Glycosyltransferase inhibitors: Synthesis of D-threo-PDMP, L-threo- PDMP, and other brain glucosylceramide synthase inhibitors from D- or L- serine

Article abstract of DOI:10.1021/jo980951j

The synthesis of enantiomerically pure (1S,2S)-1-phenyl-2- decanoylamino-3-N-morpholino-1-propanol (L-threo-PDMP) (1a) from L-serine, and the enantiomer (LR,2R)-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP] (1b) from D-serine is reported. Reductive alkylation of the fully protected O'Donnell's Schiff base (3b) derived from D-serine provided the β-amino alcohol 5b in high yield and excellent selectivity, which yielded optically pure 1b in high yield after six steps. Three other D- threo-PDMP analogues with various amine groups have been synthesized using the same methodology, including the more potent pyrrolidine compound D- threo-PDPP (1e). A key feature of the synthesis is the isolation of tosylate (8b), which allows for the divergent synthesis of many analogues from a common advanced intermediate. The synthesis is amenable to large-scale production of D-threo-PDMP, L-threo-PDMP, and similar compounds.

Full text of DOI:10.1021/jo980951j

J . Org. Chem. 1998, 63, 8837-8842
8837
Glycosyltr a n sfer a se In h ibitor s: Syn th esis of D-th r eo-P DMP ,
L-th r eo-P DMP , a n d Oth er Br a in Glu cosylcer a m id e Syn th a se
In h ibitor s fr om D- or L-Ser in e
Scott A. Mitchell, Bryan D. Oates, Hossein Razavi, and Robin Polt*
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
Received May 19, 1998
The synthesis of enantiomerically pure (1S,2S)-1-phenyl-2-decanoylamino-3-N-morpholino-1-
propanol (L-threo-PDMP) (1a ) from L-serine, and the enantiomer (1R,2R)-1-phenyl-2-decanoylamino-
3-morpholino-1-propanol (D-threo-PDMP] (1b) from D-serine is reported. Reductive alkylation of
the fully protected O’Donnell’s Schiff base (3b) derived from D-serine provided the â-amino alcohol
5b in high yield and excellent selectivity, which yielded optically pure 1b in high yield after six
steps. Three other D-threo-PDMP analogues with various amine groups have been synthesized
using the same methodology, including the more potent pyrrolidine compound D-threo-PDPP (1e).
A key feature of the synthesis is the isolation of tosylate (8b), which allows for the divergent
synthesis of many analogues from a common advanced intermediate. The synthesis is amenable
to large-scale production of D-threo-PDMP, L-threo-PDMP, and similar compounds.
The regulation of glycosphingolipids (GSLs) is critical
for normal cellular function and is an important means
of regulating cell-cell communication, cell adhesion and
proliferation, neuronal growth, cell transformation, tu-
mor progression, and immune response.1 Biochemical
F igu r e 1.
tools (potent and selective enzyme inhibitors) are re-
quired for the exploration of GSL function as well as for
The administration of D-threo-PDMP, 1b, has interest-
ing developmental consequences caused by inhibition of
the biosynthesis of gangliosides.9 More recently, D-threo-
PPMP, the hexadecanoyl analogue of 1b, has been
demonstrated to reverse multidrug resistance in cancer
cells.10 The best-studied analogue, D-threo-PDMP (1b),
inhibits glucosylceramide synthase, resulting in the
decreased de novo synthesis of glucosylceramide and
down-regulation of ganglioside biosynthesis.11 Interest-
ingly enough, the enantiomer L-threo-PDMP (1a ) in-
creased the biosynthesis of gangliosides, leading to
enhanced synapse formation and increased memory
retention in rats.12 Although it seems likely that one or
more sphingosine-, sphingomyelin-, ceramide-, or gly-
cosphingolipid-processing enzymes is affected by the
L-compounds, the precise molecular target or targets of
1a remain murky. These facts dictate that an enantio-
new therapeutic approaches. Since its discovery by
Vunnam and Radin in 1980,2 the drug D-threo-PDMP (1b)
(D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-pro-
panol) has been shown to be a potent inhibitor of the
glucosyltransferase responsible for attachment of the first
sugar to ceramide, glucosylceramide synthase.3 The
syntheses reported by Inokuchi and Radin4 in 1987,
Ganem and colleagues5 in 1994, and Ogawa et al.6 in
1997 all have significant limitations. This compound and
its congeners have broad clinical application not only as
glycosphingolipid modulation agents,7 but also as anti-
tumor agents.8
(1) (a) Hakamori, S.-I. Annu. Rev. Biochem. 1981, 50, 733-64. (b)
Hakamori, S. I. Biochem. Soc. Trans. 1993, 21, 583-595. (c) Thurin,
J .; Thurin, M.; Herlyn, M.; Elder, D. E.; Steplewski, Z.; Clark, W. H.;
Koprowski, H. FEBS Lett. 1986, 208, 17-22. (d) Schwarz, A.; Rapaport,
E.; Hirschberg, K.;, Futerman, A. H. J . Biol Chem. 1995, 270, 10990-
8. (e) Furuya, S.; Ono, K.; Hirabayashi, Y. J . Neurochem. 1995, 65,
1551-61.
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78.
(3) a) Radin, N. S.; Shayman, J . A.; Inokuchi, J .-i. Adv. Lipid Res.
1993, 26, 1 83-212. (b) Abe, A.; Inokuchi, J .-i.; J imbo, M.; Shimeno,
H.; Nagamatsu, A.; Shayman, J . A.; Shukla, G. S.; Radin, N. S. J .
Biochem. 1992, 111, 191-196.
(9) (a) Bielawska, A.; Linardic, C. M.; Hannun, Y. A. J . Biol. Chem.
1992, 267, 18493. (b) Abe, A.; Radin, N. S.; Shayman, J . A.; Wotring,
L. L.; Zipkin, R. E.; Sivakumar, R.; Ruggeieri, J . M.; Carson, K. G.;
Ganem, B. J . Lipid Res. 1995, 36, 611. (c) Bielawska, A.; Greenberg,
M. S.; Perry, D.; J ayadev, S.; Shayman, J . A.; McKay, C.; Hannun, Y.
A. J . Biol. Chem. 1996, 271, 12646.
(4) Inokuchi, J .-i.; Radin, N. S. J . Lipid Res. 1987, 28, 565-71.
