Asymmetric synthesis of alpha,alpha-difluoro-beta-amino acid derivatives from enantiomerically pure N-tert-butylsulfinimines.

Article abstract of DOI:10.1021/jo0259313

Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.

Full text of DOI:10.1021/jo0259313

Asym m etr ic Syn th esis of
r,r-Diflu or o-â-a m in o Acid Der iva tives fr om
En a n tiom er ica lly P u r e
N-ter t-Bu tylsu lfin im in es
Donnette D. Staas,*,† Kelly L. Savage,†
Carl F. Homnick,† Nancy N. Tsou,‡ and Richard G. Ball‡
F IGUR E 1. Natural product analogues containing R,R-
difluoro-â-amino acid fragments.
Merck Research Laboratories,
West Point, Pennsylvania 19486, and Merck Research
Laboratories, Rahway, New J ersey 07065
SCHEME 1. r,r-Diflu or o-â-a m in o Acid s fr om
Ch ir a l Oxa zolid in on es5
donnette_staas@merck.com
Received May 13, 2002
Abstr a ct: Addition of the Reformatsky reagent derived
from ethyl bromodifluoroacetate to alkyl- and aryl-substi-
tuted N-tert-butylsulfinimines furnishes â-tert-butylsulfin-
amyl-â-substituted R,R-difluoroproponiates in diastereomeric
ratios ranging from 80:20 to 95:5. The diastereomers are
easily separated and the enantiomerically pure, protected
â-amino esters are readily transformed to the corresponding
acid, amide, and amine derivatives as useful synthons for
medicinal chemistry targets.
roacetate to chiral 1,3-oxazolidines derived from alde-
hydes and either phenylglycinol or 2-aminobutanol
(Scheme 1). The method produces the difluoroazetidinone
precursor to the â-amino acid fragment with excellent
diastereoselection (85 to >99% de), but requires ring-
opening of the intermediate azetidinone followed by
reductive or hydrolytic cleavage of the chiral auxiliary
to liberate the desired amino acid. In addition, subse-
quent transformations of the amino acid (for example,
in peptide couplings) would require an additional protec-
tion step to block either the amine or carboxyl terminus.
The chiral auxiliary would not serve as a suitable
protecting group on nitrogen since it contains a reactive
hydroxyl and it also does not eliminate the reactivity of
that secondary nitrogen center.
Fluorinated â-amino acids have recently become of
great interest in both medicinal and synthetic organic
chemistry.1-3 In general, the introduction of fluorine
atoms in bioactive targets often produces significant
changes in the physical properties, physiological activity,
and metabolic profile of these compounds. For example,
replacement of scissile amide bonds in peptides by a gem-
difluoroketo group often leads to potent transition state
analogue inactivators of serine proteases such as elastase.1
The CH2 to CF2 transposition in the â-amino acid
fragment of the naturally occurring antifungal tetrapep-
tide Rhodopeptin4 (Figure 1) results in an improved
toxicity profile for this class of compounds.2 Fluorinated
â-amino acids have also been incorporated in the side
chain of analogues of docetaxel3 (Figure 1).
In the latter two examples, the requisite â-branched
R,R-difluoro-â-amino acid fragments were prepared via
lengthy (6 to 8 step) racemic syntheses with resolution
of the diastereomeric products after incorporation into
the target core. So far we have encountered only one
report in the current literature of stereoselective prepa-
ration of â-branched R,R-difluoro-â-amino acids.5 The key
transformation in that account is the addition of the
Reformatsky reagent 1 derived from ethyl bromodifluo-
Both Davis6 and Ellman7 have carried out extensive
studies on the stereoselective addition of organometallic
reagents (including Grignards, organolithiums, and ac-
etate enolates) to enantiomerically pure sulfinimines. We
reasoned that this methodology could be extended to the
addition of Reformatsky-type reagents to chiral sulfin-
imines, given the literature precedent of addition of these
reagents to aldimines.8 We were particularly interested
in the use of Ellman’s N-tert-butylsulfinimine 2 since in
the resulting adduct, the N-sulfinyl group has been found
to be comparable in reactivity to a Boc group and in this
context would play the dual role7b of chiral auxiliary and
protecting group for subsequent transformations. Thus,
copper sulfate-mediated condensation of commercial al-
dehydes 3a -e with (R)-29 afforded the sulfinimines 4a -e
in good yield. The sulfinimines were treated with an
excess (3 equiv) of the Reformatsky reagent 110 at room
† Merck Research Laboratories, West Point.
