Preparation of functionalized, conformationally constrained DTPA analogues from L- or D-serine and trans-4-hydroxy-L-proline. Hydroxymethyl substituents on the central acetic acid and on the backbone

Article abstract of DOI:10.1021/jo000071g

The enantio- and diastereospecific syntheses of conformationally constrained diethylenetriamine-pentaacetic acid (DTPA) analogues that are functionalized with a hydroxymethyl linker substituent on the central acetic acid or on the backbone are described. Key synthetic steps include (i) displacement of the 4-hydroxyl group of N-BOC-trans-4-hydroxy-L-proline benzyl ester, via activation as the Inflate, with suitable amines derived from L- or D-serine, (ii) the low-temperature alkylation of diethylenetriamines with the triflate of benzyl glycolate, thereby minimizing competitive lactamization, to give DTPA pentabenzyl esters, and (iii) deprotection to afford the corresponding DTPA analogues under very mild hydrogenolysis conditions.

Full text of DOI:10.1021/jo000071g

4048
J . Org. Chem. 2000, 65, 4048-4057
P r ep a r a tion of F u n ction a lized , Con for m a tion a lly Con str a in ed
DTP A An a logu es fr om L- or D-Ser in e a n d
tr a n s-4-Hyd r oxy-L-p r olin e. Hyd r oxym eth yl Su bstitu en ts on th e
Cen tr a l Acetic Acid a n d on th e Ba ck bon e
I. Fraser Pickersgill and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received J anuary 19, 2000
The enantio- and diastereospecific syntheses of conformationally constrained diethylenetriamine-
pentaacetic acid (DTPA) analogues that are functionalized with a hydroxymethyl linker substituent
on the central acetic acid or on the backbone are described. Key synthetic steps include (i)
displacement of the 4-hydroxyl group of N-BOC-trans-4-hydroxy-L-proline benzyl ester, via activation
as the triflate, with suitable amines derived from L- or D-serine, (ii) the low-temperature alkylation
of diethylenetriamines with the triflate of benzyl glycolate, thereby minimizing competitive
lactamization, to give DTPA pentabenzyl esters, and (iii) deprotection to afford the corresponding
DTPA analogues under very mild hydrogenolysis conditions.
In tr od u ction
albumin-targeting phosphate diester moiety to a Gd-
DTPA complex.8
Paramagnetic metals, in particular gadolinium, as
chelated complexes with DTPA ligands have shown
important applications as MRI contrast agents.1 Also
under investigation are Gd-DTPA and Yb-DTPA com-
plexes for use as X-ray contrast agents.2 In addition,
DTPA ligands have attracted attention as ligands for
radionuclides (e.g., 111In, 90Y, 117mSn, 153Sm, 212Bi, 64Cu,
67Cu, and 67Ga) for use as diagnostic3 or therapeutic4
radiopharmaceuticals.
Due to the possibility of forming an ester or a more
biologically stable ether linkage from a free alcohol
residue, we have also selected a hydroxymethyl moiety
as a functional attachment to our DTPA analogues. In
addition, on the basis of work previously conducted in
our laboratories,9 we have introduced conformational
constraint in the form of a pyrrolidine ring. This provides
a more rigid DTPA ligand which in theory could provide
more stable metal chelates,10 a very important consid-
eration given the toxicity of the metals employed. For
example, upon metal complex dissociation, free 90Y has
been observed to accumulate in the cortex of the bone,
potentially causing damage to the marrow.4,e,f The intro-
duction of branching groups into the ethylenediamine
backbone of DTPA ligands has been demonstrated to
improve in vivo stability of 90Y-DTPA complexes, with
the greatest improvement in stability being observed
using DTPA analogues having constraint introduced in
the form of a cyclohexyl ring.4b-h
In all these applications site-specific delivery of the
ligand-metal complex in vivo is highly desirable.5 One
method of achieving such a goal is to attach a receptor-
targeting molecule to the DTPA ligand via a linker group.
This “magic bullet” approach is well established, and
there are several examples of functionalized DTPA
ligands reported,4b-h,6 bearing either an appended amino
or carboxylic acid group to which a targeting group has
been attached using an amide6d or thiourea6e linkage. The
use of a hydroxymethyl linker also has been reported7
and has been used successfully for the attachment of an
One important consequence of functionalization of the
DTPA skeleton is the generation of stereocenters. Control
of both the absolute and relative stereochemistry in the
synthesis of the ligand is essential as the overall geom-
etry and stability of the metal complex will conceivably
be different for enantiomeric or diastereomeric ligands.4g,h
(1) (a) Caravan, P.; Ellison, J . J .; McMurry, T. J .; Lauffer, R. B.
Chem. Rev. 1999, 99, 2293. (b) Lauffer, R. B. Chem. Rev. 1987, 87,
901.
(2) Yu, S.-B.; Watson, A. D. Chem. Rev. 1999, 99, 2353.
(3) (a) Anderson, C. J .; Welch, M. J . Chem. Rev. 1999, 99, 2219. (b)
Brechbiel, M. W.; Gansow, O. A.; Atcher, R. W.; Schlom, J .; Esteban,
J .; Simpson, D. E.; Colcher, D. Inorg. Chem. 1986, 25, 2772.
(4) (a) Volkert, W. A.; Hoffman, T. J . Chem. Rev. 1999, 99, 2269. (b)
McMurry, T. J .; Pippin, C. G.; Wu, C.; Deal, K. A.; Brechbiel, M. W.;
Mirzadeh, S.; Gansow, O. J . Med. Chem. 1998, 41, 3546. (c) Brechbiel,
M. W.; Gansow, O. A. J . Chem. Soc., Perkin Trans. 1 1992, 1173. (d)
Brechbiel, M. W.; Pippin, C. G.; McMurry, T. J .; Milenic, D.; Roselli,
M.; Colcher, D.; Gansow, O. A. J . Chem. Soc., Chem. Commun. 1991,
1169. (e) Brechbiel, M. W.; Gansow, O. A. Bioconjugate Chem. 1991,
2, 187. (f) Kozak, R. W.; Raubitschek, A.; Mirzadeh, S.; Brechbiel, M.
W.; J unghaus, R.; Gansow, O. A.; Waldmann, T. A. Cancer Res. 1989,
49, 2639. (g) Wu, C.; Kobayashi, H.; Sun, B.; Yoo, T. M.; Paik, C. H.;
Gansow, O. A.; Carrasquillo, J . A.; Pastan, I.; Brechbiel, M. W. Bioorg.
Med. Chem. 1997, 5, 1925. (h) Kobayashi, H.; Wu, C.; Yoo, T. M.; Sun,
B.; Drumm, D.; Pastan, I.; Paik, C. H.; Gansow, O. A.; Carrasquillo, J .
A.; Brechbiel, M. W. J . Nucl. Med. 1998, 39, 829.
(6) (a) Williams, M. A.; Rapoport, H. J . Org. Chem. 1993, 58, 1151.
(b) Westerberg, D. A.; Carney, P. L.; Rogers, P. E.; Kline, S. J .; J ohnson,
D. K. J . Med. Chem. 1989, 32, 236. (c) Keana, J . F.; Mann, J . S. J .
Org. Chem. 1990, 55, 2868. (d) Anelli, P. L.; Fedeli, F.; Gazzotti, O.;
Lattuada, L.; Lux, G.; Rebasti, F. Bioconjugate Chem. 1999, 10, 137.
(e) Lemieux, G. A.; Yarema, K. J .; J acobs, C. L.; Bertozzi, C. R. J . Am.
Chem. Soc. 1999, 121, 4278.
(7) (a) Amedio, J . C., J r.; Bernard, P. J .; Fountain, M.; Van Wagenen,
G., J r. Synth. Commun. 1999, 29, 2377. (b) Sajiki, H.; Ong. K. Y.;
Nadler, S. T.; Wages, H. E.; McMurry, T. J . Synth. Commun. 1996,
26, 2511.
(8) Lauffer, R. B.; Parmelee, D. J .; Dunham, S. U.; Ouellet, H. S.;
Dolan, R. P.; Witte, S.; McMurry, T. J .; Walovitch, R. C. Radiology
1998, 207, 529.
(5) A discussion of the principles involved in targeted radiophar-
maceuticals is provided in Liu, S.; Edwards, D. S. Chem. Rev. 1999,
99, 2235.
(9) Williams, M. A.; Rapoport, H. J . Org. Chem. 1994, 59, 3616.
(10) Fossheim, R.; Dugstad, H.; Dahl, S. G. J . Med. Chem. 1991,
34, 819.
10.1021/jo000071g CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/25/2000

Preparartion of Functionalized DTPA Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 4049
Also, the position of attachment of the hydroxymethyl
linker to the DTPA analogue could be of importance in
determining metal complex stability.
hydroxy-L-proline and L- or D-serine, respectively. This
route was used previously in the synthesis of similarly
constrained, unfunctionalized DTPA analogues from
trans-4-hydroxy-L-proline and glycine.9
Another consideration is the isolation and purification
of the highly polar DTPA analogues. The use of DTPA
pentabenzyl esters as precursors to the corresponding
DTPA analogues has previously been shown to be an
effective methodology in DTPA synthesis.6a,9 Thus, depro-
tection by catalytic hydrogenolysis is mild and allows for
the direct isolation of the DTPA in high purity. With this
precedent in mind we now present the syntheses of
compounds 1-5.
The key synthetic step, as shown for the synthesis of
1 (Scheme 1), is the alkylation of the free amine of
L-serine benzyl ester 9 with the triflate 7 of N-BOC-4-
hydroxy-L-proline benzyl ester 6. L-Serine benzyl ester
hydrochloride 8 was prepared as reported,11 and the free
amine 9 was generated immediately prior to the alkyl-
ation reaction. Protected hydroxyproline 6 was prepared
in high yield from trans-4-hydroxy-L-proline as reported9
and was treated with triflic anhydride in the presence of
diisopropylethylamine at -20 °C to generate triflate 7
in situ. The alkylation proceeds with inversion of stere-
ochemistry on the proline ring. Previously,9 several
analogous alkylations also afforded ∼5% of the diaste-
reomer corresponding to retention of configuration which
proved inseparable by column chromatography. However,
in the present case, any retention product was removed
during purification and the cis-4-amino-L-proline ana-
logue 10 was isolated in 64% yield as a single diastere-
1
omer as shown by H NMR.