(5) (a) Carson, K. G.; Ganem, B.; Radin, N. S.; Abe, A.; Shayman,
J . A. Tetrahedron Lett. 1994, 35, 17, 2659-62. (b) ref 9b and references
therein.
(6) Ogawa, S.; Mito, T.; Taiji, E.; J imbo, M.; Yamagishi, K.; Inokuchi,
J . Biorg. Med. Chem. Lett. 1997, 7, 1915-20.
(7) (a) Rosenwald, A. G.; Pagano, R. E. J . Lipid Res. 1994, 35, 1232-
40. (b) Barbour, S.; Edidin, M.; Felding-Habermann, B.; Taylor-Norton,
J .; Radin, N. S.; Fenderson, B. A. J . Cell. Physiol. 1992, 150, 610-
619.
(8) (a) Radin, N. S.; Shayman, J . A.; Inokuchi, J . Adv. Lipid Res.
1993, 28, 183-213. (c) Inokuchi, J .-i.; Usuki, S.; J imbo, M. J . Biochem.
1995, 117, 766-73. (d) Kan, C.-C.; Kolesnick, R. N. J . Biol. Chem. 1992,
267, 9663-67. (e) Inokuchi, J .-i.; Momosaki, K.; Shimento, H.; Nag-
amatsu, A.; Radin, N. S. J . Cell. Physiol. 1989, 141, 573-83.
(10) (a) Lavie, Y.; Cao, H.; Bursten, S. L.; Giuliano, A. E.; Cabot,
M. C. J . Biol. Chem. 1996, 271, 19530. (b) Lavie, Y.; Cao, H.; Volner,
A.; Lucci, A.; Han, T.-Y.; Geffen, V.; Giuliano, A. E.; Cabot, M. C. J .
Biol. Chem. 1997, 272, 1682.
(11) (a) Shukla, A.; Radin, N. S. J . Lipid Res. 1991, 32, 713-722.
(b) Fenderson, B. A.; Ostrander, G. K.; Hausken, Z.; Radin, N. S.;
Hakamori, S.-i. Exp. Cell Res. 1992, 198, 362-66. (c) Shayman, J . A.;
Deshmukh, G. D.; Mahdiyoun, S.; Thomas, T. P.; Wu, D.; Barcelon, F.
S.; Radin, N. S. J . Biol. Chem. 1991, 266, 22968-74. (d) Shukla, G.
S.; Shukla, A.; Inokuchi, J .-i.; Radin, N. S. Biochim. Biophys. Acta 1991,
1083, 101-108.
(12) Inokuchi, J .; Mizutani, A.; J imbo, M.; Usuki, S.; Yamagishi, K.;
Mochizuki, H.; Muramato, K.; Kobayashi, K.; Kuroda, Y.; Iwasaki, K.;
Ohgami, Y.; Fujiwara, M. Biochem. Biophys. Res. Commun. 1997, 237,
595-600, and references therein.
10.1021/jo980951j CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

8838 J . Org. Chem., Vol. 63, No. 24, 1998
Mitchell et al.
Sch em e 1
CH3CN/49% HF in H2O) to yield crystalline carbamate
alcohol 7a in 92% yield. Although chlorides have been
generated under similar conditions,19 tosylation of the
primary alcohol using tosyl chloride in pyridine and
DMAP cleanly furnished 8a in 97% yield as a white
crystalline solid (mp 116-117 °C).
merically pure synthesis of 1a , 1b, and related analogues
is required. Ideally, a single advanced intermediate
should provide for the synthesis of numerous structural
analogues without reworking the entire synthetic ap-
proach for each analogue.
Our strategy focuses on the stereoselective reductive
alkylation of a serine-derived Schiff base ester such as
3b (Scheme 1). This provides the (1R,2R) diastereomer
in high yield without racemization, and with good threo-
diastereoselectivity.13,14 Easy separation of the desired
threo isomers on SiO2 has been shown to be general.15,16
Our hope was that the PDMP molecule could be gener-
ated from the carbamate tosylate, 8b,17 which could be
obtained from the corresponding â-amino diol, 5b. Thus,
diverse cyclic secondary amines and fatty acids could be
introduced at either end to produce the various PDMP
analogues from a single advanced intermediate.
Initially, the Schiff base derived from L-serine was
taken through to the less-studied isomer L-threo-PDMP
1a without isolation of the tosylate intermediate 8a .
Subsequently, the D-form of threo-PDMP (1b), as well as
a series of D-threo analogues 1c, 1d , and 1e, were
synthesized from the enantiomeric intermediate 8b,
which was easily purified by crystallization.
Imino ester 3a , obtained in three steps from L-ser-
ine,13,14b was sequentially treated with i-Bu5Al2H (1:1
mixture of i-Bu2AlH and i-Bu3Al in hexanes) followed by
PhMgBr (3.0 M in Et2O) in CH2Cl2 at -78 °C to yield
the threo imino alcohol 4a as an oil in 69% yield and 8:1
selectivity. Because of imine-oxazoline tautomeriza-
tion,16 the minor erythro product was easily removed by
flash chromatography17 along with small amounts of
over-reduced primary alcohol (Scheme 2).
Treatment of 4a with pyridinium p-toluenesulfonate
in THF:H2O (10:1) cleanly removed the Schiff base to
afford threo â-amino alcohol 5a in 72% yield. The
carbamate moiety was necessary to protect the amine,
since attempts to displace the primary tosylates and
mesylates of several threo-ceramides led to intramolecu-
lar attack of the amide on the tosylate, resulting in
formation of cyclic imino ethers. Thus, the carbamate
“ties back” the amide carbonyl, preventing intramolecular
displacement of the tosylate (oxazoline formation15), while
protecting the benzylic alcohol at the same time.18
Treatment with either carbonyl diimidazole or triphos-
gene [Cl3CO(CO)OCCl3] afforded the silyl carbamate 6a
in 70% yield as a waxy solid. Removal of the silyl group
was achieved with 10% aqueous HF in acetonitrile (10:1
L-threo-PDMP, 1a , tosylate formation and subse-
For
quent displacement with 10 equivalents of morpholine
in THF at reflux for 28 h was done in the same pot to
yield the morpholino carbamate 9a as an oil in 90% yield.
Thus, isolation of the tosylate 8a is not necessary.
