The synthesis of sterically demanding amino acid-derived cyclic phosphonamides

Article abstract of DOI:10.1021/jo005545q

The preparation and utilization of C₂-symmetric 1,4-diamines in the synthesis of amino acid-derived cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods: (i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/hydrolysis sequence. The pseudo C₂-symmetric cyclic phosphonamides 1-3 are prepared by condensation of the C₂-symmetric 1,4-diamines to P(III) centers, followed by oxidation.

Full text of DOI:10.1021/jo005545q

J . Org. Chem. 2000, 65, 7913-7918
7913
Th e Syn th esis of Ster ica lly Dem a n d in g Am in o Acid -Der ived Cyclic
P h osp h on a m id es
Kevin T. Sprott and Paul R. Hanson*
Department of Chemistry, Malott Hall, University of Kansas, Lawrence, Kansas 66045
phanson@ukans.edu
Received J une 15, 2000
The preparation and utilization of C2-symmetric 1,4-diamines in the synthesis of amino acid-derived
cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods:
(i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine
coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/
hydrolysis sequence. The pseudo C2-symmetric cyclic phosphonamides 1-3 are prepared by
condensation of the C2-symmetric 1,4-diamines to P(III) centers, followed by oxidation.
In our pursuit of novel P-heterocycles,1 we have
Sch em e 1. Du P on t-Mer ck HIV-1 P r otea se
In h ibitor s
recently become interested in the synthesis of amino acid-
based phosphorus containing compounds that may have
potential as HIV-1 protease inhibitors. Our efforts in this
area have largely been driven by the development of a
number of cyclic urea-based HIV-1 protease inhibitors
at Dupont-Merck that gave promising biological activity
(Scheme 1).2 The routes described herein allow for
incorporation of amino acid side chains into the periph-
eral P2/P2′ regions (Scheme 1)3 of the cyclic phosphona-
mides 1-3 (Scheme 2).
Sch em e 2
Our initial strategy toward the synthesis of cyclic
phosphonamides such as 7 centered on the utilization of
a ring-closing metathesis (RCM)4 approach as outlined
in Scheme 3. We recently reported the syntheses of a
multitude of 5- and 7-membered P-heterocycles via RCM
sequences.5 The successful synthesis of other 5- and
7-membered cyclic phosphonamides utilizing a RCM
strategy led us down a similar path for the compounds
(1) (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939-3942. (b) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1999,
40, 3297-3300. (c) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2,
1769-1772. (d) Hanson, P. R.; Sprott, K. T.; Wrobleski, A. D.
Tetrahedron Lett. 1999, 40, 1455-1458.
(2) (a) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.;
Ru, Y.; Bachelor, L. T.; Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong,
Y. N.; Chang, C.-H.; Weber, P. C.; J ackson, D. A.; Sharpe, T. R.;
Erickson-Vittanen, S. Science 1994, 263, 380-384. (b) Patel, M.;
Kaltenbach, R. F., III; Nugiel, D. A.; McHugh, R. J ., J r.; J adhay, P.
K.; Bacheler, L. T.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen,
S.; Garber, S.; Reid, C.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8,
1077-1082. (c) De Lucca, G. V.; Kim, U. T.; Liang, J .; Cordova, B.;
Klabe, R. M.; Garber, S.; Bacheler, L. T.; Lam, G. N.; Wright, M. R.;
Logue, K. A.; Erickson-Viitanen, S.; Ko, S. S.; Trainor, G. L. J . Med.
Chem. 1998, 41, 2411-2423. (d) De Lucca, G. V.; Lam, P. Y. S. Drugs
Future 1998, 23, 987-994. (e) Hodge, C. N.; Lam, P. Y. S.; Eyermann,
C. J .; J adhav, P. K.; Ru, Y.; Fernandez, C. H.; De Lucca, G. V.; Chang,
C.-H.; Kaltenbach, R. F., III.; Holler, E. R.; Woerner, F.; Daneker, W.
F.; Emmett, G.; Calabrese, J . C.; Aldrich, P. E. J . Am. Chem. Soc. 1998,
120, 4570-4581. (f) J adhav, P. K.; Woerner, F. J . Tetrahedron Lett.
1995, 36, 6383-6386. (g) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C.
J .; Hodge, C. N.; De Lucca, G. V.; Rodgers, J . D. US Patent 5,610,294,
1997; Chem. Abstr. 1997, 126, 293367. h) Hulte´n, J .; Bonham, N. M.;
Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; A° qvist, J .;
Classon, B.; Danielson, U. H.; Karle´n, A.; Kvarnstro¨m, I.; Samuelsson,
B.; Hallberg, A. J . Med. Chem. 1997, 40, 885-897. (i) Baeckbro, K.;
Loewgren, S.; Oesterlund, K.; Atepo, J .; Unge, T.; Hulten, J .; Bonham,
N. M.; Schaal, W.; Karle´n, A.; Hallberg, A. J . Med. Chem. 1997, 40,
898-902. (j) Hulte´n, J .; Andersson, H. O.; Schaal, W.; Danielson, H.
U.; Classon, B.; Kvarnstro¨m, I.; Karle´n, A.; Unge, T.; Samuelsson, B.;
Hallberg, A. J . Med. Chem. 1999, 42, 4054-4061.
described herein. Although this initial approach was
unsuccessful, an alternative pathway has proven to be
successful and is the topic of this paper.
Our initial proposed synthesis of cyclic phosphona-
mides 7 involved coupling R-branched amino acid methyl
esters 4 to phosphonic dichlorides, followed by allylation
of the resulting phosphonamides 5, and subsequent RCM
to derive 7 (Scheme 3).6 The coupling of various amino
acids with methylphosphonic dichloride to yield 5 was
facile, however, various attempts to allylate the phos-
phonamide all proved unsuccessful, and alternate routes
were pursued.
Our attention turned to coupling allylated amino acids
directly with phosphorus P(V) species (Scheme 4). Cou-
pling of allylated amino acids 8 with phosphonic dichlo-
rides resulted in the quantitative production of two
diastereomeric phosphonamidic chloridates 9P SS and
9P RS. The monochlorides readily dimerize in the pres-
10.1021/jo005545q CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/25/2000

7914 J . Org. Chem., Vol. 65, No. 23, 2000
Sprott and Hanson
Sch em e 3a
F igu r e 1.