The remainder of the triamine backbone was then
added by alkylation of 10 with known bromide 11.6a For
the serine-based analogues this alkylation proved to be
more difficult than for the corresponding glycine-based
analogue.9 Previously, heating the amino proline deriva-
tive with bromide 11 at 50 °C in a biphasic mixture of
acetonitrile and aqueous phosphate buffer for 22 h
afforded the alkylated product in 78% yield. An attempt
to alkylate 10 under these conditions gave essentially no
alkylated product after 24 h. It was clear that the
increased steric bulk imparted by the hydroxymethyl
substituent in the serine-based analogues was hindering
the alkylation, although refluxing conditions gave some
alkylated product 12 as observed by TLC. Under these
more drastic reaction conditions, however, bromide 11
was also being hydrolyzed to the alcohol, which subse-
Resu lts a n d Discu ssion
A. Hyd r oxym eth yl Su bstitu en ts on th e Cen tr a l
Acetic Acid . Analogues 1 and 2 were prepared using
the same convergent synthetic pathway from trans-4-
Sch em e 1. Con for m a tion a lly Con str a in ed Hyd r oxym eth yl DTP As F u n ction a lized on th e Cen tr a l Aceta te
Ar m

4050 J . Org. Chem., Vol. 65, No. 13, 2000
Pickersgill and Rapoport
Sch em e 2. En a n tiom er ic Mon op r otected Dia m in o
Alcoh ols fr om L-Ser in e
quently lactonized to give the corresponding 2-morpholi-
none and benzyl alcohol. Modification of the procedure
to replenish both the phosphate buffer and 11 every 2 h
for a total of 6 h followed by continued heating under
reflux for 15 h afforded 12 in 25% yield with a 52%
recovery of 10. Attempts to perform the alkylation under
anhydrous conditions at 50 °C using organic bases in
DMSO and DMF as solvent gave complex mixtures,
presumably due to epimerization at the amino acid chiral
centers. Also, the use of more reactive alkylating agents
analogous to 11 such as the mesylate or the triflate was
not considered because past experience has demonstrated
that these would prove of little benefit as the alkylation
is believed to proceed via the corresponding aziridinium
species.12
Removal of the N-BOC protecting group with TFA
afforded secondary amine 13, and alkylation of this
material with benzyl bromoacetate gave the DTPA
pentabenzyl ester 14 in 89% overall yield from 12.
Deprotections of DTPA pentabenzyl esters by catalytic
hydrogenolysis have typically been conducted in the
presence of aqueous hydrochloric acid and the DTPA
products isolated cleanly as their corresponding trihy-
drochloride salts.6a,9 These conditions may be useful for
unfunctionalized DTPA analogues; however, they are
unsuitable for DTPA analogues bearing acid-sensitive
functionality. Although 14 is not particularly sensitive
to acid, DTPA analogues in which a moiety is attached
via the hydroxymethyl linker may possess acid-sensitive
groups, and therefore a deprotection in the absence of
acid would be highly desirable.
With this in mind, 14 was cleanly deprotected without
the addition of aqueous hydrochloric acid to afford 1 in
95% yield. The solvent system used for the deprotection
reaction was a 6/1 MeOH/H2O mixture, the quantity of
H2O added being dictated by the necessity to keep the
DTPA pentabenzyl ester starting material in solution.
Deprotections in MeOH with 1 M HCl added have also
been shown to furnish trace amounts of methyl ester
byproducts as detected by mass spectrometry.13 However,
under the conditions described for the generation of 1 and
2 in the absence of added acid, no methyl ester impurities
were observed.
20 in 92% yield. The selection of the trityl group also
proved beneficial in the next step as, upon reduction of
amide 20 with lithium aluminum hydride (LAH) in Et2O
to give the highly polar (-)-21, purification was possible
by precipitation from CH2Cl2/hexanes due to the crystal-
linity imparted by this protecting group. Reduction of
amide 20 with BH3‚THF also was attempted; however,
this resulted in the isolation of a boron chelate of 21 from
which the boron could not be removed.
Although the trityl group, by virtue of its steric bulk,
should serve to shield the relatively acidic amino acid
ester R-proton from attack by base, both the amidation
and reduction conditions are reasonably drastic, and
therefore epimerization at the chiral center was consid-
ered to be a possibility. Chiral HPLC, however, estab-
lished the enantiomeric purity of both 20 and (-)-21 to
be >99.5%,15 demonstrating the protection against epimer-
ization provided by the N-trityl group.
The enantiomeric diamino alcohol (+)-21 was acces-
sible, using the same chemistry, from D-serine; however,
a more expedient synthesis was established from N-trityl-
L-serine methyl ester 19 (Scheme 2). Conversion of the
hydroxyl of 19 to the azide 22 via Mitsunobu reaction
with hydrazoic acid proceeded in 91% yield. The azide
and methyl ester functionalities were then simulta-
neously reduced using LAH to give (+)-21. This applica-
tion of the Mitsunobu reaction is of particular interest
in that it proceeds in high yield. Such high yields are
uncommon when Mitsunobu chemistry is performed on
serine alcohols as â-elimination is often a serious compet-
ing reaction.16 Although hydrazoic acid has previously
been demonstrated to be one of the better nucleophiles
for serine-based Mitsunobu reactions,17 the reported
The use of benzyl ester protection for DTPA analogues
therefore provides a useful alternative to the more
commonly employed tert-butyl ester protection, which
requires the use of acid, typically TFA or HCl, for
deprotection.
B. Hyd r oxym eth yl Su bstitu en ts on th e Ba ck bon e.
Diastereomeric DTPA precursors 26 and 30 were syn-
thesized in good overall yield from L-serine and trans-4-
hydroxy-L-proline (Schemes2 and 3). Again the synthetic
strategy adopted hinged on alkylation using triflate 7.
Monoprotected diamino alcohol (-)-21 was accessible
in two high-yielding steps from N-trityl-L-serine methyl
ester 19 (Scheme 2). In the first step 19 was converted
to primary amide 20 with a saturated solution of NH3(g)
in MeOH. Due to the steric bulk of the trityl group, the
reaction required heating at 80 °C in a pressure vessel
for 4-5 d to reach completion. Although these conditions
appear harsh, the reaction proceeded cleanly to afford
(14) Baldwin, J . E.; Spivey, A. C.; Schofield, C. J .; Sweeney, J . B.
Tetrahedron 1993, 49, 6309.
(15) The conditions used to establish the enantiomeric composition
were: column, Chiracel OG; temperature, 40 °C; flow rate, 0.75 mL/
min; detection, 230 nm; and eluent, 1/200/800 TFA/IPA/Hex.
(16) Mitsunobu, O. Synthesis 1981, 1.
(17) (a) Golding, B. T.; Howes, C. J . Chem. Res. 1984, 1. (b) Otsuka,
M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M.
Chem. Pharm. Bull. 1985, 33, 509.
(11) Folsch, G. Acta Chem. Scand. 1959, 13, 1407.
(12) Grote, C. W.; Kim, D. J .; Rapoport, H. J . Org. Chem. 1995, 60,
6987.
(13) Selchau, V.; Rapoport, H. Unpublished results.

Preparartion of Functionalized DTPA Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 4051
Sch em e 3. Syn th esis of Con for m a tion a lly Con str a in ed Hyd r oxym eth yl DTP A P en ta ben zyl Ester s
yields are only around 70%, significantly lower than our
observed 91%. This improvement may be attributable to
the trityl protecting group once again shielding the acidic
R-proton from attack by base. Indeed, this effect has
recently been clearly demonstrated for a serine-based
Mitsunobu reaction with p-nitrobenzoic acid.18
Monoalkylation of diamino alcohols (-)- and (+)-21
with triflate 7 at -10 °C afforded 23 and 27 in 65% and
68% yields, respectively. These protected triamine back-
bones were then functionalized to give the corresponding
diastereomeric DTPA pentabenzyl esters 26 and 30 using
the methodology depicted in Scheme 3.
Before deprotection to give the triamine, the free
alcohol of 23 was silylated with TBDPSCl to afford 24 in
91% yield. This silylation was done in anticipation of
problems of lactonization associated with the DTPA
pentabenzyl ester 38 to give 2-morpholinone 39 as a side
product. Protecting the alcohol at this stage allows for
isolation and storage of the DTPA pentabenzyl ester 26
without losses due to lactonization. As will be discussed
later, the silyl group can then be removed and the free
alcohol 38 isolated immediately prior to further manipu-
lation. The choice of the relatively acid-stable TBDPS as
the silyl group was dictated by the use of TFA in the
succeeding step to simultaneously remove both trityl and
BOC protection and afford triamine 25 in essentially
quantitative yield.
have been addressed and to some extent controlled by
the use of tert-butyl esters as protection for the acetic
acid arms of the DTPA. Indeed, it is common practice to
alkylate a diethylenetriamine backbone with tert-butyl
bromoacetate to generate the DTPA penta-tert-butyl
ester.4c,7 The bulky tert-butyl esters decrease intramo-
lecular cyclization of partially alkylated species to six-
membered lactams during the course of the alkylation
reaction. Benzyl esters do not provide the steric hin-
drance to prevent lactam formation. An analogy is the
methyl ester, and the only reported attempt to alkylate
a diethylenetriamine with methyl bromoacetate resulted
in a complex mixture of lactam products with no DTPA
pentamethyl ester being isolated.4c
Thus, it was clear that alkylation of triamine 25 with
benzyl bromoacetate would provide little, if any, of the
desired product 26. Therefore, the much more reactive
benzyl glycolate triflate was used in a low-temperature
alkylation. An initial reaction temperature of -78 °C was
maintained for 12 h before very gradual warming to -10
°C over 12 h. Holding the temperature at -10 °C for 4-5
h then ensured complete alkylation. Triethylamine was
added to quench the excess alkylating agent, and tetra-
alkylated 26 was isolated in 71% yield. The reaction is
clean, and no lactam products were observed.
Having established a synthetic route to 26 and 30, we
then synthesized a regioisomeric analogue 36 in which
the hydroxymethyl unit is one carbon displaced along the
backbone (Scheme 4). On the basis of the same methodol-
ogy (cf., Scheme 3), it is apparent that 36 is accessible
from a monoprotected diamine such as 37, which in turn
should be accessible from (-)-21, used previously in the
synthesis of 26, via a reversal in the nitrogen protection
order.
With triamine 25 in hand, all that was required was
polyalkylation to generate the DTPA pentabenzyl ester
26; however, this is not as trivial as it may first appear.
Past experience12 has demonstrated that the competitive
formation of six-membered lactams is a significant
problem in DTPA synthesis. Typically these problems
(18) Cherney, R. J .; Wang, L. J . Org. Chem. 1996, 61, 2545.

4052 J . Org. Chem., Vol. 65, No. 13, 2000
Pickersgill and Rapoport
Sch em e 4. Regioisom er ic An a logu e
Sch em e 5. Dep r otection To Give F u n ction a lized
DTP A Der iva tives
To this end the free amine of (-)-21 was protected with
a BOC group to afford 31. An attempt to remove the trityl
group selectively, however, by treatment of 31 with 105
mol % BF3‚Et2O in 4/1 CH2Cl2/AcOH at 0 °C did not
afford 37, presumably due to difficulty in extracting the
highly polar 37 from the aqueous phase. Therefore, 31
was initially silylated to afford 32. As anticipated the
early introduction of the silyl group proved beneficial,
allowing for the isolation and purification of the more
lipophilic 33 by chromatography after treatment with
BF3‚Et2O under the selective detritylation conditions.
Alkylation of 33 with triflate 7 was very slow at -10
°C; however, at 0 °C the reaction progressed smoothly to
afford the protected triamine backbone 34 in 68% yield.
Subsequent removal of the N-BOC protection with TFA
gave triamine 35 in quantitative yield, which was then
alkylated with the triflate of benzyl glycolate at low
temperature to afford 36 in 67% yield.
C. Dep r otection To Affor d DTP A An a logu es. To
demonstrate the potential of backbone-substituted DTPA
pentabenzyl esters 26, 30, and 36 as precursors to
functionalized DTPA analogues, a number of manipula-
tions were performed on 26 (Scheme 5). Removal of the
silyl group with pyridine‚HF in THF proceeded cleanly
at rt to afford alcohol 38, as a 14/1 mixture with
2-morpholinone 39, in 91% yield after rapid chromatog-
raphy at 0 °C to minimize lactonization on the silica gel.
