Synthesis of a monofluoro 3-alkyl-2-hydroxy-1,4-naphthoquinone: a potential anti-malarial drug

Article abstract of DOI:10.1016/j.tetlet.2015.10.054

Monofluorinated 3-alkyl-2-hydroxy-1,4-naphthoquinone 4 was prepared in eight steps from commercially available 8-bromooctanoic acid (10). The key step involved L-proline-catalyzed three-component reductive alkylation (TCRA) of 2-hydroxy-1,4-naphthoquinone (5) with the optically active aldehyde 7.

Full text of DOI:10.1016/j.tetlet.2015.10.054

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a monofluoro 3-alkyl-2-hydroxy-1,4-naphthoquinone:
a potential anti-malarial drug
⇑
Eliana E. Kim, Evans O. Onyango, Liangfeng Fu, Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Monofluorinated 3-alkyl-2-hydroxy-1,4-naphthoquinone 4 was prepared in eight steps from commer-
Received 27 August 2015
Revised 10 October 2015
Accepted 15 October 2015
Available online xxxx
cially available 8-bromooctanoic acid (10). The key step involved L-proline-catalyzed three-component
reductive alkylation (TCRA) of 2-hydroxy-1,4-naphthoquinone (5) with the optically active aldehyde 7.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Three-component reductive alkylation
Nucleophilic fluorination
Naphthoquinone
Malaria
Atovaquone
Atovaquone (1, Fig. 1) is a 2-hydroxynaphthoquinone that is a
potent anti-malarial compound in current clinical use, and which
generated by
alkylation (TCRA) of 5 with 7. The optically active aldehyde 7
would be obtained by chiral auxiliary-mediated asymmetric
L-proline-catalyzed three-component reductive
competitively inhibits the cytochrome bc
1
complex of the malaria
a-
parasite Plasmodium falciparum.1
methylation of commercially available 8-bromocarboxylic acid 10
or 8-fluorocarboxylic acid 9, itself obtained by fluorination of 10.
We initially attempted the synthesis of 8-fluorocarboxylic acid
9 by treating the commercially available 8-bromooctanoic acid
(10) with TBAF at 70 °C in tert-butanol. However, this reaction gave
an inseparable mixture consisting majorly of the corresponding
nine-membered lactone (not shown) and only a trace of the
desired product 9. A search of the literature revealed a precedent
2
Due to the resistance developed to atovaquone, other hydroxy-
naphthoquinones have been investigated for comparable anti-
3
–5
malarial properties.
For example, we found that S-10576 (2) is
complex that
a potent inhibitor of the yeast cytochrome bc
1
3
exhibits species selectivity higher than that of atovaquone. Despite
its efficacy, S-10576 (2) is readily metabolized in human cells via
hepatic P450-mediated hydroxylation and subsequent oxidative
6
carboxylation at the terminal position of the alkyl chain. On the
N
for TBAF-induced intramolecular S 2-type cyclization/lactoniza-
8
other hand, NQ1 (3), the trifluorinated analog of 2, is metabolically
stable and strongly inhibits atovaquone-resistant P. falciparum
sporozoites. However, its species selectivity is significantly lower
than that of S-10576 (2).4 Based on molecular modeling studies
and biological assays, we and others believe that the bulkiness of
the trifluoromethyl group may be responsible for this reduced
tion of halo-carboxylic acids. To circumvent this side reaction,
the carboxylic acid moiety in 10 was masked as its methyl ester
11 (Scheme 2). In the event, treating 10 with K CO and iodo-
2 3
,7
methane afforded a 2:1 mixture (85%) of the desired product 11
9
and its iodo-analog 12, respectively. No attempt was made to sep-
arate the mixture of 11 and 12 since both were anticipated to
5
,7
10
selectivity. Thus, we surmised that a monofluorinated 8-carbon
side chain would enhance the poor species selectivity of 3, while
retaining its metabolic stability, and would also recover the inhibi-
undergo fluorination in the next step. The fluorination of the
mixture of 11 and 12 gave the desired product 13 (75%) and a small
amount of the Hoffmann elimination side product 14 (5%).11
Attempts to separate the mixture by column chromatography were
not successful. Fortunately, though, pure fluoro ester 13 was
obtained by vacuum distillation using a Vigreux column.12 Finally,
5
,7
tion potency of 2. This led us to pursue the synthesis of monoflu-
orinated 3-alkyl-2-hydroxy-1,4-naphthoquinone derivative 4.