‡ Merck Research Laboratories, Rahway.
(1) (a) Schirlin, D.; Baltzer, S.; Altenburger, J . M.; Tarnus, C.; Remy,
J . M. Tetrahedron 1996, 52, 305-318. (b) Imperiali, B.; Abeles, R. H.
Biochemistry 1986, 25, 3760-3767.
(2) Nakayama, K.; Kawato, H. C.; Inagaki, H.; Nakajima, R.;
Kitamura, A.; Someya, K.; Ohta, T. Org. Lett. 2000, 2, 977-980.
(3) Uoto, K.; Ohsuki, S.; Takenoshita, H.; Ishiyama, T.; Iimura, S.;
Hirota, Y.; Mitsui, I.; Hirofumi, T.; Soga, T. Chem. Pharm. Bull. 1997,
45, 1793-1804.
(4) Chiba, H.; Agematu, H.; Kaneto, R.; Terasawa, T.; Sakai, K.;
Dobashi, K.; Yoshioka, T. J . Antibiot. 1999, 52, 695-699.
(5) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J .-C. J . Org.
Chem. 1999, 64, 8461-8464.
(6) (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27,
13-18. (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M. J . Org. Chem.
1995, 60, 7037-7039.
(7) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120, 8011-8019. (b) Tang, T. P.; Ellman, J . A.
J . Org. Chem. 1999, 64, 12-13.
(8) (a) Taguchi, T.; Kitagawa, O.; Yoshimitsu, S.; Ohkawa, S.;
Hashimoto, A.; Iitaka, Y.; Kobayashi, Y. Tetrahedron Lett. 1988, 29,
5291-5294. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Peet, N. P. Bioorg.
Med. Chem. Lett. 1992, 2, 1235-1238.
(9) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J .
Org. Chem. 1999, 64, 1278-1284.
10.1021/jo0259313 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/22/2002
8276
J . Org. Chem. 2002, 67, 8276-8279

SCHEME 3. Ellm a n (6)11 a n d Da vis (7)12
Tr a n sition Sta te Mod els for th e Ad d ition of
Or ga n om eta llic Rea gen ts to Ch ir a l Su lfin im in esa
TABLE 1. Dia ster eoselective Ad d ition of 1 to Ch ir a l
Su lfin im in es 4a -e
entry substrate
R
product
yield (%)a
drb
1
2
3
4
5
4a
4b
4c
4d
4e
i-C4H9
n-C3H7
Ph
c-C6H11
2-thiazolyl
5a
5b
5c
5d
5e
51
55
82
81
58
81:19
80:20
90:10
87:13
95:5
a
b
Isolated yields of diastereomeric mixtures. Diastereomeric
ratios determined by chiral HPLC.
a
Reprinted with permission from ref 11. Copyright 1999
SCHEME 2
Elsevier Science.
SCHEME 4
temperature for 18 h to afford the sulfinamide adducts
5a -e in 51 to 82% yield (Scheme 2).
Both aryl- and alkyl-derived adducts were successfully
prepared by this method (Table 1). The diastereomeric
ratios of the adduct mixtures (shown in Table 1) were
determined by chiral HPLC and ranged from 80:20 for
simple alkyl side chains such as propyl (entry 2) to 95:5
for the 2-thiazolyl case (entry 5). By comparison, Ellman
reports an 83:17 diastereomeric ratio for the addition of
the lithium enolate of methyl acetate to sulfinimine 4c7b
in THF. Our diastereomeric ratio of 90:10 for adduct 5c
compares favorably with this result. Chiral HPLC meth-
ods were also required for isolation of the diastereomers
on preparative scale.
