Three-component reductive alkylation of 2-hydroxy-1,4-naphthoquinones with lactols

Article abstract of DOI:10.1016/j.tetlet.2016.01.036

Lactols II, obtained by DIBAL reduction of their corresponding lactones I, in equilibrium with their hydroxyaldehyde tautomers III were used in a three-component reductive alkylation with 2-hydroxy-1,4-naphthoquinone to give a series of 3-alkylated 2-hydroxy-1,4-naphthoquinone derivatives IV.

Full text of DOI:10.1016/j.tetlet.2016.01.036

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component reductive alkylation of 2-hydroxy-1,
4-naphthoquinones with lactols
⇑
Eliana E. Kim, Evans O. Onyango, Jennifer R. Pace, Timothy M. Abbot, 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:
Lactols II, obtained by DIBAL reduction of their corresponding lactones I, in equilibrium with their
hydroxyaldehyde tautomers III were used in a three-component reductive alkylation with 2-hydroxy-
Received 18 November 2015
Revised 9 January 2016
Accepted 11 January 2016
Available online xxxx
1,4-naphthoquinone to give a series of 3-alkylated 2-hydroxy-1,4-naphthoquinone derivatives IV.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Three-component reductive alkylation
Lactol
Hydroxyaldehyde
Naphthoquinone
Malaria
We recently reported the synthesis of monofluorinated 3-alkyl-
-hydroxy-1,4-naphthoquinone 1 by the -proline-catalyzed three-
than the literature methods.7,8 For example, the synthesis of 9
using m-CPBA required extended reaction times (1–14 days) and
9
2
L
component reductive alkylation (TCRA) of 2-hydroxy-1,4-naphtho-
quinone (2) with chiral aldehyde 3 (Fig. 1).1 Fluorinated 1 has
been touted as a potential anti-malarial compound that could
enhance the species selectivity and metabolic stability of ato-
were often complicated by the removal of unreacted starting mate-
2
f
rial that has a nearly identical TLC R and boiling point to the prod-
7
uct. Also, other Baeyer–Villiger oxidation procedures were equally
encumbered by isolation and purification problems. With 9 in
vaquone and other inhibitors of the cytochrome bc
1
complex of
hand, a-methylation to afford 10 was achieved in 95% yield upon
the malaria parasite Plasmodium falciparum.3
treatment of 9 with lithium diisopropyl amide (LDA) at À78 °C fol-
1
0
Following our enantioselective synthesis of 1 and for the pur-
pose of determining its enantiomeric excess in order to support
further biological assays, we needed to synthesize the racemic
mixture for comparison. We had initially planned to utilize the
lowed by the addition of MeI. Even though 3-methyloxonan-2-
one (10) is a known compound, a recent article reporting on its
thermodynamic properties did not provide details for its prepara-
1
1
tion. Next, partial DIBAL reduction of 10 gave hydroxyaldehyde
11 in equilibrium with a small amount of its lactol tautomer 12.
chemistry already established. However, despite literature prece-
4
dence for
(
a
-methylation of methyl esters, our attempts to alkylate
Subsequent
L-proline-catalyzed three-component reductive
1
LDA or NaHMDS/MeI) the methyl ester 7 failed to provide suffi-
alkylation of 2 and Hantzsch ester (5) gave lawsone derivative
1
,12
cient quantities of 8 (Scheme 1).
13, a precursor to 1, in a yield of 89% (Scheme 3).
This reaction
As an alternative, we synthesized the lactone 9 in 70% yield by
mirrors the previously reported aldol reactions employing lactols
in equilibrium with their hydroxyaldehydes.
To expand the scope of this reaction, other lactones 14–18 were
either obtained from commercial sources or synthesized from their
corresponding cycloketones via standard m-CPBA oxidation.
1
3,14
2
treating 8-bromooctanoic acid (4) with TBAFÁ3H O in tert-butanol
at 70 °C overnight (Scheme 2). The trace amount of the 8-fluorooc-
tanoic acid side product from this reaction was easily removed by
column chromatography. While the tetra-n-butyl-ammonium flu-
oride trihydrate (TBAFÁ3H
2
O)-induced esterification of halo car-
Methylated lactones were also either commercially available or
5,6
synthesized via literature procedures (Table 1, entries 47 and 5
)
15
boxylic acids has been reported in the literature,
this is the
first time oxonan-2-one (9) has been synthesized by this method-
ology. Furthermore, our new synthesis of 9 is much more efficient
using LDA or NaHMDS with MeI. The TCRA reaction of DIBAL prod-
ucts from these lactones proceeded smoothly to furnish 2-
hydroxy-1,4-naphthoquinones. Representative examples, 19–
1
6,17
2
4,
are summarized in Table 1. In general, DIBAL reduction of
⇑
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
small ring lactones (butyro- and valerolactone) (Table 1, entries 1
http://dx.doi.org/10.1016/j.tetlet.2016.01.036
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.036

2
E. E. Kim et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Figure 1. Previous synthesis of monofluorinated 3-alkyl-2-hydroxy-1,4-naphthoquinone 1.