Removal of the carbamate was achieved by treatment
with 1 M KOH in a 4:1 mixture of MeOH:H2O at 65 °C
for 36 h, affording the morpholino amino alcohol 10a in
80% yield as a colorless oil. The fatty amide chain was
then introduced using either p-nitrophenyl decanoate or
pentafluorophenyl decanoate as the acylating agent and
10 mole-% HOBt in dry pyridine. After extraction with
1 N NaOH to remove p-nitrophenol or pentafluorophenol,
and flash chromatography, the desired drug enantiomer
1a was obtained as an oil in 90% yield (Scheme 3).
Starting with D-serine, the synthesis was repeated to
produce enantiomeric Schiff base 3b, which in turn
provided the enantiomeric tosylate 8b in crystalline form.
Displacement of the tosylate with cyclic amines provided
the carbamate amines 9b-9e (Scheme 4). Similarly,
each of the other alkylated amines was deprotected and
acylated as before to provide the isomeric D-threo-PDMP
1b, as well as the depicted structural analogues. Ana-
logue 1e is of particular note because reported studies
(with enantiomeric mixtures) suggest that this compound
has four times the activity of 1b against glycosylceramide
synthase.9b
Now that an efficient enantioselective synthesis has
been established, diverse analogues of D-threo-PDMP can
be easily prepared to explore the nature of the interaction
with glucosylceramide synthase and other sphingosine-
and ceramide-processing enzymes. Because a number of
the intermediates are crystalline and the protecting
group manipulations are straightforward, it is expected
that this route could also be optimized for large-scale
synthesis of these compounds. Our ongoing work will
involve the introduction of more complex secondary
amines at the glycosphingosine-like headgroup, changes
in the fatty acid amide chain of the ceramide, and
variation of the carbanion source during reductive alky-
lation to produce alterations in the sphingosine moiety.
Exp er im en ta l Section
Gen er a l In for m a tion . All air- and moisture-sensitive
reactions were performed under an argon atmosphere in flame-
dried reaction flasks. THF was dried and deoxygenated over
Ph2CdO/K°. CH2Cl2 (dichloromethane) was dried over P2O5,
CH3CN (acetonitrile) was dried over CaH2, and all solvents
were freshly distilled under an argon atmosphere before use.
For flash chromatography, 400-230 mesh silica gel 60 (E.
Merck no. 9385) was used. All compounds described were
(13) O’Donnell, M.; Polt, R. L. J . Org. Chem. 1982, 47, 2663.
(14) (a) Polt, R.; Peterson, M. A. Tetrahedron Lett. 1990, 31, 4985.
(b) Polt, R.; Peterson, M. A.; DeYoung, L. J . Org. Chem. 1992, 57,
5469-80. (c) Peterson, M. A.; Polt, R. Synth. Comm. 1992, 22, 477. (d)
Peterson, M. A.; Polt, R. J . Org. Chem. 1993, 58, 4309. (e) Sames, D.;
Polt, R. J . Org. Chem. 1994, 59, 4596. (f) Sames, D.; Polt, R. Synlett
1995, 552. (g) Razavi, H.; Polt, R. Tetrahedron Lett. 1998, 39, 3371.
(15) Wijayaratne, T.; Collins, N.; Li, Y.; Bruck, M. A.; Polt, R. Acta
Crystallogr. 1993, B49, 316.
(16) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(17) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1990, 31, 5253.
(18) We thank Professor Mukund Sibi for experimental details on
his carbamate formation: Sibi, M. P.; Renhowe, P. A. Tetrahedron Lett.
1990, 31, 7407.
1
>95% pure by H and 13C NMR, and purity was confirmed by
high-resolution fast atom bombardment (FAB) mass spectrom-
etry in most cases, and by CHN analysis for one of the final
products. The 1H and 13C NMR spectra were obtained on
either a Bruker WM 250 MHz or a Bruker 500 MHz spec-
trometer. For 13C, spectra were taken at 62.9 MHz in the form
(19) (a) Chen, K. M.; J oullie, M. M. Tetrahedron Lett. 1984, 25, 393.
(b) Kido, F.; Abe, T.; Yoshikoshi, A. J . Chem. Soc., Chem. Commun.
1986, 590.

Glycosyltransferase Inhibitors
J . Org. Chem., Vol. 63, No. 24, 1998 8839
Sch em e 2
Sch em e 3
Sch em e 4
of APTs (attached proton test spectra). Chemical shifts are
reported in δ vs Me4Si in 1H spectra and vs CDCl3 in 13C
spectra. Infrared spectra were taken on a Nicolet Impact-400D
FT-IR. Optical rotations were taken on a J asco DIP-1000
polarimeter using the NaD-line. All melting points were taken
-0.0044 (CH3′-Si-, s, 3H). 13C NMR (62.5 MHz, CDCl3): δ
171.5, 171.0, 139.5, 136.1, 130.2, 128.8, 128.6, 128.3, 128.27,
127.9, 67.7, 51.9, 25.7, 18.2, -5.4, -5.5. IR (CH2Cl2): 3060,
2952, 1740, 1625 cm-1
.
(1R,2R)-(-)-2-Am in o-N-(d ip h en ylm eth ylen e)-3-O-(ter t-
bu tyld im eth ylsilyl)-1-p h en ylp r op a n e-1,3-d iol (4b). Fully
protected D-serine 3b (20.0 g, 0.05 mol) was added to CH2Cl2
(500 mL) in a long-necked addition flask under argon and
cooled to -78 °C. To this solution was added i-Bu2AlH‚i-Bu3Al
(0.05 mol of each in 100.60 mL of hexanes) at -78 °C over 90
min. The solution turned yellow upon addition and was
allowed to stir for 60 min. Next, PhMgBr in ether (50.3 mL,
3 equiv, 0.15 mol) was added dropwise at -78 °C over 130
min and the resulting solution was allowed to stir overnight
and slowly warm from -78 to 0 °C, turning a deep orange-
yellow color. After completion of reaction the flask was cooled
to 0 °C and concentrated NaHCO3 (∼10 mL) was added
dropwise slowly to quench the reaction. The reaction turned
a light milky yellow upon quenching, and the solution was
diluted with CH2Cl2 (400 mL), the phases separated, and the
crude was washed 3× with concentrated NaHCO3, followed
by brine and dried over MgSO4. Silica gel flash chromatog-
raphy (5% EtOAc:hexanes, Rf ) 0.63) yielded 15.60 g of pure
on
a Hoover capillary melting point apparatus and are
uncorreced. Elemental analyses were performed by Desert
Analytics of Tucson, Arizona.
