Combining asymmetric catalysis with natural product functionalization through enantioselective α-fluorination

Article abstract of DOI:10.1021/jo9024072

(Chemical Equation Presented) An examination into the derivatization of various natural products using newly developed R-fluorination methodology is disclosed. An activated ketene enolate, generated from an acid chloride, is allowed to react with an electrophilic fluorine source (NFSi). Quenching the reaction with a nucleophilic natural product produces biologically relevant R-fluorinated carbonyl derivatives of select chemotherapeutics, antibiotics, and other pharmaceuticals.

Full text of DOI:10.1021/jo9024072

pubs.acs.org/joc
Combining Asymmetric Catalysis with Natural
Product Functionalization through Enantioselective
r-Fluorination
Jeremy Erb, Ethan Alden-Danforth, Nathan Kopf,
Michael T. Scerba, and Thomas Lectka*
Department of Chemistry, Johns Hopkins University,
3400 North Charles Street, Baltimore, Maryland 21218
lectka@jhu.edu
Received November 16, 2009
FIGURE 1. General scheme for asymmetric fluorination. Reaction
€
conditions are as follows: (A) trans-(PPh3)2PdCl2, BQd, Hunig’s
base, NFSi, THF, -78 °C, 8 h; (B) NuH, -78 °C to room tempera-
ture.
result from specific C-H to C-F transformations. Bioab-
sorption, binding affinity, chemical reactivity, and increased
metabolic durability are some of the properties that can be
enhanced by strategic fluorination.2 Recently, we reported a
versatile system for the catalytic, asymmetric R-fluorina-
tion of acid chlorides. Activated, chiral ketene enolates
An examination into the derivatization of various natural
products using newly developed R-fluorination metho-
dology is disclosed. An activated ketene enolate, gener-
ated from an acid chloride, is allowed to react with an
electrophilic fluorine source (NFSi). Quenching the reac-
tion with a nucleophilic natural product produces biolo-
gically relevant R-fluorinated carbonyl derivatives of
select chemotherapeutics, antibiotics, and other pharma-
ceuticals.
€
(2, Figure 1), generated in situ from acid chlorides, Hunig’s
base, benzoylquinidine (BQd), and trans-(PPh3)2PdCl2, were
allowed to react with N-fluorobenzenesulfonimide (NFSi)3
at -78 °C in THF. Upon quenching with an appropriate
nucleophile, R-fluorinated esters, amides, acids, and thioe-
sters were produced with excellent enantioselectivity and in
good yield.4,5 Herein, we present a new facet of our asym-
metric fluorination methodology involving the site-specific
derivatization of biologically relevant compounds.6
The fields of asymmetric catalysis and natural product
derivatization have both made powerful contributions to
organic synthesis and practical drug discovery alike.1 In this
note, we seek to link the two important disciplines through a
tandem process coupling catalytic, asymmetric fluorination
with the functionalization of natural products and select
analogues to produce interesting new compounds.
The fluorination of biologically active molecules and
pharmaceuticals has received increased attention in recent
years due to the extensive therapeutic benefits that often
(R)-(þ)-Aminoglutethimide, a potent inhibitor of P450 scc
and aromatase, was investigated first because of its commercial
availability, single nucleophilic site, and known biological
activity.7 Under standard reaction conditions, p-methoxy-
phenylacetyl chloride was fluorinated with NFSi and quen-
ched with (R)-(þ)-aminoglutethimide to give 3a (Table 1) in
nearly quantitative yield and 99% diastereomeric excess (de).
Kinetic resolution due to the interaction of the chiral nucleo-
phile with putative intermediate 4 (Figure 2) was negligible.
(3) (a) Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org. Lett.
2003, 5, 3225–3228. (b) Hamashima, Y.; Yagi, K.; Takano, H.; Tamas, L.;
Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530–14531.
(4) Paull, D. H.; Scerba, M. T.; Alden-Danforth, E.; Widger, L. R.;
Lectka, T. J. Am. Chem. Soc. 2008, 130, 17260–17261.