Scheme 1. Attempted a-methylation of fluoro methyl ester 7.
and 2) predominantly gave the lactol tautomer. In contrast, large
ring lactones favored the hydroxyaldehyde tautomer upon DIBAL
reduction. These results are in complete agreement with literature
1
8
observations. In all cases, a two-to-one equivalent ratio of the
lactol II or hydroxyaldehyde III to the 2-hydroxy-1,4-hydroxy-
naphthoquinone (2) was crucial for complete alkylation
(Scheme 4). Regardless of the tautomeric equilibrium composition
of the DIBAL reduction products, the reactions were all high yield-
ing. Also, whereas the reaction proceeded slowly at room temper-
ature, refluxing in CH Cl not only dramatically improved the yield,
2 2
but also prevented the tetrahydropyranylation or tetrahydrofu-
ranylation of the terminal hydroxyl group (vide infra entry 1).
We also note that the yield from the alkylation reaction with
butyrolactol was lower for the room temperature reaction and
this was attributed to tetrahydrofuranylation of the terminal
hydroxyl group (Table 1, entry 1). The same result was observed,
to a smaller extent, with valerolactol. The masking of the termi-
nal hydroxyl group leading to the formation of 20 was not sur-
prising considering the fact that the TCRA reaction employed 2
equiv of the lactol/hydroxyaldehyde in an acidic reaction med-
ium. Thus, after the initial reductive alkylation reaction, the ter-
minal hydroxyl reacts with either excess lactol or its
hydroxyaldehyde tautomer to form 20. However, at elevated
Scheme 3. Synthesis of lawsone derivative 13.
temperatures the rate of hydrolysis (reverse reaction) is probably
faster than that of tetrahydrofuranylation. We attempted to slow
down tetrahydrofuranylation by reducing the aldehyde equiva-
lents; however, in all cases a one-to-one ratio of aldehyde to
hydroxynaphthoquinone 2 did not afford complete reaction even
with extended reaction times. In any case, the overall yields of 19
and 21 could be improved by acid hydrolysis of their correspond-
ing THP or THF ethers. Furthermore, because the products from
TCRA reactions contain both enolic and terminal hydroxyl groups,
Scheme 2. Synthesis and DIBAL reduction of lactone 10.
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E. E. Kim et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 1
-Alkyl-2-hydroxy-1,4-naphthoquinone derivatives
3
Entry
Lactone
Product
Yield
8
7
9a
1
7b
2
3
4
5
6
7
95a
87a
74b
91a
88a
89a
a
These reactions were refluxed.
These reactions were run at room temperature.
b
Scheme 4. General synthetic approach to lawsone derivatives.
selective masking of the terminal hydroxyl group is a serendipi-
tous outcome that could potentially be utilized to achieve further
synthetic modifications on these molecules.
Acknowledgments
E.E.K. acknowledges support from the Zabriskie Fellowship
Fund at Dartmouth College, and J.R.P. had an iSURF fellowship. This
work was supported in part by the Donors of the Petroleum
Research Fund administered by the American Chemical Society,
and in part by an Institutional Development Award (IDeA) from
the National Institute of General Medical Sciences of the National
Institutes of Health under grant number P20GM103506.
In summary, we have synthesized 3-alkyl-2-hydroxy-1,4-
naphthoquinone 13, a precursor to (±)1, in 3 steps from commer-
cially available 8-bromooctanoic acid. Interest1
9,20
in lawsone (2-
hydroxy-1,4-naphthoquinone) derivatives with 3-alkyl side
chains ending in OH or other functional groups has increased fol-
lowing the seminal publication by Machatzke et al.2
1,22
These
derivatives are potential inhibitors of various parasites including
Plasmodium falciparum. Our work therefore not only provides a
known 2-hydroxy-1,4-naphthoquinone derivative22 but also
intermediates that could potentially be converted to known
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.036.
1
9–21
compounds.
