Indolyl-oxazaphosphorine Precursors for Stereoselective Synthesis of Phosphite Triesters and Dithymidinyl Phosphorothioates

Article abstract of DOI:10.1021/jo990242l

Several novel chiral indolyl-oxazaphosphorines 7 were synthesized, and their potential as precursors to chiral phosphorothioates was evaluated. Reaction of 7 with a thymidine derivative gave phosphite triester 8 with a large degree of stereoselectivity. Sulfurization with Beaucage's reagent provided phosphorothioate triesters 9. The chiral auxiliary 9b containing a cyano group could be easily removed with aqueous ammonia to form dithymidinyl phosphorothioate in more than 97% diastereomeric excess. The chiral indolyl-oxazaphosphorines 7 are a new class of precursors for stereoselective synthesis of phosphorothioates.

Full text of DOI:10.1021/jo990242l

8090
J . Org. Chem. 1999, 64, 8090-8097
In d olyl-oxa za p h osp h or in e P r ecu r sor s for Ster eoselective
Syn th esis of P h osp h ite Tr iester s a n d Dith ym id in yl
P h osp h or oth ioa tes
J ian-Chao Wang and George J ust*
Department of Chemistry, McGill University, Montreal H3A 2K6, Canada
Received February 9, 1999
Several novel chiral indolyl-oxazaphosphorines 7 were synthesized, and their potential as precursors
to chiral phosphorothioates was evaluated. Reaction of 7 with a thymidine derivative gave phosphite
triester 8 with a large degree of stereoselectivity. Sulfurization with Beaucage’s reagent provided
phosphorothioate triesters 9. The chiral auxiliary 9b containing a cyano group could be easily
removed with aqueous ammonia to form dithymidinyl phosphorothioate in more than 97%
diastereomeric excess. The chiral indolyl-oxazaphosphorines 7 are a new class of precursors for
stereoselective synthesis of phosphorothioates.
Sch em e 1
In tr od u ction
Oligonucleotide phosphorothioates (PS-Oligos) have
attracted much attention as a result of their therapeutic
potential.1 A still unsolved and often unappreciated
problem concerning the use of PS-Oligos in the antisense
strategy is their polydiastereoisomerism. PS-Oligos, cur-
rently employed in clinical studies and biological evalu-
ations, are obtained as mixtures of 2n diastereomers,
where n is equal to the number of internucleotidic
phosphorothioate linkages. To date the most useful
stereoselective synthesis of PS-Oligos is the oxathiaphos-
pholane approach, which has been described by Stec and
co-workers.2 Their chiral precursors, oxathiaphospholanes,
were separated chromatographically from a diastereo-
meric mixture. Recently, we developed a synthesis for
chiral cyclic phosphoramidites, which were obtained from
xylose and could be used without purification for the
preparation of diastereoisomerically enriched dithymidi-
nyl phosphorothioates.3 This procedure involves an acid-
catalyzed coupling step. It turns out that mono- or
dimethoxy trityl groups used to protect the 5′-hydroxyl
group of nucleosides are not compatible with these acidic
catalysts. This encouraged us to look for chiral auxiliaries
that might not require the acid-catalyzed coupling step.
One way to design such analogue is to incorporate an
azole leaving group (see A in Scheme 1) in lieu of the
phosphoramidite B.
with excellent de’s. However, it was too reactive to be
used routinely, and considerable difficulties were en-
countered in preparing the appropriate starting materi-
als. We therefore investigated different azole groups and
evaluated their potential as possible chiral precursors.
In our preliminary communications,5 we have described
the usefulness of indole derivative 5a and 5b as chiral
auxiliaries for stereocontrolled synthesis of phosphite
triesters and therefore of phosphorothioates. Here we
wish to report the full details of our work in this area.
Resu lts a n d Discu ssion
A comparison of imidazole (pKa 14.10) with the less
acidic indole (pKa 16.97) indicated that the latter may
be a suitable leaving group. Thus, indole was reacted
with diethyl chlorophosphite in the presence of triethyl-
amine, and stable diethyl indolphosphite 1 (31P NMR,
130.1 ppm) was obtained, which could be purified by
silica gel column chromatography. The corresponding
diethyl benzimidazolphosphite (31P NMR,129.5 ppm) and
benzotriazolphosphite (31P NMR, 135.5 ppm) were too
unstable for purification and reacted rapidly upon addi-
tion of an alcohol in the presence of triethylamine.
Interestingly, the displacement of an indole group in 1
by an alcohol required activation by a strong base such
as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and no reac-
tion occurred in the presence of triethylamine, even after
several days. These model reactions suggested that cyclic
indolides might be good precursors for the synthesis of
chiral phosphorothioates. (S)-1-(Indol-2-yl)-propan-2-ol 5a
We have reported on chiral bicyclic imidazo-oxaza-
phosphorine C, which was obtained with high de from a
chiral precursor by a simple equilibration.4 Imidazo-
oxazaphosphorine C coupled with a nucleoside in the
presence of triethylamine and gave a phosphite triester
(1) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
(2) (a) Stec, W. J .; Grajkowski, A.; Koziolkiewicz, M.; Uznanski, B.