The retrosynthetic analysis of 4 is outlined in Scheme 1. Our
target molecule 4 can be partitioned into 2-hydroxy-1,4-naphtho-
quinone (5) and S-aldehyde 7. We envisioned that 4 might be
2
saponification (LiOH, H O/MeOH) of fluoro ester 13 furnished the
corresponding fluoro acid 9 in 95% yield. Overall, even with two
additional steps for the protection of the carboxylic acid moiety
and subsequent deprotection, this three-step fluorination method
is a more efficient alternative for the preparation of fluoro acid 9
⇑
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
http://dx.doi.org/10.1016/j.tetlet.2015.10.054
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
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2
E. E. Kim et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Figure 1. 3-Alkyl-2-hydroxy-1,4-naphthoquinones that inhibit the cytochrome bc
complex and our synthetic target 4.
1
Scheme 2. Synthesis of 8-fluorooctanoic acid (9).
than that described in the literature, in which 9 was synthesized in
1
3
5
steps (61%).
The enantioselective
Scheme 3. The -fluorocarboxylic acid 9 was first treated with oxa-
a
-methylation was performed as shown in
x
lyl chloride to form 8-fluorooctanoyl chloride, followed by the
addition of (S)-4-benzyl-2-oxazolidinone using triethylamine and
DMAP to give 15 in 87% yield.14
The
the oxazolidinone 16 in 83% yield. Reductive cleavage of the
chiral auxiliary from 16 using LiAlH produced the alcohol 17 in
a yield of 92%. Dess–Martin oxidation provided aldehyde 7
92%) that was used without further purification.16
We conducted the -proline-catalyzed three-component reduc-
a-methylation using NaHMDS and iodomethane furnished
14
4
1
5
(
L
tive alkylation of naphthoquinone 5 with aldehyde 7 and the
Hantzsch ester (18) under the conditions reported by Ramach-
1
7–19
ary.
Even though the authors reported good yields during
Scheme 3. Synthesis of aldehyde 7.
the synthesis of several 3-substituted 2-hydroxy-1,4-naphtho-
quinones at room temperature,17 in our case, the reactions at room
temperature furnished the desired product 4 in only 33% yield even
with extended reaction times (more than 48 h). However, refluxing
chromatography prior to hydrolysis in order to recover and recycle
the excess aldehyde 7.
CH
2
Cl
2
not only accelerated the reaction but also improved the
The alternative strategy, which delayed the introduction of the
terminal fluorine until the final step, achieved the synthesis of
brominated 3-alkyl-2-hydroxy-1,4-naphthoquinone 6 in five steps
from bromooctanoic acid 10 (Scheme 5). This approach essentially
mirrored the sequence of steps presented in Scheme 3. Moreover,
20,21
yield from 33% to 84% (Scheme 4).
Overall, the best yields were
obtained by using 2 equiv of the aldehyde 7, consistent with the
examples reported by Ramachary.17 Purification of the final pro-
duct 4 was complicated by the presence of the pyridine by-product
(
19) from the oxidation of the Hantzsch ester (18), which exhibited
the same R value as 4. Attempts to remove 19 by washing the
mixture with 2 N HCl failed. Alternatively, stirring the mixture
with LiOH in H O/MeOH at room temperature for 4 h followed
the TCRA reaction of naphthoquinone 5 with aldehyde 8
(Scheme 1), the bromo analog of the aldehyde 7, furnished the bro-
mide 6 in 78% yield. Crystallization gave needle crystals of 6,
enabling us to assign its structure and absolute configuration using
X-ray crystallography. However, the conversion of 6 to 4 using
TBAF and tert-butanol was plagued by purification issues, in which
4 could not be separated from its mixture with other side products.