Sch em e 5a
a
Key: (a) CH3P(O)Cl2, Et3N, CH2Cl2, >95%; (b) various allyl-
ation procedures.
Sch em e 4a
a
Key: (a) fumaryl dichloride, Et3N, CH2Cl2, 99%; (b) H2/Pd-
C, 100%; (c) NaBH4, MeOH, THF, 95%; (d) NaH, BnBr, DMF, 94%;
(e) LAH, dioxane, 95%.
that steric factors inherent to secondary R-branched
amino acids prevent the coupling routes outlined in
Schemes 3 and 4, and thus our original RCM strategy
was abandoned.
We next investigated a P(III) coupling sequence in
order to diminish the steric demands imparted by P(V)
centers. However, our efforts in coupling two allylated
amino acids with various P(III) centers (MePCl2, MeOPCl2,
and PhPCl2), followed by oxidation to P(V), were unsuc-
cessful. Despite these shortcomings, we obtained a mar-
ginal result from the coupling of allylated leucine 8 to
PCl3, which after hydrolysis and metathesis, afforded a
pseudo C2-symmetric cyclic P-H compound in 47% overall
yield (Figure 1).5
In light of the difficulty associated with attaching two
allylated R-branched amino acids to P(V) and P(III)
centers, a new strategy involving the synthesis and
coupling of 1,4-diamines with phosphorus was under-
taken (Scheme 5).8 Although the issue of steric congestion
does not change, we reasoned that the entropic advantage
inherent to this route would be favorable.
The route to the phosphonamide 1, containing two
R-branched amino acids is outlined in Schemes 5 and 6.
Two equivalents of valine methyl ester 11 were coupled
to fumaryl dichloride followed by hydrogenation to afford
diamide 12. Reduction with NaBH4 and protection af-
forded bis-benzyl ether 13. Reduction of the amide with
LAH produced the 1,4-diamine 14, which was ready for
phosphorus coupling (Scheme 5).
Valine-derived diamine 14 was subjected to both phos-
phorus(III) and phosphorus(V) coupling procedures
(Scheme 6). Compound 14 did not couple with methyl
phosphonic dichloride [P(V)], however, it was successfully
coupled to dichlorophenylphosphine [P(III)]. Subsequent
a
Key: (a) CH3P(O)Cl2, Et3N, CH2Cl2, >95%; (b) Et3N, 85%.
ence of Et3N to form 3 diastereomeric phosphonamidic
anhydrides 10a -c, but fail to couple with another
equivalent of 8 to produce 6.7 It became apparent to us
(3) Functionalization of the internal P1/P1′ positions and external
P2/P2′ positions in other cyclic ureas and sulfamides has been shown
to influence the activity of HIV protease inhibitors; see: (a) ref 2 and
references therein. (b) Nugiel, D. A.; J acobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F., III; Meyer, D. T.; J adhav, P. K.; De Lucca, G. V.;
Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S.
P. J . Med. Chem. 1996, 39, 2156-2169. (c) Han, W.; Pelletier, J . C.;
Hodge, C. N. Bioorg. Med. Chem. Lett. 1998, 8, 3615-3620. (d) Patel,
M.; Bachelor, L. T.; Rayner, M. M.; Cordova, B. C.; Klabe, R. M.;
Erickson-Viitanen, S.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8,
823-828. (e) Dax, S. L.; Cook, S. C. Bioorg. Med. Chem. Lett. 1996, 6,
797-802. (f) Lam, P. Y. S.; Ru, Y.; J adhav, P. K.; Aldrich, P. E.;
DeLucca, G. V.; Eyermann, C. J .; Chang, C.-H.; Emmett, G.; Holler,
E. R.; Daneker, W. F.; Li, L.; Confalone, P. N.; McHugh, R. J .; Han,
Q.; Li, R.; Markwalder, J . A.; Sietz, S. P.; Sharpe, T. R.; Bachelor, L.
T.; Rayner, M. M.; Klabe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser,
D. M.; J ackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. J . Med.
Chem. 1996, 39, 3514-3525. (g) Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.;
J adhav, P. K.; Lam, P. Y. S. J . Med. Chem. 1998, 41, 2019-2028. (h)
Rodgers, J . D.; J ohnson, B. L.; Wang, H.; Erickson-Viitanen, S.; Klabe,
R. M.; Bacheler, L.; Cordova, B. C.; Chang, C.-H. Bioorg. Med. Chem.
Lett. 1998, 8, 715-720.
(4) (a) See ref 1. (b) For other examples of RCM on phosphorus
containing compounds using the Grubbs ruthenium catalyst, 4 see:
Bujard, M.; Gouverneur, V.; Mioskowski, C. J . Org. Chem. 1999, 64,
2119-2123. (d) Trevitt, M.; Gouverneur, V. Tetrahedron Lett. 1999,
40, 7333-7336. (e) Hetherington, L.; Greedy, B.; Gouverneur, V.
Tetrahedron 2000, 56, 2053-2060.
(5) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Synthesis 2000,
in press.
(6) We have successfully utilized this strategy in the synthesis of
amino acid-derived C2-symmetric sulfamides. Dougherty, J . M.; Probst,
D. A.; Robinson, R. E.; Moore, J . D.; Klein, T. A.; Snelgrove, K. A.;
Hanson, P. R. Tetrahedron, 2000, 56, in press.
(8) For examples of the coupling of CDI with primary R-branched
1,4-diamines to produce seven-membered cyclic ureas, see: (a) Nugiel
ref 3b. For examples of the coupling of SO2Cl2 with primary R-branched
1,5-diamines to produce eight-membered cyclic sulfamides, see: (b)
J adhav ref 2f.
(7) Sprott, K. T.; Hanson, P. R. J . Org. Chem. 2000, 65, 4721-4728.

Amino Acid-Derived Cyclic Phosphonamides
J . Org. Chem., Vol. 65, No. 23, 2000 7915
Sch em e 6a
Sch em e 9a
a
Key: (a) (i) PhPCl2, Et3N, CH2Cl2, (ii) m-CPBA, 75%; (b)
CH3P(O)Cl2, Et3N, CH2Cl2.