Nucleic Acids Res. 1991, 19, 5883. (b) Stec, W. J .; Grajkowski, A.;
Kobylanska, A.; Karwowski, B.; Koziolkiewicz, M.; Misiura, K.; Ok-
ruszek, A.; Wilk, A.; Guga, P.; Boczkowska, M. J . Am. Chem. Soc. 1995,
117, 12019. (c) Stec, W. J .; Karwowski, B.; Boczkowska, M.; Guga, P.;
Koziolkiewicz, M.; Sochacki, M.; Wieczorek, M. W.; Blaszczyk, J . J .
Am. Chem. Soc. 1998, 120, 7156.
(3) (a) Xin, Z.; J ust, G. Tetrahedron Lett. 1996, 37, 969. (b) J in, Y.;
Biancotto, G.; J ust, G. Tetrahedron Lett. 1996, 37, 973. (c) Marsault,
E.; J ust, G. Tetrahedron 1997, 53, 16945. (d) Yi, J .; J ust, G. J . Org.
Chem. 1998, 63, 3647.
(5) (a) Wang, J .-C.; J ust, G. Tetrahedron Lett. 1997, 38, 705. (b)
Wang, J .-C.; J ust, G. Tetrahedron Lett. 1997, 38, 3797.
(4) Marsault, E.; J ust, G. Tetrahedron Lett. 1996, 37, 977.
10.1021/jo990242l CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

Chiral Indolyl-oxazaphosphorines
J . Org. Chem., Vol. 64, No. 22, 1999 8091
Sch em e 2
Sch em e 4a
Sch em e 3
was chosen as a model chiral auxiliary. It was synthe-
sized from the sulfate6 of (S)-propanediol and the anion
of 1-phenylsulfonylindole,7 as outlined in Scheme 3.
Equimolar acetonitrile solutions of 5a and PCl3 were
allowed to react at 0 °C under argon, and the reaction
was followed by 31P NMR. After a few minutes, the total
disappearance of the peak corresponding to PCl3 at 221
ppm was observed, and several peaks appeared around
140-150 ppm. The mixture was warmed to 60 °C for
about 10 h until the 31P NMR showed a major peak at
144 ppm, which indicated the formation of phosphoro-
chloridite 6a . It probably exists as a rapidly equilibrating
mixture of 6a ax and 6a eq, in which 6a ax predominates
(vide infra). The mixture was cooled to 0 °C, and a
solution of 5′-O-TBDMS-thymidine (T3′OH) in CH2Cl2 was
added. Two peaks were observed, a major one at 120.67
ppm and a minor one at 121.56 ppm, corresponding to
a
(i) PCl3, Et3N, CH3CN, or THF, 0-60 °C. (ii) T3′OH. (iii) T5′OH,
DBU. (iv) Beaucage’s reagent. (v) 28% NH4OH, 50 °C, 0.5 h. (vi)
TBAF, DMF.
the formation of the two diastereoisomers 7a eq and 7a ax
.
The ratio of the two diastereoisomers of 7a was moder-
ately affected by the temperature at which T3′OH was
added. At room temperature, the ratio was 7:1, and at
-78 °C, the ratio increased to 9:1. In our previous
studies,3a,4 the two diastereoisomers at the phosphorus
of phosphoramidite B and imidazo-oxazaphosphorine C
could be equilibrated by heating their reaction solutions
containing triethylammonium chloride to form the ther-
modynamically more stable form in which the OR group
was at the axial position. In marked contrast, 7a ax and
7a eq could not be equilibrated by heating the reaction
solution. In addition, no equilibration was observed by
heating the CDCl3 solution of 7a in the presence of
triethylamine or aniline hydrochloride. The major isomer
7a eq was hydrolyzed much faster than the minor isomer
7a ax. Diastereoisomers 7a ax and 7a eq could not be sepa-
rated by flash chromatography on silica gel.
F igu r e 1. Time course of the coupling reaction of 7a with
T5′OH. The reaction was carried out in CDCl3 (1.5 mL) at 50
°C with 7a (50 mg, 89 µmol), T5′OH (43 mg, 89 µmol), DBU
(13 µL, 89 µmol), and 10 µL of trimethyl phosphate as an
internal standard.
The coupling step of 7a with 3′-O-TBDPS-thymidine
(T5′OH) was carried out in the presence of DBU. The
major diastereoisomer 7a eq reacted much faster with T5′-
OH than the minor axially substituted isomer 7a ax. The
31P NMR spectra of the reaction in CDCl3 was monitored
at various time intervals (Figure 1). By using 1 equiv of
DBU and 1 equiv of T5′OH, 95% of 7a eq was converted to
phosphite triester 8a after 5 h at 50 °C, whereas 7a ax
almost did not react. After filtration through a short silica
gel column to remove DBU, triester 8a was treated with
Beaucage’s reagent8 to give a 73:1 mixture of phospho-
rothioate triesters 9a ,31P NMR, 66.76 (major) and 66.59
(minor) ppm. The chiral auxiliary 9a could not be
removed with 28% ammonium hydroxide.
Our next step was to develop a chiral auxiliary that
could be removed at the end. We considered three
different approaches: (a) classical â-elimination of a
(6) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(7) Saulnier, M.; Gribble, G. W. J . Org. Chem. 1982, 47, 757.
(8) Iyer, R. P.; Egan, W.; Regan, J . B.; Beaucage, S. L. J . Am. Chem.
Soc. 1990, 112, 1253.

