Efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921

Article abstract of DOI:10.1021/ol0352308

(Matrix presented) An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-α-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via a

Full text of DOI:10.1021/ol0352308

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3155-3158
Efficient Asymmetric Synthesis of the
Vasopeptidase Inhibitor BMS-189921
,†
,‡
Janak Singh,* David R. Kronenthal,* Mark Schwinden,† Jollie D. Godfrey,†
Rita Fox,† Edward J. Vawter,† Bo Zhang,† Thomas P. Kissick,† Bharat Patel,†
Omar Mneimne,† Michael Humora,‡ Chris G. Papaioannou,† Walter Szymanski,‡
Michael K. Y. Wong,‡ Chien K. Chen,‡ James E. Heikes,‡ John D. DiMarco,§
Jun Qiu,‡ Rajendra P. Deshpande,‡ Jack Z. Gougoutas,§ and Richard H. Mueller‡
Process Research and DeVelopment, The Bristol-Myers Squibb Pharmaceutical
Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, Process Research
and DeVelopment, The Bristol-Myers Squibb Pharmaceutical Research Institute,
1 Squibb DriVe, New Brunswick, New Jersey 08903, and Solid State Chemistry, The
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543
janak.singh@bms.com; daVid.kronenthal@bms.com
Received July 3, 2003
ABSTRACT
An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the
common key intermediate (S)-r-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively,
enyne 12 was converted to racemic r-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
Vasopeptidase inhibitors, compounds which inhibit both
angiotensin converting enzyme (ACE) and neutral endopep-
tidase (NEP), represent potential new modalities for the
treatment of hypertension and congestive heart failure.
R-Amidoazepinones have been investigated intensively as
conformationally restricted dipeptidomimetic surrogates ca-
pable of dual inhibition of both enzymes.1-3 In this regard,
Robl et al.1 reported the design and properties of a potent
vasopeptidase inhibitor, BMS-189921, which was selected
for clinical development. In this letter, we describe two new
short and efficient routes to the key intermediate (S)-R-
aminoazepinone 6b and its efficient conversion to BMS-
189921.
In the first approach, the stereocenter in 6b was established
by asymmetric hydrogenation of olefin 3 (Scheme 1).
Addition of excess 2-nitropropane to acrolein formed crystal-
† Process Research and Development, P.O. Box 4000, Princeton, New
Jersey 08543.
(2) Delaney, N. G.; Barrish, J. C.; Neubeck, R.; Natarajan, S.; Cohen,
M.; Rovnyak, G. C.; Huber, G.; Murugesan, N.; Girotra, R.; Sieber-
McMaster, E.; Robl, J. A.; Asaad, M. M.; Cheung, H. S.; Bird, J. E.;
Waldron, T.; Petrillo, E. W. Bio. Med. Chem. Lett. 1994, 4, 1783.
(3) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982,
47, 104.
(4) (a) Rosini, G.; Marotta, E.; Ballini, R.; Petrini, M. Synthesis 1986,
237. (b) Shechter, H.; Ley, D. E.; Zeldin, L. J. Am. Chem. Soc. 1952, 74,
3664.
‡ Process Research and Development, 1 Squibb Drive, New Brunswick,
New Jersey 08903.
§ Solid State Chemistry.
(1) Robl, J. A.; Sulsky, R.; Sieber-McMaster, E.; Ryono, D. E.; Cimarusti,
M. P.; Simpkins, L. M.; Karanewski, D. S.; Chao, S.; Asaad, M. M.;
Seymour, A. A.; Fox, M.; Smith, P. L.; Trippodo, N. C. J. Med. Chem.
1999, 42, 305 and references therein.
