De novo asymmetric synthesis of fridamycin e

Article abstract of DOI:10.1021/ol203041b

A de novo asymmetric synthesis of (R)- and (S)-fridamycin E has been achieved. The entirely linear route required only nine steps from commercially available starting materials (16% overall yield). Key transformations included a Claisen rearrangement, a S

Full text of DOI:10.1021/ol203041b

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6592–6595
De Novo Asymmetric Synthesis of
Fridamycin E
Qian Chen,† Michael Mulzer,‡ Pei Shi,† Penny J. Beuning,*,† Geoffrey W. Coates,*,‡
and George A. O’Doherty*,†
Department of Chemistry and Chemical Biology, Northeastern University, Boston,
Massachusetts 02115, United States, and Department of Chemistry and Chemical Biology,
Baker Laboratory, Cornell University, Ithaca, New York 14853, United States
G.ODoherty@neu.edu; gc39@cornell.edu; p.beuning@neu.edu
Received November 10, 2011
ABSTRACT
A de novo asymmetric synthesis of (R)- and (S)-fridamycin E has been achieved. The entirely linear route required only nine steps from
commercially available starting materials (16% overall yield). Key transformations included a Claisen rearrangement, a Sharpless dihydroxylation
and a cobalt-catalyzed epoxide carbonylation to give a β-lactone intermediate. Antibacterial activities were determined for both enantiomers using
two strains of E. coli, with the natural (R)-enantiomer showing significant inhibition against a Gram-(þ)-like imp strain (MIC = 8 μM).
The anthraquinone containing vineomycin members of
the angucycline family of antibiotics have been of parti-
cular interest to both the synthetic and biological com-
munities due to their unique structures and potent
antitumor and antibacterial activities.1 With the notable
exception of fridamycin E (1), all other members of this
class of natural products are mono- or bis-glycosylated
with rare deoxysugars (Figure 1). When monoglycosylated
the mono-, di-, and trisaccharide fragments are attached
via a β-C-aryl glycoside linkage to the anthraquinone ring
system. When bis-glycosylated the additional sugar frag-
ment is attached via an R-O-glycoside to the tertiary alcohol
of the β-hydroxy carboxylic acid side chain.
rhodinose-β-D-olivose) portion of vineomycin C.2 As part
of a larger effort aimed at the development of a general-
izable late stage glycosylation strategy for the synthesis
and biological testing of this class of C-glycoside natural
products, we required access to both enantiomers of
fridamycin E (1).3 This simplest member of the angucy-
cline family of antibiotics was isolated from a mutant of
Streptomyces parvulus (strain Tu 1989)4 and shown to
possess antibacterial activity.3 Biosynthetically fridamycin
E can be regarded as the aglycon core and biosynthetic
precursor of the more complex O- and C-glycosides of
angucycline antibiotics (2ꢀ9).1ꢀ3,5ꢀ8 Its existence also
€
(3) (a) Kricke, P. Ph.D. Thesis, University Gottingen, 1984. (b)
Previously, we have described the synthesis and anti-
cancer activityof thePMB-trisaccharide (R-L-aculose-R-L-
Krohn, K.; Baltus, W. Tetrahedron 1988, 44, 49–54. (c) Matsumoto, T.;
Jona, H.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1991, 32, 5103–
5106.
€
(4) Kunzel, E.; Faust, B.; Oelkers, C.; Weissbach, U.; Bearden,
D. W.; Weitnauer, G.; Westrich, L.; Bechthold, A.; Rohr, J. J. Am.
Chem. Soc. 1999, 121, 11058–11062.
† Northeastern University.
‡ Cornell University.
(5) Maskey, R. P.; Helmke, E.; Laatsch, H. J. Antibiot. 2003, 56, 942–
949.
(6) (a) Omura, S.; Tanaka, H.; Oiwa, R.; Awaya, L.; Masuma, R.;
Tanaka, K. J. Antibiot. 1977, 30, 908–916. (b) Imamura, N.; Nakinuma,
K.; Ikekawa, N.; Tanaka, H.; Omura, S. J. Antibiot. 1981, 34, 1517–
1518.
