Exploratory studies towards a synthesis of bioactive kinamycin natural products

Article abstract of DOI:10.1016/j.tetlet.2015.11.001

A synthetic approach towards kinamycins that harnesses the proclivities of the norbornyl scaffold is unveiled to access the oxy-functionalized and actively side-armed cyclohexenoid ring-D of these bioactive natural products. This ring-D building block has been further elaborated to the tricyclic ABD ring system present in kinamycins.

Full text of DOI:10.1016/j.tetlet.2015.11.001

Tetrahedron Letters 56 (2015) 6919–6922
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Exploratory studies towards a synthesis of bioactive kinamycin
natural products
a
b
b,
⇑
Nagi Reddy Modugu , Jagadeshwar Vannada , Goverdhan Mehta
a
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic approach towards kinamycins that harnesses the proclivities of the norbornyl scaffold is
unveiled to access the oxy-functionalized and actively side-armed cyclohexenoid ring-D of these
bioactive natural products. This ring-D building block has been further elaborated to the tricyclic ABD
ring system present in kinamycins.
Received 11 October 2015
Accepted 1 November 2015
Available online 2 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Kinamycin
Lomaiviticin
Diazotetrahydrobenzo[b]fluorene
Lithium triethylborohydride reduction
Retro Diels–Alder reaction
The kinamycins are a group of closely related bioactive natural
products, first unraveled in 1970 from the cultured broth of
total syntheses. Concurrently, there have been efforts to explore
the chemical diversity space around diazobenzo[b]fluorene and
Streptomyces murayamaensis.1 Their structure was finally settled
,2
3
diazotetrahydrobenzo[b]fluorene scaffolds to map their bioactiv-
10
in 1994 and they were shown to embody a distinctive but uncom-
mon diazotetrahydrobenzo[b]fluorene framework with variation
in oxygenation patterns in ring-D. Representative kinamycins are
displayed in structures 1 and 2 with the latter bearing an epoxide
ring serving as the likely biosynthetic precursor of the former,
ity potential. During these studies, it was observed that variation in
the oxygen substitution pattern in the cyclohexenoid ring-D of the
diazotetrahydrobenzo[b]fluorene had a significant effect7
a,11
in
modulating the biological activity, an observation buttressed by
5
the variation in the anticancer efficacy among various kinamycins
1
a
(Fig. 1). In 2001, complex but related, dimeric metabolites
1–2 with diverse oxygenation patterns in ring-D. Indeed, it has
been suggested that the 2,3-epoxide bearing kinamycins 2 most
lomaiviticins and 4, having discernible structural
A
3
B
a
1
a,c
homology to kinamycins were reported from Micromonospora
likely serve as the biosynthetic precursors
of 1 and in
4
lomaivitiensis, (Fig. 1). Kinamycins 1–2 and lomaiviticins A 3 and
synthetic endeavours towards kinamycins, regio- and
stereoselective epoxide ring opening has been deployed to
generate the stereochemical pattern of the four (C1–C4)
contiguous oxygen bearing stereocentres present in these natural
products.
B 4 have been found to be potent anticancer agents with IC50 vales
in nano- to picomolar range and the latter also showing activities
5
,6
against both Gram-positive and Gram-negative bacteria, Both,
kinamycins and lomaiviticins have been shown to mediate dsDNA
cleavage under reducing conditions6 and incisive studies to
elucidate the mechanistic details of their activity continue to
It was the intricate functional and stereochemical architecture
of the cyclohexenoid ring-D and its manifestation on therapeutic
7
7a,12
appear regularly.
efficacy that drew us to kinamycins.
In numerous
On account of their unusual diazotetrahydrobenzo[b]fluorene
contributions from our group, we have harnessed the exo-face
proclivity of norbornyl-fused scaffolds to install variegated
oxygenation patterns, with stereocontrol, on cyclohexenoid
bearing architecture, intriguing biosynthesis1
a,8
and notable
activity against cancer, kinamycins 1–2 and lomaiviticins 3–4
have received considerable attention as challenging targets for
total syntheses during the past decade.9 These determined
campaigns have culminated in several imaginative and successful
1
3
segment present in diverse natural products. This proven strat-
egy appeared to be well suited for the initial construction of
ring-D of kinamycins and further elaboration towards these natu-
ral products and analogues. In this Letter, we disclose adaptation
1
3
of our ‘norbornyl-fused scaffold’ strategy to access the ring-D of
kinamycins with a functional side arm and its further elaboration
to the tricyclic ABD framework present in these natural products.
