A diastereoselective oxa-pictet-spengler-based strategy for (+)-frenolicin B and epi -(+)-frenolicin B synthesis

Article abstract of DOI:10.1021/ol4027649

An efficient diastereoselective oxa-Pictet-Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs.

Full text of DOI:10.1021/ol4027649

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
A Diastereoselective Oxa-
PictetꢀSpengler-Based Strategy for
000–000
(
Synthesis
þ)-Frenolicin B and epi-(þ)-Frenolicin B
†
†
‡
Yinan Zhang, Xiachang Wang, Manjula Sunkara, Qing Ye,
§
†
Larissa V. Ponomereva, Qing-Bai She, Andrew J. Morris, and Jon S. Thorson*
§
‡
,†
Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of
Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States, and
Division of Cardiovascular Medicine, Gill Heart Institute, and Markey Cancer Center,
University of Kentucky, 741 South Limestone Street, Lexington, Kentucky 40536,
United States
jsthorson@uky.edu
Received September 24, 2013
ABSTRACT
An efficient diastereoselective oxa-PictetꢀSpengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of
the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (þ)-frenolicin B and
epi-(þ)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such,
offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs.
1
The pyranonaphthoquinone antibiotic (þ)-frenolicin B
1) was isolated from a Streptomyces roseofulvus strain
AM-3867. Since this initial discovery, several members of
the pyranonaphthoquinone family, including frenolicin B,
have been explored in the context of anticoccidial, anti-
(
2
†
cancer, and antimalarial lead development. As a part of a
new Appalachian-based natural product discovery initia-
3
tive, we recently isolated a bacterial strain (Streptomyces
RM-4-15, isolated from soil samples near a thermal vent of
the Ruth Mullins underground coal mine fire in eastern
Kentucky) capable of producing a range of both known
College of Pharmacy
Division of Cardiovascular Medicine.
Markey Cancer Center.
‡
§
(
1) Iwai, Y.; Kora, A.; Takahashi, Y.; Hayashi, T.; Awaya, J.;
Masuma, R.; Oiwa, R.; Omura, S. J. Antibiot. 1978, 31, 959.
2) (a) Omura, S.; Tsuzuki, K.; Iwai, Y.; Kishi, M.; Watanabe, S.;
(
Shimizu, H. J. Antibiot. 1985, 38, 1447. (b) Armer, R. E.; Dutton, C. J.;
Fenner, B. R.; Greenwood, S. D. W.; Hall, K. T.; Rudge, A. J. Bioorg.
Med. Chem. Lett. 1998, 8, 139. (c) Brimble, M. A.; Duncalf, L. J.; Nairn,
M. R. Nat. Prod. Rep. 1999, 16, 267. (d) Salaski, E. J.; Krishnamurthy,
G.; Ding, W.-D.; Yu, K.; Insaf, S. S.; Eid, C.; Shim, J.; Levin, J. I.; Tabei,
K.; Toral-Barza, L.; Zhang, W.-G.; McDonald, L. A.; Honores, E.;
Hanna, C.; Yamashita, A.; Johnson, B.; Li, Z.; Laakso, L.; Powell, D.;
Mansour, T. S. J. Med. Chem. 2009, 52, 2181. (e) Fitzgerald, J. T.;
Henrich, P. P.; O’Brien, C.; Krause, M.; Ekland, E. H.; Mattheis, C.; Sa,
J. M.; Fidock, D.; Khosla, C. J. Antibiot. 2011, 64, 799.
(3) (a) Wang, X.; Shaaban, K. A.; Elshahawi, S. I.; Ponomareva,
L. V.; Sunkara, M.; Zhang, Y.; Copley, G. C.; Hower, J. C.; Kharel,
M. K.; Thorson, J. T. J. Nat. Prod. 2013, 76, 1441. (b) Shaaban, K. A.;
Wang, X.; Elshahawi, S. I.; Ponomareva, L. V.; Sunkara, M.; Zhang, Y.;
Copley, G. C.; Hower, J. C.; Kharel, M. K.; Thorson, J. T. J. Nat. Prod.
2013, 76, 1619.
1
0.1021/ol4027649 r XXXX American Chemical Society

