Enantioselective synthesis of α-fluoro-β3-amino esters: Synthesis of enantiopure, orthogonally protected α-fluoro- β3-lysine

Article abstract of DOI:10.1021/jo101600c

The scope of a tandem conjugate addition-fluorination sequence performed on α,β-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(α-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide h

Full text of DOI:10.1021/jo101600c

pubs.acs.org/joc
Enantioselective Synthesis of r-Fluoro-β3-amino Esters: Synthesis of
Enantiopure, Orthogonally Protected r-Fluoro-β3-lysine
Peter J. Duggan,*,† Martin Johnston,‡ and Taryn L. March‡
†CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia, and
‡School of Chemical and Physical Sciences, Flinders University, SA 5042, Australia
peter.duggan@csiro.au
Received August 20, 2010
The scope of a tandem conjugate addition-fluorination sequence performed on R,β-unsaturated esters
using the enantiopure lithium amide derived from (S)-N-benzyl-N-(R-methylbenzyl)amine, and the
electrophilic fluorinating agent N-fluorobenzenesulfonimide has been investigated. Using this method,
R-fluoro-β3-amino esters can be obtained in up to quantitative yield and 80:20 to >99:1 dr. This simple
methodology does not rely on the use of R-amino acids from the chiral pool and thus provides the
potential for the preparation of enantiopure R-fluoro-β3-amino acids with a wide variety of side chains.
Its utility was demonstrated through the synthesis of orthogonally protected (2S,3S)-R-fluoro-β3-lysine.
Introduction
has recently been highlighted.5 The incorporation of fluorine
into organic compounds can also have surprising conforma-
tional effects.2,6 For these reasons, there is considerable interest
in the preparation of fluorine-containing synthetic building
blocks and intermediates.
β-Amino acids are also a class of compound that have
received much attention because they are important compo-
nents of bioactive natural products and peptidomimetics, they
can enhance resistance to proteolysis, and peptides derived
from β-amino acids possess fascinating and well-defined
secondary structure.7 Our interest in protease inhibition8 led
us to seek stereoselective routes to R-fluoro-β3-amino acids,
a group of compounds that are under-represented in the
ꢀ
˚
Fluorine has a van der Waals radius of 1.47 A, which makes it
only 3% smaller than oxygen and 23% larger than hydrogen.1 It
is considered the best isosteric replacement for both of these
atoms. In addition, fluorine forms strong bonds with carbon, it
can significantly affect the lipophilicity of a compound,2 and
its high electronegativity can have a considerable influence on
the pKa of proximal functional groups. There are numerous
examples where fluorine has been successfully incorporated into
bioactive compounds in place of hydrogen and oxygen. Such
replacements can change the biological properties of the sub-
strate significantly. In fact, fluorinated compounds constitute
5-15% of all small-molecule drugs launched over the last 50
years, and this proportion has increased markedly in the last
5 years.3 Fluorinated substrates have also been widely used as
enzyme mechanism probes and as enzyme inhibitors.4 The
involvement of fluorine in orthogonal multipolar interactions
between protein-bound small molecules and protein residues
€
(5) Paulini, R.; Muller, K.; Diederich, F. Angew. Chem., Int. Ed. 2005, 44,
1788.
(6) Mathad, R. I.; Jaun, B.; Flogel, O.; Gardiner, J.; Loweneck, M.;
€
€
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Codee, J. D.; Seeberger, P. H.; Seebach, D.; Edmonds, M. K.; Graichen,
F. H. M.; Abell, A. D. Helv. Chim. Acta 2007, 90, 2251.
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(7) (a) Seebach, D.; Beck., A. K.; Capone, S.; Deniau, G.; Groselj, U.;
Zass, E. Synthesis 2009, 1. (b) Seebach, D.; Gardiner, J. Acc. Chem. Res.
2008, 41, 1366. (c) Horne, W. S.; Price, J. L.; Gellman, S. H. Proc. Natl. Acad.
Sci. U.S.A. 2008, 105, 9151. (d) Enantioselective Synthesis of β-Amino Acids,
2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; John Wiley & Sons: Hoboken,
2005. (e) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004,
1, 1111.
(1) Bondi, A. J. Phys. Chem. 1964, 68, 441.
(2) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.;
Wiley-Blackwell: Chichester, 2009.
(3) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(4) Berkowitz, D. B.; Karukurichi, K. R.; de la Salud-Bea, R.; Nelson,
D. L.; McCune, C. D. J. Fluorine Chem. 2008, 129, 731.
(8) Bromfield, K. M.; Quinsey, N. S.; Duggan, P. J.; Pike, R. N. Chem.
Biol. Drug Des. 2006, 68, 11.
DOI: 10.1021/jo101600c
r
Published on Web 10/08/2010
J. Org. Chem. 2010, 75, 7365–7372 7365
2010 American Chemical Society

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SCHEME 1. Synthesis of Protected (2S)-β3-Amino Esters 4 and
One-Pot Synthesis of Protected (2S)-r-Fluoro-β3-Amino Esters 5
from r,β-Unsaturated Esters
SCHEME 2. Synthesis of (2S,3S)-N-Fmoc-r-fluoro-β3-pheny-
lalanine from (2S,3S,rS)-5b10,12
literature.9 A number of the existing approaches to these
compounds involve homologation of natural R-amino acids.
Takei’s group prepared an R-fluoro-β3-homophenylalanine
derivative by (diethylamino)sulfur trifluoride (DAST) treat-
ment of the corresponding R-alcohol, which had been pre-
pared in five steps from L-phenylalanine.9e Seebach’s group
has prepared protected R-fluoro-β3-homoalanine by the treat-
ment of protected L-threonine with DAST, a process that
involves an aziridine intermediate.9d Abell and co-workers
have used an approachinvolving the electrophilic fluorination
of enolates derived from protected β-phenylalanine to pro-
duce R-fluoro-β3-amino acid derivatives9a or acylated oxazo-
lidinones to produce R-fluoro-β2-amino acid derivatives.9a,c
Jiang, Tan, and co-workers have developed an asymmetric
Mannich reaction involving base-promoted addition of
fluorinated β-keto acetyloxazolidinone and an N-acyloxyi-
mine followed by decarboxylation.9b
We have chosen an approach involving an adaptation of
Davies’ diastereoselective conjugate addition of chiral lithium
amides to R,β-unsaturated esters10 followed by treatment of
the intermediate enolate with the electrophilic fluorinating
agent (PhSO2)2NF (NFSI) in a tandem, one-pot reaction
(Scheme 1). This simple methodology benefits from the use
of readily prepared R,β-unsaturated esters and the high dia-
stereoselectivity of the initial conjugate addition, which typi-
cally occurs in >98:2 dr at C3.10 It also does not rely on the
homologation of R-amino acids from the chiral pool, thus
providing the potential for the preparation of R-fluoro-β3-
amino acids with a vast array of side chains. In a preliminary
study,11 we established that R-fluoro-β3-amino esters 5 posses-
sing hydrocarbon side chains could be prepared in this way
with a dr of 83:17. In the case of the R-fluoro-β3-phenylalanine
derivative 5b-anti, efficient deprotection gave the free amino
acid 7, which was Fmoc-protected, making it suitable for use in
solid phase peptide synthesis (Scheme 2).12 The amino acid 7
was also incorporated into an R-chymotrypsin inhibitor.9a
The success of the R-fluoro-β3-amino ester motif in the
inhibition of chymotrypsin9a prompted us to apply this
functionality to the inhibition of trypsin-type proteases. This
requires access to R-fluoro-β3-amino acid derivatives with
basic side chains, as trypsin-type proteases cleave proteins
adjacent to these residues. Here, we report the results of an
investigation into the scope of the conjugate addition-fluor-
ination reaction (Scheme 1) and demonstrate its utility by
applying it to the synthesis of a protected form of (2S,3S)-R-
fluorinated β3-lysine.