8092 J . Org. Chem., Vol. 64, No. 22, 1999
Wang and J ust
Sch em e 5a
Sch em e 6a
a
(i) and (ii) see steps iv and i in Scheme 5. (iii) (S)-15,
isopropylamine, 110 °C, overnight, 81%. (iv) Acetic anhydride,
CH2Cl2, 5 h, 92%.
recrystalization in CHCl3, 5b was obtained in 96% ee
from the recrystallization mother liquor.
The acetamide derivative 5c and silyl-protected indole
derivative 5d were synthesized from diol (S)-14,13 as
shown in Scheme 6.
a
(i) TBDMSCl, DMAP, Et3N, CH2Cl2, 75%. (ii) 1-Phenylsulfo-
nyl-indole, n-BuLi, -78 f 25 °C, overnight, 48%. (iii) KOH,
CH3OH/H2O (3:1), reflux, 87%. (iv) TsCl (1.1 equiv), pyridine, 0
°C, overnight, 90%. (v) NaCN, LiCN, DMF, 100 °C, 3 h, 74%.
Several solvents were tested for the formation of cyclic
compound 6b. In THF at -78 °C, the reaction of cyano
derivative 5b with PCl3 was complete in several minutes
to give phosphorochloridite 6b with a major peak at 144
ppm, whereas in acetonitrile or dichloromethane the
reaction needed several hours. Thymidine derivative T3′-
OH was then added at -78 °C. After 30 min, the reaction
mixture was purified by silica gel chromatography to
provide indolyl-oxazaphosphorines 7b. The ratio of the
two diastereomers 7 was affected by workup, especially
by flash silica gel chromatography, because 7eq is much
less stable to moisture or air. By using preparative TLC,
which was developed under argon, two diastereomers,
7beq and 7bax were obtained in a ratio of 30:1 as
established by 31P NMR [120.78 (major) and 120.65
(minor) ppm].14
cyanoethyl group (see 5b, X ) CN);9 (b) neighboring
group participation, as applied to nucleosides by Iyer et
al. (see 5c, X ) N(iPr)Ac);10 and (c) fluoride-catalyzed
desilylation resulting in the formation of an epoxide (see
5d , X ) TBDMSO).11 The reaction of silyl-protected
glycidol 12 with the anion of 1-phenylsulfonylindole gave
indole derivative 13. Both protecting groups on 13 were
removed with potassium hydroxide to provide diol 14.
The primary hydroxyl group of 14 was selectively tosy-
lated and reacted with cyanide in DMF to give nitrile
5b. During the last step, partial epimerization on the
chiral center occurred,12 as the ee in 5b was only 91% as
determined with a chiral column (Chiralcel OD). After
As for 7a eq, equatorial indolyl-oxazaphosphorine 7beq
reacted much faster than the axial (7bax). To get 8b with
high de, excess starting material 7b was used; 1.3 equiv
of 7b (in a ratio of 30:1) was treated with 1 equiv of T5′-
OH to afford phosphite triester 8b. With 2 or 5 equiv of
DBU at room temperature, the coupling was complete
in less than 10 or 5 min, respectively. Interestingly, the
corresponding reaction of 7a carrying no cyano group
with T5′OH required several hours. The explanation may
be the electric induction on the phosphorus atom by the
strong electron-withdrawing cyano group, which made
the phosphorus in 7b more positive. This may make it
easily attacked by an alcohol. Phosphite triester 8b was
stable to DBU under the conditions used. Here the
general procedure for the coupling reaction was carried
out by first mixing the two solid reagents 7b and T5′OH
and then introducing solvent and DBU under argon. No
side products were detected. After filtration through a
short silica gel column to remove DBU, sulfurization with
Beaucage’s reagent afforded phosphorothioate triester as
a single diastereomer 9b with a peak at 66.55 ppm in its
31P NMR spectrum.
(9) (a) Sinha, N. D.; Biernat, J .; Koster, H. Tetrahedron Lett. 1983,
24, 5843. (b) Sinha, N. D.; Biernat, J .; McManus, J .; Koster, H. Nucleic
Acids Res. 1984, 12, 4539.
(10) (a) Iyer, R. P.; Yu, D.; Devlin, T.; Ho, N.-H.; Agrawal, S. J . Org.
Chem. 1995, 60, 5388. (b) Iyer, R. P.; Yu, D.; Ho, N.-H.; Tan, W.;
Agrawal, S. Tetrahedron: Asymmetry 1995, 6, 1051.
(11) (a) Molander, G. A.; Swallow, S. J . Org. Chem. 1994, 59, 7148.
(b) Miyazawa, M.; Ishibashi, N.; Ohnuma, S.; Miyashita, M. Tetrahe-
dron Lett. 1997, 38, 3419.
(12) We thank Dr. S. L. Beaucage for proposing an epimerization
mechanism.
The chiral auxiliary 9b was easily removed with 28%
ammonium hydroxide at 50 °C for 30 min to form Sp-10
(31P NMR 58.98 ppm). Deprotection of silyl groups with
(13) The synthesis of diol (R)- and (S)-14 was scaled up by Dalton
Chemical Laboratories, Inc., Ontario, Canada. The chiral auxiliaries
5c and 5d were synthesized in (S) configuration because of the avaiable
of starting material (S)-14.