and new pyranonaphthoquinones, some of which dis-
played potent cancer cell line cytotoxicity in vitro. While
such studies revealed new naturally occurring bioactive
chemical entities, low yields and variability in the produc-
tion of pyranonaphthoquinone analogs via fermentation
prompted the need for a complementary robust synthetic
strategy to provide access to pyranonaphthoquinones of
interest.
synthesized from commercially available 1,5-dihydroxynap-
9
hthlene via a slightly modified procedure (Scheme 1).
Heck coupling of 7 with isobutyl but-3-enoate afforded
the desired ester 9 in good yield (84%).
Scheme 1. Synthesis of Compound 5
a
Table 1. Optimization of the Oxa-PictetꢀSpengler Reaction
Figure 1. A strategic comparsion of oxa-PictetꢀSpengler-based
approaches toward frenolicin B synthesis.
Beginning with the first asymmetric total synthesis
4
of (þ)-frenolicin B (1) by Kraus and co-workers, several
6
The most recent, by Fernandes et al., employed a Dotz
5
alternative synthetic strategies have been put forth.
Lewis
acids
temp
conversion
dr
b
c
entry
solvent
(°C)
(%)
(6aR/6aR)
benzannulation to construct the naphthquinone scaffold
from Fisher carbene 3 and chiral alkyne 4 (Figure 1). While
this method achieved the desired product, the approach
was limited by the number of steps and, more notably, the
lack of diastereoselectivity in the late stage oxa-Pictetꢀ
Spengler reaction (the degree to which is often dependent
1
2
3
BF
3
OEt
2
CH
2
Cl
2
2
2
2
2
2
2
2
0ꢀrt
80(75)
10
66:34
80:20
67:33
70:30
60:40
52:48
89:11
91:9
3
Yb(OTf)
3
CH Cl
2
0ꢀrt
0ꢀrt
ꢀ78ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
0ꢀrt
Y(OTf)
TiCl
SnCl
FeCl
3
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
23
d
4
4
70
5
6
7
4
100
100
85
3
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
7
upon the substrate architecture). To address the limita-
e
8
95(90)
(64)
(43)
(32)
(48)
(50)
tions of the prior study, herein we report the optimization
and application of a diastereoselective oxa-PictetꢀSpen-
gler reaction to afford benzoisochroman 6 in good to
excellent yields en route to the synthesis of frenolicin B,
epi-frenolicin B, and precursors for a diverse array of
9
DCE
90:10
94:6
10
Cu(OTf)2
CHCl3
f
11
Cu(OTf)
Cu(OTf)
2
CH
CH
2
Cl
Cl
2
2
93:7
g
1
1
2
3
2
2
91:9
FeCl
3
THF
34:66
8
pyranonaphthoquinone analogs.
Following prior precedent for the synthesis of inter-
mediate 5 by Bruckner, bromonaphthlene 7 was initially
a
Reaction was performed with 0.2 mmol of 5, 0.4 mmol of aldehyde,
and 50 mol % Lewis acid at 0 °C. The temperature was allowed to
subsequently raise to rt over 4 h with stirring. Conversion was
b
determined by HPLC analysis. The data in the parentheses are the
isolated yields after column chromatography. dr ratio was determined
c
d
by the proton NMR of crude products. 2 h reaction time. Overnight.
e
f
g
Using 1,1-dimethoxybutane instead of butaldehyde. Using 20 mol %
Lewis acid.
(
4) (a) Kraus, G. A.; Li, J.; Gordon, M. S.; Jensen, J. H. J. Am. Chem.
Soc. 1993, 115, 5859. (b) Kraus, G. A.; Li, J.; Gordon, M. S.; Jensen,
J. H. J. Org. Chem. 1995, 60, 1154.
(5) (a) Masquelin, T.; Hengartner, U.; Streith, J. Helv. Chim. Acta
1
1
997, 80, 43. (b) Contant, P.; Haess, M.; Riegl, J.; Scalone, M. Synthesis
999, 821. (c) Donner, C. D. Synthesis 2010, 415. (d) Donner, C. D.;
However, subsequent direct Sharpless asymmetric dihy-
droxylation of 9 failed to provide 5 in >30% yield.
Suspecting steric infringement to be a limiting factor,
simple isobutyl- to methyl-ester substitution (9 f 10)
followed by Sharpless asymmetric dihydroxylation afforded
Casama, M. I. Tetrahedron Lett. 2012, 53, 1105.
6) (a) Fernandes, R. A.; Chavan, V. P. Tetrahedron: Asymmetry
011, 22, 1312. (b) Fernandes, R. A.; Chavan, V. P.; Mulay, S. V.;
Manchoju, A. J. Org. Chem. 2012, 77, 10455.
7) For reviews: (a) Larghi, E. L.; Kaufman, T. S. Eur. J. Org. Chem.
011, 5195. (b) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 187.
8) All the relative configurations were determined by key NOE
(
2
(
2
(
(9) (a) Fernandes, R. A.; Bruckner, R. Synlett 2005, 8, 1281. (b) Eid,
C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423.
correlations (see Supporting Information).
B
Org. Lett., Vol. XX, No. XX, XXXX