(7) Aivi, K. A.; Baker, D. D.; Stienecker, V.; Hosken, M.; Nair, B. J.
J. Antibiot. 2000, 53, 496–501.
(8) Kawamura, N.; Sawa, R.; Takahashi, Y.; Sawa, T.; Kinoshita,
N.; Naganawa, H.; Hamada, M.; Takeuchi, T. J. Antibiot. 1995, 48,
1521–1524.
(1) (a) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103–137. (b)
Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127–195. (c) Andriy, L.;
Andreas, V.; Andreas, B. Mol. BioSyst. 2005, 1, 117–126.
(2) (a) Yu, X.; O’Doherty, G. A. Org. Lett. 2008, 10, 4529–4532. For
related approaches, see: (b) Yu, X.; Li, M.; O’Doherty, G. A. Hetero-
cycles 2011, 82, 1577–1584. (c) Sobti, A.; Kyungjin Kim, K.; Sulikowski,
G. A. J. Org. Chem. 1996, 61, 6–7. (d) Sasaki, K.; Matsumura, S.;
Toshima, K. Tetrahedron Lett. 2007, 48, 6982–6986. (e) Zhou, M.;
O’Doherty, G. A. Org. Lett. 2008, 10, 2283–2286. (f) Zhou, M.;
O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493. (g) Zhou, M.;
O’Doherty, G. A. Org. Lett. 2006, 8, 4339–4342.
r
10.1021/ol203041b
Published on Web 11/22/2011
2011 American Chemical Society

anthraquinone substrates) also provided us an excellent
opportunity to test the functional group compatibility of
the Co-catalyzed epoxide to β-lactone carbonylation
reaction.10
Our approach to fridamycin E (1) is depicted in Scheme 1.
We envisioned that 1 could be accessed from β-lactone 10,
which in turn could be prepared via a Co-catalyzed
carbonylation of epoxide 11. An asymmetric epoxidation
of a disubstituted alkene 12 could be used to install the
desired asymmetry. Finally, alkenes like 12 could be
prepared by a two-step ortho-C-methallylation sequence
of commercially available anthrarufin 13.11
Scheme 1. De Novo Retrosynthesis of (R)-Fridamycin E
Our synthesis of fridamycin E began with the mono-
methallylation of anthrarufin (methallylCl, KI/K2CO3)
to give 14 in 42% yield (Scheme 2). In situ dithionate
reduction of 14 to an anthraquinol intermediate was
followed by thermally promoted Claisen rearrangement
to give C-methallylated anthrarufin 15. Finally the two
phenol hydroxyl groups were protected as benzyl ethers
(BnBr/K2CO3, 89% yield).11
Figure 1. Sample angucyclines with a (R)-fridamycin E nucleus.
suggests the existence of a biosynthetic C-glycosylation
and the potential for a synthetic variant.4
The total syntheses of fridamycin E, and its unnatural
(S)-enantiomer, havebeenachieved by several groups.3b,c,9
While these approaches vary in terms of overall effi-
ciency, the routes all suffered in how asymmetry was
introduced into the molecule. These methods varied from
the use of chiral starting materials ((S)-lactic acid)3b and
auxiliaries (menthol based titanium enolate)9a,b to the use
of enzyme-(lipase and hydrolase)3c,9c catalyzed kinetic
resolutions. The most recent and arguably most success-
ful of these routes was developed by Faber, who utilized a
resolution of a rac-2,2-disubstituted epoxide to install the
asymmetry of (R)-fridamycin E (84% ee).9c Despite the
success of these previous approaches, we felt a catalytic
asymmetric approach had the potential for making the
synthesis more efficient and providing access to either
enantiomer for future synthetic and biological studies
(vide infra). Herein, we describe our development of a new
enantio-divergent route to natural (R)-fridamycin E
and unnatural (S)-fridamycin E that uses the Sharpless
dihydroxylation to install asymmetry and our initial eva-
luation of these enantiomers as antimicrobial agents.