In an attempt to optimize nucleophilic fluorination, we screened
f
2
by acid work up afforded the desired product 4 as a pale yellow
solid. It is important to note that the addition of LiOH to the
H O/MeOH solution of the crude reaction mixture could have
2
certainly furnished the final product 4; however, we ran column
Scheme 1. Retrosynthetic analysis.
Scheme 4. Synthesis of target compound 4 via a TCRA method.
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.054

E. E. Kim et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
1
1
5. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–1739.
6. Feutrill, J. T.; Lilly, M. J.; White, J. M.; Rizzacasa, M. A. Tetrahedron 2008, 64,
4880–4895.
17. Ramachary, D. B.; Kishor, M. Org. Biomol. Chem. 2010, 8, 2859–2867.
18. Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011, 9, 1277–1300.
19. Ramachary, D. B.; Barbas, C. F. Chem. Eur. J. 2004, 10, 5323–5331.
20. Mahrwald, R. In Modern Aldol Reactions. Vol. 1: Enolates, Organocatalysis,
Biocatalysis and Natural Product Synthesis; WILEY-VCH Verlag GmbH & Co.
KGaA, 2004; Vol. 1, p 344.
21.
A
mixture of the aldehyde
naphthoquinone (54.0 mg, 0.312 mmol), the Hantzsch ester (79.0 mg,
.312 mmol), and -Proline (18.0 mg, 0.156 mmol) in CH Cl (30 mL) was
refluxed for 12 h. After cooling to room temperature, SiO (1 g) was added to
the reaction mixture, which was concentrated in vacuo, then purified via dry-
pack column chromatography (SiO
, 10:1 hexanes/ethyl acetate). 1H NMR
confirmed as the major product contaminated with diethyl 2,6-
dimethylpyridine-3,5-dicarboxylate (19). LiOHÁH O (82 mg, 1.2 mmol) was
added, and the mixture was allowed to stir in 3:1 MeOH/H O (10 mL) for 4 h.
After the removal of MeOH under reduced pressure, the mixture was washed
with CH Cl and the organic extracts were discarded. The aqueous layer was
covered with CH Cl and acidified with 2 N HCl. After the two layers were
separated, the aqueous layer was further extracted with CH Cl three times
and the combined organic extracts were washed with brine, dried over MgSO
and concentrated in vacuo to give 4 as a yellow solid (50 mg, 63%). R = 0.70
3:1 hexanes/ethyl acetate). 1
NMR (500 MHz, CDCl 8.11–8.13 (dd,
7 (100 mg, 0.624 mmol), 2-hydroxy-1,4-
0
L
2
2
2
2
4
Scheme 5. Summary of two different approaches to the total synthesis of 4.
2
2
2
2
2
2
2
2
different reaction conditions: CsF in tert-amyl alcohol, TBAF in
2
2
1
1
tert-amyl alcohol,
conditions.
and TBAF in acetonitrile in ‘wet’
4
,
2
3,24
f
All these conditions invariably produced mixtures
(
H
3
) d
consisting of the product 4, alkene elimination product, and other
unidentified side products that were inseparable by chromato-
graphic techniques. Also, vacuum distillation, which had
completely removed the fluorination side products in the first syn-
thetic approach (vide supra), could not be employed in this case
due to the solid nature of 4. Thus, even though the second
approach with fluorination at the last step would have shortened
the total synthesis by two steps, the first approach with early
fluorination was ultimately used to obtain pure and reliable
quantities of the target compound 4.
J = 7.81, 0.79 Hz, 1H), 8.08–8.09 (dd, J = 7.61, 0.79 Hz, 1H), 7.74–7.77 (td,
J = 7.75, 1.26 Hz, 1H), 7.67–7.70 (td, J = 7.55, 1.26 Hz, 1H), 7.29 (s, 1H), 4.38–
4
2
1
.48 (dt, J = 47.40, 6.27 Hz, 2H), 2.58–2.62 (dd, J = 12.58, 6.15 Hz, 1H), 2.43–
.46 (dd, J = 12.63, 8.33 Hz, 1H), 1.81–1.86 (m, 1H), 1.64–1.73 (m, 2H), 1.21–
13
3
.44 (m, 8H), 0.88 (d, J = 6.61 Hz, 3H). C NMR (150 MHz, CDCl ) d 185.1,
181.6, 153.7, 135.1, 133.2, 133.1, 129.7, 127.1, 126.3, 124.2, 85.0, 83.9, 37.4,
À1
3
2
3.0, 31.0, 30.7, 30.5, 29.7, 27.2, 25.4, 25.4, 19.9. FT-IR (CH
Cl
2 2
, cm ) estim.