Results and Discussion
We first needed to establish that a range of precursors to
ammonium side chains were compatible with the conditions
used for the conjugate addition, as well as the combined con-
jugate addition-fluorination procedure. Thus, a series of R,β-
unsaturated tert-butyl esters 1a-f (Table 1) were prepared and
subjected to conjugate addition-protonation to produce 4
and the one-pot conjugate addition-fluorination methodol-
ogy that yields 5. The results of this investigation, including
yields and diastereoselectivities, are shown in Table 1.13 Entry
2 is reproduced from a preliminary report.11 In addition to the
reactions of 1a-f, similar experiments were also performed on
the corresponding 6-chlorohexenoate; however, this com-
pound did not appear to be compatible with our methodology
(see the Supporting Information).
Table 1 reveals that the desired monofluorides 5 can be
obtained in moderate (entries 5 and 6) to high yield (entry 3).
In most cases, the fluorination stage of the one-pot proce-
dure does not appear to be yield-limiting, as the yield of the
fluoride 5 was only slightly lower than that of the unfluori-
nated product 4. The fluorination step does, however, appear
to be yield-limiting in the case of the silapiperazine 5f (entry 6).
In this case, the low yield of 5f reflects a susceptibility of the
silapiperazine to decomposition on exposure to NFSI.
With respect to the diastereoselectivity of the conjugate
addition-fluorination sequence, there are two diastereose-
lective reactions that need to be considered. The first is the
addition of (S)-lithium amide 2 to the R,β-unsaturated esters 1.
This reaction is well-known to give the 3S isomer in >98:2 dr,10
and this was also found to be the case here; no measurable
amounts of the 3R isomer were obtained. The second diaste-
reoselective reaction is the fluorination with NFSI. Trapping of
the intermediate enolates such as 3 with electrophiles typically
(9) (a) Peddie, V.; Pietsch, M.; Bromfield, K. M.; Pike, R. N.; Duggan,
P. J.; Abell, A. D. Synthesis 2010, 1845. (b) Pan, Y.; Zhao, Y.; Ma, T.; Yang,
Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem.;Eur. J. 2010, 16, 779. (c) Edmonds,
M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D. Org. Lett. 2008, 10, 885.
(d) Hook, D. F.; Gessier, F.; Noti, C.; Kast, P.; Seebach, D. ChemBioChem
2004, 5, 691. (e) Ohba, T.; Ikeda, E.; Takei, H. Bioorg. Med. Chem. Lett.
1996, 6, 1875.
(10) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833.
(11) Andrews, P. C.; Bhaskar, V.; Bromfield, K. M.; Dodd, A. M.; Duggan,
P. J.; Duggan, S. A. M.; McCarthy, T. D. Synlett 2004, 791.
(12) The yields shown for the second and third steps in Scheme 2 result
from optimization performed after the publication of ref 11. Bromfield, K. M.
Ph.D. Dissertation, Monash University, Clayton, Victoria, Australia, 2005.
(13) A preliminary report11 describes a reaction similar to the one that
produced 5a from the crotonate 1a, but in the previous study, the experiment
was performed with the corresponding ethyl ester. While the dr’s obtained
with the ethyl and tert-butyl esters were very similar, the yield was much
lower for the ethyl ester (39%), presumably as a result of competing 1,2-
addition of the lithium amide 2. The use of the bulkier tert-butyl ester is
known to limit this undesired side reaction.10
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TABLE 1. Results of Conjugate Addition-protonation and Conjugate Addition-Fluorination Experiments Performed on r,β-Unsaturated Esters 1a-f
aNFSI added at -78 °C for 5a,b,d, -60 °C for 5e, -50 °C for 5c, and -45 °C for 5f. b>99:1 dr. cAfter chromatography. dDetermined from the crude
reaction mixture by integration of 1H NMR resonances due to R-protons. eMcWhorter reported an equivalent yield for this reaction.14 fDavies reported
an equivalent yield for this reaction.15 gFrom ref 11.
SCHEME 3. Stepwise Conjugate Addition-fluorination Involving Deprotonation of Isolated (2S)-β3-Amino Esters 4b and 4c Followed
by Fluorination with NFSI
gives the anti-compound as the major product; the 2S,3S,RS
diastereomer in the case of 5. This was previously confirmed to
be the case for the reaction of the enolate 3b with NFSI by
X-ray crystallography performed on 5b.11 It was also con-
firmed for the reaction that produced the ethyl ester analogue
of 5a. NMR-based similarities between these previously pub-
lished compounds and 5a,c-f suggest that the anti-product or
the 2S,3S,RS diastereomer is also the major product produced
here. X-ray crystallography performed on a single crystal of 5c
(see the Supporting Information) supports this conclusion.
The dr’s for the fluorination step were optimized by varia-
tion of the temperature of the NFSI addition and range from
moderate (Table 1, entry 3) to very high (Table 1, entry 6).
Using standard chromatographic and recrystallization tech-
niques the 2S diastereomers of 5a,c,d,f could be obtained in
>9 9 : 1 d r w h i l e t h e 2 S diastereomer of 5e was purified to
a dr of 98:2.
Analternativetothe one-pot sequence shownin Scheme1 is
a stepwise procedure (Scheme 3). In order to compare these
sequences, two β-amino esters 4b and 4c were deprotonated
withLDAandquenched withNFSIat-78°C. While yields of
the fluorides 5b and 5c were equivalent to those obtained with
the tandem method (quantitative and 93% respectively), the
dr’s were inferior. The reaction with 4c was also repeated with
the NFSI quench performed at -55 °C, but the result was
equivalent to that obtained at -78 °C. These findings are in
accord with the stereoselectivities recently reported for the
stepwise fluorination of amide and Boc-protected forms of 4b
performed under very similar reaction conditions.9a
Three attempts to prepare an epimeric or (2R,3S,RS)-R-
fluoro-β3-amino ester, 5-syn were made. In the first, the 2-
fluorocinnamate 916 was treated with the lithium amide 2 then
(14) Fleck, T. J.; McWhorter, W. W., Jr.; DeKam, R. N.; Pearlman, B. A.
J. Org. Chem. 2003, 68, 9612.
(15) Bull, S. D.; Davies, S. G.; Roberts, P. M.; Savory, E. D.; Smith, A. D.
Tetrahedron 2002, 58, 4629.
(16) Elkik, E.; Imbeaux-Oudotte, M. Bull. Soc. Chim. Fr. 1987, 861.
J. Org. Chem. Vol. 75, No. 21, 2010 7367

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SCHEME 4. Treatment of 2-Fluorocinnamate 9 with Lithium
Amide 2
SCHEME 6. Synthesis of N β-Fmoc-N ε-Boc-2S-r-fluoro-β3-
lysine 17
SCHEME 5. Synthesis of Protected (3S,rS)-r,r-Difluoro-β3-
homoalanine 12
quenched with satd NH4Cl. As protonation of the proposed
enolate intermediate is predicted to occur anti to the large
amine substituent, 5b-syn was expected to be the major pro-
duct. Instead, the lithium amide deprotonated the fluoroalkene,
leading to elimination of fluoride and the formation of the alkyne
10 (Scheme 4). In the second approach, 5a was deprotonated
with LDA and quenched with the bulky proton source, 2,6-
di-tert-butylphenol. This was expected to be an effective epimer-
ization method as reprotonation was again expected to occur anti
to the amine group, as seen previously with 2-alkyl-β-amino
esters.10 Unfortunately, the reprotonation proved to be unselec-
tive with an anti/syn dr of 48:52 being the result. As an alternative
to this kinetically controlled enolate protonation, an epimeriza-
tion under thermodynamic control was performed. In this case,
pure 5a-anti was treated with t-BuOH/t-BuOLi in THF over 6
days, but this only gave a dr of 80:20 in favor of the 5a-anti.
