Nitromethyl benzoate annulation reactions: A rapid construction of the stealthin skeleton

Article abstract of DOI:10.1016/j.tetlet.2012.06.051

The annulation of 2-(nitromethyl)benzoates with enones gave 4-nitro-1-naphthols in good yields. The carbocyclic framework of the stealthins was synthesized.

Full text of DOI:10.1016/j.tetlet.2012.06.051

Tetrahedron Letters 53 (2012) 4444–4446
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Tetrahedron Letters
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Nitromethyl benzoate annulation reactions: a rapid construction of the
stealthin skeleton
⇑
George A. Kraus , Divya Chaudhary, Yi Yuan, Andrew Schuster
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The annulation of 2-(nitromethyl)benzoates with enones gave 4-nitro-1-naphthols in good yields. The
carbocyclic framework of the stealthins was synthesized.
Received 11 May 2012
Revised 8 June 2012
Accepted 11 June 2012
Available online 16 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Annulation
Quinone
Stealthin
Nitro
Carbanion
Quinones can be conveniently and regioselectively prepared
using annulation reactions with phthalide 1 or ester 2 and suitable
Michael acceptors.1–3 As part of a program to enhance natural anti-
oxidants,4 we needed a flexible synthesis of the stealthin skeleton
shown in Figure 1. Stealthin A (3) and stealthin C (4) are members
of a class of tetracyclic natural products isolated from Streptomyces
viridochromogenes.6 Stealthin A inhibited peroxylipid formation at
IC50 of 0.04 mg/mL versus 10.8 mg/mL for vitamin E.7 Syntheses
of these compounds were reported by Snieckus and others.8
Although a cyclopentenone or an indenone would be the logical
Michael acceptor, annulation reactions involving cyclopentenones
and indenones can proceed in low yields due to their sensitivity
to strongly basic conditions. Based on reports that nitroalkanes un-
dergo efficient Michael addition to cyclopentenones,5 we envis-
aged a direct route to compounds such as 3 or 4 beginning from
indenones. Our route generates the naphthol more efficiently than
previous approaches.
Ester 5 was readily prepared in 32% yield from the methyl ester
of ortho-toluic acid by bromination followed by displacement of
the bromide with silver nitrite in ether.9 As shown in Scheme 1, es-
ter 5 was treated with cyclopentenone in acetonitrile to form the
Michael adduct which cyclized using NaOMe in THF in 54% yield.
Conversion to phenol 6 proceeded smoothly using DDQ in toluene
or air in DMSO.10
with indenone, dicyclopentadienone,11 tetrahydroindenone, and
phenyl vinyl ketone afforded phenols 7, 8, 9, and 10 in yields of
64%, 47%, 27%, and 22%, respectively, as shown in Figure 2. The
melting point of 10 matched that reported in the literature.12
Our strategy for assembling the stealthin skeleton, depicted be-
low in Scheme 2, begins with ester 11, readily available from ethyl
acetoacetate.13 Benzylic bromination using NBS and AIBN in ben-
zene produced the benzylic bromide in 75% yield. Treatment with
silver nitrite in ether produced ester 12 in 50% yield.
Indenone 14 was prepared from 6-methyldihydrocoumarin (13)
as shown in Scheme 3. An intramolecular Friedel–Crafts acylation
generated the indanone in 71% yield. The phenol was protected
as a benzenesulfonate in 87% yield. Treatment with HIO3 in
DMSO14 afforded indenone 14 in 87% yield.
As shown in Scheme 4, the reaction of 12 and 14 with DBU in
acetonitrile produced a Michael addition product in 72% yield.
The product was treated at À78 °C with 2.2 equiv of lithium
diisopropylamide (LDA) to generate tetracyclic ketone 15 in 23%
yield.