19
922, 2851, 1640, 1589, 1363, 1272, 1223, 726. F NMR (565 MHz, CDCl
3
) d
+
À217.95. HRMS (ESI) calcd for C19
H O F [M+H] : 319.1709, found 319.1702.
24 3
23
[a
]
D 2 2
+7.9 (CH Cl ).
2
2. Kim, D. W.; Ahn, D.; Oh, Y.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee, S. J.; Kim, J. S.; Ryu, J.
S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006, 128, 16394–16397.
3. Landini, D.; Maia, A.; Rampoldi, A. J. Org. Chem. 1989, 54, 328–332.
2
In conclusion, we have synthesized monofluorinated 3-alkyl-2-
24. Albanese, D.; Landini, D.; Penso, M. J. Org. Chem. 1998, 63, 9587–9589.
25. Methyl 8-fluorooctanoate (13). Clear oil. R = 0.75 (3:1 hexanes/ethyl acetate).
) d 4.37–4.49 (dt, J = 47.47, 6.26 Hz, 2H), 3.67 (s, 3H),
hydroxy-1,4-naphthoquinone 4 in 8 steps in 31% overall yield from
f
1
-bromooctanoic acid (10).2
5–31
Biological evaluation of this
complex of the
H NMR (600 MHz, CDCl
.29–2.32 (t, J = 7.52 Hz, 2H), 1.60–1.73 (m, 4H), 1.33–1.40 (m, 6H). C NMR
150 MHz, CDCl ) d 174.4, 84.9, 83.8, 51.7, 34.2, 30.6, 30.5, 29.2, 29.1, 27.8,
25.2, 25.0. F NMR (565 MHz, CDCl
) d À218.15.
6. 8-Fluorooctanoic acid (9). Clear oil. R
= 0.45 (3:1 hexanes/ethyl acetate). 1
NMR (600 MHz, CDCl ) d 4.38–4.49 (dt, J = 47.42, 6.13 Hz, 2H), 2.34–2.37 (t,
3
8
13
2
(
compound as an inhibitor of the cytochrome bc
1
3
19
malaria parasite is in progress and will be reported in due course.
3
2
f
H
3
Acknowledgments
13
J = 7.59 Hz, 2H), 1.62–1.74 (m, 4H), 1.35–1.43 (m, 6H). C NMR (150 MHz,
CDCl
CDCl
3
) d 179.0, 84.9, 83.8, 34.0, 30.6, 30.5, 29.1, 25.2, 24.8. 19F NMR (565 MHz,
) d À218.16.
3
E.E.K. acknowledges support from the Zabriskie Fellowship
Fund at the Dartmouth College. This work was supported in part
by the Donors of the Petroleum Research Fund administered by
the American Chemical Society.
2
f
7. (S)-4-Benzyl-3-(8-fluorooctanoyl)oxazolidin-2-one (15). Clear oil. R = 0.50 (3:1
hexanes/ethyl acetate). 1H NMR (600 MHz, CDCl
4.70 (m, 1H), 4.38–4.50 (dt, J = 47.49, 6.41 Hz, 2H), 4.15–4.22 (m, 2H), 3.28–
3
) d 7.20–7.35 (m, 5H), 4.65–
3
9
.31 (dd, J = 13.29, 3.08 Hz, 1H), 2.87–3.01 (m, 2H), 2.74–2.79 (dd, J = 13.90,
.72 Hz, 1H), 1.65–1.75 (m, 4H), 1.37–1.45 (m, 6H). 13C NMR (150 MHz, CDCl
3
)
d 173.5, 153.7, 135.5, 129.6, 129.2, 127.6, 84.9, 83.8, 66.4, 55.4, 38.2, 35.7, 29.2,
25.3, 25.2, 24.3. 19F NMR (565 MHz, CDCl
) d À218.10. FT-IR (CH
Cl
, cm
3
À1
)
Supplementary data
3
2
2
estim. 2932, 1781, 1698, 1387, 1212, 703. HRMS (ESI) calcd for C18
H
24NO
FNa
+
[
M+Na] : 344.1638, found 344.1634.