Meth yl-O-(ter t-bu tyld im eth ylsilyl)-N-(d ip h en ylm eth -
ylen e)-D-ser in a te (3b). Methyl-N-(diphenylmethylene)-D-
serinate (28.00 g, 0.099 mol) was dried over P2O5 in vacuo and
added to a RB-flask and dry dimethyl formamide (DMF) (90
mL) was added. TBDMS-Cl (23.83 g, 0.16 mol) and imidazole
(17.5 g, 0.257 mol) were added in one portion and stirred at
room temperature (RT) under argon for 24 h. The sample was
then poured over ether (200 mL) and washed 2× with 1%
NaHCO3. The organic layer was pooled, washed with brine,
dried over MgSO4, and concentrated in vacuo. The resultant
oil solidified on standing to give 33.60 g of a crystalline mass
in 86% yield. MP: 56-58 °C. [R]25 ) +100.68° (c ) 0.76,
D
CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.66-7.20 (Ar-H, m,
10H), 4.32 (RCH, dd, J ) 7.58, 5.4 Hz, 1H), 4.13 (âH, dd, J )
9.75, 5.4 Hz, 1H), 3.94 (â′H, dd, J ) 9.73, 7.63 Hz, 1H), 3.70
(OCH3, s, 3H), 0.84 [(CH3)3C-, s, 9H], 0.02 (CH3-Si-, s, 3H),
threo product as a colorless oil in 70% yield. [R]25 ) -109°
D

8840 J . Org. Chem., Vol. 63, No. 24, 1998
Mitchell et al.
(c ) 1.70, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.83-7.14
(Ar-H, m, 15H), 4.94 (CH-O, d, J ) 6.23 Hz, 1H), 3.86 (âH,
dd, J ) 10.73, 3.05 Hz, 1H), 3.64 (â′H, dd, J ) 12.08, 1.43 Hz,
1H), 3.14 (RCH, dt, J ) 8.25 Hz, 1H), 0.85 [(CH3)3C-, s, 9H],
0.08 (CH3-Si-, s, 3H), 0.04 (CH3′-Si-, s, 3H). 13C NMR (62.5
MHz, CDCl3): δ 145.6, 145.3, 140.4, 128.44, 128.33, 128.12,
128.07, 127.8, 127.6, 127.5, 127.3, 126.9, 126.6, 125.9, 125.7,
100.1, 81.9, 68.3, 59.1, 25.7, 18.1, -5.5. IR (CH2Cl2): 3061,
(62.5 MHz, CDCl3): δ 158.5, 145.6, 137.4, 131.9, 130.1, 129.2,
129.0, 127.9, 125.5, 79.3, 68.9, 58.8, 21.6. IR (CH2Cl2): 3018,
1771, 1221, 758 cm-1
HRMS calcd. 348.0906, found 348.0913.
. MS (FAB) [M + H] for C17H18O5NS;
(4R,5R)-(+)-4-[(N-Mor p h olin o)m eth yl]-5-p h en yloxa zo-
lid in -2-on e (9b). Tosylate 8b (585.5 mg, 1.69 mmol) was
dissolved in THF (5.0 mL) and morpholine (0.44 mL, 5.0 mmol,
3 equiv) was added, and the resultant mixture was heated to
reflux for 34 h. THF was removed in vacuo, the residue was
dissolved in CH2Cl2 and extracted with NaHCO3, and flash
chromatography (CH2Cl2:MeOH 20:1, Rf ) 0.34) yielded 335
mg as a colorless oil in 75.2% yield. [R]25D ) +36.5° (c ) 0.325,
CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.38 (Ar-H, m, 5H),
6.24 (NH, bs, 1H), 5.22 (CH-OPh, d, J ) 5.65 Hz, 1H), 3.84
(CH-NH, dd, J ) 6.74, 6.26 Hz, 1H), 3.67 (CH2-OMOR, t, 4.59
Hz, 4H), 2.74 (âCH2-N, ddd, 4.74, 3.46 Hz, 2H), 2.46 (CH2-
NMOR, tq, 13.2, 4,6 Hz, 4H). 13C NMR (62.5 MHz, CDCl3): δ
159.0, 138.5, 128.5, 125.4, 81.4, 66.4, 62.1, 57.4, 53.6. IR
(neat): 3434, 3018, 1759 cm-1. HRMS C14H19N2O3 [M + H]
calcd. 263.1396, found 263.1396.
(4R ,5R )-(+)-4-[(N -Th iom or p h olin o)m e t h yl]-5-p h e n -
yloxa zolid in -2-on e (9c). Tosylate 8b (235.5 mg, 0.68 mmol)
was dissolved in THF (5.0 mL) and thiomorpholine (0.52 mL,
5.2 mmol, 7.7 equiv) was added, and the resultant mixture
was heated to reflux for 47 h. THF was removed in vacuo,
the residue was dissolved in CH2Cl2 and extracted with
NaHCO3, and flash chromatography (CH2Cl2:MeOH 20:1, Rf
2953, 1450 cm-1
.
(1R,2R)-(+)-2-a m in o-3-O-(ter t-b u t yld im et h ylsilyl)-1-
p h en ylp r op a n e-1,3-d iol (5b). Threo product 4b (12.90 g,
2.89 mmol) was dissolved in THF (200 mL) and H2O (20 mL).
Pyridinium p-toluenesulfonate (14.55 g, 5.79 mmol, 2 equiv)
was added and reacted for 4.5 h, the solvent was removed in
vacuo, and the residue was redissolved in CH2Cl2 (150 mL)
and washed with concentrated NaHCO3 (3 × 50 mL), brine,
and dried over K2CO3. The crude product was then chromato-
graphed on silica gel (9:1, CH2Cl2:MeOH, Rf ) 0.5) yielding
6.54 g as a colorless oil in 80% yield. [R]25 ) +3.14° (c )
D
1.34, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.36-7.27 (Ar-
H, m, 5H), 4.64 (CH-OH, d, J ) 5.26 Hz, 1H), 3.65 (âH, dd,
J ) 10.07, 4.12 Hz, 1H), 3.58 (â′H, dd, J ) 10.11, 5.00 Hz,
1H), 2.21 (OH, bs, 1H), 0.91 [(CH3)3C-, s, 9H] 0.06 [(CH3)2-
Si-, s, 6H]. 13C NMR (62.5 MHz, CDCl3): δ 142.4, 128.2,
127.3, 126.2, 73.9, 65.0, 58.3, 25.8, 18.1, -5.60. IR (neat):
3444, 2956, 912, 740 cm-1
.