To rationalize the origin of the observed diastereo-
selectivity of the reaction, we examined transition state
models proposed by Ellman11 and Davis12 as shown in
Scheme 3. For the addition of Grignard and alkyllithium
reagents to N-tert-butylsulfinimines Ellman proposes the
six-membered transition state 6 in which coordination
of the metal M to the sulfinyl oxygen directs addition of
the incoming R2 group to the Si face of the sulfinimine
with >80% stereoselectivity.11 For the addition of lithium
enolates to sulfinimines Davis proposes the modified
eight-membered bicyclic transition state 7 in which the
metal ion is coordinated to the sulfinyl oxygen, the imine
nitrogen, and the enolate oxygen, again leading to
delivery of the incoming nucleophile to the Si face.12 It
has long been debated whether the structure of the zinc
enolate of an ester is better described as a C-metalated
versus an O-metalated species.13 Orsini and co-workers
have shown that in solution the reagent formed from tert-
butylbromoacetate and zinc exists as a dimer of the
C-metalated species.13 The Reformatsky reagent derived
from ethyl bromodifluoroacetate has also been described
as a C-metalated species.14 However, it has been proposed
that in the reaction of these zinc enolates with carbonyl
compounds, the reagent dissociates and undergoes rate-
determining conversion to the O-metalated species.15
Finally, though the thermodynamically preferred sulfin-
imine is expected to be the E isomer, some amounts of
the Z isomer may be generated in the reaction mixture.
Ellman reports such isomerization in the reaction of
Grignard reagents with sulfinimines derived from ke-
tones.11
The transition states 8-11 shown in Scheme 4 reflect
consideration of all these factors, namely a six- versus
eight-membered transition state, a C-metalated versus
O-metalated form of 1, and the E versus Z isomers of
the sulfinimine. Transition states 8 and 9 would give rise
to the same stereochemical outcome of addition to the Si
face of the sulfinimine, i.e., yielding the (R) isomer.
Transition states 10 and 11 would give rise to the
opposite outcome of addition to the Re face, i.e., yielding
the (S) isomer; hence the facial selectivity of the addition
would be predicted to be the same regardless of whether
the reaction proceeds through the six-membered or eight-
membered transition state, and would thus be solely
dependent on sulfinimine geometry. One would predict
that larger R groups on the sulfinimine would favor the
E isomer (transition states 8 and 9) and would result in
improved selectivity for the (R)-diastereomer of the
adduct, with the minor (S)-diastereomer arising from the
less favorable Z-sulfinimine (transition states 10 and 11).
As illustrated in Table 1, the highest diastereomeric
ratios are obtained with the more bulky aryl or cycloalkyl
R groups (entries 3-5). To determine the absolute
configuration at C-3, the major diastereomer of adduct
(10) Reagent 1 was prepared from zinc powder and ethyl bromodi-
fluoroacetate in THF.
(11) Cogan, D. A.; Liu, G.; Ellman, J . A. Tetrahedron 1999, 55,
8883-8904.
(12) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992,
57, 6387-6389.
(13) (a) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron Lett. 1982,
23, 3945-3948. (b) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron 1984,
40, 2781-2787.
(14) Burton, D. J .; Easdon, J . C. J . Fluorine Chem. 1988, 38, 125-
129.
(15) Fu¨rstner, A. Synthesis 1989, 8, 571-590.
J . Org. Chem, Vol. 67, No. 23, 2002 8277

SCHEME 5
Boc-proline and BOC removal afforded the tripeptide 22,
which now bears an R,R-difluoro-â-amino acid linker
(Scheme 6).
In summary, we have developed a highly convergent,
stereoselective route to â-branched R,R-difluoro-â-amino
esters via reaction of the Reformatsky reagent derived
from ethyl bromodifluoroacetate with chiral N-tert-bu-
tylsulfinimines. The diastereomeric adducts are readily
purified by chiral HPLC and the tert-butylsulfinyl group
serves as a sturdy protecting group on nitrogen during
subsequent transformations of the ester moiety. These
adducts provide the corresponding carboxylic acids as
well as novel monoprotected 2,2-difluoro-1,3-diaminopro-
pane fragments (in 2 steps), both of which undergo facile
peptide coupling reactions. The ease of manipulation of
these sulfinamide adducts should render this method
readily applicable to solid-phase peptide synthesis.