8. (S)-4-Benzyl-3-((S)-8-fluoro-2-methyloctanoyl)oxazolidin-2-one (16). Clear
oil. R ) d 7.21–
= 0.60 (3:1 hexanes/ethyl acetate). 1H NMR (600 MHz, CDCl
.35 (m, 5H), 4.65–4.70 (m, 1H), 4.37–4.49 (dt, J = 47.26, 6.19 Hz, 2H), 4.16–
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
2
f
3
7
4
1
0
54.
.22 (m, 2H), 3.69–3.73 (m, J = 6.85 Hz, 1H), 3.25–3.28 (dd, J = 13.24, 3.44 Hz,
H), 2.74–2.79 (dd, J = 13.54, 9.54 Hz, 1H), 1.63–1.79 (m, 3H), 1.30–1.44 (m,
3
) d 177.5, 153.3, 135.5,
29.2, 127.6, 84.9, 83.8, 66.2, 55.6, 38.1, 37.9, 33.5, 30.6, 29.4, 27.3, 25.3. FT-IR
13
References and notes
7H), 1.21 (d, J = 7.05 Hz, 3H). C NMR (150 MHz, CDCl
1
À1
19
(
CH
2 2 3
Cl , cm ) estim. 2931, 1774, 1697, 1386, 1208. F NMR (565 MHz, CDCl )
+
1
.
Kessl, J. J.; Lange, B. B.; Merbitz-Zahradnik, T.; Zwicker, K.; Hill, P.; Meunier, B.;
d À218.10. HRMS (ESI) calcd for C19
H
3
26NO FNa [M+Na] : 358.1794, found
Pálsdóttir, H.; Hunte, C.; Meshnick, S.; Trumpower, B. L. J. Biol. Chem. 2003, 278,
23
3
58.1787. [
9. (S)-8-Fluoro-2-methyloctan-1-ol (17). Clear oil. R
acetate). 1H NMR (600 MHz, CDCl
) d 4.38–4.49 (dt, J = 47.40, 6.26 Hz, 2H),
.49–3.52 (dd, J = 10.43, 5.87 Hz, 1H), 3.40–3.44 (dd, J = 10.41, 6.48 Hz, 1H),
.64–1.74 (m, 2H), 1.58–1.63 (m, 1H), 1.24–1.41 (m, 8H), 0.91 (d, J = 6.76, 3H).
D 2 2
a] +76.3 (CH Cl ).
3
1312–31318.
2
f
= 0.50 (3:1 hexanes/ethyl
2
3
.
.
Kessl, J. J.; Meshnick, S. R.; Trumpower, B. L. Trends Parasitol. 2007, 23, 494–501.
Kessl, J. J.; Moskalev, N. V.; Gribble, G. W.; Nasr, M.; Meshnick, S. R.;
Trumpower, B. L. Biochim. Biophys. Acta 2007, 1767, 319–326.
Hughes, L. M.; Lanteri, C. A.; O’Neil, M. T.; Johnson, J. D.; Gribble, G. W.;
Trumpower, B. L. Mol. Biochem. Parasitol. 2011, 177, 12–19.
3
3
1
4
.
.
13
C NMR (150 MHz, CDCl
3
) d 129.1, 85.0, 83.9, 68.6, 36.0, 33.2, 29.7, 27.1, 25.4,
À1
19
2
5.3, 16.8. FT-IR (CH
2
Cl
3
2
, cm ) estim. 3355, 2930, 2858, 2360, 1458, 1038.
F
5
Barton, V.; Fisher, N.; Biagini, G. A.; Ward, S. A.; O’Neill, P. M. Curr. Opin. Chem.
Biol. 2010, 14, 440–446.