(14) Although nitrile 5b (96% ee) was used, only two diastereomers
of indolyl-oxazaphosphorine 7b were observed. Probably because of the
limitation of detection, the minor compounds could not be detected.

Chiral Indolyl-oxazaphosphorines
J . Org. Chem., Vol. 64, No. 22, 1999 8093
Sch em e 7
synthesis of phosphorothioates. The indole group in 7
could be diastereoselectively replaced by a nucleoside,
and the replacement proceeds by inversion of configura-
tion. The chiral auxiliaries 9b and 9Sb containing a
cyano group could be easily removed by aqueous am-
monia, and the acetamido chiral auxiliary 9Sc was
eliminated spontaneously. Even though the application
on solid-support synthesis was not successful, we dem-
onstrated that indole is a good leaving group and can be
advantageously modified to potential chiral precursors
for stereocontrolled synthesis of phosphite triesters and
phosphorothioates.
TBAF afforded dithymidinyl phosphorothioate Sp-11. The
two diastereomers of Sp- and Rp-11 can be easily identi-
fied by the 31P NMR in D2O. There is more than 0.3 ppm
difference in their chemical shifts, and the Rp-isomer is
at lower field. Only one diastereomer Sp-11 (31P NMR in
D2O 55.45 ppm) was identified from this experiment. In
a parallel run, (S)-5b was transformed to 7Sb (a mixture
of two diastereomers in a ratio of 6:1) after purification
by flash column chromatography.15 Phosphorothioate Rp-
11 was obtained in a ratio of 24:1 by the reaction of
equimolar 7Sb and T5′OH followed by sulfurization and
desilylation. The absolute stereochemistry of dimers Rp-
and Sp-11 were confirmed by snake venom phosphodi-
esterase and P1 nuclease digestion and HPLC analysis.16
The stereoconfiguration of 11 proved that the replace-
ment of the indole group in indolyl-oxazaphosphorine 7
with an alcohol proceeded with inversion.
As described for the formation of 7a , acetoamide
derivative 5c was transformed to indolyl-oxazaphospho-
rine 7Sc with two diastereomers in a ratio of 6.8:1, a
major one at 120.68 ppm and a minor one at 120.76 ppm.
Phosphorothioate triester 9Sc (31P NMR in THF, 68.89
ppm) was obtained via the intermediate phosphite tri-
ester 8Sc (31P NMR in THF, 143.26 ppm). In contrast to
the cyano derivative 9b, the acetoamide derivative 9Sc
in tetrahydrofuran solution hydrolyzed spontaneously
upon sulfurization within several hours to provide 10 (31P
NMR in THF, 58.65 ppm). By adding a base such as
triethylamine, the reaction was complete in several
minutes.
Exp er im en ta l Section
Melting points (mp) are uncorrected. NMR spectra were
1
recorded at 500 or 270 MHz for H NMR, 125 or 67.9 MHz for
13C NMR, and 202 MHz for 31P NMR. THF was dried by
distillation on sodium-benzophenone ketyl, dichloromethane
from phosphorus pentoxide, acetonitrile and triethylamine on
calcium hydride, and pyridine on barium oxide. DBU was
distilled under vacuum and then stored over 4 Å Linde
molecular sieves under argon. PCl3 was first degassed by
refluxing for 2 h under argon followed by fractional distillation
and was used within a week. Beaucage’s reagent and 3′-O-
TBDPS-thymidine were generously given by ISIS Pharma-
ceuticals (Carlsbad, CA).
(S)-1,2-P r op a n ed iol Cyclic Su lfa te (3). To a 100-mL, two-
necked, round-bottomed flask equipped with a reflux condenser
and topped with a CaCl2 drying tube, connected to an HCl trap,
and a rubber septum were added (S)-1,2-propanediol (2.3 g,
40 mmol) and CCl4 (20 mL). Thionyl chloride (4 mL, 54.8
mmol) was added via a syringe, and the resulting solution was
refluxed for 30 min. The solution was then cooled with an ice
bath and diluted with CH3CN (20 mL). Next, RuCl3‚3H2O (7.8
mg, 0.03 mmol) and NaIO4 (12 g, 56 mmol) were added
followed by water (40 mL). The resulting mixture was stirred
at room temperature for 1 h. The mixture was then diluted
with ethyl acetate, and the two phases were separated. The
organic layer was washed with water, saturated aqueous
sodium bicarbonate, and brine. After drying over anhydrous
sodium sulfate, the solution was filtered through a small pad
of silica gel to remove the brown impurities. The filtrate was
concentrated to afford 4.0 g (98%) of (S)-1,2-propanediol cyclic
sulfate 3 as a colorless liquid.1H NMR (270 MHz, CDCl3): δ
5.10 (ddq, J ) 8.2, 6.0, 6.2 Hz, 1H), 4.72 (dd, J ) 8.7, 6.0 Hz,
1H), 4.28 (dd, J ) 8.7, 8.2 Hz, 1H), 1.55 (d, J ) 6.2 Hz, 3H).
13C NMR (67.9 MHz, CDCl3): δ 80.0, 74.3, 17.7.
We also briefly investigated the chiral auxiliary 9Sd
(X ) TBDMSO). Using TBAF, after a week at 50 °C,
phosphorothioate 11 was released only partially as
established by 31P NMR. So far we have not found an
efficient way to eliminate the silyloxyl chiral auxiliary.