(1) (a) Taylor, M. S.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5368–5373. (b) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature 2008,
455, 323–332. (c) Clardy, J.; Walsh, C. Nature 2004, 432, 829–837. (d)
Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis, 4th ed.;
Cambridge University Press: New York, 2006. (e) Gershon, H.; Schulman, S. G.;
Spevack, A. D. J. Med. Chem. 1967, 10, 536–541. (f) Ismail, F. M. D. J. Fluorine
Chem. 2002, 118, 27–33. (g) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93–99.
(2) For recent texts on the impact of fluorine on bioactivity, see: (a) Kirk,
K. L. J. Fluorine Chem. 2006, 127, 1013–1029. (b) Thomas, C. J. Curr. Top.
Med. Chem. 2006, 6, 1529–1543. (c) Liu, P.; Sharon, A.; Chu, C. K. J.
Fluorine Chem. 2008, 129, 743–766. (d) Park, B. K.; Kitteringham, N. R.
Drug Metab. Rev. 1994, 26, 605–643. (e) Smart, B. E. J. Fluorine Chem. 2001,
109, 3–11. (f) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
Wiley-Blackwell: Chichester, U.K., 2009. (g) Chambers, R. D. Fluorine in
Organic Chemistry; Wiley: New York,: 1973.
(5) A generalized reaction scheme with specific reaction conditions is
outlined in Figure 1.
(6) It should be noted that stereochemical assignment of the products
listed in Table 1 was inferred from prior investigations in our laboratory. No
autocatalytic functionalization of any nucleophile was observed. Catalysis
by the pseudoenantiomeric alkaloid benzoylquinine (BQ) gives direct access
to the other diastereomeric product with identical yield and diastereomeric
excess. Achiral alkaloid catalysts were tested and gave mixtures of diaster-
eomers.
(7) Siraki, A. G.; Bonini, M. G.; Jiang, J.; Ehrenshaft, M.; Mason, R. P.
Chem. Res. Toxicol. 2007, 20, 1038–1045.
DOI: 10.1021/jo9024072
r
Published on Web 12/29/2009
J. Org. Chem. 2010, 75, 969–971 969
2009 American Chemical Society

Erb et al.
JOCNote
TABLE 1. Fluorinated Natural Product Derivativesa
decreased cytotoxicity in vivo while maintaining potency.11
Using our fluorination methodology, mitomycin C is acylated
(3c, Table 1) exclusively on the aziridine nitrogen as opposed
to its enamino (c, Figure 3), a result that can be rationalized by
simple resonance arguments. The structural integrity of the
acylaziridine is maintained under the mild conditions of our
reaction, and is verified by IR spectroscopy.
entry acid chloride
NuH
product % de % yield
1
2
3
4
5
6
7
8
9
P-MeO-PACc aminoglutethimide
3a
3b
3c
3d
3e
3f
99
81
99
99
99
99
99
99
99
98
75
58
43
77
75
40
32
74
phthPCd
phthPCd
artemisinin lactol
mitomycin C
P-MeO-PACc taxol
P-MeO-PACc cholesterol
P-MeO-PACc vitamin D3
phthPCd
phthPCd
phthPCd
glutathione diethyl ester 3g
The next logical progression was to explore molecules
containing multiple (and potentially competing) nucleophilic
sites. Controlling site reactivity in natural product chemistry
can be extremely difficult and often requires the use of
protecting groups to ensure reaction at the desired site.
Methods that bypass the need for such laborious and costly
protections and deprotections would most certainly be a
welcome addition to the synthetic repertoire.12 With this in
mind, our attention turned to the chemotherapeutic drug
taxol,13 which has three distinct and potentially nucleophilic
hydroxyl groups. When p-methoxylphenylacetyl chloride was
fluorinated and quenched with taxol, the sole product, result-
ing from attack by the secondary hydroxyl of the side chain,
was obtained in 43% yield and excellent diastereoselectivity.