⇑
Corresponding author. Tel.: +91 40 23134848; fax: +91 40 23010785.
E-mail address: gmehta43@gmail.com (G. Mehta).
http://dx.doi.org/10.1016/j.tetlet.2015.11.001
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

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N. R. Modugu et al. / Tetrahedron Letters 56 (2015) 6919–6922
N(CH3)2
CH3
N(CH )2
3
CH3
OH
OH
O
CH3
O
O
OH
N
N
N
OCH3
HO
O
D
HO
N
N
O
Et
O
N
Et O
O
O
O
7OH O
OH O
O
O
HO
N
N
O
C
D
O
OH
6
5
HO
H
H
8
9
OR1
3 CH3
OR2
OR3
OR
CH3
O
4
B
B
C
H
OH
H
OH
A
HO
D
A
D
O
O
D
2
D
O
O
10
11
O
O
1
O Et
Et
N
OH
N
OH
O
O
R4O
HO
H3CO
HO
N
N
O
FL-120B'(2a) R : Ac
FL-120B (2b)R : C(O)iPr
CH3
(
O
kinamycin (1)
O
(
1)
R1 R2 R3 R4
HO
HO
CH3
CH3)2N
CH3
(CH3)2N
A (1a)
B (1b)
H
H
Ac Ac Ac
Ac
H
H
H
lomaiviticinA (3)
lomaiviticinB (4)
C (1c) Ac
D (1d) Ac
E (1e) Ac
Ac Ac
H
Ac
H
H
H
H
H
H
F (1f)
H
H
Figure 1. Representative diazobenzofluorene natural products.
Our approach to kinamycins emanated from cheap, readily
available 2-methyl-p-benzoquinone 5, which we identified as a
putative’ ring D surrogate, amenable to stereocontrolled manipu-
lations through its Diels–Alder adduct endo-6 with 1,3-cyclopenta-
diastereomer.14 Preferred borohydride addition to 10 from the
-face may be understood through the intervention of boron
a
‘
chelate 11 on the epoxy bearing b-face and preferred addition of
borohydride to the complexed C4 carbonyl from the opposite face,
Scheme 1. Since the separation of the diastereomeric mixture of C4
hydroxy compounds proved capricious, their imbedded 1,3-diol
moiety was protected as the corresponding acetonides. This
manoeuver resulted in concurrent deprotection of the TES moiety
and the resulting acetonides 12 and 13 were amenable to clean
chromatographic separation. Their stereostructures were secured
1
3p,s
diene.
The norbornyl-fused tricyclic 6 underwent smooth
nucleophilic epoxidation to stereoselectively furnish the exo-
1
3p
epoxide 7, Scheme 1.
and hydroxyl group protection with TESCl delivered 8. Base
mediated hydroxymethylation in was stereoselective and
Stage was now set to dismantle the norbornyl
Regio- and stereoselective reduction in 7
8
1
3p,14
delivered 9.
1
6
scaffold and a retro-Diels–Alder reaction in 9 readily led to the
epoxycyclohexenone 10, Scheme 1. In 10, the requisite carbon
framework was in place, but, installation of cis disposed hydroxyl
groups at C1 and C4, syn to the pre-existing epoxide ring at
through single crystal X-ray structure determination of the major
diastereomer 12.