The cyano indolyl-oxazaphosphorine was tried on the
solid-phase synthesis. Unfortunately, its application to
solid phase was not very successful, because a large
amount of DBU has to be used to activate the nucleoside
on solid support.17 Work on the use of the acetamido
group in solid-phase synthesis is at present being inves-
tigated and will be reported in due course.
(S)-(1-P h en ylsu lfon ylin d ol-2-yl)p r op a n -2-ol (4). To a
solution of 1-phenylsulfonylindole (2.57 g, 10 mmol) in dry THF
(30 mL) was added dropwise 8 mL of n-butyllithium (1.6 M in
hexane, 12.8 mmol) over 10 min under argon at -78 °C. The
mixture was stirred for 1.5 h below -70 °C and then allowed
to warm slowly to 5 °C over 1 h. The solution was cooled to
-78 °C again and then treated via a syringe with a solution
of 3 (1.5 g, 10.8 mmol) in dry THF (10 mL). The mixture was
allowed to warm slowly to room temperature overnight, poured
into 20% sulfuric acid (100 mL), and stirred for 3 h. The
solution was extracted with ethyl acetate. The combined
extracts were washed with H2O, saturated sodium bicarbonate
solution, and brine; dried over anhydrous sodium sulfate; and
evaporated to give a light amber oil. This oil was crystallized
in ether/hexane (1:1) to provide 2.85 g (90%) of (S)-(1-
phenylsulfonylindol-2-yl)propan-2-ol 4 as white crystals, mp
88-89 °C. [R]D295 -56.11° (c 0.875, ethyl acetate). 1H NMR (270
MHz, CDCl3): δ 7.17-8.16 (m, 9H), 6.51 (d, J ) 0.76 Hz, 1H),
4.26 (m, 1H), 3.25, 3.01 (m, 2H), 1. 91 (s, br, 1H), 1.30 (d, J )
6.2 Hz, 3H). 13C NMR (67.9 MHz, CDCl3): δ 138.8, 138.5,
137.4, 133.8, 129.7, 129.3, 126.3, 124.4, 123.9, 120.5, 115.1,
111.6, 67.2, 39.1, 23.1. MS (CI, NH3): m/e 316 (MH+, 29.4),
298 (11.6), 271 (40.4). HRMS (FAB, glycerol): m/e calcd for
Con clu sion
We investigated a number of chiral indolyl-oxazaphos-
phorines 7 as potential precursors for the stereocontrolled
(15) A mixture of dry dichloromethane and acetonitrile (1:10) was
used as eluting solvent. Using ethyl acetate instead of acetonitrile gave
very low yield of 7b. The trace of acids in ethyl acetate probably
accelerated the decomposition of 7b.
(16) The snake venom phosphodiesterase and P1 nuclease digestion
and HPLC analysis were carried out at ISIS Pharmaceuticals (Carls-
bad, CA) by Dr. M. Manoharan.
C
17H18NO3S [MH+] 316.10074, found 316.10084.
(S)-In d ol-2-ylp r op a n -2-ol (5a ). A solution of 4 (2.85 g, 9.0
mmol) in 50 mL of methanol/water (3:1) containing KOH (2.5
(17) Wang, J .-C.; J ust, G.; Guzaev, A. P.; Manoharan, M. J . Org.
Chem. 1999, 64, 2595.

8094 J . Org. Chem., Vol. 64, No. 22, 1999
Wang and J ust
g, 44.6 mmol) was refluxed for 5 h and extracted with ethyl
acetate. The combined extracts were washed with H2O and
brine, dried over anhydrous sodium sulfate, and evaporated
to room temperature and stirred for 5 h. Triethylammonium
chloride was filtered off and washed with dichloromethane.
The filtrate was washed with brine, dried over anhydrous
sodium sulfate, and concentrated. The residue was passed
through a short silica gel column to remove polar impurities
and eluted with hexane/ethyl acetate (3:2). After removal of
the solvent, a light yellow oil was collected and distilled under
to afford 1.65 g (95%) of 5a as a light amber oil. [R]D 9.12°
295
(c 1.035, ethyl acetate). 1H NMR (270 MHz, CDCl3): δ 8.51 (s,
1H), 7.58-7.05 (m, 4H), 6.28 (s, 1H), 4.10 (m, 1H), 2.93, 2.76
(m, 2H), 2.06 (s, br, 1H), 1.25 (d, J ) 6.2 Hz, 3H). 13C NMR
(67.9 MHz, CDCl3): δ 136.6, 136.2, 128.9, 121.3, 119.9, 119.7,
110.7, 100.9, 68.0, 37.5, 23.3. MS (CI, NH3): m/e 176 (MH+,
47.0), 175 (M+, 62.6), 130 (100.0). HRMS (FAB, glycerol): m/e
calcd for C11H14NO [MH+] 176.107539, found 176.10746.