O
O
OH
O
NH2
OMe
O
CH2X
The successful annulation with cyclopentenone prompted us to
examine indenone and other Michael acceptors. The reaction of 5
A
A
OH
HO
2
1
3
4
A = CN, SPh, SO2Ph
: X = OH
: X = H
⇑
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0105.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
Figure 1. Stealthin skeleton.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.051

G. A. Kraus et al. / Tetrahedron Letters 53 (2012) 4444–4446
4445
O
Acknowledgments
OH
O
O
OMe
a - c
We thank the Iowa State Department of Chemistry for under-
graduate research support for AS and for graduate student stipend
support for DC.
+
NO2
NO2
6
5
References and notes
Scheme 1. Reagents and conditions: (a) Bu4NOH, MeOH 74%; (b) NaOMe, THF 54%;
(c) air, DMSO 90%.
1. (a) Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. J. Org.
Chem. 1983, 48, 3439–3444; (b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett.
1978, 19, 2263–2266; (c) Kraus, G. A.; Sugimoto, H. Synth. Commun. 1977, 7,
505–508; (d) Hauser, F. M.; Rhee, R. P. J. Am. Chem. Soc. 1979, 101, 1628–1629.
2. (a) Hauser, F. M.; Yin, H. Org. Lett. 2000, 2, 1045–1047; (b) Ray, S.; Patra, A.; Mal,
D. Tetrahedron 2008, 64, 3253–3267.
3. (a) Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3965–3968; (b) Wildeman, J.;
Borgen, P. C.; Pluim, H.; Rouwette, P. H. F. M.; Van Leusen, A. M. Tetrahedron
Lett. 1978, 19, 2213–2216.
OH
OH
O
O
4. Kraus, G. A.; Kumar, G.; Phillips, G.; Michalson, K.; Mangano, M. Bioorg. Med.
Chem. Lett. 2008, 18, 2329–2332.
NO2
NO2
5. (a) Barr, L.; Easton, C. J.; Lee, K.; Lincoln, S. F. Org. Biomol. Chem. 2005, 3, 2990–
2993; (b) Knobloch, K.; Koch, J.; Keller, M.; Eberbach, W. Eur. J. Org. Chem. 2005,
2715–2733; (c) Wang, L.; Meegalla, S. K.; Fang, C.-L.; Taylor, N.; Rodrigo, R. Can.
J. Chem. 2002, 80, 728–738; (d) Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett.
2006, 8, 4787–4790.
8
7
OH
O
OH
O
6. Shinya, K.; Furihata, K.; Teshima, Y.; Hayakawa, Y.; Seto, H. Tetrahedron Lett.
1992, 33, 7025–7028.
7. Seto H.; Hayakawa Y.; Shimazu A. (Kirin Brewery, Japan). Jpn. Kokai Tokkyo
Koho, 12 pp. JP5085998, 1993; Chem. Abstr. 1993, 119:70550.
8. (a) Koyama, H.; Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 203–210; (b)
Mohri, S.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997, 62(21), 7072–7073; (c)
Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187–7194.
NO2
NO2
10
9
9. (a) Hellwinkel, D.; Bohnet, S. Chem. Ber. 1987, 120, 1151–1173; (b) Gandler, J.
R.; Saunders, O. L.; Barbosa, R. J. Org. Chem. 1997, 62, 4677–4682.
10. Danikiewicz, W.; Makosza, M. Tetrahedron Lett. 1985, 26, 3599–3600.
11. Firouzabadi, H.; Sharifi, A. Synthesis 1992, 10, 999–1002.
Figure 2. Adducts of 5 with enones.
12. Compound 10: Ettlinger, M. G. J. Am. Chem. Soc. 1950, 72, 3666–3672.
13. Hauser, F. M.; Pogany, S. A. Synthesis 1980, 814–815.
14. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 1386.