The next task was the inversion of the C1-hydroxy stereochem-
istry to align it with that present in the ring-D of kinamycins. Initial
exploration with Mitsunobu-type inversion was unproductive and
therefore recourse was taken to an indirect protocol. PDC oxidation
of 12 led to enone 14 and its lithium triethylborohydride
(superhydride) mediated reduction proceeded stereoselectively
C2–C3 required orchestration of
a
few stereocontrolled
operations. After some trials with different reducing agents, we
found that the C4 carbonyl group in 10 could be reduced with
1
5
4 2
reasonable stereoselectivity (8:2) in NaBH /MeOBEt milieu to
furnish the desired C4 b-hydroxy compound as the major
from the
istry in 15, Scheme 2. Acetonide deprotection in 15 led to the triol
6 and chemoselective TEMPO oxidation delivered aldehyde 17
a-face to generate the desired C1-hydroxy stereochem-
1
quite uneventfully. The cis-1,4-dihydroxy groups in 17 were pro-
tected as TES derivative 18 for further elaboration, Scheme 2. In
18, we had the complete, stereochemically defined component of
ring-D of kinamycins 2. Since the epoxide ring of the type present
in 18 has been previously shown to deliver through nucleophilic
opening the requisite stereochemistry present (C1–C4) in
O
a
d
H
b
e
H
c
O
O
D
H
H
O
O
O
5
O
6
7
HO
OH O
D
H
H
f
O
O
H
O
O
O
O
O
O
O
TESO
TESO
O
OTES
O
O
c
a
d
b
e
O
O
O
O
O
8
9
10
O
OH
15
Et
Et
OH
12
B
H
H
H
H
14
B
O
O
O
O
O
g
O
O
O
OH OH
O
OH
D
O
OTES
OH
H
H
OH
OTES
O
8:2
11
12
13
OH
OH
OTES
Scheme 1. Reagents and conditions: (a) cyclopentadiene, MeOH, 0 °C, 2 h, 98%; (b)
16
17
18
1
6
2
0% Na
5%; (ii) TEA, TESCl, DMAP, 0 °C, 4 h, 80%; (d) DBU, HCHO, THF, 3 h, 85%; (e) Ph
20 °C, 15 min, 70%; (f) MeOBEt , NaBH , THF/MeOH (8:2), À72 °C, 4 h, 80%: (g)
2
CO
3
, 30% H
2
O
2
, acetone, 0 °C, 40 min, 92%; (c) (i) DIBAL-H, THF, À78 °C, 2 h,
2
O,
Scheme 2. Reagents and conditions: (a) PDC, DCM, rt, 8 h, 79%; (b) superhydride,
2
4
THF, À78 °C, 2 h, 80%; (c) Amberlyst-15, MeOH, rt, 5 h, 82%; (d) TEMPO, O
2
, CuCl,
PPTS, 2,2-dimethoxy propane, DCM, rt, 6 h, 80%.
DMF, rt, 6 h, 80%; (e) TEA, TESCl, DMAP, DCM, 0 °C, 5 h, 75%.

N. R. Modugu et al. / Tetrahedron Letters 56 (2015) 6919–6922
6921
kinamycins 1, our acquisition of 18 paves the way for further
advance towards these natural products.
a seco-kinamycin precursor embodying the ABD framework of
these novel bioactive natural products. We also note that the broad
contours of our kinamycins approach are amenable to adaptation
towards the more ambitious and challenging lomaiviticins and
efforts in that context are underway.
In this quest, AB ring precursor, a bromonaphthalene 19, was
readily assembled from commercially available 1,5-dihydroxynaph-
1
7,18
thalene essentially adopting literature procedures, Scheme 3.
Bromonaphthalene 19 was well poised for connecting with the
ring-D precursor 18. Halogen-metal exchange in 19 and addition
of the resulting anion to the aldehyde 18 led to a diastereomeric
mixture which was directly oxidized with PDC to furnish a single
ketone 20, Scheme 3. TES deprotection in 20 readily led to kinamycin
precursor embodying the ABD ring system 21, Scheme 3. However,
numerous attempts to install ring-C in 21 through either Nazarov-
type cyclization in its many variations or through metal mediated
Acknowledgments
N.R.M. thanks Department of Science and Technology, Govern-
ment of India for the award of INSPIRE faculty fellowship and the
Director Indian Institute of Chemical Technology for providing
research facilities. J.V. wishes to thank the CSIR, India for the award
of
a Senior Research Associateship. G.M. acknowledges the
2 2
(sp –sp ) C–H activation have not been fruitful so far. Attempts are
research support from Eli Lilly and Jubilant-Bhartia Foundations.
underway to access an activated derivative of 21 to affect the ring-C
generating cyclization.
References and notes
Lastly, in order to reinforce the basic premise of our strategy
towards kinamycins, acetonide 13 (see, Scheme 1), the minor
ring-D precursor, was elaborated to TES protected 25 via 23 and
1
2
3
.
.
.
For reviews on kinamycins and lomaiviticins, see: (a) Gould, S. J. Chem. Rev.
997, 97, 2499–2510; (b) Arya, D. P. Top. Heterocycl. Chem. 2006, 2, 129–152;
c) Nawrat, C. C.; Moody, C. J. Nat. Prod. Rep. 2011, 28, 1426–1444; (d) Herzon, S.