Exp er im en ta l Section 17
N-(1-Cycloh exylm eth ylid en e)-2-m eth ylp r op a n e-2-su lfin -
a m id e (4d ). To a solution of R-(+)-2-methyl-2-propanesulfin-
amide (2, 2.7 g, 22.3 mmol) in CH2Cl2 (30 mL) was added copper
sulfate (17.8 g, 111.4 mmol) and molecular sieves. A solution of
cyclohexane carboxaldehyde (3d , 5.0 g, 44.6 mmol) in CH2Cl2 (7
mL) was then added dropwise. The mixture was stirred at room
temperature for 18 h. The resulting mixture was filtered through
Celite and the filter cake was washed with CH2Cl2. The filtrate
was concentrated in vacuo giving the crude product, which was
purified by silica gel chromatography (gradient elution with
hexane to 1:9 ethyl acetate/hexane to 1:1 ethyl acetate/hexane)
to afford 4d as a clear oil (85% yield): 1H NMR (CDCl3, 400
MHz) δ 7.96 (d, J ) 4.8 Hz, 1 H), 2.47-2.46 (m, 1 H), 1.89-1.68
(m, 5 H), 1.37-1.24 (m, 5 H), 1.19 (s, 9 H) ; 13C NMR (CDCl3, 75
MHz) δ 172.85, 56.57, 44.17, 29.48, 26.05, 25.53, 22.48; FTIR
(cm-1) 2925 and 2849 (C-H), 1618 (CdN), 1086 (SdO), 687 (C-
S); HRMS (FAB) calculated for (C11H22NOS)+ (M + H) 216.1417,
found 216.1446.
SCHEME 6
Eth yl 3-[(ter t-Bu tylsu lfin yl)a m in o]-3-cycloh exyl-2,2-d i-
flu or op r op a n oa te (5d ).18 To a suspension of zinc (∼100 mesh
powder, 2.73 g, 41.8 mmol) in anhydrous, degassed THF (27 mL)
was added ethyl bromodifluoroacetic (5.36 mL, 41.8 mmol). The
mixture was warmed to 30 °C, resulting in a vigorous exothermic
reaction that gave a green-gray mixture. The oil bath was
removed and additional ethyl bromodifluoroacetic (2.0 mL, 15.6
mmol) was added to consume the zinc. After cooling to room
temperature, the resulting solution [ca. 3 equiv of Reformatsky
reagent (1)] was cannulated into a solution of N-(1-cyclohexyl-
methylidene)-2-methylpropane-2-sulfinamide (4d , 3.0 g, 13.9
mmol) in anhydrous, degassed THF (15 mL). The reaction was
stirred at room temperature under inert atmosphere for 18 h.
The solvent was removed in vacuo, and the resulting oil was
redissolved in ethyl acetate. To this solution was added 3%
aqueous ammonium hydroxide. The resulting precipitate was
removed by filtration. The filtrate layers were separated, and
the aqueous layer was extracted twice more with ethyl acetate.
The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. Silica gel chromatography (gradient
elution with 1:5 ethyl acetate/hexane to ethyl acetate) afforded
the diastereomeric mixture 5d as a clear oil (3.70 g, 81%). The
minor and major diastereomers eluted at 5.86 and 8.02 min
respectively by analytical chiral HPLC (Chiralpak AD column
eluting with 98:2 A/B, where A ) hexane and B ) 2-propanol);
diastereomeric ratio 13:87. Data for the diastereomeric mixture
5d :19 1H NMR (CDCl3, 400 MHz) δ 4.38 (app q, J ) 7.2 Hz, 2 H,
from major diastereomer) and 4.30 (m, 2 H, from minor diaste-
5d was converted to the crystalline primary amide 12
by ammonolysis (Scheme 5). X-ray crystallographic analy-
sis of 12 shows the absolute configuration at the newly
formed stereocenter to be R.16 The stereochemical results
presented in Table 1 are therefore consistent with the
analysis presented above, in that either transition state
model 8 or 9 correctly predicts the observed configuration
at C-3 of the major diastereomer (Scheme 4).