(4R,5R)-(+)-4-(tert-Butyldimethylsilyloxymethyl)-5-phen-
yloxa zolid in -2-on e (6b). Amino alcohol 5b (1.92 g, 6.82
mmol) was dissolved in 20 mL of dry CH2Cl2 under argon and
cooled to 0 °C. Triethylamine was then added in one portion
(2.87 mL, 20.6 mmol) at 0 °C. A solution of triphosgene (682.5
mg, 2.3 mmol, 0.33 equiv) in CH2Cl2 (20 mL) was added
dropwise over 60 min. After 4 h the reaction was complete,
and all solvent was removed in vacuo. The residue was then
redissolved in Et2O, filtered, and washed with concentrated
NaHCO3 (3 × 100 mL) and dried over MgSO4. Flash chro-
matography (3:2 hexanes:EtOAc, Rf ) 0.57) yielded 1.52 g as
) 0.55) yielded 175 mg as a colorless oil in 93.1% yield. [R]25
D
) +30.9° (c ) 0.25, CHCl3). 1H NMR (250 MHz, CDCl3): δ
7.42-7.35 (Ar-H, m, 5H), 5.60 (NH, bs, 1H), 5.17 (CH-OPh,
d, J ) 5.53 Hz, 1H), 3.82 (CH-NH, q, J ) 7.65 Hz, 1H), 2.81-
2.77 (m, 2H), 2.72-2.68 (m, 2H), 2.66-2.56 (m, 6H). 13C NMR
(62.5 MHz, CDCl3): δ 159.1, 138.6, 128.7, 125.5, 81.5, 62.6,
57.7, 55.3, 27.7. IR (neat): 3426, 2923, 1754, 1657 cm-1
.
HRMS C14H19N2O2S [M + H] calcd. 279.1167, found 279.1179.
(4R,5R)-(+)-4-[(N-P ip er id in o)m et h yl]-5-p h en yloxa zo-
lid in -2-on e (9d ). Tosylate 8b (330 mg, 0.95 mmol) was
dissolved in THF (5.0 mL) and piperidine (0.94 mL, 9.5 mmol,
10 equiv) was added, and the resultant mixture was heated
to reflux for 16 h. THF was removed in vacuo, the residue
was dissolved in CH2Cl2 and extracted with NaHCO3, and flash
chromatography (CH2Cl2:MeOH 20:1, Rf ) 0.35) yielded 196
mg as a colorless oil in 76.7% yield. [R]25D ) +40.7° (c ) 0.245,
CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.38 (Ar-H, m, 5H),
6.24 (NH, bs, 1H), 5.22 (CH-OPh, d, J ) 5.65 Hz, 1H), 3.84
(CH-NH, dd, J ) 6.74, 6.26 Hz, 1H), 3.67 (CH2-OMOR, t, 4.59
Hz, 4H), 2.74 (âCH2-N, ddd, 4.74, 3.46 Hz, 2H), 2.46 (CH2-
a waxy solid in 72.8% yield. MP: 88-90 °C. [R]25 ) +31.1°
D
(c ) 0.405, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.42-7.34
(Ar-H, m, 5H), 6.58 (NH, bs, 1H), 5.35 (CH-OH, d, J ) 4.63
Hz, 1H), 3.79 (CH-NH, p, J ) 5.78, 4.98 Hz, 1H), 3.74 (âCH2,
d, J ) 4.75 Hz, 2H), 0.91 [(CH3)3C-Si, s, 9H], 0.094 (CH3-Si,
s, 6H). 13C NMR (62.5 MHz, CDCl3): δ 159.7, 139.0, 128.6,
128.4, 125.3, 79.8, 64.0, 61.5, 25.6, 18.0, -5.6. IR (CH2Cl2):
3416, 2955, 1757 cm-1. HRMS C16H26NO3Si [M + H] calcd.
308.1681, found 308.1682.
(4R,5R)-(+)-4-(Hyd r oxym eth yl)-5-p h en yloxa zolid in -2-
on e (7b). Carbamate 6b (1.00 g, 3.25 mmol) was dissolved
in 20 mL of acetonitrile and HF (49% aqueous, 0.5 mL, 12.25
mmol, 3.8 equiv) was added via syringe at RT and stirred for
75 min. After TLC showed full conversion, solvent was
removed in vacuo. The crude product was redissolved in 9:1
CH2Cl2:MeOH and passed through a plug of silica gel (Rf )
0.44). Isolation and concentration yielded 0.60 g as white
N
MOR, tq, 13.2, 4.6 Hz, 4H). 13C NMR (62.5 MHz, CDCl3): δ
159.0, 138.5, 128.5, 125.4, 81.4, 66.4, 62.1, 57.4, 53.6. IR
(neat): 3419, 3066, 2935, 1755, 1655 cm-1. HRMS C15H21N2-
O2 [M + H] calcd. 261.1603, found 261.1606.
(4R,5R)-(+)-4-[(N-P yr r olid in o)m eth yl]-5-p h en yloxa zo-
lid in -2-on e (9e). Tosylate 8b (187.6 g, 0.54 mmol) was
dissolved in THF (5.0 mL) and pyrrolidine (0.45 mL, 5.4 mmol,
10 equiv) was added and heated to reflux for 11 h. THF was
removed in vacuo, the residue was dissolved in CH2Cl2 and
extracted with NaHCO3, and flash chromatography (CH2Cl2:
MeOH 20:1, Rf ) 0.35) yielded 87.9 mg as a colorless oil in
70.1% yield. [R]25D ) +43.8° (c ) 0.665, CHCl3). 1H NMR (250
MHz, CDCl3): δ 7.42-7.35 (Ar-H, m, 5H), 5.59 (NH, bs, 1H),
5.19 (CH-OPh, d, J ) 5.73 Hz, 1H), 3.80 (CH-NH, dt, J )
6.74, 8.55 Hz, 1H), 2.84 (âH, dd, J ) 12.02, 8.95 Hz, 1H), 2.65
(â′H, dd, J ) 12.13, 4.97 Hz, 1H), 2.59 (RCH2PYR, m, 2H), 2.51
(R′CH2PYR, m, 2H), 1.78 (âCH2PYR, m, 4H). 13C NMR (62.5 MHz,
CDCl3): δ 158.9, 138.7, 128.7, 128.6, 125.6, 81.4, 59.9, 59.3,
crystals in 95% yield. MP: 96-97 °C. [R]25 ) +44.0° (c )
D
0.345, MeOH). 1H NMR (250 MHz, CD3OD + D2O): δ 7.37
(Ar-H, m, 5H), 5.37 (CH-OD, d, J ) 5.6 Hz, 1H), 3.83 (âCH2,
dt, J ) 9.41, 3.21 Hz, 2H), 3.67 (CH-ND2, dd, J ) 12.61, 5.46
Hz, 1H). 13C NMR (62.5 MHz, CD3OD): δ 159.9, 138.3, 128.9,
125.7, 79.8, 62.7, 61.8. IR (CH2Cl2): 3292, 3057, 1707, 1268
cm-1
. MS (FAB) [M + H] for C10H12NO3; HRMS calcd.