15. Representative experimental:
OBs O
OBs O
a, b
OEt
CH3
OEt
Representative synthesis of compound 7
NO2
To a solution of nitro ester 5 (0.196 g, 1.0 mmol) and 1H-inden-1-one (0.130 g,
1.0 mmol) in acetonitrile (3 mL) was added triton B solution in methanol
(0.085 mL, 40% w/w, 0.2 equiv) at 0 °C. The temperature was allowed to reach
rt and the reaction was monitored by TLC. Then the reaction was quenched
with saturated NH4Cl solution and extracted with EtOAc. Purification on
column chromatography on silica gel using EtOAc/hexane as eluent gave
0.221 g of the open-chain intermediate in 68% yield. Intermediate: mixture of
11
12
Scheme 2. Reagents and conditions: (a) NBS, AIBN, benzene reflux, 75%; (b) AgNO2,
ether 0 °CÀrt, 50%.
two diastereoisomers in
a
ratio of 3:2. Major isomer: 1H NMR (CDCl3,
400 MHz): 8.06 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (m, 1H), 7.71
(m, 2H), 7.56 (m, 2H), 7.39 (m, H), 7.07 (d, J = 8.0 Hz, 1H), 4.42 (m, 1H), 3.73 (s,
3H), 2.81 (m, 2H), 2.42 (m, 1H). 13C NMR (CDCl3, 100 MHz):203.7, 166.7, 151.7,
137.8, 135.6, 134.8, 134.2, 133.4, 131.8, 130.2, 129.8, 127.6, 126.0, 124.2, 88.7,
63.0, 42.6, 40.9. Minor isomer: 1H NMR (CDCl3, 400 MHz): 7.99 (d, J = 8.0 Hz,
1H), 7.79 (d, J = 8.0 Hz, 1H), 7.61 (m, 2H), 7.50 (m, 2H), 7.38 (m, 1H), 6.79 (d,
J = 10.8 Hz, 1H), 6.66 (m, 1H), 4.63 (m, 1H), 3.82 (s, 3H), 2.80 (m, 2H), 2.41 (m,
1H). 13C NMR (CD3COCD3, 100 MHz): 203.2, 167.2, 152.9, 137.1, 135.0, 134.5,
134.0, 133.4, 131.4, 130.4, 129.3, 127.6, 126.1, 124.5, 88.4, 52.8, 42.0, 40.0.
To a solution of intermediate (0.174 g, 0.535 mmol) in THF (20 mL) was added
a solution of sodium methoxide in methanol (0.238 mL, 4.5 M, 2 equiv) at 0 °C,
and it was stirred at rt. After the disappearance of the starting material on TLC,
it was quenched with ice, followed by a saturated NH4Cl solution. The crude
product was extracted with EtOAc, dried over MgSO4, and the solvent was
removed under vacuo. Then the crude product was dissolved in toluene (2 mL)
O
CH3
a - c
CH3
O
O
OSO2Ph
13
14
Scheme 3. Reagents and conditions: (a) AlCl3, NaCl, 200 °C, 71%; (b) Et3N, PhSO2Cl,
THF, rt, 87%; (c) HIO3, DMSO 50 °C, 87%.
OR OH
O
a, b
and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(0.123 g,
0.554 mmol,
12
+ 14
1 equiv) was added in portion at 0 °C. The reaction was stirred at rt. After
the reaction was finished ice was added and it was extracted with EtOAc and
purification on column chromatography on silica gel gave 0.100 gram of
compound 7 in 64% yield. Compound 7: 1H NMR (CD3COCD3, 300 MHz): 8.25 (t,
J = 7.8 Hz, 2H), 8.01 (d, J = 7.8 Hz, 1H), 7.70 (m, 2H), 7.62 (m, 2H), 7.31 (t,
J = 7.8 Hz, 1H). (EI) m/z Calculated for C17H9NO4: 291.0532, Found: 291.0536.
Compound 6: 1H NMR (CD3COCD3, 400 MHz): 8.46 (m, 2H), 7.96 (t, J = 8.0 Hz,
1H), 7.75 (t, J = 8.0 Hz, 1H), 3.58 (m, 2H), 2.58 (m, 2H). HRMS (EI) m/z
Calculated for C13H9NO4: 243.0532; Found: 243.0535.
