactone B
III
calopin
gua
ophiodilactone A
gua
NHCOPh
O
R
R
O
O
O
V
VI
R = H, I
gua = guanidine residue
trypsin-like protease inhibitors
Barbier-type allylation followed by lactonization/transesterification
this work
R1
O
R2
stereoselective lactonization
generation of 3 stereocenters
polysubstituted δ-lactones
R2
R3OOC
H2O
R4
ZnL
R4
workup
Zn
O
COOR3
O
C
1
O
R2
R3
+
R4
O
COOR3
O
Br
R3OOC
formation of only 2 diastereomers
R1
3
R1
2
Scheme 1
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Table 1 Optimization of the Reaction Conditions for the Construction of Polysubstituted δ-Lactones 3a and 3ba
R
Br
2a
metal (0.37 mmol)
O
O
solvent (mL)
30 °C, 2–30 h
EtOOC
O
COOEt
COOEt
R
(major isomer)
3a: R = OMe
3b: R = Cl
(0.25 mmol)
1a: R = OMe
1b: R = Cl
Entry
R
Metal
Solvent (mL)
Time (h)
Product
Yield (%)
dr
1
2
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Cl
In
In
In
THF (1.5)
7
7
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
3b
3a
86
78
25
<5
28
15
17
0
75:25
65:35
50:50
–
DMF (1)
3
EtOH (1)
7
4
Zn or In
In
MeOH (1)
DMSO (1)
1,4-dioxane (1)
DCE (1)
8
5
12
12
30
12
12
7
47:53
50:50
46:54
–
6
In
7
In
8
In
H2O (5)
9
In
THF–H2O (3, 1:1)
THF (1.5)
0
–
10
11
12
13
14
15
Zn
Zn
Zn
Zn
Al
98
76
89
50
40
0
75:25
75:25
56:44
62:38
60:40
–
THF (1.5)
2
OMe
OMe
Cl
DMF (1.5)
1,4-dioxane (1)
THF (1.5)
6.5
6.5
3.5
7
OMe
Sn
THF (1.5)
a Reaction conditions: 1a/1b (0.25 mmol), allyl bromide (0.5 mmol), metal powder (0.37 mmol).
Finally, we sought to extend the scope of this protocol to
obtain cyclohexenylated δ-lactone scaffolds with multiple
stereocenters (Scheme 4). Accordingly, we performed the
zinc-mediated Barbier-type reaction of substrate 1d with
3-bromocyclohexene and we obtained the polysubstituted
δ-lactone 4a in 90% yield and high diastereoselectivity (dr
90:10) (Scheme 4). Notably, we observed the formation of
only two diastereomers of 4a. Encouraged by this result, we
carried out the reactions of various dialkyl 2-(3-oxo-1,3-di-
arylpropyl)malonates 1 with 3-bromocyclohexene in the
presence of zinc powder, and we obtained the correspond-
ing polysubstituted δ-lactones 4b–h containing four stereo-
centers in 40–98% yield and moderate to high diastereose-
lectivities (dr ≤ 95:5); once more, in each case we observed
the formation of only two diastereomers of the δ-lactone
4b–h.
structure analyses of the major compounds 3b, 3c, 3t, and
4b (Figure 1).8,9 On the basis of the X-ray analyses of the
major compounds 3b, 3c, 3t, and 4b and the similarity in
the NMR spectroscopic patterns of the respective series 3a–r,
3s–u, and 4a–h (see Supporting Information), we propose
the structures of the major diastereomers shown in
Schemes 2–4 and Table 1. On the basis of the X-ray analyses
(Figure 1), the relative stereochemistry of the major isomer
3c at the C3(H), C4(H), and C6 stereocenters was assigned to
be 3S*,4S*,6S*. Furthermore, with the help of 1H, 13C, DEPT-
135, H,H-COSY, and HMQC NMR analyses of compounds 3c
(major isomer) and 3c′ (minor isomer), the stereochemistry
of the representative minor isomer 3c′ at the C3(H), C4(H),
and C6 stereocenters was assigned to be 3S*,4S*,6R* (Figure
2, see also the Supporting Information). Accordingly, the as-
sumption is that all other minor isomers are expected to
have a stereochemistry similar to 3c′ (minor isomer). Fur-
thermore, the assignment of the stereochemistry of 3c (ma-
jor isomer) and 3c′ (minor isomer) indicates, plausibly, the
diastereomers that are formed in the Barbier reaction pro-
cess.10a However, because the lactones have an acidic α-hy-
drogen at the C3 stereocenter, we cannot ignore the possi-
Generally, in all the zinc-mediated ketone-group allyla-
tion/intramolecular lactonization reactions of substrates
1a–n and 1o–q, we observed the formation of only two cor-
responding diastereomers of each of 3a–r, 3s–u, and 4a–h.
