Design and synthesis of diversely substituted azacyclic inhibitors of endothelin converting enzyme

Article abstract of DOI:10.1021/jo052649y

A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid, 6-oxo-L-pipecolic acid, and their enantiomers. The objective was to study the effect of constraining acyclic inhibitors of endothelin converting enzyme on inhibitory activit

Full text of DOI:10.1021/jo052649y

Design and Synthesis of Diversely Substituted Azacyclic Inhibitors
of Endothelin Converting Enzyme
Stephen Hanessian,* Ce´cile Gauchet, Guillaume Charron, Julien Marin, and
Philippe Nakache
Department of Chemistry, UniVersite´ de Montre´al, C. P. 6128, Succ. Centre-Ville,
Montre´al, P. Q., Canada H3C 3J7
stephen.hanessian@umontreal.ca
ReceiVed December 24, 2005
A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid, 6-oxo-L-pipecolic
acid, and their enantiomers. The objective was to study the effect of constraining acyclic inhibitors of
endothelin converting enzyme on inhibitory activity. Potential pharmacophoric tethers were introduced
by stereocontrolled reactions to give highly substituted pyrrolidine- and piperidine-R-phosphonic acids.
Weak inhibitory activity was observed for one diastereomer in each series having the same relative
orientation of substituents.
Introduction
conjunction with other enzymatic events, notably the phospho-
rylation of the light chain of myosin, leads to the contraction
of blood vessels.
The role of endogenous vasoactive peptides in physiologically
important processes has been known for some time.1 Among
these peptides is a family of potent vasoconstrictors acting on
smooth muscle tissues and the central nervous system, known
as the endothelins.2 They consist of three isoforms in humans
that are encoded by different genes but differ in only a few
amino acids.3 A series of biochemical conversions mediated by
endopeptidases converts the initially formed pure proendothelin
into big ET-1. Subsequently, endothelin-converting enzyme
(ECE) cleaves big ET-1 at the Trp-Val site to produce the 21-
amino acid peptide ET-1, which is the most powerful local
vasoconstricting peptide known.4 ET-1 binds to its receptor on
a G-coupled protein resulting in the activation of phospholipase
C and stimulation of protein kinase C. As a consequence, the
concentration of intracellular Ca2+ is increased, which in
Thus, in addition to other targets such as ACE5 and renin,6
the inhibition of ECE has been considered as a relevant strategy
to control hypertension.7 The physiopathologic implications of
ECE cover a wide range of serious disorders beyond hyperten-
sion, such as asthma, renal failure, cancer, and atherosclerosis
to mention a few.8 Another endogenous endopeptidase, NEP
(neutral endopeptidase), is responsible for the degradation of
natural natriuretic peptide, which is a potent vasodilator. ECE
and NEP are zinc metalloproteases that share a substantial degree
of homology.9 Thus, the search for an effective inhibitor of ECE
has been the focus of intensive efforts.7b,10
(5) (a) Ryan, M. J.; Sigmund, C. D. Circulation Res. 2004, 94, 1-3. (b)
White, M. C. Pharmacotherapy 1998, 18, 588-599.
(1) (a) Mione, M. C.; Ralevic, V.; Burnstock, G. Pharmacol. Ther. 1990,
46, 429-468. (b) Said, S. I. Hypertension 1983, 5, I17-26.
(2) (a) Turner, A. J.; Murphy, L. J. Biochem. Pharmacol. 1996, 51, 91-
102. (b) Vane, J.; Masaki, T.; Vanhoutte, P. M.; Botting, R. J. CardioVasc.
Pharmacol. 1995, 26, S-521. (c) Rubanyi, G. M.; Polokoff, M. A.
Pharmacol. ReV. 1994, 46, 325-415. (d) Turner, A. J. Neuropeptides
Process. Metabol. 1993, 697-701. (e) Opgenorth, T. J.; Wu-Wong, J. R.;
Shiosaki, K. FASEB J. 1992, 6, 2653-2659.
(3) Inoue, A.; Yanagisawa, M.; Kimura, S.; Kasuya, Y.; Miyauchi, T.;
Goto, K.; Masaki, T. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 2863-2867.
(4) Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Kobayashi,
M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T. Nature 1988, 332, 411-
415.
(6) (a) Stanton, A. Am. J. Cardio. Drugs 2003, 3, 389-394. (b) Rahuel,
J.; Rasetti, V.; Maibaum, J.; Ru¨eger, H.; Go¨schke, R.; Cohen, N.-C.; Stutz,
S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Gru¨tter, M. G. Chem. Biol. 2000,
7, 493-504.
(7) (a) Jeng, A. Y. Curr. Opin. InVest. Drugs 2003, 4, 1076-1081. (b)
Jeng, A. Y.; Mulder, P.; Kwan, A.-L.; Battistini, B. Can. J. Physiol.
Pharmacol. 2002, 80, 440-449. (c) Battistini, B.; Jeng, A. Y. Handbook
Exp. Pharmacol. 2001, 152, 155-208. (d) Haynes, W. G.; Webb, D. J. J.
Hypertens. 1998, 16, 1081-1098. (e) Vemulapalli, S.; Chintala, M.;
Stamford, A.; Watkins, R.; Chiu, P.; Sybertz, E.; Fawzi, A. B. CardioVasc.
Drug ReV. 1997, 15, 260-272. (f) Jeng, A. Y.; De Lombaert, S. Curr.
Pharmaceut. Design 1997, 3, 597-614. (g) Goto, K.; Hama, H.; Kasuya,
Y. Jpn. J. Pharmacol. 1996, 72, 261-290.
10.1021/jo052649y CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/09/2006
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J. Org. Chem. 2006, 71, 2760-2778

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
selective modes of binding.14 By choosing substituted prolines15
as the azacyclic core units, we wished to maintain the relative
positions of pharmacophores compared to the acyclic models 2
and 3. In the absence of crystallographic data on the 3-dimen-
sional structure of ECE, we deemed it necessary to address the
stereochemical issues related to the arrangement of the phar-
macophoric sites by making available a diVerse set of diaster-
eomeric compounds within each enantiomeric series, as shown
in the generic structure 4. Our choice of a phosphonic acid as
a potential zinc chelator was based on known precedents16 and
synthetic convenience adopting a disconnective analysis that
was amenable to functional and stereochemical diversity as
shown in Scheme 1.
For the series A analogues, stereocontrolled enolate alkylation
of an L-pyroglutamic acid17 ester would introduce the R2 group
at C4. Sequential introduction of requisite R1 and R2 groups
via conjugate addition to an R,â-unsaturated lactam derived from
pyroglutamic acid15,18 or 6-oxopipecolic acid,19 followed by
enolate alkylation,20 respectively, would give analogues in series
C and E. The phosphonic acid group in each series would be
introduced via the corresponding N-acyloxyiminium ions.21
Functional group adjustments and amide coupling would
ultimately produce the 4-substituted or 3,4-disubstituted
5-phosphono-L-prolylamides 4 and 4,5-disubstituted 6-phosphono-
D-pipecolic acid amides 5. An identical sequence starting with
D-pyroglutamic acid and 6-oxo-L-pipecolic acid would provide
a selection of compounds in the enantiomeric series. Our initial
studies focused on the elaboration of a strategy toward obtaining
4-alkyl-5-phosphono-L-proline esters as intermediates corre-
sponding to series A (Scheme 1), relying on an anticipated anti-
selectivity in the enolate alkylation. Since previous inhibitors
in the acyclic series such as 2 and 3 deployed a bulky aromatic
group as an R-alkyl appendage, we chose cinnamyl, isobutyl,
and N-(1,8-dicarboxynaphthalimido)ethyl groups as potential
mimics of the presumed hydrophobic P2′ pharmacophore. For
FIGURE 1. Examples of ECE inhibitors and projected constrained
analogues A and B.
The interaction of phosphoramidon 1 (Figure 1), a naturally
occurring L-rhammosyl phosphoramidite of Trp-Lys with NEP,
has identified specific binding domains in the S1, S1′, and S2′
sites.9 Phosphoramidon is also an inhibitor of ECE.11 Although
the ultimate aim is to develop a dual or triple inhibitor, capable
of inhibiting ECE, NEP, and ACE,12 we focused on gaining
insights into the functional and stereochemical requirements for
inhibitory activity of ECE. Our objective was to synthesize
azacyclic compounds related to the R-aminophosphonic acids
27b and 3.7b Since the 3-dimensional spatial disposition of the
various groups in these compounds is not known, we hoped
that the stereocontrolled synthesis of individual substituted
5-phosphonoproline amides13 with stereochemically fixed ap-
pendages on a rigid scaffold would provide insights into
SCHEME 1. Disconnective Strategy toward Diverse Substitution on L-Proline and L-Pipecolic Acid Scaffolds
J. Org. Chem, Vol. 71, No. 7, 2006 2761

Hanessian et al.
SCHEME 2a
series C, the eventual C3-substituent was kept constant as an
isobutyl group. The above protocol also allowed for the
introduction of other zinc-chelating groups such as a carboxylic
or hydroxamic acid at C5.22
Results and Discussion
Formation of the Li+ enolate from L-pyroglutamic acid methyl
ester 6 and treatment with allyl iodide afforded a 2:1 mixture
of the trans and cis C4 allyl derivatives 7a and 7b, respectively
(Scheme 2). Analogous treatment with cinnamyl bromide
afforded a modest trans-selectivity to give 8a and 8b in a 3.5:1
ratio. On the other hand, treatment of the enolate with the bulkier
1-naphthyl-2-propenyl bromide led to a preponderance of the
(8) ECE inhibitors have been shown to be beneficial for the treatment
of others diseases. (a) Heart failure: Wada, A.; Tsutamoto, T.; Ohnishi,
M.; Sawaki, M.; Fukai, D.; Maeda, Y.; Kinoshita, M. Circulation 1999,
99, 570-577. (b) Cerebral vasospasm: Matsumura, Y.; Ikegawa, R.; Suzuki,
Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.;
Watanabe, M.; Morimoto, S. Life Sci. 1991, 49, 841-848. (c) Renal
dysfunction: Vemulapalli, S.; Chiu, P. J.; Chintala, M.; Bernardino, V.
Pharmacology 1993, 47, 188-193. For endothelin receptor antagonists and
therapeutic applications, see: (a) Dasgupta, F.; Mukherjee, A. K.; Gan-
gadhar, N. Curr. Med. Chem. 2002, 9, 549-575. (b) Boss, C.; Bolli, M.;
Weller, T. Curr. Med. Chem. 2002, 9, 349-383.
(9) (a) Roques, B. P. Path. Biol. 1998, 46, 191-200. (b) Keller, P. M.;
Lee, C.-P.; Fenwick, A. E.; Atkinson, S. T.; Elliott, J. D.; DeWolf, W. E.
Jr. Biochem. Biophys. Res. Commun. 1996, 223, 372-378. (c) Roques, B.
P.; Noble, F.; Dauge´, V.; Fournie´-Zaluski, M.-C.; Beaumont, A. Pharmacol.
ReV. 1993, 45, 87-146.
(10) (a) Otter, W.; Kentsch, M. Curr. Opin. CardioVasc. Pulm. Ren.
InVest. Drugs 2000, 2, 316-329. (b) Doherty, A. M. Annu. Rep. Med. Chem.
1991, 26, 83-92.
a Reagents and conditions: (a) LiHMDS, RBr, THF, -78 °C, 30-57%;
(b) Super Hydride, THF, -78 °C; (c) Ac2O, Et3N, DMAP, DCM, rt; (d)
P(OMe)3, BF3‚OEt2, DCM, -78 °C to rt, 45-80%.
(11) (a) De Nanteuil, G.; Benoist, A.; Remond, G.; Descombes, J. J.;
Barou, V.; Verbeuren, T. J. Tetrahedron Lett. 1995, 36, 1435-8. (b) Fukami,
T.; Hayama, T.; Amano, Y.; Nakamura, Y.; Arai, Y.; Matsuyama, K.; Yano,
M.; Ishikawa, K. Bioorg. Med. Chem. Lett. 1994, 4, 1257-1262. (c) Roques,
B. P. Biochem. Soc. Trans. 1993, 21, 678-685. (d) McMahon, E. G.;
Palomo, M. A.; Moore, W. M.; McDonald, J. F.; Stern, M. K. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 703-707. (e) Fukuroda, T.; Noguchi, K.;
Tsuchida, S.; Nishikibe, M.; Ikemoto, F.; Okada, K.; Yano, M. Biochem.
Biophys. Res. Commun. 1990, 172, 390-395. (f) Suda, H.; Aoyagi, T.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1973, 26, 621-623.
(12) Lo¨ffler, B.-M. Curr. Opin. CardioVasc. Pulm. Ren. InVest. Drugs
1999, 1, 352-364.
trans-isomer 9a (trans/cis ∼8:1). The above diastereomers were
easily separable by flash chromatography. Since our aim was
to produce a diverse set of diastereomers from a common
intermediate within the same enantiomeric series, we did not
attempt to optimize the ratios of products. Their ease of
separation by chromatography allowed us to prepare sufficient
quantities of each diastereomer to pursue the functionalization
of the resulting lactams at C5. Thus, reduction of the lactams
7a, 8a, and 9a with Super hydride,23 followed by acetylation
and treatment with trimethyl phosphite,24 gave three sets of
diastereomeric C5 dimethylphosphonates 11a/11b, 12a/12b, and
13a/13b in excellent overall yields. In each pair, the proportion
of C2/C5 cis-isomer was favored, ranging from 1.5 to 1.9:1 (as
determined by 1H NMR). Furthermore, the C5 epimeric dimethyl
phosphonates could be separated into individual enantiomerically
pure compounds. Their stereochemistry was determined by NOE
studies of the respective H2/H5 in cis-phosphonates and by
single-crystal structure determination of the allyl analogues 11a
and 11b (Scheme 2).
(13) Diel, P. J.; Maier, L. Phosphorus Sulfur 1984, 20, 313-321.
(14) (a) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000,
43, 305-341. (b) Babine, R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359-
1472.
(15) For related examples, see: Hanessian, S.; MacKay, B. D.; Moitessier,
N. J. Med. Chem. 2001, 44, 3074-3082.
(16) Shetty, S. S.; Savage, P.; Delgrande, D.; De Lombaert, S.; Jeng, A.
Y. J. Cardio. Pharm. 1998, 31, S68-S70.
(17) Na´jera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-
2303.
(18) (a) Qiao, L.; Zhao, L.-Y.; Rong, S.-B.; Wu, X.-W.; Wang, S.; Fujii,
T.; Kazanietz, M. G.; Rauser, L.; Savage, J.; Roth, B. L.; Flippen-Anderson,
J.; Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2001, 11, 955-959. (b)
Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213-21.
(c) Hanessian, S.; Ratovelomanana, V. Synlett 1990, 9, 501-503.
(19) (a) Hanessian, S.; van Otterlo, W. A. L.; Nilsson, I.; Bauer, U.
Tetrahedron Lett. 2002, 43, 1995-1998. (b) Hanessian, S.; Seid, M.;
Nilsson, I. Tetrahedron Lett. 2002, 43, 1991-1994. (c) Muller, M.;
Schoenfelder A.; Didier, B.; Mann, A.; Wermuth, C.-G. Chem. Commun.
1999, 683-684.
(20) (a) Beard, M. J.; Bailey, J. H.; Cherry, D. T.; Moloney, M. G.;
Shim, S. B.; Statham, K. A.; Bamford, M. J.; Lamont, R. B. Tetrahedron
1996, 52, 3719-40. (b) Ezquerra, J.; Pedregal, C.; Rubio, A.; Yruretagoyena,
B.; Escribano, A.; Sa´nchez-Fernando, F. Tetrahedron 1993, 49, 8665-8678.
(21) (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628. (b) Speckamp, W.
N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
It is of interest that the orientation of the N-Boc and ester
carbonyl groups in the crystalline solid state were different in
the trans- and cis-phosphonates 11a and 11b, respectively. The
minimization of A1,2 strain between the ester and N-Boc
groups,25 coupled with the trans- or cis-disposition of the
dimethylphosphonate, result in significant changes compared
(23) (a) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60,
5011-15. (b) Miller, S. A.; Chamberlin, R. A. J. Am. Chem. Soc. 1990,
112, 2, 8100-8112. (c) Fisher, M. J.; Overman, L. E. J. Org. Chem. 1990,
55, 1447-1459. (d) Herbert, C. B.; Krishnamurthy, S. J. Am. Chem. Soc.
1973, 95, 1669-71.
(24) Shono, T.; Matsumura, Y.; Tsubata, K. Tetrahedron Lett. 1981, 22,
3249-3252.
(25) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett. 2002, 43,
1991-1994.
(22) (a) Moradei, O.; Maroun, C. R.; Paquin, I.; Vaisburg, A. Curr. Med.
Chem. Anti-Cancer Agents 2005, 5, 529-560. (b) Muri, E. M. F.; Nieto,
M. J.; Sindelar, R. D.; Williamson, J. S. Curr. Med. Chem. 2002, 9, 1631-
1653.
2762 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
SCHEME 3a
SCHEME 4a
a Reagents and conditions: (a) H2 (60 psi), Pd(OH)2/C, EtOH, rt; (b)
Super Hydride, THF, -78 °C; (c) Ac2O, Et3N, DMAP, DCM, rt; (d)
P(OMe)3, BF3‚OEt2, DCM, -78 °C to rt, 69%; (e) LiOH‚H2O, THF/H2O/
MeOH (5:4:1), 0 °C to rt; (f) i-Pr2NEt, EDCI, HOBt, H-Phe-Ot-Bu‚HCl or
H-Trp-OMe‚HCl, DCM, rt; (g) HCl (gas), dioxane, reflux or LiOH‚H2O,
THF/H2O/MeOH (5:4:1), H-Trp-OMe‚HCl; (h) TMSBr, DCM then 1 equiv
of NaOH 0.05M, 40-70%; (i) (i) BH3‚THF, THF, 0 °C, (ii) NaOH, H2O2
30% v/v, rt; (j) TsCl, Et3N, DMAP, DCM, rt; (k) N-(1,8-dicarboxynaph-
thalimido) Na+ salt, DMF, rt, 30%.
orientation due to A1,2 strain.28 However, in the 11-13 series,
the sterically favored trans-approach of trimethyl phosphite is
counterbalanced by the presence of the C4 R-oriented alkyl
group. The slight variations in favor of the C2/C5 cis-phospho-
nates with increasing bulk of the C4 alkyl group in going from
allyl to cinnamyl or its naphthyl counterpart could be due to a
more pronounced vicinal steric effect.
a Reagents and conditions: (a) (i) ozone, DCM/MeOH (1:1), -78 °C;
(ii) Me2S, -78 to 0 °C; (b) NaBH4, MeOH, 0 °C to rt, 79-81%; (c) TsCl,
Et3N, DMAP, DCM, rt; (d) N-(1,8-dicarboxynaphthalimido) Na+ salt, DMF,
33-42%; (e) LiOH‚H2O, THF/H2O/MeOH (5:4:1), 0 °C to rt; (f) i-Pr2NEt,
EDCI, HOBt, H-Xaa-OR2‚HCl, DCM, 33-79%; (g) HCl (gas), dioxane,
reflux; (h) LiOH‚H2O, THF/H2O/MeOH (5:4:1), 0 °C to rt; (i) TMSBr,
DCM then 1 equiv of NaOH 0.05 M, 38-70%.
It was of interest to incorporate the imidoyl group, like in
structure 3, in our constrained azacyclic scaffold. The most
practical approach was to utilize the diastereomeric unsaturated
alkyl appendages at C4 as precursors. Thus, ozonolysis of 11a
and 11b, respectively, followed by reduction of the resulting
aldehydes with NaBH4, afforded the corresponding 1-hydroxyl-
ethyl derivatives 14a and 14b, respectively (Scheme 3). At-
tempts to introduce the naphthalimido group by a Mitsunobu
reaction29 of 14b were not successful, affording starting alcohol
even upon heating to 60 °C. Therefore, a two-step procedure
was adopted which consisted of displacing the corresponding
tosylates with the Na+ salt of the imide to afford 15a and 15b
(Scheme 3). We then proceeded with their elaboration into the
intended target structures in this Serie A (Scheme 1). Hydrolysis
to N-Boc L-proline.26 The deviation from planarity is more
pronounced in 11a and 11b (rms N, C2, C3, C5 ) 0.0312 and
0.0505 Å, respectively), compared to N-Boc proline (rms C2,
N, C5, C4 ) 0.018 Å). In both diastereomers 11a and 11b, C4
is puckered out of plane compared to C3 in N-Boc proline. Two
rotamers can be observed by 1H and 13C NMR for several peaks,
with a characteristic downfield shift for C5 in the trans-analogue
11a (C5 ) 58.9 ppm, compared to C5 ) 53.2 ppm for 11b).
The moderately higher proportion of the C2/C5 cis-phospho-
nates in the three series of products 11-13 was of interest. In
the absence of a C4 substituent, the attack of nucleophiles on
the corresponding N-acyloxyiminium ions is expected to be
mostly trans to the ester group27 by virtue of its pseudoaxial
(26) See the Supporting Information.
(28) Overman, L. E.; Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc.
1983, 105, 5373-5379. For a review, see: Johnson, F. Chem. ReV. 1968,
68, 375-413.
(29) (a) Hughes, D. L. Org. React. 1992, 42, 335-656. (b) Mitsunobu,
O. Synthesis 1981, 1981, 1-28.
(27) For nucleophilic additions on iminium ions, see: (a) Hanessian,
S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L. J.
Am. Chem. Soc. 2002, 124, 13342-13343. (b) Collado, I.; Ezquerra, J.;
Pedregal, C. J. Org. Chem. 1995, 60, 5011-5015.
J. Org. Chem, Vol. 71, No. 7, 2006 2763