B.; Woo, C. M. Nat. Prod. Rep. 2012, 29, 87–118.
(a) Ito, S.; Matsuya, T.; Omura, S.; Otani, M.; Nakagawa, A. J. Antibiot. 1970, 23,
1
(
2
4, Scheme 4. Connecting metallated 19 to 25 through addition
to its aldehyde functionality, PDC oxidation to 26 and TES depro-
tection led to the diastereomeric tricyclic ABD analogue 27 of
kinamycins.
In conclusion, we have outlined a straightforward approach to
kinamycins with focus on the generation of sterochemically and
functionally endowed ring-D. This has led to the construction of
315–317; (b) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A.;
Watanabe, T. Chem. Pharm. Bull. 1971, 19, 2428–2430; (c) Omura, S.; Nakagawa,
A.; Yamada, H.; Hata, T.; Furusaki, A. Chem. Pharm. Bull. 1973, 21, 931–940.
(a) Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem Soc. 1994,
1
16, 2207–2208; (b) Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I.
J. Am. Chem. Soc. 1994, 116, 2209–2210.
4. He, H.; Ding, W. D.; Bernan, V. S.; Richardson, A. D.; Ireland, C. M.; Greenstein,
M.; Ellestad, G. A.; Carter, G. T. J. Am. Chem. Soc. 2001, 123, 5362–5363.
5.
(a) Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2002, 124, 1854–1855; (b)
Marco-Contelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7, 1433–1442; (c)
Feldman, K. S.; Eastman, K. J. J. Am. Chem. Soc. 2005, 127, 15344–15345; (e)
Hasinoff, B. B.; Wu, X.; Yalowich, J. C.; Goodfellow, V.; Laufer, R. S.; Adedayo, O.;
Dmitrienko, G. I. Anti-Cancer Drugs 2006, 17, 825–837.
MeO OMe
O
OTES
MeO OMeO OTES
Br
H
a
A
B
D
O
A
B
D
O
6
.
.
(a) Heinecke, C. L.; Melander, C. Tetrahedron Lett. 2010, 51, 1455–1458; (b)
O’Hara, K. A.; Wu, X.; Patel, D.; Liang, H.; Yalowich, J. C.; Chen, N.; Goodfellow,
V.; Adedayo, O.; Dmitrienko, G. I.; Hasinoff, B. B. Free Radical Biol. Med. 2007, 43,
1132–1144.
(a) Mulcahy, S. P.; Woo, C. M.; Ding, W.; Ellestad, G. A.; Herzon, S. B. Chem. Sci.
2012, 3, 1070–1074; (b) Colis, L.; Hegan, D. C.; Kaneko, M.; Glazer, P. M.;
Herzon, S. B. J. Am. Chem. Soc. 2015, 137, 5741–5747.
OMe
9
OTES
18
OMe
OTES
1
20
7
b
8
.
.
Wang, B.; Ren, J.; Li, l.; Guo, F.; Pan, G.; Ai, G.; Aigle, B.; Fan, K.; Yang, K. Chem.
Commun. 2015, 8845–8848.
MeO OMe O OH
MeO OMe O OH
9
(a) Lei, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2006, 128, 14790–14791; (b)
Kumamoto, T.; Kitani, Y.; Tsuchiya, H.; Yamaguchi, K.; Seki, H.; Ishikawa, T.
Tetrahedron 2007, 63, 5189–5199; (c) Nicolaou, K. C.; Li, H.; Nold, A. L.; Pappo,
D.; Lenzen, A. J. Am. Chem. Soc. 2007, 129, 10356–10357; (d) Chen, N.; Carriere,
M. B.; Laufer, R. S.; Taylor, N. J.; Dmitrienko, G. I. Org. Lett. 2008, 10, 381–384;
A
B
C
D
O
A
B
D
O
OMe
OH
OMe
OH
22
21
(
(
e) Nicolaou, K. C.; Nold, A. L.; Li, H. Angew. Chem., Int. Ed. 2009, 48, 5860–5863;
f) Woo, C. M.; Lu, L.; Gholap, S. L.; Smith, D. R.; Herzon, S. B. J. Am. Chem. Soc.
