Stereoselective, oxidative C-C bond coupling of naphthopyran induced by DDQ: Stereocontrolled total synthesis of deoxyfrenolicin

Article abstract of DOI:10.1021/ol9909738

(matrix presented). A formal total synthesis of pyranonaphthoquinone natural product deoxyfrenolicin 1 is described. The key step in the synthesis involves the use of stereoselective 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-induced C-C bond couplin

Full text of DOI:10.1021/ol9909738

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1599-1602
Stereoselective, Oxidative C−C Bond
Coupling of Naphthopyran Induced by
DDQ: Stereocontrolled Total Synthesis
of Deoxyfrenolicin†
Yao-Chang Xu,* Dan T. Kohlman, Sidney X. Liang, and Chad Erikkson‡
DiscoVery Chemistry Research, Lilly Research Laboratories, Lilly Corporate Center,
Indianapolis, Indiana 46285
xu_yao-chang@lilly.com
Received August 20, 1999
ABSTRACT
A formal total synthesis of pyranonaphthoquinone natural product deoxyfrenolicin 1 is described. The key step in the synthesis involves the
use of stereoselective 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-induced C−C bond coupling of the naphthopyran 10 with allyltriphenyltin
to give exclusively 1,3-trans naphthopyran derivative 23. The naphthopyran 10 was obtained via oxa-Pictet−Spengler cyclization of substituted
naphthalene 22, which was derived by regioselective benzannulation of chromium carbene complex 12 with acetylene 18. This newly developed
synthetic route employing a tandem benzannulation/oxa-Pictet−Spengler cyclization/DDQ-induced coupling strategy should also be applicable
to the synthesis of other pyranonaphthoquinone natural products such as kalafungin 4 and nanaomycin 5.
Deoxyfrenolicin 1, isolated from cultures of Streptomyces
roseofulVus, is a member of the relatively larger pyrano-
naphthoquinone family of natural products (Figure 1).1,2
Many members in this family exhibit significant biological
activity against fungi, cancers, and cocci.1-4 The therapeutic
potential of these natural products has attracted considerable
attention from the synthetic organic chemistry community.
Several approaches toward the synthesis of deoxyfrenolicin
11
1,5-10 frenolicin A 2,10 and frenolicin B 310, have been
reported.
† Part of this work was presented at the 218th National Meeting of the
American Chemical Society, Aug 22-26, 1999; ORGN, poster 545.
‡ Department of Chemistry, George State University. Eli Lilly &
Company, Summer Intern, 1996.
(1) Ellestead, G. A.; Kunstman, M. P.; Whaley, H. A.; Patterson, E. L.
J. Am. Chem. Soc. 1968, 90, 1325.
(2) Iwai, Y.; Kora, A.; Takahashi, Y.; Hayashi, T.; Awaya, J.; Masuma,
R.; Oiwa, R.; Omura, S. J. Antibiot. 1978, 31, 959.
(3) Van Meter, J. C.; Dann, M.; Bohonos, N. Antimicrobial Agents
Figure 1.
Annual 1960; Plenum Press: New York, 1961; p 77.
(4) Moore, H. W. Science 1977, 197, 527.
(5) Brimble, M. A.; Lynds, S. M. J. Chem. Soc., Perkin Trans. 1 1994,
Our interest in developing a novel synthetic route to these
493.
pyranonaphthoquinone natural products stems from our
10.1021/ol9909738 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/09/1999