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.036

4
E. E. Kim et al. / Tetrahedron Letters xxx (2016) xxx–xxx
2
1
2
.06 (m, 4H), 1.54–1.72 (m, 4H). 13C NMR (125 MHz, CDCl
) d 184.9, 181.7,
3
53.4, 135.1, 133.2, 133.1, 129.7, 127.0, 126.3, 124.6, 104.0, 67.2, 67.0, 32.5,
9.9, 25.2, 23.7, 23.3.
References and notes
1
2
3
.
.
.
Kim, E. E.; Onyango, E. O.; Fu, L.; Gribble, G. W. Tetrahedron Lett. 2015, 56,
707–6710.
Hughes, L. M.; Covian, R.; Gribble, G. W.; Trumpower, B. L. Biochim. Biophys.
Acta 2010, 1797, 38–43.
Kessl, J. J.; Moskalev, N. V.; Gribble, G. W.; Nasr, M.; Meshnick, S. R.;
Trumpower, B. L. Biochim. Biophys. Acta 2007, 1767, 319–326.
Dickschat, J. S.; Bruns, H.; Riclea, R. Beilstein J. Org. Chem. 2011, 7, 1697–1712.
Ooi, T.; Sugimoto, H.; Doda, K.; Maruoka, K. Tetrahedron Lett. 2001, 42, 9245–
Compound 21. Yellow solid (95%). Mp 97–99 °C. R
f
= 0.50 (1:1 hexanes/ethyl
6
acetate). 1H NMR (500 MHz, CDCl
3
) d 8.11–8.13 (dd, J = 7.65, 0.93 Hz, 1H),
.07–8.08 (dd, J = 7.54, 1.21 Hz, 1H), 7.74–7.77 (td, J = 7.45, 1.40 Hz, 1H), 7.66–
.70 (td, J = 7.45, 1.21 Hz, 1H), 7.34 (br s, 1H), 3.64–3.67 (t, J = 6.37 Hz, 2H),
8
7
2
1
2
1
2
13
3
.61–2.64 (t, J = 7.66 Hz, 2H), 1.42–1.65 (m, 6H). C NMR (150 MHz, CDCl ) d
85.0, 181.7, 153.3, 135.1, 133.2, 133.1, 129.7, 127.0, 126.3, 124.7, 63.1, 32.7,
4
5
.
.
À1
8.2, 26.0, 23.4. FT-IR (CH
2
Cl
2
, cm ) estim. 3350, 2930, 2860, 1670, 1640,
590, 1460, 1370, 1270, 1210, 1020, 720. HRMS (ESI) calcd for C15
59.0970, found 259.0969.
15 4
H O :
9
248.
6.
7.
8.
Wu, C.; Brik, A.; Wang, S.; Chen, Y.; Wong, C. ChemBioChem 2005, 6, 2176–2180.
Lei, Z.; Ma, G.; Wei, L.; Yang, Q.; Su, B. Catal. Lett. 2008, 125, 330–333.
Van der Mee, L.; Helmich, F.; de Bruijin, R.; Vekemans, J. A. J. M.; Palmans, A. R.
A.; Meijer, E. W. Macromolecules 2006, 39, 5021–5027.
Compound 22. Yellow solid (87%). Mp 104 °C. R
f
= 0.45 (1:1 hexanes/ethyl
acetate). 1H NMR (500 MHz, CDCl
3
) d 8.11–8.13 (dd, J = 7.62, 0.86 Hz, 1H),
.07–8.09 (dd, J = 7.59, 0.89 Hz, 1H), 7.74–7.77 (td, J = 7.51, 1.30 Hz, 1H), 7.67–
.70 (td, J = 7.54, 1.20 Hz, 1H), 7.29 (br s, 1H), 3.63–3.65 (t, J = 6.51 Hz, 2H),
8
7
2
1
2
1
9
.
Koopmans, C.; Iannelli, M.; Kerep, P.; Klink, M.; Schmitz, S.; Sinnwell, S.; Ritter,
H. Tetrahedron 2006, 62, 4709–4724.
13
3
.60–2.62 (t, J = 7.65 Hz, 2H), 1.40–1.59 (m, 8H). C NMR (150 MHz, CDCl ) d
85.0, 181.7, 153.3, 135.1, 133.2, 133.1, 129.7, 127.0, 126.3, 124.9, 63.2, 32.9,
1
1
1
1
0. Temme, O.; Taj, S.; Andersson, P. G. J. Org. Chem. 1998, 63, 6007–6015.
1. Stepurko, E.; Roganov, G. Fibre Chem. 2015, 2, 80–89.
2. Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011, 9, 1277–1300.