Scheme 3. Reagents and conditions: (a) (i) n-BuLi, THF, À78 °C, 2 h; (ii) PDC, DCM,
rt, 3 h, 35% (over two steps); (b) TBAF, THF, 0 °C, 30 min, 78%.
2010, 132, 2540–2541; (g) Scully, S. S.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
2011, 50, 9722–9726; (h) Herzog, S. B. Synlett 2011, 2105–2144; (i) Woo, C. M.;
Gholap, S. L.; Lu, L.; Kaneko, M.; Li, Z.; Ravikumar, P. C.; Herzon, S. B. J. Am.
Chem. Soc. 2012, 134, 17262–17273.
1
0. Zeng, W.; Ballard, T. E.; Tkachenko, A. G.; Burns, V. A.; Feldheim, D. L.;
OH OH
O
OH
O
OTES
Melander, C. Bioorg. Med. Chem. Lett. 2006, 16, 5148–5151.
a
b
H
c
H
11. For synthetic approaches to D-ring of kinamycins, see: (a) Kumamoto, T.; Tabe,
N.; Yamaguchi, K.; Ishikawa, T. Tetrahedron Lett. 2000, 41, 5693–5697; (b)
Kumamoto, T.; Tabe, N.; Yamaguchi, K.; Yagishita, H.; Iwasa, H.; Ishikawa, T.
Tetrahedron 2001, 57, 2717–2728; (c) Ouzouni, M.-D.; Fokas, D. Eur. J. Org.
Chem. 2013, 6181–6189.
13
O
O
O
OH
OH
24
OTES
23
25
12. Woo, C. M.; Ranjan, N.; Arya, D. P.; Herzon, S. B. Angew. Chem., Int. Ed. 2014, 53,
MeO
OMe
B
Br
9325–9328.
A
13. (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,
d
OMe
8
(
11–813; (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,
985–3988; (h) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 7683–7687; (i)
1
9
MeO OMeO OH
MeO OMeO OR
3
Mehta, G.; Roy, S. Tetrahedron Lett. 2005, 46, 7927–7930; (j) Mehta, G.; Roy, S.
Chem. Commun. 2005, 3210–3212; (k) Mehta, G.; Pan, S. C. Tetrahedron Lett.
O
A
B
O
2
5
005, 46, 3045–3048; (l) Mehta, G.; Pan, S. C. Tetrahedron Lett. 2005, 46, 5219–
223; (m) Mehta, G.; Pujar, S. R.; Ramesh, S. S.; Islam, K. Tetrahedron Lett. 2005,
OMe
OH
OMe
OR
2
6, R = TES
2
8
e
46, 3373–3376; (n) Mehta, G.; Roy, S. Tetrahedron Lett. 2008, 49, 1458–1460;
o) Mehta, G.; Sunil Kumar, Y. C.; Khan, T. B. Tetrahedron Lett. 2010, 51, 5112–
2
7, R = H
(
5
115; (p) Mehta, G.; Sunil Kumar, Y. C.; Das, Manabendra Tetrahedron Lett.
Scheme 4. Reagents and conditions: (a) Amberlyst-15, MeOH, rt, 6 h, 80%; (b)
TEMPO, O , CuCl, DMF, rt, 4 h, 80%; (c) TEA, TESCl, DMAP, DCM, 0 °C, 8 h, 75%. (d) (i)
n-BuLi, THF, À78 °C, 3 h; (ii) PDC, DCM, rt, 4 h, 30% (over two steps); (e) TBAF, THF,
°C, 40 min, 74%.
2011, 52, 3505–3508; (q) Mehta, G.; Shinde, H. M.; Senthil Kumar, R.
2
Tetrahedron Lett. 2012, 53, 4320–4323; (r) Mehta, G.; Roy, S.; Pan, S. C.
Tetrahedron Lett. 2012, 53, 4093–4095; (s) Modugu, N. R.; Mehta, G.
Tetrahedron Lett. 2015, 56, 6030–6033.
0

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N. R. Modugu et al. / Tetrahedron Letters 56 (2015) 6919–6922
1
4. All compounds reported here are racemic and were fully characterized on the
basis of IR, 1H NMR, C NMR and HRMS spectral data. Spectral data of selected
compounds are given here: compound 12: mp 130–132 °C, IR (thin film): 3382,
127.7, 122.1, 116.0, 107.4, 100.4, 68.3, 67.9, 66.6, 63.3, 61.0, 58.8, 57.6, 18.1;
+
13
7
HRMS (ESI-MS) calcd for C21H22NaO 409.1263 (M+Na) , found 409.1263.
15. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron
Lett. 1987, 28, 155.
À1
1
2
933, 2864, 1226, 1062 cm
3
; H NMR (400 MHz, CDCl ) d 5.46 (m, 1H), 4.64
(
s, 1H), 4.53 (d, J = 4 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 4.23 (d, J = 14.8 Hz, 1H),
16. Single crystal X-ray diffraction data for 12 was collected at 293 K on a
1
3
3
1
C
3
4
3
.18 (s, 1H), 1.52 (s, 6H), 1.43 (s, 3H); C NMR (100 MHz, CDCl ) d 135.9, 117.4,
CrysAlisPro, Oxford Diffraction Ltd, Version 1.171.35.19, equipped with Cu-K
a
00.5, 68.2, 64.3, 62.3, 60.1, 57.3, 26.5, 21.6, 18.7; HRMS (ESI-MS) calcd for
a radiation (k = 1.5418 Å) source. The crystal structure was solved by direc2t
+
11
H
16NaO
472, 2923, 2853, 1219, 1086 cm
.44 (s, 1H), 4.32 (m, 3H), 3.34 (s, 1H), 1.50 (s, 6H), 1.45 (s, 3H); C NMR
) d 132.3, 119.2, 100.3, 68.1, 65.4, 62.2, 60.8, 58.7, 26.9, 21.1,
4
(M+Na) 235.0946, found 235.0946. Compound 13: IR (neat):
methods using SIR92 and refined by the full-matrix least-squares method on F
À1
1
;
H NMR (400 MHz, CDCl
3
) d 5.27 (s, 1H),
using SHELXL97. Crystal data for 12: CCDC no. 1040529, C11
monoclinic, P2 /c, a = 8.0598(3) Å, b = 9.7397(4) Å,
V = 1103.50(8) Å , Z = 4, calcd = 1.277 g/m ,
unique = 4156/2063 [R(int) = 0.0432], R = 0.0582 and wR
H
16
O
4
, M = 212.24,
c = 14.1021(6) Å,
reflections collected/
= 0.1534.
13
1
3
3
(
1
100 MHz, CDCl
3
q
+
8.9; HRMS (ESI-MS) calcd for C11
H
16NaO
4
(M+Na) 235.0946, found 235.0946.
1
2
À1
1
Compound 17: IR (neat): 3349, 2943, 2868, 1683, 1213, 1018 cm
400 MHz, CDCl ) d 9.48 (s, 1H), 6.58 (s, 1H), 4.62 (d, J = 3.6 Hz, 1H), 4.36 (d,
J = 14.8 Hz, 1H), 3.64 (s, 1H), 1.48 (s, 3H); C NMR (100 MHz, CDCl
; H NMR
(
3
1
3
3
) d 194.2,
10NaO
93.0477 (M+Na) , found 193.0477. Compound 18: IR (neat): 2926, 1698,
1
1
1
43.5, 135.4, 64.8, 63.8, 60.4, 58.2, 14.9; HRMS (ESI-MS) calcd for C
8
H
4
+
À1
1
219, 1042 cm
3
; H NMR (400 MHz, CDCl ) d 9.51 (s, 1H), 6.48 (m, 1H), 4.78
(
d, J = 4.0 Hz, 1H), 4.67 (d, J = 4.0 Hz, 1H), 3.19 (s, 1H), 1.59 (s, 3H), 0.98 (m,
13
1
6
4
1
8H), 0.68 (m, 12H); C NMR (100 MHz, CDCl
3
) d 195.2, 145.5, 137.9, 65.8,
38NaO Si
21.2206 (M+Na) , found 421.2206. Compound 20: IR (neat): 2926, 2854,
4.2, 61.9, 59.7, 19.4, 6.7, 4.7; HRMS (ESI-MS) calcd for
C
20
H
4
2
+
À1
1
731, 1274, 1058 cm
3
; H NMR (400 MHz, CDCl ) d 7.89 (m, 1H), 7.47 (t,
J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.25 (m, 1H), 4.93 (s, 1H),
.86 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.73 (s, 3H), 3.16 (s, 1H), 1.63
4
1
3
(
s, 3H), 0.91 (t, 18H), 0.61 (m, 12H); C NMR (100 MHz, CDCl
3
) d 195.2, 157.6,
57.2, 151.9, 145.6, 137.8, 132.5, 129.3, 125.6, 120.1, 115.1, 107.6, 99.4, 68.7,
7.4, 64.5, 64.3, 63.9, 60.4, 58.4, 19.4, 6.7, 4.7; HRMS (ESI-MS) calcd for
X-ray structure of 12
1
6
C
3
+
17. (a) Tanoue, Y.; Terada, A.; Matsumoto, Y. Bull. Chem. Soc. Jpn. 1989, 62, 2736–
2738; (b) Hannan, R. L.; Barber, R. B.; Rapoport, H. J. Org. Chem. 1979, 44, 2153–
33
H
50NaO
7 2
Si 637.2993 (M+Na) , found 637.2995. Compound 21: IR (neat):
À1
1
438, 2945, 2868, 1734, 1245, 1017 cm
;
3
H NMR (400 MHz, CDCl ) d 7.86 (d,
2
158.