CH3
RO
15: R = PhSO2
16: R = H
Scheme 4. Reagents and conditions: (a) DBU, CH2Cl2, 0 °C, 72%; (b) 2.2 equiv LDA,
THF, À78–0 °C, 23%.
Compound 8: 1H NMR (CDCl3/CD3COCD3, 400 MHz): 8.40 (d, J = 8.4 Hz, 1H),
8.33 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 5.98 (m,
1H), 5.61 (m, 1H), 4.44 (m, 1H), 3.43 (m, 2H), 2.68 (m, 1H), 1.80 (m, 2H).
Compound 9: 1H NMR (CDCl3/CD3COCD3, 400 MHz): 8.38 (d, J = 8.0 Hz, 1H),
8.33 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 5.85 (m,
1H), 5.71 (m, 1H), 4.23 (m, 1H), 3.09 (m, 1H), 2.59 (m, 2H), 2.42 (m, 2H). HRMS
(EI) m/z Calculated for C17H13NO4:295.0845; Found: 295.0848.
In summary, the Michael addition/Claisen condensation se-
quence affords good overall yields of tricyclic and tetracyclic ad-
ducts.15 It provides an effective route to tetracyclic stealthin
analogs. This pathway will permit the synthesis of an array of ana-
logs similar to 15 for biological testing.
10-hydroxy-2-methyl-11-oxo-11H-benzo[b]fluorene-4, 9-diyl dibenzenesulfonate
(15). To
a stirred solution of ethyl 2-(nitromethyl)-6-((phenylsulfonyl)
oxy)benzoate, 12 (968 mg, 2.65 mmol) and 6-methyl-1-oxo-1H-inden-4-yl
benzenesulfonate, 14 (398 mg, 1.33 mmol) in 10 mL acetonitrile was added

4446
G. A. Kraus et al. / Tetrahedron Letters 53 (2012) 4444–4446
DBU (0.4 ml, 2.65 mmol) at 0 °C and stirred at rt overnight, where it was
washed with brine, dried over MgSO4, and evaporated in vacuo. Purification via
silica gel chromatography (30% ethyl acetate in hexanes) yielded the desired
cyclized product as a yellow compound (86 mg, 25% yield).
worked up with 5% aqueous HCl and extracted with ethyl acetate three times.
The combined organic extracts were washed with brine, dried over MgSO4, and
evaporated in vacuo. Purification via silica gel chromatography (40% ethyl
acetate in hexanes) yielded the desired Michael adduct (637 mg, 72% yield).
To a stirred solution of freshly prepared LDA (2.2 equiv) in THF at À78 °C was
added a solution of the Michael adduct (405 mg, 0.61 mmol) in dry THF
(10 mL). The reaction mixture was allowed to warm to rt, where it was stirred
for 3 h. The reaction mixture was then worked-up with aqueous NH4Cl and
extracted with ethyl acetate three times. The combined organic extracts were
1H NMR (300 MHz, CDCl3): d 7.94 (d, J = 7.2 Hz, 4H), 7.66–7.62 (m, 2H), 7.53–
7.51 (m, 6H), 7.46–7.43 (m, 2H), 7.32 (s, 1H), 7.11(d, J = 8.1 Hz, 1H), 7.09 (s, 1H),
2.38 (s, 3H). 13C NMR (300 MHz, CDCl3): d 21.62, 113.64, 116.39, 119.76,
121.49, 123.67, 128.61, 128.94, 129.22, 129.60, 130.13, 132.73, 134.47, 134.98,
136.19, 138.52, 141.35, 142.03, 145.56, 147.72, 156.65, 194.28.
HRMS (EI) m/z exact mass calculated for C30H21O8S2 [M+H]+: 573.0672. Found
573.0677.