3. Masuyama, Y.; Kobayashi, Y.; Kurusu, Y. J. Chem. Soc., Chem. Commun. 1994,
À1
9.6, 28.4, 25.7, 23.4. FT-IR (CH
Cl
2 2
, cm ) estim. 3440, 2930, 1670, 1630, 1590,
460, 1350, 1270, 1210, 1020, 720. HRMS (ESI) calcd for C16
H
17
O
4
: 273.1127,
found 273.1125.
Compound 23. Thick brown oil (74%). 1H NMR (500 MHz, CDCl
3
) d 8.07–8.11 (m,
1
123.
4. Tomooka, K.; Okinaga, T.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28,
335–6338.
J = 10.0 Hz, 2H), 7.67–7.75 (dd, J = 35.5, 12.5 Hz, 2H), 7.40 (br s, 1H), 3.62–3.67
(m, 2H), 2.53–2.55 (m, 2H), 1.10–1.25 (m, 7H), 0.87–0.92 (d, J = 10.0 Hz, 3H).
13
1
6
C NMR (150 MHz, CDCl
26.3, 124.8, 63.5, 44.7, 34.8, 34.0, 32.0, 28.2, 27.9, 24.0. HRMS (ESI) calcd for
: 329.1753, found 329.1746.
3
) d 185.0, 181.7, 153.3, 135.1, 133.1, 129.7, 127.0,
1
5. Arnold, W.; Mohr, P. Synlett 1996, 1215–1217.
1
C
1
6. General Procedure for the TCRA reaction. A mixture of the DIBAL reduction
product (lactol/hydroxyaldehyde) (2 equiv), 2-hydroxy-1,4-naphthoquinone
20
25 4
H O
Compound 24. Thick brown oil (91%). 1H NMR (500 MHz, CDCl
3
) d 8.07–8.13
dd, J = 24.52, 7.55 Hz, 2H), 7.67–7.76 (dt, J = 42.77, 7.68 Hz, 1H), 7.33 (br s, 1H),
(
1 equiv), the Hantzsch ester (1 equiv), and
L
-Proline (0.5 equiv) in CH
2 2
Cl
(
(
0.3 M) was refluxed overnight. After cooling to room temperature, SiO
2
was
3
.65–3.70 (m, 2H), 2.57–2.60 (t, J = 7.74 Hz, 2H), 1.25–1.60 (m, 7H), 0.90–0.91
added to the reaction mixture, which was then concentrated in vacuo, and
purified via dry-pack column chromatography to afford the final product.
13
(
3
d, J = 6.53 Hz, 3H). C NMR (125 MHz, CDCl ) d 185.0, 181.7, 153.3, 135.1,
1
33.2, 133.1, 129.7, 127.0, 126.3, 124.9, 61.4, 40.3, 37.1, 29.4, 25.8, 23.6, 19.8.
1
7. Compound1 13. Yellow solid (89%). Mp 98 °C.
acetate). H NMR (500 MHz, CDCl ) d 8.08–8.13 (dd, J = 7.53, 0.97 Hz, 1H),
.08–8.09 (dd, J = 7.53, 0.97 Hz, 1H), 7.74–7.77 (td, J = 7.57, 1.19 Hz, 1H), 7.67–
R
f
= 0.50 (1:1 hexanes/ethyl
À1
FT-IR (CH
1
2
Cl
2
, cm ) estim. 3350, 2930, 1670, 1640, 1590, 1460, 1370, 1270,
3
220, 1040, 730. HRMS (ESI) calcd for C17
H
19
O
4
: 287.1283, found 287.1282.
= 0.45 (1:1 hexanes/ethyl
8
7
2
1
Compound 25. Yellow solid (88%). Mp 93 °C.
