Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl) ethyl]-dihydrofuran-2-one

Article abstract of DOI:10.1016/j.tetlet.2004.07.097

Phthalic anhydride as thiolate scavenger effectively preserved the enantiopurity of α-aminoketone, thus affording the convenient synthesis of the titled lactone. A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the α-aminoketone 4 product obtained from the reaction of organozincate 3 with thioester 2.

Full text of DOI:10.1016/j.tetlet.2004.07.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6887–6890
Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-
(3-fluorophenyl)ethyl]-dihydrofuran-2-one
Bryan Li,* Richard A. Buzon, Charles K.-F. Chiu, Stephen T. Colgan,
MatthewL. Jorgensen and Narasim Kasthurikrishnan
Chemical Research and Development, Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road,
Groton, CT 06340, USA
Received 26 April 2004; revised 21 July 2004; accepted 22 July 2004
Available online 10 August 2004
Abstract—A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofu-
ran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the a-amino-
ketone 4 product obtained from the reaction of organozincate 3 with thioester 2.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Compounds containing c-hydroxy-d-amino functional
groups, such as lactone 1, are key precursors to
Our first approach was inspired by Fukuyama and co-
workers who described a novel ketone synthesis via
addition of organozincates to thioester catalyzed by
hydroxyethylene dipeptide isosteres,
a
class of
PdCl2(PPh3)2,4 Pd(OH)2
and Ni(acac)2.6 These
5
compounds that have shown therapeutic potential as
HIV and renin inhibitors.1 Accordingly, in the past
two decades, many reports have described the synthesis
of these functionalized lactones.2 We had a need to
prepare multi-kilogram quantities of lactone 1a.
Commercially available a-amino acids and their deriva-
tives are attractive starting materials as they are readily
accessible in both enantiomeric forms, but direct conver-
sion of these amino acids to lactones 1 has frequently
been accomplished by utilizing racemization-prone a-
amino aldehyde intermediates.2f,j,3 We therefore pro-
ceeded to look at routes that avoided aldehyde
intermediates.
prompted us to explore the synthesis of a-aminoketone
by alkylation with organozinc homoenolate
4
BrZnCH2CH2COOEt (3) in THF7 as shown in Scheme
1. Conversion of the c-keto ester 4 to lactone 1a was
expected to be straightforward via an established stereo-
selective reduction with N-Selectride8 followed by
acid-catalyzed cyclization. Other hydride (NaBH4,9
LiBH4,10 L-Selectride11) reduction and catalytic hydro-
genation of similar systems2h,12 were known in the
literature but with lower diastereoselectivity.
Thioester 2, prepared from commercially available Boc-
L-3-(fluorophenyl)alanine,13 is a crystalline material and
nearly odorless. Surprisingly, reaction of 2 with 3
(2.0equiv) in the presence of PdCl2(PPh3)2 (5mol%)
gave a-aminoketone 4 that was completely racemized.14
We ascribed the loss of enantiopurity to the presence of
catalytic amounts of ethoxide, which was generated by
the displacement of the ethyl esters 3 or 415 by thiolate
anion. The presence of ethyl ester 5 (ꢀ15% by HPLC16)
in the reaction mixture supported this hypothesis
(Scheme 2).
R
S
P
NH
S
R = alkyl, aryl
P = protecting group
O
O
1
To eliminate racemization in this reaction, we investi-
gated the effect of added thiolate scavengers, which
would minimize ethoxide generation. Phenyl acetate
Keywords: Thioester; Aminoketone; Organozincate.
*
Corresponding author. Tel.: +1 860 715 1448; fax: +1 860 715
7305; e-mail: bryan_li@groton.pfizer.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.097

6888
B. Li et al. / Tetrahedron Letters 45 (2004) 6887–6890
F
F
F
O
BrZn
SPrn
OEt
1. [H]
3
O
BOC-HN
2. H+
[Pd]
BOC-HN
OEt
BOC-HN
O
O
O
O
2
4
1a
Scheme 1.
F
F
3
O
SPrn
+
SPrn
[Pd]
BOC-HN
OEt
BOC-HN
O
O
2
4
OEt
O
3 or 4
OEt
OEt
F
F
OEt
O
OEt
BOC-HN
OEt
BOC-HN
O
O
5
racemic-4
Scheme 2.
(6a), 4-fluorophenyl acetate (6b), and 4-nitrophenyl ace-
tate (6c) were chosen for initial experiments (Eq. 1), as
we reasoned that phenoxide anions generated (7, Eq.