J = 8.0 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.36
m, 1H), 4.98 (d, J = 7.2 Hz, 1H), 4.91 (s, 1H), 3.95 (s, 6H), 3.75 (s, 3H), 3.28 (s,
1
7
1
8. Bromonaphthalene 19 was prepared from commercial (i) via (ii) as shown:
(
1
1
5
4
H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl
36.7, 132.3, 128.6, 124.4, 119.9, 116.0, 108.5, 99.9, 67.1, 66.5, 65.7, 65.5, 61.0,
3
) d 194.6, 158.0, 157.8, 150.0, 144.5,
+
OH
MeO CHO
OMe
MeO OMe
Br
9.9, 58.3, 18.5; HRMS (ESI-MS) calcd for C21
09.1263. Compound 23: IR (neat): 3406, 2926, 2855, 1219, 1050 cm
) d 5.45 (s, 1H), 4.63 (s, 1H), 4.52 (d, J = 4.8 Hz, 1H), 4.32
H22NaO 409.1263 (M+Na) , found
7
À1
1
;
H
a, b
c-f
NMR (400 MHz, CDCl
m, 2H), 3.17 (s, 1H), 1.49 (s, 3H); C NMR (100 MHz, CDCl
8.2, 64.2, 62.3, 60.2, 57.4, 18.7; HRMS (ESI-MS) calcd for C
3
A
B
1
3
(
6
(
3
) d 135.7, 124.5,
12NaO 195.0633
M+Na) , found 195.0635. Compound 25: IR (neat): 2926, 1698, 1219,
8
H
4
OH
OMe
+
À1
1
(i)
(
ii)
19
1
3
042 cm ; H NMR (400 MHz, CDCl ) d 9.68 (s, 1H), 6.26 (m, 1H), 4.67 (d,
J = 4.4 Hz, 1H), 4.39 (d, J = 14.8 Hz, 1H), 3.44 (s, 1H), 1.43 (s, 3H), 0.98 (m, 18H),
0
6
+
1
.69 (m, 12H); 13C NMR (100 MHz, CDCl
1.4, 58.7, 14.9, 6.6, 4.8; HRMS (ESI): calcd for C20
3
) d 195.4, 138.7, 135.7, 64.8, 63.4,
38NaO Si 421.2206 (M
Na) , found 421.2206. Compound 27: IR (neat): 3438, 2945, 2868, 1734, 1245,
H
4
2
+
Reagents and conditions: (a) Me
CHCl , 0 °C—reflux, 85%: (c) mCPBA, CH
2%; (e) Br , CCl , 0 °C, 85%; (f) Me SO , K
2
SO
4
, K
2
CO
Cl
CO
3
, Acetone, reflux, 60%; (b) POCl
,0 °C—rt, 83%: (d) NaBH , MeOH, 0 °C,
, Acetone, 95%.
3
, DMF,
À1
1
017 cm
;
3
H NMR (400 MHz, CDCl ) d 7.89 (d, J = 8.4 Hz, 1H), 7.55 (t,
3
2
2
4
J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.34 (m, 1H), 4.78 (s, 1H),
.68 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.19 (s, 1H), 1.64 (s, 3H); 13
NMR (100 MHz, CDCl ) d 200.9, 156.9, 155.4, 151.4, 147.4, 136.9, 135.4, 132.9,
7
2
4
2
4
2
3
4
C
3