R,R-Difluorinated-β3-amino esters are also of consider-
able interest9d,e,17 and an example of such a compound (12)
was produced when the enolate 11 was quenched with NFSI
(Scheme 5). The sequence of tandem conjugate addition-
fluorination-deprotonation-fluorination thus provides ac-
cess to enantiopure R,R-difluoro-β3-amino esters. Alternative
routes to this class of compounds involving the stereoselective
addition of organozinc reagents to imines and sulfinimines have
been described.18
addition reaction, and the diBoc-protected hexanoate 5e19 and
the silapiperazine 5f were produced in low yield.
Enantiopure 5d-anti was thus converted to a protected
form of R-fluoro-β3-lysine 17 suitable for use in solid-phase
peptide synthesis via a series of routine and high yielding
steps (Scheme 6). This involved silyl ether cleavage to give the
terminal alcohol 13, conversion to the phthalimide 14 using
Mitsunobu conditions, cleavage of the phthalimide to give
the primary amine, and then Boc protection to furnish 15.
Removal of the benzyl groups by hydrogenolysis in the
presence of Pearlman’s catalyst followed by Fmoc protection
gave 16, and finally, cleavage of the tert-butyl ester and
reprotection of the amine gave 17.
Conclusion
A tandem procedure involving chiral lithium amide con-
jugate addition and fluorination with NFSI provides anti-R-
fluoro-β3-amino esters 5 from R,β-unsaturated esters 1 in
80:20 to >99:1 dr. In contrast, a stepwise approach involving
deprotonation of enantiopure β3-amino esters 4b,c followed
by fluorination yielded 5b,c with lower dr’s. Attempts to
prepare selectively a syn-R-fluoro-β3-amino ester by either
epimerization of anti-5a or conjugate addition to a 2-fluoro-
R,β-unsaturated ester 9 wereunsuccessful. Deprotonation of a
monofluoro-β3-amino ester 5a followed by fluorination with
NFSI gave the corresponding R,R-difluorinated-β3-amino
ester 12. Using the tandem methodology as a key step, an
R,β-unsaturated ester bearing a siloxyl side chain 1d was con-
verted into enantiopure, orthogonally protected (2S,3S)-R-
fluoro-β3-lysine 17. The methodology described here is not
limited by the range of R-amino acids available from the chiral
pool, and thus promises to provide access to a wide range of
enantiopure anti-R-fluoro-β3-amino acid derivatives.
Having established the effectiveness of the tandem conju-
gate addition-fluorination method, our attention turned to the
synthesis of a fluorinated enantiopure β3-lysine derivative. Of
the potential terminal amine precursor functionalities de-
scribed here, namely the N,N-diBoc-protected, silapiperazine,
chloro, and siloxane, the R-fluoro-β3-amino ester bearing the
siloxane side chain 5d was chosen for use in the synthesis of the
target compound. This is because, as mentioned above, the
6-chlorohexenoate precursor is incompatible with the conjugate
(17) Mathad, R; Gessier, F.; Seebach, D.; Jaun, B. Helv. Chim. Acta 2005,
88, 266.
(18) (a) Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.;
Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332. (b) Sorochinsky, A.;
Voloshin, N.; Markovsky, A.; Belik, M.; Yasuda, N.; Uekusa, H.; Ono,
T.; Berbasov, D. O.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448. (c)
March, T. L.; Johnston, M. R.; Duggan P. J. Book of Abstracts, 19th
International Symposium on Fluorine Chemistry, Jackson Hole, WY,
2009; Abstract 160, p 87.
(19) In this case, the yield of the conjugate addition reaction is compro-
mised by isomerization of the double bond: Davies, S. G.; Garrido, N. M.;
Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mortimer,
A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793.
Experimental Section
General Experimental Procedures. DCM was distilled from
CaH, and THF was distilled from sodium benzophenone ketyl
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Duggan et al.
JOCArticle
immediately before use. All other reagents were purified accord-
ing to Perrin,20 with dried solvents stored over molecular sieves.
TBAF (1 M in THF) was stored over molecular sieves after
opening. The temperatures of the conjugate addition and fluor-
ination experiments were controlled using an acetone/dry ice
cryobath, with the periodic addition of dry ice used to maintain
the temperature between (3 °C of that stated. Thin-layer chro-
matography (TLC) was performed on precoated sheets of
Merck silica gel 60 and visualized under UV light (254 nm),
with ninhydrin or with KMnO4. Column chromatography was
carried out at atmospheric pressure using Davisil silica gel
(3S,rS)-tert-Butyl 6-(N,N-Di-tert-butylcarbonyloxy)amino-(N-
benzyl-r-methylbenzylamino)hexanoate, 4e. The di-Boc-protected
aminohexanoate 4e was prepared from (E)-tert-butyl 6-(N,N-di-
tert-butylcarbonyloxy)aminohex-2-enoate 1e21 (156 mg, 0.40
mmol) according to representative procedure A. The product 4e
was obtained after column chromatography (1:4 diethyl ether/
hexane) as a colorless oil (106 mg, 44%, dr g 98:2): [R]20D = -7
(c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.2
Hz, 2H), 7.34-7.29 (m, 6H), 7.25-7.20 (m, 2H), 3.80 (q, J = 6.8
Hz, 1H), 3.76 (d, J = 14.8 Hz, 1H), 3.60-3.52 (m, 2H), 3.47 (d,
J = 15.2 Hz, 1H), 3.35-3.28 (m, 1H), 2.01-1.90 (m, 1H), 1.89-
1.82 (m, 2H), 1.60-1.44 (m, 20H), 1.39 (s, 9H), 1.37-1.23 (m,
2H), 1.34 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 171.9, 152.7, 142.7, 141.5, 128.3, 128.1, 127.9, 126.9, 126.6, 81.9,
79.9, 57.8, 53.9, 50.1, 46.6, 37.9, 30.9, 28.1, 28.0, 27.2, 20.1; HRMS
calcd for C35H53N2O6 597.3898, found 597.3909 [M þ H]þ.
(3S,rS)-tert-Butyl 6-(4,4-Diphenyl-1-aza-4-silacyclohex-1-yl)-
3-(N-benzyl-r-methylbenzylamino)hexanoate, 4f. The silylpiper-
azine aminohexanoate 4f was prepared from 1f (138 mg, 0.33
mmol) according to representative procedure A, with the following
variation: after being stirred at -78 °C for 2.5 h, the reaction was
allowed to warm to -60 °C over 30 min before quenching. After
a standard workup, the crude residue was redissolved in THF
(3 mL), and phenyl isocyanate (0.016 mL, 0.144 mmol) was added
in order to remove excess (S)-N-benzyl-N-(R-methylbenzyl)amine.
After being stirred under N2 for 4 h, the solution was concentrated
in vacuo and subjected to column chromatography (5:44:1 diethyl
˚
(LC60 A, 40-63 μm).
Melting points were obtained with a hot-stage microscope
and are uncorrected. Optical rotations are referenced to the
sodium D line (589 nm) at the temperature specified. All NMR
spectra were recorded at 293 K unless otherwise stated. Peaks
were assigned with the aid of homonuclear (1H-1H) correlation
spectroscopy (COSY) and heteronuclear (1H-13C) correlation
spectroscopy (HMQC and HMBC) when required. 19F NMR
spectra are referenced to internal CFCl3. HRMS data were
obtained using positive-ion electrospray ionization (ESI-MS).
Representative Procedure A: Conjugate Addition-Protonation.