1) were weak bases that would not cause epimerization
of the a-aminoketone 4. The use of 6a or 6b (3equiv) re-
duced but did not eliminate formation of 5 (5% by
HPLC), and racemic 4 was isolated. Use of 6c (3equiv)
inhibited the formation of 5 completely and the a-ami-
noketone obtained was enantiomerically pure (>99%
ee by HPLC chiral assay17). However, the odor from
n-propylthioacetate generated in the reaction could not
be adequately purged from the isolated product
(Eq. 1). The use of phthalic anhydride, which was
known to react slowly with PhZnCl at room tempera-
ture (3% conversion after 8h),18 resulted in formation
of 4 without any racemization, and no 5 was detected.
Byproducts 8 (Eq. 2), 9 (Eq. 3), and phthalic acid (from
the hydrolysis of the unreacted phthalic anhydride19)
were readily removed by an aqueous NaHCO3 wash.
PdCl2(PEt3)2 was a good catalyst for the reaction,
although extensive screening of palladium catalysts
was not performed. The reaction required 6equiv of 3
and 3equiv of phthalic anhydride for complete conver-
sion of 2 in 14h at room temperature due to acceleration
of the reaction of phthalic anhydride with the organo-
zinc (Eq. 3).20,21
ð1Þ
ð2Þ
ð3Þ

B. Li et al. / Tetrahedron Letters 45 (2004) 6887–6890
6889
Conversion of a-aminoketone 4 to lactone 1a22 was
straightforward (Scheme 1). In a one-pot process, stereo-
selective ketone reduction with N-Selectride11a at ꢁ78ꢁC
was followed by acetic acid quench, and the crude
reaction mixture was directly brought to reflux to
afford lactone 1a. The product obtained was of
comparable quality with material obtained from other
routes.1f,3,8
8. (a) Urban, F. J.; Jasys, V. J. Org. Process Res. Dev. 2004,
8, 169; (b) Urban, F.; Jasys, V. J.; Li, Z. B.; Kath, J. C.
PCT Int. Appl. WO 2003095440, 2003.
9. (a) Hanessian, S.; Claridge, S.; Johnstone, S. J. Org.
Chem. 2002, 67, 4261; (b) Wuts, P. G. M.; Putt, S. R.;
Ritter, A. R. J. Org. Chem. 1988, 53, 4503; (c) Hilborn, J.
W.; Lu, Z.-H.; Jurgens, A. R.; Fang, Q. K.; Byers, P.;
Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2001,
42, 8919.
10. Radunz, H. E.; Eiermann, V.; Schneider, G.; Riethmuel-
ler, A. Tetrahedron 1991, 47, 1887.
11. (a) Estiarte, M. A.; Diez, A.; Rubiralta, M.; Jackson, R. F.
W. Tetrahedron 2001, 57, 157; (b) Jackson, R. F. W.;
Rettie, A. B.; Wood, A.; Wythes, M. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 13, 1719.
12. (a) Sakurai, M.; Hata, T.; Yabe, Y. Tetrahedron Lett.
1993, 34, 5939; (b) Hoffman, R. V.; Kim, H. O. Tetrahe-
dron Lett. 1992, 33, 3579; (c) Noyori, R.; Kitamura, M.;
Ookuma, T.; Morisawa, Y.; Nishi, T. Jpn. Kokai Tokkyo
Koho, JP 03002151, 1991; Chem. Abstr. 1991, 114 206574;
(d) Nishi, T.; Kataoka, M.; Morisawa, Y. Chem. Lett.
1989, 11, 1993.
In summary, we have described a short and convenient
synthesis of lactone 1a. The use of phthalic anhydride
as thiolate scavenger in the organozinc reaction effec-
tively preserved the enantiopurity of a-aminoketone 4.
Furthermore, the addition of phthalic anhydride offered
a convenient workup in removing the thiolate species,
thus affording an attractive alternative for the prepara-
tion of 1a.
Acknowledgements
13. Preparation of thioester 2. To a dry and nitrogen purged
1L flask was added Boc-L-3-(fluorophenyl)alanine (pur-
chased from Synthetech, 18g, 63.5mmol). Anhydrous
methylene chloride (180mL) was added, and the solution
was subsequently cooled to ꢁ10ꢁC. Triethylamine (7.14g,
69.9mmol) was added over 10min while keeping temper-
ature below ꢁ10ꢁC. The mixture was stirred at ꢁ5 to
ꢁ10ꢁC for 30min, and isobutyl chloroformate (9.55g,
69.9mmol) was added via a drop funnel. After 30min at
ꢁ5ꢁC, n-propyl mercaptan (5.32g, 69.9mmol) was added
over 10min via addition funnel while keeping the temper-
ature at ꢁ5ꢁC. The mixture was allowed to warm to 0ꢁC,
and stirred for 30min. HPLC assay of reaction aliquot
showed complete conversion. Water (90mL) was added,
and layers were separated. The methylene chloride layer
was washed once more with water, dried over MgSO4, and
concentrated. The residue was granulated in hexanes
(50mL). The mixture was filtered, and the filtrate was
concentrated and filtered again to give a second crop. Both
crops were of similar purity by HPLC assay; 21.3g was
obtained; as a crystalline solid (98.2% yield). HPLC:
99.7% pure by area (242nm). Chiral assay not available
due to lack of reference. 1H NMR (400MHz, CDCl3) d
0.92 (t, J = 7.46Hz, 3H), 1.38 (s, 9H), 1.56–1.60 (m, 2H),
2.82 (t, J = 7.25Hz, 2H), 2.95–3.13 (m, 2H), 4.54–4.62 (m,
1H), 4.94–4.99 (m, 1H), 6.83–7.25 (m, 4H); LC–MS: 364
(M + Na)+, 242 (M + H ꢁ Boc group)+.
