Enantioselective syntheses of bioactive epoxyquinone natural products (+)-harveynone and (-)-asperpentyn

Article abstract of DOI:10.1016/j.tetlet.2012.05.115

Stereo- and enantioselective syntheses of (+)-harveynone and (-)-asperpentyn are reported.

Full text of DOI:10.1016/j.tetlet.2012.05.115

Tetrahedron Letters 53 (2012) 4093–4095
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Tetrahedron Letters
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Enantioselective syntheses of bioactive epoxyquinone natural products
(+)-harveynone and (ꢀ)-asperpentyn
Goverdhan Mehta a,b, , Subhrangsu Roy a, Subhas Chandra Pan a
⇑
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
b School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereo- and enantioselective syntheses of (+)-harveynone and (ꢀ)-asperpentyn are reported.
Received 11 May 2012
Revised 23 May 2012
Accepted 23 May 2012
Available online 7 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Epoxyquinone natural products
Enantioselective total synthesis
Retro-Diels–Alder reaction
Sonogashira coupling
Natural products based on epoxyquinone motif 1 are well
known for their occurrence among diverse sources like bacteria,
fungi, higher plants, and marine sources.1 Epoxyquinone class of
natural products also exhibit remarkable variation in terms of
structural complexity, functional group density, and distribution.
While phyllostine 2,2a ambuic acid 32b, and cycloepoxydone 42c
represent mono and bicyclic variants with relatively modest com-
plexity, heptacyclic torreyanic acid 52d and nonacyclic pestaloqui-
nol A 62e are among the more complex members of this family,
Figure 1. Epoxyquinone natural products exhibit wide-ranging bio-
O
HO
OH
O
C
O
C
R
O
O
CO2H
C5H11
O
OH
O
1 R= OH, =O
2 (-)-Phyllostine
3 (+)-Ambuic acid
HO
COOH
O
O
O
O
OH
O
O
H
O
O
O
O
O
O
COOH
O
O
H
O
O
OH OH
R
H
O
O
R
O
H
R= pentyl
4 (-)-Cycloepoxydone
5 Torreyanic acid
6 Pestaloquinol A
Figure 1. Representative epoxyquinone natural products.
⇑
Corresponding author. Tel.: +91 4023010785; fax: +91 4023012460.
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.115

4094
G. Mehta et al. / Tetrahedron Letters 53 (2012) 4093–4095
ucts that embody an intriguing diene-enyne functionality. Among
O
OR
O
OR
LnRu
them, (+)- and (ꢀ)-harveynone have been shown to arrest mitosis
by inhibiting spindle formation in sea-urchin eggs.6b Over the
years, natural products 7–9 have emerged as commonly pursued
targets for total synthesis both as a testing bed for new tactics
and as end objectives in their own right.4 As an extension and
adaptation of our norbornyl based general approach4 to epoxyqui-
none natural products, we report here a synthesis of (+)-harvey-
none and (–)-asperpentyn from a common precursor.
O
O
X
R
OR1
11
10. X= Br, I
12
Scheme 1. Approaches to harveynone and asperpentyn.
Earlier synthetic approaches4 to harveynone 7 and asperpentyn
8, with one notable exception,4j have involved Sonogashira or Stille
coupling between a 2-halocyclohexenone 10 and an appropriate
1,3-enyne partner 11, Scheme 1. The exception being an interest-
ing tandem enyne metathesis-metallotropic [1,3]-shift based strat-
egy on 12 which incorporates a disposable tether, Scheme 1.4j Our
approach to 7 and 8 reported here is a new variant involving Sono-
OTBS
H
ref. 5b
O
O
O
H
O
HO
14
15
gashira coupling between 2-alkynylcyclohexenol and
halide.