Sch em e 7a
a
Key: (a) phthaloyl dichloride, Et3N, DMAP, CH2Cl2, 96%; (b)
Grubbs catalyst, CH2Cl2, 99%; (c) MeOH/HCl, 44%; (d) (i) PhPCl2,
Et3N, CH2Cl2, (ii) m-CPBA, 86%.
acid-derived 1,4-diamine (Scheme 9). Two equivalents of
N-allylated leucine methyl ester (8) was coupled with
phthaloyl dichloride to yield the diamide, which was
subjected to RCM conditions to yield the bicyclic diamide
17 as predominately the Z-geometric isomer (∼10:1 Z/E)
in excellent yield. Amide cleavage with MeOH‚HCl
provided the Z-configured 1,4-diamine 18 with complete
stereochemical integrity. Cyclic phosphonamide 3 was
synthesized in excellent yield by the coupling of 18 with
dichlorophenylphosphine, followed by m-CPBA oxidation
(Scheme 9). The synthesis of 3 completes our original goal
and provides an olefin moiety for further functionaliza-
tion.
In summary, the synthesis of amino acid-derived
pseudo-C2-symmetric cyclic phosphonamides has been
described. Various steric issues have been addressed
through the synthesis and coupling of 1,4-diamines with
P(III) followed by oxidation. Current efforts toward the
synthesis and biological evaluation of these compounds
and additional novel P-heterocycles are in progress and
will be reported in due course.
a
Key: (a) HBTU, 1,4-diaminobutane, Et3N, CH3CN, 88%; (b)
LAH, dioxane, 83%; (c) (i) PhPCl2, Et3N, CH2Cl2, (ii) m-CPBA, 85%.
Sch em e 8a
a
Key: (a) Cl2(PCy3)2RudCHPh, CH2Cl2.
oxidization with m-CPBA produced the cyclic phospho-
namide 1 in good yield. The lack of coupling to phospho-
rus (V) and the successful coupling to phosphorus (III)
supports the hypothesis that these targets have signifi-
cant steric issues. Pre-assembly of the 1,4-diamine 14
appears to be crucial in synthesizing these sterically
demanding molecules.
A similar synthetic route to phosphonamide 2 contain-
ing two â-branched amines is outlined in Scheme 7. Two
equivalents of N,N-dimethyl phenylalanine 15 were
coupled to 1,4-diamino butane in good yield to produce
the diamide. Subsequent reduction with LAH provided
the C2-symmetric diamine 16. The coupling of diamine
16 with dichlorophenylphosphine occurred without inci-
dence, and oxidization with m-CPBA afforded phospho-
namide 2 in good yield (Scheme 7).
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under an argon atmosphere using
standard gastight syringes, cannulaes, and septa. Stirring was
accomplished with oven-dried magnetic stir bars. Methylene
chloride was purified by distillation over CaH2. Triethylamine
was distilled from CaH2 and stored over KOH. DMAP was
purchased from Reilly Chemicals and was not further purified.
m-CPBA was purchased from Aldrich at a 75%-85% purity
level and was used without further purification. All amino acid
precursors were purchased from Advanced Chem Tech. Deu-
teriochloroform (CDCl3) was purchased from Cambridge Iso-
tope Laboratories and stored over molecular sieves (4 Å) at
room temperature. Mass spectra were performed by the Mass
Spectrometry Laboratory at the University of Kansas. Flash
column chromatography was performed with Merck silica gel
(EM-9385-9, 230-400 mesh). Thin-layer chromatography was
performed on silica gel 60F254 plates (EM-5715-7, Merck).
Visualization of TLC spots was effected using KMnO4 stain
and UV irradiation.
To augment this strategy, we investigated the utiliza-
tion of olefin metathesis to synthesize 1,4-diamines. A
number of allylated amino acid analogues were subjected
to intermolecular cross-metathesis; however, all proved
to be unsuccessful, as consistent with the findings of
Grubbs9 (Scheme 8).
We next pursued a template-promoted RCM route10
utilizing phthaloyl dichloride to synthesize the amino
(9) O’Leary, D. J .; Miller, S. J .; Grubbs, R. H. Tetrahedron Lett. 1998,
39, 1689-1690.
(10) (a) Grubbs and co-workers utilized catechol in their strategy,
see ref 8. (b) We also employed a similar strategy utilizing catechol to
access 18; however, a 1:1 mixture of cis/ trans isomers resulted.
Va lin e-Der ived Cyclic P h osp h on a m id e (1). A solution
of compound 14 (6.5 mg, 0.048 mmol) and CH2Cl2 (100ul) was
cooled in a 0 °C ice bath, and Et3N (23 µL, 0.17 mmol) was
slowly added. Dichlorophenylphosphine (6.5 µL, 48.0 µmol) was

7916 J . Org. Chem., Vol. 65, No. 23, 2000
Sprott and Hanson
dissolved in CH2Cl2 (100 µL) and added dropwise over 1 min.
The reaction was warmed to room temperature for 5 min, then
recooled in a 0 °C ice bath. mCPBA (17.7 mg, 0.072 mmol)
was added to the salt slurry. After being warmed to room
temperature, the reaction was concentrated under reduced
pressure, and the slurry was subjected to flash chromatogra-
phy (EtOAc) to afford 18.5 mg (75%) of 1 as a colorless oil:
[R]25 ) -54.1° (c ) 0.15, CHCl3); FTIR (neat) 1468, 1453, 1384,
1362, 1207 (PdO), 725, 698 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.92-7.69 (m, 2H), 7.41-7.24 (m, 13H), 4.61 (d, J ) 11.8
Hz, 1H), 4.37, (d, J ) 13.0 Hz, 1H), 4.36 (s, 2H), 3.77-3.67
(m, 2H), 3.66-3.58 (m, 1H), 3.53 (dd, J ) 10.0, 7.0 Hz, 1H),
3.47-3.38 (m, 2H), 3.34-3.17 (m, 3H), 2.92 (dddd, J HH ) 14.2
Hz, J HP ) 10.4 Hz, J HH ) 7.0, 3.2 Hz, 1H), 1.98-1.87 (m, 2H),
1.78-1.54 (m, 4H), 1.01 (d, J ) 6.7 Hz, 3H), 0.80 (d, J ) 6.5
EtOAc) afforded 2.94 g (95%) of 9P SS and 9P RS as a light
yellow oil. Further chromatography (8:1 hexanes/EtOAc)
yielded portions of the separated diastereomers for character-
ization.