The structures and stereochemistries of the major diaste-
reomers were established by means of single-crystal X-ray
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C. Reddy, S. A. Babu
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R
aryl
O
Br
Br
2a
Zn
THF
(het)aryl
R1OOC
O
O
O
O
2b
O
aryl
Zn (0.37 mmol)
(het)aryl
30 °C
1.5–14 h
EtOOC
COOR1
COOR1
THF (1.5 mL)
30–32 °C, 2–2.5 h
COOEt
(major isomer)
3: yield (%) (dr)
COOEt
R
1c–n
(0.25 mmol)
1d: R = Me
1a: R = OMe
(major isomer)
3o: R = Me; 64% (80:20)
3p: R = OMe; 56% (75:25)
Cl
OMe
Cl
Br
Br
O
O
O
Br
O
O
O
2c
O
O
COOEt
Zn (0.37 mmol)
EtOOC
O
R
COOEt
COOEt
THF (1.5 mL)
70 °C, 12 h
COOEt
3e: 77 (74:26)b
3c: R = Br; 98 (80:20)a
3d: R = Me; 90 (74:26)b
COOEt
3f: 61 (72:28)b
Cl
(major isomer)
1b (0.25 mmol)
3q: 0%
Me
Me
Br
O
Me
O
O
O
O
2d
O
Zn (0.37 mmol)
O
EtOOC
O
O
THF (1.5 mL)
25–30 °C, 2 h
COOMe
COOEt
COOMe
X
X
COOEt
Cl
COOEt
Me
3r: 91% (70:30)
3g: X = S; 65 (61:39)c
3h: X = O; 88 (56:44)c
3i: 78 (71:29)d
3j: X = S; 90 (60:40)a
3k: X = O; 89 (55:45)a
1d (0.25 mmol)
Br
ROOC
ROOC
O
O
2a
Zn (0.37 mmol)
Me
O
O
O
THF (1.5 mL)
–10 to 32 °C, 2.5–9 h
O
Me
ROOC
(major isomer)
3s: R = Et (9 h); 70% (76:24)a
3t: R = t-Bu (2.5 h); 75% (88:12)b
3u: R = Me; 58% (80:20)c
O
O
(0.25 mmol)
1o: R = Et
1p: R = t-Bu
1q: R = Me
O
COOt-Bu
COOBn
COOt-Bu
MeO
Cl
Cl
3n: 90 (80:20)f
3l: 60 (76:24)e
3m: 81 (76:24)d
Scheme 3 Synthesis of γ- and δ-lactones 3o–u. Reaction tempera-
Scheme 2 Synthesis of the δ-lactone scaffolds 3c–n. Reaction condi-
tions: 1 (0.25 mmol), allylbromide (0.5 mmol), Zn powder (0.37 mmol),
THF (1.5 mL). Reaction times: a 1.5 h. b 2 h. c 3 h. d 2.5 h. e 14 h. f 7 h.
tures: a 25 °C. b 32 °C. c –10 °C for 2 h followed by r.t. for 1 h.
bility that epimerization at the C3 stereocenter during the
reaction might contribute to the stereochemistry of the C3
stereocenter, a possibility regarding which we have no con-
vincing evidence at this stage.10b
In summary, we have described our preliminary investi-
gations on the Barbier-type zinc-mediated allylation and
cyclohexenylation of ketones with subsequent intramolecu-
lar lactonization. This protocol has led to the assembly of a
variety of polysubstituted δ-lactones.
Acknowledgment
We thank IISER-Mohali for funding this research work and the NMR,
HRMS, and X-ray facilities. C.R. thanks CSIR, New Delhi, for an SRF fel-
lowship. We thank the reviewers for their valuable suggestions.
Figure 1 X-ray structures of 3b, 3c, 3t, and 4b
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References and Notes
H
Br
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R3
R2
O
2e
O
R2
R1OOC
Zn (0.37 mmol)
O
THF (1.5 mL)
32–35 °C, 2–14 h
COOR1
COOR1
(major isomer)
4: yield (%) (dr)
R3
1 (0.25 mmol)
Cl
OMe
H
H
H
O
O
O
O
O
O
COOEt
COOEt
COOEt
Me
4b: 98 (80:20)c
4a: 90 (90:10)a,b
4c: 65 (75:25)a
(3) (a) Matsubara, T.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Angew. Chem. Int. Ed. 2014, 53, 757. (b) Ueoka, R.; Fujita, T.;
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Yang, C. S. Bioorg. Med. Chem. Lett. 2005, 15, 873.