While this material is of sufficient purity for further
derivatization of the alcohol, for example, via esterifica-
tion with N-BOC-glycine to afford 41, it was not consid-
ered suitable for direct deprotection to afford DTPA 3,
primarily because of the absence of any subsequent
purification of the deprotected product. For this purpose,
38 of greater purity could be obtained by a second column
chromatography at 0 °C using a less polar eluent, to
afford pure 38 in 55% yield. Hydrogenolysis of pure 38
in 7/1 MeOH/H2O then gave 3 in 98% yield.
To test the objective of attaching and retaining an acid-
sensitive moiety, N-BOC-glycine was selected as the
attachment. A 14/1 mixture of 38/39, isolated in >90%
yield, was esterified with N-BOC-glycine using DCC as
the coupling agent in the presence of catalytic DMAP, to
afford 41 in 81% yield. Subsequent hydrogenolysis of 41
in 8/1 MeOH/H2O then cleanly afforded 42 in 99% yield.
Although 2-morpholinone 39 was an undesirable side
product, it provided an interesting example of a precursor
to a diethylenetriaminetetraacetic acid ligand. Once
again taking a 14/1 mixture of 38 and 39 and heating
under reflux in benzene with a catalytic amount of
p-TsOH allowed isolation of pure 39 in 91% yield. An
attempt to generate the tetraacid 40 cleanly was not
successful, with a mixture of 40, 38, and the monomethyl
ester derivative of 38 being observed by 1H and 13C NMR
and mass spectrometry. This result is consistent with
reported methanolysis and hydrolysis of 2-morpholinones
in MeOH and aqueous solutions, respectively.19
Con clu sion
The synthesis of several hydroxymethyl-substituted,
conformationally constrained DTPA analogues from trans-
4-hydroxy-L-proline and L- or D-serine has been described.
The polyalkylation of diethylenetriamine backbones with
benzyl glycolate triflate to give DTPA pentabenzyl esters
has been established at low temperature, minimizing
competitive lactamization. In addition, attachment of an
external acid-sensitive functionality in the form of an
N-BOC-glycine ester linked via the hydroxymethyl sub-
stituent has been demonstrated to be stable under the
(19) Kashima, C.; Harada, K. J . Org. Chem. 1989, 54, 789.

Preparartion of Functionalized DTPA Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 4053
mg, 1.77 mmol) in CH3CN (1 mL) was added to the organic
phase followed by a fresh aliquot of phosphate buffer (3 mL),
and the reaction heated at reflux again. This procedure was
repeated for two further additions of 11, after which heating
at reflux was continued for a further 15 h. Separation of the
organic phase and evaporation of the solvent gave a residue
which was purified by chromatography (2/1 hexanes/ EtOAc
+ 1% NEt3 to 1/1 hexanes/EtOAc + 1% NEt3) to afford
recovered 10 (228 mg, 52%) and alkylated product 12 (187 mg,
25%) as a pale yellow oil: [R]22D -50.9 (c 1.1, CHCl3); 1H NMR
(CDCl3) rotamers δ 1.33 and 1.43 (2s, 9H), 1.78-1.89 (m, 1H),
2.29 (m, 1H), 2.61 (m, 1H), 2.74 (m, 2H), 2.85 (m, 1H), 3.13
(m, 1H), 3.44-3.70 (m, 8H), 3.79 (m, 2H), 4.12 (m, 0.6H), 4.20
(m, 0.4H), 5.06-5.27 (m, 8H), 7.24-7.31 (m, 20H); 13C NMR
(CDCl3) rotamers δ 28.2, 28.4, 34.2, 35.1, 46.6, 47.8, 48.1, 54.4,
55.2, 57.2, 57.5, 59.3, 59.8, 60.3, 63.6, 65.0, 66.5, 66.6, 66.8,
80.2, 126.9, 127.3, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7,
135.5, 135.7, 153.5, 154.2, 170.6, 171.8, 171.9, 172.4, 172.6.
Anal. Calcd for C47H55N3O11: C, 67.4; H, 6.6; N, 5.0. Found:
C, 67.4; H, 6.4; N, 5.0.
N-[2-Bis[(b en zyloxyca r b on yl)m et h yl]a m in oet h yl]-N-
[(2S,4S)-4-[2-(ben zyloxyca r bon yl)-1-[(ben zyloxyca r bon -
yl)m eth yl]p yr r olid in yl]]-L-ser in e Ben zyl Ester (14). To
a solution of 12 (110 mg, 0.131 mmol) in CH2Cl2 (0.6 mL),
cooled to 0 °C, was added dropwise TFA (0.6 mL). The reaction
mixture was warmed to rt and stirred for 1 h. Evaporation
gave a residue which was dissolved in CH2Cl2 (2 mL) and
washed with cold (0 °C) 1 M NaOH (2 mL). The aqueous phase
was extracted with CH2Cl2 (2 mL), and the combined organic
phases were washed with brine (2 mL), dried, filtered, and
evaporated to afford secondary amine 13 (96 mg, 99%) as a
yellow oil which was used directly without further purifica-
tion: 1H NMR (CD3OD) δ 1.71 (m, 1H), 2.17 (m, 1H), 2.55-
2.95 (m, 6H), 3.41-3.81 (m, 9H), 5.00-5.17 (m, 8H), 7.15-
7.36 (m, 20H). To a solution of 13 (96 mg, 0.130 mmol) in THF
(1 mL) cooled to 0 °C were added DIEA (25 µL, 0.144 mmol)
and benzyl 2-bromoacetate (22 µL, 0.139 mmol). The reaction
was stirred for 2 h at 0 °C and then 15 h at rt. The precipitated
salt was removed by filtration, the filtrate evaporated, and the
residue chromatographed (2/1 hexanes/EtOAc + 1% NEt3) to
afford pentabenzyl ester 14 (103 mg, 89% from 12) as a pale
yellow oil: [R]22D -60.0 (c 1.1, CHCl3); 1H NMR (CDCl3) δ 1.90
(m, 1H), 2.30 (m, 1H), 2.65-2.83 (m, 4H), 2.94-3.00 (m, 1H),
3.07 (dd, J ) 9.5, 5.6 Hz, 1H), 3.41 (ABq, J ) 17.5 Hz, 2H),
3.53-3.64 (m, 8H), 3.73 (dd, J ) 11.3, 5.0 Hz, 1H), 3.80 (dd, J
) 9.7, 5.0 Hz, 1H), 5.03-5.15 (m, 10H), 7.28-7.33 (m, 25H);
13C NMR (CDCl3) δ 35.5, 45.7, 52.6, 53.9, 54.2, 55.1, 58.2, 60.1,
62.2, 63.0, 66.2, 66.34, 66.40, 66.5, 128.2, 128.30, 128.34, 128.4,
128.5, 128.60, 128.61, 128.63, 135.65, 135.71, 135.8, 170.4,
170.7, 172.4, 172.9. Anal. Calcd for C51H55N3O11: C, 69.1; H,
6.3; N, 4.7. Found: C, 68.9; H, 6.4; N, 4.7.
mild hydrogenolysis conditions used for the deprotection
of the DTPA pentabenzyl esters to the corresponding
DTPA analogues. Presumably this protocol will be com-
patible with other acid-sensitive receptor targeting mol-
ecules similarly attached.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were performed under
an atmosphere of nitrogen or argon unless indicated otherwise.
THF and Et2O were distilled from Na-benzophenone ketyl;
iPr2NEt, Et3N, CH3CN, and CH2Cl2 were distilled from CaH2;
MeOH was distilled from Mg, trifluoromethanesulfonic anhy-
dride was prepared as reported20 and distilled off P2O5 (10%
w/v) prior to use. 1H and 13C NMR chemical shifts are reported
in δ (ppm). 1H NMR spectra were referenced as follows: CDCl3
(internal tetramethylsilane, δ ) 0.0 ppm), CD3OD (internal
tetramethylsilane, δ ) 0.0 ppm), D2O (HOD, δ ) 4.80 ppm).
13C NMR spectra were referenced as follows: CDCl3 (δ ) 77.24
ppm), CD3OD (δ ) 49.15 ppm), D2O (internal dioxane, δ )
67.19 ppm). Melting points were determined in an open
capillary and are uncorrected. All organic solutions from
extractive isolation of products were dried over Na2SO4 and
evaporated at 35-40 °C and aspirator pressure. Column
chromatography was performed using silica gel 60, 230-400
mesh (EM Science). TLC analysis was performed on aluminum-
backed silica gel 60 F254, 0.2 mm plates (EM Science), visual-
ized by UV light (254 nm) and/or ethanolic phosphomolybdic
acid followed by heating. Elemental analyses and mass spectra
were determined by the Micro-Mass Analytical Facility, Uni-
versity of California, Berkeley.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
ca r bon yl)p yr r olid in yl]]-L-ser in e Ben zyl Ester (10). Amine
9 was prepared by partitioning hydrochloride salt 8 (3.00 g,
12.9 mmol) between CHCl3 (10 mL) and 0.5 M Na2CO3 (30
mL). The organic phase was washed with a second portion of
0.5 M Na2CO3 (30 mL), and the combined aqueous phase was
extracted with CHCl3 (2 × 10 mL). The combined organic
phase was washed with brine (30 mL), dried, filtered, and
evaporated to afford 9 (2.18 g, 86%) as a pale yellow oil which,
after drying under high vacuum for 30 min, was used directly
in the following procedure: To a solution of 6 (1.48 g, 4.61
i
mmol) in CH2Cl2 (10 mL) cooled to -20 °C was added Pr2NEt
(DIEA; 1.69 mL, 9.70 mmol) followed by the dropwise addition
of triflic anhydride (0.82 mL, 4.87 mmol). The resulting orange
solution was stirred for 45 min at -20 °C before the dropwise
addition of a solution of 9 (1.36 g, 6.93 mmol) in CH2Cl2 (5
mL). The reaction was allowed to warm to -8 °C over 1 h and
held at this temperature overnight, then diluted with CH2Cl2
(45 mL), and washed with 0.5 M Na2CO3 (2 × 30 mL) and
brine (30 mL). Drying, filtering, and evaporating left an oil
which was chromatographed (1/1 hexanes/EtOAc + 1% NEt3)
to afford amino alcohol 10 (1.46 g, 64%) as a pale yellow oil:
N-[2-Bis(ca r b oxym et h yl)a m in oet h yl]-N-[(2S,4S)-4-[2-
ca r boxy-1-(ca r boxym eth yl)-p yr r olid in yl]]-L-ser in e (1). To
a degassed solution of 14 (450 mg, 0.51 mmol) in MeOH (43
mL) and H2O (7 mL) was added Pearlman’s catalyst (45%
moisture, 20% Pd(OH)2 by dry weight, 450 mg), and the
mixture was shaken on a Parr apparatus at 50 psi of H2 for
10 h. The catalyst was removed by filtration through a bed of
Celite and washed with H2O (4 mL) and the filtrate partially
evaporated at 35 °C to afford an aqueous solution. Water (20
mL) was then added and the solution evaporated to dryness
at 50 °C to give a colorless gum which under high vacuum
[R]22 -56.7 (c 1.1, CHCl3); 1H NMR (CDCl3) rotamers δ 1.33,
D
1.45 (2s, 9H), 1.85 (br s, 1H), 1.95 (m, 1H), 2.32 (m, 1H), 3.10
(br s, 1H), 3.22-3.56 (m, 5H), 3.70 (m, 1H), 4.27 (dd, J ) 8.7,
4.4 Hz, 0.6H), 4.41 (dd, J ) 8.7, 3.5 Hz, 0.4H), 5.00-5.30 (m,
4H), 7.32-7.35 (m, 10H); 13C NMR (CDCl3) rotamers δ 28.2,
28.4, 36.9, 37.6, 51.4, 51.7, 54.7, 55.5, 57.9, 58.1, 60.8, 60.9,
63.1, 66.9, 67.0, 80.2, 128.2, 128.3, 128.4, 128.51, 128.56, 128.6,
128.7, 135.4, 135.6, 135.8, 153.8, 154. 3, 172.7, 172.8, 172.9.