Hanessian et al.
SCHEME 5a
SCHEME 6. Possible Mechanistic Pathways for Ester
Hydrolysisa
a C3 substituent omitted for clarity.
a Reagents and conditions: (a) Super Hydride, THF, -78 °C; (b) Ac2O,
Et3N, DMAP, DCM, rt; (c) P(OMe)3, BF3‚OEt2, DCM, -78 °C to rt, 68%;
(d) (i) ozone, DCM/MeOH (1:1), -78 °C, (ii) Me2S, -78 to 0 °C; (e)
NaBH4, MeOH, 0 °C to rt, 84%; (f) TsCl, Et3N, DMAP, DCM, rt; (g)
N-(1,8-dicarboxynaphthalimido) Na+ salt, DMF, rt, 42%; (h) LiOH‚H2O,
THF/H2O/MeOH (5:4:1), rt; (i) i-Pr2NEt, EDCI, HOBt, H-Phe-Ot-Bu‚HCl,
DCM, rt, 65%; (j) HCl (gas), dioxane, reflux; (k) TMSBr, DCM then 1
equiv of NaOH 0.05 M, 38%.
trimethyl phosphite gave the C5-trans phosphonate 28 as the
predominant product, although it could not be separated from
a minor quantity of its C5-epimer (Scheme 5). Oxidative
cleavage of the allyl group and installation of the 1,8-
dicarboxynaphthalimido group as described above afforded 29.
Cleavage of the methyl ester, peptide coupling to 30, and
deprotection gave enantiopure 31. The same transformations
were effected starting from D-pyroglutamic acid to afford 32
(series B).
of the methyl ester 15a with LiOH in a mixture of aqueous
MeOH and THF required heating at 60 °C for 2 days. The
resulting acid was coupled with L-PheO-t-Bu in the presence
of HOBt and Hunig’s base to give the corresponding tert-butyl
ester 16a. Similar treatment of 15b on the other hand, resulted
in a surprisingly facile hydrolysis, requiring LiOH at room
temperature for only 2 h. Coupling with L-PheO-t-Bu gave 16b.
The Trp analogue 17a and 17b corresponding to the C2/C5 trans-
and cis-isomer, respectively, were prepared as described for 16.
The L-homoPhe analogue 18 corresponding to the C2/C5 trans-
isomer was also prepared. Hydrolysis of the tert-butyl esters
and the N-Boc group in 16a, 16b, 17a, 17b, and 18 with HCl
gas in dioxane, followed by cleavage of the phosphonate with
TMSBr,30 gave, after preparative HPLC, the sodium salts of
the first intended prototypes 19a, 19b, 20a, 20b, and 21,
respectively. Compounds in the diastereomeric series were
prepared by the same transformations starting from D-pyro-
glutamic acid to give 22a and 22b (series B).
The same protocol was used to transform the 3-[1-(naphthyl)-
propenyl] analogues obtained from 13a and 13b and the
4-(isobutyl) counterparts 23a, 23b into their PheOH amides 24a,
24b, 25a, and 25b, respectively (Scheme 4). The homologated
analogue 27 was prepared by hydroboration of the allyl
intermediate 11b, followed by tosylation of the resulting alcohol,
and introduction of the naphthalimide group to give 26.
Hydrolysis of the methyl ester, peptide coupling, and then
cleavage of the phosphonate esters afforded 27.
Before proceeding to the synthesis of analogues in series C,
we studied the course of basic hydrolysis of trans- and cis-
phosphonates esters 11a and 11b, respectively. As observed also
for the C4 naphthalimido series 15a and 15b, the cis-isomer
11b was cleaved to the acid with 2 equiv of LiOH/THF-H2O
within 2 h at room temperature. The trans-isomer 11a required
60 °C for 2 days. The reaction course was followed by 31P NMR
for both compounds.31 Thus, for 11a the signal corresponding
to the starting ester at 26.6 ppm diminished gradually in favor
of a new peak at 27.9 ppm corresponding to the carboxylic acid,
whereas for 11b, two 31P peaks, corresponding to rotamers of
the carboxylic acid, appear at 28.0 and 27.7 ppm within 5 min
at room temperature and continued to grow until the starting
ester was no longer observed after 1 h. It is possible that the
hydrolysis of the cis-ester is accelerated due to anchimeric
assistance from the favorably disposed phosphonate 11b.
Alternatively, Li+-chelated tetrahedral intermediates may be
favored in the cis-ester (Scheme 6). We are not aware of sim-
ilar acceleration effects in the hydrolysis of mixed carboxylic
phosphonic esters in which proximity may play a role. The
distance of the PdO oxygen atom from the carbonyl of the ester
in the X-ray crystal structure of 11b is 3.99 Å. However, it
is speculative to extrapolate such a proximity effect in solu-
tion.
We then turned our attention to the preparation of 3,4-
disubstituted proline 5-phosphonic acids (series C and D). Since
this involved the elaboration of three new vicinal stereo-
genic centers starting with D- and L-pyroglutamic acids, we
Access to different diastereomers in series A was possible
from the minor C2/C4-cis allyl isomer 7b, which resulted from
the enolate alkylation reaction shown in Scheme 2. Thus,
formation of the iminium ion from 7b and treatment with
(31) For related 31P NMR values, see: (a) Davis, F. A.; Wu, Y.; Xu, H.;
Zhang, J. Org. Lett. 2004, 6, 4523-4525. (b) Pietri, S.; Miollan, M.; Martel,
S.; Le Moigne, F.; Blaive, B.; Culcasi, M. J. Biol. Chem. 2000, 275, 19505-
19512.
(30) (a) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M.-C.
Tetrahedron Lett. 1977, 18, 155-158. (b) Rabinowitz, R. J. Org. Chem.
1963, 28, 2975-2978.
2764 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
SCHEME 7a
SCHEME 8a
a Reagents and conditions: (a) i-BuMgBr, CuBr‚Me2S, Et2O, -40 °C,
85%.
allyl iodide gave the trans/trans-adduct 35a and its C4 epimer
35b in a 4:1 ratio, respectively. Desilylation of the major isomer
35a with fluoride ion, followed by a Jones oxidation33 and
esterification, gave the corresponding ester 36 in good yield.
Formation of the N-acyliminium ion and treatment with tri-
methyl phosphite gave the trans/trans/trans-product 37a and
the C5 epimer 37b in a 1:2 ratio, respectively. Oxidative cleavage
of the allyl group in 37b, reduction to the primary alcohol and
displacement of the corresponding tosylate with the Na+ salt
of the 1,8-dicarboxynaphthalimido group, afforded the adduct
38. Hydrolysis of the ester, followed by coupling with L-Phe-
(O-t-Bu), L-homoPhe(OMe), or L-Trp(O-t-Bu), and deprotection
as described previously, gave the intended phosphonic acids
42, 43, and 44, respectively. The analogues 45, 46, and 47 were
obtained starting from L-pyroglutamic acid (series C).
The elaboration of the pipecolic acid in series E (Scheme 1)
presented challenges regarding the stereocontrolled introduction
of the requisite substituents. The readily available19b,34 6-oxo-
4,5-dehydro-D-pipecolic acid ester 48 was treated with isobu-
tylmagnesiocuprate to give the mixture of 4-isobutyl adducts
49a and 49b in a 1.1:1 ratio as shown in Scheme 8.
a Reagents and conditions: (a) (CH3)2CHCH2MgBr, CuI cat., Et2O, -20
°C, 87%; (b) LiHMDS, allyl iodide, -78 °C, 46%; (c) TBAF, AcOH, THF,
rt; (d) Jones’ reagent, acetone, rt; (e) CH2N2, Et2O, 0 °C, 65%; (f) Super
Hydride, THF, -78 °C; (g) Ac2O, Et3N, DMAP, DCM, rt; (h) P(OMe)3,
BF3‚OEt2, DCM, -78 °C to rt, 87%; (i) i. ozone, DCM/MeOH (1:1), -78
°C; ii. Me2S, -78 to 0 °C; (j) NaBH4, MeOH, 0 °C to rt; (k) TsCl, Et3N,
DMAP, DCM, rt; (l) N-(1,8-dicarboxynaphthalimido) Na+ salt, DMF, rt,
27%; (m) LiOH‚H2O, THF/H2O/MeOH (5:4:1), rt; (n) i-Pr2NEt, EDCI,
HOBt, H-Xaa-OR2‚HCl, DCM, rt, 42-52%; (o) HCl (gas), dioxane, reflux
or LiOH‚H2O, THF/H2O/MeOH (5:4:1), rt; (q) TMSBr, DCM then 1 equiv
of NaOH 0.05M, 78-82%.
Their stereochemistry was unambiguously assigned from
1
detailed H NMR analysis. Since the isomers could not be
separated by column chromatography, we proceeded with the
alkylation of the lactam enolates of a mixture of 49a and 49b.
The yield and selectivity of alkylation with cinnamyl bromide
was found to be highly dependent on the solvent and counter-
cation present (Table 1). The best condition for 4,5-trans product
50a was a mixture of THF and DME (1:1) in conjunction with
LiHMDS. This led to a 2:1 separable mixture of 50a and 50b,
each in high diastereomeric excess (Table 1, entry 7). The
recovered lactam (25%) was enriched in the trans-isomer 49b.
directed our effort toward the development of methodology
and stereochemical feasibility first. Thus, the readily available
3,4-unsaturated lactam 3315,32 was treated with isobutylmagne-
siocuprate to give the trans-adduct 34 as the only isomer
(Scheme 7). Formation of the Li+ enolate and alkylation with
(33) For recent references, see: (a) Jao, E.; Bogen, S.; Saksena, A. K.;
Girijavallabhan, V. Tetrahedron Lett. 2003, 44, 5033-5035. (b) Flamant-
Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, N. A. Tetrahedron 2002, 58,
10475-10484. (c) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61,
5418-5424.
(34) Davies, C. E.; Heightman, T. D.; Hermitage, S. A.; Moloney, M.
G. Synth. Commun. 1996, 26, 687-696.
(32) (a) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001,
57, 6353-6359. (b) Woo, K.-C.; Jones, K. Tetrahedron Lett. 1991, 32,
6949-6952. (c) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104,
3511-3513.
J. Org. Chem, Vol. 71, No. 7, 2006 2765

Hanessian et al.
SCHEME 9a
TABLE 1. Counterion and Solvent Study for Preparation of 50a
and 50b
yield (%)
entry
solvents
base
50a (ratio)a 50b (ratio)a 49 (ratio)a
1
2
3
4
5
6
7
THF
THF
LiHMDS 44 (>98:2) 17 (72:28) 21 (0:100)
LiHMDS 17 (>98:2) 13 (75:25) 50 (20:80)b
THF/DME (1:1) LiHMDS 48 (>98:2) 24 (80:20) 26 (5:95)
THF/DME (1:1) NaHMDS 11 (>98:2) 10 (79:21) 56c
THF/DME (1:10) LiHMDS 37 (>98:2) 15 (88:12) 43 (30:70)
Et2O/DME (1:10) LiHMDS 25 (>98:2) 15 (91:9)
51 (37:63)
THF/DME (1:1) LiHMDS 48 (>98:2) 25 (90:10) 25 (5:95)d
1
a Ratio determined by H NMR analysis. b Only 0.6 equiv of cinnamyl
bromide was used. c Not determined. d Cinnamyl bromide in THF was added
over 30 min using a syringe pump.
SCHEME 10a
a Reagents and conditions: (a) (i) Super Hydride, THF, -78 °C, (ii)
H2O2, 0 °C; (b) Ac2O, Et3N, DMAP, DCM, rt; (c) P(OMe)3, BF3•Et2O,
DCM, -78 °C to rt, 81-94%; (d) (i) ozone, DCM/MeOH (1:1), -78 °C,
(ii) Me2S, -78 °C to 0 °C; (e) NaBH4, MeOH, rt, 79-87%; (f) N-1,8-
dicarboxynaphthalimide, PPh3, methyl azodicarboxylate, THF, rt, 86-87%;
(g) TsCl, Et3N, DMAP, DCM, rt; (h) N-(1,8-dicarboxynaphthalimido) Na+
salt, DMF, rt, 42-60%.
Other combinations of solvent and bases led to inferior results,
especially in the case of NaHMDS. The structures of 50a and
50b were determined by NOE measurements (Table 1).
With 50a and 50b in hand, we proceeded to their elaboration
into the intended target compounds in this series (Scheme 9).
Thus, formation of the N-Boc iminium ion from 50a and
treatment with P(OMe)3 in the presence of BF3‚Et2O as
previously described afforded a 1.5:1 separable mixture of C2/
C6 cis- and trans-dimethylphosphonates 51a and 51b in excellent
yield (Scheme 9). Each isomer was subjected to ozonolysis,
and hydride reduction of the resulting aldehyde to give alcohols
52a and 52b. A Mitsunobu reaction with 1,8-dicarboxynaph-
thalimide was highly successful in this series to afford 53a and
53b. An analogous sequence was performed on the diastereo-
meric 50b. The alcohols 52c and 52d did not react under
Mitsunobu conditions, but displacement of the corresponding
tosylates afforded 53c and 53d (Scheme 9).
a Reagents and conditions: (a) LiOH‚H2O, THF/H2O/MeOH (5:4:1), 50
°C; (b) H-Trp-OMe‚HCl, EDCI, HOBt, DIEA, DMF, rt, 67-82%; (c) (i)
LiOH‚H2O, THF/H2O/MeOH (5:4:1), 0 °C, (ii) TMSBr, CH2Cl2, rt, then 1
equiv of NaOH 0.05 M, 68-95%.
yields (Scheme 10). Deprotection of the ester groups and
purification by column chromatography afforded 55a and 55b
respectively. The diastereomeric pairs series 54c/55c and 54d/
55d were similarly prepared as were two representative com-
Compounds 53a and 53b were individually converted into
the diastereomeric protected indolyl amides 54a and 54b in good
2766 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
3H), 2.86-2.69 (m, 2H), 2.53-2.35 (m, 2H), 1.87-1.71 (m, 1H),
1.50 (s, 9H); 13C (100 MHz, CDCl3) δ 174.4, 171.9, 149.2, 136.8,
132.9, 128.5, 127.4, 126.1, 126.0, 83.8, 57.3, 52.5, 42.5, 34.4, 27.8,
26.7.
pounds 56 and 57 starting from the enantiomeric 6-oxo-L-
pipecolic acid (Series F).
Conclusions
(2S,4R)- 4-(3-Naphthalen-1-ylallyl)-5-oxopyrrolidine-1,2-di-
carboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (9a) and
(2S,4S)-4-(3-Naphthalen-1-ylallyl)-5-oxopyrrolidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (9b). Following
the preparation of 7a and 7b gave compounds 9a and 9b (7.8:1 in
favor of 9a). For 9a: 1.1 g (63%); [R]D -20.7 (c 0.7, CHCl3); IR
Biological testing of the phosphonic acids as inhibitors of
ECE did not reveal a distinct SAR. However, two compounds
stood out with promising results. The analogues 44 and 55d,
each originating from D-pyroglutamic acid and 6-oxo-D-pipecolic
acid, respectively, showed 91% and 98% inhibition of ECE at
10-5 M.35 Clearly, the expected improved binding of the
constrained analogues was not observed despite a high level of
stereochemical diversity. This may in part be due to nonoptimal
deployment of the pharmacophoric group on the rigid 5- and
6-membered scaffolds compared to the acyclic inhibitors shown
in Figure 1.
1
(neat/NaCl) 2981, 1790, 1750, 1717, 1314 cm-1; H (300 MHz,
CDCl3) δ 8.06 (d, 1H, J ) 8.8 Hz), 7.84 (d, 1H, J ) 7.2 Hz), 7.80
(m, 1H), 7.50 (m, 3H), 7.36 (m, 1H), 7.20 (d, 1H, J ) 15.5 Hz),
6.15 (m, 1H), 4.59 (d, 1H, J ) 9.4 Hz), 3.77 (s, 3H), 2.90 (m, 2H),
2.52 (m, 1H), 2.27-2.08 (m, 2H), 1.50 (s, 9H); 13C (100 MHz,
CDCl3) δ 174.2, 171.7, 149.3, 134.6, 133.4, 130.9, 130.3, 129.0,
128.4, 127.7, 126.0, 125.7, 125.5, 123.7, 83.6, 56.9, 52.5, 41.6,
33.8, 27.8, 27.6; LRMS (FAB, NBA, m/z) 409, 309; HRMS for
C24H27NO5 calcd 409.188923, obsd 409.187996. For 9b: 141 mg
(8%);1H (300 MHz, CDCl3) δ 8.14 (d, 1H, J ) 7.2 Hz), 7.82 (d,
1H, J ) 7.2 Hz), 7.77 (d, 1H, J ) 7.0 Hz), 7.61-7.40 (m, 4H),
7.19 (m, 1H), 6.16 (m, 1H), 4.57 (m, 1H), 3.75 (s, 3H), 2.98-2.78
(m, 2H), 2.61-2.46 (m, 2H), 1.94-1.81 (m, 1H), 1.51 (s, 9H);
LRMS (FAB, NBA, m/z) 409; HRMS for C24H27NO5 calcd
409.188923, obsd 409.188142.
Experimental Section
(2S,4R)-4-Allyl-5-oxopyrrolidine-1,2-dicarboxylic Acid 1-tert-
Butyl Ester 2-Methyl Ester (7a) and (2S,4S)-4-Allyl-5-oxopyr-
rolidine-1,2-dicarboxylic acid 1-tert-Butyl Ester 2-Methyl Ester
(7b). Lactam 6 (2.6 g, 10.7 mmol) was placed in a flame-dried,
argon-filled flask, dissolved in dry THF (100 mL), and cooled to
-78 °C. LiHMDS (11.8 mL, 11.8 mmol) was introduced as a 1 M
solution in THF over 30 min (hypodermic syringe). The solution
was stirred (30 min) prior to the addition of a solution of allyl
bromide (1.39 mL, 16.0 mmol) in THF (160 mL), precooled to 0
°C, via a cannula. The solution was then stirred at -78 °C until
completion (monitored by TLC). A saturated solution of NaHCO3
was added, and the solution was allowed to reach rt. The aqueous
layer was extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The resulting oil was
purified by flash column chromatography (hexanes/EtOAc, 9:1) to
yield the two alkylated compounds 7a and 7b (2:1 in favor of 7a).
For 7a: 1.2 g (40%); [R]D -32.4 (c 1.0, CHCl3); IR (neat/NaCl)
2961, 1793, 1752, 1718, 1317 cm-1;1H NMR (300 MHz, CDCl3)
δ 5.65 (m, 1H), 5.01 (dd, 2H, J ) 6.4, 13.6 Hz), 4.48 (dd. 1H, J
) 1.6, 9.6 Hz), 3.69 (s, 3H), 2.65 (m, 1H), 2.52 (m, 1H), 2.12 (m,
2H), 1.95 (m, 1H), 1.41 (s, 9H); 13C (100 MHz, CDCl3) δ 174.7,
172.2, 149.8, 134.7, 118.2, 84.0, 57.3, 52.9, 41.6, 34.8, 28.3, 28.1;
LRMS (FAB, NBA, m/z) 283, 183. For 7b: 611 mg (20%); [R]D
+12.0 (c 3.5, CHCl3); IR (neat/NaCl) 2981, 1792, 1752, 1719, 1320
cm-1; 1H NMR (300 MHz, CDCl3) δ 5.68 (m, 1H), 5.08 (dd, 2H,
J ) 7.0, 13.0 Hz), 4.50 (dd. 1H, J ) 1.8, 6.9 Hz), 3.78 (s, 3H),
2.68 (m, 2H), 2.45 (m, 1H), 2.20 (m, 1H), 1.78 (m, 1H), 1.47 (s,
9H); 13C (100 MHz, CDCl3) δ 174.4, 171.9, 149.1, 134.4, 117.6,
83.6, 57.3, 52.4, 41.9, 35.0, 27.7, 26.7; LRMS (FAB, NBA, m/z)
284, 228, 184.
(2S,4R)-5-Oxo-4-(3-phenylallyl)pyrrolidine-1,2-dicarboxylic
Acid 1-tert-Butyl Ester 2-Methyl Ester (8a) and (2S,4S)-5-Oxo-
4-(3-phenylallyl)pyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl
Ester 2-Methyl Ester (8b). Following the preparation of 7a and
7b gave compounds 8a and 8b (3.5:1 in favor of 8a). For 8a: 5.1
g (57%); mp 107 °C; [R]D -33.3 (c 1.3, CHCl3); IR (neat/NaCl)
2981, 1792, 1751, 1717, 1318 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.34-7.25 (m, 5H), 6.45 (d, 1H, J ) 15.8 Hz), 6.11 (m, 1H),
4.55 (dd, 1H, J ) 1.6, 9.4 Hz), 3.75 (s, 3H), 2.78 (m, 2H), 2.39
(m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 1.48 (s, 9H); 13C (100 MHz,
CDCl3) δ 174.1, 171.6, 149.2, 136.7, 132.8, 128.1, 127.3, 125.9,
125.6, 83.4, 56.8, 52.4, 41.4, 33.3, 28.1, 27.7; LRMS (FAB, NBA,
m/z) 360, 304, 260; HRMS for C20H25NO5, (MH+) calcd 360.183778,
obsd 360.182100. For 8b: 1.5 g (16%); [R]D -47.2 (c 1.0, CHCl3);
IR (neat/NaCl) 2981, 1791, 1751, 1718, 1318, 1150 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 6.42 (d, 1H, J ) 15.8
Hz), 6.21-6.08 (m, 1H), 4.52 (dd, 1H, J ) 6.9, 8.8 Hz), 3.72 (s,
(2S,4R)-4-(2-Methylallyl)-5-oxopyrrolidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (10a) and (2S,4S)-4-(2-Meth-
ylallyl)-5-oxopyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (10b). Following the preparation of 7a and 7b gave
compounds 10a and 10b (1.5:1 in favor of 10a). For 10a: 620 mg
(30%); as a white solid; mp 55 °C; [R]D -41.0 (c 2.0, CHCl3); IR
1
(neat/NaCl) 2979, 1792, 1751, 1717 cm-1; H NMR (300 MHz,
CD3OD) δ 4.60 (d, 2H, J ) 23.8 Hz), 4.54 (dd, 1H, J ) 1.7, 9.6
Hz), 3.66 (s, 3H), 2.67 (m, 1H), 2.54 (dd, 1H, J ) 3.7, 14.4 Hz),
2.05 (dddd, 1H, J ) 1.7, 8.6, 13.5, 22.2 Hz), 1.89 (m, 1H), 1.82
(m, 1H), 1.58 (s, 3H), 1.37 (s, 9H); 13C (100 MHz, CDCl3) δ 174.3,
171.5, 148.9, 141.7, 112.2, 83.1, 56.5, 52.1, 39.6, 38.5, 27.8, 27.4,
21.7; LRMS (FAB, NBA, m/z) 297, 250, 197, 241; HRMS for
C15H23NO5 calcd 297.157623, obsd 297.158752. For 10b: 413 mg
(20%); as an amorphous solid; IR (neat/ NaCl) 2981, 1792, 1752,
1719 cm-1; 1H NMR (300 MHz, CD3OD) δ 4.68 (d, 2H, J ) 40.8
Hz), 4.47 (dd, 1H, J ) 6.5, 9.0 Hz), 3.72 (s, 3H), 2.68 (m, 1H),
2.59 (dd, 1H, J ) 3.7, 14.5 Hz), 2.40 (ddd, 1H, J ) 9.1, 9.1, 13.3
Hz), 2.06 (dd, 1H, J ) 11.1, 14.4 Hz), 1.65 (s, 3H), 1.64 (m, 1H),
1.43 (s, 9H); 13C (100 MHz, CDCl3) δ 174.8, 171.9, 149.1, 141.9,
112.6, 83.5, 57.2, 52.3, 40.6, 39.1, 27.7, 26.7, 21.7; LRMS (FAB,
NBA, m/z) 298, 242, 198.
(2S,4R,5R)-4-Allyl-5-(dimethoxyphosphoryl)pyrrolidine-1,2-
dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (11a) and
(2S,4R,5S)-4-Allyl-5-(dimethoxyphosphoryl)pyrrolidine-1,2-di-
carboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (11b). Lactam
7a (500 mg, 1.77 mmol) was placed in a flame-dried, argon-filled
flask, dissolved in dry THF (10 mL), and cooled to -78 °C. A 1
M solution of LiEt3BH (2.12 mL, 2.12 mmol) in THF was added
dropwise over 30 min (hypodermic syringe). After being stirred
for 2 h, the reaction was quenched by addition of saturated NaHCO3
and allowed to reach 0 °C. A few drops of H2O2 (30% v/v) were
added, and the mixture was stirred for 1 h at 0 °C. The solvents
were evaporated and replaced by CH2Cl2, and the organic phase
was washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo at rt to give the crude hemiacetal which was directly used
in the next step. The residue was dissolved in CH2Cl2 (6 mL) and
cooled to 0 °C prior to the addition of Et
3N (740 µL, 5.31 mmol),
Ac2O (501 µL, 5.31 mmol), and a catalytic amount of DMAP. The
mixture was allowed to reach rt and stirred for 16 h, and then the
reaction was quenched by the addition of saturated NaHCO3, and
the aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo at rt to furnish an oil which was directly
(35) See the Supporting Information.
J. Org. Chem, Vol. 71, No. 7, 2006 2767