When baccatin III (containing the basic taxol core) was used
as a nucleophile, no product could be isolated, further sup-
porting that under standard fluorination conditions, taxol
reacts selectively from the secondary hydroxyl of its side chain
(Figure 2). Another useful application of this fluorination
method manifests in the modification of peptide-based ther-
apeutic agents.14 By transacylation of the putative reactive
fluorinate intermediate 4 with nucleophilic amino acid deri-
vatives, a virtually limitless number of fluorinated peptides
can be accessed. For example, 3-phthalimidopropionyl chlor-
ide was fluorinated and then quenched with glutathione
diethyl ester affording 3g in 40% yield and with 99% de.
The solubility of the nucleophile used to quench the
reaction proved critical during this investigation. Whereas
nonpolar nucleophiles such as cholesterol and vitamin D3
dissolved readily in organic solvents and gave products in
high yield, other substrates such as glutathione, morphine,
and 6-aminopenicillanic acid displayed marginal solu-
bility, and led to drastically decreased yields of the target
compounds. However, simple modifications to these nu-
cleophiles improved their solubility and yields increased
(Table 1). Glutathione and 6-aminopenicillanic acid were
esterified with ethanol and diphenyldiazomethane,15 respec-
tively. Morphine was derivatized16 by acylation and N-
demethylation to provide a soluble nucleophile with an
accessible secondary amine that was acylated in 32% yield.
diacetylnormorphine
dpm-6-APEb
3h
3i
aAll reactions were run with standard reaction conditions. bdpm-
6-APE = diphenylmethyl-6-aminopenicillanic ester. cp-MeO-PAC =
p-methoxyphenylacetyl chloride. dphthPC = 3-phthalimidopropionyl
chloride.
FIGURE 2. Reactivity with taxol and baccatin III.
We then examined several other biologically relevant com-
pounds in order to determine the scope and versatility of this
method. Artemisinin was an attractive target due to its role in
combating multiple drug-resistant strains of malaria.8 Quen-
ching the fluorination of 3-phthalimidopropionyl chloride
with artemisinin lactol affords 3b in 75% yield and 81% de.9
Mitomycin C, a drug possessing both antibiotic and che-
motherapeutic properties, contains an aziridine ring that is
essential for its mechanism of action.10 Studies have shown
that N-acylaziridine derivatives of mitomycin C demonstrate
(11) Fishbein, P. L.; Kohn, H. J. Med. Chem. 1987, 30, 1767–1773.
(12) The pioneering work of Miller utilizes synthetic peptides to achieve
site-selectivity in natural product derivatization. For recent examples, see:
(a) Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed. 2006, 45, 5616–5619. (b)
ꢀ
Sanchez-Rosello, M.; Puchlopek, A. L. A.; Morgan, A. J.; Miller, S. J. J. Org.
Chem. 2008, 73, 1774–1782. (c) Morgan, A. J.; Komiya, S.; Xu, Y.; Miller, S.
J. J. Org. Chem. 2006, 71, 6923–6931. (d) Lewis, C. A.; Longcore, K. E.;
Miller, S. J.; Wender, P. A. J. Nat. Prod. 2009, 72, 1864–1869.
(13) Mathew, A. E.; Mejillano, M. R.; Nath, J. P.; Himes, R. H.; Stella, V.
J. J. Med. Chem. 1992, 35, 145–151.
(14) Salwiczek, M.; Samsonov, S.; Vagt, T; Nyakatura, E.; Fleige, E.;
€
Numata, J.; Colfen, H.; Pisabarro, M. T.; Koksch, B. Chem.;Eur. J. 2009,
15, 7628-7636 and references cited therein.
(15) (a) Smith, L. I.; Howard, K. L. Organic Syntheses; Wiley: New York,
1955; Collect. Vol. III, p 351. (b) Jensen, S. E.; Westlake, D. W. S.; Bowers, R. J.;
Wolfe, S. J. Antibiot. 1982, 35, 1351–1360.
(16) Cooper, G. K.; Rapoport, H. J. Label. Compd. Radiopharm. 1985,
22, 1201–1207.
(8) White, N. J. J. Clin. Invest. 2004, 113, 1084–1092.
(9) Posner, G. H.; McRiner, A. J.; Paik, I.; Sur, S.; Borstnik, K.; Xie, S.;
Shapiro, T. A.; Alagbala, A.; Foster, B. J. Med. Chem. 2004, 47, 1299–1301.