This route and structural complexity (e.g., the easily reduced
Scheme 2. De Novo Asymmetric Synthesis of Epoxide 17
With the desired alkene 16 in hand, we then focused on
its direct asymmetric epoxidation, which proved proble-
matic. For instance, when alkene 16 was subjected to the
(10) For a review, see: Church, T. L.; Getzler, Y. D. Y. L.; Byrne,
C. M.; Coates, G. W. Chem. Commun. 2007, 657–674.
(9) (a) Pausler, G. M.; Rutledge, P. S. Tetrahedron Lett. 1994, 35,
3345–3348. (b) Pausler, M. G.; Rutledge, P. S. Aust. J. Chem. 1994, 47,
2135–2147. (c) Ueberbacher, B. J.; Osprian, I.; Mayer, S. F.; Faber, K.
Eur. J. Org. Chem. 2005, 1266–1270.
(11) (a) Beauregard, D. A.; Cambie, R. C.; Higgs, K. C.; Rutledge,
P. S.; Woodgate, P. D. Aust. J. Chem. 1994, 47, 1321–1333. (b) Bercich,
M. D.; Cambie, R. C.; Howe, T. A.; Rutledge, P. S.; Thomson, S. D.;
Woodgate, P. D. Aust. J. Chem. 1995, 48, 531–549.
Org. Lett., Vol. 13, No. 24, 2011
6593

typical Jacobsen epoxidation conditions (5 mol % of (S,
S)-Mn-salen catalyst and buffered NaOCl(aq) in CH2Cl2
at 0 °C)12 only trace amounts of epoxide 17 were detected.
Improved yields of epoxide 17 were found for the Shi
epoxidation of 16 (30% yield at ∼33% conversion),
however the relatively low levels of asymmetric induction
dampened our enthusiasm for this direct approach
(∼15% ee).13
to us that other linkers might give different and/or
improved facial selectivities. Several ligand systems and
conditions were screened (entries 2ꢀ5 and 7ꢀ10) and var-
ious selectivities were found. To our delight, we found that
when alkene 16 was dihydroxylated with the Sharpless
DPP-linker ligand systems, diols with more than satisfac-
tory enantiopurity were afforded. For instance, asym-
metric dihydroxylation of 16 with (DHQD)2DPP formed
(S)-diol (ent)-18 in 98% yield with 90% ee (entry 5).
Similarly, the (DHQ)2DPP ligand gave the (R)-diol 18
in 98% yield with 88% ee (entry 10).16
We eventually resorted to the Sharpless dihydroxy-
lation of 16 to install asymmetry (Table 1).14 This was
With the desired stereochemistry installed, we then
turned our attention to the conversion of diol 18 into
the desired epoxide 17 for a subsequent cobalt-catalyzed
epoxide to β-lactone carbonylation reaction (17 to 20,
Scheme 3). While we had a high degree of confidence in
the outcome of this transformation, we were concerned
with the possibility of catalyst oxidation by the anthraqui-
none functional group or competing Lewis acid catalyzed
isomerization of the epoxide substrate to an allylic alcohol.
Table 1. Optimization of Asymmetric Dihydroxylation of 16a
entry
ligand
yieldb
[R]D
ee %d
conf.