A sin gle d ia ster eom er (9P SS or 9P RS): Rf ) 0.39 (1:1
hexanes/EtOAc); [R]25 ) -42.3° (c ) 2.44, CHCl3);. FTIR (neat)
1742, 1445, 1368, 1240 (PdO) cm-1 1H NMR (400 MHz,
;
CDCl3) δ 5.78 (dddd, J ) 16.9, 10.2, 6.5, 6.5 Hz, 1H), 5.22 (dd,
J ) 17.2, 1.2 Hz, 1H), 5.14 (d, J ) 10.1 Hz, 1H), 4.40 (ddd,
J HP ) 12.1 Hz, J HH ) 7.5, 7.5 Hz, 1H), 3.75-3.67 (m, 2H), 3.68
(s, 3H), 1.96 (d, J HP ) 16.3 Hz, 3H), 1.70 (dd, J ) 7.3, 6.3 Hz,
2H), 1.65-1.52 (m, 1H), 0.91 (d, J ) 6.4 Hz, 3H), 0.90 (d, J )
6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.37, 134.68 (d,
J CP ) 3.0 Hz), 118.04, 55.87, 52.05, 47.16 (d, J CP ) 4.5 Hz),
38.49 (d, J CP ) 5.7 Hz), 24.52, 22.65 (d, J CP ) 118.9 Hz), 22.65,
21.53; 31P NMR (162 MHz, CDCl3) δ 48.02; HRMS calcd for
C11H23ClNO3P (M + H)+ required 282.1026, found 282.1049.
A sin gle d ia ster eom er (9P SS or 9P RS): Rf ) 0.38 (1:1
hexanes/EtOAc); [R]25 ) -13.1° (c ) 1.44, CHCl3); FTIR (neat)
Hz, 3H), 0.80 (d, J ) 6.5 Hz, 3H), 0.44 (d, J ) 6.7 Hz, 3H); 13
NMR (100 MHz, CDCl3) δ 138.70, 138.39, 133.71 (d, J CP
C
)
145.7 Hz), 130.64 (d, J CP ) 2.8 Hz), 128.27, 128.14, 127.73,
127.68, 127.60, 127.55, 127.51, 127.27, 73.09, 72.76, 71.57,
71.52, 62.46 (d, J CP ) 7.0 Hz), 61.44 (d, J CP ) 6.4 Hz), 42.23,
42.45, 29.32, 28.36, 27.14, 27.09, 21.42, 21.09. 20.37, 20.26;
31P NMR (162 MHz, CDCl3) δ 29.05; HRMS calcd for
1742, 1440, 1373, 1245 (PdO) cm-1 1H NMR (400 MHz,
;
CDCl3) δ 5.81-5.69 (m, 1H), 5.20-5.08 (m, 2H), 4.51 (ddd, J HP
) 9.2 Hz, J HH ) 6.2, 6.2 Hz, 1H), 3.76-3.66 (m, 2H), 3.62 (s,
3H), 1.98 (d, J HP ) 16.0 Hz, 3H), 1.73-1.64 (m, 2H), 1.64-
1.51 (m, 1H), 0.89 (d, J ) 6.3 Hz, 3H), 0.88 (d, J ) 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.56 (d, J CP ) 6.2 Hz),
134.08 (d, J CP ) 2.8 Hz), 118.06, 55.35 (d, J CP ) 2.0 Hz), 51.97,
46.47 (d, J CP ) 5.1 Hz), 37.14 (d, J CP ) 2.1 Hz), 24.31, 22.80,
22.28 (d, J CP ) 117.3 Hz), 21.20; 31P NMR (162 MHz, CDCl3)
δ 47.98; HRMS calcd for C11H23ClNO3P (M + H)+ required
282.1026, found 282.1047.
Leu cin e-Der ived Meth yl P h osp h on a m id ic An h yd r id es
(10a -c). To a neat mixture of diastereomeric leucine phos-
phonamidic chloridates 9P SS and 9P RS (260 mg, 0.92 mmol)
cooled in a 0 °C ice bath was added Et3N (450 µL, 3.22 mmol).
The mixture was heated at 45 °C and monitored by TLC and
31P NMR. The resulting salty slurry was diluted with EtOAc
(10 mL), filtered (10 mL), and concentrated under reduced
pressure to yield 236 mg (100%) of 10a -c as a yellow oil.
Further purification, to separate 10a and 10b sufficiently for
characterization purposes, was accomplished by flash chro-
matography (1:1 Hexanes/EtOAc) and afforded 46 mg (20%)
of the pseudo-meso diastereomer 10c, and 132 mg (56%) of a
mixture of C2-symmetric diastereomers 10a and 10b. The
mixture was comprised of 16 mg (7%) of a single C2-symmetric
diastereomer 10a or 10b, 104 mg (44%) of a mixture of C2-
symmetric diastereomers 10a and 10b, and 12 mg (5%) of a
sample of C2-symmetric diastereomer 10a or 10b at 90%
purity, all as colorless oils.
C
34H48N2O3P (M + H)+ required 563.3403, found 563.3417.