Hanessian et al.
used in the next step. The crude oil and P(OMe)3 (417 µL, 3.54
mmol) were dissolved in CH2Cl2 (20 mL) and cooled to -78 °C.
Then, BF3‚OEt2 (449 µL, 3.54 mmol) was introduced by dropwise
addition, and the solution was stirred for 1 h at -78 °C, 1 h at 0
°C and 1 h at rt. Water was added to the mixture, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatography
(hexanes/EtOAc, 1:1) to give the two phosphonates 11a and 11b
(1.5:1 in favor of 11b). For 11a: 193 mg (29%, three steps); mp
108 °C; [R]D -9.4 (c 1.0, CHCl3); IR (neat/NaCl) 3478, 2958, 1749,
8.8 Hz), 7.83 (d, 1H, J ) 3.05 Hz), 7.80 (d, 1H, J ) 2.1 Hz),
7.53-7.38 (m, 4H), 7.21 (d, 1H, J ) 15.5 Hz), 6.18 (m, 1H), 4.53
(dd, 1H, J ) 2.7, 7.2 Hz), 4.34 (d, 1H, J ) 8.2 Hz), 3.81-3.77
(m, 6H),3.69 (s, 3H), 2.80 (m, 2H), 2.59 (m, 2H), 2.03 (m, 1H),
1.48 (s, 3H), 1.40 (s, 6H); 13C (100 MHz, CDCl3) δ 173.4, 153.1,
134.9, 133.4, 131.1, 130.9, 128.9, 128.3, 127.5, 125.8, 125.6, 125.5,
123.7, 123.5, 80.7, 58.9, 56.9 (d), 53.3, 52.3, 52.2, 39.4, 34.9, 33.2,
28.1 and 27.9; LRMS (FAB, NBA, m/z) 503, 447, 270; HRMS for
C26H34NO7P (MH+) calcd 503.207291, obsd 503.206184. 13b: 249
mg (40%, three steps); [R]D +0.8 (c 1.0, CHCl3); for a mixture of
1
two rotamers H (300 MHz, CDCl3) δ 8.04 (d, 1H, J ) 8.2 Hz),
1
1711, 1381 cm-1; for a mixture of two rotamers H NMR (300
7.80 (d, 1H, J ) 8.3 Hz), 7.72 (d, 1H, J ) 8.0 Hz), 7.50-7.36 (m,
4H), 7.15 (d, 1H, J ) 15.4 Hz), 6.08 (m, 1H), 4.40 (m, 1H), 4.20
(m, 1H), 3.87 (d, 3H, J ) 10.3 Hz), 3.78 (d, 3H, J ) 11.8 Hz),
3.72 (s, 3H), 2.76 (m, 1H), 2.59 (m, 1H), 2.34 (m, 2H), 2.21 (m,
1H), 1.44 (s, 3H), 1.38 (s, 6H); 31P (161.3 MHz, CDCl3) δ 25.8;
LRMS (FAB, NBA, m/z) 505, 448, 294; HRMS for C26H34NO7P
(MH+) calcd 504.215116, obsd 504.214216.
MHz, CDCl3) δ 5.77 (m, 1H), 5.05 (m, 2H), 4.41 (dd, 0.70H, J )
2.6, 7.5 Hz), 4.30 (m, 1.30H), 3.73 (d, 3H, J ) 10.4 Hz), 3.70 (d,
3H, J ) 10.5 Hz), 3.69 (s, 3H), 2.66 (m, 1H), 2.55 (m, 2H), 2.25
(m, 1H), 1.92 (m, 1H), 1.44 (s, 3H), 1.36 (s, 6H); 13C (100 MHz,
CDCl3) δ 173.4, 153.1, 136.2 and 130.4, 116.3, 80.9 and 80.7, 58.9
and 58.6, 56.1, 55.2, 53.2 (d), 52.3, 40.2 and 39.0, 34.8, 33.2, 28.1
and 27.9; 31P (161.3 MHz, CDCl3) δ 26.1 (minor rotamer), 24.9
(major rotamer); LRMS (FAB, NBA, m/z) 377, 378; HRMS for
C16H28NO7P calcd 377.160341, obsd 377.159649. For 11b: 293
mg (44%, three steps); mp 68 °C; [R]D +1.5 (c 1.0, CHCl3); IR
(neat/NaCl) 3481, 2957, 1761, 1739, 1703, 1382 cm-1; for a mixture
of two rotamers1H NMR (300 MHz, CDCl3) δ 5.72 (m, 1H), 5.06
(m, 2H) 4.35-4.26 (m, 1H), 4.04 (m, 1H), 3.83 (d, 3H, J ) 10.3
Hz), 3.76 (d, 3H, J ) 10.5 Hz), 3.71 (s, 3H), 2.57 (m, 1H), 2.48
(m, 1H), 2.08 (m, 3H), 1.43 (s, 3H), 1.40 (s, 6H); 13C (100 MHz,
CDCl3) δ 173.4 and 173.0, 155.4 and 154.8, 135.6, 118.6, 81.4,
59.2, 58.9 (d), 54.3, 52.9, 52.3, 39.7 and 39.0, 38.2 and 38.0, 33.9
and 33.2, 28.4 and 28.2; 31P (161.3 MHz, CDCl3) δ 25.5; LRMS
(FAB, NBA, m/z) 377, 378; HRMS for C16H28NO7P calcd
377.160341, obsd 377.159546.
(2S,4R,5R)-5-(Dimethoxyphosphoryl)-4-(2-hydroxyethyl)pyr-
rolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(14a). The phosphonate 11a (385 mg, 1.02 mmol) was dissolved
in a mixture of CH2Cl2/MeOH 1:1 (10 mL) and cooled to -78 °C.
After 15 min, ozone was bubbled until a light blue coloration of
the solution persisted. The ozone flow was stopped and replaced
by argon until the solution turned colorless. Then, Me2S (150 µL,
2.04 mmol) was added, and the resulting mixture was allowed to
reach 0 °C and then stirred for 1 h. After addition of saturated
NaHCO3, the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The formed benzaldehyde
was removed by filtration through a plug of silica gel (hexanes/
EtOAc, 8:2). The pure aldehyde was dissolved in anhydrous MeOH
(0.1 M) and placed under argon at 0 °C. After portionwise addition
of NaBH4 (77 mg, 2.04 mmol), the mixture was allowed to reach
rt and was stirred until completion (monitored by TLC). The
reaction was quenched by addition of saturated NH4Cl. The organic
solvents were removed by evaporation, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated to furnish
the desired alcohol 14a as a colorless oil which was used as a crude
in the next step, (315 mg, 81%, two steps): for a mixture of two
rotamers 1H NMR (300 MHz, CDCl3) δ 4.49 (dd, 1H, J ) 2.0, 8.2
Hz), 4.19 (d, 1H, J ) 9.6 Hz), 3.72-3.64 (m, 9H), 3.59-3.52 (m,
2H), 2.81-2.56 (m, 1H), 2.45-2.33 (m, 1H), 2.13-1.87 (m, 2H),
1.75-1.65 (m, 1H), 1.39 (s, 3H), 1.32 (s, 6H).
(2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-(2-hydroxyethyl)pyr-
rolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(14b). Following the preparation of 14a gave compound 14b as a
colorless oil: 286 mg (79%, two steps); [R]D +16.1 (c 1.1, CHCl3);
for a mixture of two rotamers 1H NMR (300 MHz, CDCl3) δ 4.40
(t, 1H, J ) 8.8 Hz), 4.10 (m, 1H), 3.88 (m, 3H), 3.80 (d, 3H, J )
10.6 Hz), 3.74 (s, 3H), 3.62 (t, 2H, J ) 6.1 Hz), 2.64 (m, 1H),
2.43 (m, 1H), 2.18 (m, 1H), 1.58 (m, 2H), 1.50 (s, 3H), 1.44 (s,
6H); 13C (100 MHz, CDCl3) δ 172.3, 153.8, 80.9, 59.9, 58.8 and
57.7, 53.2 (d), 51.9, 36.5, 36.5, 36.2, 34.6 and 33.9, 28.0; 31P (161.3
MHz, CDCl3) δ 27.1; LRMS (FAB, NBA, m/z) 381, 325, 272, 216;
HRMS for C15H28NO8P calcd 381.155256, obsd 381.154572.
(2S,4R,5R)-5-(Dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (15a). To a solution of the
alcohol 14a (530 mg, 1.39 mmol) in dry CH2Cl2 (3 mL) at 0 °C
were added TsCl (292 mg, 1.53 mmol), Et3N (213 µL, 1.53 mmol),
and a catalytic amount of DMAP. The resulting mixture was
allowed to reach rt and was stirred for 24 h. The reaction was
quenched by addition of saturated NH4Cl, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated
in vacuo to yield the desired tosylate, which was used without
further purification. Then, NaH (222 mg, 5.56 mmol, 60%
(2S,4R,5R)-5-(Dimethoxyphosphoryl)-4-(3-phenylallyl)pyrro-
lidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(12a) and (2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-(3-phenylal-
lyl)pyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl
Ester (12b). Following the preparation of 11a and 11b gave
compounds 12a and 12b (1.9:1 in favor of 12b). For 12a: 1.72 g
(28%, three steps); as a white solid; mp 121 °C; [R]D -1.4 (c 1.0,
CHCl3); IR (neat/NaCl) 3468, 2956, 1748, 1704, 1382 cm-1; for a
1
mixture of two rotamers H NMR (300 MHz, CDCl3) δ 7.35 (m,
4H), 7.12 (m, 1H), 6.48 (d, 1H, J ) 13.3 Hz), 6.10 (m, 1H), 4.46
(dd, 1H, J ) 2.5, 7.2 Hz), 4.32 (m, 1H), 3.76-3.74 (m, 6H), 3.68
(s, 3H), 2.70-2.68 (m, 1H), 2.63-2.43 (m, 3H), 1.98 (m, 1H),
1.46 (s, 3H), 1.38 (s, 6H); 13C (100 MHz, CDCl3) δ 173.9 and
173.5, 154.2 and 153.6, 137.8, 132.2, 128.9, 128.3, 127.6, 126.4,
81.4 and 81.2, 59.4, 56.3 (d), 53.7, 52.8, 52.5, 41.1 and 39.9, 35.4,
33.1, 28.6 and 28.4; 31P (161.3 Mz, CDCl3) δ 25.2 (minor rotamer),
24.9 (major rotamer); HRMS for C22H32NO7P (MH+) calcd
454.19946, obsd 454.20050. For 12b: 3.32 g (53%, three steps);
as a colorless oil; [R]D +3.6 (c 0.8, CHCl3); IR (neat/NaCl) 3473,
1
2956, 1760, 1702, 1381 cm-1; for a mixture of two rotamers H
NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 4H), 7.21 (m, 1H), 6.44
(d, 1H, J ) 15.1 Hz), 6.10 (dd, 1H, J ) 6.7, 15.1 Hz), 4.33 (m,
1H), 4.13 (m, 1H), 3.88 (d, 3H, J ) 10.3 Hz), 3.74 (s, 3H), 3.36
(d, 3H, J ) 10.5 Hz), 2.71 (m, 1H), 2.53 (m, 1H), 2.27 (m, 2H),
2.18 (m, 1H), 1.59 (s, 3H), 1.41 (s, 6H); 13C (100 MHz, CDCl3) δ
172.8, 154.2, 137.4, 133.5, 133.3, 128.9, 127.8, 126.5, 81.4, 59.3,
59.2 (d), 54.4, 53.0 (d), 52.5, 39.5, 37.8 and 37.6, 34.1, 28.6 and
28.4; 31P (161.3 MHz, CDCl3) δ 25.5; HRMS for C22H32NO7P
(MH+) calcd 454.19946, obsd 454.19820.
(2S,4R,5R)-5-(Dimethoxyphosphoryl)-4-(3-naphthalen-1-ylal-
lyl)pyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl
Ester (13a) and (2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-(3-naph-
thalen-1-ylallyl)pyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl
Ester 2-Methyl Ester (13b). Following the preparation of 11a and
11b gave compounds 13a and 13b (1.6:1 in favor of 13b). For
13a: 152 mg (25%, three steps); [R]D +20.0 (c 1.1, CHCl3); for a
mixture of two rotamers 1H (300 MHz, CDCl3) δ 8.09 (d, 1H, J )
2768 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
dispersion in oil), washed three times with dry hexanes, was
suspended in dry DMF. The mixture was cooled to 0 °C prior to
the addition of 1,8-dicarboxynaphthalimide (1.23 g, 6.25 mmol).
After 30 min, a solution of the tosylate in dry DMF was introduced
via a cannula, and the resulting suspension was stirred for 48 h at
rt. After evaporation of DMF, H2O was added to the residue, and
the aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The excess of reagent was removed by flash
chromatography (hexanes/EtOAc, 1:1) prior to the recovery of the
desired compound (hexanes/EtOAc, 3:7) 15a, (210 mg, 27%, two
steps): mp 58 °C; [R]D -8.1 (c 0.9, CHCl3); IR (neat/NaCl) 2956,
1747, 1701, 1667, 1366 cm-1; for a mixture of rotamers 1H NMR
(300 MHz, CDCl3) δ 8.47 (dd, 2H, J ) 7.2 Hz), 8.13 (d, 2H, J )
8.2 Hz), 7.66 (t, 2H, J ) 7.8 Hz), 4.41 (dd, 1H, J ) 2.5, 7.2 Hz),
4.32 (dd, 1H, J ) 7.9, 13.5 Hz), 4.25-3.97 (m, 2H), 3.73 (d, 3H,
J ) 4.9 Hz), 3.70 (d, 3H, J ) 7.2 Hz), 3.67 (s, 3H), 2.58 (m, 2H),
2.22 (m, 2H), 1.88 (m, 1H), 1.41 (s, 3H), 1.33 (s, 6H); 13C (100
MHz, CDCl3) δ 173.2 and 172.9, 163.9, 153.6 and 153.0, 133.8,
131.3, 130.9, 127.8, 126.7, 122.3, 80.7 and 80.5, 58.6, 55.9 (d),
53.0 (d), 52.4 (d), 51.9, 38.8, 38.0 and 37.0, 34.8, 30.4, 27.8 and
27.4; 31P (161.3 MHz, CDCl3) δ 25.16 (minor rotamer), 25.48
(major rotamer); LRMS (FAB, NBA, m/z) 561, 505, 351, 326;
HRMS for C27H33N2O9P (MH+) calcd 561.200195, obsd 561.199200.
(2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (15b). Following the preparation
of 15a gave compound 15b, 92 mg (42%, two steps): [R]D +5.3
Hz), 2.97 (m, 1H), 2.57 (m, 2H), 2.22 (m, 2H), 1.97 (m, 1H), 1.47
(s, 3H), 1.35 (s, 6H), 1.33 (s, 9H); 13C (100 MHz, CDCl3) δ 172.0,
170.5 and 170.4, 164.0, 153.3, 136.3, 133.8, 131.5, 131.2, 129.8,
129.3, 128.4, 128.2, 126.9, 122.6, 82.4 and 82.2, 80.8 and 80.7,
60.4 and 60.2, 56.2 (d), 53.9 and 53.7, 53.1 (d), 52.3 (d), 39.2 and
39.1, 38.7 and 38.6, 37.2, 35.8, 34.6, 28.2 and 27.9, 28.1; 31P (161.3
MHz, CDCl3) δ 25.7 (major rotamer), 25.3 (minor rotamer); LRMS
(FAB, NBA, m/z) 750, 650, 484; HRMS for C39H48N3O10P (MH+)
calcd 750.315559, obsd 750.317400.
(2S,3R,5S)-5-[(1S)-tert-Butoxycarbonyl-2-phenylethylcarbam-
oyl]-2-(dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-benzo[de]-
isoquinolin-2-yl)ethyl]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (16b). Following the preparation of 16a gave compound 16b
as a white foam, 65 mg (79%, two steps): [R]D +3.0 (c 1.3, CHCl3);
IR (neat/NaCl) 3279, 2977, 1735, 1701, 1663 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.75 (d, 2H, J ) 7.3 Hz), 8.20 (d, 2H, J ) 8.3
Hz), 7.73 (dd, 2H, J ) 7.4, 8.1 Hz), 7.25 (m, 5H), 4.75 (m, 1H),
4.30 (t, 1H, J ) 7.5 Hz), 4.15 (m, 2H), 4.02 (m, 1H), 3.82 (d, 3H,
J ) 10.5 Hz), 3.75 (d, 3H, J ) 10.6 Hz), 3.09 (dd, 1H, J ) 6.8,
13.7 Hz), 3.00 (dd, 1H, J ) 8.0, 13.7 Hz), 2.49 (m, 1H), 2.29 (m,
1H), 2.15-1.86 (m, 2H), 1.66 (m, 1H), 1.42 (s, 9H), 1.33 (s, 9H);
13C (100 MHz, CDCl3) δ 172.3, 171.0, 164.3, 154.8, 137.4, 134.4,
131.9, 131.6, 129.9, 128.7, 128.5, 127.3, 126.9, 122.9, 82.1, 81.6,
62.8, 61.3, 59.1, 54.0, 53.1, 39.0, 38.7, 38.1, 35.0, 32.2, 28.4, 28.3;
31P (161.3 MHz, CDCl3) δ 29.5; LRMS (FAB, NBA, m/z) 750,
540, 484.
(2R,3R,5S)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-5-[2-(3H-inden-1-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]pyrrolidine-1-carboxylic Acid tert-
Butyl Ester (17a). Following the preparation of 16a gave compound
17a, 26 mg (36%, two steps): [R]D +27.4 (c 1.2, CHCl3); IR (neat/
NaCl) 3284, 2953, 1702, 1699, 1660 cm-1; for a mixture of two
rotamers 1H NMR (300 MHz, CDCl3) δ 8.62 (d, 2H, J ) 7.3 Hz),
8.20 (d, 2H, J ) 8.2 Hz), 7.78 (m, 2H), 7.56 (m, 1H), 7.38 (m,
1H), 7.18-7.01 (m, 3H), 6.32 (d, 0.4H), 6.04 (d, 0.6H), 4.81 (m,
1H), 4.27-4.10 (m, 3H), 4.02 (m, 1H), 3.80-3.68 (m, 9H), 3.33
(m, 2H), 2.55 (m, 1H), 2.20 (m, 2H), 1.92 (m, 2H), 1.59 (s, 3H),
1.34 (s, 6H); 13C (100 MHz, CDCl3) δ 172.2, 172.0, 168.5, 153.6
and 153.0, 136.4, 134.0, 131.5, 128.1, 127.4, 123.1, 121.8, 119.8,
118.2, 111.6, 109.3, 81.0, 60.3, 57.0, 54.9, 53.1, 52.8, 52.3, 39.4,
37.7, 35.7, 34.7, 29.6, 28.1 and 27.4; 31P (161.3 MHz, CDCl3) δ
25.6 (minor rotamer), 25.0 (major rotamer); LRMS (FAB, NBA,
m/z) 747, 647.
(2S,3R,5S)-2-(Dimethoxy-phosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-5-[2-(3H-inden-1-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]pyrrolidine-1-carboxylic Acid tert-
Butyl Ester (17b). Following the preparation of 16a gave compound
17b as a yellow foam, 63 mg (74%, two steps): mp 45 °C; [R]D
-5.5 (c 1.0, CHCl3); IR (neat/NaCl) 3285, 2956, 1745, 1700, 1661,
1368 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.75 (bs, 1H), 8.60 (d,
2H, J ) 7.2 Hz), 8.37 (bs, 1H), 8.22 (d, 2H, J ) 8.2 Hz), 7.76 (t,
2H, J ) 7.8 Hz), 7.61 (d, 1H, J ) 7.6 Hz), 7.31 (d, 1H, J ) 7.6
Hz), 7.12 (m, 3H), 5.06 (m, 1H), 4.38 (t, 1H, J ) 5.8 Hz), 4.10
(m, 2H), 3.86 (m, 1H), 3.78 (d, 3H, J ) 9.8 Hz), 3.69 (s, 3H), 3.58
(d, 3H, J ) 10.7 Hz), 3.40 (dd, 1H, J ) 5.03, 14.8 Hz), 3.28 (dd,
1H, J ) 8.9, 14.9 Hz), 2.41 (m, 1H), 2.17 (m, 1H), 2.05 (m, 2H),
1.73 (m, 1H), 1.44 (s, 9H); 13C (100 MHz, CDCl3) δ 172.8, 172.4,
164.5, 154.7, 136.7, 134.6, 132.0, 131.8, 128.5, 127.8, 127.4, 123.5,
122.8, 122.2, 119.6, 119.2, 111.5, 111.3, 82.1, 62.0 (d), 59.2, 54.7,
52.6, 52.5, 39.1, 39.0, 38.6, 35.6, 31.9, 28.4; 31P (161.3 MHz,
CDCl3) δ 30.3; LRMS (FAB, NBA, m/z) 747, 537, 307; HRMS
for C38H43N4O10P (MH+) calcd 747.279508, obsd 747.277900.
(2R,3R,5S)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-5-[(1S)-methoxycarbonyl-3-
phenylpropylcarbamoyl]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (18). Following the preparation of 16a gave compound 18,
25 mg (35%, two steps): [R]D +5.3 (c 1.2, CHCl3); IR (neat/NaCl)
3282, 2954, 1744, 1701, 1663 cm-1; for a mixture of two rotamers
1H NMR (300 MHz, CDCl3) δ 8.56 (m, 2H), 8.18 (m, 2H), 7.73
(c 0.9, CHCl3); IR (neat/NaCl) 2957, 2360, 1700, 1661, 1367 cm-1
;
for a mixture of two rotamers 1H NMR (300 MHz, CDCl3) δ 5.58
(dd, 2H, J ) 1.1, 7.5 Hz), 8.22 (dd, 2H, J ) 1.1, 8.5 Hz), 7.77 (t,
2H, J ) 7.5 Hz), 4.43 (m, 1H), 4.25 (m, 2H), 4.19 (m, 1H), 3.87
(d, 3H, J ) 10.8 Hz), 3.76 (d, 3H, J ) 10.9 Hz), 3.74 (s, 3H), 2.63
(m, 2H), 2.38 (m, 1H), 1.90-1.62 (m, 2H), 1.51 (s, 3H), 1.41 (s,
6H); 13C (100 MHz, CDCl3) δ 172.3 and 172.0, 164.0, 153.7, 134.6
and 134.1, 131.5, 131.2 and 130.9, 128.1, 126.9, 122.4, 81.1 and
80.9, 59.8 (d), 58.6 and 58.4, 54.0, 52.5, 51.9, 38.2, 37.5, 33.5,
31.7, 28.1; 31P (161.3 MHz, CDCl3) δ 25.2; LRMS (FAB, NBA,
m/z) 561, 460, 410; HRMS for C27H33N2O9P (MH+) calcd
561.200195, obsd 561.198600.
(2R,3R,5S)-5-[(1S)-tert-Butoxycarbonyl-2-phenylethylcarbam-
oyl]-2-(dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-benzo[de]-
isoquinolin-2-yl)ethyl]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (16a). The methyl ester 15a (147 mg, 0.26 mmol) was
dissolved in THF/H2O/MeOH 5:4:1 (3 mL) and cooled to 0 °C.
LiOH‚H2O (22 mg, 0.52 mmol) was added, and the solution was
stirred for 2 h at rt. In the case of the C2/C5 trans derivatives the
hydrolysis was done at 60 °C over 48 h. The aqueous layer was
washed with CH2Cl2, acidified to pH 3 with HCl 1 N, and extracted
with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo to give the
carboxylic acid, which was used in the next step without further
purification. The HCl salt of H-Phe-Ot-Bu (81 mg, 0.31 mmol)
was suspended in CH2Cl2 (1.5 mL) at 0 °C. Diisopropylethylamine
(54 µL, 0.31 mmol) was added, followed by HOBt (50 mg, 0.37
mmol) and a solution of the described carboxylic acid in CH2Cl2
(1.5 mL). The resulting mixture was stirred for 15 min at 0 °C,
and EDCI (65 mg, 0.34 mmol) was added. The solution was stirred
for 16 h at rt. The organic layer was washed with saturated
NaHCO3, 1 N HCl, and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (CH2-
Cl2/MeOH, 10:0 to 9.8:0.2) afforded pure 16a (65 mg, 33%, two
steps) as a white solid: mp 79-82 °C; [R]D +2.3 (c 1.1, CHCl3);
IR (neat/NaCl) 2955, 1721, 1500 cm-1; for a mixture of two
rotamers1H NMR (300 MHz, CDCl3) δ 8.54 (m, 2H), 8.18 (d, 2H,
J ) 8.2 Hz), 7.72 (m, 2H), 7.26 (m, 3H), 7.16 (m, 2H), 6.23 (bd,
0.30H), 6.05 (bd, 0.70H), 4.68 (m, 1H), 4.51 (d, 0.70H, J ) 7.4
Hz), 4.45 (d, 0.30H, J ) 7.5 Hz), 4.20 (m, 3H), 3.75 (d, 3H, J )
10.4 Hz), 3.73 (d, 3H, J ) 10.2 Hz), 3.12 (dd, 1H, J ) 5.7, 13.8
J. Org. Chem, Vol. 71, No. 7, 2006 2769