Preparation of (3S,rS)-tert-Butyl-6-(tert-butyldimethylsilyloxy)-
3-(N-benzyl-r-methylbenzylamino)hexanoate, 4d. To a stirred
solution of (S)-N-benzyl-N-(R-methylbenzyl)amine (0.11 mL,
0.55 mmol) in THF (2 mL) at -78 °C, under N2, was added
nBuLi (1.6 M in hexanes, 0.34 mL, 0.55 mmol). After 30 min,
(E)-tert-butyl 6-(tert-butyldimethylsilyloxy)hex-2-enoate (1d)
(110 mg, 0.37 mmol) in THF (1.5 mL) was added dropwise and
the mixture stirred at -78 °C for 1.5 h before being quenched with
saturated aq NH4Cl (5 mL). The mixture was allowed to warm
to 0 °C and then diluted with diethyl ether (20 mL) and H2O
(20 mL), the layers were separated, and the aqueous layer was
further extracted with diethyl ether (2 ꢀ 10 mL). The combined
organic layers were washed with brine (30 mL), dried (Na2SO4),
and concentrated in vacuo. Column chromatography on silica
gel (1:19 diethyl ether/hexane) gave the product 4d as a colorless
oil (152 mg, 81%, dr g 98:2): [R]20D=-5 (c=1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.37 (d, J=7.2 Hz, 2H), 7.29-7.22
(m, 6H), 7.21-7.15 (m, 2H), 3.76 (q, J=7.2 Hz, 1H), 3.73 (d, J=
14.8 Hz, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.43 (d, J=14.8 Hz, 1H),
3.25 (nonet, J =4.4 Hz, 1H), 1.90-1.79 (m, 3H), 1.51-1.38 (m,
3H), 1.34 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H), 0.83 (s, 9H), -0.01 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 172.1, 143.0, 141.8, 128.24,
128.21, 128.1, 128.0, 126.9, 126.5, 79.9, 63.3, 58.1, 54.0, 50.1, 38.0,
30.7, 29.8, 28.0, 26.0, 20.3, -5.2; HRMS calcd for C31H50NO3Si
512.3554, found 512.3562 [M þ H]þ.
ether/hexane/Et3N) to give the product 4f as a colorless gum
1
(180 mg, 87%, dr>99:1): [R]20 = þ2 (c = 1.0, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 7.57-7.54 (m, 4H), 7.43-7.20 (m, 16
H), 3.83 (q, J = 6.8 Hz, 1H), 3.80 (d, J = 15.2 Hz, 1H), 3.50 (d,
J = 15.2 Hz, 1H), 3.33-3.27 (m, 1H), 2.82 (t, J = 6.2 Hz, 4H),
2.43-2.31 (m, 2H), 1.98 (dd, J = 14.8, 3.6 Hz, 1H), 1.88 (dd, J =
14.6, 9.4 Hz, 1H), 1.84-1.76 (m, 1H), 1.57-1.42 (m, 2H), 1.39
(s, 9H), 1.38-1.34 (m, 7H), 1.31-1.23 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 172.2, 143.2, 142.0, 134.8, 129.5, 128.3, 128.20,
128.18, 128.1, 128.0, 127.0, 126.6, 80.1, 58.6, 57.9, 54.1, 52.2, 50.1,
37.7, 31.6, 28.1, 24.1, 20.7, 10.8; HRMS calcd for C41H53N2O2Si
633.3871, found 633.3871 [MþH]þ.
Representative Procedure B: Tandem Conjugate Addition-
Fluorination. Synthesis of (2S,3S,rS)-tert-Butyl 6-(tert-Butyldime-
thylsilyloxy)-3-(N-benzyl-r-methylbenzylamino)-2-fluorohexanoate,
5d. To a stirred solution of (S)-N-benzyl-N-(R-methylbenzyl)amine
(0.135 mL, 0.65 mmol) in THF (2 mL) at -78 °C, under N2, was
added nBuLi (1.6 M in hexanes, 0.41 mL, 0.65 mmol). After 30 min,
(E)-tert-butyl 6-(tert-butyldimethylsilyloxy)hex-2-enoate (1d) (E/Z
97:3, 130 mg, 0.43 mmol) in THF (1.5 mL) was added dropwise,
and the mixture was stirred at -78 °C for 2.5 h and then allowed
to warm to -30 °C over 30 min. The solution was recooled to
-78 °C, and NFSI (205 mg, 0.65 mmol) in THF (1 mL, dissolu-
tion aided by sonication for <1 min) was added dropwise. After
being stirred at -78 °C for 1 h, the solution was allowed to warm
to 0 °C over 30 min then quenched with saturated aq NH4Cl
(4 mL). The mixture was diluted with H2O (20 mL) and poured
into hexane (20 mL). The layers were separated, and the organic
layer was washed with H2O (2 ꢀ 10 mL) and brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. Analysis of the crude pro-
duct showed dr = 94:6. Column chromatography (1:19 diethyl
ether/hexane) gave the 2S-fluoride 5d-anti as a colorless oil (177
mg, 77%, dr = 98:2): [R]20D = þ7 (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz, 2H), 7.37-7.25 (m, 8H),
4.45 (d, J = 50.0 Hz, 1H), 4.16 (d, J = 15.2 Hz, 1H), 3.94 (q, J =
6.8 Hz, 1H), 3.67 (d, J = 15.2 Hz, 1H), 3.56 (t, J = 6.4 Hz), 3.39
(ddd, J = 31.2, 9.6, 3.6 Hz), 1.96-83 (m, 1H), 1.73-1.60 (m, 1H),
1.54-1.50 (m, 1H), 1.45 (s, 9H), 1.39-1.27 (m, 1H), 1.34 (d, J =
6.8 Hz, 3H), 0.90 (s, 9H), 0.048 (s, 6H); 13C NMR (100 MHz,
(3S,rS)-tert-Butyl 5-(tert-Butyldimethylsilyloxy)-3-(N-benzyl-
r-methylbenzylamino)pentanoate, 4c. The silyloxyaminopentano-
ate 4c was prepared from (E)-tert-butyl 5-(tert-butyldimethylsily-
loxy)pent-2-enoate (1c) (354 mg, 1.24 mmol) according to
representative procedure A, with the following variation: after
stirring at -78 °C for 2.5 h, the reaction was allowed to warm
to -40 °C over 1 h before quenching. The product 4c was obtained
as a colorless oil that crystallized on standing (518 mg, 94%). A
sample was recrystallized from 95% aq EtOH to give white needles,
dr > 99:1: mp 77 °C; [R]20D =-6(c=1.0, CHCl3);1HNMR(400
MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 2H), 7.35-7.22 (m, 8H),
3.85-3.71 (m, 4H), 3.56-3.49 (m, 2H), 1.96-1.88 (m, 2H),
1.77-1.68 (m, 1H), 1.58-1.50 (m, 1H), 1.41 (s, 9H), 1.36 (d J =
7.2 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ171.8, 142.7, 141.5, 128.2, 128.1, 128.0, 126.9, 126.6, 79.9,
61.1, 58.0, 50.8, 50.1, 38.2, 36.4, 28.1, 26.0, 19.9, 18.3, -5.2,
-5.3. HRMS calcd for C30H48NO3Si 498.3398, found 498.3395
[MþH]þ.
(20) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon: Oxford, 1966.
ꢀ
(21) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1998, 63, 2993.
J. Org. Chem. Vol. 75, No. 21, 2010 7369

Duggan et al.
JOCArticle
CDCl3) δ 168.4 (d, J = 24.4 Hz), 142.1, 141.7, 128.2, 128.1, 128.0,
127.9, 127.0, 126.5, 90.0 (d, J = 188.8 Hz), 82.2, 63.0, 58.1, 57.9,
50.7 (d, J = 4.5 Hz), 30.6, 27.9, 25.9, 23.4 (d, J = 5.2 Hz), 20.0,
18.2, -5.36, -5.38. 19F NMR (282 MHz, CDCl3) δ -200.0 (dd,
J = 50.7, 31.2 Hz); HRMS calcd for C31H49FNO3Si 530.3460,
found 530.3465 [M þ H]þ.