the desired alcohol 5 in good yield and excellent ee
1
to the desired benzoisochromanes 6bꢀi with equal or
better diastereoselectivity than the model n-butyraldehyde
reaction (6a) with one exception, isopropionaldehyde
(leading to 6g). Yields with the aliphatic set were also
comparable to the model reaction (g80%), with one
exception, vinylacetaldehyde (leading to 6f), possibly due
to aldehyde decomposition. For the aromatic aldehydes
examined, the reaction afforded the desired products 6jꢀl
with comparative yields (g86%) but varied diastereoselec-
tivity with dramatic improvements in R-selectivity ob-
served upon aromatic ring substitution. Nevertheless,
unlike most aliphatic counterparts, all the aromatic dia-
stereomers were readily resolved via standard silica gel
chromatography.
0
(
>99.5%).
With the core reaction established, we next explored
optimization of the oxa-PictetꢀSpengler reaction by first
assessing the potential of the Lewis acid to favor the
production of the R- or β-configured product. Among
1
2
the Lewis acids tested, 50 mol % Cu(OTf) offered the
2
best yield and R-diastereoselectivity (Table 1, entries 2ꢀ7;
1
1
see also Table S1 in Supporting Information). Further
investigation of solvents and reaction time in the context of
the Cu(OTf) reaction revealed a slight improvement in
2
yield and dr ratio with overnight stirring in dichloro-
methane (Table 1, entries 8ꢀ10). In contrast, FeCl was
3
the only Lewis acid to favor the production β-configured
product (2:1 β/R; Table 1, entry 13, and Supporting
Information) and this poor diastereoselectivity could not
be improved upon via further optimization (solvents,
temperature, and/or variant aldehyde source; data not
shown).
Table 2. Optimization of the Oxa-PictetꢀSpengler Reaction
a
with Trimethyl Orthoformate
a
Scheme 2. Scope of the R-Reaction with Varying R Group
Lewis
acids
temp
time
(h)
conversion
b,c
entry
solvent
(°C)
(%)
1
2
3
4
5
6
7
8
9
FeCl
BF
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
0
1
40(31)
20
3
3
OEt
2
0
1
Fe(OTf)
AlCl
SnCl
EtAlCl
Et AlCl
3
0
2
23
3
0
1
<10
4
0
1
45(33)
60(51)
2
0
1
d
<10
2
0
2
EtAlCl
EtAlCl
EtAlCl
EtAlCl
2
2
2
2
ꢀ40
ꢀ20
ꢀ20
ꢀ20
16
16
16
16
45(36)
80(70)
74(62)
78(65)
10
DCE
CH Cl
e
11
2
2
a
Reaction was performed with 0.2 mmol of 5, 0.24 mmol of trimethyl
orthoformate, and 100 mol % Lewis acid at 0 °C with 1 h of stirring.
Conversion was determined by HPLC analysis. The data in the
b
c
parentheses are the isolated yields after column chromatography. dr
d
ratio was determined by the proton NMR of crude products. Forma-
e
tion of the side product 11 in 60% yield. 2 mmol of 5 were loaded.
As previously indicated, FeCl was the only Lewis acid
3
a
Reaction was performed with 0.2 mmol of 5, 0.4 mmol of aldehyde,
to favor the production β-configured product (2:1 β/R;
Table 1, entry 13 and Supporting Information). Thus,
focus was next shifted to developing an orthogonal route
to bias the production β-configured products. Considering
that the oxocarbenium formed either by the oxidation of
isochroman or by the reduction ofisochroman acetalcould
and 50 mol % Cu(OTf) at 0 °C and allowed the temp raise to room temp
2
b
with overnight stirring. Isolated yields after column chromatography;
dr ratio (R/β) was determined by the proton NMR of crude products.
Using the optimized conditions for R-configured ben-
zoisochromane synthesis developed in Table 1, we next
explored the scope of aldehyde substrates in the context of
this reaction (Scheme 2). The aliphatic aldehydes tested led
1
3
be intercepted by a range of nucleophiles, we envi-
sioned the rigid lactone ring located on the si face of the
(
10) Enantioselectivities were determined by HPLC analysis [chiral
IC column (Daciel Chemical Ind. Ltd.) 25.0 mm ꢁ 4.6 mm, 80/20
hexane/iPrOH, 0.6 mL/min, UV 254 nm, tmajor = 39.2 min, tminor
1.8 min]. The observed ee value is consistent with the data reported in
ref 9a.
11) The epimers can be slightly isolated on a preparative reversed-
phase HPLC (Column: Supelco C18, 25 cm ꢁ 21.2 mm, 10 μm; eluent:
gradient 35%ꢀ50% CH CN in water; rate: 10 mL/min; t = 58.2 min,
= 62.3 min; loading amount: 5 mg).
(12) (a) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L.
Synth. Commun. 1998, 28, 3675. (b) Airiau, E.; Spangenberg, T.; Girard,
N.; Breit, B.; Mann, A. Org. Lett. 2010, 12, 528.
(13) (a) Elmore, S. W.; Coghlan, M. J.; Anderson, D. D.; Pratt, J. K.;
Green, B. E.; Wang, A. X.; Stashko, M. A.; Lin, C. W.; Tyree, C. M.;
Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.; Lane, B. C. J. Med. Chem.
2001, 44, 4481. (b) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45,
1949. For a review: (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
=
4
(
3
β
t
R
Org. Lett., Vol. XX, No. XX, XXXX
C