194.0817, found 194.0814.
(4R,5R)-(+)-4-(4′-p-Tolu en esu lfon yloxym eth yl)-5-p h en -
yloxa zolid in -2-on e (8b). Alcohol 7b (330.8 mg, 1.71 mmol)
was dissolved in dry pyridine (2.0 mL) and tosyl chloride (502.5
mg, 2.635 mmol, 1.5 equiv) was added in one portion. The
resulting mixture was reacted at RT for 4 h, the solvent was
removed in vacuo and the crude was purified by flash chro-
matography (EtOAc:hexanes 1:1, Rf ) 0.33), yielding 585.5 mg
as a white crystalline solid in 98.5% yield. MP: 116-117 °C.
54.2, 23.4. IR (neat): 3390, 2960, 1755 cm-1. HRMS C14H19
N2O2 [M + H] calcd. 247.1447, found 247.1447.
(1R,2R)-(+)-2-Am in o-3-(N-m or p h olin o)-1-p h en yl-1-ol
-
(10b). Carbamate 9b (330 g, 1.26 mmol) was dissolved in
MeOH:H2O (4:1) and treated with) 2 M KOH (5.0 mL) and
heated under reflux conditions at 70 °C, and the reaction
progress was monitored by TLC. After 16 h the sample was
concentrated in vacuo and redissolved in CH2Cl2 and washed
with concentrated NaHCO3. Passing the sample through silica
gel using 20% MeOH:CH2Cl2 yielded 192.4 mg as a colorless
[R]25 ) +39.6° (c ) 0.75, CHCl3). 1H NMR (250 MHz,
D
CDCl3): δ 7.80 (Ar-H, 2H, d, J ) 8.3 Hz), 7.41-7.27 (Ar-H,
m, 7H), 6.28 (NH, bs, 1H), 5.23 (CH-OPh, d, J ) 5.45 Hz,
1H), 4.15 (CH2-OTos, dd, J ) 5.22, 5.41 Hz, 2H), 3.96 (CH-
NH, dd, J ) 5.32, 5.24 Hz, 1H), 2.46 (CH3, s, 3H). 13C NMR

Glycosyltransferase Inhibitors
J . Org. Chem., Vol. 63, No. 24, 1998 8841
oil in 65.4% yield. [R]25D ) +5.86° (c ) 0.25, CHCl3). 1H NMR
(250 MHz, CDCl3): δ 7.38-7.25 (Ar-H, m, 5H), 4.55 (CH-
OH, d, J ) 3.29 Hz, 1H), 3.70 (CH2-OMOR, t, J ) 4.6 Hz, 4H),
3.21 (CH-NH2, ddd, J ) 6.57, 5.33 Hz, 1H), 2.56 (âH, dd, J )
11.28, 4.23 Hz, 1H), 2.36 (â′H, dd, J ) 12.58, 5.44 Hz, 1H),
2.45 (CH2-NMOR, m, 4H). 13C NMR (62.5 MHz, CDCl3): δ
142.5, 128.2, 127.2, 125.9, 75.1, 66.9, 61.9, 53.9, 52.7. IR
(neat): 3450, 3018, 1641 cm-1. HRMS C13H21N2O2 [M + H]
calcd. 237.1603, found 237.1603.
(1R,2R)-(+)-2-Am in o-1-p h en yl-3-(N-th iom or p h olin o)-1-
ol (10c). Carbamate 9c (105.4 mg, 0.399 mmol) was dissolved
in MeOH:H2O (4:1) and treated with) 2 M KOH (5.0 mL) and
heated under reflux conditions at 70 °C, and the reaction
progress was monitored by TLC. After 18 h the sample was
concentrated in vacuo and redissolved in CH2Cl2 and washed
with concentrated NaHCO3. Passing the sample through silica
gel using 20% MeOH:CH2Cl2 yielded 100.6 mg as a colorless
oil in 81.3% yield. [R]25D ) +5.23° (c ) 0.32, CHCl3). 1H NMR
(250 MHz, CDCl3 + D2O): δ 7.37-7.26 (Ar-H, m, 5H), 4.54
(CH-OH, d, J ) 3.17 Hz 1H), 3.22 (CH-NH2, dt, J ) 3.4,
6.87 Hz 1H), 2.82 (CH2-NTM, m, 2H), 2.71 (CH2′-NTM, m, 2H),
2.67 (CH2-STM, m, 4H), 2.44 (âCH2, d, J ) 6.66 Hz). 13C NMR
(62.5 MHz, CDCl3): δ 142.5, 128.2, 127.2, 125.9, 75.1, 62.2,
55.4, 52.9, 27.9.
t, 6.61 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 173.6, 140.9,
128.2, 127.5, 125.9, 75.0, 66.8, 59.6, 54.2, 51.1, 36.6, 31.8, 29.3,
29.2, 29.0, 25.6, 22.6, 14.0. IR (neat): 3428, 3017, 2956, 1656,
1509 cm-1. MS (FAB) [M + H] for C23H39O3N2; HRMS calcd.
391.2961, found 391.2980.