H
H
H
O
O
O
O
O
O
COOCH2Ph
COOMe
COOt-Bu
Cl
S
MeO
4d: 63 (62:38)d
4e: 40 (85:15)e
4f: 77 (90:10)a
(4) For selected papers dealing with iodolactonization, see:
(a) Wzorek, A.; Gawdzik, B.; Gładkowski, W.; Urbaniak, M.;
Barańska, A.; Malińska, M.; Woźniak, K.; Kempińska, K.;
Wietrzyk, J. J. Mol. Struct. 2013, 1047, 160. (b) Časar, Z. Synlett
2008, 2036. (c) Oderinde, M. S.; Hunter, H. N.; Bremner, S. W.;
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thesis 2014, 46, 2333.
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2013, 24, 2216. For the synthesis of prelactone B, see: (g) Dias, L.
C.; Steil, L. J.; Vasconcelos, V. de A. Tetrahedron: Asymmetry
2004, 15, 147. (h) Exner, C. J.; Laclef, S.; Poli, F.; Turks, M.; Vogel,
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see: (i) Doran, R.; Duggan, L.; Singh, S.; Duffy, C. D.; Guiry, P. J.
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NHC redox catalysis, see: (k) Davies, A. T.; Pickett, P. M.; Slawin,
A. M. Z.; Smith, A. D. ACS Catal. 2014, 4, 2696. For organocata-
lytic cascade reactions, see: (l) Ren, Q.; Sun, S.; Huang, J.; Li, W.;
Wu, M.; Guo, H.; Wang, J. Chem. Commun. 2014, 50, 6137. For a
one-pot multistep method, see: (m) Saito, A.; Kumagai, N.;
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product-based methods, see: (n) Peed, J.; Domínguez, I. P.;
H
H
O
O
O
O
COOEt
COOEt
MeO
Cl
4g: 45 (95:5)f
4h: 62 (93:7)c
Scheme 4 Synthesis of δ-lactones 4a–h. The starting materials for
products 4a–h were 1d, 1e, 1f, 1g, 1l, 1m, 1a, and 1b, respectively. Re-
agents and conditions: 1 (0.25 mmol), 3-bromocyclohexene (0.5 mmol),
Zn powder (0.37 mmol). Reaction times: a 2 h. b 1 h at –10 °C, then 1 h
at r.t. c 3 h. d 2.5 h at –10 °C, then 1 h at r.t. e 2.5 h. f 14 h.
6
6
5
5
O 1
O 1
4
4
2
2
O
O
3
3
COOEt
COOEt
Br
Br
3c' (minor)
3S*,4S*,6R*
3c (major isomer)
3S*,4S*,6S*
Figure 2 Stereochemistry of the major and minor isomers
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560052.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2121–2126

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C. Reddy, S. A. Babu
Letter
Synlett
Davies, I. R.; Cheeseman, M.; Taylor, J. E.; Kociok-Köhn, G.; Bull,
S. D. Org. Lett. 2011, 13, 3592. (o) Davies, S. G.; Nicholson, R. L.;
Smith, A. D. Org. Biomol. Chem. 2004, 2, 3385. (p) Ošlaj, M.;
Cluzeau, J.; Orkić, D.; Kopitar, G.; Mrak, P.; Časar, Z. PLoS One
2013, 8, e62250. (q) Vajdič, T.; Ošlaj, M.; Kopitar, G.; Mrak, P.
Metab. Eng. 2014, 24, 160.
obtained free of charge from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
(9) γ-Lactones 3s–u and δ-Lactones 3a–r and 4a–h; General Pro-
cedure
(6) For selected papers on the synthesis of γ-lactones: for metal-
based synthesis, see: (a) Mladenova, M.; Gaudemar-Bardone, F.;
Goasdoue, N.; Gaudemar, M. Synthesis 1986, 937.
(b) Gaudemar-Bardone, F.; Gaudemar, M.; Mladenova, M. Syn-
thesis 1987, 1130. (c) Babu, S. A.; Yasuda, M.; Okabe, Y.; Shibata,
I.; Baba, A. Org. Lett. 2006, 8, 3029 and references cited therein.
(d) Habel, A.; Boland, W. Org. Biomol. Chem. 2008, 6, 1601.
(e) Fillion, E.; Carret, S.; Mercier, L. G.; Trépanier, V. É. Org. Lett.
2008, 10, 437. (f) Rollin, Y.; Derien, S.; Duñach, E.; Gebehenne,
C.; Perichon, J. Tetrahedron 1993, 49, 7723. (g) Pisani, L.;
Superchi, S.; D’Elia, A.; Scafato, P.; Rosini, C. Tetrahedron 2012,
68, 5779. For the dihydroxylation route, see: (h) Kapferer, T.;
Brückner, R. Eur. J. Org. Chem. 2006, 2119. For a C–H abstrac-
tion-based protocol, see: (i) Dohi, T.; Takenaga, N.; Goto, A.;
Maruyama, A.; Kita, Y. Org. Lett. 2007, 9, 3129. For TfOH-based
construction of γ-lactones, see: (j) Elford, T. G.; Arimura, Y.; Yu,
S. H.; Hall, D. G. J. Org. Chem. 2007, 72, 1276. (k) Aslam, N. A.;
Babu, S. A. Tetrahedron 2014, 70, 6402. For a reduction/lacton-
ization sequence-based method, see: (l) Steward, K. M.; Gentry,
E. C.; Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 7329.
(7) For selected papers and reviews on Barbier-type reactions, see:
(a) Barbier, P. C. R. Hebd. Seances Acad. Sci. 1899, 128, 110.