(10) Tomasz, M. Chem. Biol. 1995, 2, 575–579.
970 J. Org. Chem. Vol. 75, No. 3, 2010

Erb et al.
JOCNote
FIGURE 3. Natural product derivatives. Derived from the following: (a) (R)-(þ)-aminoglutethimide, (b) artemisinin lactol, (c) mitomycin C,
(d) taxol, (e) cholesterol, (f) vitamin D3, (g) glutathione, (h) diacetylnormorphine, and (i) 6-aminopenicillanic acid.
In conclusion, we have demonstrated that our R-fluorina-
tion methodology pairs successfully with natural product
derivatization to form biologically relevant molecules with
consistently excellent diastereoselectivity. This new method
should appeal to the synthetic chemist who seeks to utilize
mild conditions for the asymmetric installation of fluorine.
Future efforts will focus on a detailed mechanistic investigation
of this method and an expansion to hybrid drug synthesis.
0.055 mmol, 0.33 equiv) were added as a solution in THF
(0.50 mL), and the reaction was warmed to room temperature
overnight. The product was then subjected to column chromato-
graphy on silica gel with a mixture of ethyl acetate/hexanes as
the eluent (unless otherwise noted).
(R)-2-Fluoro-2-(4-methoxyphenyl)-N-(R)-(þ)-aminoglutethi-
mide (3a): yellow solid, yield 98%, % de = 99; mp 55-60 °C;
[R]20D -3.42 (c 0.012, CH2Cl2); 1H NMR (CDCl3) (at 25 °C) δ
8.32 (br s, 1H), 8.20 (s, 1H), 7.65 (d, 2H), 7.40 (d, 2H), 7.25 (d,
2H), 6.95 (d, 2H), 5.85 (d, 1H, J = 49.8 Hz), 3.80 (s, 3H), 2.55 (d,
1H), 2.40-2.30 (m, 2H), 2.30-2.10 (m, 1H), 1.95-1.80 (m, 1H),
1.25 (t, 1H), 0.85 (t, 3H); 13C NMR (CDCl3) δ 175.3, 172.5,
161.0, 160.1, 136.5, 134.5, 129.5, 129.5, 127.8, 120.4, 114.5, 92.2
(d, J = 190.4 Hz), 56.0, 52.0, 34.0, 29.5, 27.0, 9.0; 19F NMR
(CDCl3) δ -169.9 (ddd, J = 49.8, 15.5, 5.8 Hz); IR (cm-1, CaF2,
CH2Cl2) 1706; HRMS (ESIþ) calcd for C22H23FN2O4Naþ
421.153407, found 421.152714.
Experimental Section
General Procedure for the Syntheses of Fluorinated Products.
To a dry 10 mL round-bottomed flask equipped with a stir bar
was added trans-(PPh3)2PdCl2 (3.5 mg, 0.0083 mmol, 0.050
equiv) and benzoylquinidine (BQd) (7.1 mg, 0.016 mmol, 0.10
equiv), and the mixture was kept under an atmosphere of
nitrogen. THF (1.0 mL) was added, and the mixture was cooled
€
to -78 °C. Hunig’s base (0.030 mL, 0.18 mmol, 1.1 equiv) was
Acknowledgment. T.L. thanks the NIH (Grant GM064559)
for support. MTS thanks Johns Hopkins University for a Marks
Fellowship.
then added neat to the mixture. Thereupon a solution of
N-fluorobenzenesulfonimide (NFSi, 52 mg, 0.16 mmol, 1.0 equiv)
in 0.33 mL of THF was added, followed by a solution of freshly
distilled p-methoxyphenylacetyl chloride (0.021 mL, 0.16 mmol,
1.0 equiv) in 0.66 mL of THF. The reaction was maintained at
-78 °C for 8 h. 4-Dimethylaminopyridine (DMAP, 2.0 mg,
0.016 mmol, 0.10 equiv) and (R)-(þ)-aminoglutethimide (12 mg,
Supporting Information Available: General experimental
procedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 971