a vinyl
ref. 5k
Our synthesis of (+)-7 and (ꢀ)-8 emanated from tricyclic chiron
(+)-13, readily available from the Diels–Alder adduct 14 of cyclo-
pentadiene and p-benzoquinone via an embellished intermediate
15 reported earlier by us.5b A lipase mediated enzymatic resolution
protocol on 15 delivered (+)-13 (ꢁ99% ee) and (ꢀ)-16 (ꢁ99% ee),
Scheme 2.9 Retro-Diels–Alder reaction in (+)-13 was smooth and
led to the functionalized epoxyquinone derivative (+)-17,
Scheme 3. Controlled base hydrolysis in (+)-17 delivered the hy-
droxyl derivative (+)-18.9 Since, the free secondary hydroxyl group
in (+)-18 already had the requisite stereochemical disposition pres-
ent in the target natural products, it needed to be protected in a
more robust and compatible manner along with the deprotection
of the TBS-protected primary hydroxyl group for further maneu-
vers. This proved to be somewhat tricky to execute but could be
implemented by smooth conversion to the bis-TBS derivative 19
and selective deprotection of the primary TBS protection to yield
the requisite mono-protected (+)-20,9 Scheme 3. Stereoselective
carbonyl reduction in (+)-20 by DIBAL-H was mediated through
the coordination of aluminum in the reducing reagent with epox-
ide oxygen on the b-face and hydride delivery from the same face
to furnish (+)-21.9 Regioselective oxidation of the allylic primary
OTBS
O
OTBS
OAc
+
O
O
O
HO
(-)-16
(+)-13
Scheme 2. Preparation of the chiral synthon (+)-13.
activity profile that includes phytotoxic, anti-fungal, anti-bacterial,
anti-tumor, and specific enzyme inhibitory activity. For these rea-
sons, epoxyquinone natural products have been objects of sus-
tained interest from synthetic chemists world-wide1,3,4 and our
group5 has also been active in this arena.
(+)-Harveynone 7 from the tea gray blight fungus Pestalotiopsis
theae6a and its antipode (ꢀ)-harveynone from Curvularia harveyi,6b
(ꢀ)-asperpentyn 8 from Aspergillus duricaulis7a and more recently7b
from Pestalotiopsis sp. PSU-MA69, and tricholomenyn A 9 from
Tricholoma acerbum8 are among the epoxyquinone natural prod-
TBSO
OH
OAc
H
OAc
O
a
b
c
O
O
O
TBSO
TBSO
O
TBSO
O
TBSO
O
O
(+)-19
(+)-13
(+)-17
(+)-18
d
OTBS
TBSO
OTBS
TBSO
g
f
e
O
O
O
O
O
H
Cl
OH
(+)-23
h
OH OH
OH
OH O
(+)-22
(+)-21
(+)-20
OTBS
OTBS
OH
OTBS
i
j
k
O
O
O
O
O
OH
O
OH
(+)-24
(+)-25
(+)-26
(+)-7
Scheme 3. Reagents and conditions: (a) Ph2O, 230 °C, 20 min, 83%; (b) LiOH, MeOH, 0 °C, 1 h; (c) TBSOTf, 2,6-lutidine, 0 °C, 10 min, 88%; (d) PPTS, MeOH, 25 °C, 2 h, 75%; (e)
DIBAL-H (under N2), ꢀ78 °C, 25 min, 73%; (f) MnO2, CH2Cl2, 25 °C, 4 h, 93%; (g) ClCH2PPh3Cl, n-BuLi, THF-HMPA, 0–25 °C, 1.5 h, 72%; (h) n-BuLi, THF, ꢀ78 °C, 4 h, 77%; (i) 2-
bromopropene, PdCl2(PPh3)2, i-Pr2NH, CuI, THF, 25 °C, 3 h, 41%; (j) DMP, CH2Cl2, 25 °C, 2 h, 90%; (k) 40%HF, CH3CN, 25 °C, 2 h, 92%.

G. Mehta et al. / Tetrahedron Letters 53 (2012) 4093–4095
4095
McKerrecher, D.; Davies, D. H.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37,
7445–7448; (c) Graham, A. E.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1997,
1087–1089; (d) Kamikubo, T.; Ogaswara, K. Heterocycles 1998, 47, 69–72; (e)
Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582–1583; (f) Negishi, E.-I.;
Tan, Z.; Liou, S.-Y.; Liao, B. Tetrahedron 2000, 56, 10197–10207; (g) Barros, M. T.;
Maycock, C. D.; Ventura, M. R. Chem. Eur. J. 2000, 6, 3991–3996; (h) Tachihara,
T.; Kitahara, T. Tetrahedron 2003, 59, 1773–1780; (i) Carreño, M. C.; Merino, E.;
Ribagorda, M.; Somoza, Á.; Urbano, A. Chem. Eur. J. 2007, 13, 1064–1077; (j) Li, J.;
Park, S.; Miller, R. L.; Lee, D. Org. Lett. 2009, 11, 571–574; (k) Pinkerton, D. M.;
Banwell, M. G.; Willis, A. C. Org. Lett. 2009, 11, 4290–4293; (l) Hookins, D.;
Taylor, R. J. K. Tetrahedron Lett. 2010, 51, 6619–6621.