Hanessian et al.
(m, 2H), 7.29-7.13 (m, 5H), 4.66 (m, 1H), 4.50 (dd, 1H, J ) 7.5,
17.2 Hz), 4.29-4.20 (m, 3H), 3.83-3.70 (m, 9H), 2.73-2.63 (m,
3H), 2.31-2.16 (m, 3H), 2.16-2.02 (m, 1H), 2.02-1.91 (m, 2H),
1.45 (s, 9H); 13C (100 MHz, CDCl3) δ 172.6, 172.5, 171.9, 164.1,
153.7 (d), 140.7 (d), 133.8, 131.2, 128.7, 128.5, 128.3, 126.9, 126.1
(d), 122.7, 80.8 (d), 60.3, 57.0 (d), 55.8 (d), 52.7 (d), 52.4, 39.0,
37.9 (d), 35.0 (d), 34.6, 31.5 (d), 30.9, 28.2, 27.6; 31P (161.3 MHz,
CDCl3) δ 25.8 (major rotamer), 25.2 (minor rotamer); LRMS (FAB,
NBA, m/z) 722, 623, 513.
(2S,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (19a). The phosphonate 16a (60 mg, 0.08
mmol) was placed in a flame-dried flask and dissolved in dry
dioxane (1 mL). After bubbling of HCl for 1 h, the solution was
refluxed for 6 h and stirred at rt until completion. The solvent was
evaporated and replaced by CH2Cl2. The suspension was cooled to
0 °C, and TMSBr (42 µL, 0.32 mmol) was added dropwise. The
solution was stirred for 24-48 h (monitored by TLC). The solvent
was removed, and deionized H2O (few mL) was added. The
resulting suspension was stirred in the cold room (4 °C) for 16 h.
The suspension was transferred in a conic 2 mL Eppendorf tube
and centrifuged at 4 °C for 10 min. The supernatant was removed
and replaced by fresh H2O, and the same operation was repeated
twice. The amorphous solid was suspended in 2 mL of deionized
H2O, and the pH value was adjusted to 7 by addition of an aqueous
solution of NaOH 0.05 M (1.6 mL, 0.08 mmol). The solution was
filtered on a 0.45 µm filter and lyophilized to give 19a. Purification
by preparative C18 RP-HPLC gave a yellow foam (7 mg, 15%):
of 16a and the preparation of 19a gave compound 20b; 22 mg
(69%, four steps): [R]D -22.5 (c 1.2, H2O); IR (KBr) 3428, 1654,
1
1591, 1129 cm-1; H NMR (300 MHz, D2O) δ 8.03 (d, 2H, J )
6.3 Hz), 7.98 (d, 2H, J ) 7.5 Hz), 7.67 (d, 1H, J ) 7.5 Hz), 7.59
(d, 2H, J ) 7.5 Hz), 7.50 (d, 1H, J ) 7.0 Hz), 7.17 (m, 2H), 7.08
(t, 1H, J ) 6.8 Hz), 4.51 (t, 1H, J ) 4.6 Hz), 3.90 (m, 1H), 3.80
(m, 1H), 3.65 (m, 1H), 3.31 (m, 1H), 3.13 (dd, 1H, J ) 9.0, 13.5
Hz), 2.97 (t, 1H, J ) 8.3 Hz), 2.19 (m, 1H), 2.01 (m, 1H), 1.89
(m, 1H), 1.70 (m, 1H), 1.41 (m, 1H); 13C (100 MHz, D2O) δ 178.9,
171.6. 165.5, 136.8, 135.6, 131.9, 131.1, 127.9, 127.5, 127.0, 125.1,
122.4, 120.9, 119.9, 119.3, 112.6, 111.3, 63.5, 59.7, 56.8, 39.9,
38.6, 36.3, 31.3, 28.1; 31P (161.3 MHz, D2O) δ 13.4; LRMS (FAB,
NBA, m/z) 605.
(2S,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-4-
phenylbutyric Acid (21). Following the preparation of 16a and
the preparation of 19a gave compound 21, 15 mg (90%, four
steps): [R]D -50.2 (c 0.4, H2O); IR (KBr) 3389, 2927, 1699, 1656,
1
1591 cm-1; H NMR (300 MHz, D2O) δ 8.07 (m, 3H), 7.53 (m,
3H), 7.03 (m, 3H), 6.82 (m, 2H), 4.15 (m, 1H), 4.01-3.62 (m,
3H), 3.58 (m, 1H), 3.46 (m, 1H), 2.64 (m, 1H), 2.24 (m, 4H), 2.05
(m, 1H), 1.91 (m, 1H), 1.70 (m, 1H); 13C (100 MHz, D2O) δ 179.4,
175.2, 166.1, 141.8, 135.9, 132.3, 131.5, 129.2, 129.0, 127.7, 127.4,
126.7, 121.1, 61.4 (d), 59.5, 55.5, 40.5, 38.7, 35.6, 34.3, 32.4, 28.0;
31P (161.3 MHz, D2O) δ 14.0.
(2R,4S,5S)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (22a). Prepared following the synthetic
sequence for the preparation of 19a, starting from D-pyroglutamic
acid: 36 mg; [R]D -47.8 (c 0.1, H2O); 1H NMR (300 MHz, D2O)
δ 7.76 (m, 3H), 7.56 (m, 1H), 7.28-7.07 (m, 4H), 6.93 (m, 1H),
6.85 (m, 1H), 6.71 (m, 1H), 4.31 (m, 2H), 3.70 (m, 1H), 3.57 (m,
1H), 3.49 (m, 1H), 3.00 (m, 1H), 2.60 (t, 1H, J ) 0.8 Hz), 2.24
(m, 1H), 1.98 (m, 1H), 1.87 (m, 1H), 1.48 (m, 1H), 1.25 (m, 1H);
13C (100 MHz, D2O) δ 178.1, 169.7, 165.4, 138.0, 135.4, 131.7,
130.4, 129.4, 129.2, 128.6, 127.3, 126.7, 120.6, 60.8, 58.8, 56.5,
39.7, 38.3, 35.1, 30.1, 27.2; 31P (161.3 MHz, D2O) δ 9.0; LRMS
(FAB, NBA, m/z) 566.
(2R,4S,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (22b). Prepared following the synthetic
sequence for the preparation of 19b, starting from D-pyroglutamic
acid: 31 mg; [R]D +14.3 (c 0.1, H2O); 1H NMR (300 MHz, D2O)
δ 7.82 (m, 4H), 7.47-7.01 (m, 7H), 4.59 (m, 1H), 4.31 (m, 1H),
3.69 (m, 1H), 3.60 (m, 1H), 3.24 (m, 1H), 3.05 (m, 1H), 2.84 (m,
1H), 2.06 (m, 3H), 1.75 (m, 1H), 1.35 (m, 1H); 13C (100 MHz,
D2O) δ 178.1, 169.3, 164.8, 138.1, 135.1, 131.3, 130.6, 129.5,
128.9, 127.1, 126.3, 121.2, 120.3, 63.6, 61.9, 58.9, 56.5, 39.4, 38.2,
36.6, 30.5; 31P (161.3 MHz, D2O) δ 10.3; LRMS (FAB, NBA, m/z)
566.
(2S,4R,5R)-5-(Dimethoxyphosphoryl)-4-isobutylpyrrolidine-
1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (23a)
and (2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-isobutylpyrrolidine-
1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (23b).
The lactam 10a (406 mg, 1.36 mmol) was dissolved in EtOH (15
mL), and a catalytic amount of Pd(OH)2, 20% over carbon, was
added. The reaction was kept under 60 psi of H2 for 3 h at rt. The
suspension was filtered through a pad of Celite and concentrated
in vacuo to afford the desired intermediate in quantitative yield.
Following the procedure for the preparation of 11a and 11b gave
the two phosphonates 23a and 23b (1.2:1 in favor of 23b). For
23a: 172 mg (32%, three steps); [R]D -22.6 (c 0.9, CHCl3); IR
(neat/NaCl) 2957, 1749, 1712, 1367 cm-1; for a mixture of two
rotamers 1H NMR (300 MHz, CDCl3) δ 4.35 (dd, 1H, J ) 2.6, 7.8
Hz), 4.24 (m, 1H), 3.71-3.68 (m, 6H), 3.67 (s, 3H), 2.64 (m, 1H),
2.46 (m, 2H), 1.84 (dd, 1H, J ) 5.8, 12.6 Hz), 1.54 (m, 2H), 1.42
(s, 3H), 1.35 (s, 6H), 0.86 (d, 3H, J ) 6.1 Hz), 0.81 (d, 3H, J )
5.8 Hz); 13C (100 MHz, CDCl3) δ 173.4, 153.0, 80.7 and 80.5,
58.8 and 58.5, 56.6 (d), 53.0, 52.1, 51.9, 37.6, 37.1, 35.1 and 33.9,
[R]D -78.7 (c 0.5, H2O); IR (KBr) 3433, 1698, 1656, 1591 cm-1
;
1H NMR (300 MHz, D2O) δ 8.15 (m, 4H), 7.58 (t, 2H, J ) 7.7
Hz), 7.24 (m, 2H), 7.11 (m, 3H), 4.70 (dd, 1H, J ) 2.3, 3.2 Hz),
4.35 (dd, 1H,, J ) 5.1, 9.0 Hz), 4.24 (dd, 1H,, J ) 5.4, 9.5 Hz),
3.88 (t, 2H, J ) 6.5 Hz), 3.48 (dd, 1H, J ) 9.2, 6.0 Hz), 3.10 (dd,
1H, J ) 5.0, 13.9 Hz), 2.87 (dd, 1H, J ) 9.1, 13.9 Hz), 2.39 (m,
1H), 2.18 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.62 (m, 1H); 13
C
(100 MHz, D2O) δ 178.4, 171.8, 166.2, 138.6, 136.0, 132.4, 131.7,
130.0, 129.3, 127.9, 127.6, 127.5, 121.5, 61.8, 59.6, 57.6, 40.0,
38.8, 38.2, 35.0, 27.7; 31P (161.3 MHz, D2O) δ 11.6; LRMS (FAB,
NBA, m/z) 565, 549, 485.
(2S,4R,5S)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (19b). Following the preparation of 19a gave
compound 19b, 30 mg (64%, two steps): IR (KBr) 3443, 1697,
1656, 1591, 1456 cm-1; 1H NMR (300 MHz, D2O) δ 8.24 (d, 2H,
J ) 8.2 Hz), 8.17 (d, 2H, J ) 7.7 Hz), 7.63 (t, 2H, J ) 8.2 Hz),
7.33 (t, 2H, J ) 7.5 Hz), 7.25 (t, 3H, J ) 9.2 Hz), 4.45 (dd, 1H,
J ) 5.2 8.9 Hz), 4.36 (dd, 1H, J ) 5.1, 9.5 Hz), 3.99 (m, 1H), 3.87
(m, 1H), 3.26 (t, 1H, J ) 10.0 Hz), 3.21 (dd, 1H, J ) 5.4, 14.1
Hz), 2.98 (dd, 1H, J ) 8.8, 13.6 Hz), 2.44 (m, 1H), 2.34 (m, 1H),
2.23 (m, 1H), 2.13 (m, 1H), 1.54 (m, 1H); 13C (100 MHz, D2O) δ
178.0, 169.2, 165.3, 138.6, 135.7, 131.9, 131.1, 130.0, 129.8, 129.4,
127.6, 126.9, 120.7, 62.6, 61.2, 59.9, 39.4, 38.6, 38.0, 36.4, 30.0;
31P (161.3 MHz, D2O) δ 10.8; LRMS (FAB, NBA, m/z) 566.
(2S,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
(1H-indol-3-yl)propionic Acid (20a). Following the preparation
of 16a and the preparation of 19a gave compound 20a, 16 mg (80%,
four steps): [R]D -3.2 (c 0.4, H2O); IR (KBr) 3413, 2926, 1698,
1654, 1590 cm-1; 1H NMR (300 MHz, D2O) δ 8.02 (m, 2H), 7.56
(m, 2H), 7.44 (m, 1H), 7.24 (m, 1H), 7.04 (m, 2H), 6.95 (m, 2H),
6.72 (m, 1H), 4.42 (m, 1H), 3.85 (m, 2H), 3.48 (m, 2H), 3.02 (m,
2H), 2.07 (m, 2H), 1.98 (m, 1H), 1.70-1.25 (m, 2H); 13C (100
MHz, D2O) δ 179.2, 175.6, 166.1, 136.6, 135.7, 132.1, 131.0, 128.0,
127.7, 126.9, 124.7, 122.3, 121.2, 119.7, 119.1, 112.4, 111.0, 62.3,
59.6, 56.3, 40.4, 38.6, 35.0, 28.3; 31P (161.3 MHz, D2O) δ 14.6.
(2S,4R,5S)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
(1H-indol-3-yl)propionic Acid (20b). Following the preparation
2770 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
28.0 and 27.8, 26.4, 22.8, 22.2; 31P (161.3 MHz, CDCl3) δ 25.7
(minor rotamer), 25.4 (major rotamer); LRMS (FAB, NBA, m/z)
394, 338, 307; HRMS for C17H32NO7P (MH+) calcd 394.199466,
obsd 394.199019. For 23b: 204 mg (37%, three steps); [R]D +12.7
(c 0.8, CHCl3); IR (neat/NaCl) 2958,1761, 1706, 1368 cm-1; for a
(2S,4R,5S)-5-(Dimethoxyphosphoryl)-4-[3-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)propyl]pyrrolidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (26). The olefin 11b (100 mg,
0.26 mmol) was placed in a flame-dried flask and dissolved in dry
THF (4 mL). BH3‚THF (278 µL, 0.28 mmol, 1 M in THF) was
slowly added at 0 °C, and the resulting mixture was stirred for 1.5
h. NaOH (344 µL, 0.34 mmol, 1 M in H2O) was added dropwise,
followed by H2O2 30% v/v (300 µL, 2.65 mmol). The solution was
stirred for 10 min before addition of brine. The aqueous phase was
extracted with Et2O. The combined organic layers were washed
with water and brine, dried over Na2SO4, and concentrated in vacuo
to afford the desired alcohol. Following the procedure for the
preparation of 15a gave compound 26 (45 mg, 30%, three steps):
[R]D +5.8 (c 1.1, CHCl3); IR (neat/NaCl) 2956, 1759, 1702, 1662
cm-1; for a mixture of two rotamers 1H NMR (300 MHz, CDCl3)
δ 8.60 (d, 2H, J ) 7.2 Hz), 8.22 (d, 2H, J ) 8.2 Hz), 7.76 (t, 2H,
J ) 7.6 Hz), 4.40-4.22 (m, 1H), 4.18 (m, 2H), 4.10-3.95 (m,
1H), 3.86 (d, 3H, J ) 10.4 Hz), 3.76 (d, 3H, J ) 10.6 Hz), 3.73 (s,
3H), 2.50 (m, 2H), 2.08 (t, 1H, J ) 9.7 Hz), 1.80 (m, 3H), 1.55
(m, 1H), 1.42 (s, 9H); 13C (100 MHz, CDCl3) δ 172.3, 164.2, 156.8,
134.0, 131.6, 128.2, 126.9, 122.5, 81.0, 58.7, 58.4, 54.0 (d), 52.5,
52.0, 39.9, 39.8, 33.9, 32.4, 28.1, 26.1; 31P (161.3 MHz, CDCl3) δ
26.3 (major rotamer), 26.2 (minor rotamer); LRMS (FAB, NBA,
m/z) 575; HRMS for C28H35N2O9P calcd 575.215845, obsd
575.215957.
1
mixture of two rotamers H NMR (300 MHz, CDCl3) δ 4.35 (m,
1H), 4.21 (m, 1H), 3.80 (d, 3H, J ) 10.4 Hz), 3.70 (d, 3H, J ) 9.8
Hz), 3.66 (s, 3H), 2.52 (m, 2H), 1.96 (m, 1H), 1.52 (m, 1H), 1.42
(s, 3H), 1.36 (s, 6H), 1.18 (m, 1H), 1.10 (m, 1H), 0.85 (d, 3H, J )
3.3 Hz), 0.83 (d, 3H, J ) 3.3 Hz); 13C (100 MHz, CDCl3) δ 172.4,
153.9, 80.8, 59.1 (d), 58.7, 53.9, 52.3, 51.8, 42.7 (d), 38.0 and 37.2,
34.4 and 33.5, 28.0, 25.7, 22.3, 22.1; 31P (161.3 MHz, CDCl3) δ
25.7; LRMS (FAB, NBA, m/z) 394, 338; HRMS for C17H32NO7P
(MH+) calcd 394.199466, obsd 394.199255.
(2S,4R,5R)-(2S)-{[4-(3-Naphthalen-1-ylallyl)-5-phosphonopyr-
rolidine-2-carbonyl]amino}-3-phenylpropionic Acid (24a). Fol-
lowing the preparation of 16a and the preparation of 19a gave
compound 24a, 16 mg (41%, four steps): mp 102 °C; [R]D -10.6
1
(c 0.9, MeOH); IR (KBr) 3360, 2926, 1676 cm-1; H NMR (300
MHz, CD3OD) δ 8.15 (m, 1H), 7.83 (d, 1H, J ) 7.7 Hz), 7.75 (d,
1H, J ) 8.5 Hz), 7.59 (d, 1H, J ) 6.2 Hz), 7.48 (m, 3H), 7.24 (m,
5H), 7.10 (m, 1H), 6.23 (m, 1H), 4.68 (dd, 1H, J ) 4.6, 9.8 Hz),
4.45 (m, 1H), 3.88 (d, 1H, J ) 10.8 Hz), 3.65 (d, 1H, J ) 10.4
Hz), 3.31 (t, 1H, J ) 1.6 Hz), 3.26 (m, 1H), 2.95 (dd, 1H, J )
10.0, 14.0 Hz), 2.58 (m, 1H), 2.33 (m, 2H); 13C (100 MHz, CD3-
OD) δ 172.5, 168.2, 137.9, 136.1, 134.7, 132.0, 129.9, 129.1, 128.5,
126.8, 125.9, 125.7, 123.8, 123.7, 123.6, 59.2, 54.8, 41.1, 36.9,
35.0, 32.8, 29.7; 31P (161.3 MHz, CD3OD) δ 12.9; LRMS (FAB,
NBA, m/z) 509, 427, 421.
(2S,4R,5S)-(2S)-({4-[3-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)propyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
(1H-indol-3-yl)propionic Acid (27). Following the preparations
of 16a and of 19a gave compound 27, 11 mg (53%, four steps):
[R]D +2.6 (c 0.6, H2O); IR (KBr) 3402, 2955, 1754, 1701, 1663
(2S,4R,5S)-(2S)-{[4-(3-Naphthalen-1-ylallyl)-5-phosphonopyr-
rolidine-2-carbonyl]amino}-3-phenylpropionic Acid (24b). Fol-
lowing the preparation of 16a and the preparation of 19a gave
compound 24b, 16 mg (40%, four steps): mp 97° C; [R]D -72.7
1
cm-1; H NMR (300 MHz, D2O) δ 7.82 (m, 2H), 7.34 (m, 2H),
6.99 (m, 2H), 6.79 (m, 2H), 6.66 (m, 2H), 6.50 (m, 1H), 4.36 (m,
1H), 3.79 (m, 1H), 3.50 (m, 2H), 3.19 (m, 1H), 3.08 (m, 1H), 2.76
(m, 1H), 2.06 (m, 1H), 1.75 (m, 2H), 1.25 (m, 2H), 1.16 (m, 2H);
13C (100 MHz, D2O) δ 176.6, 172.2, 163.2, 134.0, 133.2, 130.6,
129.5, 127.8, 125.3, 125.1, 122.3, 119.5, 118.5, 117.1, 116.5, 109.4,
108.5, 57.5, 53.9, 38.7, 37.9, 34.3, 28.2, 25.4, 23.8, 16.0; 31P (161.3
MHz, D2O) δ 14.3.
1
(c 0.8, MeOH); IR (neat/NaCl) 3360, 2925, 1678 cm-1; H NMR
(300 MHz, CD3OD) δ 8.15 (d, 1H, J ) 7.7 Hz), 7.85 (d, 1H, J )
7.4 Hz), 7.77 (d, 1H, J ) 8.5 Hz), 7.62 (m, 1H), 7.49 (m, 3H),
7.22 (m, 5H), 7.10 (m, 1H), 6.24 (m, 1H), 4.69 (t, 1H, J ) 4.3
Hz), 4.28 (m, 1H), 3.67 (m, 2H), 3.29 (m, 1H), 3.01 (m, 2H), 2.38
(m, 3H); 13C (100 MHz, CD3OD) δ 173.4, 170.8, 138.3, 136.2,
135.1, 132.4, 131.0, 129.5, 128.7, 127.8, 127.0, 126.7, 126.6, 124.8,
124.7, 60.4, 59.6, 55.7, 37.7, 30.7, 30.1, 24.0; 31P (161.3 MHz,
CD3OD) δ 11.6; LRMS (FAB, NBA, m/z) 522, 508, 505; HRMS
calcd for C27H28N2O6P 507.168500, obsd 507.168697.
(2S,4S)-4-Allyl-5-(dimethoxyphosphoryl)pyrrolidine-1,2-di-
carboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (28). Following
the preparation of 11 gave compound 28, 789 mg (68%, three steps,
inseparable mixture): IR (neat/NaCl) 3479, 2958, 1761, 1706, 1381
cm-1; for a mixture of two rotamers 1H NMR (300 MHz, CDCl3)
δ 5.76 (m, 1H), 5.08 (d, 1H, J ) 17.3 Hz), 4.98 (d, 1H, J ) 9.9
Hz), 4.29 (m, 1H), 4.18 (m, 1H), 3.87 (d, 3H, J ) 10.3 Hz), 3.72
(d, 3H, J ) 10.7 Hz), 3.70 (s, 3H), 2.51 (m, 1H), 2.32-2.28 (m,
4H), 1.44 (s, 3H), 1.39 (s, 6H); 13C (100 MHz, CDCl3) δ 172.0,
153.6, 136.1, 116.4, 80.8, 59.4, 57.9, 55.8, 54.0, 51.9, 41.2, 34.4,
33.2, 28.2 and 28.0; 31P (161.3 MHz, CDCl3) δ 25.5; LRMS (FAB,
NBA, m/z) 378, 322; HRMS for C16H28NO7P (MH+) calcd
378.168166, obsd 378.169900.
(2S,4R,5R)-(2S)-[(4-Isobutyl-5-phosphonopyrrolidine-2-car-
bonyl)amino]-3-phenylpropionic Acid (25a). Following the prepa-
ration of 16a and the preparation of 19a gave compound 25a, 19
mg (66%, four steps): [R]D -63.0 (c 0.3, H2O); IR (KBr) 3420,
1
2959, 1683, 1455 cm-1; H NMR (300 MHz, D2O) δ 7.34-7.16
(m, 5H), 4.55 (d, 1H, J ) 1.89 Hz), 4.45 (d, 1H, J ) 9.4 Hz), 4.22
(t, 1H, J ) 8.7 Hz), 3.22 (dd, 1H, J ) 4.4, 14.2 Hz), 3.07 (dd, 1H,
J ) 4.4, 14.1 Hz), 1.82 (m, 1H), 1.63 (m, 1H), 1.45-1.38 (m,
4H), 0.81 (d, 3H, J ) 6.2 Hz), 0.73 (d, 3H, J ) 6.2 Hz); 13C (100
MHz, D2O) δ 178.5, 172.5, 135.3, 130.6, 129.0, 127.9, 61.1 (d),
56.9, 56.7, 38.9, 38.8, 36.5, 32.7, 26.5, 21.4, 24.0; 31P (161.3 MHz,
D2O) δ 14.4; LRMS (FAB, NBA, m/z) 395, 299.
(2S,4S)-5-(Dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-ben-
zo[de]isoquinolin-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (29). Following the preparation
of 14a and of 15a gave compound 29 as a white solid, 355 mg
(32%, four steps): IR (neat/NaCl) 3470, 2957, 1757, 1699, 1660,
(2S,4R,5S)-(2S)-[(4-Isobutyl-5-phosphonopyrrolidine-2-carbo-
nyl)amino]-3-phenylpropionic Acid (25b). Following the prepara-
tion of 16a and the preparation of 19a gave compound 25b, 26 mg
(70%, four steps): [R]D -56.0 (c 0.3, H2O); IR (KBr) 3437, 2957,
1618, 1385 cm-1; 1H NMR (300 MHz, D2O) δ 7.31 (m, 2H), 7.23
(m, 3H), 4.42 (dd, 1H, J ) 5.0, 8.8 Hz), 4.14 (dd, 1H, J ) 5.6, 9.5
Hz), 3.17 (dd, 1H, J ) 5.05, 13.9 Hz), 2.99 (t, 1H, J ) 3.2 Hz),
2.92 (dd, 1H, J ) 8.8, 13.9 Hz), 2.28 (m, 1H), 2.20 (m, 1H), 1.99
(m, 1H), 1.52 (m, 2H), 1.14 (m,1H), 0.84 (d, 3H, J ) 6.2 Hz),
0.81 (d, 3H, J ) 6.0 Hz); 13C (100 MHz, D2O) δ 178.3, 170.2,
138.5, 130.0, 129.4, 127.6, 63.9 (d), 59.5, 57.8, 42.3, 38.9, 38.2,
36.7, 26.7, 23.9, 21.5; 31P (161.3 MHz, D2O) δ 11.0; LRMS (FAB,
NBA, m/z) 421, 307; HRMS for C18H26N2O6P (MH+) calcd
421.150445, obsd 421.152400.
1
1366, 1327 cm-1; for a mixture of two rotamers H NMR (300
MHz, CDCl3) δ 8.55 (m, 2H), 8.19 (m, 2H), 7.70 (m, 2H), 4.35
(m, 1H), 4.25 (m, 2H), 4.08 (m, 1H), 3.88 (d, 3H, J ) 10.2 Hz),
3.74 (d, 3H, J ) 10.6 Hz), 3.71 (s, 3H), 2.58 (m, 1H), 2.31-2.18
(m, 3H), 2.01 (m, 1H), 1.46 (s, 3H), 1.38 (s, 6H); 13C (100 MHz,
CDCl3) δ 172.0, 164.1, 153.5, 133.9, 131.4, 131.2, 128.0, 126.8,
122.4, 80.7 and 80.6, 59.4, 59.2 (d), 55.9, 54.1, 52.1, 38.9, 38.2,
34.6, 33.6, 28.0 and 27.6; 31P (161.3 MHz, CDCl3) δ 24.6 (minor
rotamer), 24.4 (major rotamer); LRMS (FAB, NBA, m/z) 561, 505,
351; HRMS for C27H33N2O9P (MH+) calcd 561.200195, obsd
561.198600.
(2R,3S,5S)-5-[(1S)-tert-Butoxycarbonyl-2-phenylethylcarbam-
oyl]-2-(dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-benzo[de]-
J. Org. Chem, Vol. 71, No. 7, 2006 2771