c
1
(DHQD)2PHAL
(DHQD)2AQN
(DHQD)2PYR
(DHQD)PHN
(DHQD)2DPP
(DHQ)2PHAL
(DHQ)2PYDZ
DHQ-4-Me-2-Quin
(DHQ)2DPP
98%
96%
96%
94%
98%
98%
94%
94%
98%
98%
ꢀ5.0
ꢀ5.2
þ2.4
þ4.6
ꢀ7.2
þ5.9
þ2.1
ꢀ1.1
þ6.5
þ6.9
70
S
S
R
R
S
R
R
S
R
R
2
66e
30e
59e
90
Scheme 3. Synthesis of β-Lactone 20
3
4
5
6
75e
27e
14e
83e
88
7
8
9
10f
(DHQ)2DPP
a Reaction conditions: 16 (0.1 mmol), OsO4 (0.004 mmol), ligand
(0.02 mmol), K3Fe(CN)6 (0.3 mmol), K2CO3 (0.3 mmol), MeSO2NH2
(0.11 mmol), t-BuOH/H2O (1 mL/1 mL), 0 °C to rt. b Isolated yield based
on 16. c All rotations were taken in CH2Cl2. d The ee values were
determined by the use of Mosher’s reagent. e The ee values were
determined by comparison of their optical rotations. f No MeSO2NH2
was used.
Treatment of (R)-diol 18 with TsCl in the presence of
Bu2SnO and Et3N in CH2Cl2 afforded tosylate 19 in 91%
yield. Subsequent deprotonation of 19 with NaH smoothly
converted it into epoxide 17 in 92% yield. To our delight,
similar success was found when we turned to the proposed
Co(ꢀI)-catalyzed carbonylation.17 Thus, when 17 was trea-
ted with 10 mol % of [ClTPPAl]þ[Co(CO)4]ꢀ (ClTPP =
meso-tetra(4-chlorophenyl)porphyrinato) in THF under a
carbon monoxide atmosphere (900 psi) at 40 °C, the desired
β-lactone 20 was obtained in 70% yield. Despite our con-
cerns to the contrary, we found this Co(ꢀI)-catalyzed
carbonylation at 40 °C proceeded cleanly without any signs
of competing reaction pathways. Yet, when the reaction was
carried out at a higher temperature (60 °C) a significant
amount (∼20%) of alkene 16 was also detected.
done begrudgingly because of the recognition of the addi-
tional steps required and the precedent from Rutledge
and Woodgate, which suggested the dihydroxylation would
occur with less than ideal enantioexcesses (<70% ee).15
For instance, when (DHQD)2PHAL was used as the
ligand for the dihydroxylation (entry 1), diol 18 (S) was
produced in excellent yield but only moderate enantio-
purity (70% ee). Using the pseudoenantiomeric ligand
system (entry 6, (DHQ)2PHAL), the (R)-diol 18 was
obtained (98%, 75% ee). To our surprise, the configura-
tion of diols obtained using these PHAL-ligands were the
opposite from what is predicted by the Sharpless
mnemonic.14 This reversal in facial selectivity suggested
The synthesis of fridamycin E was completed by a two-
step sequence as outlined in Scheme 4. This began with
(12) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng,
L. J. Am. Chem. Soc. 1991, 113, 7063–7064. (b) Brandes, B. D.;
Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378–4380.
(13) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224–11235.
(14) For a review, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1994, 94, 2483–2547.
(15) Related substrates to 16 gave diols with moderate %ee’s
(< 70%), see: Beauregard, D. A.; Cambie, R. C.; Dansted, P. C.; Rutledge,
P. S.; Woodgate, P. D. Aust. J. Chem. 1995, 48, 669–676.
(16) While not perfect, the crystalline nature of this class of
compounds provided ideal opportunities to improve the product
enantioexcess.
(17) (a) Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.;
Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174–1175. (b) Rowley,
J. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129,
4948–4960.