OTBS
OH
a
O
O
OH
OH
(+)-25
(-)-8
Scheme 4. Reagents and conditions: (a) 20% HF, CH3CN, rt, 2 h, 95%.
5. For synthetic work towards diverse epoxyquinone natural products from our
group, see: (a) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569–3572; (b)
Mehta, G.; Islam, K. Org. Lett. 2004, 6, 807–810; (c) Mehta, G.; Pan, S. C. Org. Lett.
2004, 6, 811–813; (d) Mehta, G.; Ramesh, S. S. Tetrahedron Lett. 2004, 45, 1985–
1987; (e) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611–3615; (f) Mehta,
G.; Roy, S. Org. Lett. 2004, 6, 2389–2392; (g) Mehta, G.; Pan, S. C. Org. Lett. 2004,
6, 3985–3988; (h) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 7683–7687; (i)
Mehta, G.; Roy, S. Tetrahedron Lett. 2005, 46, 7927–7930; (j) Mehta, G.; Roy, S.
Chem. Commun. 2005, 3210–3211; (k) Mehta, G.; Pujar, S. R.; Ramesh, S. S.;
Islam, K. Tetrahedron Lett. 2005, 46, 3373–3376; (l) Mehta, G.; Roy, S. Tetrahedron
Lett. 2008, 49, 1458–1460; (m) Mehta, G.; Sunil Kumar, Y. C.; Khan, T. B.
Tetrahedron Lett. 2010, 51, 5112–5115.
6. (a) Nagata, T.; Ando, Y.; Hirrota, A. Biosci., Biotechnol., Biochem. 1992, 56, 810–
811; (b) Kawazu, K.; Kobayashi, A.; Oe, K. Chem. Abstr. 1991, 115, 181517.
7. (a) Muhlenfeld, A.; Achenbach, H. Phytochemistry 1988, 27, 3853–3855; (b)
Klaiklay, S.; Ruckachairsirikul, V.; Tadpetch, K.; Sukpondma, Y.; Phongpaichit, A.;
Buatong, J.; Sakayaroj, J. Tetrahedron 2012, 68, 2299–2305.
hydroxyl group in (+)-21 was uneventful and delivered the alde-
hyde (+)-22 in high yield, Scheme 3. Wittig olefination in (+)-22
with the ylide derived from chloromethyl(triphenyl)phosphorane
hydrochloride furnished a mixture of E-, Z-chloroolefins 23 which
was subjected to dehydrohalogenation to eventuate in the alkyne
(+)-24. Pd+2 mediated Sonogashira coupling between (+)-24 and
2-bromopropene generated (+)-25 with the key ene-enyne bearing
a side arm in place, Scheme 3. Dess–Martin periodinane oxidation
in (+)-25 led to the enone (+)-26 and further TBS deprotection
delivered the natural product (+)-7 whose spectral data were found
to be identical with those reported in the literature,4 Scheme 3.
Lastly, TBS deprotection in (+)-25 was carried out routinely with
aq. HF to furnish asperpentyn (ꢀ)-8, Scheme 4, whose spectral data
were found to be identical with those reported4 for the natural
product.
8. Garlaschelli, L.; Magisrali, E.; Vidari, G.; Zuffardi, O. Tetrahedron Lett. 1995, 36,
5633–5636.
9. All new compounds were characterized on the basis of their spectroscopic data
(IR, 1H, 13C, MS). Spectral data for some of the key compounds are as follows: 19:
½ ꢂ ;
a 2D5: (+)-94.3 (c 2.97, CHCl3); IR (neat): tmax 1683, 1257, 1093, 838 cmꢀ1 1H
In summary, we have outlined enantio- and stereoselective syn-
theses of epoxyquinone natural products (+)-harveynone and (ꢀ)-
asperpentyn bearing a diene-enyne functionality, thereby further
demonstrating the efficacy and utility of our general norbornyl
based strategy for the synthesis of this class of compounds.