As an example of the utility of the method, (R,R)-12
was reduced with borane to obtain the monoprotected
diamine fragment 13 (Scheme 5). EDC coupling to Fmoc-
proline provided peptide 14, which was subjected to mild
acidic conditions (4 M HCl-Et2O, rt, 30 min) to remove
the sulfinyl group followed by EDC coupling to Fmoc-D-
phenylalanine and Fmoc removal to afford the pseudo-
tripeptide 17, in which a substituted 2,2-difluoro-1,3-
diaminopropyl fragment has been inserted as a linker
(Scheme 5).
Alternatively, ester (R,R)-5d was hydrolyzed to the
corresponding acid 18 (Scheme 6), which was then
coupled to phenylalanine methyl ester. Cleavage of the
sulfinyl group followed by a second peptide coupling to
(17) Full experimental details and compound characterization ap-
pear in the Supporting Information.
(18) Oven-dried glassware was used for the protocol described in
this procedure.
(16) See the Supporting Information.
8278 J . Org. Chem., Vol. 67, No. 23, 2002

reomer), 3.78-3.60 (m, 2 H), 3.49 (d, J ) 9.7 Hz, 1 H, from minor
diastereomer), 1.88-1.56 (m, 8 H), 1.37 (t, J ) 7.1 Hz, 3 H),
1.26 (s, 9 H), 1.10-1.04 (m, 3 H); 13C NMR (CDCl3, 75 MHz) δ
63.58, 63.46, 63.17, 62.84, 60.52, 57.33, 38.11, 31.06, 27.05, 26.50,
26.01, 23.09, 22.95, 21.16, 14.34, 14.00; FTIR (cm-1) 2934 and
2857 (C-H), 1768 (CdO), 1096 (C-O), 1042 (SdO); HRMS
(FAB) calculated for (C15H28F2NO3S)+ (M + H) 340.1752, found
340.1770. The diastereomers were separated on preparative
scale under the conditions described above and were character-
ized as follows: Minor diastereomer of 5d : 1H NMR (CDCl3,
400 MHz) δ 4.30 (qd, J ) 2.8, 7.2 Hz, 2 H), 3.75-3.64 (m, 1 H),
3.47 (d, J ) 10 Hz, 1 H), 1.82-1.57 (m, 4 H), 1.67-1.61 (m, 4
H), 1.36 (t, J ) 7.2 Hz, 3 H), 1.21 (s, 9 H), 1.31-1.13 (m, 3 H);
13C NMR (CDCl3, 100 MHz) δ 164.11, 163.78, 163.47, 118.29,
115.76, 113.20, 64.12, 63.87, 63.65, 63.18, 57.01, 37.73, 30.91,
27.92, 26.65, 26.28, 25.94, 22.75, 14.13; FTIR (cm-1) 2924 and
2850 (C-H), 1775 (CdO), 1069 (C-O), 1042 (SdO); HRMS
(APCI) calculated for (C15H28F2NO3S)+ (M + H) 340.1752, found
340.1735. Major diastereomer of 5d : 1H NMR (CDCl3, 300 MHz)
δ 4.38 (app q, J ) 7.2 Hz, 2 H), 3.74-3.63 (m, 2 H), 1.83-1.56
(m, 8 H), 1.40-1.03 (m, 6 H), 1.26 (s, 9 H); 13C NMR (CDCl3, 75
MHz) δ 118.76, 115.36, 63.62, 57.46, 42.45, 26.01, 23.92, 22.34,
12.02, 10.44; FTIR (cm-1) 2984 and 2857 (C-H), 1771 (CdO),
1097 (C-O), 1044 (SdO); HRMS (ES) calculated for (C15H28F2-
NO3S)+ (M + H) 340.1752, found 340.1750.
Ack n ow led gm en t. We thank Drs. Peter Williams,
Philip Sanderson, Philippe Nantermet, and J ames Bar-
row for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterization including spectral data for
1
compounds 4a -c, 4e, 5a -c, 5e, and 12-22, H NMR spectra
for compounds 4d and 5d , and X-ray crystal structure of 12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Peaks of the major and minor diastereomers overlap unless
otherwise noted.
J O0259313
J . Org. Chem, Vol. 67, No. 23, 2002 8279