corresponding oxocarbenium generated by isochroman
acetal 8 to favor re face nucleophilic attack and thereby
favor formation of the β-diastereomer. Several C1 cation
building block (formaldehyde, dimethoxymethane, methyl
chloromethyl ether, methyl formate, and trimethyl ortho-
formate)/Lewis acid combinations were examined for
isochroman or isochroman acetal formation. Table 2
cS i cn h Be m2e 4. Synthesis of (þ)-Frenolicin B 1 and epi-(þ)-Frenoli-
Scheme 3. Scope of the β-Oriented Nucleophilic Attack with
Different Nucleophiles
While 6aβ was previously reported to display notable
2
d
cancer cell line cytotoxicity, the cytotoxicity of 6aR was
not previously reported. A comparison of the in vitro
anticancer activities of 6aR and 6aβ (Figure S1) revealed
similar potencies against the colon cancer cell line HCT116
(
IC50 of 109 ( 24 nM and 215 ( 21 nM, respectively)
compared to a slight reduction (∼5-fold) in potency for
aR against the nonsmall cell lung cancer cell line A549
IC50 of 965 ( 60 nM and 179 ( 29 nM, respectively),
6
(
suggesting the relativeconfigurationof theC-ringtohavea
moderate influence upon cancer cell line cytotoxicity/
specificity.
In summary, a diastereoselective oxa-PictetꢀSpengler
reaction has been established for the construction of
naphthoquinone analogs. The targeted strategy for the
synthesis of R-configured congeners hinges upon the use
highlights optimization of the reaction containing 5 and
trimethyl orthoformate ultimately affording isochroman
acetal 8 in good isolated yield (70%) on a reasonable scale
of Cu(OTf) , while desired β-configured analogs were as-
2
sembled via nucleophilic substitution upon a suitable iso-
chroman acetal precursor. The route has been successfully
applied in the synthesis of various frenolicin derivatives with
good to excellent diastereoselectivity/yields. Further antic-
ancer structureꢀactivity assessments are ongoing.
(
Table 2, entries 8ꢀ11). To test the feasibility of this
strategy to access β-configured adducts, the reaction of
acetal 8 with a small set of representative nucleophiles was
subsequently examined (Scheme 3). As anticipated, both
allyltrimethylsilane and cyanide led to β-configured pro-
ducts (6f and 12, respectively) in g85% yield, the former of
which could be hydrogenated to frenolicin precursor
Acknowledgment. This work was supported, in part, by
the University of Kentucky College of Pharmacy, the
University of Kentucky Markey Cancer Center, National
Institutes of Health Grant CA175105 (to Q.-B.S.), and the
National Center for Advancing Translational Sciences
6
aβ. Acetophenone led to a 5:1 β/R product distribu-
tion, likely due to an influence of phenylnaphthalene
π-stacking upon selectivity. Notably, compound 14 was
inaccessible via the previously discussed oxa-Pictetꢀ
Spengler reaction with 5.
(UL1TR000117).
Supporting Information Available. Complementary
Final maturation of 6aβ and 6aR to the desired
frenolicin B and epi-frenolicin B, respectively, followed
a slight modification of previously reported strategies
Table 1 for screening Lewis acids, experimental proce-
dures for compounds 1ꢀ2, 5ꢀ14, and compounds char-
acterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
6b
(Scheme 4). Specifically, while boron tribromide medi-
ated demethylation led to product epimerization
6
b
in prior reports, we found this could be avoided
by simply replacing boron tribromide with boron
trichloride.
The authors declare the following competing financialinterest(s): The
authors report competing interests. J.S.T. is a co-founder of Centrose
(Madison, WI).
D
Org. Lett., Vol. XX, No. XX, XXXX