NMR (300 MHz, CDCl3): d 6.62–6.60 (m, 1H), 4.74–4.72 (m, 1H), 4.47 (dd, 1H,
J = 1.2, 15.5 Hz), 4.24 (dd, 1H, J = 1.8, 15.9 Hz), 3.68–3.65 (m, 1H), 3.46 (dd, 1H,
J = 0.6, 3.3 Hz), 0.92 (s, 9H), 0.91 (s, 9H), 0.18 (s, 3H), 0.15 (s, 3H), 0.07 (s, 6H); 13
C
NMR (75 MHz, CDCl3): d 193.1, 137.7, 135.8, 63.8, 59.2, 58.5, 53.5, 25.8, 25.7,
18.2, ꢀ4.4, ꢀ4.6, ꢀ5.5; HRMS (ES): m/z for C19H36NaO4Si2 [M++Na], calcd
407.2050, found 407.2058. 20:
½
a 2D5
ꢂ
:
(+)-219.4 (c 0.72, CHCl3); 1H NMR
)
(300 MHz, CDCl3
: d 6.51 (s, 1H), 4.72 (d, 1H, J = 4.5 Hz), 4.37 (d, 1H,
J = 14.4 Hz), 4.26 (d, 1H, J = 14.7 Hz), 3.67 (s, 1H), 3.48 (d, 1H, J = 3.9 Hz), 0.93
(s, 9H), 0.19 (s, 3H), 0.16 (s, 3H); 13C NMR (75 MHz, CDCl3) d 194.0, 139.4, 135.3,
63.7, 60.7, 58.5, 53.4, 25.7, 18.2, ꢀ4.4, ꢀ4.6; HRMS (ES): m/z for C13H22NaO4Si
Acknowledgments
[M++Na], calcd 293.1185, found 293.1177. 21: ½a 2D4
ꢂ
: (+)-43.1 (c 1.67, CHCl3); IR
G.M. and S.R. thank the CSIR, India for the award of Bhatnagar
Fellowship and Research Fellowship, respectively. This research
was carried out at the Indian Institute of Science, Bangalore. G.M.
thanks the GOI for the award of National Research Professorship
and wishes to acknowledge current research support from Eli Lilly
and Jubilant-Bhartia Foundations at the University of Hyderabad.
(neat): t ;
max 3400, 1471, 1255, 1075 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.57 (dd,
1H, J = 3.3, 1.5 Hz), 4.48 (d, 1H, J = 3.9 Hz), 4.32 (d, 1H, J = 8.1 Hz), 4.18–4.07 (m,
2H), 3.45 (br s, 1H), 3.35 (t, 1H, J = 1.5 Hz), 3.18 (d, 1H, J = 1.2 Hz), 0.90 (s, 9H),
0.14 (s, 3H), 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3): d 137.0, 121.4, 64.3, 63.7,
63.0, 53.2, 52.7, 25.8, 18.2, ꢀ4.7, ꢀ4.9; HRMS (ES): m/z for
C
13H24NaO4Si
[M++Na], calcd 295.1342, found 295.1358. 22: ½a 2D5
ꢂ
: (+)-98.5 (c 1.23, CHCl3); IR
(neat): t ;
max 3457, 1696, 1257, 1082 cmꢀ1 1H NMR (300 MHz, CDCl3): d 9.53 (s,
1H), 6.48 (dd, 1H, J = 1.5, 3.0 Hz), 4.84 (s, 1H), 4.70–4.68 (m, 1H), 3.45 (d, 1H,
J = 3.0 Hz), 3.29 (d, 1H, J = 0.9 Hz), 2.91 (br s, 1H), 0.92 (s, 9H), 0.18 (s, 3H), 0.17
(s, 3H); 13C NMR (75 MHz, CDCl3): d 194.3, 144.8, 137.4, 63.4, 59.8, 53.1, 53.0,
References and notes
25.6, 18.1, ꢀ4.6, ꢀ4.7; HRMS (ES): m/z for
C
13H22NaO4Si [M++Na], calcd
1. For reviews see: (a) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004,
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Miyashita, K.; Imanishi, T. Chem. Rev. 2005, 105, 4515–4536.