D-threo-PDMP (150 mg, 0.384 mmol) was dissolved in MeOH
(5.0 mL), cooled to 0 °C, and acidified to pH 4.0 with HCl (3
M). The resulting mixture was concentrated in vacuo to afford
a white crystalline compound. The crystalline product was
recrystallized (CHCl3:Et2O) to give D-threo-PDMP‚HCl‚H2O
(126.5 mg, 0.296 mmol) in 77% yield. MP: 94-96 °C; [R]25
D
) -12.1° (c ) 0.40, CHCl3). IR (CH2Cl2): 3442, 2932, 1635
cm-1
. Elemental analysis (C, H, N): C23H38N2O3‚HCl‚H2O
calcd. 62.08% C, 9.29% H, and 6.30% N; found 61.76% C, 9.19%
H, and 6.25% N.
(1R,2R)-(+)-1-P h en yl-2-d eca n oyla m in o-3-(N-th iom or -
p h olin o)-1-p r op a n ol [D-th r eo-P DTMP ] (1c). Compound
10c (81.4 mg, 0.323 mmol) was dissolved in pyridine (dried
over sieves) and was sequentially treated with p-nitrophenyl
decanoate (95 mg, 0.322 mmol) and 1-hydroxybenzotriazole (10
mol %, 5.0 mg, 0.032 mmol). Upon completion judged by TLC,
the solvent was removed, and the residue was dissolved in
CH2Cl2 and extracted with NaOH (5 × 20 mL, 1 M). The crude
was chromatographed (20:1 CH2Cl2:MeOH, Rf ) 0.48) to give
90 mg of 1b as a light brown oil in 81.3% yield. [R]25D ) +2.83°
(c ) 1.17, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.36-7.25
(Ar-H, m, 5H), 5.82 (NH, d, J ) 7.03 Hz, 1H), 4.93 (CH-OH,
d, J ) 3.69 Hz, 1H), 4.25 (CH-NH, ddd, J ) 10.77, 6.63, 3.94
Hz, 1H), 2.82 (CH2-NTM, m, 4H), 2.69 (CH2-STM, t, J ) 5.18
Hz, 4H), 2.59 (âH, dd, J ) 13.17, 6.60 Hz, 1H), 2.48 (â′H, dd,
J ) 13.15, 5.59 Hz, 1H), 2.09 (RCH2, t, J ) 7.44 Hz, 2H), 1.50
(âCH2, p, J ) 7.51 Hz, 2H), 1.24 [(CH2)6, m, 12H], 0.88 (CH3,
t, J ) 6.82 Hz, 3H). 13C NMR: (62.5 MHz, CDCl3): δ 173.6,
140.9, 128.3, 127.5, 126.0, 75.1, 59.8, 55.7, 51.2, 36.7, 31.8, 29.3,
29.2, 29.18, 29.04, 27.9, 25.6, 22.6, 14.0. IR (neat): 3309, 2952,
1642, 1534 cm-1. MS (FAB) [M + H] for C23H39N2O2S; HRMS
calcd. 407.2732, found 407.2724.
(1R,2R)-(+)-2-Am in o-1-ph en yl-3-(N-piper idin o)-1-ol(10d).
Carbamate 9d (167 mg, 0.64 mmol) was dissolved in MeOH:
H2O (4:1) and treated with) 2 M KOH (5.0 mL) and heated
under reflux conditions at 70 °C, and the reaction progress
was monitored by TLC. After 16 h the sample was concen-
trated in vacuo and redissolved in CH2Cl2 and washed with
concentrated NaHCO3. Passing the sample through silica gel
using 20% MeOH:CH2Cl2 yielded 150 mg as a colorless oil in
99.7% yield. [R]25D ) -6.35° (c ) 0.29, CHCl3). 1H NMR (250
MHz, CDCl3 + D2O): δ 7.29-7.14 (Ar-H, m, 5H), 4.55 (CH-
OH, d, J ) 3.37 Hz 1H), 3.16 (CH-NH2, dt, 6.72, 3.36 Hz 1H),
2.36 (RCH2PIP, m, 4H), 2.32 (âH, dd, J ) 12.8, 6.95 Hz, 1H),
2.22 (â′H, dd, J ) 12.7, 6.63 Hz, 1H), 1.50 (âCH2PIP, p, J ) 5.6
Hz, 4H), 1.36 (γCH2PIP, bp, J ) 4.975 Hz, 2H). 13C NMR (62.5
MHz, CDCl3): δ 142.3, 127.9, 126.9, 126.2, 76.0, 62.4, 55.1,
(1R,2R)-(+)-1-P h en yl-2-decan oylam in o-3-(N-piper idin o)-
1-p r op a n ol [D-th r eo-P DP iP ] (1d ). Compound 10d (144.5
mg, 0.617 mmol) was dissolved in pyridine (dried over sieves)
and was sequentially treated with p-nitrophenyl decanoate
(181 mg, 0.617 mmol) and 1-hydroxybenzotriazole (10 mol %,
10 mg, 0.062 mmol). Upon completion judged by TLC, the
solvent was removed, and the residue was dissolved in CH2-
Cl2 and extracted with NaOH (5 × 20 mL, 1 M). The crude
was chromatographed (9:1 CH2Cl2:MeOH, Rf ) 0.58) to give
52.3, 25.9, 24.1. IR (neat): 3373, 3017, 2933, 1452 cm-1
.
HRMS C14H23N2O [M + H] calcd. 235.1810, found 235.1812.
(1R,2R)-(+)-2-Am in o-1-p h en yl-3-(N-p yr r olid in o)-1-ol
(10e). Carbamate 9e (88 mg, 0.036 mmol) was dissolved in
MeOH:H2O (4:1) and treated with) 2 M KOH (5.0 mL) and
heated to 70 °C under reflux conditions and the reaction
progress was monitored by TLC. After 16 h the sample was
concentrated in vacuo and redissolved in CH2Cl2 and washed
with concentrated NaHCO3. Passing the sample through silica
gel using 20% MeOH:CH2Cl2 yielded 79 mg as a colorless oil
164 mg of 1b as a light brown oil in 68.8% yield. [R]25
)
D
+6.33° (c ) 0.215, CHCl3). 1H NMR (250 MHz, CDCl3): δ
7.37-7.22 (Ar-H, m, 5H), 5.91 (NH, d, J ) 7.19 Hz, 1H), 4.96
(CH-OH, d, J ) 3.56 Hz, 1H), 4.31 (CH-NH, dt, J ) 11.25
Hz, 1H), 2.62 (âH, dd, J ) 13.24, 6.37 Hz, 1H), 2.50 (â′H, dd,
J ) 13.49, 5.26 Hz, 1H), 2.54 (RCH2PIP, m, 4H), 2.08 (RCH2, t,
J ) 7.28 Hz, 2H), 1.63 (âCH2PIP, bp, J ) 5.28 Hz, 4H), 1.49
(γCH2PIP, m, 4H), 1.23 [(CH2)6, m, 12H], 0.87 (CH3, t, J ) 6.38
Hz, 3H). 13C NMR (62.5 MHz, CDCl3): δ 173.4, 140.9, 128.1,
127.3, 126.0, 75.5, 59.9, 55.4, 50.6, 36.6, 31.7, 29.3, 29.2, 29.16,
28.9, 25.9, 25.5, 23.7, 22.5, 14.0. IR (neat): 3308, 2926, 1644,
1537 cm-1. MS (FAB) [M + H] for C24H41O2N2; HRMS calcd.