P h en yla la n in e-Der ived Cyclic P h osp h on a m id e (2). In
a procedure similar to that of compound 1 compound 16 (47
mg, 0.12 mmol), CH2Cl2 (500 µL), Et3N (66 µL, 0.48 mmol),
dichlorophenylphosphine (19 µL, 0.14 mmol), and m-CPBA (35
mg, 0.21 mmol) afforded a slurry that was subjected to flash
chromatography (10% Et3N in EtOAc, then 20% Et3N in CH3-
CN) to yield 48 mg (68%, nonoptimized) of 2 as a colorless oil:
[R]25 ) +18.5° (c ) 0.054, CHCl3); FTIR (neat) 1453, 1437,
1378, 1201 (PdO), 737, 698 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.83-7.78 (m, 2H), 7.52-6.96 (m, 13H), 3.29-2.92 (m, 6H),
2.84-2.55 (m, 5H), 2.35-2.27 (m, 3H), 2.18 (s, 6H), 2.06 (s,
6H), 1.81-1.48 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 140.93,
140.85, 132.37 (d, J CP ) 8.5 Hz), 130.64, 129.59 (d, J CP ) 212.0
Hz), 128.99, 128.85, 128.25, 128.11, 127.79 (d, J CP ) 13.3 Hz),
125.61, 125.50, 65.25, 65.21, 64.79, 64.79, 64.76, 47.08, 46.94,
40.34, 40.29, 33.00, 32.36, 28.39, 28.02; 31P NMR (162 MHz,
CDCl3) δ 29.14; HRMS calcd for C32H46N4OP (M + H)+
required 533.3409, found 533.3427.
Leu cin e-Der ived Cyclic P h osp h on a m id e (3). In a pro-
cedure similar to that of compound 1, compound 18 (10.5 mg,
30.7 µmol), CH2Cl2 (1 mL), Et3N (20 µL, 0.14 mmol), dichlo-
rophenylphosphine (54 µL, 39.9 µmol) and mCPBA (12 mg,
0.05 mmol) afforded a slurry that was subjected to flash
chromatography (EtOAc) to yield 12.3 mg (86%) of a colorless
oil: [R]25 ) +108.3° (c ) 0.072, CHCl3); FTIR (neat) 1731, 1430,
1
1388, 1368, 1204 (PdO), 748, 702 cm-1; H NMR (400 MHz,
Pseudo-meso-leucine-derived methyl phosphonamidic an-
CDCl3) δ 7.86 (dd, J HP ) 12.1 Hz, J HH ) 6.8 Hz, 2H), 7.55-
7.50 (m, 1H), 7.47-7.43 (m, 2H), 5.75-5.64 (m, 2H), 4.18 (ddd,
J ) 9.1, 6.3, 6.3 Hz, 1H), 4.08 (ddd, J HP ) 13.3 Hz, J HH ) 5.8,
5.8 Hz, 1H), 4.02-3.81 (m, 3H), 3.76-3.70 (m, 1H), 3.68 (s,
3H), 3.46 (s, 3H), 1.78-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.55
(ddd, J ) 14.3, 7.2, 7.2 Hz, 1H), 1.40 (ddd, J ) 13.9, 6.3, 6.3
Hz, 1H), 0.90 (d, J ) 6.4 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H),
0.73 (d, J ) 6.6 Hz, 3H), 0.68 (d, J ) 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.49, 173.16, 132.71 (d, J CP ) 9.0 Hz),
131.81, 131.78, 129.2 (d, J CP ) 181.1 Hz), 128.23 (d, J CP ) 13.4
Hz), 128.22, 56.43 (d, J CP ) 7.0 Hz), 55.80 (d, J CP ) 6.0 Hz),
51.88, 51.46, 41.37 (d, J CP ) 2.8 Hz), 40.53 (d, J CP ) 2.8 Hz),
39.47, 39.15 (d, J CP ) 4.9 Hz), 24.62, 24.42, 22.97, 22.61, 22.30,
21.96; 31P NMR (162 MHz, CDCl3) δ 29.56; HRMS calcd for
hydride (10c): Rf ) 0.4 (EtOAc); [R]25 ) -17.1° (c ) 0.59,
CHCl3); FTIR (neat) 1749, 1714, 1422, 1363, 1222 (PdO) cm-1
;
1H NMR (400 MHz, CDCl3) δ 5.87-5.75 (m, 2H), 5.18 (dd, J
) 17.1, 1.3 Hz, 1H), 5.14 (dd, J ) 17.1, 1.3 Hz, 1H), 5.12-5.06
(m, 2H), 4.49 (ddd, J HP ) 10.7 Hz, J HH ) 10.7, 5.4 Hz, 1H),
4.34 (ddd, J HP ) 9.2 Hz, J HH ) 9.2, 5.3 Hz, 1H), 3.75-3.58 (m,
4H), 3.68 (s, 3H), 3.66 (s, 3H), 1.83-1.60 (m, 6H), 1.74 (d, J HP
) 16.8 Hz, 3H), 1.69 (d, J HP ) 16.7 Hz, 3H), 0.92 (d, J ) 6.2
Hz, 6H), 0.91 (d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 173.67 (d, J CP ) 2.2 Hz), 173.20, 135.34, 135.34, 117.77,
117.48, 56.32 (d, J CP ) 2.9 Hz), 55.93 (d, J CP ) 3.6 Hz), 51.94,
51.90, 47.24 (d, J CP ) 4.9 Hz), 46.45 (d, J CP ) 4.9 Hz), 38.98
(d, J CP ) 3.7 Hz), 37.57 (d, J CP ) 2.6 Hz), 24.51, 24.19, 22.95,
22.87, 21.51, 21.33, 15.49 (dd, J CP ) 129.5, 4.3 Hz), 14.80 (dd,
J CP ) 127.7, 4.5 Hz); 31P NMR (162 MHz, CDCl3) δ 29.19 (d,
J PP ) 35.5 Hz), 28.41 (d, J PP ) 35.5 Hz); HRMS calcd for
C
24H38N2O5P (M + H)+ required 465.2518, found 465.2521.
Leu cin e-Der ived Meth yl P h osp h on a m id ic Ch lor id a tes
(9P SS, 9P RS). A solution of methylphosphonic dichloride (1.0
mL, 11.04 mmol) and CH2Cl2 (20 mL) was cooled in a 0 °C ice
bath. Et3N (6.26 mL, 45.0 mmol) was added dropwise, followed
by a catalytic amount of DMAP (5 mol %), and the reaction
was stirred for 5 min. Allylated leucine methyl ester 8 (2.0 g,
10.82 mmol) in CH2Cl2 (5 mL) was added via cannulae, and
the reaction mixture was refluxed and monitored by TLC. Once
complete, the reaction mixture was concentrated under re-
duced pressure, diluted with EtOAc, filtered, and concentrated
under reduced pressure. Flash chromatography (3:1 hexanes/
C
23H43N2O7P2 (M + H)+ required 509.2546, found 509.2545.