recent findings that benzopyran derivatives such as 6 undergo
oxidative couplings with a variety of carbon nucleophiles in
the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ).12 As shown in Scheme 1, treatment of 3-methyl-
pyran substrate was yet to be proven. Compound 10 could
be prepared from 2-substituted-1,4,5-trimethoxynaphthalene
11 via oxa-Pictet-Spengler cyclization.13 Finally, preparation
of 11 could be realized via a benzannulation reaction of
chromium carbene complex 12 with properly functionalized
terminal acetylene 13.14,15 The simplicity of this route using
tandem benzannulation/oxa-Pictet-Spengler cyclization/
DDQ-induced C-C coupling makes it an attractive approach
to deoxyfrenolicin 1.
Scheme 1
The detailed synthesis of deoxyfrenolicin 1 is presented
in Scheme 2 starting from 3-buten-1-ol. Installation of the
benzyl protecting group on the alcohol of 14 using benzyl
bromide, NaOH, and triethylamine,16 followed by epoxida-
tion of the terminal olefin with MCPBA in dichloromethane,
gave rise to the epoxide 16 in 80% overall yield.17 The
reaction of 16 with lithium acetylide in DMSO at room
temperature resulted in the regioselective ring opening of
the epoxide, affording 91% of the terminal acetylene 17,18
of which the secondary alcohol could be efficiently blocked
as either the methoxymethyl ether (MOM) or the acetate
(Ac).
Our initial attempts to build the multisubstituted naphtha-
lene 19 via the benzannulation reaction of chromium carbene
complex 12 with the MOM-protected acetylene 13 fell short
of expectation. While the chromium carbene complex 12 is
readily accessible,19 the benzannulation reaction in either
benzene or THF solvent using reported procedures gave the
expected product 19 in only about 10-25% yield.20 Although
the benzannulation reaction of chromium carbene complexes
with acetylene is a well-studied process,21 such a reaction
with an acetylene bearing a MOM group at the â-position is
not known.22 We suspect that coordination of the MOM
group with the oxophilic chromium carbene complex might
have retarded the normal benzannulation processes.21
5,8-dimethoxyisochroman 6 with DDQ in dichloromethane
at room temperature followed by addition of allyltriphenyltin
gave rise to 1-allyl substituted isochromans 7 and 8 in 97%
yield. The most important feature of this efficient C-C bond-
forming reaction is the high stereoselectivity, providing
predominantly the 1,3-trans isomer 7. Application of this
C-C bond coupling reaction into a naphthopyran system
such as 10 would generate functionalized tricyclic compound
9, which could serve as a late-stage precursor to deoxy-
frenolicin 1 (Figure 2). The anticipated 1,3-trans stereo-
chemistry for compound 9 will be the key to the success of
our efficient synthesis of deoxyfrenolicin 1.
The retrosynthetic pathway is presented in Figure 2.
Deoxyfrenolicin 1 could be derived from compound 9 via
functional group manipulation. Key in the retrosynthetic
analysis of naphthopyran 9 was the DDQ-induced introduc-
tion of a C-1 propyl group as discussed above. While an
efficient process in the bicyclic system (Scheme 1), success
of such a stereoselective reaction with a tricyclic naphtho-
Selection of the MOM protecting group had a special
purpose at the beginning of synthesis because naphthalene
derivative 19 or 11 bearing a MOM ether at the C-2
substituent could be directly cyclized to give tricycle 10 using
TiCl4.23 The low yield in the benzannulation reaction
prompted us to consider other protecting groups. We were
Figure 2.
1600
Org. Lett., Vol. 1, No. 10, 1999

Scheme 2a
a (a) PhCH2Br, NaOH, Et3N, hexane, reflux, 5h, 98%; (b) MCPBA, CH2Cl2, rt, 24 h, 91%; (c) LiCtCH‚EDA, DMSO, rt, 40 min, 91%;
(d) CH2(OMe)2, P2O5, CHCl3, rt, 79%; (e) AcCl, Ac2O, Py, CH2Cl2, rt, 91%; (f) 12, THF, 60 °C, 15 h, 74%; (g) MeI, K2CO3, acetone,
reflux, 3 h, 81%; (h) K2CO3, MeOH, H2O, rt, 6 h, 85%; (i) CH2(OMe)2, BF3‚Et2O, Et2O, rt, 85%; (j) H2, Pd/C (10%), EtOH, rt, 2 days,
77%; (k) CrO3, acetone, CH3CO2H, H2O, rt, 40 min; (l) MeOH, H2SO4, rt, 12 h, 43% for last two steps; (m) BBr3, CH2Cl2, -78 to 0 °C,
85%; (n) KOH, MeOH, rt, 3 h, 97%.9
delighted to find that the benzannulation reaction of 12 with
the acetylene ester 18 proceeded smoothly, affording naph-
thol 20 in 74% isolated yield. It should be noted that the
benzannulation reaction with this terminal acetylene is highly
regioselective to give only 2-substituted naphthol, consistent
with what had been reported in the literature.14 Methylation
of the phenol using iodomethane and K2CO3 gave 81% of
1,4,5-trimethoxynaphthalene 21,24 which was converted to
alcohol derivative 22 in an 85% yield upon hydrolysis of
the acetyl group (K2CO3, MeOH, H2O). The oxa-Pictet-
Spengler cyclization of 22 with dimethoxymethane was
carried out in Et2O using BF3 etherate to give an 86% yield
of the functionalized naphthopyran 10.25
(6) Foland, L. D.; Decker, O. H. W.; Moore, H. W. J. Am. Chem. Soc.
1989, 111, 989.
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1988, 6, 203.
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139.
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C.; Gilbertson, S. R. Tetrahedron 1985, 41, 5813.
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E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: 1995; Vol.
12.
(22) The effect of propargyl oxygen substituents in the benzannulation
has been studied: Semmelhack, M. F.; Jeong, N.; Lee, G. R. Tetrahedron
Lett. 1990, 31, 609.
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Org. Lett., Vol. 1, No. 10, 1999
1601