Hanessian et al.
isoquinolin-2-yl)ethyl]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (30). Following the preparation of 16a gave compound 30,
131 mg (65%, two steps): [R]D -2.9 (c 1.1, CHCl3); mp 82 °C;
IR (neat/NaCl) 2978, 1703, 1664, 1364 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.54 (d, 2H, J ) 7.2 Hz), 8.18 (d, 2H, J ) 7.6 Hz), 7.84
(bs, 1H), 7.72 (t, 2H, J ) 7.8 Hz), 7.25 (m, 5H), 4.71 (dd, 1H, J
) 7.52 Hz), 4.46 (m, 1H), 4.23 (m, 2H), 4.08 (m, 1H), 3.82-3.79
(m, 6H), 3.02 (d, 2H, J ) 7.3 Hz), 2.46-2.35 (m, 2H), 2.25 (m,
1H), 2.11 (m, 1H), 1.95 (m, 1H), 1.38 (s, 9H), 1.28 (s, 9H); 13C
(100 MHz, CDCl3) δ 171.9, 170.4, 164.1, 154.4, 136.7, 133.9,
131.5, 131.2, 129.6, 128.2, 128.0, 126.8, 126.5, 122.4, 81.4, 81.2,
63.5, 54.0, 53.7, 52.5, 52.4, 39.3, 39.0, 38.8, 35.9, 28.2, 27.9, 27.1;
31P (161.3 MHz, CDCl3) δ 25.7; LRMS (FAB, NBA, m/z) 750,
540, 484; HRMS for C39H48O10N3P (MH+) calcd 750.315559, obsd
750.318900.
(2S,4S,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (31). Following the preparation of 19a gave
compound 31, 13 mg (38%, two steps): [R]D -8.2 (c 0.4, H2O);
IR (KBr) 3407, 1699, 1658, 1591, 1388 cm-1; 1H NMR (300 MHz,
D2O) δ 8.10 (d, 2H, J ) 8.1 Hz), 8.08 (d, 2H, J ) 6.9 Hz), 7.55
(t, 2H, J ) 7.7 Hz), 7.34-7.29 (m, 2H), 7.10 (m, 2H), 6.94 (t, 1H,
J ) 6.8 Hz), 4.70 (m, 1H), 4.38 (dd, 1H, J ) 5.0, 7.9 Hz), 4.08
(dd, 1H, J ) 5.9, 9.7 Hz), 3.77 (t, 2H, J ) 7.2 Hz), 3.44 (dd, 1H,
J ) 7.2, 9.9 Hz), 3.08 (dd, 1H, J ) 5.1, 14.0 Hz), 2.90 (dd, 1H, J
) 8.1, 14.0 Hz), 2.44 (m, 1H), 2.36 (m, 1H), 2.16-2.08 (m, 2H);
13C (100 MHz, D2O) δ 178.3, 172.2, 165.8, 138.5, 135.8, 132.1,
131.5, 130.0, 129.2, 127.8, 127.4, 121.2, 62.6, 60.8, 60.0, 40.0,
38.9, 38.4, 35.2, 28.3; 31P (161.3 MHz, D2O) δ 12.3; LRMS (FAB,
NBA, m/z) 588, 566, 484.
(2R,4R,5S)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquino-
lin-2-yl)ethyl]-5-phosphonopyrrolidine-2-carbonyl}amino)-3-
phenylpropionic Acid (32). Prepared following the synthetic
sequence for the preparation of 31, starting from D-pyroglutamic
acid: 11 mg; [R]D +28.6 (c 0.05, H2O); 1H NMR (300 MHz, D2O)
δ 7.87 (m, 4H), 7.37 (m, 2H), 7.25-7.07 (m, 5H), 4.42 (dd, 1H, J
) 5.5, 8.4 Hz), 4.12-4.06 (m, 1H), 3.52 (m, 2H), 3.25 (dd, 1H, J
) 6.0, 11.1 Hz), 3.05 (dd, 1H, J ) 5.0, 13.7 Hz), 2.79 (dd, 1H, J
) 8.5, 13.2 Hz), 2.25 (m, 2H), 2.04-1.95 (m, 1H), 1.65-1.59 (m,
1H), 1.33-1.25 (m, 1H); 13C (100 MHz, D2O) δ 178.2, 169.7,
165.5, 137.9, 135.3, 131.6, 131.0, 129.6, 128.9, 127.2, 127.0, 121.2,
120.8, 62.7, 59.5, 56.9, 39.2, 38.3, 38.1, 35.1, 27.5; 31P (161.3 MHz,
D2O) δ 9.2; LRMS (FAB, NBA, m/z) 566.
(2R,3R)-2-(tert-Butyldiphenylsilanyloxymethyl)-3-isobutyl-5-
oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (34). A cata-
lytic amount of CuI (232 mg, 1.22 mmol), previously flame-dried
under vacuum until bright yellow, was added in one portion to a
solution of Me2CHCH2MgBr (8.52 mL, 17.0 mmol, 2 M in Et2O)
in dry Et2O (170 mL) cooled at -20 °C. After 15 min, the solution
turned black, and the unsaturated lactam 33 (5.5 g, 12.2 mmol),
dissolved in dry Et2O (120 mL), was added dropwise via a cannula.
The mixture was stirred at -20 °C until completion (monitored by
TLC ca. 3 h). After addition of saturated NH4Cl and a 0.5 M
solution of NH4OH, the solution was allowed to reach rt. The
aqueous layer was extracted with Et2O, and the combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting oil was purified by flash
chromatography (hexanes/EtOAc, 8:2) to give 34 (5.4 g, 87%): [R]D
+19.9 (c 3.7, CHCl3); IR (neat/NaCl) 3410, 3073, 3050, 2958, 2933,
2900, 2860, 1789, 1753, 1713, 1590, 1568, 1472, 1428, 1392, 1368,
1311, 1257, 1207, 1155, 1113 cm-1; 1H NMR (300 MHz, CHCl3)
δ 7.59 (m, 4H), 7.33-7.25 (m, 6H), 3.88-3.81 (m, 2H), 3.69 (d,
1H, J ) 9.2 Hz), 2.86 (dd, 1H, J ) 8.8, 17.6 Hz), 2.37 (m, 1H),
2.09 (d, 1H, J ) 17.6 Hz), 1.60-1.53 (m, 1H), 1.39 (s, 9H), 1.33-
1.21 (m, 2H), 1.01 (s, 9H), 0.85 (d, 6H, J ) 6.4 Hz); 13C (100
MHz, CDCl3) δ 175.0, 150.4, 135.9, 133.3, 130.3, 128.3, 83.2, 65.0,
64.8, 44.9, 39.0, 31.4, 28.4, 27.2, 25.7, 23.2, 22.8, 19.6; LRMS
(FAB, NBA, m/z) 410.2.
(3R,4R,5R)-3-Allyl-5-(tert-butyldiphenylsilanyloxymethyl)-4-
isobutyl-2-oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester
(35a) and (3S,4R,5R)-3-Allyl-5-(tert-butyldiphenylsilanyloxy-
methyl)-4-isobutyl-2-oxopyrrolidine-1-carboxylic Acid tert-Butyl
Ester (35b). Following the preparation of 7a and 7b gave
compounds 35a and 35b (4:1 in favor of 35a). For 35a: 2.1 g
(37%); [R]D +14.9 (c 1.5, CHCl3); IR (neat/NaCl) 3638, 3470,
3074, 3052, 3002, 2959, 2933, 2893, 2860, 1959, 1887, 1822, 1780,
1722, 1591, 1568, 1473, 1429, 1393, 1364, 1305, 1259, 1189, 1153,
1
1119, 1030 cm-1; H NMR (300 MHz, CHCl3) δ 7.66-7.61 (m,
4H), 7.46-7.35 (m, 6H), 5.82-5.73 (m, 1H), 5.11-5.04 (m, 2H),
3.83-3.69 (m, 3H), 2.60-2.54 (m, 1H), 2.40-2.22 (m, 3H), 1.65-
1.56 (m, 1H), 1.42 (s, 9H), 1.38-1.29 (m, 2H), 1.07 (s, 9H), 0.94
(d, 3H, J ) 6.3 Hz), 0.89 (d, 3H, J ) 6.3 Hz); 13C (100 MHz,
CDCl3) δ 175.8, 149.9, 135.5, 132.9, 132.7, 129.7, 127.7, 117.3,
82.7, 64.1, 63.7, 49.6, 46.3, 36.1, 33.8, 27.8, 26.7, 25.1, 22.6, 19.1;
LRMS (FAB, NBA, m/z) 450; HRMS for C33H47NO4Si (MNa+)
calcd 572.317208, obsd 572.318400. For 35b: 0.5 g (9%); [R]D
+31.6 (c 0.6, CHCl3); IR (neat/NaCl) 3448, 3073, 2958, 1789, 1755,
1714, 1642, 1590, 1560, 1541, 1508, 1472, 1429, 1392, 1369, 1312,
1258, 1157, 1113 cm-1; 1H NMR (300 MHz, CHCl3) δ 7.69-7.62
(m, 4H), 7.50-7.37 (m, 6H), 5.83 (dddd, 1H, J ) 5.8, 7.4, 10.2,
17.4 Hz), 5.17-5.09 (m, 2H), 3.94 (dd, 1H, J ) 3.2, 5.7 Hz), 3.86-
3.74 (m, 2H), 3.06 (ddd, 1H, J ) 4.6, 7.9, 10.8 Hz), 2.62 (ddd,
1H, J ) 5.1, 5.1, 15.8 Hz), 2.49 (ddd, 1H, J ) 3.8, 8.0, 11.5 Hz),
2.12 (ddd, 1H, J ) 7.4, 10.8, 15.6 Hz), 1.72-1.62 (m, 1H), 1.48
(s, 9H), 1.17 (ddd, 2H, J ) 3.7, 10.8, 10.8 Hz), 1.07 (s, 9H), 0.96
(d, 3H, J ) 6.6 Hz), 0.89 (d, 3H, J ) 6.5 Hz); 13C (100 MHz,
CDCl3) δ 175.8, 150.8, 136.3, 135.9, 133.2, 130.3, 128.3, 116.6,
83.1, 64.1, 61.6, 45.6, 36.9, 34.9, 29.6, 27.2, 25.6, 24.7, 21.5, 19.6;
LRMS (FAB, NBA, m/z) 450; HRMS for C33H47NO4Si (MNa+)
calcd 572.317208, obsd 572.315500.
(2R,3R,4R)-4-Allyl-3-isobutyl-5-oxopyrrolidine-1,2-dicarbox-
ylic Acid 1-tert-Butyl Ester 2-Methyl Ester (36). Glacial acetic
acid (833 µL, 14.6 mmol) and TBAF (4.73 mL, 4.73 mmol, 1 M
in THF) were added to a solution of lactam 35a (2.0 g, 3.64 mmol)
in dry THF (72 mL) at rt. The solution was stirred until completion
(monitored by TLC, ca. 48 h). An aqueous saturated solution of
NaHCO3 was added, and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The crude alcohol was
dissolved in acetone (72 mL), and Jones’ reagent was added
dropwise until an orange-red color persisted. The solution was
stirred at rt until completion (monitored by TLC). A solution of
brine was added, and the aqueous layer was extracted with Et2O
and then with EtOAc. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude acid was
suspended in dry Et2O (72 mL) at 0 °C. A freshly prepared CH2N2
etheral solution was added dropwise until a yellow color persisted.
After 1 h, the solvent was removed in vacuo at rt. Purification by
flash chromatography (hexanes/EtOAc, 8:2) gave the desired methyl
ester 36 (0.8 g, 65%, three steps): [R]D -30.7 (c 0.8, CHCl3); 1H
NMR (300 MHz, CHCl3) δ 5.73 (m, 1H), 5.10-5.03 (m, 2H), 4.17
(d, 1H, J ) 4.3 Hz), 3.77 (s, 3H), 2.55-2.49 (m, 1H), 2.39-2.27
(m, 2H), 2.14-2.07 (m, 1H), 1.76-1.69 (m, 1H), 1.49 (s, 9H),
1.49-1.45 (m, 1H), 1.38-1.31 (m, 1H), 0.93 (d, 3H, J ) 6.6 Hz),
0.87 (d, 3H, J ) 6.6 Hz); 13C (100 MHz, CDCl3) δ 175.0, 172.6,
149.8, 135.1, 118.4, 84.1, 63.9, 52.8, 49.8, 45.6, 36.8, 35.6, 28.3,
25.5, 23.2, 22.5; LRMS (FAB, NBA, m/z) 240.1; HRMS for C18H29-
NO5 (MNa+) calcd 362.194343, obsd 362.194900.
(2R,3R,4R,5S)-4-Allyl-5-(dimethoxyphosphoryl)-3-isobutylpyr-
rolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(37a) and (2R,3R,4R,5R)-4-Allyl-5-(dimethoxyphosphoryl)-3-
isobutylpyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (37b). Following the preparation of 11a and 11b
gave compounds 37a and 37b; (2:1 in favor of 37b). For 37a: 262
mg (29%, three steps); [R]D +36.9 (c 2.0, CHCl3); IR (neat/NaCl)
3486, 3078, 2956, 1752, 1706, 1641, 1456, 1392, 1254, 1177 cm-1
;
for a mixture of two rotamers 1H NMR (300 MHz, CHCl3) δ 5.60-
2772 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
5.51 (m, 1H), 4.94-4.88 (m, 2H), 3.94 (m, 1H), 3.84 (d, 1H, J )
3.7 Hz), 3.64-3.59 (m, 9H), 2.34-2.11 (m, 3H), 1.99 (m, 1H),
1.53-1.37 (m, 2H), 1.25 (s, 10H), 0.72 (m, 6H); 13C (100 MHz,
CDCl3) δ 173.7 and 173.0, 153.7, 135.9, 118.0, 81.1 and 81.0, 66.4,
60.6, 58.5, 53.5 (d), 53.2 (d), 52.2, 46.8, 45.0 (d), 40.4, 28.3, 25.9,
23.1, 22.3; 31P (161.3 MHz, CDCl3) δ 28.8; LRMS (FAB, NBA,
m/z) 434; HRMS for C20H36NO7P (MH+) calcd 434.230766, obsd
434.232700. For 37b: 544 mg (58%, three steps); [R]D +36.5 (c
1.2, CHCl3); IR (neat/NaCl) 3491, 2957, 2871, 1758, 1707, 1641,
1455, 1387, 1367, 1250, 1175, 1147, 1123 cm-1; for a mixture of
54.5, 53.2, 52.4, 46.6, 42.6, 39.8, 34.6, 32.5, 28.9, 28.6, 27.2, 25.7,
24.4, 22.1; 31P (161.3 MHz, CDCl3) δ 26.9; LRMS (FAB, NBA,
m/z) 777.
(2R,3R,4R,5R)-2-[(1S)-tert-Butoxycarbonyl-2-(1H-indol-3-yl)-
ethylcarbamoyl]-5-(dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-3-isobutylpyrrolidine-1-carbox-
ylic Acid tert-Butyl Ester (41). Following the preparation of 16a
gave compound 41, 35 mg (42%, two steps): [R]D +34.7 (c 1.0,
CHCl3); IR (neat/NaCl) 3295, 2957, 1734, 1702, 1662, 1626, 1591,
1537, 1458, 1368, 1236, 1156 cm-1; for a mixture of two rotamers
1H NMR (300 MHz, CHCl3) δ 8.60 (d, 2H, J ) 7.2 Hz), 8.21 (d,
2H, J ) 8.3 Hz), 7.75 (t, 2H, J ) 7.4 Hz), 7.45 (m, 1H), 7.31 (m,
1H), 7.19-7.03 (m, 4H), 4.85 (ddd, 1H, J ) 5.5, 5.5, 7.9 Hz),
4.73 (m, 1H), 4.34 (m, 2H), 3.92 (m, 3H), 3.78 (m, 4H), 3.34-
3.21 (m, 1H), 3.18 (m, 2H), 2.58 (m, 1H), 2.14 (m, 2H), 1.93 (m,
1H), 1.88-1.77 (m, 1H), 1.58 (m, 1H), 1.39 (s, 9H), 1.25 (s, 9H),
0.98-0.88 (m, 1H), 0.76 (m, 6H); 13C (100 MHz, CDCl3) δ 185.3,
172.5, 171.1, 164.1, 135.9, 133.8, 131.4, 131.1, 128.0, 127.4, 126.8,
122.5, 121.9, 121.7, 119.1, 118.6, 111.1, 110.8, 81.4, 81.2, 70.1,
65.0, 60.2, 53.3, 52.8, 52.6, 45.9, 41.7, 39.3, 28.3, 27.9, 27.6, 26.6,
25.2, 23.7, 21.7; 31P (161.3 MHz, CDCl3) δ 27.4; LRMS (FAB,
NBA, m/z) 846.
1
two rotamers H NMR (300 MHz, CHCl3) δ 5.77-5.66 (m, 1H),
4.94-4.82 (m, 2H), 4.24-4.09 (m, 1H), 3.77-3.63 (m, 4H), 3.57-
3.54 (m, 6H), 2.45-2.35 (m, 2H), 2.17-2.12 (m, 1H), 1.92-1.77
(m, 1H), 1.61-1.57 (m, 1H), 1.29-1.16 (s, 11H), 0.81 (d, 3H, J
) 6.5 Hz), 0.53 (d, 3H, J ) 6.5 Hz); 13C (100 MHz, CDCl3) δ
172.9, 153.6, 137.0, 116.2, 81.1, 66.5, 58.0, 55.9, 54.1, 52.0, 48.4,
45.0, 41.7, 31.8, 28.3, 26.3, 23.9, 22.3; 31P (161.3 MHz, CDCl3) δ
24.6; LRMS (FAB, NBA, m/z) 434; HRMS for C20H36NO7P (MH+)
calcd 434.230766, obsd 434.232200.
(2R,3R,4R,5R)-5-(Dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-3-isobutylpyrrolidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (38). Following
the preparation of 14a and the preparation of 15a gave compound
38, 100 mg (27%, four steps): [R]D +18.6 (c 1.1, CHCl3); IR (neat/
NaCl) 3455, 2957, 2361, 1756, 1703, 1663, 1627, 1591, 1439, 1386,
(2R,3R,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]iso-
quinolin-2-yl)ethyl]-3-isobutyl-5-phosphonopyrrolidine-2-
carbonyl}amino)-3-phenylpropionic Acid (42). Following the
preparation of 19a gave compound 42, 40 mg (82%, two steps):
[R]D +7.1 (c 0.2, H2O); 1H NMR (300 MHz, D2O) δ 7.72 (d, 2H,
J ) 6.9 Hz), 7.63 (d, 2H, J ) 6.6 Hz), 7.20-7.02 (m, 7H), 4.43 (t,
1H, J ) 6.2 Hz), 3.73 (m, 1H), 3.42 (m, 3H), 3.03 (d, 1H, J )
10.1 Hz), 2.89-2.81 (m, 1H), 2.08 (m, 3H), 1.38-1.23 (m, 4H),
0.69 (m, 6H); 13C (100 MHz, D2O) δ 178.1, 169.8, 164.5, 137.9,
134.9, 131.3, 130.8, 129.4, 129.0, 127.1, 127.0, 126.7, 120.6, 66.1,
61.4, 60.1, 57.0, 47.1, 44.2, 39.3, 37.7, 27.4, 26.0, 22.9, 22.1; 31P
(161.3 MHz, D2O) δ 8.9; LRMS (FAB, NBA, m/z) 624.
(2R,3R,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]iso-
quinolin-2-yl)ethyl]-3-isobutyl-5-phosphonopyrrolidine-2-
carbonyl}amino)-4-phenylbutyric Acid (43). Following the prepa-
ration of 19a gave compound 43, 7 mg (18%, three steps): [R]D
1
1248, 1175 cm-1; for a mixture of two rotamers H NMR (300
MHz, CHCl3) δ 8.54 (d, 2H, J ) 7.2 Hz), 8.16 (m, 2H), 7.70 (m,
2H), 4.63-4.58 (m, 1H), 4.41-4.17 (m, 2H), 3.86 (m, 7H), 3.69
(s, 3H), 2.71-2.53 (m, 1H), 2.37-2.15 (m, 1H), 2.08-1.86 (m,
2H), 1.78-1.12 (m, 1H), 1.48 (s, 3H), 1.40 (s, 6H), 1.40-1.18
(m, 2H), 0.85-0.67 (m, 6H); 13C (100 MHz, CDCl3) δ 172.6 and
172.2, 163.9, 156.3 and 153.1, 133.7, 131.4, 131.0, 127.9, 126.7,
122.4, 80.7, 66.0 and 63.5, 57.5, 55.9, 53.9, 51.9, 51.7, 46.3 and
46.1, 44.6 and 44.0, 41.6 and 41.0, 39.4, 28.1 and 28.0, 26.0 and
25.8, 23.5, 21.9; 31P (161.3 MHz, CDCl3) δ 24.4 (major rotamer),
24.1 (minor rotamer); LRMS (FAB, NBA, m/z) 617; HRMS for
C31H41N2O9P (MH+) calcd 617.262795, obsd 617.260922.
(2R,3R,4R,5R)-2-[(1S)-tert-Butoxycarbonyl-2-phenylethylcar-
bamoyl]-5-(dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-benzo-
[de]isoquinolin-2-yl)ethyl]-3-isobutylpyrrolidine-1-carboxylic Acid
tert-Butyl Ester (39). Following the preparation of 16a gave
compound 39, 63 mg (50%, two steps): [R]D +36.1 (c 1.4, CHCl3);
IR (neat/NaCl) 3265, 2957, 1737, 1703, 1664, 1627, 1591, 1544,
1498, 1456, 1368, 1236, 1154 cm-1; 1H NMR (300 MHz, CHCl3)
δ 8.58 (d, 2H, J ) 7.1 Hz), 8.19 (d, 2H, J ) 8.1 Hz), 8.13 (bd,
1H), 7.73 (t, 2H, J ) 7.5 Hz), 7.23-7.18 (m, 5H), 4.74 (m, 2H),
4.36 (m, 2H), 3.92 (d, 3H, J ) 9.3 Hz), 3.74 (m, 1H), 3.67 (d, 3H,
J ) 10.2 Hz), 3.06-2.99 (m, 2H), 2.54 (m, 1H), 2.21-1.92 (m,
4H), 1.77 (m, 1H), 1.39 (s, 9H), 1.30 (s, 10H), 0.75 (m, 6H); 13C
(100 MHz, CDCl3) δ 171.1, 164.6, 154.9, 137.4, 134.3, 132.0,
131.6, 129.8, 128.6, 127.3, 126.9, 123.1, 81.7, 81.6, 71.1, 60.9,
54.3, 53.8, 53.2, 46.5, 41.0, 39.9, 39.0, 28.6, 28.3, 28.2, 27.3, 25.8,
24.2, 22.4; 31P (161.3 MHz, CDCl3) δ 26.5; LRMS (FAB, NBA,
m/z) 807.
(2R,3R,4R,5R)-2-[(1S)-Methoxycarbonyl-3-phenylpropylcar-
bamoyl)-5-(dimethoxyphosphoryl)-4-[2-(1,3-dioxo-1H,3H-benzo-
[de]isoquinolin-2-yl)ethyl]-3-isobutylpyrrolidine-1-carboxylic Acid
tert-Butyl Ester (40). Following the preparation of 16a gave
compound 40, 49 mg (52%, two steps): [R]D +26.9 (c 1.3, CHCl3);
IR (neat/NaCl) 3267, 2956, 1747, 1702, 1663, 1627, 1591, 1551,
1498, 1455, 1366, 1236, 1173 cm-1; 1H NMR (300 MHz, CHCl3)
δ 8.60 (d, 2H, J ) 7.3 Hz), 8.58 (bd, 1H), 8.22 (d, 2H, J ) 8.1
Hz), 7.76 (t, 2H, J ) 7.8 Hz), 7.29-7.14 (m, 5H), 4.77 (m, 1H),
4.57 (ddd, 1H, J ) 4.9, 8.4, 8.4 Hz), 4.39 (m, 1H), 4.31 (m, 1H),
3.96 (d, 3H, J ) 10.6 Hz), 3.85 (d, 3H, J ) 10.5 Hz), 3.84 (m,
1H), 3.65 (s, 3H), 2.71-2.59 (m, 3H), 2.16-1.98 (m, 5H), 1.89-
1.78 (m, 1H), 1.43 (bs, 9H), 1.32 (t, 2H, J ) 6.8 Hz), 0.78 (m,
6H); 13C (100 MHz, CDCl3) δ 172.9, 164.7, 154.8, 141.4, 134.4,
132.0, 131.7, 128.8, 128.6, 127.4, 126.4, 123.0, 81.5, 70.9, 60.8,
1
+9.3 (c 0.1, H2O); H NMR (300 MHz, CHCl3) δ 7.89 (d, 2H, J
) 7.9 Hz), 7.83 (d, 2H, J ) 7.0 Hz), 7.36 (t, 1H, J ) 7.3 Hz), 7.26
(t, 2H, J ) 6.9 Hz), 7.19 (d, 2H, J ) 6.3 Hz), 7.12 (d, 2H, J ) 7.3
Hz), 4.14 (dd, 1H, J ) 4.0, 9.0 Hz), 3.80 (m, 1H), 3.73-3.68 (m,
1H), 3.66-3.61 (m, 1H), 3.49 (dd, 1H, J ) 5.5, 12.7 Hz), 2.53-
2.38 (m, 2H), 2.28 (m, 2H), 2.18-2.14 (m, 1H), 1.96-1.87 (m,
1H), 1.86-1.81 (m, 1H), 1.78-1.62 (m, 1H), 1.47 (t, 1H, J ) 7.6
Hz), 1.40-1.31 (m, 1H), 1.16-1.11 (m, 1H), 0.97 (d, 3H, J ) 6.5
Hz), 0.77 (d, 3H, J ) 6.7 Hz); 13C (100 MHz, CDCl3) δ 178.8,
165.0, 160.8, 141.9, 135.2, 131.7, 129.1, 128.9, 127.3, 127.2, 126.6,
120.9, 66.2, 61.2, 55.6, 45.3, 44.6, 39.5, 34.4, 32.4, 27.2, 25.9, 22.6,
22.3; 31P (161.3 MHz, CDCl3) δ 8.9; LRMS (FAB, NBA, m/z)
637.
(2R,3R,4R,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]iso-
quinolin-2-yl)ethyl]-3-isobutyl-5-phosphonopyrrolidine-2-
carbonyl}amino)-3-(1H-indol-3-yl)propionic Acid (44). Follow-
ing the preparation of 19a gave compound 43, 26 mg (86%, two
1
steps): [R]D +11.1 (c 0.1, H2O); H NMR (300 MHz, CHCl3) δ
8.31 (d, 2H, J ) 7.4 Hz), 8.27 (d, 2H, J ) 8.2 Hz), 7.71 (t, 2H, J
) 7.6 Hz), 7.53 (d, 1H, J ) 8.0 Hz), 7.19 (s, 1H), 7.10 (d, 1H, J
) 8.7 Hz), 6.61 (t, 1H, J ) 6.5 Hz), 6.52 (t, 1H, J ) 7.3 Hz), 4.56
(dd, 1H, J ) 4.1, 9.6 Hz), 3.92 (d, 1H, J ) 1.7 Hz), 3.56-3.48
(m, 1H), 3.30 (dd, 1H, J ) 4.2, 14.8 Hz), 2.99 (dd, 1H, J ) 10.5,
15.2 Hz), 2.28-2.23 (m, 1H), 2.17-2.12 (m, 1H), 1.89-1.83 (m,
1H), 1.58-1.49 (m, 2H), 1.45-1.28 (m, 2H), 1.25 (d, 2H, J ) 6.9
Hz), 0.81 (d, 3H, J ) 6.3 Hz), 0.71 (d, 3H, J ) 6.4 Hz); 13C (100
MHz, D2O) δ 178.4, 172.4, 163.9, 162.1, 135.6, 134.1, 130.5, 130.0,
126.6, 126.3, 126.0, 123.1, 121.0, 119.9, 118.3, 117.8, 111.0, 109.6,
66.8 (d), 60.9, 59.5, 55.4, 47.2 (d), 45.0, 44.1, 38.9, 27.4, 27.1,
25.2, 22.8, 22.2, 21.8, 21.3; 31P (161.3 MHz, CDCl3) δ 8.5; LRMS
(FAB, NBA, m/z) 683.1.
J. Org. Chem, Vol. 71, No. 7, 2006 2773