C2-sym m etr ic leu cin e-d er ived m eth yl p h osp h on a m id -
ic a n h yd r id e, a sin gle d ia ster eom er (10a or 10b, top Rf):
Rf ) 0.22 (EtOAc); [R]25 ) -37.8° (c ) 0.32, CHCl3); FTIR
(neat) 1740, 1437, 1387, 1241 (PdO) cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.79 (dddd, J ) 16.9, 10.2, 6.2, 6.2 Hz, 2H), 5.21 (dd,
J ) 15.9, 1.2 Hz, 2H), 5.12 (dd, J ) 9.8, 0.9 Hz, 2H), 4.49-
4.42 (m, 2H), 3.79-3.57 (m, 4H), 3.67 (s, 6H), 1.81-1.59 (m,
6H), 1.75 (d, J HP ) 17.0 Hz, 6H), 0.94 (d, J ) 6.0 Hz, 6H), 0.93
(d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 173.33,

Amino Acid-Derived Cyclic Phosphonamides
J . Org. Chem., Vol. 65, No. 23, 2000 7917
135.59, 117.62, 56.11, 51.95, 46.95, 38.71, 24.57, 22.94, 21.31,
15.67 (dd, J CP ) 130.9, 5.6 Hz); 31P NMR (162 MHz, CDCl3) δ
29.88; HRMS calcd for C23H43N2O7P2 (M + H)+ required
509.2546, found 509.2526.
and allowed to stir for 10 min. The slurry was partitioned
between EtOAc (2 mL) and water (2 mL), the layers were
separated, and the aqueous layer was reextracted with EtOAc
(2 × 2 mL). The organic layers were combined, washed once
with brine, dried (Na2SO4), and concentrated under reduced
pressure. Flash chromatography (1:1 Hexanes/EtOAc, then
10% MeOH in EtOAc) afforded 31 mg (95%) of 13 as white
crystals: [R]25 ) -57.7° (c ) 0.052, CHCl3); FTIR (neat) 1629,
C2-sym m etr ic leu cin e-d er ived m eth yl p h osp h on a m id -
ic a n h yd r id e, a sin gle d ia ster eom er (10b or 10a , bottom
Rf a t 90% p u r ity): Rf ) 0.22 (EtOAc); [R]25 ) -5.0° (c ) 0.24,
1
CHCl3); FTIR (neat) 1740, 1437, 1387, 1241 (PdO) cm-1; H
NMR (400 MHz, CDCl3) δ 5.79 (dddd, J ) 16.8, 10.1, 6.6, 6.6
Hz, 2H), 5.17 (dd, J ) 16.7, 1.3 Hz, 2H), 5.10 (dd, J ) 9.1, 1.0
Hz, 2H), 4.52-4.42 (m, 2H), 3.66-3.54 (m, 4H), 3.68 (s, 6H),
1.80 (d, J HP ) 15.8 Hz, 6H), 1.78-1.53 (m, 6H), 0.94 (d, J )
6.0 Hz, 6H), 0.93 (d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 173.48, 135.13, 117.47, 55.65, 51.91, 46.35, 37.46,
24.34, 22.99, 21.21, 15.27 (dd, J CP ) 130.9, 5.6 Hz); 31P NMR
(162 MHz, CDCl3) δ 30.14 HRMS calcd for C23H43N2O7P2 (M
+ H)+ required 509.2546, found 509.2561.
1540, 1465, 1437, 1387, 1357, 737, 694 cm-1 1H NMR (400
;
MHz, CDCl3) δ 7.37-7.27 (m, 10H), 6.06 (d, J ) 9.3 Hz, 2H),
4.50 (d, J ) 12.0 Hz, 2H), 4.45 (d, J ) 12.0 Hz, 2H), 3.87-
3.82 (m, 2H), 3.55 (dd, J ) 9.7, 4.0 Hz, 2H), 3.40 (dd, J ) 9.7,
4.2 Hz, 2H), 2.59-2.42 (m, 4H), 1.95-1.86 (m, 2H), 0.90 (d, J
) 7.0 Hz, 6H), 0.88 (d, J ) 7.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 171.74, 138.14, 128.39, 127.61, 127.65, 73.16, 70.03,
54.11, 32.04, 29.26, 19.49, 18.85; HRMS calcd for C28H41N2O4
(M + H)+ required 469.3066, found 469.3076.
Va lin e-Der ived Dia m id e (12). A solution of valine methyl
ester 11 (3.80 g, 28.9 mmol), Et3N (5.24 mL, 37.7 mmol), and
DMF (30 mL) was cooled in a -10 °C (NaCl saturated) ice
bath. Fumaryl dichloride (1.42 mL, 13.2 mmol) was added
dropwise over a 1.5 h period. After addition was complete, the
reaction was warmed to room temperature and stirred for 15
min. The resulting slurry was portioned between EtOAc (100
mL) and water (100 mL). The water layer was extracted twice
with EtOAc (30 mL), and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The
resulting white solid is dissolved in minimal hot CH2Cl2, and
crystallized from hexanes to afford 4.43 g (98%) of the
unsaturated diamide as white crystals: [R]25 ) +8.3° (c ) 0.47,
Va lin e-Der ived Dia m in e (14). LAH (316 mg, 8.3 mmol)
was added to a solution of compound 13 (193 mg, 0.42 mmol)
and dioxane (2 mL) at room temperature. The flask was
equipped with a condenser and heated to reflux for 3 h. The
reaction was cooled to room temperature and quenched over
a 30 min period with water and Glauber’s salt (Na2SO4‚
10H2O). The reaction mixture was stirred for an additional
30 min, and filtered over a pad of Celite (EtOAc). The solution
was concentrated and subjected to flash chromatography (SiO2,
10% MeOH in EtOAc) to afford 164 mg (91%) of 14 as a
colorless oil: [R]25 ) +5.8° (c ) 1.36, CHCl3); FTIR (neat) 1466,
1383, 1364, 735, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-
7.26 (m, 10H), 4.51 (s, 6H), 3.50 (dd, J ) 9.4, 4.4 Hz, 2H), 3.77
(dd, J ) 9.4, 6.8 Hz, 2H), 2.62-2.56 (m, 4H), 2.53 (dt, J ) 6.6,
4.7 Hz, 2H), 1.54-1.47 (m, 4H), 1.23 (bs, 2H), 0.91 (d, J ) 6.9
Hz, 6H), 0.89 (d, J ) 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 138.45, 128.27, 127.54, 127.45, 73.14, 70.33, 62.62, 48.00,
28.86, 28.36, 18.91, 18.25; HRMS calcd for C28H45N2O2 (M +
H)+ required 441.3481, found 441.3504.