We thank Dr. Frank J. Urban for his helpful sugges-
tions in this work and Dr. Martin A. Berliner for his
valuable comments in preparation of the manuscript.
References and notes
1. (a) Nadin, A.; Owens, A. P.; Castro, J. L.; Harrison, T.;
Shearman, M. S. Bioorg. Med. Chem. Lett. 2003, 13, 37;
(b) Dias, L. C.; Diaz, G.; Ferreira, A. A.; Meira, P. R. R.;
Ferreira, E. Synthesis 2003, 4, 603; (c) Benedetti, F.; Berti,
F.; Norbedo, S. J. Org. Chem. 2002, 67, 8635; (d) Meek, T.
D. J. Enzym. Inhib. 1992, 6, 65; (e) Lecki, B. J.; Grant, J.;
Hallett, A.; Hughes, M.; Jones, D. M.; Szelke, M.; Tree,
M. Scot. Med. J. 1984, 29, 125; (f) Kath, J.C.; Brown,
M.F.; Poss, C.S. PCT Int. Apl. WO 9940061, 1999; Chem.
Abstr. 1999, 131, 157767.
2. (a) Nadin, A.; Sanchez Lopez, J. M.; Neduvelil, J. G.;
Thomas, S. R. Tetrahedron 2001, 57, 1861; (b) Brewer, M.;
Rich, D. H. Org. Lett. 2001, 3, 945; (c) Benedetti, F.;
Magnan, M.; Miertus, S.; Norbedo, S.; Parat, D.; Tossi,
A. Bioorg. Med. Chem. Lett. 1999, 9, 3027; (d) Kang, S.
H.; Ryu, D. H. Bioorg. Med. Chem. Lett. 1995, 5, 2959; (2)
Dondoni, A.; Perrone, D.; Semola, M. T. J. Org. Chem.
1995, 60, 7927; (f) Fray, A. H.; Kaye, R. L.; Kleiman, E.
F. J. Org. Chem. 1986, 51, 4828; (g) Ghosh, A. K.; Shin,
D.; Mathivanan, P. Chem. Commun. 1999, 9, 1025; (h)
Lagu, B.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 547; (i)
Ghosh, A. K.; McKee, S. P.; Thompson, W. J. J. Org.
Chem. 1991, 56, 6500; (j) DeCamp, A. E.; Kawaguchi, A.
T.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1991, 32,
1867.
14. Fukuyama and co-workers (Ref. 4a) reported reaction of
N-CBZ-L-a-phenylalanine thiol ester with IZn(CH2)3-
CO2Et to give the corresponding ketone without appre-
ciable racemization.
15. The thioester resulting from reaction of the thiolate with 4
was not detected. LC–MS analysis of the reaction mixture
suggested it further reacted with 3.
3. Jasys, V. J.; Urban, F. J. Tetrahedron: Asymmetry 2001,
12, 361.
16. Achiral HPLC conditions: SB-CN column 4.6 · 150mm;
mobile phase: acetonitrile/buffer (0.6% NEt3 and 0.2%
H3PO4 in water): 45/54; flow rate: 2mL/min, 210nm.
17. Chiral HPLC conditions: ChiralPak column OD
4.6 · 250mm; mobile phase: n-hexane/isopropanol/trieth-
ylamine: 1000/20/1; flowrate: 1.5mL/min, 40 ꢁC, 210nm.
18. Tarbell, D. S.; Weaver, C. J. Am. Chem. Soc. 1940, 62,
2747.
19. Allowing at least 30min of good stirring with the saturated
bicarbonate solution for the phthalic anhydride hydrolysis
before layer separation.
20. For examples of reactions of organozinc with mixed
anhydrides in the presence of Pd catalyst: Jabri, N.;
4. (a) Tokuyama, H.; Yomoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189; (b)
Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Lin,
S.-C.; Li, L.; Fukuyama, T. J. Brazil. Chem. Soc. 1998,
9, 381.
5. Mori, Y.; Seki, M. J. Org. Chem. 2003, 68, 1571.
6. Shimizu, T.; Seki, M. Tetrahedron Lett. 2002, 43,
1039.