In d olyl-oxa za p h osp h or in e (7a ). A dried 25-mL round-
bottomed flask containing 10 mL of dry CH3CN was flushed
with argon and sealed with a septum, and then 100 µL of PCl3
(1.15 mmol) was added via a microsyringe. The flask was
cooled to 0 °C, and a solution of 5a (200 mg, 1.15 mmol) in
CH3CN (0.35 mL) containing triethylamine (525 µL, 3.8 mmol)
was introduced. The reaction mixture was stirred for 30 min
at 0 °C and then warmed to 60 °C for 10 h. The flask was
cooled to -78 °C, and a solution of 5′-O-TBDMS-thymidine
(410 mg, 1.15 mmol) in CH2Cl2 (0.4 mL) was added. The
reaction mixture was stirred for 30 min. Triethylammonium
chloride was filtered off and washed with CH2Cl2. The filtrate
was concentrated and purified with flash chromatography
(CH2Cl2/CH3CN 1:10) to give 346 mg (54%) of white solid
indolyl-oxazaphosphorine 7a , mp 80-82 °C. Two diastereo-
isomers of indol-oxazaphosphorine 7a were obtained in a ratio
of 9:1 as established by 31P NMR. 31P NMR (202.3 MHz,
CDCl3): δ 121.56 (12.4%), 120.67 (87.6%). 1H NMR (500 MHz,
CDCl3): δ 8.81 (s, br, 1H), 7.39 (s, 1H), 7.54, 7.17 (m, 4H),
6.36 (dd, J ) 9.0, 5.5 Hz, 1H), 6.33 (s, 1H), 4.72 (m, 1H), 4.41
(m, 1H), 3.94 (m, 1H), 3.58 (m, 1H), 3.06-3.10 (m, 3H), 2.36
(m, 1H), 1.97 (m, 1H), 1.87 (s, 3H), 1.48 (d, J ) 5.5 Hz, 3H),
0.84 (s, 9H), -0.05 (ss, 6H). 13C NMR (67.9 MHz, CDCl3): δ
163.7, 150.2, 137.8, 137.5, 136.4, 136.3, 135.2, 129.8 (d, J )
2.1 Hz), 122.2, 121.5, 120.4, 111.0, 110.6, 110.4, 103.2, 86.1
(d, J ) 3.1 Hz), 84.7, 73.6 (d, J ) 3.6 Hz), 71.6, 71.5, 62.9,
40.3 (d, J ) 2.1 Hz), 26.0, 25.9, 22.9 (d, J ) 3.6 Hz), 18.3, 12.5,
-5.4, -5.7. HRMS (FAB, glycerol): m/e calcd for C27H39N3O6-
SiP [MH+] 560.234578, found 560.234590.
vacuum (55-60 °C/3 mmHg) to provide 19 g (75%) of colorless
1
liquid 12. [R]D -6.09° (c 6.47, ethyl acetate). H NMR (500
295
MHz, CDCl3): δ 3.84, 3.65 (m, 2H), 3.08 (m, 1H), 2.76, 2.63
(m, 2H), 0.88 (s, 9H), 0.07 (ss, 6H). 13C NMR (125.7 MHz,
CDCl3): δ 63.5, 52.2, 44.27, 25.6, 18.1, -5.51, -5.55. MS (CI,
NH3): m/e 206 (MNH4+, 12.1), 189 (MH+, 12.0), 131 (100.0).
(S)-Glycid yl ter t-bu tyld im eth ylsilyl eth er [(S)-12] was
obtained from (R)-glycidol in 81% yield as described for 12.
[R]D
+6.11° (c 2.75, ethyl acetate). 1H NMR (270 MHz,
295
CDCl3): δ 3.81, 3.61 (m, 2H), 3.04 (m, 1H), 2.72, 2.59 (m, 2H),
0.86 (s, 9H), 0.036 (ss, 6H). 13C NMR (67.9 MHz, CDCl3): δ
63.78, 52.44, 44.45, 25.90, 18.38, -5.28, -5.32. MS (CI, NH3):
206 (MNH4+, 3.4), 189 (MH+, 18.2), 131 (78.5), 74 (100.0).
(R)-1-ter t-Bu tyldim eth ylsilyloxy-3-(1-ph en ylsu lfon ylin -
d ol-2-yl)p r op a n -2-ol (13). To a solution of 1-phenylsulfo-
nylindole (6.2 g, 24 mmol) in dry THF (60 mL) was added
dropwise 18 mL of n-butyllithium (1.6 M in hexane, 28.8 mmol)
over 10 min under argon at -78 °C. The mixture was stirred
for 1.5 h below -70 °C and then allowed to warm slowly to 5
°C over 1 h. The solution was cooled to -78 °C again, and a
solution of 12 (4.5 g, 24 mmol) in dry THF (10 mL) was added.
The mixture was allowed to warm slowly to room temperature
overnight and poured into saturated NH4Cl solution (80 mL).