One would expect that the extension of this oxa-Pictet-
Spengler cyclization with alkyl aldehyde will give 1-alkyl-
naphthopyran directly. Such an approach was previously
employed in the synthesis of other related pyranonaphtho-
quinones.26 Unfortunately, only the 1,3-cis isomer of the
naphthopyran derivative was obtained. For that purpose, this
approach will not directly lead to the requisite 1,3-trans
stereochemistry of deoxyfrenolicin 1.
isolation, the carboxylate 25 was converted to methyl ester
26 using MeOH and H2SO4 in 43% overall yield for last
two steps. The deprotection of the methyl ether 26 was
effected by BBr3 in CH2Cl2 to provide deoxyfrenolicin
methyl ester 27 in 85% yield.28 The spectroscopy data (NMR,
IR, MS) for compound 27 were in good agreement with those
reported in the literature.5,9 The final hydrolysis of the methyl
ester has been reported by use of KOH to afford deoxyfre-
nolicin 1.9
The oxidative coupling reaction of 10 with allyltriphenyltin
in CH2Cl2 in the presence of DDQ provided the allyl-
substituted naphthopyran 23 in 95% yield. This outcome is
significant for the following reasons. The oxidative C-C
coupling reaction with naphthopyran is as efficient as the
benzopyran system. Nearly identical yields were obtained
from both compounds 10 and 6. The reaction is highly
stereoselective, resulting in the exclusive formation of the
trans isomer, which has exactly the same stereochemistry
as that of deoxyfrenolicin 1. No cis isomer was detected from
the reaction. The C1-C3 trans stereoselectivity is unique in
our approach because most previous reported syntheses
suffered more or less from this stereochemical control.5-9,11
With the basic framework built and the proper substituents
installed, the final stage of the synthesis basically involves
functional group manipulation. The benzyl protecting group
was removed under hydrogenation conditions using 10%
Pd/C catalyst in ethanol, and under such conditions, the
terminal double bond was also reduced to provide compound
24 in 77% overall yield. The primary alcohol in 24 can be
oxidized to carboxylic acid using CrO3 in acetone and an
acetic acid solvent mixture.27 To our surprise, the central
benzene ring bearing two methoxy groups was also oxidized
to the quinone, affording compound 25 in a single-step
operation. While CrO3 is a known strong oxidant, oxidative
demethylation of 1,4-dimethoxybenzene to 1,4-benzoquinone
using CrO3 is not precedented in the literature. To facilitate
Ichihara et al. reported that the conversion of deoxyfre-
nolicin 1 to frenolicin A 2 could be effected by tert-butyl
hydroperoxide and Triton B.10 The same authors have also
reported that simple reflux of deoxyfrenolicin 1 in CHCl3
afforded frenolicin B 3 in quantitative yield.10 Therefore the
current synthesis of deoxyfrenolicin 1 also constitutes a
formal synthesis of frenolicin A 2 and frenolicin B 3.
In conclusion, we have developed an efficient approach
toward deoxyfrenolicin 1 and similar analogues such as
frenolicin A and B. We have demonstrated that the DDQ-
induced, oxidative C-C bond coupling reaction provided
an efficient, stereoselective entry into the functionalized
naphthopyran system. The convergent approach to deoxy-
frenolicin using a tandem benzannulation/oxa-Pictet-Spen-
gler cyclization/DDQ-induced coupling strategy should be
also applicable to the synthesis of other pyranonaphtho-
quinone natural products such as kalafungin 4 and nanao-
mycin 5.
Acknowledgment. We wish to thank Dr. John M. Schaus
for helpful discussion and Drs. Paul L. Ornstein and Philip
A. Hipskind for manuscript proof-reading.
Supporting Information Available: Experimental pro-
cedures for the preparationof compounds 15-27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Neninno, M. P.; Perner, R. J.; Morton, H. E.; Didomenico, S. Jun.
J. Org. Chem. 1992, 57, 7115.
(26) (a) Li, T.; Ellison, R. H. J. Am. Chem. Soc. 1978, 100, 6263. (b)
Pyrek, J. St.; Achmatowicz, Jr. O.; Zamojski, A. Tetrahedron 1977, 33,
673.
OL9909738
(28) Cameron, D. W.; Feutrill, G. I.; Gibson, C. L. Tetrahedron Lett.
1993, 34, 6109.
(27) Sita, L. R. J. Org. Chem. 1993, 58, 5285.
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