7. Commercially available from Rieke Metals, Inc. See also:
Smith, R. D.; Simmons, H. E. Org. Synth. Collect. 1973, 5,
855.

6890
B. Li et al. / Tetrahedron Letters 45 (2004) 6887–6890
Alexakis, J. F.; Normant, J. F. Tetrahedron 1986, 42,
1369.
dichlorobis-(triethylphosphine)palladium(II) (0.05equiv;
0.1mmol; 42.8mg) in DMAc (3.4mL). After overnight
stirring at ambient temperature, the reaction was assayed
by HPLC, and showed desired product, but the reaction
was incomplete (28% starting material by HPLC area).
The reaction was worked up as described in method 1. The
final concentrated residue was chromatographed on silica
gel eluting with 20% ethyl acetate/hexanes to give 285mg
of desired product (54% yield, 192mg of 2 was recovered).
Note: the product obtained should be treated once with
DarCo-G60 to purge the residual palladium in order to
obtain high diastereoselectivity in the N-Selectride reduc-
tion reaction.
21. Preparation of a-aminoketone 4. Method 1. To a dry and
nitrogen purged 500mL flask was charged 2 (10mmol;
3.41g), phthalic anhydride (3.00equiv; 30.0mmol; 4.48g),
and dichlorobis(triethylphosphine)palladium(II) (0.05
equiv; 0.499mmol; 214mg). Anhydrous THF (17mL)
was added, followed by addition 3-ethoxy-3-oxopropyl-
zinc bromide (6.00equiv; 60mmol; 120mL, 0.5M solution
in THF). After overnight stirring, the reaction was assayed
by HPLC, and showed complete conversion. HCl (1N,
34mL) and ethyl acetate (50mL) were added, and the
mixture was stirred for 5min before layer separation. The
organic phase was stirred with saturated sodium bicarbo-
nate solution for 30min, followed by layer separation. The
organic phase was washed once with brine solution, then
dried over MgSO4. The solution was concentrated under
vacuum to give an oil. Upon standing overnight, the
residue solidified. It was then triturated in isopropyl ether
(7mL) and filtered to give 2.46g (67.0% yield) of the
desired product. HPLC purity: 98.6% achiral; 99.8%
chiral. NMR (400MHz, CDCl3) d 1.24 (t, J = 7.0Hz,
3H), 1.39 (s, 9H), 2.53–2.60 (m, 2H), 2.72–2.78 (m, 2H),
2.91 (dd, J = 13.9 and 7.0Hz, 1H), 3.17 (dd, J = 5.8 and
13.9Hz, 1H), 4.11 (q, J = 7.0Hz), 4.52 (dd, J = 7.0
and 13.8Hz), 5.08 (d, J = 7.0Hz), 6.87–7.27 (m, 4H);
MS: 390 (M + Na)+, 268 (M + H ꢁ Boc group)+. Method
2. To a dry and nitrogen purged 50mL flask was charged
0.5M ZnCl2 solution in THF (4equiv, 8mmol, 16mL).
[1-(Ethoxycyclopropyl)oxy]-trimethylsilane (8equiv, 16
mmol, 2.81g) was added via a syringe. The mixture was
stirred at ambient temperature for 4h, then stripped to an
oil under vacuum at 25–30ꢁC. THF (10mL) was added.
This solution was transferred to another dry and nitrogen
purged 25mL flask that contained 2 (682mg, 2.0mmol),
phthalic anhydride (3.00equiv; 6.0mmol; 897mg), and
22. Preparation of lactone 1a. To a dry and nitrogen purged
100mL flask was added a-aminoketone
4
(1.0g,
2.72mmol) and THF (10mL). The resultant solution was
cooled to ꢁ78ꢁC. N-Selectride (1.0M, 3mmol, 3mL) in
THF was added dropwise while keeping reaction below
ꢁ72ꢁC over 30min. After 10min stirring at ꢁ78ꢁC, HPLC
assay showed reaction completion. Acetic acid (0.62mL)
in THF (10mL) was added dropwise. The reaction was
allowed to warm to room temperature and subsequently
heated at reflux for 10min. After cooling to room
temperature, ethyl acetate (10mL) and 1N HCl (10mL)
were added. The layers were separated, the organic layer
was washed with saturated sodium bicarbonate and brine
solutions. After drying over MgSO4, the organic phase
was concentrated to an oil in vacuo. The resulting residue
was granulated in isopropylether (2mL) for 10min, then
hexanes (2mL) was added. The mixture was stirred at
ambient temperature for 1h, and filtered. This gave the
desired product as a white solid (673mg, 76.5%). HPLC
purity: chiral 97.8% (enantiomer 1.1%, diastereomer
1.0%); achiral 98.0%. The material obtained co-eluted
with an authentic sample in HPLC, and the spectroscopic
data were identical to those reported.8