126.6, 90.1 (d, J = 190.0 Hz), 82.4, 82.0, 58.1 (d, J = 4.6 Hz),
57.6, 50.8, 46.5, 28.04, 27.97, 27.2, 24.6, 19.9; 19F NMR (282
MHz, CDCl3) δ -199.1 (dd, J = 51.8, 32.3 Hz); HRMS calcd for
C35H51FN2NaO6 637.3623, found 637.3645 [M þ Na]þ.
(2S,3S,rS)-tert-Butyl 6-(4,4-Diphenyl-1-aza-4-silacyclohex-
1-yl)-3-(N-benzyl-r-methylbenzylamino)-2-fluorohexanoate, 5f.
The fluoroamino hexanoate 5f was prepared from 1f (136 mg,
0.32 mmol) according to representative procedure B, with the
following variation: NFSI was added at -45 °C, and after 2 h the
reaction mixture was allowed to warm to -10 °C over 45 min
before being quenched. After a standard workup, the sulfoni-
mide byproducts were removed by filtration through a plug of
silica (1:2 diethyl ether/hexane), and the filtrate was concen-
trated in vacuo. The residue was redissolved in dry DCM (2 mL),
and phenyl isocyanate (22 μL, 0.20 mmol) was added in order to
remove excess (S)-N-benzyl-N-(R-methylbenzyl)amine. After
being stirred under N2 for 3.5 h, the mixture was concentrated
invacuoand subjectedtocolumnchromatography (5:44:1diethyl
ether/hexane/Et3N) to give 5f-anti as a colorless gum (107 mg,
51%, dr > 99:1): [R]20D = þ13 (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.56-7.54 (m, 4H), 7.45-7.23 (m, 16H), 4.50 (d,
J = 50.4 Hz, 1H), 4.16 (d, J = 15.8 Hz, 1H), 3.94 (q, J = 6.8 Hz,
1H), 3.66 (d, J = 15.8 Hz, 1H), 3.37 (ddd, J = 30.8, 10.0, 3.6 Hz,
1H), 2.81 (t, J = 6.0 Hz, 4H), 2.42-2.30 (m, 2H), 1.85-1.75 (m,
1H), 1.70-1.59 (m, 1H), 1.53-1.40 (m, 10H), 1.40-1.27 (m, 8H);
13C NMR (100 MHz, CDCl3) δ 168.4 (d, J = 25.0 Hz), 142.4,
141.8, 135.6, 134.6, 129.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.1,
126.5, 89.9 (d, J = 189.0 Hz), 82.2, 58.3, 58.1 (d, J = 19.0 Hz),
57.9, 52.0, 50.7 (d, J = 5.0 Hz), 27.9, 25.2 (d, J = 5.0 Hz), 24.4,
20.3, 11.0; 19F NMR (282 MHz, CDCl3) δ -200 (bs); HRMS
calcd for C41H52FN2O2Si 651.3777, found 651.3777 [M þ H]þ.
Representative Procedure C-Stepwise Fluorination. Fluorina-
tion of 4c. Fluorination at -55 °C: To a solution of diisopropy-
lamine (0.034 mL, 0.24 mmol) in dry THF (2 mL) at 0 °C was
(2S,3S,rS)-tert-Butyl 3-(N-Benzyl-r-methylbenzylamino)-2-
fluorobutanoate, 5a. The fluoroaminobutanoate 5a was pre-
pared from (E)-tert-butyl crotonate 1a (134 mg, 0.94 mmol)
according to representative procedure B, with the following varia-
tion: after NFSI addition, stirring was continued at -78 °C for 1 h,
and then the reaction mixture was allowed to warm to -30 °C over
1.5 h before being quenched. Analysis of the crude product by 1H
NMR showed dr = 92:8. Column chromatography (3:7 diethyl
ether/hexane) gave a mixture of the C2 epimers as a colorless oil
(217 mg, 62%). Recrystallization from hexane gave the 2S-fluoride
5a-anti (195 mg, 56%) as white needles: mp 82.5-84 °C; [R]20
=
D
þ22 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J =
7.6 Hz, 2H), 7.36-7.20 (m, 8 H), 4.65 (dd, J = 50.4, 2.0 Hz, 1H),
3.99 (q, J = 6.8 Hz, 1H), 3.98 (d, J =14.8 Hz, 1H), 3.84 (d, J =14.8
Hz, 1H), 3.47-3.33(m, 1H), 1.38 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H),
1.15 (dd, J = 7.2, 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.4 (d, J = 24.8 Hz), 143.6, 141.9, 128.23, 128.18, 128.1, 127.7,
126.8, 126.6, 92.3 (d, J = 188.0 Hz), 82.1, 58.1, 53.4 (d, J = 18.8
Hz), 50.6 (d, J= 4.0 Hz), 27.9, 17.2, 12.2 (d, J=5.7 Hz);19FNMR
(282 MHz, CDCl3) δ -202.5 (dd, J = 49.7, 30.2 Hz); HRMS calcd
for C23H31FNO2 372.2333, found 372.2336 [M þ H]þ.
(2S,3S,rS)-tert-Butyl 5-(tert-Butyldimethylsilyloxy)-3-(N-ben-
zyl-r-methylbenzylamino)-2-fluoropentanoate, 5c. The fluoroamino
pentanoate 5c was prepared from (E)-tert-butyl 5-(tert-
butyldimethylsilyloxy)pent-2-enoate 1c (105 mg, 0.37 mmol) ac-
cording to representative procedure B, with the following varia-
tion: NFSI was added at -50 °C, and stirring was continued for
1 h, after which time the solution was quenched and allowed to
warm to 0 °C. The product was obtained as a colorless oil which
crystallized on standing (171 mg, 90%, dr 80:20). Recrystalliza-
tion from acetone (slow evaporation) gave the major isomer 2S-
fluoride 5c-anti as white needles (118 mg, 62%): mp 109-110 °C;
[R]20D = þ4 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.43-7.24 (m, 10H), 4.26 (dd, J = 50.4, 0.8 Hz, 1H), 4.12 (d, J =
14.4 Hz, 1H), 3.94-3.86 (m, 2H), 3.83-3.71 (m, 2H), 3.65 (dd,
J = 15.2, 1.6Hz, 1H), 1.86-1.78 (m, 1H), 1.55-1.48(m, 1H), 1.49
(s, 9H), 1.38 (d, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4 (d, J = 24.7 Hz),
141.3, 141.2, 128.4, 128.3, 128.2, 128.1, 127.2, 126.7, 90.7 (d, J =
187.3 Hz), 82.3, 59.7, 57.0, 53.6 (d, J = 18.7 Hz), 50.7, 30.3 (d, J =
4.9 Hz), 28.0, 26.1, 19.4, 18.4, -5.2, -5.3; 19F NMR (282 MHz,
CDCl3) δ -199.1 (dd, J = 51.8, 32.3 Hz); HRMS calcd for
C30H47FNO3Si 516.3304, found 516.3306 [M þ H]þ.
n
added BuLi (1.6 M in hexanes, 0.16 mL, 0.24 mmol) and the
solution stirred for 20 min, after which time it was cooled to -78 °C.