Hanessian et al.
(2S,3S,4S,5R)-(2S)-({4-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-3-isobutyl-5-phosphonopyrrolidine-2-carbonyl}-
amino)-3-phenylpropionic Acid (45). Prepared following the
synthetic sequence for the preparation of 42, starting from L-
pyroglutamic acid: 5 mg; [R]D -79.0 (c 0.2, H2O); IR (KBr) 3453,
1654, 1465 cm-1; 1H NMR (300 MHz, D2O) δ 8.25 (m, 4H), 7.68
(m, 2H), 6.98 (m, 2H), 6.84 (m, 2H), 6.59 (m, 1H), 4.24 (dd, 1H,
J ) 4.8, 7.3 Hz), 3.85-3.80 (m, 2H), 3.60 (s, 1H), 3.55 (dd, 1H,
J ) 6.1, 9.7 Hz), 2.98 (dd, 1H, J ) 4.4, 13.8 Hz), 2.86 (dd, 1H, J
) 7.7, 14.1 Hz), 2.35 (m, 1H), 2.21 (m, 1H), 2.05 (m, 1H), 1.59
(m, 1H), 1.38 (t, 2H, J ) 7.2 Hz), 1.22 (m, 1H), 0.91 (d, 3H, J )
6.4 Hz), 0.80 (d, 3H, J ) 6.4 Hz); 13C (100 MHz, D2O) δ 178.0,
174.3, 165.7, 138.1, 136.0, 132.3, 131.8, 129.7, 128.9, 127.9, 127.7,
126.9, 121.5, 66.2 (d), 60.9, 57.5, 47.5, 45.3, 44.3, 39.9, 38.2, 28.7,
26.2, 22.9, 22.7; 31P (161.3 MHz, D2O) δ 14.8; LRMS (FAB, NBA,
m/z) 622.
(2S,3S,4S,5R)-(2S)-{[3-Isobutyl-4-(3-phenylallyl)-5-phospho-
nopyrrolidine-2-carbonyl]amino}-3-phenylpropionic Acid (46).
Following the synthetic sequence for the preparation of 37b, starting
from L-pyroglutamic acid and using cinnamoyl bromide instead of
allyl bromide gave a phosphonate which, following sequentially
the preparation of 16a and 19a, gave 46: 24 mg; [R]D -0.4 (c 0.8,
H2O); IR (KBr) 3429, 1619, 1222 cm-1; 1H NMR (300 MHz, D2O)
δ 7.37 (m, 3H), 7.32 (m, 2H), 7.21 (m, 5H), 6.23 (d, 2H, J ) 16.0
Hz), 6.14 (m, 1H), 4.36 (dd, 1H, J ) 4.8, 8.5 Hz), 3.71 (d, 1H, J
) 4.1 Hz), 3.60 (dd, 1H, J ) 6.2, 11.5 Hz), 3.19 (dd, 1H, J ) 5.0,
14.1 Hz), 2.98 (dd, 1H, J ) 8.5, 14.0 Hz), 2.73 (d, 1H, J ) 13.7
Hz), 2.30-2.24 (m, 2H), 1.99 (td, 1H, J ) 9.8, 13.6 Hz), 0.71 (d,
3H, J ) 6.5 Hz), 0.62 (d, 3H, J ) 6.4 Hz); 13C (100 MHz, D2O)
δ 177.5, 170.4, 138.6, 138.1, 133.1, 130.0, 129.6, 129.4, 128.1,
127.5, 126.9, 66.6, 61.1, 57.7, 58.0, 45.9 (d), 44.6, 38.1, 33.9, 26.2,
23.1, 21.7; 31P (161.3 MHz, D2O) δ 10.03; LRMS (FAB, NBA,
m/z) 515, 433.
27.7, 27.4, 24.6, 24.4, 22.5, 22.4, 22.3, 22.3; LCMS (MNa+) 336.1;
HRMS for C16H27NO5 (MH+) calcd 314.19620, obsd 314.19682;
(MNa+) calcd 336.17814, obsd 336.17885.
(2R,4R,5S)-4-Isobutyl-6-oxo-5-(3-phenylallyl)piperidine-1,2-
dicarboxylic Acid 1-tert-Butyl 2-Methyl Ester (50a) and
(2R,4S,5R)-4-Isobutyl-6-oxo-5-(3-phenylallyl)piperidine-1,2-di-
carboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (50b). The
diastereomeric mixture of 49a and 49b (244 mg, 0.78 mmol) was
placed in an argon-filled round-bottom flask, dissolved in THF/
DME 1:1 (5 mL), and cooled to -78 °C. LiHMDS (934 µL, 0.93
mmol) was introduced as a 1 M solution in THF via a hypodermic
syringe. The solution was allowed to reach -50 °C and stirred for
2.5 h. After the solution was cooled to -78 °C, cinnamoyl bromide
(230 mg, 1.17 mmol) in solution in THF (2 mL) was added over
30 min using a syringe pump. After 4 h, the reaction was quenched
by the addition of an excess of saturated NH4Cl. The mixture was
allowed to reach rt and vigorously stirred for few minutes. The
THF was evaporated and replaced by EtOAc, which was washed
with water. The organic layer was dried over Na2SO4, filtered,
concentrated, and purified by flash column chromatography (CH2-
Cl2/Et2O, 95:5) to give 50a and 50b. For 50a: 160 mg (48%, sole
diastereomer); colorless oil; [R]D +52.3 (c 1.1, CHCl3); IR (neat/
NaCl) 2956, 1778, 1748, 1715, 1598, 1448, 1368, 1288, 1153 cm-1
;
1H (400 MHz, CDCl3) δ 7.35-7.27 (m, 4H), 7.24-7.20 (m, 1H),
6.45 (d, 1H, J ) 15.7 Hz), 6.16 (ddd, 1H, J ) 6.4, 8.5, 15.6 Hz),
4.54 (dd, 1H, J ) 6.0, 9.3 Hz), 3.76 (s, 3H), 2.95-2.89 (m, 1H),
2.59-2.52 (m, 1H), 2.35-2.29 (m, 2H), 1.90-1.81 (m, 1H), 1.71-
1.64 (m, 1H), 1.62-1.57 (m, 1H), 1.50 (s, 9H), 1.39 (ddd, 1H, J )
3.3, 10.3, 13.6 Hz), 1.10 (ddd, 1H, J ) 3.8, 10.5, 13.6 Hz), 0.94
(d, 3H, J ) 6.6 Hz), 0.86 (d, 3H, J ) 6.5 Hz); 13C (100 MHz,
CDCl3) δ 172.8, 172.0, 151.7, 137.2, 132.9, 128.3, 127.0, 126.1,
126.0, 83.4, 57.9, 52.2, 50.1, 42.7, 32.6, 31.6, 30.0, 27.7, 24.9, 23.9,
21.3; LCMS (MNa+) 452.1. For 50b: 84 mg (25%, inseparable
mixture with the corresponding diastereomer, 9:1); colorless oil;
[R]D -4.4 (c 0.9, CHCl3); IR (neat/NaCl) 2955, 1778, 1748, 1715,
1598, 1448, 1368, 1288, 1153 cm-1; 1H (400 MHz, CDCl3) δ 7.37-
7.35 (m, 2H), 7.30-7.26 (m, 2H), 7.20-7.17 (m, 1H), 6.40 (d,
1H, J ) 15.7 Hz), 6.18 (ddd, 1H, J ) 6.0, 8.8, 15.6 Hz), 4.72 (dd,
1H, J ) 3.3, 5.1 Hz), 3.56 (s, 3H), 3.06-3.00 (m, 1H), 2.56-2.49
(m, 1H), 2.34 (dt, 1H, J ) 13.4, 2.9 Hz), 2.30-2.25 (m, 1H), 1.75-
1.69 (m, 1H), 1.68-1.59 (m, 2H), 1.51 (s, 9H), 1.35 (ddd, 1H, J )
3.1, 10.4, 13.6 Hz), 1.07 (ddd, 1H, J ) 4.2, 10.0, 13.7 Hz), 0.92
(d, 3H, J ) 6.6 Hz), 0.76 (d, 3H, J ) 6.5 Hz); 13C (100 MHz,
CDCl3) δ 172.1, 171.5, 152.0, 137.1, 132.0, 128.0, 126.6, 126.5,
125.7, 83.1, 57.4, 52.0, 50.0, 42.5, 32.2, 30.2, 29.7, 27.5, 24.5, 23.6,
20.8; LCMS (MNa+) 452.0.
(2S,3S,4S,5R)-(2S)-{[3-Isobutyl-4-(3-phenylpropyl)-5-phospho-
nopyrrolidine-2-carbonyl]amino}-3-phenylpropionic Acid (47).
Following the preparation of 23b starting from 46 gave compound
47: 13 mg; [R]D -59.0 (c 0.6, H2O); IR (neat/NaCl) 3434, 2927,
1
1638, 1455, 1385 cm-1; H NMR (300 MHz, D2O) δ 7.47-7.06
(m, 10H), 4.87 (m, 1H), 3.71 (m, 1H), 3.56 (m, 1H), 3.13 (m, 1H),
2.96 (m, 1H), 2.64 (m, 2H), 2.47 (m, 1H), 2.12 (m, 1H), 1.84 (m,
1H), 1.52 (m, 3H), 1.22 (m, 2H), 1.10 (m, 1H), 0.76 (s, 6H); 13C
(100 MHz, D2O) δ 177.4, 169.5, 143.7, 138.4, 130.0, 129.4, 127.6,
126.7, 66.2, 60.1, 57.6, 46.6, 46.2, 44.5, 38.0, 35.7, 29.9, 29.1, 26.3,
22.9, 22.2; 31P (161.3 MHz, D2O) δ 9.61; LRMS (FAB, NBA, m/z)
517, 435.
(2R,4R)- and (2R,4S)-4-Isobutyl-6-oxopiperidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (49a and 49b).
A solution of i-BuMgBr (7.83 mL, 15.7 mmol, 2 M in Et2O) was
added dropwise to a suspension of CuBr‚SMe2 (160 mg, 0.78 mmol)
in Et2O (10 mL) at -40 °C. The suspension was stirred for 1 h
prior to the addition of 48 (2.0 g, 7.83 mmol) in solution Et2O (5
mL). The mixture was stirred for an additional 5 h and quenched
by the addition of saturated NH4Cl. The resulting mixture was
diluted with water and extracted twice with Et2O. The combined
organic layers were dried over Na2SO4, filtered, and evaporated to
give a colorless oil. Purification by flash column chromatography
(hexanes/EtOAc, 8:2) gave compounds 49a and 49b as an
inseparable mixture, (2.09 g, 85%, 1.1:1 in favor of 49a): colorless
oil; [R]D +15.6 (c 1.1, CHCl3); IR (neat/NaCl) 2957, 1780, 1748,
1715, 1456, 1368, 1287, 1143 cm-1; 1H (400 MHz, CDCl3) δ 4.70
(dd, 1H, J ) 2.6, 5.8 Hz, 49b), 4.54 (dd, 1H, J ) 6.4, 10.3 Hz,
49a), 3.74 (s, 3H, 49b), 3.73 (s, 3H, 49a), 2.67-2.62 (m, 1H, 49b),
2.61-2.57 (m, 1H, 49a), 2.32-2.26 (m, 1H, 49a), 2.23-2.18 (m,
1H, 49b), 2.07-2.00 (m, 2H), 1.95-1.81 (m, 2H), 1.65-1.56 (m,
4H), 1.47 (s, 9H, 49a), 1.47 (s, 9H, 49b), 1.15-1.08 (m, 4H), 0.86
(d, 3H, J ) 2.3 Hz, 49a), 0.85 (d, 3H, J ) 2.1 Hz, 49a), 0.84 (d,
3H, J ) 6.6 Hz, 49b), 0.81 (d, 3H, J ) 6.6 Hz, 49b); 13C (100
MHz, CDCl3) δ 172.0, 171.9, 170.1, 169.8, 152.0, 151.8, 83.6, 83.4,
58.5, 58.0, 52.4, 52.3, 44.7, 44.6, 41.3, 41.2, 32.5, 31.7, 28.8, 27.7,
(2R,4R,5S,6R)-6-(Dimethoxyphosphoryl)-4-isobutyl-5-(3-phen-
ylallyl)piperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-
Methyl Ester (51a) and (2R,4R,5S,6S)-6-(Dimethoxyphospho-
ryl)-4-isobutyl-5-(3-phenylallyl)piperidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (51b). Following the preparation
of 11a and 11b gave compounds 51a and 51b (1.5:1 in favor of
51a) as colorless oils. For 51a: 92 mg (58%, three steps); [R]D
-24.9 (c 1.0, CHCl3); IR (neat/NaCl) 2955, 1760, 1700, 1455, 1382,
1
1254, 1170, 1032 cm-1; for a mixture of two rotamers H (400
MHz, CDCl3) δ 7.34-7.17 (m, 5H), 6.46 (d, 1H, J ) 15.7 Hz),
6.19-6.13 (m, 1H), 4.69 (d, 0.67H, J ) 21.6 Hz), 4.50 (d, 0.33H,
J ) 22.0 Hz), 4.27 (dd, 0.33H, J ) 6.6, 12.4 Hz), 4.13 (dd, 0.67H,
J ) 5.7, 12.9 Hz), 3.85 (d, 3H, J ) 10.6 Hz), 3.73-3.66 (m, 6H),
2.47-2.38 (m, 1H), 2.30-2.11 (m, 3H), 2.03-1.92 (m, 2H), 1.74-
1.61 (m, 1H), 1.44 (s, 3H), 1.41 (s, 6H), 1.34-1.27 (m, 2H), 0.93
(d, 3H, J ) 6.5 Hz), 0.87 (d, 3H, J ) 6.5 Hz); 13C (100 MHz,
CDCl3) δ 172.2, 154.6, 137.3 and 137.0, 133.2 and 133.0, 128.4
and 128.2, 126.9, 126.3, 126.0 and 125.8, 80.9 and 80.8, 56.8 and
56.0, 53.6 (d), 52.2 (d), 51.7 and 51.6, 49.2 and 48.6 (d), 44.4,
41.2 and 41.0 (d), 38.3 and 38.2 (d), 34.2 and 33.4, 29.5, 28.1 and
27.8, 25.1 and 25.0, 23.8, 21.5;31P (161.3 MHz, CDCl3) δ 28.0
(major rotamer), 27.7 (minor rotamer); LCMS (MH+) 524.9,
(MNa+) 546.1; HRMS for C27H42NO7P (MH+) calcd 524.27717,
2774 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
obsd 524.27738; (MNa+) calcd 546.25911, obsd 546.25901. For
51b: 60 mg (38%, three steps); [R]D +1.4 (c 0.9, CHCl3); IR (neat/
NaCl) 2955, 1751, 1700, 1454, 1384, 1250, 1169, 1033 cm-1; for
a mixture of two rotamers 1H (400 MHz, CDCl3) δ 7.37-7.28 (m,
4H), 7.25-7.19 (m, 1H), 6.50 (d, 1H, J ) 15.7 Hz), 6.27-6.19
(m, 1H), 4.70 (dd, 0.67H, J ) 5.0, 13.1 Hz), 4.58 (dd, 0.33H, J )
3.6, 12.8 Hz), 4.40-4.36 (m, 1H), 3.79 (d, 3H, J ) 9.1 Hz), 3.77
(d, 3H, J ) 8.7 Hz), 3.74 (s, 3H), 2.61-2.40 (m, 2H), 2.15-2.05
(m, 1H), 2.03-1.94 (m, 2H), 1.92-1.85 (m, 1H), 1.69-1.57 (m,
1H), 1.43 (s, 3H), 1.42 (s, 6H), 1.21-1.14 (m, 1H), 0.97-0.92
(m, 1H), 0.89 (d, 3H, J ) 6.6 Hz), 0.85 (d, 3H, J ) 6.5 Hz); 13C
(100 MHz, CDCl3) δ 174.1, 154.2, 137.3, 132.2 and 132.0, 128.3,
127.8, 126.9, 126.0, 80.7, 53.6 and 53.3, 53.0 (d), 52.2 (d), 51.7,
50.0 (d), 42.8 and 42.7, 42.2, 34.5 and 33.5, 31.1, 29.5, 28.0, 25.3,
24.1, 21.2;31P (161.3 MHz, CDCl3) δ 29.3 (major rotamer), 29.1
(minor rotamer); LCMS (MH+) 524.3; HRMS for C27H42NO7P
(MH+) calcd 524.27717, obsd 524.27691; (MNa+) calcd 546.25911,
obsd 546.25814.
2.03 (m, 1H), 1.96-1.78 (m, 3H), 1.70-1.60 (m, 1H), 1.48 (s,
2H), 1.42 (s, 7H), 1.36-1.10 (m, 4H), 0.90 (d, 3H, J ) 6.6 Hz),
0.85 (d, 3H, J ) 6.4 Hz); 13C (100 MHz, CDCl3) δ 172.6, 155.6,
81.7, 59.4, 56.9 and 55.9, 53.9 and 53.8 (d), 53.5 and 53.3 (d),
52.3 and 52.1, 49.9 and 48.1 (d), 44.3, 38.6 and 37.7 (d), 37.7 and
37.6, 35.5 and 35.2, 29.0, 28.7 and 28.5, 25.8, 24.4, 21.9; 31P (161.3
MHz, CDCl3) δ 29.7 (major rotamer), 29.1 (minor rotamer).
(2R,4R,5S,6S)-6-(Dimethoxyphosphoryl)-5-(2-hydroxyethyl)-
4-isobutylpiperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (52b). Following the preparation of 14a gave
compounds 52b, 163 mg (79%, two steps), as a colorless oil: [R]D
-12.7 (c 1.0, CHCl3); IR (neat/NaCl) 3423, 2955, 1751, 1698, 1456,
1
1390, 1254, 1176, 1056 cm-1; for a mixture of two rotamers H
(400 MHz, CDCl3) δ 4.75 (dd, 0.67H, J ) 5.1, 14.0 Hz), 4.63 (dd,
0.33H, J ) 4.1, 13.1 Hz), 4.32-4.28 (m, 1H), 3.74 (d, 3H, J ) 6.0
Hz), 3.72 (d, 3H, J ) 5.8 Hz), 3.71-3.66 (m, 2H), 3.68 (s, 3H),
3.05 (bs, 1H), 2.51-2.43 (m, 0.67H), 2.36-2.29 (m, 0.33H), 2.08-
1.98 (m, 1H), 1.96-1.66 (m, 4H), 1.63-1.51 (m, 1H), 1.44 (s,
3H), 1.38 (s, 6H), 1.08-1.02 (m, 1H), 0.87-0.81 (m, 1H), 0.83
(d, 3H, J ) 6.5 Hz), 0.79 (d, 3H, J ) 6.4 Hz); 13C (100 MHz,
CDCl3) δ 174.6, 154.9, 81.6 and 81.3, 61.4 and 61.0, 54.0, 53.4
(d), 53.0 (d), 52.4 and 52.3, 50.7 (d), 43.2 and 43.1, 38.6 (d), 34.0,
31.6, 28.5, 28.1, 25.8 and 25.6, 24.6, 21.6; 31P (161.3 MHz, CDCl3)
δ 29.6.
(2R,4S,5R,6S)-6-(Dimethoxyphosphoryl)-4-isobutyl-5-(3-phen-
ylallyl)piperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-
Methyl Ester (51c) and (2R,4S,5R,6R)-6-(Dimethoxyphospho-
ryl)-4-isobutyl-5-(3-phenylallyl)piperidine-1,2-dicarboxylic Acid
1-tert-Butyl Ester 2-Methyl Ester (51d). Following the preparation
of 11a and 11b gave compounds 51c and 51d (2:1 in favor of 51c)
as colorless oils. For 51c: 206 mg (54%, three steps); [R]D -65.3
(c 1.1, CHCl3); IR (neat/NaCl) 2955, 1755, 1699, 1455, 1390, 1253,
(2R,4S,5R,6S)-6-(Dimethoxyphosphoryl)-5-(2-hydroxyethyl)-
4-isobutylpiperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (52c). Following the preparation of 14a gave
compounds 52c, 75 mg (87%, two steps), as a colorless oil: [R]D
+31.0 (c 1.0, CHCl3); IR (neat/NaCl) 3428, 2956, 1751, 1705, 1455,
1
1174, 1033 cm-1; for a mixture of two rotamers H (400 MHz,
CDCl3) δ 7.37-7.35 (m, 2H), 7.32-7.25 (m, 2H), 7.23-7.16 (m,
1H), 6.50 (d, 1H, J ) 15.8 Hz), 6.25-6.16 (m, 1H), 4.69 (d, 0.60H,
J ) 18.6 Hz), 4.50 (d, 0.40H, J ) 18.5 Hz), 4.39-4.36 (m, 1H),
3.74-3.65 (m, 9H), 2.53-2.34 (m, 3H), 2.00-1.77 (m, 2H), 1.65-
1.54 (m, 1H), 1.41-1.39 (m, 1H), 1.41 (s, 5H), 1.39 (s, 4H), 1.33-
1.26 (m, 2H), 0.91-0.88 (m, 3H), 0.79 (d, 1.20H, J ) 6.5 Hz),
0.76 (d, 1.80H, J ) 6.5 Hz); 13C (100 MHz, CDCl3) δ 173.1 and
172.3, 154.7 and 154.3, 137.2 and 136.9, 132.9 and 132.6, 128.2
and 128.0, 127.5 and 127.2, 126.8 and 126.6, 125.8 and 125.6,
80.6 and 80.5, 55.5 and 54.8, 52.7 and 52.6 (d), 52.4 and 52.3 (d),
51.6 and 51.4, 49.0 and 48.3 (d), 44.5 and 44.4, 40.5 and 40.6 (d),
38.1 and 38.0 (d), 30.4 and 30.0, 28.0, 27.7 and 27.6, 24.7 and
24.6, 23.4 and 23.3, 21.0 and 20.9;31P (161.3 MHz, CDCl3) δ 29.1
(minor rotamer), 29.0 (major rotamer); LCMS (MNa+) 546.1;
HRMS for C27H42NO7P (MH+) calcd 524.27717, obsd 524.27716;
(MNa+) calcd 546.25911, obsd 546.25835. For 51d: 104 mg (27%,
three steps); [R]D -3.8 (c 1.0, CHCl3); IR (neat/NaCl) 2954, 1757,
1700, 1454, 1392, 1254, 1166, 1033 cm-1; for a mixture of two
rotamers 1H (400 MHz, CDCl3) δ 7.36-7.26 (m, 4H), 7.21-7.17
(m, 1H), 6.46 (d, 1H, J ) 15.6 Hz), 6.24-6.19 (m, 1H), 4.69 (dd,
0.70H, J ) 5.5, 17.2 Hz), 4.59-4.53 (m, 0.30H), 4.30-4.27 (m,
0.30H), 4.15-4.10 (m, 0.70H), 3.88 (d, 3H, J ) 10.6 Hz), 3.78-
3.75 (m, 3H), 3.73 (s, 0.77H), 3.72 (s, 2.24H), 2.70-2.61 (m, 1H),
2.57-2.41 (m, 2H), 1.98-1.90 (m, 1H), 1.70-1.54 (m, 3H), 1.41
(s, 9H), 1.25-1.18 (m, 2H), 0.91 (d, 3H, J ) 6.6 Hz), 0.85 (d, 3H,
J ) 6.4 Hz); 13C (100 MHz, CDCl3) δ 172.8, 154.3, 137.1, 131.8,
128.1, 127.7, 126.7, 125.7, 81.1, 53.6 (d), 52.6, 51.6 (d), 51.6, 50.2
(d), 44.7, 42.4, 34.5, 30.9, 28.5, 27.7, 25.1, 23.8, 20.9;31P (161.3
MHz, CDCl3) δ 26.8 (major rotamer), 26.4 (minor rotamer); LCMS
(MH+) 524.0, (MNa+) 546.1; HRMS for C27H42NO7P (MH+) calcd
524.27717, obsd 524.27706; (MNa+) calcd 546.25911, obsd
546.25925.
1
1384, 1178, 1036 cm-1; for a mixture of two rotamers H (400
MHz, CDCl3) δ 4.63 (dd, 0.77H, J ) 1.4, 17.9 Hz), 4.50 (dd, 0.23H,
J ) 1.0, 18.6 Hz), 4.31-4.29 (m, 1H), 3.74 (d, 3H, J ) 6.7 Hz),
3.74-3.70 (m, 2H), 3.71 (d, 3H, J ) 6.8 Hz), 3.69 (s, 0.64H),
3.68 (s, 2.36H), 2.81 (bs, 1H), 2.21-2.13 (m, 1H), 1.97-1.88 (m,
1H), 1.81-1.72 (m, 2H), 1.66-1.50 (m, 2H), 1.43 (s, 2H), 1.37
(s, 7H), 1.30-1.19 (m, 2H), 1.17-1.10 (m, 1H), 0.84 (d, 3H, J )
6.6 Hz), 0.72 (d, 3H, J ) 6.5 Hz); 13C (100 MHz, CDCl3) δ 173.1,
154.6, 80.9 and 80.8, 59.3 and 58.9, 55.3 and 54.5, 53.0 and 52.8
(d), 52.6 and 52.5 (d), 51.7 and 51.5, 48.0 (d), 44.0 and 43.7, 36.9
(d), 36.6 (d), 30.3 and 30.1, 27.8 and 27.6, 28.2, 24.8, 23.4, 20.8;
31P (161.3 MHz, CDCl3) δ 29.9 (major rotamer), 29.5 (minor
rotamer).
(2R,4S,5R,6R)-6-(Dimethoxyphosphoryl)-5-(2-hydrox-ethyl)-
4-isobutylpiperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (52d). Following the preparation of 14a gave
compounds 52d, 70 mg (81%, two steps), as a colorless oil: [R]D
+17.5 (c 1.0, CHCl3); IR (neat/NaCl) 3421, 2955, 1755, 1700, 1456,
1
1392, 1254, 1171, 1034 cm-1; for a mixture of two rotamers H
(400 MHz, CDCl3) δ 4.78 (dd, 1H, J ) 5.3, 17.6 Hz), 4.42-4.39
(m, 0.22H), 4.20-4.17 (m, 0.76H), 3.82 (d, 3H, J ) 10.6 Hz),
3.73 (d, 3H, J ) 10.6 Hz), 3.76-3.70 (m, 2H), 3.69 (s, 3H), 2.59-
2.51 (m, 2H), 1.93-1.85 (m, 1H), 1.84-1.75 (m, 2H), 1.74-1.57
(m, 2H), 1.55-1.48 (m, 1H), 1.46 (s, 2.13H), 1.41 (s, 6.85H), 1.16-
1.12 (m, 2H), 0.90 (d, 3H, J ) 6.6 Hz), 0.84 (d, 3H, J ) 6.4 Hz);
13C (100 MHz, CDCl3) δ 172.6, 154.4, 81.1, 60.3, 53.1 (d), 52.5,
52.0 (d), 51.4, 50.0 (d), 42.2, 40.4 (d), 33.0, 30.7, 28.7, 27.8 and
27.7, 25.0, 23.8, 20.9; 31P (161.3 MHz, CDCl3) δ 27.6.
(2R,4R,5S,6R)-6-(Dimethoxyphosphoryl)-5-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-4-isobutylpiperidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (53a). 1,8-
Dicarboxynaphthalimide (32 mg, 0.16 mmol) and PPh3 (43 mg,
0.16 mmol) were added to a solution of 52a (37 mg, 0.08 mmol)
in THF (2 mL). The resulting suspension was cooled to 0 °C prior
to the dropwise addition of a solution of methyl azodicarboxylate
(24 mg, 0.16 mmol) in THF (0.5 mL). The solution was stirred
overnight with a slow increase of temperature from 0 °C to rt. The
suspension was filtered off, and the solid was washed with EtOAc.
The filtrate was evaporated to afford a residue, which was purified
by flash column chromatography (hexanes/EtOAc, 1:9) to give 53a
(2R,4R,5S,6R)-6-(Dimethoxyphosphoryl)-5-(2-hydroxyethyl)-
4-isobutylpiperidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester
2-Methyl Ester (52a). Following the preparation of 14a gave
compound 52a, 144 mg (84%, two steps), as a colorless oil: [R]D
-34.2 (c 1.0, CHCl3); IR (neat/NaCl) 3423, 2956, 1760, 1698, 1456,
1
1388, 1252, 1172, 1044 cm-1; for a mixture of two rotamers H
(400 MHz, CDCl3) δ 4.71 (d, 0.67H, J ) 20.4 Hz), 4.64 (d, 0.33H,
J ) 22.5 Hz), 4.35 (dd, 0.33H, J ) 6.8, 12.7 Hz), 4.20 (dd, 0.67H,
J ) 6.3, 12.7 Hz), 3.81 (d, 3H, J ) 10.6 Hz), 3.77 (d, 3H, J )
10.9 Hz), 3.76-3.68 (m, 2H), 3.71 (s, 3H), 3.23 (bs, 1H), 2.09-
J. Org. Chem, Vol. 71, No. 7, 2006 2775