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Phytochemistry 2001, 56, 463–468; (c) Gehrt, A.; Erkel, G.; Anke, T.; Sterner, O. J.
Antibiot. 1998, 51, 455–463; (d) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.; Clardy, J. J.
Org. Chem. 1996, 61, 3232–3233; (e) Ding, G.; Zhang, F.; Chen, H.; Guo, L.; Zou, Z.;
Che, Y. J. Nat. Prod. 2011, 74, 286–291.
3. Selected lead references towards the synthesis of epoxyquinone natural
products: (a) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y.
Angew. Chem., Int. Ed. 2002, 41, 3192–3194; (b) Li, C.; Bardhan, S.; Pace, E. A.;
Liang, M.-C.; Gilmore, T. D.; Porco, J. A. Org. Lett. 2002, 4, 3267; (c) Porco, J. A.; Su,
S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006, 45, 5790–
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2010, 5, 1298–1302; (f) Hookins, D. R.; Burns, A. R.; Taylor, R. J. K. Eur. J. Org.
Chem. 2011, 451–454.
293.1185, found 293.1195. 24: ½a D24
ꢂ : (+)-21.4 (c 0.70, CHCl3); IR (neat): tmax
3272, 2929, 1251, 1055 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.02 (dd, 1H, J = 1.5,
;
4.9 Hz), 4.54 (d, 1H, J = 3.6 Hz), 4.41 (d, 1H, J = 8.4 Hz), 3.42 (t, 1H, J = 1.8 Hz),
3.22 (dd, 1H, J = 0.9, 1.9 Hz), 2.97 (s, 1H), 2.36 (d, 1H, J = 8.4 Hz), 0.92 (s, 9H), 0.16
(s, 3H), 0.14 (s, 3H); 13C NMR (75 MHz, CDCl3): d 133.5, 121.3, 82.3, 78.6, 65.4,
63.4, 52.5, 52.0, 25.8, 18.2, ꢀ4.6, ꢀ4.8; HRMS (ES): m/z for
C
14H22NaO3Si
[M++Na], calcd 289.1236, found 289.1237. 25: ½a 2D4
ꢂ
: (+)-22.7 (c 0.44, CHCl3); IR
(neat): t ;
max 3434, 2929, 1472, 1256 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.93 (dd,
1H, J = 1.8, 5.1 Hz), 5.35 (dd, 1H, J = 1.2, 1.8 Hz), 5.29 (t, 1H, J=1.8 Hz), 4.56-4.54
(m, 1H), 4.41 (d, 1H, J = 8.4 Hz), 3.44–3.42 (m, 1H), 3.23–3.22 (m, 1H), 2.28 (d,
1H, J = 15.0 Hz), 1.92 (t, 3H, J = 1.2 Hz), 0.92 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H); 13
C
NMR (75 MHz, CDCl3): d 131.7, 126.3, 122.9, 122.3, 91.8, 86.9, 65.7, 63.6, 52.5,
51.9, 25.8, 23.3, 18.2, ꢀ4.5, ꢀ4.8; HRMS (ES): m/z for C17H26NaO3Si [M++Na],
calcd 329.1549, found 329.1534. (+)-7: mp 78.3–78.7 °C; IR (neat) tmax
1701 cmꢀ1 1H NMR (300 MHz) (CDCl3) d 6.85 (dd, 1H, J = 2.7, 5.1 Hz), 5.43
;
(dd, 1H, J = 0.6, 1.8 Hz), 5.35 (t, 1H, J = 1.5 Hz), 4.78 (t, 1H, J = 6.0 Hz), 3.83–3.81
(m, 1H), 3.58 (dd, 1H, J = 1.2, 3.6 Hz), 2.26 (d, 1H, J = 6.9 Hz), 1.94 (t, 3H,
J = 0.6 Hz); 13C NMR (75 MHz ,CDCl3) d 190.3, 145.0, 125.9, 124.1, 123.2, 95.9,
81.2, 63.3, 57.3, 53.4, 23.0; HRMS (ES) m/z (M+Na)+ 213.0530.
4. Syntheses related to harveynone and/or asperpentyne: (a) Kamikubo, T.;
Ogaswara, K. Chem. Commun. 1996, 1679–1680; (b) Graham, A. E.;