6594
Org. Lett., Vol. 13, No. 24, 2011

hydrolysis of β-lactone 20 (NaOH(aq)/THF) to afford β-
hydroxyl carboxylic acid 21 in 97% yield. Finally, deben-
zylation with 1,4-cyclohexadiene and Pd/C in ethanol
gave (R)-fridamycin E in 88% yield.18 This synthetic
(R)-fridamycin E material had physical and spectroscopic
data in good agreement with literature values (e.g., [R] =
þ8.3 (c = 1.0, dioxane) ([R] = þ8.9)).3c
Interestingly, while both enantiomers showed no activity
(>64 μM) against the wild-type E. coli (Gram-(ꢀ)), the
natural enantiomer 1 was significantly more active (8 μM)
than the unnatural enantiomer (ent)-1 (64 μM) against
the Gram-(þ)-like E. coli imp mutant. The lack of anti-
bacterial activity against the wild type E. coli suggests
poor cell wall permeability of the natural product. In con-
trast, the 8-fold difference in activity for the two enantio-
meric forms suggests the importance of the tertiary
alcohol on the mechanism ofaction againstthe Gram-(þ)-
like E. coli imp mutant.
Scheme 4. Synthesis of (R)-Fridamycin E (1)
Table 2. MIC Values for (R/S)-Fridamycin Ea
MIC (μM)
imp
MG1655
With the success of the (R)-fridamycin E synthesis, we
then turned to synthesize its enantiomer (Scheme 5).
Following a nearly identical procedure (switching (DHQ)2-
DPP to (DHQD)2DPP), (S)-fridamycin E (ent)-1 was
enantioselectively prepared in 47% overall yield (6 steps)
from alkene 16.
(R)-Fridamycin E
(S)-Fridamycin E
8
>64
>64
64
a Overnight bacterial cultures were diluted 10-fold into fresh LB
medium and grown to the desired OD600 value (depending on strain
used). The cell cultures were again diluted by 1000-fold into fresh LB
medium containing serial dilutions (2-fold) of the fridamycin E, then
grown at 37 °C in agitated 96-well microtiter plates and incubated for
20 h. Cell densities (OD600) were recorded on an automated plate reader.
MG1655 and BAS901 (imp-4213) were gifts from Prof. Kim Lewis
(NEU). Data are reported for the average of at least three independent
sets of experiments.
Scheme 5. Synthesis of (S)-Fridamycin E (ent)-1
In summary, the de novo asymmetric synthesis of both
natural (R)- and unnatural (S)-fridamycin E was accom-
plished in 9 steps and 16% overall yield. This stereodi-
vergent strategy shows the importance of ligand choice in
the Sharpless asymmetric dihydroxylation for control
of absolute stereochemistry. The route also shows the
efficiency and functional group compatibility of the
Co-catalyzed epoxide to β-lactone carbonylation for
the synthesis of tertiary β-hydroxyl carboxylic acids. The
antibacterial activity of both enantiomers of fridamycin
E showed the importance of stereochemistry to its anti-
bacterial SAR. Further synthetic/biological investigations
are ongoing and will be reported in due course.
With adequate supplies of both enantiomers of frida-
mycin E in hand, we began our analysis of the antibacter-
ial Structure Activity Relationship (SAR) using two
different strains of E. coli. The first is a wild-type E. coli
(K-12 MG1655) which served as a Gram-(ꢀ) model
organism, and the second a genetically modified E. coli
imp (K-12 BAS901) which served as a Gram-(þ)-like
model organism. E. coli imp has a mutation (imp-4213)
that increases the permeability of the outer membrane.19
Minimal inhibitory concentrations (MIC) were deter-
mined for both fridamycin E enantiomers (Table 2).
Acknowledgment. We are grateful to NIH (G.A.O.,
GM090259 and GM088839), NSF (G.A.O., CHE-0749451;
P.J.B., MCB-0845033) and DOE (G.W.C., DE-FG02-
05ER15687) for their financial support of this research.
P.J.B. isa CottrellScholar ofthe ResearchCorporation for
Science Advancement.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds (1 and
14ꢀ21), as well as biological assay protocols and data are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Evidence of the anthraquinone sensitivity to reducing conditions
can be seen by the fact that when 21 is reduced under typical hydro-
genolysis conditions (Pd/C, H2 (1 atm), EtOH, rt) products with B-ring
reduction were produced.
(19) Sampson, B. A.; Misr, R.; Benson, S. A. Genetics 1989, 122,
491–501.
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