The amino ester 4c (96 mg, 0.19 mmol) in THF (1.5 mL) was
added dropwise and the solution stirred for another 1 h before
being warmed to -55 °C. A solution of NFSI (89 mg, 0.28 mmol)
in THF (1.5 mL) was added and stirring continued at -55 °C for
3 h followed by warming to 0 °C over a further 1 h before quench-
ing with saturated aq NH Cl (4 mL). Ether (25 mL) and H2O
4
(25 mL) were added and the layers separated. The ether layer was
washed with H2O (25 mL) and brine (25 mL) and then dried
(Na2SO4) and concentrated in vacuo. Crude 1H NMR showed a
69:31 mixture of anti/syn isomers. Passage through a plug of silica
(1:9 ether/hexane) gave a white solid (93 mg, 93%), which was
recrystallized from acetone to give 5c-anti (59 mg, 59%) as white
needles. Fluorination at -78 °C: To a solution of diisopropyla-
mine(0.033mL, 0.23 mmol) in dry THF (2 mL) at0 °C was added
nBuLi (1.5 M in hexanes, 0.15 mL, 0.23 mmol) and the solution
stirred for 20 min, after which time it was cooled to -78 °C. The
amino ester 4c (94 mg, 0.19 mmol) in THF (1.5 mL) was added
dropwise and the solution stirred for another 1 h. A solution of
NFSI (86 mg, 0.27 mmol) in THF (1.5 mL) was added dropwise
with stirring continued at -78 °C for 3 h, after which the solu-
tionwas allowed towarmto -35 °C over 1.5 h andthenquenched
withsaturated aqNH4Cl(4 mL). Ether (25mL) andH2O (25mL)
were added and the layers separated. The ether layer was washed
with H2O (25 mL) and brine (25 mL) and then dried (Na2SO4)
(2S,3S,rS)-tert-Butyl 6-(N,N-Di-tert-butylcarbonyloxy)amino-
(N-benzyl-r-methylbenzylamino)-2-fluorohexanoate, 5e. The fluor-
oamino hexanoate 5e was prepared from (E)-tert-butyl 6-(N,N-di-
tert-butylcarbonyloxy)aminohex-2-enoate 1e (130 mg, 0.34 mmol)
according to representative procedure B, with the following varia-
tion: NFSI was added at -60 °C, and after 1.5 h the reaction was
allowedtowarmto-35 °C over 30 min before quenching. Analysis
of the crude mixture by 1H NMR showed a dr of 88:12. Column
chromatography (1:9 to 1:3 diethyl ether/hexane) gave a colorless
oil as a mixture of isomers (277 mg, 48%, dr 93:7). A portion of this
was further purified by chromatography (1:9 diethyl ether/hexane)
to give a sample with a dr of 98:2: [R]20D = þ5 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.43(d, J = 7.6 Hz, 2H), 7.36-7.23
(m, 8H), 4.36 (d, J = 50.0 Hz, 1H), 4.12 (d, J = 14.4 Hz, 1H), 3.91
(q, J = 6.8 Hz, 1H), 3.64 (d, J = 16.4 Hz, 1H), 3.62-3.53 (m, 2H),
3.40 (ddd, J = 31.5, 9.6, 3.2 Hz, 1H), 2.03-1.92 (m, 1H), 1.70-
1.58 (m, 1H), 1.57-1.40 (m, 2H), 1.50 (s, 18H), 1.44 (s, 9H), 1.33
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0 (d, J =
25.0 Hz), 152.60, 152.55, 141.9, 128.3, 128.2, 128.13, 128.06, 127.2,
1
and concentrated in vacuo. A H NMR spectrum of the crude
reactionmixtureshowed5cas a 72:28 mixture of anti/syn isomers.
The product was not further purified.
Treatment of (Z)-tert-Butyl-r-fluorocinnamate 9 with Lithium
(S)-N-Benzyl-N-(R-methylbenzyl)amide, 2. To a stirred solution
of (S)-N-benzyl-N-(R-methylbenzyl)amine (0.11 mL, 0.54 mmol)
n
in THF (2 mL) at -78 °C, under N2, was added BuLi (1.5 M
in hexanes, 0.36 mL, 0.54 mmol). After 20 min, a solution of
7370 J. Org. Chem. Vol. 75, No. 21, 2010

Duggan et al.
JOCArticle
(Z)-tert-butyl-R-fluorocinnamate22 (85 mg, 0.38 mmol) in THF
(1.5 mL) was added dropwise. The resulting dark yellow solu-
tion was stirred at -78 °C for 2 h and then quenched with
saturated aq NH4Cl (2 mL). After being warmed to rt, the mix-
ture was diluted with DCM (10 mL), and H2O (10 mL) was
added. The layers were separated, the aqueous layer was further
extracted with DCM (2 ꢀ 10 mL), and the combined organic
extracts were washed with brine (20 mL), dried (Na2SO4), and
concentrated in vacuo. Some decomposition of the crude reac-
tion mixture appeared to occur, and subsequent column chro-
matography (1:2 DCM/hexane) yielded the known23 phenylace-
NMR (600 MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 2H), 7.33-7.21
(m, 8H), 4.06 (q, J = 7.2 Hz, 1H), 3.97 (d, J = 14.4 Hz, 1H), 3.75
(d, J = 14.4 Hz, 1H), 3.64-3.56 (m, 1H), 1.46 (s, 9H), 1.30 (d,
J = 6.6 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 163.5 (t, J = 31.3 Hz), 142.8, 141.1, 128.7, 128.2,
128.04, 127.96, 126.9, 126.7, 116.8 (dd, J = 258.8, 252.9 Hz),
83.9, 59.3, 54.7 (dd, J = 25.8, 20.8 Hz), 50.3, 27.7, 16.3, 10.3; 19
F
NMR (282 MHz, CDCl3) δ -108.0 (dd, J = 254.5, 11.6 Hz),
-117.0 (dd, J = 253.1, 18.1); HRMS calcd for C23H30F2NO2
390.2239, found 390.2241 [M þ H]þ.
(2S,3S,rS)-tert-Butyl 6-Hydroxy-3-(N-benzyl-r-methylben-
zylamino)-2-fluorohexanoate, 13. To the 2S-fluoride 5d-anti
(842 mg, 1.59 mmol) in dry THF (8 mL) were added TBAF (1 M
in THF, 3.33 mL, 3.33 mmol) and glacial AcOH (0.29 mL, 4.99
mmol), and the resulting solution was stirred at 40 °C for 6 h.
The reaction mixture was then concentrated in vacuo and the
residue redissolved in diethyl ether (50 mL), washed with satu-
rated aq NaHCO3 (50 mL), H2O (2 ꢀ 30 mL), and brine (50 mL),
and then dried (Na2SO4) and again concentrated in vacuo.
Column chromatography (1:4 EtOAc/hexane) performed on the
residue yielded 13 (614 mg, 93%) as a colorless oil: [R]20D = þ6
(c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2
Hz, 2H), 7.38-7.22 (m, 8H), 4.51 (dd, J = 50.0, 0.8 Hz, 1H), 4.18
(d, J = 15.2, 1H), 3.96 (q, J = 6.8 Hz, 1H), 3.68 (d, J = 15.6 Hz,
1H), 3.55 (t, J = 6.4 Hz, 2H), 3.41 (ddd, J = 31.2, 9.6, 3.2 Hz,
1H), 1.93-1.83 (m, 1H), 1.75-1.56 (m, 2H), 1.47-1.37 (m, 1H),
1.46 (s, 9H), 1.35 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.6 (d, J = 24.0 Hz), 142.4, 141.8, 128.4, 128.3, 128.1,
128.0, 127.3, 126.6, 89.9 (d, J = 188.8 Hz), 82.5, 62.7, 58.4, 58.0
(d, J = 18.8 Hz), 50.8 (d, J = 4.4 Hz), 30.0, 28.0, 23.3 (d, J = 5.6
Hz), 20.4; 19F NMR (282 MHz, CDCl3) δ -199.9 (dd, J = 50.7,
31.2 Hz); HRMS calcd for C25H35FNO3 416.2595, found
416.2601 [M þ H]þ.