Anal. Calcd for C27H34N2O7: C, 65.0; H, 6.9; N, 5.6. Found: C,
64.9; H, 7.1; N, 5.5.
afforded 1 as a pale yellow solid (210 mg, 95%): mp 151-152
1
°C dec; [R]22 -39.2 (c 0.9, H2O); H NMR (D2O + 3 drops of
D
N-[2-Bis[(b en zyloxyca r b on yl)m et h yl]a m in oet h yl]-N-
[(2S,4S)-4-[2-(ben zyloxyca r bon yl)-1-(ter t-bu tyloxyca r bo-
n yl)p yr r olid in yl]]-L-ser in e Ben zyl Ester (12). To a solution
of amino alcohol 10 (440 mg, 0.88 mmol) and bromide 11 (743
mg, 1.77 mmol) in CH3CN (3 mL) was added pH 8 phosphate
buffer solution (2.2 M, 3 mL). The vigorously stirred biphasic
mixture was heated at reflux for 2 h and cooled to ambient
temperature, and the phases were separated. Bromide 11 (743
Tf2O) δ 2.07 (m, 1H), 2.68 (m, 1H), 3.23 (m, 2H), 3.49 (m, 2H),
3.56 (dd, J ) 12.5, 8.8 Hz, 1H), 3.76 (m, 2H), 3.91 (m, 2H),
4.11 (m, 1H), 4.22 (ABq, J ) 17.0 Hz, 2H), 4.23 (s, 4H), 4.41
(dd, J ) 11.2, 6.6 Hz, 1H); 13C NMR (D2O) δ 32.6, 43.5, 54.8,
55.6, 56.6, 57.1, 57.9, 61.1, 62.3, 67.0, 169.7, 169.8, 171.7, 175.6;
MS (FAB, G) m/ z 436 (M + H).+ Anal. Calcd for C16H25N3O11
‚
1/2H2O: C, 43.2; H, 5.9; N, 9.5. Found: C, 43.5; H, 5.5; N, 9.4.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
ca r bon yl)p yr r olid in yl]]-D-ser in e ben zyl ester (15), struc-
ture not shown, was prepared by the same procedure as for
10 using D-serine benzyl ester hydrochloride as starting
(20) Burdon, J .; Farazmand, I.; Stacey, M.; Tatlow, J . C. J . Chem.
Soc. 1957, 2574.

4054 J . Org. Chem., Vol. 65, No. 13, 2000
Pickersgill and Rapoport
material: 15 (68%) isolated as a pale yellow oil; [R]22 -9.2 (c
until hydrogen evolution ceased. After the white suspension
was stirred at rt for 1 h, 3/1 CHCl3/IPA (150 mL) was added,
and the solvent was decanted from the white residue which
was subsequently extracted with further portions of 3/1 CHCl3/
IPA (3 × 150 mL). The combined organic phase was dried,
filtered, and evaporated to afford a crude solid (2.36 g, 97%)
which was precipitated from CH2Cl2/hexanes to give (-)-21
(two crops, 2.05 g, 84%) as a colorless gelatinous material
D
1
1.0, CHCl3); H NMR (CDCl3) rotamers δ 1.33 and 1.45 (2s,
9H), 2.00 (m, 1H), 2.14-2.31 (m, 1H), 2.50 (br s, 1-2H), 3.22-
3.40 (m, 3H), 3.52 (m, 1H), 3.58-3.71 (m, 2H), 4.27 (dd, J )
8.7, 4.4 Hz, 0.6H), 4.40 (dd, J ) 8.7, 3.9 Hz, 0.4H), 5.05-5.22
(m, 4H), 7.27-7.37 (m, 10H); 13C NMR (CDCl3) rotamers δ
28.2, 28.4, 35.2, 36.2, 52.8, 53.4, 54.6, 55.5, 57.7, 58.0, 61.1,
62.98, 63.17, 66.9, 67.0, 80.1, 80.2, 128.1, 128.18, 128.21, 128.4,
128.5, 128.6, 128.7, 135.4, 135.5, 135.7, 153.8, 154.2, 172.6,
172.8, 172.9. Anal. Calcd for C27H34N2O7: C, 65.0; H, 6.9; N,
5.6. Found: C, 64.8; H, 6.8; N, 5.6.
N-[2-Bis[(b en zyloxyca r b on yl)m et h yl]a m in oet h yl]-N-
[(2S,4S)-4-[2-(ben zyloxyca r bon yl)-1-(ter t-bu toxyca r bon -
yl)p yr r olid in yl]]-D-ser in e Ben zyl Ester (16), structure not
shown, was prepared by the same alkylation procedure as for
12: recovered 15 (55%) and 16 (27%) isolated as a pale yellow
oil; [R]D22-2.5 (c 1.0, CHCl3); 1H NMR (CDCl3) rotamers δ 1.33
and 1.43 (2s, 9H), 1.73 (m, 1H), 2.30 (m, 1H), 2.53-2.94 (m,
4H), 3.21 (t, J ) 9.9 Hz, 1H), 3.41-3.82 (m, 9H), 4.09-4.22
(m, 2H), 5.03-5.23 (m, 8H), 7.23-7.38 (m, 20H); 13C NMR
(CDCl3) rotamers δ 28.1, 28.3, 32.1, 33.8, 46.3, 46.9, 49.4, 49.7,
53.5, 54.2, 54.8, 55.1, 57.5, 57.7, 59.5, 59.6, 60.2, 63.1, 63.9,
66.4, 66.7, 80.1, 128.0, 128.2, 128.36, 128.41, 128.53, 128.55,
128.6, 135.35, 135.45, 135.5, 135.7, 153.4, 154.1, 170.5, 171.6,
171.8, 172.2, 172.3. Anal. Calcd for C47H55N3O11: C, 67.4; H,
6.6; N, 5.0. Found: C, 67.0; H, 6.7; N, 4.9.
which solidifies on drying: mp 98-99 °C; [R]22 -21.1 (c 0.9,
D
CHCl3); enantiomeric purity >99.5% by chiral HPLC;15 1H
NMR (CD3OD) δ 2.25 (dd, J ) 13.1, 6.6 Hz, 1H), 2.44 (dd, J )
13.1, 3.3 Hz, 1H), 2.58 (m, 1H), 2.92 (dd, J ) 11.0, 6.5 Hz,
1H), 3.22 (dd, J ) 11.0, 3.8 Hz, 1H), 7.14-7.28 (m, 9H), 7.56
(m, 6H); 13C NMR (CDCl3) δ 46.2, 52.9, 65.8, 71.2, 126.5, 127.9,
128.7, 146.9. Anal. Calcd for C22H24N2O: C, 79.5; H, 7.3; N,
8.4. Found: C, 79.1; H, 7.6; N, 8.1.
N-Tr iph en ylm eth yl-â-azido-L-alan in e Meth yl Ester (22).
To N-trityl-L-serine methyl ester 1914 (1.00 g, 2.77 mmol) in
benzene (30 mL) was added PPh3 (0.80 g, 3.05 mmol), and the
mixture was stirred at rt until a solution was obtained.
Hydrazoic acid (1.64 M in benzene,21 1.86 mL, 3.05 mmol) was
added followed by the dropwise addition of DEAD (0.48 mL,
3.05 mmol). The reaction was stirred at rt for 15 min and
filtered, and the solvent evaporated. The crude residue was
chromatographed (9/1 hexanes/EtOAc) to afford 22 (0.97 g,
91%) as a colorless solid: mp 96-97 °C; [R]22 -18.1 (c 1.4,
D
1
N-[2-Bis[(b en zyloxyca r b on yl)m et h yl]a m in oet h yl]-N-
[(2S,4S)-4-[2-(ben zyloxyca r bon yl)-1-[(ben zyloxyca r bon -
yl)m eth yl]p yr r olid in yl]]-D-ser in e ben zyl ester (18), struc-
ture not shown, was prepared by the same deprotection/
CHCl3); H NMR (CDCl3) δ 2.93 (d, J ) 9.9 Hz, 1H), 3.22 (S,
3H), 3.35 (m, 2H), 3.57 (m, 1H), 7.13-7.25 (m, 9H), 7.50 (m,
6H); 13C NMR (CDCl3) δ 52.3, 55.1, 56.7, 71.4, 126.8, 128.1,
128.8, 145.6, 173.0. Anal. Calcd for C23H22N4O2: C, 71.5; H,
5.7; N, 14.5. Found: C, 71.2; H, 5.9; N, 14.4.
alkylation procedure as for 14: 18 (86%) isolated as a pale
1
yellow oil; [R]22 +6.4 (c 1.4, CHCl3); H NMR (CDCl3) δ 1.97
D
(2S)-Tr ip h en ylm et h yla m in o-3-a m in op r op a n ol ((+)-
21). To a suspension of LAH (1.73 g, 45.5 mmol) in Et2O (60
mL) cooled to 0 °C was added portionwise 22 (2.50 g, 6.47
mmol), the resultant suspension was heated at reflux for 2 h
and cooled to 0 °C, and water was added dropwise until
hydrogen evolution ceased. The solvent was decanted from the
resultant white paste which was then extracted with 3/1
CHCl3/IPA (4 × 150 mL). The combined organic phase was
washed with brine (100 mL), dried, filtered, and evaporated
to afford a crude solid (2.05 g, 95%) which was precipitated
from CH2Cl2/n-pentane to give (+)-21 (3 crops, 1.66 g, 77%)
(m, 1H), 2.20 (m, 1H), 2.64-2.85 (m, 4H), 2.92 (m, 1H), 3.06
(dd, J ) 9.5, 5.9 Hz, 1H), 3.47 (ABq, J ) 17.6 Hz, 2H), 3.58-
3.68 (m, 8H), 3.74 (dd, J ) 11.3, 4.9 Hz, 1H), 3.82 (dd, J )
9.6, 4.9 Hz, 1H), 5.03-5.09 (m, 10H), 7.29 (m, 25H); 13C NMR
(CDCl3) δ 32.6, 45.8, 52.7, 53.6, 54.8, 56.6, 58.1, 60.1, 62.6,
62.8, 66.1, 66.25, 66.29, 128.1, 128.19, 128.22, 128.25, 128.28,
129.5, 135.5, 135.59, 135.61, 135.7, 170.4, 170.7, 172.2, 172.8.
Anal. Calcd for C51H55N3O11: C, 69.1; H, 6.3; N, 4.7. Found:
C, 69.0; H, 6.4; N, 4.7.