The mixture was extracted with ethyl acetate. The combined
extracts were washed with H2O, saturated sodium bicarbonate
solution, and brine; dried over anhydrous sodium sulfate; and
evaporated to afford a deep red oil. This oil was purified by
flash chromatography (ethyl acetate/hexane 1:1) to provide 5.2
g (48%) of pale light yellow solid 13, mp 77-78.5 °C. [R]D
295
1
-26.90° (c 0.875, ethyl acetate). H NMR (500 MHz, CDCl3):
δ 7.20-8.16 (m, 9H), 6.57 (s, 1H), 4.15 (m, 1H), 3.74, 3.59 (m,
2H), 3.24, 3.10 (m, 2H), 2.42 (s, broad, 1H), 0.93 (s, 9H), 0.105
(ss, 6H). 13C NMR (125.7 MHz, CDCl3): δ 138.7, 138.1, 137.1,
133.4, 129.6, 129.0, 126.0, 124.0, 123.5, 120.2, 114.7, 111.0,
70.6, 66.3, 32.8, 25.71, 18.12, -5.50, -5.54. MS (FAB, NBA):
m/e 446 (MH+, 53.5). HRMS (FAB, glycerol): m/e calcd for
P h osp h or oth ioa te Tr iester (9a ). To a dried 5-mL round-
bottomed flask was added indolyl-oxazaphosphorine 7a (50 mg,
85 µmol) and 3′-O-TBDPS-thymidine (T5′OH) (40.8 mg, 85
µmol). The flask was flushed with argon and sealed with a
septum, and then 2 mL of dry CHCl3 was added followed by
DBU (14 µL, 94 µmol). The reaction mixture was stirred at
room temperature overnight, passed though a short silica gel
column to filter off DBU, and eluted with dried CH2Cl2/CH3-
CN (1:1). The filtrate was evaporated to afford a colorless oil.
The oil was redissolved in dry CH2Cl2 (5 mL), and Beaucage’s
reagent (30 mg, 1.5 mmol) was added. Evaporation of the
solvent followed by flash chromatography (dichloromethane/
acetone 5:1) afforded 71 mg (78%) of white solid phospho-
rothioate triester 9a , mp 115-116 °C. 31P NMR (202.3 MHz,
C
23H32NO4SiS [MH+] 446.18213, found 446.18232.
(S)-1-ter t-Bu tyldim eth ylsilyloxy-3-(1-ph en ylsu lfon ylin -
d ol-2-yl)p r op a n -2-ol [(S)-13] was obtained from (S)-12 in
40% yield as described for 13, mp 78-79.5 °C. [R]D +26.88°
295
(c 1.09, ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.19-
8.16 (m, 9H), 6.57 (s, 1H), 4.14 (m, 1H), 3.74, 3.58 (m, 2H),
3.23, 3.09 (m, 2H), 2.57 (d, 1H, 3J ) 4.5 Hz), 0.93 (s, 9H), 0.10
(ss, 6H). 13C NMR (125.7 MHz, CDCl3): δ 138.76, 138.13,
137.11, 133.49, 129.64, 129.04, 126.01, 124.01, 123.55, 120.20,
114.75, 111.06, 70.69, 66.32, 32.84, 25.72, 18.12, -5.50, -5.54.
MS (CI, NH3): 446 (MH+, 72.4), 388 (40.0), 247 (80.0), 130
(100.0).
1
CDCl3): δ 66.76 (98.65%), 66.59(1.35%). H NMR (500 MHz,
CDCl3): δ 9.93 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 7.62-6.93
(m, 16H), 6.46 (dd, J ) 8.0, 6.0 Hz, 1H), 6.26 (s, 1H), 6.05 (dd,
J ) 9.2, 5.5 Hz, 1H), 4.92 (m, 1H), 4.76 (m, 1H), 4.31 (m, 1H),
4.03 (m, 1H), 3.82 (m, 1H), 3.80, 3.50 (m, 2H), 3.67, 3.58 (m,
2H), 3.00 (m, 2H), 2.31 (m, 1H), 1.94 (s, 3H), 1.90 (s, 3H), 1.85
(m, 1H), 1.60 (m, 1H), 1.26 (d, J ) 6.0 Hz, 3H), 1.14 (m, 1H),
1.80 (s, 9H), 0.89 (s, 9H), 0.07 (ss, 6H). 13C NMR (125.7 MHz,
CDCl3): δ 163.83, 163.80, 150.7, 150.3, 135.5 (d, J ) 3.6 Hz),
134.5, 134.1, 132.7, 132.5, 130.1, 130.0, 128.4, 127.9, 127.8,
120.9, 119.5, 119.3, 111.2, 110.4, 100.6, 85.2 (d, J ) 8.1 Hz),
85.1 (d, J ) 9.1 Hz), 84.8, 84.2, 79.7 (d, J ) 2.6 Hz), 76.8, 73.3,
66.8 (d, J ) 6.4 Hz), 63.0, 40.1, 37.5, 36.0 (d, J ) 9.1 Hz), 26.6,
25.7, 21.2, 18.8, 18.1, 12.4, 12.3, -5.61, -5.56. MS (FAB,
NBA): m/e 1072 (MH+, 1.3).
(R)-3-In d ol-2-yl-p r op a n e-1,2-d iol [(R)-14]. A solution of
13 (4.5 g, 10.1 mmol) in 50 mL of methanol/water (3:1)
containing KOH (2.8 g, 50 mmol) was refluxed for 5 h and
extracted with ethyl acetate. The combined extracts were
washed with H2O and brine, dried over anhydrous sodium
sulfate, and evaporated to afford 1.68 g (87%) of pale solid (R)-
1
14, mp 57.5-58.5 °C. [R]D +10.8° (c 1.0, ethyl acetate). H
295
NMR (500 MHz, CDCl3): δ 8.54 (s, 1H), 7.54-7.12 (m, 4H),
6.21 (s, 1H), 3.82 (m, 1H), 3.52, 3.34 (m, 2H), 3.28 (s, broad,
2H), 2.72 (m, 2H). 13C NMR (125.7 MHz, CDCl3): δ 135.9,
135.4, 128.2, 121.2, 119.7, 119.5, 110.5, 100.64, 71.5, 65.7, 31.6.