P h en yla la n in e-Der ived Dia m in e (16). N,N-Dimethyl
phenylalanine 15 (1.19 g, 6.2 mmol), Et3N (1.29 mL, 9.3 mmol),
and 1,4-diamino butane (303 µL, 3.0 mmol) were dissolved in
CH3CN (50 mL). HBTU was added, and the reaction was
stirred at room temperature for 30 min and then concentrated
under reduced pressure. The mixture was vacuum filtered
(EtOAc), concentrated under reduced pressure, and subjected
to flash chromatography (EtOAc, then 10% Et3N in EtOAc) to
afford 1.06 g (80%, nonoptimized) of the diamide as white
crystals: [R]25 ) -105.7° (c ) 0.19, CHCl3); FTIR (neat) 1649,
1455, 1384, 748, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19-
7.16 (m, 8H), 6.89 (t, J ) 5.7 Hz, 2H), 6.40 (s, 1H), 5.90 (s,
1H), 3.13-3.04 (m, 6H), 3.12 (dd, J ) 12.7, 5.3 Hz, 2H), 2.79
(dd, J ) 13.4, 5.1 Hz, 2H), 2.23 (s, 12H), 1.24 (s, 4H); 13C NMR
(100 MHz, CDCl3) δ 171.68, 139.44, 128.88, 127.91, 125.69,
70.61, 41.91, 38.25, 32.84, 26.52; HRMS calcd for C26H39N4O2
(M + H)+ required 439.3073, found 439.3074.
LAH (304 mg, 8.0 mmol) was added to a solution of the diol
(433 mg, 0.99 mmol) and dioxane (5 mL) at room temperature.
The flask was equipped with a condenser and heated to reflux
for 3 h. The reaction was cooled to room temperature and
quenched over a 30 min period with water and Glauber’s salt
(Na2SO4‚10H2O). The reaction mixture was stirred for an
additional 30 min, and filtered over a pad of Celite (CH2Cl2).
The CH2Cl2 was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure to afford 338 mg (83%,
nonoptimized) of 16 as a colorless oil: [R]25 ) +18.8° (c ) 2.43,
CHCl3); FTIR (neat) 1495, 1454, 1373, 740, 699 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.25-7.21 (m, 4H), 7.15-7.10 (m, 6H),
2.92-2.82 (m, 4H), 2.52-2.42 (m, 6H), 2.28 (s, 12H), 1.44-
1.40 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 140.02, 128.94,
128.23, 125.71, 64.84, 49.50, 49.46, 40.05, 31.40, 27.63; HRMS
calcd for C26H43N4 (M + H)+ required 411.3488, found 411.3495.
Leu cin e-Der ived Bicyclic Dia m id e (17). A solution of
allylated leucine methyl ester 8 (308 mg, 1.67 mmol), DMAP
(20 mg, 0.17 mmol), Et3N (405 µL, 2.91 mmol) and CH2Cl2 (7
mL) was cooled in a 0 °C ice bath. Phthaloyl dichloride (120
µL, 0.83 mmol) was added dropwise, and the slurry was
warmed to room temperature. After 30 min, the reaction was
CHCl3); FTIR (neat) 1740, 1637, 1540, 1436, 1355 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.06 (s, 2H), 7.05 (d, J ) 10.3 Hz,
2H), 4.69 (dd, J ) 9.0, 5.3 Hz, 2H), 3.74 (s, 6H), 2.20 (m, 2H),
0.94 (d, J ) 6.9 Hz, 6H), 0.91 (d, J ) 6.9 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 172.44, 164.24, 133.25, 57.34, 52.26, 31.29,
18.92, 17.84; HRMS calcd for C16H27N2O6 (M + H)+ required
343.1869, found 343.1840.
The diamide (970 mg, 3.8 mmol) was dissolved in CH2Cl2
(50 mL) in a 100 mL flask under argon atmosphere. 10% Pd/C
(440 mg) was added to the solution and hydrogen gas was
purged over the reaction mixture for 5 min. The solution was
then stirred at room temperature under 1 atm of hydrogen
gas for 30 min. Filtration over a pad of Celite and concentra-
tion yields 973 mg (99%) of 12 as white crystals: [R]25 +13.0°
(c ) 0.83; CHCl3); FTIR (neat) 1748, 1641, 1436, 1374 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.53 (d, J ) 8.6 Hz, 2H), 4.50
(dd, J ) 8.7, 5.1 Hz, 2H), 3.70 (s, 6H), 2.67-2.49 (m, 4H), 2.16-
2.07 (m, 2H), 0.90 (d, J ) 6.9 Hz, 6H), 0.87 (d, J ) 6.9 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 172.42, 172.01, 57.16, 52.03,
31.46, 31.05, 18.89, 17.76; HRMS calcd for C16H29N2O6 (M +
H)+ required 345.2026, found 345.2042.
Va lin e-Der ived Bis-Ben zyl Eth er (13). To a solution of
compound 12 (1.21 g, 3.5 mmol) and THF (17 mL) was added
NaBH4 (669 mg, 17.6 mmol) at room temperature, and the
reaction was equipped with a condenser and heated to 55 °C.