N-[2-Bis(ca r b oxym et h yl)a m in oet h yl]-N-[(2S,4S)-4-[2-
car boxy-1-(car boxym eth yl)-pyr r olidin yl]]-D-ser in e (2) was
prepared by the same procedure as for 1. Pentaacid 2 was
as a colorless solid after drying: mp 99-100 °C; [R]22 +20.8
D
(c 1.1, CHCl3); 1H NMR (CD3OD) δ 2.26 (dd, J ) 13.1, 6.6 Hz,
1H), 2.44 (dd, J ) 13.1, 3.3 Hz, 1H), 2.58 (m, 1H), 2.92 (dd, J
) 11.0, 6.5 Hz, 1H), 3.22 (dd, J ) 11.0, 3.8 Hz, 1H), 7.15-7.28
(m, 9H), 7.56 (m, 6H); 13C NMR (CDCl3) δ 46.5, 53.0, 66.2, 71.3,
126.5, 127.9, 128.7, 146.9.
isolated as a pale pink solid (97%): mp 144-145 °C dec; [R]22
D
-8.6 (c 1.0, H2O); 1H NMR (D2O + 3 drops of Tf2O) δ 2.03 (m,
1H), 2.68 (m, 1H), 3.24 (m, 2H), 3.45 (m, 2H), 3.52 (dd, J )
12.6, 8.5 Hz, 1H), 3.72 (m, 2H), 3.84 (m, 2H), 4.07 (m, 1H),
4.20 (ABq, J ) 17.1 Hz, 2H), 4.21 (s, 4H), 4.37 (dd, J ) 11.5,
6.6 Hz, 1H); 13C NMR (D2O) δ 31.4, 43.9, 54.9, 56.4, 56.7, 57.3,
58.6, 61.4, 62.3, 67.7, 169.8, 169.9, 171.8, 175.6; MS (FAB, G)
m/z 436 (M + H)+. Anal. Calcd for C16H25N3O11‚1/2H2O: C, 43.2;
H, 5.9; N, 9.5. Found: C, 43.3; H, 5.8; N, 9.2.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
ca r b on yl)p yr r olid in yl]]-(2R)-t r ip h en ylm et h yla m in o-3-
h ydr oxypr opylam in e (23). To a solution of N-BOC-4-hydroxy-
L-proline benzyl ester 6 (2.03 g, 6.32 mmol) in CH2Cl2 (40 mL)
cooled to -30 °C was added DIEA (2.19 mL, 12.6 mmol)
followed by triflic anhydride (1.06 mL, 6.32 mmol) dropwise.
The resultant orange mixture was stirred at -30 °C for 60
min, and then (-)-21 (2.00 g, 6.02 mmol) was added dropwise
as a solution in CH2Cl2 (25 mL). The reaction was held at -10
°C for 76 h, diluted with CH2Cl2 (150 mL), and then washed
with 0.5 M Na2CO3 (2 × 120 mL) and brine (120 mL). Drying,
Filtering, and Evaporating gave a crude product which was
chromatographed (1/1 hexanes/EtOAc + 1% NEt3 to EtOAc +
1% NEt3) to afford 23 (2.49 g, 65%) as a colorless solid: mp
N-Tr ip h en ylm eth yl-L-ser in a m id e (20). A stirred suspen-
sion of N-trityl-L-serine methyl ester14 19 (3.00 g, 8.30 mmol)
in MeOH (30 mL) was cooled to 0 °C and saturated with NH3.
The resultant pale yellow solution was heated to 80 °C in a
stainless steel pressure vessel for a total of 4 d, with resatu-
ration of the reaction solution with NH3 at 0 °C every 24 h.
The volatiles were evaporated to leave a yellow solid which
was chromatographed (14/1 CH2Cl2/MeOH) to afford 20 (2.64
g, 92%) as a colorless solid: mp 135-136 °C (CH2Cl2/hexanes);
[R]22 -84.3 (c 0.9, CHCl3); enantiomeric purity >99.5% by
D
89-91 °C; [R]22 -40.5 (c 0.7, CHCl3); 1H NMR (CD3OD)
D
chiral HPLC;15 1H NMR (CD3OD) δ 2.75 (dd, J ) 10.8, 5.2 Hz,
1H), 3.21 (dd, J ) 5.2, 3.7 Hz, 1H), 3.52 (dd, J ) 10.8, 3.7 Hz,
1H), 7.15-7.26 (m, 9H), 7.50 (m, 6H); 13C NMR (CDCl3) δ 59.2,
63.0, 71.6, 126.9, 128.2, 128.8, 146.1, 177.9. Anal. Calcd for
rotamers δ 1.30 and 1.45 (2s, 9H), 1.71 (m, 1H), 1.96 (dd, J )
11.7, 6.4 Hz, 0.4H), 2.05 (dd, J ) 11.6, 6.5 Hz, 0.6H), 2.21-
2.33 (m, 2H), 2.61 (m, 1H), 2.93 (m, 1H), 3.00-3.12 (m, 2H),
3.34 (m, 1H), 3.46 (m, 1H), 4.22 (m, 1H), 5.01-5.21 (m, 2H),
7.13-7.35 (m, 14H), 7.55 (m, 6H); 13C NMR (CDCl3) rotamers
δ 28.3, 28.6, 35.7, 36.8, 51.5, 51.6, 51.7, 52.4, 52.8, 53.0, 56.6,
57.4, 57.9, 58.1, 67.0, 67.1, 67.4, 67.6, 71.4, 80.28, 80.34, 126.6,
128.0, 128.2, 128.3, 128.60, 128.63, 128.70, 128.76, 128.80,
C
22H22N2O2: C, 76.3; H, 6.4; N, 8.1. Found: C, 75.9; H, 6.6; N,
8.1.
(2R)-Tr ip h en ylm et h yla m in o-3-a m in op r op a n ol ((-)-
21). To a stirred suspension of LAH (1.95 g, 51.3 mmol) in
Et2O (70 mL) cooled to 0 °C was added 20 (2.54 g, 7.33 mmol)
portionwise over 15 min, the resultant mixture was heated at
reflux for 60 h and then cooled to 0 °C, and wet Et2O (60 mL)
was gradually added followed by dropwise addition of water
(21) Equi, A. M.; Brown, A. M.; Cooper, A.; Ner, S. K.; Watson, A.
B.; Robins, D. J . Tetrahedron 1991, 47, 507.

Preparartion of Functionalized DTPA Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 4055
135.6, 135.8, 146.7, 153.9, 154.4, 173.0, 173.3. Anal. Calcd for
128.14, 128.17, 128.24, 128.26, 128.29, 128.34, 128.5, 128.60,
128.63, 129.76, 129.78, 133.3, 135.7, 135.8, 135.9, 135.97,
C
39H45N3O5: C, 73.7; H, 7.1; N, 6.6. Found: C, 73.4; H, 7.5; N,
6.5.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
136.04, 170.5, 171.8, 172.0, 172.9. Anal. Calcd for C67H73N3O11
Si: C, 71.6; H, 6.5; N, 3.7. Found: C, 71.2; H, 6.6; N, 3.7.
-
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
ca r b on yl)p yr r olid in yl]]-(2S)-t r ip h en ylm et h yla m in o-3-
h ydr oxypr opylam in e (27). To a solution of N-BOC-4-hydroxy-
L-proline benzyl ester 6 (2.76 g, 8.59 mmol) in CH2Cl2 (50 mL)
cooled to -30 °C was added DIEA (3.00 mL, 17.2 mmol)
followed by triflic anhydride (1.45 mL, 8.61 mmol) dropwise.
The resultant orange mixture was stirred at -30 °C for 60
min, and then (+)-21 (2.72 g, 8.18 mmol) added dropwise as a
solution in CH2Cl2 (35 mL). The reaction was held at -10 °C
for 76 h, diluted with CH2Cl2 (200 mL), and then washed with
0.5 M Na2CO3 (2 × 150 mL) and brine (150 mL). Drying,
Filtering, and Evaporating gave a residue which was chro-
matographed (1/1 hexanes/EtOAc + 1% NEt3 to EtOAc +1%
NEt3) to afford 27 (3.54 g, 68%) as a colorless solid: mp 90-
92 °C; [R]22D +11.1 (c 1.0, CHCl3); 1H NMR (CD3OD) rotamers
δ 1.30 and 1.44 (2s, 9H), 1.71 (m, 1H), 2.07-2.37 (m, 3H), 2.63
(m, 1H), 2.95-3.12 (m, 3H), 3.38 (m, 1H), 3.51 (m, 1H), 4.22
(m, 1H), 5.03-5.18 (m, 2H), 7.13-7.40 (m, 14H), 7.56 (m, 6H);
13C NMR (CDCl3) rotamers δ 28.3, 28.5, 35.0, 36.2, 51.6, 51.8,
51.9, 52.7, 52.9, 53.1, 56.7, 57.4, 57.9, 58.2, 67.0, 67.1, 67.2,
67.3, 71.4, 80.3, 126.60, 126.64, 128.0, 128.2, 128.3, 128.6,
128.7, 135.5, 135.7, 146.7, 153.7, 154.4, 173.1, 173.2. Anal.
Calcd for C39H45N3O5: C, 73.7; H, 7.1; N, 6.6. Found: C, 73.8;
H, 7.1; N, 6.7.
ca r b on yl)p yr r olid in yl]]-(2R)-t r ip h en ylm et h yla m in o-3-
(ter t-bu tyld ip h en ylsilyloxy)p r op yla m in e (24). A solution
of 23 (2.80 g, 4.40 mmol), NEt3 (0.67 mL, 4.84 mmol), DMAP
(107 mg, 0.88 mmol), and TBDPSCl (1.26 mL, 4.84 mmol) in
CH2Cl2 (70 mL) was stirred at rt for 1 h, then diluted with
CH2Cl2 (100 mL), and washed with saturated aqueous NaH-
CO3 (2 × 100 mL) and brine (100 mL). Drying, filtering, and
evaporating gave a residual oil which was chromatographed
(4/1 hexanes/EtOAc + 1% NEt3) to give 24 (3.49 g, 91%) as a
1
colorless solid: mp 84-85 °C; [R]22 -13.7 (c 1.0, CHCl3); H
D
NMR (CD3OD) rotamers δ 0.99 (s, 9H), 1.29 and 1.44 (2s, 9H),
1.64 (m, 1H), 1.93-2.06 (m, 1H), 2.24 (m, 1H), 2.36 (m, 1H),
2.61 (m, 1H), 2.86 (m, 1H), 2.94 and 3.03 (2m, 1H), 3.19 (m,
1H), 3.42 (m, 1H), 3.52 (dd, J ) 10.1, 4.0 Hz, 1H), 4.18 (m,
1H), 4.94-5.12 (m, 2H), 7.10-7.60 (m, 30H); 13C NMR (CDCl3)
rotamers δ 19.1, 26.9, 28.1, 28.4, 36.0, 36.8, 47.8, 51.9, 52.3,
52.9, 53.0, 56.4, 57.2, 57.9, 58.1, 64.7, 66.4, 70.8, 79.65, 79.70,
126.1, 127.6, 127.69, 127.73, 127.8, 127.9, 128.2, 128.26,
128.30, 128.5, 128.6, 129.6, 133.4, 135.5, 135.6, 147.0, 153.5,
154.2, 172.4, 172.6. Anal. Calcd for C55H63N3O5Si: C, 75.6; H,
7.3; N, 4.8. Found: C, 75.4; H, 7.3; N, 4.9.