Hanessian et al.
as a colorless oil (45 mg, 87%): [R]D -25.7 (c 0.9, CHCl3); IR
(s, 5H), 1.25-1.00 (m, 3H), 0.93-0.80 (m, 7H); 13C (100 MHz,
CDCl3) δ 172.8 and 172.4, 163.8 and 163.6, 154.5 and 154.3, 133.6
and 133.4, 131.2, 130.8, 127.8, 126.6 and 126.5, 122.3 and 122.2,
81.0 and 80.8, 53.8 and 53.5 (d), 52.6, 51.9 and 51.5 (d), 51.6 and
51.5, 51.3 and 50.0 (d), 42.8 and 41.5 (d), 42.2 and 42.0, 38.8 and
38.0, 31.0 and 30.5, 29.2 and 28.8, 28.5 and 28.4, 27.8 and 27.7,
25.0 and 24.8, 23.8, 20.9; 31P (161.3 MHz, CDCl3) δ 26.7 (minor
rotamer), 26.5 (major rotamer); LCMS (MH+) 631.5, (MNa+)
653.5; HRMS for C32H43N2O9P (MH+) calcd 631.27789, obsd
631.27768; (MNa+) calcd 653.25984, obsd 653.25961.
(neat/NaCl) 2958, 1750, 1700, 1663, 1591, 1438, 1366, 1237, 1175,
1
1033 cm-1; for a mixture of two rotamers H (400 MHz, CDCl3)
δ 8.60-8.58 (m, 2H), 8.22-8.19 (m, 2H), 7.77-7.72 (m, 2H), 4.77
(dd, 1H, J ) 12.6, 21.3 Hz), 4.30-4.05 (m, 3H), 3.93-3.87 (m,
3H), 3.77 (d, 3H, J ) 10.5 Hz), 3.73 (s, 3H), 2.18-2.07 (m, 1H),
1.95-1.82 (m, 3H), 1.74-1.65 (m, 1H), 1.60 (s, 4.5H), 1.42 (s,
4.5H), 1.35-1.29 (m, 4H), 0.93-0.86 (m, 6H); 13C (100 MHz,
CDCl3) δ 172.3 and 171.6, 163.7 and 163.6, 154.9 and 154.7, 133.8
and 133.7, 131.5 and 131.4, 131.0, 128.0, 126.7, 122.5, 81.3 and
81.0, 56.6 and 55.8, 53.8 (d), 52.3 (d), 51.7 and 51.6, 50.6 and
49.6 (d), 44.8 and 44.0, 39.9 and 39.5 (d), 37.8 and 37.5, 34.2 and
34.0, 28.1, 28.1 and 27.9, 27.7, 25.1 and 25.0, 23.8, 21.3; 31P (161.3
MHz, CDCl3) δ 27.7; LCMS (MNa+) 653.2; HRMS for C32H43N2O9P
(MH+) calcd 631.27789, obsd 631.27656; (MNa+) calcd 653.25984,
obsd 653.25818.
(2R,4R,5S,6S)-6-(Dimethoxyphosphoryl)-5-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-4-isobutylpiperidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (53b). Following
the preparation of 53a gave compounds 53b as a white solid, 60
mg (86%): [R]D -9.3 (c 1.0, CHCl3); mp 154-156 °C; IR (neat/
NaCl) 2954, 1750, 1700, 1662, 1590, 1436, 1367, 1235, 1175, 1030
cm-1; for a mixture of two rotamers 1H (400 MHz, CDCl3) δ 8.57
(d, 2H, J ) 7.2 Hz), 8.19 (m, 2H), 7.75-7.70 (m, 2H), 4.90-4.84
(m, 1H), 4.46-4.10 (m, 3H), 3.91 (d, 1.67H, J ) 10.9 Hz), 3.86
(d, 1.33H, J ) 10.9 Hz), 3.79 (d, 3H, J ) 10.4 Hz), 3.66 (s, 1.67H),
3.60 (s, 1.33H), 2.60-2.52 (m, 0.55H), 2.42-2.35 (m, 0.45H),
2.03-1.87 (m, 4H), 1.53 (s, 4H), 1.42 (s, 5H), 1.29-1.19 (m, 2H),
1.14-1.06 (m, 1H), 0.83-0.73 (m, 7H); 13C (100 MHz, CDCl3) δ
174.4 and 174.0, 164.4 and 164.3, 155.1 and 154.9, 134.3 and 134.2,
132.0, 131.6, 128.5, 127.3, 123.2 and 123.1, 81.5 and 81.3, 54.2,
54.0 and 53.7 (d), 53.8 (d), 52.8 and 52.6 (d), 52.3, 43.2 and 43.0,
40.6 and 40.4 (d), 39.6 and 39.2, 31.9 and 31.7, 29.7, 28.6, 28.2,
25.8 and 25.6, 24.6, 21.6; 31P (161.3 MHz, CDCl3) δ 29.1 (minor
rotamer), 28.9 (major rotamer); LCMS (MNa+) 653.0; HRMS for
C32H43N2O9P (MH+) calcd 631.27789, obsd 631.27702; (MNa+)
calcd 653.25984, obsd 653.25859.
(2R,3S,4R,6R)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-6-[2-(1H-indol-3-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]-4-isobutylpiperidine-1-carboxyl-
ic Acid tert-Butyl Ester (54a). Compound 53a (32 mg, 0.05 mmol)
was dissolved in a mixture of THF/H2O/MeOH 5:4:1 (1 mL). LiOH‚
H2O (4 mg, 0.10 mmol) was added, and the solution was stirred
for 24 h at 50 °C. The organic layer was extracted with CH2Cl2,
and the aqueous layer was acidified to pH 3 with 1 N KHSO4. The
aqueous phase was extracted with EtOAc, washed with brine, dried
over Na2SO4, and concentrated in vacuo to give the crude carboxylic
acid used in the next step without further purification. Diisopro-
pylethylamine (25 µL, 0.14 mmol) was added dropwise to a solution
of the acid, EDC (14 mg, 0.07 mmol), HOBt (10 mg, 0.07 mmol)
and HCl‚H-Trp-OMe (19 mg, 0.07 mmol) in DMF (2 mL) at rt.
The solution was stirred for 16 h before quenching by addition of
saturated NH4Cl. The solution was extracted with EtOAc and the
combined organic layers were washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography (CH2Cl2/MeOH, 95:5) to give 54a
(34 mg, 86%) as a yellowish oil: [R]D -26.5 (c 1.0, CHCl3); IR
(neat/NaCl) 3288, 2955, 1747, 1700, 1661, 1591, 1438, 1367, 1234,
1
1052 cm-1; for a mixture of two rotamers H (400 MHz, CDCl3)
δ 8.66 (bd, 1H), 8.57 (d, 2H, J ) 7.3 Hz), 8.20-8.18 (m, 2H),
8.36 (bs, 1H), 7.73 (t, 2H, J ) 7.8 Hz), 7.64-7.55 (m, 1H), 7.34-
7.32 (m, 2H), 7.13 (t, 1H, J ) 7.1 Hz), 7.07 (t, 1H, J ) 7.2 Hz),
4.94-4.82 (m, 1.3H), 4.68-4.63 (m, 0.7H), 4.22-4.18 (m, 2H),
4.00-3.79 (m, 7H), 3.67 (s, 2H), 3.57 (s, 1H), 3.31 (dd, 1H, J )
14.6, 5.4 Hz), 3.20 (dd, 1H, J ) 14.6, 8.8 Hz), 2.20-2.08 (m, 1H),
2.01-1.79 (m, 2H), 1.78-1.59 (m, 3H), 1.52 (s, 2.6H), 1.33-1.23
(m, 3H), 1.09 (s, 6.4H), 0.89-0.83 (m, 6H); 13C (100 MHz, CDCl3)
δ 173.3, 172.9, 163.5, 155.1, 136.0, 133.6, 131.2, 130.8, 127.7,
126.8, 126.5, 123.5, 122.2, 121.5, 118.9, 118.1, 110.8, 110.2, 81.4,
59.6, 53.6, 53.1 (d), 52.9 (d), 51.6, 49.3 (d), 45.1, 39.4 (d), 37.6,
34.6, 34.0 (d), 29.2, 27.4, 27.2, 24.6, 23.6, 21.0; 31P (161.3 MHz,
CDCl3) δ 31.3 (major rotamer), 30.5 (minor rotamer); LCMS
(MH+) 817.2, (MNa+) 839.2; HRMS for C43H53N4O10P (MH+)
calcd 817.35721, obsd 817.35755; (MNa+) calcd 839.33915, obsd
839.34013.
(2R,4S,5R,6S)-6-(Dimethoxyphosphoryl)-5-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-4-isobutylpiperidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (53c). Following
the preparation of 15a gave compounds 53c as a colorless oil, 39
mg (47%, two steps): [R]D +19.8 (c 1.2, CHCl3); IR (neat/NaCl)
2955, 1749, 1701, 1662, 1591, 1438, 1367, 1237, 1175, 1033 cm-1
;
1
for a mixture of two rotamers H (400 MHz, CDCl3) δ 8.59 (m,
2H), 8.22-8.18 (m, 2H), 7.77-7.71 (m, 2H), 4.76 (dd, 1H, J )
9.2, 18.4 Hz), 4.38 (dd, 1H, J ) 6.8, 14.6 Hz), 4.29-4.19 (m, 2H),
3.81-3.77 (m, 6H), 3.73 (s, 1.60H), 3.70 (s, 1.40H), 2.43-2.31
(m, 1H), 2.04-1.82 (m, 4H), 1.58 (s, 4.20H), 1.51-1.45 (m, 1H),
1.41 (s, 4.80H), 1.32-1.26 (m, 2H), 0.88 (m, 3H), 0.79 (d, 3H, J
) 6.5 Hz); 13C (100 MHz, CDCl3) δ 173.1 and 172.3, 163.5 and
163.4, 154.9 and 154.4, 133.5 and 133.4, 131.2, 130.7 and 130.6,
127.8, 126.5, 122.4, 81.1 and 80.6, 55.6 and 54.9, 53.0 and 52.8
(d), 52.5 and 52.4 (d), 51.6 and 51.5, 51.0 and 49.4 (d), 44.7 and
44.2, 39.1 and 38.9 (d), 37.6 and 37.5, 33.3 and 32.6 (d), 30.0,
28.1, 27.8 and 27.7, 24.7 and 24.6, 23.5 and 23.4, 20.8; 31P (161.3
MHz, CDCl3) δ 29.0 (major rotamer), 28.8 (minor rotamer); LCMS
(MNa+) 653.1; HRMS for C32H43N2O9P (MH+) calcd 631.27789,
obsd 631.27816; (MNa+) calcd 653.25984, obsd 653.26048.
(2R,4S,5R,6R)-6-(Dimethoxyphosphoryl)-5-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-4-isobutylpiperidine-1,2-dicar-
boxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (53d). Following
the preparation of 15a gave compounds 53d as a colorless oil, 59
mg (73%, two steps): [R]D +24.5 (c 1.0, CHCl3); IR (neat/NaCl)
(2S,3S,4R,6R)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-6-[2-(1H-indol-3-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]-4-isobutylpiperidine-1-carboxyl-
ic Acid tert-Butyl Ester (54b). Following the preparation of 54a
gave compounds 54b as a yellowish oil, 89 mg (78%, two steps):
[R]D -10.6 (c 1.0, CHCl3); IR (neat/NaCl) 3289, 2954, 2244, 1744,
1662, 1591, 1439, 1386, 1236, 1175, 1034 cm-1; for a mixture of
rotamers 1H (400 MHz, CDCl3) δ 8.59 (d, 2H, J ) 7.2 Hz), 8.31-
8.29 (bd, 1H), 8.22-8.20 (m, 3H), 7.77-7.73 (m, 2H), 7.62-7.60
(m, 1H), 7.32-7.30 (bd, 1H), 7.18 (bs, 1H), 7.14 (t, 1H, J ) 7.2
Hz), 7.07 (t, 1H, J ) 7.1 Hz), 4.96-4.89 (m, 2H), 4.24-4.12 (m,
3H), 3.76-3.72 (m, 6H), 3.59 (s, 3H), 3.33 (dd, 1H, J ) 6.5, 14.8
Hz), 3.26 (dd, 1H, J ) 6.8, 14.6 Hz), 2.08-1.64 (m, 9H), 1.39 (s,
6H), 1.25 (s, 3H), 0.90 (d, 3H, J ) 6.3 Hz), 0.84 (d, 3H, J ) 6.4
Hz); 13C (100 MHz, CDCl3) δ 173.3, 172.9, 163.7, 155.3, 135.8,
133.8, 131.4, 131.0, 128.0, 127.5, 126.8, 123.1, 122.5, 121.6, 119.1,
118.7, 110.7, 110.4, 81.8, 60.1, 53.4, 52.8 (d), 52.7 (d), 51.8, 49.5
(d), 45.3, 39.7 (d), 37.8, 34.8, 34.2 (d), 29.5, 28.1, 27.8, 24.8, 23.8,
21.3; 31P (161.3 MHz, CDCl3) δ 29.2 (major rotamer), 29.0 (minor
2955, 1755, 1701, 1662, 1591, 1439, 1366, 1243, 1175, 1036 cm-1
;
1
for a mixture of two rotamers H (400 MHz, CDCl3) δ 8.56 (d,
2H, J ) 7.2 Hz), 8.21-8.17 (m, 2H), 7.76-7.70 (m, 2H), 4.98
(dd, 0.40H, J ) 4.9, 16.8 Hz), 4.85 (dd, 0.60H, J ) 5.0, 17.4 Hz),
4.45-4.30 (m, 1H), 4.27-4.09 (m, 2H), 3.93-3.83 (m, 6H), 3.70
(s, 3H), 2.70-2.56 (m, 1H), 2.14-1.81 (m, 4H), 1.56 (s, 4H), 1.44
2776 J. Org. Chem., Vol. 71, No. 7, 2006