10.1021/ol0352308 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003

line alcohol 1 (70% yield)4 via conjugate addition followed
by a Henry reaction.
tions (Pt, Pd, or Rh catalysts) resulted in partial hydrogenoly-
sis of the Cbz moiety as well as saturation of the phenyl
ring in the protecting group. On the other hand, reduction
using Zn in methanolic HCl smoothly provided amine 4b.8
N-Alkylation of this compound with tert-butyl bromoacetate
furnished amino diester 5a (90% yield), which was selec-
tively saponified (LiOH, aq THF) to 5b (98% yield) with
no detectable racemization at the stereogenic center. Lac-
tamization of the amino acid was effected using EDC in the
presence of HOBT (DIPEA, CH3CN), providing the pro-
tected azepinone 6a (90% yield). Under these conditions,
epimerization was less than 2% as determined by chiral
HPLC. In the absence of HOBT, epimerization increased to
4%. Removal of the Cbz protecting group [H2, Pd(OH)2,
MeOH] was facile and gave amine 6b in 92% yield and 97%
ee. The optical purity of this material was further enhanced
by crystallization of the corresponding MSA salt 6c followed
by regeneration of the free base with NaOH (92% yield,
99.9% ee).
Scheme 1. Synthesis of R-Aminoazepinone 6b via
Enantioselective Reduction of Nitroenamide 3a
While this eight-step synthesis of R-aminoazepinone 6b
was reasonably efficient, it proved to be difficult to maintain
a reasonable substrate/catalyst ratio as the asymmetric
hydrogenation of 3 was scaled up. The DuPHOS catalyst
proved to be sensitive to the presence of impurities carried
over from the Wadsworth-Emmons reaction used to prepare
the hydrogenation substrate. Multiple charges of catalyst were
required, especially on >100 g inputs of olefin, to drive the
hydrogenation to completion. Passing the olefin through a
silica gel pad prior to hydrogenation was helpful but did not
provide a complete remedy. This issue, as well as concerns
around the toxicity of 2-nitropropane and the introduction
of the azepinone nitrogen in the incorrect oxidation state,
made this path unattractive when envisioning a multikilogram
scale synthesis.
a Reaction conditions: (a) Acrolein, Et3N. (b) DBU, CH2Cl2. (c)
[(COD)Rh-(S,S)-Et-DUPHOS]OTf, H2, MeOH, 40 psi. (d) Zn, HCl.
(e) BrCH2CO2-t-Bu, DIPEA, CH3CN. (f) LiOH (aq), THF. (g) EDC,
HOBT, DIPEA, CH2Cl2. (h) H2, Pd(OH)2, MeOH; MSA.
As a result, we developed an alternative synthesis of 6b
involving a conceptually different approach (Scheme 2) in
which enyne 12, constructed via Heck-Sonogashira-type
coupling9 of alkyne 8 with vinyl bromide 11, was converted
to racemic aminoazepinone 15b. An efficient crystallization-
driven dynamic resolution was then developed for conversion
This product, which was considerably easier to isolate and
handle than the initially formed Michael adduct and readily
amenable to base-catalyzed retro-Henry reaction, was con-
densed (DBU, CH2Cl2) with commercially available phos-
phonate 2 to produce 3 (90% yield, 92% (Z)-selectivity).5
The assignment of (Z)-geometry to the predominant isomer
was based on literature precedent and later confirmed by
single-crystal X-ray analysis.6a Enantioselective hydrogena-
tion of the mixture of olefins [(COD)Rh-S,S-EtDuPHOS]-
OTf7 (MeOH, 40 psi) provided 4a (90% yield, 99% ee). As
expected with this catalyst system,7a the presence of the
corresponding (E)-isomer (8%) did not adversely affect the
enantioselectivity of hydrogenation.
(6) (a) Crystallographic Data for 3: C17H22O6N2; colorless rods from
neat oil; cell parameters (T ) 22 °C) a ) 16.539(2) Å, b ) 6.287(1) Å, c
) 17.498(2) Å, â ) 100.69(1)°, V ) 787.9(8) Å3; space group P21/n, Z )
4; R ) 0.062, Rw ) 0.081 for refinement based on 2059 observed [I J
3σ(I)] reflections. (b) For 18: C21H28N2O5S; colorless prisms from CH2-
Cl2/hexanes; cell parameters (T ) -31 °C) a ) 12.542(1) Å, b ) 15.434(1)
Å, c ) 11.167(1) Å, V ) 2161.5(5) Å3; space group P212121, Z ) 4; R )
0.061, Rw ) 0.086 for refinement based on 2203 observed [I J 3σ(I)]
reflections. Coordinates from the X-ray determinations have been deposited
in the Cambridge Crystallographic Database and can be obtained upon
request to the Director, Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB2 1EZ, UK.
(7) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 101125. (b) Stammers, T. A.; Burk, M. J.