N-[(2S,4S)-4-[2-(Ben zyloxycar bon yl)pyr r olidin yl]]-(2R)-
a m in o-3-(ter t-bu tyld ip h en ylsilyloxy)p r op yla m in e (25).
To a stirred solution of 24 (3.34 g, 3.82 mmol) and triethylsi-
lane (640 µL, 4.01 mmol) in CH2Cl2 (16 mL) cooled to 0 °C
was added dropwise TFA (16 mL). The resultant colorless
solution was allowed to warm to rt, with stirring continued
for 1 h. The solvents were evaporated, the residue was
triturated with hexanes (5 × 50 mL), the hexane extracts were
discarded, and the oily residue was partitioned between 3/1
CHCl3/IPA (250 mL) and 1 M NaOH (precooled to 0 °C, 100
mL). The aqueous phase was extracted with further portions
of 3/1 CHCl3/IPA (2 × 200 mL), and the combined organic
phase was dried, filtered, and evaporated to give 25 (2.04 g,
100% crude yield) as a pale yellow oil: 1H NMR (CD3OD) δ
1.06 (s, 9H), 1.70 (m, 1H), 2.29 (m, 1H), 2.43 (dd, J ) 11.8, 7.3
Hz, 1H), 2.61 (dd, J ) 11.9, 4.6 Hz, 1H), 2.80 (dd, J ) 11.0,
4.3 Hz, 1H), 2.89 (m, 2H), 3.15 (m, 1H), 3.60 (m, 2H), 3.74 (m,
1H), 5.11 (ABq, J ) 12.3 Hz, 2H), 7.26-7.45 (m, 11H), 7.67
(m, 4H); 13C NMR (CDCl3) δ 20.2, 27.6, 37.7, 51.8, 53.3, 53.6,
58.1, 60.0, 65.2, 67.9, 129.0, 129.5, 129.7, 130.6, 131.2, 134.5,
136.8, 137.3, 175.5.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
ca r b on yl)p yr r olid in yl]]-(2S)-t r ip h en ylm et h yla m in o-3-
(ter t-bu tyld ip h en ylsilyloxy)p r op yla m in e (28). A solution
of 27 (3.00 g, 4.72 mmol), Et3N (0.72 mL, 5.17 mmol), DMAP
(115 mg, 0.94 mmol), and TBDPSCl (1.35 mL, 5.19 mmol) in
CH2Cl2 (75 mL) was stirred at rt for 1 h. The reaction mixture
was diluted with CH2Cl2 (100 mL) and washed with saturated
aqueous NaHCO3 (2 × 100 mL) and brine (100 mL). Drying,
filtering, and evaporating gave a crude oil which was chro-
matographed (4/1 hexanes/EtOAc + 1% NEt3) to give 28 (3.84
g, 93%) as a colorless solid: mp 83-84 °C; [R]22 -19.1 (c 1.0,
D
1
CHCl3); H NMR (CD3OD) rotamers δ 0.99 (s, 9H), 1.30 and
1.43 (2s, 9H), 1.58 (m, 1H), 1.91 (m, 1H), 2.21 (m, 1H), 2.33
(m, 1H), 2.58 (m, 1H), 2.81 (m, 1H), 2.98 (m, 1H), 3.24 (m,
1H), 3.43 (m, 1H), 3.53 (m, 1H), 4.18 (m, 1H), 4.96-5.13 (m,
2H), 7.12-7.58 (m, 30H); 13C NMR (CDCl3) rotamers δ 19.4,
27.1, 28.3, 28.6, 36.2, 37.1, 48.2, 48.3, 52.2, 52.7, 53.2, 56.6,
57.3, 58.0, 58.3, 64.7, 64.9, 66.8, 71.1, 80.0, 80.1, 126.4, 127.8,
127.9, 128.2, 128.5, 128.6, 128.7, 128.8, 129.8, 133.6, 133.7,
135.7, 135.8, 147.2, 153.7, 154.4, 172.7, 173.0. Anal. Calcd for
N-[(Ben zyloxyca r b on yl)m et h yl]-N-[(2S,4S)-4-[2-(b en -
zyloxyca r bon yl)-N-[(ben zyloxyca r bon yl)m eth yl]p yr r ol-
idin yl]]-(2R)-N,N-[bis[(ben zyloxycar bon yl)m eth yl]am in o]-
3-(ter t-bu tyldiph en ylsilyloxy)pr opylam in e (26). To a stirred
solution of 25 (1.80 g, 3.38 mmol) and DIEA (4.71 mL, 27.0
mmol) in CH2Cl2 (85 mL) cooled to -78 °C was added dropwise
over 30 min a precooled solution (-50 °C) of the triflate of
benzyl glycolate22 (8.06 g, 27.0 mmol) in CH2Cl2 (55 mL). The
resultant solution was held at -78 °C for 14 h and then
allowed to warm to -10 °C over 10 h, at which it was
maintained for a further 5 h before the addition of Et3N (11
mL). After being warmed to rt over 1 h, the mixture was
partitioned between CH2Cl2 (110 mL) and saturated aqueous
NaHCO3 (275 mL), and the organic phase was washed with
brine (150 mL), dried, filtered, and evaporated. The residue
was chromatographed (3/1 hexanes/EtOAc +1% NEt3) to afford
C
55H63N3O5Si: C, 75.6; H, 7.3; N, 4.8. Found: C, 75.3; H, 7.3;
N, 4.9.
N-[(2S,4S)-4-[2-(Ben zyloxycar bon yl)pyr r olidin yl]]-(2S)-
a m in o-3-(ter t-bu tyld ip h en ylsilyloxy)p r op yla m in e (29).
To a stirred solution of 28 (3.17 g, 3.63 mmol) and triethylsi-
lane (609 µL, 3.81 mmol) in CH2Cl2 (15 mL) cooled to 0 °C
was added dropwise TFA (15 mL), and the resultant colorless
solution was allowed to warm to rt, with stirring continued
for 1 h. The solvents were evaporated, the residue was
triturated with hexanes (5 × 50 mL), the hexane extracts were
discarded, and the oily residue was partioned between 3/1
CHCl3/IPA (3 × 250 mL) and 1 M NaOH solution (precooled
to 0 °C, 100 mL). The combined organic phase was dried,
filtered, and evaporated to give 29 (1.93 g, 100% crude yield)
as a pale yellow oil: 1H NMR (CD3OD) δ 1.05 (s, 9H), 1.71 (m,
1H), 2.30 (m, 1H), 2.38 (dd, J ) 11.8, 7.8 Hz, 1H), 2.61 (dd, J
) 11.8, 4.6 Hz, 1H), 2.79-2.90 (m, 3H), 3.16 (m, 1H), 3.55 (dd,
J ) 10.1, 6.0 Hz, 1H), 3.62 (dd, J ) 10.1, 5.5 Hz, 1H), 3.74
(dd, J ) 8.9, 6.1 Hz, 1H), 5.12 (ABq, J ) 12.2 Hz, 2H), 7.26-
7.45 (m, 11H), 7.67 (m, 4H); 13C NMR (CD3OD) δ 20.2, 27.6,
37.9, 52.0, 53.1, 53.8, 59.9, 60.0, 68.0, 68.1, 129.0, 129.5, 129.7,
130.6, 131.1, 134.6, 136.8, 137.4, 175.6.
26 (2.70 g, 71%) as a pale yellow oil: [R]22 -18.7 (c 1.0,
D
CHCl3); 1H NMR (CDCl3) δ 1.01 (s, 9H), 1.80 (m, 1H), 2.18
(m, 1H), 2.67 (m, 1H), 2.75-2.83 (m, 2H), 3.01 (m, 2H), 3.39
(1/2 ABq, J ) 17.6 Hz, 1H), 3.48 (ABq, J ) 17.6 Hz, 2H), 3.56-
3.71 (m, 9H), 4.99-5.09 (m, 10H), 7.25-7.37 (m, 31H), 7.62
(m, 4H); 13C NMR (CDCl3) δ 19.1, 27.0, 33.6, 51.9, 52.4, 52.9,
53.5, 56.0, 60.2, 62.2, 62.8, 64.1, 66.0, 66.1, 66.2, 66.4, 127.8,
N-[(Ben zyloxyca r b on yl)m et h yl]-N-[(2S,4S)-4-[2-(b en -
zyloxyca r bon yl)-N-[(ben zyloxyca r bon yl)m eth yl]p yr r ol-
idin yl]]-(2S)-N,N-[bis[(ben zyloxycar bon yl)m eth yl]am in o]-
3-(ter t-bu tyldiph en ylsilyloxy)pr opylam in e (30). To a stirred
solution of 29 (1.65 g, 3.10 mmol) and DIEA (4.32 mL, 24.8
(22) Generated from benzyl glycolate in CH2Cl2 with triflic anhy-
dride (100 mol %) at 0 °C in the presence of 100 mol % 2,6-lutidine.
Evaporation and subsequent trituration of the residue with hexanes
cleanly extracted the desired triflate from the solid lutidine salts. The
triflate was used directly without further purification.

4056 J . Org. Chem., Vol. 65, No. 13, 2000
Pickersgill and Rapoport
mmol) in CH2Cl2 (80 mL) cooled to -78 °C was added dropwise
over 30 min a precooled solution (-50 °C) of the triflate of
benzyl glycolate (7.40 g, 24.8 mmol)22 in CH2Cl2 (50 mL). The
resultant solution was held at -78 °C for 12 h and then
allowed to warm to -10 °C over 12 h. This temperature was
maintained for a further 4 h before the addition of Et3N (10
mL). After being warmed to rt over 1 h, the mixture was
partitioned between CH2Cl2 (100 mL) and saturated aqueous
NaHCO3 (250 mL), and the organic phase was washed with
brine (150 mL), dried, filtered, and evaporated, leaving a
residue which was chromatographed (4/1 hexanes/EtOAc +1%
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)-1-(ter t-bu tyloxy-
car bon yl)pyr r olidin yl]]-(1R)-[(ter t-bu tyldiph en ylsilyloxy)-
m eth yl]-2-(ter t-bu tyloxyca r bon yl)a m in oeth yla m in e (34).
To a solution of N-BOC-4-hydroxy-L-proline benzyl ester 6
(1.00 g, 3.12 mmol) in CH2Cl2 (10 mL) cooled to -30 °C was
added DIEA (1.19 mL, 6.86 mmol) followed by triflic anhydride
(0.58 mL, 3.43 mmol) dropwise. The resultant orange mixture
was stirred at -30 °C for 60 min and then 33 (0.89 g, 2.08
mmol) was added dropwise as a solution in CH2Cl2 (5 mL).