Azacyclic Inhibitors of Endothelin ConVerting Enzyme
rotamer); LCMS (MNa+) 839.2; HRMS for C43H53N4O10P (MH+)
calcd 817.35721, obsd 817.35747; (MNa+) calcd 839.33915, obsd
839.33967.
mmol). The solution was filtered through a 0.45 µm filter and
lyophilized to give 55a as a foam (82 mg, 95%): [R]D -15.8 (c
0.5, H2O); IR (KBr) 3395, 2954, 1700, 1658, 1591, 1441, 1389,
1
1356, 1238, 1074 cm-1; H NMR (400 MHz, D2O) δ 7.74 (bd,
(2S,3R,4S,6R)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-6-[2-(1H-indol-3-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]-4-isobutylpiperidine-1-carboxyl-
ic Acid tert-Butyl Ester (54c). Following the preparation of 54a
gave compounds 54c as a yellowish oil, 23 mg (67%, two steps):
[R]D +75.6 (c 1.0, CHCl3); IR (neat/NaCl) 3279, 2955, 1744, 1699,
1661, 1591, 1439, 1367, 1236, 1174, 1034 cm-1; for a mixture of
2H), 7.55 (bd, 2H), 7.14 (m, 2H), 7.04-7.02 (m, 1H), 6.93 (bs,
2H), 6.59-6.55 (m, 1H), 6.50-6.47 (m, 1H), 4.43 (dd, 1H, J )
5.5, 5.8 Hz), 3.84-3.72 (m, 2H), 3.24-3.19 (m, 1H), 2.99-2.86
(m, 2H), 2.77 (t, 1H, J ) 10.1 Hz), 1.93-1.81 (m, 2H), 1.37-
1.29 (m, 1H), 1.10-0.90 (m, 3H), 0.76-0.69 (m, 1H), 0.56-0.49
(m, 1H), 0.42-0.34 (m, 1H), 0.22 (m, 3H), 0.01 (m, 3H); 13C (100
MHz, D2O) δ 177.1, 170.2, 163.1, 135.1, 133.9, 130.6, 130.0, 127.1,
126.2, 126.1, 123.5, 120.5, 120.2, 118.2, 117.5, 110.9, 109.4, 58.5,
57.6 (d), 55.2, 40.5, 39.3, 37.3, 34.6, 31.6, 26.5, 25.3, 23.3, 22.8,
19.2; 31P (161.3 MHz, D2O) δ 10.9; LCMS (MH+) 675.0, (MNa+)
697.1; HRMS for C35H39N4O8P (MH+) calcd 675.25783, obsd
675.25819; (MNa+) calcd 697.23977, obsd 697.24023.
1
rotamers H (400 MHz, CDCl3) δ 9.00 (bs, 1H), 8.69-8.62 (m,
2H), 8.29-8.25 (m, 2H), 7.83-7.77 (m, 2H), 7.44-7.42 (bd, 1H),
7.17-7.15 (m, 1H), 7.00-6.85 (m, 3H), 6.56-6.52 (m, 1H), 4.93-
4.83 (m, 1H), 4.76 (d, 0.66H, J ) 17.6 Hz), 4.70 (d, 0.34H, J )
17.6 Hz), 4.31-4.12 (m, 3H), 3.82-3.76 (m, 6H), 3.48 (s, 2H),
3.46-3.37 (m, 1H), 3.35 (s, 1H), 3.14-3.07 (m, 1H), 2.24-2.11
(m, 1H), 2.01-1.62 (m, 5H), 1.55 (s, 3H), 1.55-1.48 (m, 1H),
1.39 (s, 6H), 1.29-1.21 (m, 2H), 0.84-0.80 (m, 3H), 0.67 (d, 1H,
J ) 6.4 Hz), 0.63 (d, 2H, J ) 6.5 Hz); 13C (100 MHz, CDCl3) δ
172.0, 171.7, 164.1, 156.1, 136.1, 134.1, 131.5, 131.2, 128.0, 126.9,
122.8, 122.5, 121.9, 118.3, 119.2, 110.9, 109.0, 81.9, 57.8, 53.0
(d), 52.8 (d), 52.1 and 51.6, 51.0 (d), 50.8, 45.4, 39.2 (d), 38.9,
32.7 (d), 30.8, 28.8, 28.0 and 27.9, 27.8, 24.8, 23.7, 21.1; 31P (161.3
MHz, CDCl3) δ 29.7 (minor rotamer), 29.5 (major rotamer); LCMS
(MNa+) 839.2; HRMS for C43H53N4O10P (MH+) calcd 817.35721,
obsd 817.35697; (MNa+) calcd 839.33915, obsd 839.33882.
(2R,3R,4S,6R)-2-(Dimethoxyphosphoryl)-3-[2-(1,3-dioxo-1H,3H-
benzo[de]isoquinolin-2-yl)ethyl]-6-[2-(1H-indol-3-yl)-(1S)-meth-
oxycarbonylethylcarbamoyl]-4-isobutylpiperidine-1-carboxyl-
ic Acid tert-Butyl Ester (54d). Following the preparation of 54a
gave compounds 54d as a yellowish oil, 55 mg (77%, two steps):
[R]D +7.2 (c 1.0, CHCl3); IR (neat/NaCl) 3270, 2955, 1745, 1698,
1662, 1591, 1439, 1384, 1234, 1174, 1050 cm-1; appeared as a
(2R,4R,5S,6S)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (55b). Following the
preparation of 55a gave compound 55b as a yellowish foam, 42
mg (93%, two steps): [R]D -47.6 (c 0.5, H2O); IR (KBr) 3403,
2956, 1696, 1657, 1590, 1442, 1386, 1347, 1238, 1179, 1078 cm-1
;
1H NMR (400 MHz, D2O) δ 7.50 (m, 2H), 7.15 (m, 2H), 7.07 (m,
1H), 6.92 (s, 1H), 6.81 (m, 2H), 6.75 (m, 1H), 6.33 (m, 2H), 4.46
(t, 1H, J ) 6.4 Hz), 3.95 (bd, 2H), 3.68 (bd, 1H), 3.49 (m, 1H),
3.12 (bd, 1H), 2.90-2.82 (m, 1H), 1.96-1.69 (m, 3H), 1.21-1.02
(m, 2H), 0.87-0.77 (m, 1H), 0.72-0.61 (m, 1H), 0.36 (m, 3H),
0.24 (m, 4H), 0.20-0.00 (m, 1H); 13C (100 MHz, D2O) δ 177.9,
168.5, 164.2, 135.1, 133.7, 130.3, 129.6, 126.8, 125.9, 125.6, 123.4,
120.3, 119.6, 118.1, 117.7, 110.7, 109.5, 55.2, 54.1 (d), 53.8, 41.5,
38.3, 37.8, 32.0, 30.0, 26.7, 26.1, 23.3, 23.1, 19.9; 31P (161.3 MHz,
D2O) δ 8.7; LCMS (MH+) 674.9, (MNa+) 697.1; HRMS for
C35H39N4O8P (MH+) calcd 675.25783, obsd 675.25900; (MNa+)
calcd 697.23977, obsd 697.24136.
1
mixture of rotamers H (400 MHz, CDCl3) δ 8.78 (bd, 1H), 8.60
(d, 2H, J ) 7.2 Hz), 8.21 (d, 2H, J ) 8.1 Hz), 8.14 (bs, 1H), 7.75
(t, 2H, J ) 7.8 Hz), 7.65-7.63 (m, 1H), 7.37 (bs, 1H), 7.31-7.29
(m, 1H), 7.14 (t, 1H, J ) 7.4 Hz), 7.11 (t, 1H, J ) 7.4 Hz), 4.99-
4.93 (m, 1H), 4.62-4.57 (m, 1H), 4.35-4.28 (m, 1H), 4.25-4.18
(m, 1H), 3.97 (d, 3H, J ) 11.4 Hz), 3.94 (d, 3H, J ) 11.2 Hz),
3.92-3.88 (m, 1H), 3.67 (s, 3H), 3.30 (dd, 1H, J ) 4.8, 14.4 Hz),
3.18 (dd, 1H, J ) 9.2, 14.5 Hz), 2.12-2.00 (m, 2H), 1.91-1.86
(m, 1H), 1.72-1.55 (m, 3H), 1.47 (m, 1H), 1.05 (s, 9H), 0.86-
0.80 (m, 8H); 13C (100 MHz, CDCl3) δ 174.8, 173.8, 164.4, 155.4,
136.7, 134.4, 132.0, 131.7, 128.6, 127.7, 127.3, 124.4, 123.0, 119.7,
118.9, 122.2, 111.4, 111.2, 82.1, 55.6, 54.3, 53.7 (d), 53.6 (d), 52.4,
50.4 (d), 43.5, 43.1, 39.4, 32.3, 30.2, 29.1, 28.1, 27.9, 25.6, 24.3,
21.6; 31P (161.3 MHz, CDCl3) δ 33.4; LCMS (MH+) 817.2, (MNa+)
839.2; HRMS for C43H53N4O10P (MH+) calcd 817.35721, obsd
817.35750; (MNa+) calcd 839.33915, obsd 839.33998.
(2R,4R,5S,6R)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (55a). The phosphonate
54a (100 mg, 0.122 mmol) was dissolved in a mixture of THF/
H2O/MeOH 5:4:1 (2 mL) and cooled to 0 °C. LiOH‚H2O (10 mg,
0.245 mmol) was added, and the solution was stirred at 0 °C until
completion (monitoring by TLC). The organic layer was extracted
with CH2Cl2, and the aqueous layer was acidified to pH 3 with 1
N KHSO4. The aqueous phase was extracted with EtOAc, washed
with brine, dried over Na2SO4, and concentrated in vacuo. The oily
residue was dissolved in CH2Cl2 and cooled to 0 °C. After dropwise
addition of TMSBr (64 µL, 0.488 mmol), the solution was allowed
to reach rt and stirred for 48 h. Solvent was removed,and deionized
H2O (few mL) was added. The suspension was stirred in a cold
room (4 °C) for 16 h. The suspension was transferred in a conic 2
mL Eppendorf tube and centrifuged at 4 °C for 10 min. The
supernatant was removed and replaced by fresh H2O and the same
operation was repeated twice. The amorphous powder was sus-
pended in 2 mL of deionized H2O and the pH value was adjusted
to 7 with an aqueous solution of NaOH 0.05 M (2.44 mL, 0.122
(2R,4S,5R,6S)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (55c). Following the
preparation of 55a gave compound 55c as a yellowish foam, 29
mg (93%, two steps): [R]D +8.8 (c 0.5, H2O); IR (KBr) 3408,
2956, 1698, 1657, 1590, 1442, 1386, 1351, 1237, 1178, 1089 cm-1
;
1H NMR (400 MHz, D2O) δ 7.78 (m, 2H), 7.62 (m, 2H), 7.22 (m,
1H), 7.17 (m, 2H), 6.97 (bs, 2H), 6.60 (m, 2H), 4.50 (m, 1H), 4.06
(m, 1H), 3.60-3.46 (m, 2H), 3.18 (t, 1H, J ) 9.0 Hz), 3.04-3.01
(m, 1H), 2.89-2.84 (m, 1H), 1.86-1.78 (m, 1H), 1.62-1.41 (m,
3H), 1.36-1.23 (m, 1H), 1.10-0.82 (m, 3H), 0.73-0.62 (m, 1H),
0.40 (m, 3H), -0.08 (m, 3H); 13C (100 MHz, D2O) δ 178.1, 168.4,
164.2, 135.5, 134.3, 130.7, 130.2, 126.6, 126.4, 126.2, 122.9, 120.9,
120.1, 118.4, 117.7, 111.0, 109.5, 55.3, 53.5 (d), 53.1, 40.5, 38.1,
36.8, 30.1, 28.1, 26.0, 27.2, 23.2, 23.0, 19.5; 31P (161.3 MHz, D2O)
δ 10.5; LCMS (MH+) 675.1, (MNa+) 697.1; HRMS for C35H39N4O8P
(MH+) calcd 675.25783, obsd 675.25870; (MNa+) calcd 697.23977,
obsd 697.24019.
(2R,4S,5R,6R)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (55d). Following the
preparation of 55a gave compound 55d as a yellowish foam, 29
mg (68%, two steps): [R]D -23.8 (c 0.5, H2O); IR (KBr) 3408,
1
2957, 1695, 1652, 1590, 1441, 1385, 1352, 1237, 1111 cm-1; H
NMR (400 MHz, D2O) δ 7.88 (m, 4H), 7.38-7.34 (m, 2H), 7.16
(d, 1H, J ) 7.6 Hz), 6.90 (m, 2H), 6.61 (t, 1H, J ) 7.0 Hz), 6.52
(t, 1H, J ) 6.6 Hz), 4.43 (dd, 1H, J ) 5.3, 8.4 Hz), 3.69-3.60 (m,
1H), 3.58-3.45 (m, 2H), 3.11-2.96 (m, 2H), 2.82 (dd, 1H, J )
8.9, 14.2 Hz), 2.21-2.13 (m, 1H), 1.77-1.73 (m, 1H), 1.41-1.34
(m, 1H), 1.31-1.21 (m, 1H), 1.13-1.03 (m, 2H), 0.96-0.82 (m,
2H), 0.77-0.68 (m, 1H), 0.61 (d, 3H, J ) 5.5 Hz), 0.41 (d, 3H, J
) 5.3 Hz); 13C (100 MHz, D2O) δ 177.9, 170.0, 164.2, 135.2, 134.5,
130.9, 130.3, 126.9, 126.5, 126.3, 123.4, 120.7, 120.1, 118.4, 117.8,
110.9, 109.5, 55.1, 54.1 (d), 52.5, 39.4, 39.1, 35.7, 30.2, 26.8, 25.1,
24.4, 24.0, 22.0, 21.0; 31P (161.3 MHz, D2O) δ 11.0; LCMS (MH+)
J. Org. Chem, Vol. 71, No. 7, 2006 2777

Hanessian et al.
674.8, (MNa+) 697.1; HRMS for C35H39N4O8P (MH+) calcd
675.25783, obsd 675.25818; (MNa+) calcd 697.23977, obsd
697.24061.
MHz, D2O) δ 7.92-7.84 (m, 4H), 7.39-7.37 (m, 2H), 7.11 (m,
2H), 7.01 (s, 1H), 6.74 (m, 2H), 4.26-4.24 (m, 1H), 3.87-3.82
(m, 2H), 3.67-3.64 (m, 2H), 1.91 (m, 2H), 1.76 (m, 1H), 1.60 (m,
1H), 1.11-1.03 (m, 5H), 0.50 (d, J ) 6.3 Hz, 3H), 0.46 (m, 5H);
31P (161.3 MHz, D2O) δ 10.3; LCMS (MH+) 675.1; HRMS for
C35H39N4O8P (MH+) calcd 675.25783, obsd 675.25760; (MNa+)
calcd 697.23977, obsd 697.23952.
(2S,4S,5R,6S)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (56). Prepared following
the synthetic sequence for the preparation of 55a, starting from
L-oxopipecolic acid: 13 mg; [R]D -4.3 (c 0.5, H2O); 1H (400 MHz,
D2O) δ 8.01 (m, 4H), 7.47 (m, 2H), 7.35 (m, 1H), 7.16 (m, 1H),
7.01 (s, 1H), 6.82 (m, 2H), 4.32 (t, 1H, J ) 7.0 Hz), 3.98 (m, 1H),
3.78 (m, 1H), 3.12-3.02 (m, 3H), 2.82 (t, 1H, J ) 7.0 Hz), 2.05-
1.76 (m, 2H), 1.29-0.87 (m, 4H), 0.47-0.28 (m, 2H), 0.21 (m,
3H), 0.04 (m, 1H), 0.01 (m, 3H); 31P (161.3 MHz, D2O) δ 12.9;
LCMS (MNa+) 697.1; HRMS for C35H39N4O8P (MH+) calcd
675.25783, obsd 675.25757; (MNa+) calcd 697.23977, obsd
697.23928.
Acknowledgment. We thank the NSERC of Canada for
financial assistance through the Medicinal Chemistry Chair
Program. We thank Dr. G. Tucker, Laboratoires Servier, France,
for the biological assays and financial support.
Supporting Information Available: Experimental procedures
for ECE inhibition determination, 1H and 13C NMR spectra copies,
HPLC profile of final compounds, and X-ray CIF files for 11a,
11b, and 53b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S,4S,5R,6R)-(2S)-({5-[2-(1,3-Dioxo-1H,3H-benzo[de]isoquin-
olin-2-yl)ethyl]-4-isobutyl-6-phosphonopiperidine-2-carbonyl}-
amino)-3-(1H-indol-3-yl)propionic Acid (57). Prepared following
the synthetic sequence for the preparation of 55a, starting from
1
L-oxopipecolic acid: 12 mg; [R]D +17.1 (c 0.5, H2O); H (400
JO052649Y
2778 J. Org. Chem., Vol. 71, No. 7, 2006