Tetrahedron Lett. 1999, 40, 3325. (c) Xiao, D.; Zhang, Z.; Zhang, X. Org.
Lett. 1999, 1, 1679. (d) Zhou, Y. G.; Tang, W.; Wang, W. B.; Li, W.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952. (e) Reetz, M. T.; Mehler,
G.; Meiswinkel, A.; Sell, T. Tetrahedron Lett. 2002, 43, 7941.
(8) (a) Hoover, F. W.; Hass, H. B. J. Org. Chem. 1947, 12, 506. (b)
Bryce, M. R.; Gardiner, J. M.; Hursthouse, M. B.; Short, R. L. Tetrahedron
Lett. 1987, 28, 577. (c) Adams, J. P.; Box, D. S. J. Chem. Soc., Perkin.
Trans. 1 1999, 749.
Initial efforts to reduce the nitro group in 4a to the
corresponding amine under catalytic hydrogenation condi-
(5) (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53. (b)
Kazmaier, U. Tetrahedron Lett. 1996, 37, 5351. (c) Treatment of 1 with
NaBH4 resulted in retro-Henry reaction and produced the corresponding
alcohol in high yield. Similarly, treatment of 1 with the enolate of tert-
butyl dichloroacetate provided the corresponding glycidic ester. We are
currently investigating the scope and applications of this process.
3156
Org. Lett., Vol. 5, No. 17, 2003

colored product was produced in low yield. We found that
a stoichiometric amount of NBS in the bromination and
catalytic Et3N for the isomerization produced much cleaner
product in acceptable yield. The (Z)-olefin geometry was
based on literature precedents for similar compounds.10
Cross-coupling9 of 11 with alkyne 8 [0.002 equiv of Pd-
(Ph3P)4, 0.02 equiv of CuI, Et3N) furnished enyne 12 in 90%
yield, which was purified by crystallization of the corre-
sponding MSA salt 12a. The geometry of the olefin was
preserved during the coupling and purification operations.9
Saturation of 12 via catalytic hydrogenation was initially
problematic due to competing hydrogenolysis of the glycine
subunit (to produce 13b) as well as general catalyst poison-
ing.11 Employment of the MSA salt 12a effectively neutral-
ized the issue of catalyst poisoning; however, the hydro-
genolysis side reaction remained significant (10-30%) when
using Rh-Al2O3 or Pt-C catalysts. After considerable
experimentation, we found that reduction of 12a over 5%
Rh-C at 0 °C effectively minimized hydrogenolysis to ∼2%.
Crystallization of the resulting salt 13c efficiently purged
low levels of 13b. Saponification of this material (2.1 equiv
of LiOH, aq THF) formed the amino acid, which was isolated
as the hydrochloride salt 14 and then cyclized (EDC, HOBT,
DIPEA) to azepinone 15a. Selective removal of the Boc
protecting group in the presence of the tert-butyl ester was
unsuccessful using formic acid, TFA, or HCl under a variety
of conditions.12 However, reaction with MSA (aq EtOH)
produced racemic R-aminoazepinone 15b with high selectiv-
ity in 75% overall yield from 13c.
Scheme 2. Synthesis of Racemic R-Aminoazepinone 15b via
Enyne 12 and Its Dynamic Resolution to 6ba
Dynamic resolution comprises the preferential crystalliza-
tion of an enantiomer (or diastereomeric salt) with concomi-
tant racemization of the undesired enantiomer in solution,
and, in principle, can reach 100% efficiency.13 Armstrong13e
and Wetter13f have reported dynamic resolutions of phenyl-
ring fused R-aminoazepinones. In these examples, racem-
ization of the unwanted enantiomer was brought about via
enolization of the azomethine formed with 2-hydroxy-5-nitro
benzaldehyde (HNB) used in catalytic amounts.
a Reaction conditions: (a) BrCH2CO2-t-Bu, THF. (b) MsCl, Et3N,
CH2Cl2. (c) NBS, Et3N. (d) Pd(PPh3)4, CuI, Et3N. (e) MSA. (f)
H2, 5% Rh/C, MeOH. (g) LiOH, THF (aq). (h) HCl (aq). (i) EDC,
HOBT, DIPEA. (j) MSA, EtOH (aq); NaOH (aq), EtOAc. (k) (R)-
CSA, 2-hydrozy-5-nitro-benzaldehyde, toluene, 70 °C; NaOH (aq),
EtOAc.