(b) Roush, R. W. In Comprehensive Organic Synthesis; Vol. 2;
Trost, B. M.; Fleming, I.; Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991, 1. (c) Chemler, S. R.; Roush, W. R. In Modern Car-
bonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 11, 403. (d) Denmark, S. E.; Almstead, N. G. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 10 299. (e) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S. Tetra-
hedron 2004, 60, 1959. (f) Takao, K.-i.; Miyashita, T.; Akiyama,
N.; Kurisu, T.; Tsunoda, K.; Tadano, K.-i. Heterocycles 2012, 86,
147. (g) Gao, Y. Z.; Wang, X.; Sun, L. D.; Xie, L. G.; Xu, X. H. Org.
Biomol. Chem. 2012, 10, 3991. (h) Lim, J. W.; Kim, K. H.; Park, B.
R.; Kim, J. N. Tetrahedron Lett. 2011, 52, 6545. (i) Reddy, C.;
Babu, S. A.; Aslam, N. A. RSC Adv. 2014, 4, 40199; and references
cited therein. See also Ref. 6 (a).
Zn powder (0.37 mmol) and allylbromide or 3-bromocyclohex-
ene (0.5 mmol) were added to a solution of the appropriate
malonate substrate 1 (0.25 mmol) in anhyd THF (1.5 mL) under
N2, and the mixture was stirred at 30–35 °C for the appropriate
time (see Table 1 and Schemes 2–4). The reaction was then
quenched by adding H2O (2 mL), and the mixture was allowed
to stand. The mixture was transferred to a separatory funnel
and extracted with EtOAc (3 × 8 mL), and the organic layers
were combined, dried (Na2SO4), filtered, and concentrated
under vacuum. The resulting crude product was purified by
column chromatography (silica gel, EtOAc–hexane).
Ethyl (3S*,4S*,6S*)-6-Allyl-4-(4-chlorophenyl)-2-oxo-6-phen-
yltetrahydro-2H-pyran-3-carboxylate (3b)
Prepared by the general procedure from 1b, and purified by
column chromatography [silica gel, EtOAc–hexanes (13: 87)] as
a colorless solid (major isomer); yield: 97 mg (98%; dr 75:25);
mp 87–89 °C. IR (KBr): 1747, 1726, 1494 and 1155 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.28 (m, 5 H), 7.32 (d, J = 8.4 Hz,
2 H), 7.13 (d, J = 8.4 Hz, 2 H), 5.66–5.56 (m, 1 H), 5.16–5.11 (m,
2 H), 4.16–4.10 (m, 2 H), 3.81 (td, J1 = 12.2 Hz, J2 = 4.7 Hz, 1 H),
3.54 (d, J = 12.2 Hz, 1 H), 2.92 (dd, J1 = 14.2 Hz, J2 = 6.7 Hz, 1 H),
2.84 (dd, J1 = 14.2 Hz, 1 H, J2 = 7.6 Hz), 2.67 (dd, J1 = 14.3 Hz,
J2 = 4.7 Hz, 1 H), 2.29 (dd, J1 = 14.3 Hz, J2 = 12.2 Hz, 1 H), 1.14 (t,
J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 167.9, 166.9,
143.2, 138.8, 133.6, 131.4, 131.4, 129.2, 128.7, 128.4, 128.0,
124.6, 120.0, 86.1, 61.8, 54.2, 47.0, 39.3, 38.3, 14.0. HRMS (ESI):
m/z [M
421.1174.
+
Na]+ calcd for C23H23ClNaO4: 421.1183; found:
(10) (a) This observation implies the stereoselection might occur at
the Barbier reaction step through a plausible chelation effect
involving the malonate moiety. This possibility is based on the
observation that reaction in polar protic solvents such as EtOH
gave no selectivity (Compare entries 1 and 3 in Table 1).
(b) There was no significant change in the diastereoselectivity
with respect to the two diastereomers obtained from reactions
performed for different times. Furthermore, the diastereoselec-
tivity of the crude reaction mixture did not differ significantly
from that of the pure mixture of diastereomers obtained after
isolation by column chromatography on silica gel.
(8) Crystallographic data for compounds 3b, 3c, 3t, and 4b have
been deposited with the accession numbers CCDC 1048540,
1048541, 1048542, and 1048543, respectively, and can be
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2121–2126