23
NMR (565 MHz, CDCl
) d À218.05. [
a
]
D
À11.7 (CH
= 0.80 (3:1 hexanes/ethyl
) d 9.61–9.62 (d, J = 2.04 Hz, 1H), 4.38–
.49 (dt, J = 47.25, 6.11 Hz, 2H), 2.30–2.37 (m, 1H), 1.69–1.74 (m, 2H), 1.63–
.68 (m, 2H), 1.33–1.43 (m, 7H), 1.09 (d, J = 7.18 Hz, 3H). 13C NMR (150 MHz,
) d 205.5, 85.0, 83.7, 46.5, 30.6, 30.4, 29.4, 27.0, 25.3, 13.6. FT-IR (CH Cl
cm ) estim. 2936, 2860, 2359, 1811, 1706, 1457, 1004. F NMR (565 MHz,
2 2
Cl ).
3
0. (S)-8-Fluoro-2-methyloctanal (7). Clear oil.
R
f
6
7
.
.
Fieser, L. F.; Chang, F. C. J. Pharmacol. Exp. Ther. 1948, 94, 85–96.
Hughes, L. M.; Covian, R.; Gribble, G. W.; Trumpower, B. L. Biochim. Biophys.
Acta 2010, 1797, 38–43.
acetate). 1H NMR (500 MHz, CDCl
3
4
1
8
9
.
.
Wu, C.; Brik, A.; Wang, S.; Chen, Y.; Wong, C. ChemBioChem 2005, 6, 2176–2180.
Xia, Y.; Qu, F.; Maggiani, A.; Sengupta, K.; Liu, C.; Peng, L. Org. Lett. 2011, 13,
CDCl
3
2
2
,
À1
19
4
248–4251.
+
CDCl
59.1184. [
1. (S)-2-(8-Bromo-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (6). Yellow
solid. Mp 81–82 °C. R
= 0.70 (3:1 hexanes/ethyl acetate). 1H NMR (500 MHz,
CDCl ) d 8.10–8.12 (dd, J = 7.63, 0.83 Hz, 1H), 8.07–8.08 (dd, J = 7.57, 0.91 Hz,
3
) d À218.26. HRMS (ESI) calcd for C
9
H11OF [M+H] : 159.1174, found
1
1
1
1
1
0. Buckle, F. J.; Pattison, F. L. M.; Saunders, B. C. J. Chem. Soc. 1949, 1471–1479.
1. Kim, D. W.; Jeong, H.; Lim, S. T.; Sohn, M. Tetrahedron Lett. 2010, 51, 432–434.
2. Ji, Q.; Miljanic, O. J. Org. Chem. 2013, 78, 12710–12716.
3. Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373–383.
4. Chen, H.; Feng, Y.; Xu, Z.; Ye, T. Tetrahedron 2005, 61, 11132–11140.
23
1
D 2 2
a] +11.7 (CH Cl ).
3
f
3
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.054

4
E. E. Kim et al. / Tetrahedron Letters xxx (2015) xxx–xxx
1
7
2
H), 7.73–7.76 (td, J = 7.48, 1.33 Hz, 1H), 7.66–7.69 (td, J = 7.45, 1.21 Hz, 1H),
.33 (s, 1H), 3.39 (t, J = 7.21 Hz, 2H), 2.57–2.61 (dd, J = 12.31, 5.96 Hz, 1H),
.42–2.45 (dd, J = 12.51, 8.41 Hz, 1H), 1.81–1.85 (m, J = 7.56 Hz, 3H), 1.29–1.42
153.7, 135.1, 133.2, 133.1, 129.7, 127.0, 126.3, 124.2, 37.3, 34.2, 33.0, 33.0,
À1
30.9, 29.1, 28.4, 27.1, 19.9. FT-IR (CH
2
Cl
2
, cm ) estim. 3350, 2900, 1630, 1600,
Br: 379.0909, found 379.0894.
1350, 1250, 700. HRMS (ESI) calcd for C19
24 3
H O
1
3
23
(
m, 8H), 0.88 (d, J = 6.52 Hz, 3H). C NMR (150 MHz, CDCl
3
) d 185.1, 181.6,
D 2 2
[a] +0.9 (CH Cl ).
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.054