Following these leads, a dynamic resolution of 15b was
developed by systematically screening the relative solubilities
of diastereomeric salts derived from a variety of acids.14,15
of 15b to (S)-R-aminoazepinone 6b. In this approach, the
azepinone ring nitrogen is introduced at the correct oxidation
state.
Thus, N-alkylation of commercially available 1,1-dimeth-
ylpropargylamine 7 with tert-butyl bromoacetate formed ester
8 in 93% yield. Vinyl bromide 11 was prepared from N-(t-
butoxycarbonyl)-L-serine methyl ester 9 by dehydration
(MsCl, Et3N, CH2Cl2) followed by bromination and isomer-
ization (NBS, Et3N).9f,10 Under the literature9f conditions,
which employed excess reagents for similar conversions,
(10) (a) Yamada, M.; Nakao, K.; Fukui, T.; Nunami, K. Tetrahedron
1996, 52, 5751. (b) Das, J.; Reid, J. A.; Kronenthal, D. R.; Singh, J.;
Pansegrau, P. D.; Mueller, R. H. Tetrahedron Lett. 1992, 33, 7835.
(11) Misiti, D.; Zappia, G.; Monache, G. D. Synthesis 1999, 873 and
references therein.
(12) Gibson, F. S.; Bergmeier, S. C.; Rappoport, H. J. Org. Chem. 1994,
59, 3216 and references therein.
(13) (a) Dinh, P. M.; Williams, J. M. J. Tetrahedron Lett. 1999, 40, 749.
(b) Shieh, W. C.; Carlson, J. A.; Zaunius, G. M. J. Org. Chem. 1997, 62,
8271. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 447. (d) Stock,
H. T.; Turner, N. J. Tetrahedron Lett. 1996, 37, 6575. (e) Armstrong, J.
D.; Eng, K. K.; Keller, J. L.; Purick, R. M.; Hartner, F. W.; Choi, W. B.;
Askin, D.; Volante, R. P. Tetrahedron Lett. 1994, 35, 3239. (f) Boyer, S.
K.; Pfund, R. A.; Portmann, R. E.; Sedelmeier, G. H.; Wetter, H. F. HelV.
Chim. Acta 1988, 71, 337. (g) Reider, P. J.; Davis, P.; Hughes, D. L.;
Grabowski, E. J. J. J. Org. Chem. 1987, 52, 955. (h) Boyle, W. J.; Sifniades,
S.; Peppen, J. F. V. J. Org. Chem. 1979, 44, 4841. (i) Konoike, T.;
Matsumura, K.; Yorifugi, T.; Shinomoto, S.; Ide, Y.; Ohya, T. J. Org. Chem.
2002, 67, 7741.
(9) (a) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551. (b) Miller,
M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582. (c) Nussbaumer, P.;
Leitner; I.; Mraz; K.; Stutz, A. J. Med. Chem. 1995, 38, 1831. (d)
Mladenova, M.; Alami, M.; Linstrumelle, G. Synth. Comm. 1995, 25, 1401.
(e) Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
(f) Miossec, B.; Danion-Bougot, R.; Danion, D. Synthesis 1994, 1171. (g)
Wender, P. A.; Tebbe, M. J. Tetrahedron 1994, 50, 1419. (h) Cassar, L. J.
Organomet. Chem. 1975, 93, 253. (j) Dieck, H. A.; Heck, F. R. J.
Organomet. Chem. 1975, 93, 259. (j) Sonogashira, K.; Tohda, Y.; Hagihara,
N. Tetrahedron Lett. 1975, 16, 4467. (k) Stephens, R. D.; Castro, C. E. J.
Org. Chem. 1963, 28, 3313. (l) Liu, C. Y.; Luh, T. Y. Org. Lett. 2002, 4,
4305.
(14) (a) Classical resolution14b of racemic 15b with D-tartaric acid and
(R)-CSA gave the corresponding salts in 30% (99% ee) and 44% (99.8%
ee) yields (50% theoretical maximum), respectively. (b) Brenner, M.;
Rickenbacher, H. R. HelV. Chim. Acta 1958, 21, 181.