MeOH was added dropwise over a 20 min period, and the
reaction was monitored by TLC. The reaction was cooled to
room temperature, and quenched slowly with a minimal
amount of distilled water. The reaction slurry was subjected
to flash chromatography (10% MeOH in EtOAc) to afford 954
mg (95%) of the diol as white crystals: [R]25 ) -18.2° (c ) 0.49,
1:1 CH3CN/H2O); FTIR (neat) 1635, 1543, 1457, 1418 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.63 (d, J ) 8.9 Hz, 2H), 3.99 (s,
2H), 3.76-3.67 (m, 4H), 3.50 (dd, J ) 10.9, 7.8 Hz, 2H), 2.71
(d, J ) 9.8 Hz, 2H), 2.49 (d, J ) 9.9 Hz, 2H), 1.82-1.74 (m,
2H), 0.93 (d, J ) 6.8 Hz, 6H), 0.91 (d, J ) 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 173.63, 63.29, 57.06, 32.27, 29.30,
19.48, 18.79; HRMS calcd for C14H29N2O4 (M + H)+ required
289.2127, found 289.2152.
A solution of the diol (20 mg, 0.07 mmol) in DMF (150 µL)
was cooled in a 0 °C ice bath. NaH (8.4 mg, 0.22 mmol) was
added, and the reaction was warmed to room temperature.
After gas evolution was complete, the reaction was recooled
in a 0 °C ice bath, and benzyl bromide (18.4 µL, 0.16 mmol)
was added. The reaction was warmed to room temperature,

7918 J . Org. Chem., Vol. 65, No. 23, 2000
Sprott and Hanson
partitioned between EtOAc (10 mL) and H2O (10 mL), and the
water layer was extracted twice with EtOAc (5 mL). The
organic layers were combined, washed with brine, dried (Na2-
SO4), and concentrated under reduced pressure. Flash chro-
matography (2:1 hexanes/EtOAc) afforded both a single spot
(TLC) and a single peak (GC, 97%) of 398 mg (96%) of phthalic
diamide as a mixture of rotamers: [R]25 ) -64.8° (c ) 0.66,
Leu cin e-Der ived Dia m in e (18). In a sealable Pyrex test
tube, compound 17 (100 mg, 0.21 mmol) was dissolved in HCl
saturated MeOH (3 mL), capped, and heated in a 115° oil bath.
After 72 h, the reaction was cooled to room temperature, then
concentrated under reduced pressure. EtOAc (2 mL) was added
and the reaction was cooled in a 0 °C ice bath. Et3N (1 mL)
was added, then the reaction was slowly warmed to room
temperature and stirred for 1 h. The reaction was concentrated
under reduced pressure and subjected to flash chromatography
(1:1 Hexanes/EtOAc) to afford 24 mg (36%) of 18 as a colorless
oil: [R]25 ) +12.0° (c ) 0.05, CHCl3); FTIR (neat) 1737, 1468,
CHCl3); FTIR (neat) 1743, 1647, 1456, 1436, 1410, 754 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 4H), 5.93-5.79
(m, 2H), 5.23-5.10 (m, 4H), 4.32 (bs, 2H), 3.97-3.87 (m, 2H),
3.78-3.68 (m, 8H), 2.11-1.60 (m, 6H), 0.96-0.70 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 171.97, 170.75, 136.44, 135.21,
129.07, 126.80, 117.83, 56.78, 52.10, 46.86, 38.74, 25.79, 23.18,
22.99; HRMS calcd for C28H41N2O6 (M + H)+ required 501.2965,
found 501.2971.
1
1433, 1368 cm-1; H NMR (400 MHz, CDCl3) δ 5.56 (dd, J )
4.5, 4.5 Hz, 2H), 3.72 (s, 6H), 3.29-3.21 (m, 4H), 3.09 (dd, J )
13.2, 4.8 Hz, 2H), 1.76-1.66 (m, 2H), 1.54 (bs, 2H), 1.47-1.43
(m, 4H), 0.92 (d, J ) 6.6 Hz, 6H), 0.89 (d, J ) 6.6 Hz, 6H); 13
C
A solution the diamide (70 mg, 0.14 mmol) and CH2Cl2 (14
mL) was purged with argon gas for 5 min. The solution was
brought to reflux and Grubbs catalyst (18 mg, 21.9 µmol) was
added in three (6 mg) portions over a 24 h period. After 36 h
the reaction was concentrated under reduced pressure and
subjected to flash chromatography (1:1 Hexanes/EtOAc) to
afford 64 mg (97%) of 17 as a colorless oil: [R]25 ) -43.6° (c )
0.51, CHCl3); FTIR (neat) 1741, 1650, 1430, 1412, 1367, 1331,
NMR (100 MHz, CDCl3) δ 176.44, 130.17. 59.34, 51.60, 44.62,
42.85, 24.90, 22.66, 22.35; HRMS calcd for C18H35N2O4 (M +
H)+ required 343.2597, found 343.2619.
Ack n ow led gm en t. This investigation was gener-
ously supported by funds provided by the National
Institutes of Health (National Institute of General
Medical Sciences, RO1-GM58103). The authors also
thank Dr. Martha Morton and Dr. David Vander Velde
for their assistance with NMR measurements and Dr.
Todd Williams for HRMS analysis.
756 cm-1 1H NMR (400 MHz, CDCl3) δ 7.46-7.44 (m, 2H),
;
7.39-7.37 (m, 1H), 7.31-7.28 (m, 1H), 5.85 (s, 1H), 5.75 (s,
1H), 5.09 (s, 1H), 4.35 (s, 1H), 4.09-4.01 (m, 1H), 3.96 (dd, J
) 15.2, 6.0 Hz, 1H), 3.75 (s, 3H), 3.75 (s, 3H), 3.70-3.57 (m,
2H), 2.20-2.13 (m, 1H), 1.98-1.86 (m, 1H), 1.75-1.61 (m, 4H),
1.00-0.96 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 172.25,
171.75, 169.93, 169.47, 134.62, 134.49, 131.59, 129.54, 129.42,
129.24, 127.44, 126.73, 56.92, 56.02, 52.18, 52.18, 45.66, 42.83,
39.27, 38.37, 25.36, 25.11, 22.76, 22.64, 22.30, 22.18; HRMS
calcd for C26H37N2O6 (M + H)+ required 473.2652, found
473.2646.
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra of
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O005545Q