R
f
.70 (td, J = 7.57, 1.19 Hz, 1H), 7.32 (br s, 1H), 3.63–3.65 (t, J = 6.55 Hz, 2H),
.59–2.62 (dd, J = 12.39, 6.29 Hz, 1H), 2.43–2.46 (dd, J = 12.39, 8.53 Hz, 1H),
.82–1.85 (m, 1H), 1.54–1.59 (m, 2H), 1.22–1.42 (m, 8H), 0.88–0.89 (d,
acetate). 1H NMR (500 MHz, CDCl
) d 8.12–8.13 (dd, J = 7.81, 0.89 Hz, 1H),
.07–8.09 (dd, J = 7.60, 0.95 Hz, 1H), 7.74–7.77 (td, J = 7.62, 1.35 Hz, 1H), 7.67–
7.69 (td, J = 7.52, 1.20 Hz, 1H), 7.29 (br s, 1H), 3.63–3.65 (t, J = 6.45 Hz, 2H),
3
8
13
J = 6.89 Hz, 3H). C NMR (150 MHz, CDCl
3
) d 185.1, 181.6, 153.8, 135.1, 133.2,
Cl
cm ) estim. 3360, 2930, 2850, 1640, 1590, 1460, 1370, 1270, 1220, 1020, 730.
HRMS (ESI) calcd for C19 : 315.1596, found 315.1593.
Compound 19. Yellow solid (89%). Mp 143–144 °C. R = 0.40 (1:1 hexanes/ethyl
13
2
3
.59–2.61 (t, J = 7.53 Hz, 2H), 1.33–1.58 (m, 12H). C NMR (150 MHz, CDCl ) d
1
33.1, 129.7, 127.1, 126.3, 124.3, 63.3, 37.4, 31.0, 27.2, 20.0. FT-IR (CH
2
2
,
À1
185.0, 181.7, 153.4, 148.8, 134.9, 133.1, 133.0, 129.7, 126.9, 126.2, 125.0, 63.2,
3
À1
2.9, 32.8, 32.6, 29.8, 29.5, 29.3, 28.3, 28.2, 25.8, 23.5. FT-IR (CH
Cl
2 2
, cm
)
23 4
H O
estim. 3500, 3210, 2920, 2850, 2360, 2340, 1670, 1640, 1590, 1460, 1360, 1270,
1220, 1030, 720. HRMS (ESI) calcd for C : 301.1440, found 301.1433.
8. Valters, R. E.; Flitsch, W. Ring-Chain Tautomerism; Plenum Press: New York,
985.
19. Lu, X.; Altharawi, A.; Gut, J.; Rosenthal, P. J.; Long, T. E. ACS Med. Chem. Lett.
012, 3, 1029–1033.
f
acetate). 1H NMR (500 MHz, CDCl
) d 8.11–8.13 (dd, J = 7.42, 0.90 Hz, 1H),
.09–8.08 (dd, J = 7.63, 0.90 Hz, 1H), 7.74–7.78 (td, J = 7.56, 1.33 Hz, 1H), 7.67–
.70 (td, J = 7.60, 1.33 Hz, 1H), 7.34 (br s, 1H), 3.70 (t, J = 6.15 Hz, 2H), 2.65 (t,
18 21 4
H O
3
1
8
7
1
1
3
J = 7.27 Hz, 2H), 1.66–1.26 (m, 4H). C NMR (150 MHz, CDCl
3
) d 185.0, 181.6,
2
1
53.4, 135.1, 133.2, 133.1, 129.7, 127.0, 126.3, 124.5, 62.9, 32.6, 24.6, 23.0. FT-
À1
20. Nasiri, H. R.; Madej, M. G.; Panisch, R.; Lafontaine, M.; Bats, J.; Lancaster, C.;
IR (CH
Cl
2 2
, cm ) estim. 2920, 2360, 2340, 1630, 1590, 1460, 1350, 1210, 1070,
: 245.0814, found 245.0811.
Compound 20. Yellow solid (77%). Mp 84 °C. = 0.70 (1:1 hexanes/ethyl
Schwalbe, H. J. Med. Chem. 2013, 56, 9530–9541.
1. Machatzke, H.; Vaughan, W. R.; Warren, C. L.; White, G. R. J. Pharm. Sci. 1967,
56, 86–91.
7
13 4
20. HRMS (ESI) calcd for C14H O
2
R
f
acetate). 1H NMR (500 MHz, CDCl
) d 8.09 (ddd, J = 20.0, 9.0, 2.0 Hz, 2H), 7.71
dtd, J = 36.0, 8.0, 2.0 Hz, 2H), 7.32–7.43 (br s, 1H), 5.10 (dd, J = 5.0, 2.0 Hz, 1H),
3
2
2. Machatzke, H.; Vaughan, W. R.; Warren, C. L.; White, G. R. J. Pharm. Sci. 1968,
(
5
7, 520–523.
3
.80–3.92 (m, 2H), 3.53 (ddt, J = 142.5, 9.5, 6.0 Hz), 2.59–2.67 (m, 2H), 1.74–
Please cite this article in press as: Kim, E. E.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.036