The reaction was allowed to warm to 0 °C, stirred at 0 °C for
72 h, diluted with CH2Cl2 (50 mL), and then washed with 0.5
M Na2CO3 (2 × 50 mL) and brine (50 mL). Drying, filtering,
and evaporating gave a residue which was chromatographed
(4/1 hexanes/EtOAc + 1% NEt3 to 3/1 hexanes/EtOAc + 1%
NEt3) to afford 30 (2.58 g, 74%) as a pale yellow oil: [R]22
D
-22.1 (c 1.4, CHCl3); 1H NMR (CDCl3) δ 1.02 (s, 9H), 1.82 (m,
1H), 2.22 (m, 1H), 2.76 (m, 3H), 3.02 (m, 2H), 3.42-3.63 (m,
6H), 3.66 (s, 4H), 3.71 (m, 2H), 5.01-5.09 (m, 10H), 7.22-7.38
(m, 31H), 7.61-7.63 (m, 4H); 13C NMR (CDCl3) δ 19.3, 27.1,
34.0, 51.9, 52.5, 53.1, 53.6, 55.6, 60.4, 62.2, 62.9, 64.2, 66.1,
66.28, 66.32, 66.5, 127.9, 128.26, 128.27, 128.29, 128.37,
128.39, 128.5, 128.6, 128.70, 128.74, 129.8, 129.9, 133.4,
135.80, 135.83, 135.9, 136.0, 136.1, 170.7, 171.9, 172.1, 173.0.
Anal. Calcd for C67H73N3O11Si: C, 71.6; H, 6.5; N, 3.7. Found:
C, 71.2; H, 6.4; N, 3.6.
NEt3) to afford 34 (1.04 g, 68%) as a colorless solid: mp 42-
1
43 °C; [R]22 -19.6 (c 1.0, CHCl3); H NMR (CDCl3) rotamers
D
δ 1.05 and 1.06 (2s, 9H), 1.33 and 1.46 (2s, 9H), 1.41 (s, 9H),
1.62 (br s, 1H), 1.86 (m, 1H), 2.23 (m, 1H), 2.64 (m, 1H), 3.05-
3.28 (m, 4H), 3.52-3.69 (m, 3H), 4.26 (dd, J ) 8.6, 5.0 Hz,
0.6H), 4.36 (dd, J ) 8.6, 4.8 Hz, 0.4H), 4.93 (br m, 1H), 5.09-
5.29 (m, 2H), 7.28-7.45 (m, 11H), 7.63 (d, J ) 7.3 Hz, 4H);
13C NMR (CDCl3) rotamers δ 18.85, 18.86, 26.7, 28.0, 28.2,
35.7, 36.6, 41.9, 52.7, 53.1, 54.2, 56.4, 56.5, 57.6, 57.9, 63.6,
63.8, 66.5, 78.6, 79.56, 79.61, 127.60, 127.61, 127.80, 127.82,
128.1, 128.2, 128.28, 128.31, 129.7, 132.7, 132.8, 135.3, 135.4,
135.6, 153.4, 153.9, 155.9, 172.4, 172.7. Anal. Calcd for
(2R)-Tr ip h en ylm eth yla m in o-3-(ter t-bu tyloxyca r bon y-
l)a m in op r op a n ol (31). To a stirred suspension of (-)-21 (3.46
g, 10.4 mmol) in CH3CN (75 mL) cooled to 0 °C was added
dropwise a solution of di-tert-butyl dicarbonate (2.52 g, 11.5
mmol) in CH3CN (25 mL). The reaction was stirred at 0 °C
for 30 min and then at rt for 1 h. The solvent was evaporated
and the residue chromatographed (4/1 hexanes/EtOAc + 1%
NEt3 to 3/1 hexanes/EtOAc + 1% NEt3) to give 31 (4.09 g, 91%
C
41H57N3O7Si: C, 67.3; H, 7.9; N, 5.7. Found: C, 67.0; H, 7.8;
N, 5.7.
N-[(2S,4S)-4-[2-(Ben zyloxyca r bon yl)p yr r olid in yl]]-1R-
[(t er t -b u t y ld ip h e n y ls ily lo x y )m e t h y l]-2-a m in o e t h y l-
a m in e (35). To a stirred solution of 34 (941 mg, 1.29 mmol)
in CH2Cl2 (4.8 mL) cooled to 0 °C was added dropwise TFA
(4.8 mL), and the mixture was stirred at 0 °C for 30 min and
then at rt for 1 h. The solvents were evaporated, and the
residue was partioned between 3/1 CHCl3/IPA (3 × 60 mL)
and cold (0 °C) 1 M NaOH (30 mL). The combined organic
phase was dried and evaporated to give 35 (685 mg, 100%) as
a pale yellow oil: 1H NMR (CDCl3) δ 1.05 (s, 9H), 1.60 (br s,
4H), 1.76 (m, 1H), 2.16 (m, 1H), 2.47 (m, 1H), 2.61 (dd, J )
12.7, 6.9 Hz, 1H), 2.74 (m, 2H), 2.95 (dd, J ) 10.7, 5.2 Hz,
1H), 3.22 (m, 1H), 3.60 (m, 2H), 3.78 (dd, J ) 9.0, 5.2 Hz, 1H),
5.15 (ABq, J ) 12.4 Hz, 2H), 7.26-7.44 (m, 11H), 7.63 (d, J )
6.7 Hz, 4H); 13C NMR (CDCl3) δ 19.3, 27.0, 37.1, 43.6, 54.3,
55.7, 59.1, 63.7, 66.8, 127.8, 128.3, 128.4, 128.6, 129.9, 133.4,
135.6, 135.8, 175.1.
N-[(Ben zyloxyca r b on yl)m et h yl]-N-[(2S,4S)-4-[2-(b en -
zyloxyca r bon yl)-N-[(ben zyloxyca r bon yl)m eth yl]p yr r ol-
id in yl]]-(1R)-[(ter t-bu tyld ip h en ylsilyloxy)m eth yl]-2-N,N-
[bis[(ben zyloxy-car bon yl)m eth yl]am in o]eth ylam in e (36).
To a solution of 35 (300 mg, 0.56 mmol) in CH2Cl2 (15 mL)
cooled to -78 °C was added DIEA (0.98 mL, 5.60 mmol)
followed by the dropwise addition of a precooled solution (-78
°C) of the triflate of benzyl glycolate (1.67 g, 5.60 mmol)22 in
CH2Cl2 (10 mL) over 20 min. The temperature was held at
-78 °C for 10 h, then allowed to warm to -10 °C over 17 h,
and held at -10 °C for 6 h. A further quantity of DIEA (175
µL, 1.01 mmol) and benzyl glycolate triflate (300 mg, 1.01
mmol) was added and the reaction held at -10 °C for a further
4 h. Triethylamine (2 mL) was added and the reaction allowed
to warm to rt, diluted with CH2Cl2 (20 mL), and washed with
saturated NaHCO3 (50 mL) and brine (30 mL). Drying,
filtering, and evaporating gave a residue which was chromato-
graphed (4/1 hexanes/EtOAc + 1% NEt3) to afford 36 (421 mg,
67%) as a pale yellow oil: [R]D22 -15.1 (c 1.2, CHCl3); 1H NMR
(CDCl3) δ 1.00 (s, 9H), 1.87 (m, 1H), 2.15 (m, 1H), 2.76 (m,
2H), 2.96 (m, 3H), 3.45 (ABq, J ) 17.5 Hz, 2H), 3.54-3.74 (m,
10H), 5.03-5.10 (m, 10H), 7.26-7.39 (m, 31H), 7.60 (m, 4H);
13C NMR (CDCl3) δ 19.1, 27.0, 34.6, 49.7, 52.7, 53.9, 55.3, 56.3,
57.7, 61.1, 62.7, 64.2, 66.1, 66.17, 66.20, 66.4, 127.8, 128.1,
128.18, 128.24, 128.26, 128.29, 128.4, 128.5, 128.59, 128.64,
129.76, 129.79, 133.25, 133.29, 135.69, 135.74, 135.8, 135.9,
yield) as a colorless solid: mp 70-71 °C; [R]22 -38.9 (c 1.0,
D
CHCl3); 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.00 (br s, 1H), 2.53-
2.68 (m, 3H), 3.05 (m, 1H), 3.16 (br d, 1H), 3.63 (br s, 1H),
4.58 (br t, 1H), 7.16-7.30 (m, 9H), 7.55 (m, 6H); 13C NMR
(CDCl3) δ 28.5, 41.2, 53.9, 61.7, 71.1, 80.2, 126.7, 128.2, 128.7,
147.0, 157.8. Anal. Calcd for C27H32N2O3: C, 75.0; H, 7.5; N,
6.5. Found: C, 74.9; H, 7.5; N, 6.6.
O-(ter t-Bu tyldiph en ylsilyl)-(2R)-(tr iph en ylm eth yl)am i-
n o-3-(ter t-bu tyloxyca r bon yl)a m in op r op a n ol (32). To a
solution of 31 (1.95 g, 4.51 mmol) in CH2Cl2 (50 mL) were
added Et3N (0.69 mL, 4.96 mmol), DMAP (110 mg, 0.90 mmol),
and TBDPSCl (1.29 mL, 4.96 mmol), and the resulting solution
was stirred at rt for 40 h. The mixture was partitioned between
CH2Cl2 (80 mL) and 0.5 M Na2CO3 (80 mL), the organic phase
was further washed with 0.5 M Na2CO3 (80 mL) and brine
(80 mL), the combined organic phase was dried, filtered, and
evaporated, and the residue was chromatographed (9/1 hex-
anes/Et2O) to give 32 (2.69 g, 89%) as a colorless solid: mp
54-56 °C; [R]22 -10.3 (c 1.0, CHCl3); 1H NMR (CDCl3)
D
rotamers δ 1.01 (s, 9H), 1.40 (br s, 9H), 2.44 (br s, 1H), 2.72
(m, 1H), 2.88 (m, 1H), 2.98 (m, 1H), 3.09 (m, 1H), 3.19 (m,
1H), 4.54 (m, 1H), 7.10-7.53 (m, 25H); 13C NMR (CDCl3)
rotamers δ 19.3, 27.1, 28.6, 43.3, 53.2, 65.1, 71.1, 78.8, 126.5,
127.8, 127.9, 128.0, 128.8, 129.9, 133.3, 133.4, 135.76, 135.82,
146.9, 156.2. Anal. Calcd for C43H50N2O3Si: C, 77.0; H, 7.5; N,
4.2. Found: C, 76.8; H, 7.6; N, 4.1.
O-(ter t-Bu t yld ip h en ylsilyl)-(2R)-a m in o-3-(ter t-b u t yl-
oxyca r bon yl)a m in op r op a n ol (33). To a solution of 32 (2.67
g, 3.98 mmol) in CH2Cl2 (27 mL) cooled to 0 °C were added
glacial acetic acid (6.7 mL) and BF3‚Et2O (529 µL, 4.17 mmol)
dropwise, and the mixture was stirred at 0 °C for 2 h. Cold (0
°C) 1 M NaOH (160 mL) was added and the mixture partioned
between 3/1 CHCl3/IPA (320 mL) and cold (0 °C) 1 M NaOH
(66 mL), followed by extraction with further portions of 3/1
CHCl3/IPA (2 × 160 mL). The combined organic phase was
dried, filtered, and evaporated to a residue which was chro-
matographed (19/1 CH2Cl2/MeOH to 9/1 CH2Cl2/MeOH) to give
33 (1.50 g, 88%) as a colorless oil: [R]22 +3.1 (c 1.0, CHCl3);
D
1H NMR (CDCl3) δ 1.07 (s, 9H), 1.42 (s, 9H), 1.51 (br s, 2H),
2.97 (m, 1H), 3.05 (m, 1H), 3.23 (m, 1H), 3.53 (dd, J ) 10.1,
5.4 Hz, 1H), 3.63 (dd, J ) 10.1, 4.7 Hz, 1H), 5.21 (m, 1H), 7.35-
7.43 (m, 6H), 7.66 (m, 4H); 13C NMR (CDCl3) δ 19.3, 26.9, 28.4,
44.2, 52.6, 67.3, 79.0, 127.8, 129.9, 133.2, 135.6, 156.3. Anal.