1
tylene derivative 10 (55 mg, 72%) as a colorless oil: H NMR
(300 MHz, CDCl3) δ 7.58-7.55 (d, J = 6.9 Hz, 2H), 7.45-7.32
(m, 3H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.0,
132.7, 130.1, 128.3, 119.9, 83.6, 83.3, 81.9, 27.9; HRMS calcd for
C13H14O2Na 225.0891, found 225.0886 [M þ Na]þ.
Attempted Epimerization of Fluoroamino Ester 5a. Kineti-
cally Controlled Epimerization. To a solution of diisopropyla-
mine (0.047 mL, 0.33 mmol) in dry THF (1.5 mL) at 0 °C was
n
added BuLi (1.5 M in hexanes, 0.22 mL, 0.33 mmol) and the
solution stirred for 20 min. The amino ester 5a (89 mg, 0.24
mmol) in THF (1.5 mL) was added dropwise and the solution
stirred at 0 °C for 30 min before being cooled to -78 °C. A
solution of 2,6-di-tert-butylphenol (68 mg, 0.33 mmol) in THF
(1.5 mL) was added dropwise and stirring continued at -78 °C
for 2 h, after which time the solution was quenched with satu-
rated aq NH4Cl (5 mL) and allowed to warm to rt. Ether (20 mL)
and H2O (20 mL) were added and the layers separated. The
aqueous layer was extracted with ether (10 mL), and the com-
bined organic layers were washed with saturated NaHCO3
(20 mL) and brine (20 mL), dried (Na2SO4), and concentrated
1
in vacuo. A H NMR spectrum of the crude reaction mixture
showed 5a as a 48:52 mixture of anti/syn isomers, which were not
isolated or resolved.
(2S,3S,rS)-tert-Butyl 6-(Isoindole-1,3-dione)-3-(N-benzyl-r-
methylbenzylamino)-2-fluorohexanoate, 14. A solution of the
alcohol 13 (240 mg, 0.58 mmol), PPh3 (227 mg, 0.87 mmol), and
phthalimide (128 mg, 0.87 mmol) in dry THF (6 mL) was cooled
to 0 °C, and DIAD (0.18 mL, 0.87 mmol) was added dropwise.
The resulting mixture was allowed to warm to rt overnight, con-
centrated in vacuo, and then subjected to column chromatog-
raphy (1:4 EtOAc/hexane) to give the phthalimide (307 mg, 97%)
as a colorless oil: [R]20D = þ9 (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.73-7.70 (m, 2H), 7.42
(d, J = 7.2 Hz, 2H), 7.36-7.21 (m, 8H), 4.35 (d, J = 50.0 Hz, 1H),
4.13 (d, J = 15.2 Hz, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.74-3.60 (m,
3H), 3.44 (ddd, J = 15.6, 9.2, 2.2 Hz, 1H), 2.14-2.04 (m, 1H),
1.78-1.65 (m, 2H), 1.42 (s, 9H), 1.37-1.27 (m, 1H), 1.35 (d, J =
7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 168.3 (d, J = 24.2 Hz),
168.2, 141.7, 141.3, 133.8, 132.2, 128.4, 128.3, 128.1, 128.0, 127.2,
126.6, 123.1, 90.0 (d, J= 189.4 Hz), 82.5, 57.8, 57.6 (d, J=18.6Hz),
Thermodynamically Controlled Epimerization. A solution of
dry tBuOH (0.12 mL, 1.61 mmol) in THF (1.5 mL) was cooled
to 0 °C, and LiHMDS (1 M in THF; 0.74 mL, 0.74 mmol) was
added. After the solution was stirred for 15 min, a solution of 5a
(71 mg, 0.19 mmol) in THF (1 mL) was added dropwise and
the mixture allowed to stir under N2 at rt for 6 days. The solvent
was then removed in vacuo, brine (25 mL) was added, and the
mixture was poured into ether (25 mL). The ether layer was
separated, dried (Na2SO4), and concentrated in vacuo. Column
chromatography (1:9 ether/hexane) afforded 51 mg (72%) of 5a
as an 80:20 mixture of anti/syn C2 epimers.
(3S,rS)-tert-Butyl 3-(N-Benzyl-r-methylbenzylamino)-2,2-
difluorobutanoate, 12. BuLi (1.6 M in hexanes, 0.13 mL, 0.21
n
mmol) was added to a solution of diisopropylamine (30 μL, 0.21
mmol) in THF (2 mL) and stirred for 20 min. The solution was
then cooled to -78 °C, and the monofluoroamino ester 5a-anti
(52 mg, 0.14 mmol) in THF (1 mL) was added dropwise. After
the reaction mixture was allowed to warm to 0 °C over 2 h, the
solution was recooled to -60 °C, NFSI (53 mg, 0.17 mmol) in
THF (1 mL) was added dropwise, and the mixture was allowed
to warm to rt overnight. The resulting dark yellow solution was
diluted with diethyl ether (20 mL) and H2O (20 mL), the layers
were separated, and the aqueous layer was further extracted
with diethyl ether (20 mL). The organic layers were combined
and washed with brine (25 mL), dried (Na2SO4), and concen-
trated in vacuo. Column chromatography (1:1 DCM/hexane)
performed on the residues gave the difluoro compound 12
(30 mg, 55%) as a colorless oil that could be crystallized from
cold hexane: mp 61-63 °C; [R]20D = -8 (c = 1.0, CHCl3); 1H
50.8 (d, J = 4.7 Hz), 38.0, 27.9, 26.1, 24.5 (d, J = 5.3 Hz), 20.0; 19
F
NMR (282 MHz, CDCl3) δ -199.7 (dd, J = 49.7, 30.2 Hz); HRMS
calcd for C33H38FN2O4 545.2810, found 545.2815 [M þ H]þ.
(2S,3S,rS)-tert-Butyl 6-(N-tert-Butylcarbonyloxy)amino-3-(N-
benzyl-r-methylbenzylamino)-2-fluorohexanoate, 15. The phthali-
mide 14 (139 mg, 0.26 mg) was dissolved in EtOH (6 mL), and
MeNH2 in H2O (41% w/w, 1.25 mL) was added. After being
stirred for 2.5 h, the resulting mixture was concentrated in vacuo,
and H2O (20 mL) and diethyl ether (20 mL) were added. The
aqueous layer was extracted with diethyl ether (2 ꢀ 10 mL), and
the combined organic layers were washed with 2 M NaOH
(40 mL), dried (Na2SO4), and concentrated in vacuo. The residue
was redissolved in THF/H2O(4:1, 2mL), andthenNa2CO3 (54mg,
0.51 mmol) and Boc2O (0.062 mL, 0.27 mmol) were added. After
3 h, saturated aq NH4Cl (10 mL) and diethyl ether (20 mL) were
added. The layers were then separated, and the ether layer was
washed with H2O (2 ꢀ 10 mL) and brine (20mL), dried (Na2SO4),
and concentrated in vacuo. Column chromatography (1:4 diethyl
(22) Elkik, E.; Imbeaux-Oudotte, M. Bull. Soc. Chim. Fr. 1987, 861.
(23) Lipshutz, B. H.; Huff, B. E.; McCarthy, K. E.; Miller, T. A.;
Mukarram, S. M. J.; Siahaan, T. J.; Vaccaro, W. D.; Webb, H.; Falick,
A. M . J. Am. Chem. Soc. 1990, 112, 7032.
J. Org. Chem. Vol. 75, No. 21, 2010 7371

Duggan et al.