Org. Lett., Vol. 5, No. 17, 2003
3157

coupling reactions at ambient temperature, >5% acetyl
transfer from the sulfur to the amine nitrogen was observed.
This side reaction, as well as the epimerization, was almost
completely suppressed when couplings were performed
below -20 °C. Selective deprotection of the tert-butyl ester
in 17 required careful control of conditions due to the labile
thioester and the instability of the product 18 to strongly
acidic conditions.17 Reaction of 17 with TFA (15 mol equiv,
CH2Cl2, 25 °C, 5 h) followed by workup with pH 5 buffer
(NaH2PO4, aq NaOH) resulted in formation of crystalline
acid 18 (93% yield). The absolute configurations of the two
chiral centers in 18 were confirmed by single-crystal X-ray
analysis.6b Deprotection of 18 required rigorous attention to
detail in order to minimize formation of disulfide 19, which
was very prone to epimerization under the basic reaction
conditions.18 Control experiments in similar systems estab-
lished that 19 is a significant source of diastereomer found
in BMS-189921 resulting from cleavage of the epimerized
disulfide by free thiol in solution. After experimenting with
different additives capable of acting as reducing agents, we
found that conducting the saponification in the presence of
5 mol % dithiothreitol19 with rigorous exclusion of oxygen
minimized disulfide formation and the resulting epimeriza-
tion. Ultimately, deacetylation of 18 (aq NaOH, DTT,
deoxygenated MeOH) provided BMS-189921 in 95% yield.20
Material from this process was typically >99.5% pure by
HPLC. To fuel advanced toxicology and clinical studies, the
synthesis of BMS-189921 proceeding through the dynamic
resolution of 15b was chosen for further development. Details
of this work will be reported soon.21
Scheme 3. Conversion of R-Amino Azepinone 6b to
BMS-189921a
a Reaction conditions: (a) EDC, CH2Cl2, -20 to 0 °C. (b) TFA,
CH2Cl2, 25 °C, 5 h; NaH2PO4, NaOH (aq). NaOH (aq), DTT,
CH3OH.
We found that employment of 0.95 equiv of (R)-CSA
(Scheme 2) in the presence of HNB in toluene solvent gave
the (R)-CSA salt of 6b in 79% yield (99.8% ee) on a
multikilogram scale. Careful removal of the HNB from the
resolved salt prior to neutralization to the free base was
essential in order to avoid erosion of the enantiopurity
resulting from racemization of the corresponding Schiff base.
The coupling of R-aminoazepinone 6b with (S)-2-(acetyl-
thio)benzenepropanoic acid 1616 (EDC, CH2Cl2, -30 to 0
°C) furnished amide 17 (96% yield, Scheme 3). Up to ∼1%
epimerization of the stereocenter adjacent to the thioester
was observed during this reaction. In addition, during
Acknowledgment. We thank Analytical R & D for their
valuable support and the Science Information Department,
Bristol-Myers Squibb, for helpful literature searches during
the course of this work.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) We also investigated the suitability of other esters in the dynamic
resolution. For example, it was not possible to resolve the corresponding
methyl ester. This work will be published as part of a full paper.
(16) (a) Commercially available from Davos Chemical Corporation. (b)
Allegrini, P.; Soriato, G. Patent WO 9942438, Jan. 26, 1999; Chem. Abstr.
1999, 131, 157650.
OL0352308
(18) Marked sensitivity of chiral R-mercaptoacyl amides to epimerization
during deacylation procedures has been reported. Strijtveen, B.; Kellog, R.
M. J. Org. Chem. 1986, 51, 3664.
(19) (a) Cleland, W. W. Biochemistry 1964, 3, 480. (b). Hovinen, J.;
Guzaev, A.; Azhayev, A.; Lonnberg, H. Tetrahedron Lett. 1993, 34, 8169.
(20) Kronenthal, D. R.; Deshpande, R. P. U.S. Patent 6444810, Sept. 3,
2002.
(17) On extended exposure to TFA, azepinone 18 was converted to
azalactone (i).
(21) All new compounds were characterized by spectroscopic methods
and gave satisfactory elemental analyses.
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Org. Lett., Vol. 5, No. 17, 2003