Calcd for C24H36N2O3Si: C, 67.3; H, 8.5; N, 6.5. Found: C, 66.9;
H, 8.3; N, 6.4.
136.1, 170.5, 171.2, 173.0, 173.1. Anal. Calcd for C67H73N3O11
Si: C, 71.6; H, 6.5; N, 3.7. Found: C, 71.4; H, 6.4; N, 3.5.
-
N-[(Ben zyloxyca r b on yl)m et h yl]-N-[(2S,4S)-4-[2-(b en -
zyloxyca r bon yl)-N-[(ben zyloxyca r bon yl)m eth yl]p yr r ol-

Preparartion of Functionalized DTPA Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 4057
idin yl]]-(2R)-N,N-[bis[(ben zyloxycar bon yl)m eth yl]am in o]-
3-h yd r oxy-p r op yla m in e (38). To a solution of 26 (1.00 g, 0.89
mmol) in THF (22 mL) was added dropwise pyridine‚HF (1.44
mL), and the mixture was stirred at rt for 90 min. Saturated
aqueous NaHCO3 solution was added dropwise until CO2
evolution ceased, and then the mixture was partitioned
between saturated aqueous NaHCO3 (40 mL) and CH2Cl2 (100
mL). The aqueous phase was extracted with further portions
of CH2Cl2 (2 × 50 mL), and the combined organic phase was
dried and evaporated to leave a crude oil which was chromato-
graphed (1/1 hexanes/EtOAc) at 0 °C to afford 38 as a ∼14/1
mixture with lactone 39, 717 mg, 91%. By further chromatog-
raphy (3/2 hexanes/EtOAc) at 0 °C pure 38 (430 mg, 55%) was
obtained as a colorless oil: [R]22D -37.1 (c 0.9, CHCl3); 1H NMR
(CDCl3) δ 1.87 (m, 1H), 2.29 (m, 1H), 2.51 (m, 1H), 2.74 (m,
2H), 2.96 (m, 1H), 3.08 (m, 1H), 3.37-3.49 (m, 4H), 3.50-3.67
(m, 8H), 4.07 (br s, 1H), 5.06 (m, 10H), 7.28 (m, 25H); 13C NMR
(CDCl3) δ 33.4, 51.3, 52.66, 52.71, 52.77, 54.9, 59.8, 61.9, 62.0,
62.6, 66.0, 66.1, 66.3, 66.4, 127.97, 128.04, 128.1, 128.17,
128.20, 128.3, 128.40, 128.44, 128.5, 135.51, 135.53, 135.58,
128.45, 128.47, 128.51, 135.3, 135.49, 135.54, 135.6, 169.5,
170.2, 170.3, 171.2, 172.5. Anal. Calcd for C44H47N3O10: C, 67.9;
H, 6.1; N, 5.4. Found: C, 67.7; H, 5.9; N, 5.3.
N-[(Ben zyloxyca r b on yl)m et h yl]-N-[(2S,4S)-4-[2-(b en -
zyloxyca r bon yl)-N-[(ben zyloxy-ca r bon yl)m eth yl]p yr r o-
lid in yl]]-(2R)-N,N-[bis[(ben zyloxyca r bon yl)m eth yl]a m i-
n o]-3-h yd r oxy-O-[[N -(t er t -b u t yloxyca r b on yl)]a m in o-
a cetyl]p r op yla m in e (41). To a stirred mixture of N-BOC-
glycine (149 mg, 0.85 mmol) and DMAP (11 mg, 0.09 mmol)
in CH2Cl2 (10 mL) cooled to 0 °C was added DCC (175 mg,
0.85 mmol). After the mixture was stirred at 0 °C for 5 min, a
solution of 38 (14/1 mixture with lactone 39, 500 mg, 0.56
mmol) in CH2Cl2 (7 mL) was added dropwise. A reaction
temperature of 0 °C was maintained for 30 min, and then the
reaction was allowed to warm to rt. The solvents were
evaporated, Et2O (80 mL) was added, the white precipitate
was removed by filtration, and the filtrate was washed with
saturated NaHCO3 (60 mL) and brine (60 mL). Drying,
filtering, and evaporating left a residue which was chromato-
graphed (2/1 Et2O/hexanes) to afford 41 (477 mg, 81%) as a
colorless oil: [R]22 -31.2 (c 1.1, CHCl3); H NMR (CDCl3) δ
135.60, 170.1, 171.5, 172.2, 172.5. Anal. Calcd for C51H55N3O11
C, 69.1; H, 6.3; N, 4.7. Found: C, 68.8; H, 6.3; N, 4.7.
:
1
D
1.42 (s, 9H), 1.86 (m, 1H), 2.26 (m, 1H), 2.61 (m, 1H), 2.81 (m,
2H), 3.09 (m, 2H), 3.39-3.68 (m, 10H), 3.82 (br d, 2H), 4.24
(m, 2H), 5.06 (m, 10H), 5.25 (m, 1H), 7.30 (m, 25H); 13C NMR
(CDCl3) δ 28.2, 33.8, 42.4, 51.3, 52.7, 52.8, 55.2, 59.2, 60.4,
62.6, 64.2, 66.0, 66.1, 66.2, 66.3, 79.5, 128.0, 128.15, 128.19,
128.21, 128.24, 128.4, 128.5, 135.55, 135.62, 135.7, 155.6,
N-[Ca r b oxym et h yl]-N-[(2S,4S)-4-[2-(ca r b oxy)-N-[ca r -
boxym eth yl]p yr r olid in yl]]-(2R)-N,N-[bis(ca r boxym eth -
yl)a m in o]-3-h yd r oxyp r op yla m in e (3). To a degassed solu-
tion of 38 (400 mg, 0.45 mmol) in MeOH (40 mL) and H2O (6
mL) was added Pearlman’s catalyst (45% moisture, 20% Pd-
(OH)2 dry weight, 400 mg). The mixture was shaken on a Parr
apparatus at 50 psi of H2 for 13 h, the catalyst was removed
by filtration through a bed of Celite and washed with H2O (4
mL), and the filtrate was partially evaporated at 35 °C to
afford an aqueous solution. Water (19 mL) was then added
and the solution slowly evaporated to dryness at 40 °C to give
a pink gum which upon further drying under high vacuum
170.1, 170.3, 171.5, 171.6, 172.6. Anal. Calcd for C58H66N4O14
C, 66.8; H, 6.4; N, 5.4. Found: C, 67.0; H, 6.6; N, 5.3.
:
N-[Ca r b oxym et h yl]-N-[(2S,4S)-4-[2-(ca r b oxy)-N-[ca r -
boxym eth yl]p yr r olid in yl]]-(2R)-N,N-[bis(ca r boxym eth -
yl)a m in o]-3-h yd r oxy-O-[[N-(ter t-b u t oxyca r b on yl)]a m i-
n oa cet yl]p r op yla m in e (42). To a degassed solution of 41
(432 mg, 0.41 mmol) in MeOH (41 mL) and H2O (5.1 mL) was
added Pearlman’s catalyst (45% moisture, 20% Pd(OH)2 dry
weight, 432 mg). The mixture was shaken on a Parr apparatus
at 50 psi of H2 for 10 h, the catalyst was removed by filtration
through a bed of Celite and washed with H2O (3 mL), and the
filtrate was partially evaporated at 25 °C to afford an aqueous
solution. Water (5 mL) was then added and the solution slowly
evaporated to dryness at 40 °C to give a pale yellow gum which
upon further drying under high vacuum afforded 42 (243 mg,
afforded 3 (192 mg, 98%) as a pale pink solid: mp 112-114
1
°C dec; [R]22 -2.1 (c 0.9, H2O); H NMR (D2O + 3 drops of
D
Tf2O) δ 2.05 (m, 1H), 2.73 (m, 1H), 2.90 (m, 1H), 3.01 (m, 1H),
3.47-3.70 (m, 3H), 3.73-3.93 (m, 4H), 4.13 (m, 1H), 4.24 (ABq,
J ) 17.0 Hz, 2H), 4.28 (s, 4H), 4.43 (dd, J ) 11.8, 6.5 Hz, 1H);
13C NMR (D2O) δ 29.5, 49.7, 51.1, 54.5, 56.2, 57.2, 57.9, 59.1,
63.1, 68.0, 169.8, 170.9, 171.8, 174.5. MS (FAB, G) m/z 436
(M + H)+. Anal. Calcd for C16H25 N3O11‚1/2H2O: C, 43.2; H,
5.9; N, 9.5. Found: C, 42.8; H, 5.5; N, 9.0.
99%) as a pale yellow solid: mp 125-127 °C dec; [R]22 +4.1
D
4-[(Ben zyloxyca r bon yl)m eth yl]-(5R)-a m in om eth yl-[N-
(ben zyloxyca r bon yl)m eth yl-N-[(2S,4S)-4-[2-(ben zyloxy-
car bon yl)-N-[(ben zyloxycar bon yl)m eth yl]pyr r olidin yl]]]-
2-m or p h olin on e (39). To a solution of 38 (14/1 mixture with
lactone 39, 570 mg, 0.64 mmol) in benzene (30 mL) was added
p-TsOH‚H2O (6 mg, 0.032 mmol), and the mixture was heated
at reflux for 2 h. The solvent was evaporated and the residue
chromatographed (3/2 hexanes/EtOAc) to afford 39 (455 mg,
91%) as a pale yellow oil: [R]22D -49.8 (c 1.2, CHCl3); 1H NMR
(CDCl3) δ 2.01 (m, 1H), 2.40 (m, 1H), 2.64 (dd, J ) 13.7, 8.5
Hz, 1H), 2.83-2.94 (m, 2H), 3.18 (m, 2H), 3.40-3.81 (m, 10H),
4.35 (dd, J ) 11.5, 5.5 Hz, 1H), 4.45 (dd, J ) 11.6, 3.9 Hz,
1H), 5.20 (m, 8H), 7.41 (m, 20H); 13C NMR (CDCl3) δ 33.4,
51.3, 51.8, 52.7, 53.5, 54.0, 55.6, 60.6, 62.6, 66.1, 66.2, 66.31,
66.34, 68.6, 128.1, 128.17, 128.21, 128.24, 128.31, 128.35,
1
(c 1.0, H2O); H NMR (D2O) δ 1.41 (s, 9H), 2.10 (m, 1H), 2.76
(m, 1H), 3.22 (m, 2H), 3.61-3.98 (m, 12H), 4.15-4.51 (m, 5H);
13C NMR (D2O) δ 28.3, 29.8, 42.7, 51.1, 51.9, 54.2, 55.8, 56.9,
59.8, 61.9, 67.5, 82.3, 158.7, 170.1, 171.7, 172.1, 172.3, 173.1;
MS (FAB, TG/G) m/z 615 (M + Na), 593 (M + H). Anal. Calcd
for C23H36 N4O14•H2O: C, 45.3; H, 6.3; N, 9.2. Found: C, 45.3;
H, 6.4; N, 9.0.
Ack n ow led gm en t. We thank Al Mical of the Du-
Pont Pharmaceuticals Co. for his most generous and
expert assistance in determining enantiomeric purities
by chiral HPLC.
J O000071G