389.3168, found 389.3170.
in 80.7% yield. [R]25 ) +3.51° (c ) 0.91, CHCl3). 1H NMR
D
(250 MHz, CDCl3 + D2O): δ 7.38-7.26 (Ar-H, m, 5H), 4.68
(CH-OH, d, J ) 3.35 Hz, 1H), 3.19 (CH-NH2, dt, J ) 6.38,
3.38 Hz, 1H), 2.74 (âH, dd, J ) 12.7, 6.6 Hz, 1H), 2.53 (â′H,
dd, J ) 12.4, 5.8 Hz, 1H), 2.63 (RCH2PYR, m, 4H), 1.75 (âCH2PYR
,
m, 4H). 13C NMR (62.5 MHz, CDCl3): δ 142.5, 128.2, 127.2,
125.9, 75.1, 66.9, 61.9, 53.9, 52.7. IR (neat): 3362, 3296, 3086,
2926, 1451 cm-1. HRMS C13H21N2O [M + H] calcd. 221.1654,
found 221.1649.
(1R,2R)-(+)-1-P h en yl-2-d eca n oyla m in o-3-(N-m or p h oli-
n o)-1-pr opan ol [D-th r eo-P DMP ] (1b). Compound 10b (192.4
mg, 0.814 mmol) was dissolved in pyridine (dried over sieves)
and was sequentially treated with p-nitrophenyl decanoate
(239 mg, 0.814 mmol) and 1-hydroxybenzotriazole (10 mol %,
12.5 mg, 0.0814 mmol). Upon completion judged by TLC, the
solvent was removed, and the residue was dissolved in CH2Cl2
and extracted with NaOH (5 × 20 mL, 1 M). The crude was
chromatographed (4:1 CH2Cl2:MeOH, Rf ) 0.42) to give 280
(1R,2R)-(+)-1-P h en yl-2-d eca n oyla m in o-3-(N-p yr r olid i-
n o)-1-p r op a n ol [D-th r eo-P DP P ] (1e). Compound 10b (33
mg, 0.015 mmol) was dissolved in pyridine (dried over sieves)
and was sequentially treated with p-nitrophenyl decanoate (43
mg, 0.015 mmol) and 1-hydroxybenzotriazole (10 mol %, 2.5
mg, 0.0015 mmol). Upon completion judged by TLC, the
solvent was removed, and the residue was dissolved in CH2Cl2
and extracted with NaOH (5 × 20 mL, 1 M). The crude was
chromatographed (9:1 CH2Cl2:MeOH, Rf ) 0.23) to give 41 mg
mg of 1b as a light brown oil in 88% yield. [R]25 ) 8.05° (c )
D
0.3, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.36-7.25 (Ar-H,
m, 5H), 5.89 (NH, bd, J ) 6.75 Hz, 1H), 4.96 (CH-OH, d, J )
3.73 Hz, 1H), 4.29 (CH-NH, ddd, J ) 6.30, 6.9 Hz, 1H), 3.73
(CH2-OMOR, t, J ) 4.53 Hz, 4H), 2.64 (âH, dd, J ) 6.63, 13.05
Hz, 1H), 2.58 (CH2-NMOR, t, J ) 5.53 Hz, 4H), 2.51 (â′H, dd,
J ) 6.63, 13.05 Hz, 1H), 2.10 (RCH2, t, J ) 7.52 Hz, 2H), 1.49
(âCH2, p, J ) 6.90 Hz, 2H), 1.23 [(CH2)6, m, 12H], 0.87 (CH3,
of 1b as a light brown oil in 74.2% yield. [R]25 ) +2.26° (c )
D
0.96, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.29-7.17 (Ar-
H, m, 5H), 5.84 (NH, d, J ) 7.05 Hz, 1H), 4.99 (CH-OH, d, J
) 3.2 Hz, 1H), 4.19 (CH-NH, ddd, 8.04, 4.98, 4.92 Hz, 1H),
2.81 (âCH2, d, J ) 5.12 Hz, 2H), 2.68 (RCH2PYR, m, 2H), 2.64
(âCH2PYR, m, 2H), 1.99 (R′CH2, m, J ) 11.63, 4.63 Hz, 2H),
1.75 (m, 4H), 1.40 (â′CH2, p, J ) 7.29 Hz, 2H), 1.27-1.09

8842 J . Org. Chem., Vol. 63, No. 24, 1998
Mitchell et al.
[(CH2)6, m, 12H], 0.812 (CH3, t, J ) 7.12 Hz, 3H). 13C NMR
(62.5 MHz, CDCl3): δ 173.5, 140.9, 128.2, 127.4, 125.8, 75.3,
57.7, 55.2, 52.3, 36.7, 31.8, 29.7, 29.4, 29.3, 29.0, 25.6, 23.6,
22.6, 14.0. IR (neat): 3352, 2924, 1645, 1536 cm-1. MS (FAB)
[M + H] for C23H39N2O2; HRMS calcd. 375.3012, found
375.3005.
thank Dr. Michael C. Seidel of Matreya, Inc. for the
purchase of needed materials.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C data for
compounds 1b-e, 4b, 5b, 8b, 9b-e, and 10b-e (29 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. We thank the NSF for financial
support (CHE-9526909), and Dr. Norman Radin for
useful discussions regarding the physiological effects of
the PDMP compounds. H.R. thanks the University of
Arizona Graduate College for a Dean’s Fellowship. We
J O980951J