JOCArticle
ether/hexane) performed on the residue gave the Boc-protected
amine 15 as a colorless gum (130 mg, 99%): [R]20D = þ10 (c =
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz,
2H), 7.38-7.23 (m, 8H), 4.48 (d, J = 50.0 Hz, 1H), 4.49 (bs, 1H),
4.15 (d, J = 15.2 Hz, 1H), 3.94 (q, J = 6.8 Hz, 1H), 3.66 (d, J =
15.6 Hz, 1H), 3.38 (ddd, J = 31.0, 9.8, 3.2 Hz, 1H), 3.07-2.99 (m,
2H), 1.86-1.76 (m, 1H), 1.71-1.60 (m, 1H), 1.54-1.44 (m, 1H),
1.49 (s, 9H), 1.45 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H), 1.35-1.28 (m,
1H); 13CNMR(100MHz, CDCl3) δ168.4 (d, J= 24.1Hz), 155.8,
142.2, 141.6, 128.3, 128.2, 128.01, 127.98, 127.3, 126.6, 89.9 (d, J=
189.3 Hz), 82.5, 79.0, 58.2, 57.8 (d, J= 18.5 Hz), 50.8 (d, J=4.5Hz),
40.4, 28.4, 28.0, 27.2, 24.4 (d, J= 5.4 Hz), 20.2; 19F NMR (282 MHz,
CDCl3) δ-200.7 (dd, J = 49.1, 31.0 Hz); HRMS calcd for C30H44-
FN2O4 515.3280, found 515.3286 [M þ H]þ.
(2S,3S)-6-(N-tert-Butylcarbonyloxy)amino-3-(9H-fluoren-9-
ylmethoxycarbonylamino)-2-fluorohexanoic Acid, 17. The ester
16 (47 mg, 0.087 mmol) was dissolved in dry DCM (2 mL), and
TFA (1 mL) was added. After being stirred for 3 h, the solution
was concentrated in vacuo, and excess TFA was removed via
coevaporation with CHCl3 (2 ꢀ 5 mL). The residue was redis-
solved in THF/H2O (1:1, 3 mL), and Na2CO3 (37 mg, 0.35 mmol)
was added, followed by Boc2O (0.024 mL, 0.10 mmol). The
resulting mixture was allowed to stir overnight. The THF was
thenremovedinvacuo, andthe residue was dilutedwithsaturated
aq NaHCO3 (10 mL) and then washed with diethyl ether (10 mL).
The aqueous layer was acidified to pH 2 with 6 M HCl, at which
time a white precipitate was formed. The whole mixture was then
extracted with CHCl3 (3 ꢀ 10 mL), and the combined organic
layers were washed with brine (20 mL), dried (Na2SO4), and
concentrated to give a white foam. This was passed over a plug of
silica (1:1 EtOAc/hexane to 100% EtOAc) to give the Fmoc-
protected 2S-fluoro-β3-amino acid 17 as a white powder (34 mg,
(2S,3S)-tert-Butyl 6-(N-tert-Butylcarbonyloxy)amino-3-(9H-
fluoren-9-ylmethoxycarbonylamino)-2-fluorohexanoate, 16. The
Boc-protected amine 15 (138 mg, 0.26 mmol) was dissolved in
MeOH/H2O/AcOH (45:4:1, 3 mL), and Pd(OH)2/C (20 wt %,
53 mg) was added. After being stirred under an atmosphere of
H2 for 7 h, the mixture was filtered through Celite and concen-
trated in vacuo. The residue was diluted with EtOAc (20 mL),
and saturated aq NaHCO3 (20 mL) was added. The layers were
separated, and the organic layer was washed with H2O (20 mL).
The aqueous layer was then extracted with EtOAc (2 ꢀ 20 mL),
and the combined organic layers were washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was
dissolved in THF/H2O (4:1, 2 mL), and Na2CO3 (54 mg, 0.51
mmol) was added. The mixture was cooled to 0 °C and Fmoc-
OSuc (91 mg, 0.27 mmol) added portionwise, with stirring con-
tinued at 0 °C for 1 h and then at rt for 1.5 h. DCM (25 mL)
and H2O (25 mL) were then added, the layers were separated,
and the aqueous layer was extracted with DCM (2 ꢀ 10 mL). The
combined organic layers were washed with brine (30 mL), dried
(Na2SO4), and concentrated in vacuo. Column chromatography
(1:1 diethyl ether/hexane) performed on the residue gave the
protected 2S-fluoro-β3-lysine 16 as a colorless oil that solidified
on standing (144 mg, 98%): mp = 89-91 °C; [R]20D = -6 (c =
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz,
2H), 7.60 (d, J = 7.4 Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.42 (t, J =
7.4 Hz, 2H), 5.21 (bs, 1H), 4.84 (dd, J = 49.2, 2.4 Hz, 1H), 4.58 (bs,
1H), 4.50-4.40 (m, 2H), 4.42-4.10 (m, 1H), 4.21 (t, J = 6.8 Hz,
1H), 3.16-3.06 (m, 2H), 1.60-1.45 (m, 4H), 1.50 (s, 9H), 1.44 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 166.4 (d, J = 23.5 Hz),
155.96, 155.92, 143.7, 141.3, 127.7, 127.0, 125.01, 124.95, 119.97,
119.94, 90.1 (d, J = 186.8 Hz), 83.4, 79.2, 66.8, 52.2 (d, J = 19.3
Hz), 47.2, 40.0, 28.4, 28.0, 26.4, 25.8; 19F NMR (282 MHz, CDCl3)
δ -203.6 (dd, J = 49.4, 26.0 Hz); HRMS calcd for C30H39FN2O6-
Na 565.2690, found 565.2683 [M þ Na]þ.
1
81%): mp =152-155 °C; [R]20D =-5 (c = 0.65, CHCl3); H
NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.6 Hz, 2H), 7.71 (d.
J = 7.2 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.4 Hz,
2H), 7.33 (t, J = 7.4 Hz, 2H), 6.78 (t, J = 5.0 Hz, 1H), 4.90 (dd,
J = 49.0, 3.0 Hz, 1H), 4.34-4.21 (m, 3H), 3.91-3.82 (m, 1H),
3.35 (bs, 1H), 2.89 (q, J = 6.0 Hz, 2H), 1.55-1.42 (m, 2H),
1.41-1.27 (m, 2H), 1.40 (s, 9H); 13C NMR (150 MHz, (CD3)2O)
δ 169.5 (d, J = 23.0 Hz), 156.9, 156.7, 145.1, 144.0, 142.1, 128.5,
127.9, 126.2, 126.1, 120.8, 91.1 (d, J = 188.1 Hz), 79.2, 78.5, 68.0,
67.0, 53.6 (d, J = 20.4 Hz), 48.0, 40.6, 28.6, 27.5, 26.2 (d, J = 3.84
Hz); 19F NMR (282 MHz, CDCl3) δ-204.8 (dd, J= 49.1, 25.7 Hz);
HRMS calcd for C26H31FN2O6Na 509.2064, found 509.2059
[M þ Na]þ.
Acknowledgment. We are grateful to Flinders University
for providing a Graduate Scholarship for T.L.M. and
CSIRO for providing a scholarship top-up for T.L.M. and
research funding. We thank Jonathan White, University of
Melbourne, for determining the X-ray crystal structure of 5c
and Franziska Conrad for her early work with compounds 4e
and 5e. The Australian Research Council is acknowledged
for LIEF funding (LE0668489) for NMR spectrometers.
Supporting Information Available: Detailed experimental
procedures for the preparation of 1d and 1f, characteristic H
1
NMR data for syn and anti diastereomers of 5a-f, 1H and 13
C
NMR spectra for all new compounds, and X-ray data for 5c.
This material is available free of charge via the Internet at http://
pubs.acs.org.
7372 J. Org. Chem. Vol. 75, No. 21, 2010