MS (EI): m/e 191 (M+•, 40.8), 130 (100.0). HRMS (EI): m/e
calcd for C11H13NO2 [M+] 191.09462, found 191.09468.
(R)-Glycid yl ter t-Bu tyld im eth ylsilyl Eth er (12). To a
solution of (S)-glycidol (10 g, 135 mmol, 98% ee from Aldrich
Chemical Co.) in dichloromethane (60 mL) containing triethyl-
amine (20 mL, 144 mmol) were added a solution of TBDMSCl
(22.4 g, 148 mmol) in dichloromethane (50 mL) and DMAP
(0.6 g, 5.4 mmol) at 0 °C. The mixture was allowed to warm
(S)-3-In d ol-2-yl-p r op a n e-1,2-d iol [(S)-14] was obtained
from (S)-13 in 98% yield as described for (R)-14, mp 58.5-60
1
°C. [R]D -8.53° (c 0.92, ethyl acetate). H NMR (270 MHz,
295
CDCl3): δ 8.58 (s, 1H), 7.53-7.00 (m, 4H), 6.21 (s, 1H), 3.88
(m, 1H), 3.56, 3.40 (m, 2H), 3.2 (s, broad, 1H), 2.79 (m, 2H),
2.00 (s, broad, 1H). 13C NMR (67.9 MHz, CDCl3): δ 136.24,

Chiral Indolyl-oxazaphosphorines
J . Org. Chem., Vol. 64, No. 22, 1999 8095
135.71, 128.46, 121.45, 119.96, 119.78, 110.75, 100.93, 71.80,
66.06, 31.8. MS (CI, NH3): 192 (MH+, 100.0), 130 (68.6).
(R)-3-In d ol-2-yl-2-h yd r oxyp r op yl p-Tolu en esu lfon a te
[(R)-15]. To a solution of (R)-14 (15 g, 78.5 mmol) in dry
pyridine (120 mL) was added p-toluenesulfonyl chloride (15.5
g, 81.3 mmol) at 0 °C. After stirring for 5 h at 0 °C, the solution
was poured into 100 mL of cold HCl (6 N) and extracted with
ether. The combined extracts were washed with HCl (6 N) and
brine, and dried over anhydrous sodium sulfate. The solvent
was evaporated, and the residue was purified by flash chro-
matography (hexane/ethyl acetate 1:5) to give 24.5 g (90%) of
100.6, 69.3, 51.8, 49.0, 33.3, 23.1, 22.8. MS (CI, NH3): 233
(MH+, 100.0), 130 (31.9). HRMS (FAB, glycerol): m/e calcd for
C14H21N2O [MH+] 233.16538, found 233.16539.
(S)-N-(3-In d ol-2-yl-2-h yd r oxy)-p r op yl-N-isop r op yla cet-
a m id e (5c). To a solution of 16 (0.2 g, 0.86 mmol) in dry CH3-
CN (20 mL) was added acetic anhydride (0.1 mL, 1.06 mmol).
The mixture was stirred for 4 h at room temperature, washed
with saturated sodium bicarbonate solution and brine, and
dried over anhydrous sodium sulfate. The solvent was evapo-
rated, and the residue was purified by flash chromatography
(ethyl acetate) to give 0.22 g (92%) of light yellow solid 5c, mp
white solid (R)-15, mp 112-113 °C. [R]D
-1.03° (c 1.035,
122-123 °C. [R]D -13.56° (c 0.78, ethyl acetate). 1H NMR
295
295
1
ethyl acetate). H NMR (270 MHz, CDCl3): δ 8.52 (s, br, 1H),
7.77-7.03 (m, 8H), 6.19 (s, 1H), 4.15 (m, 1H), 3.97 (m, 2H),
2.92 (m, 2H), 2.71 (d, J ) 4.5 Hz, 1H), 2.42 (s, 3H). 13C NMR
(67.9 MHz, CDCl3): δ 145.4, 136.3, 134.2, 132.4, 130.1, 128.3,
128.0, 121.5, 119.9, 119.7, 110.8, 101.4, 72.7, 69.2, 31.5, 21.7.
MS (FAB, NBA): m/e 346 (MH+, 80.5). HRMS (FAB, glyc-
erol): m/e calcd for C18H20NO4S [MH+] 346.11130, found
346.11123.
(270 MHz, CDCl3): δ 9.17 (s, br, 1H), 7.0-7.5 (m, 4H), 6.25
(s, 1H), 3.98 (m, 2H), 3.50, 3.10 (m, 2H), 2.94 (m, 2H), 2.15 (s,
3H),1.14, 1.12 (d, J ) 6.42 Hz, 6H). 13C NMR (67.9 MHz,
CDCl3): δ 173.5, 136.3, 136.1, 128.2, 121.1, 119.7, 119.4, 110.8,
100.8, 73.4, 50.1, 47.9, 34.1, 21.9, 21.3, 20.7. MS (CI, NH3):
m/e 275 (MH+, 100.0), 257 (75.0), 256 (74.1). HRMS (FAB,
glycerol): m/e calcd for C16H23N2O2 [MH+] 275.17595, found
275.17602.
(S)-3-In d ol-2-yl-2-h yd r oxyp r op yl p-t olu en esu lfon a t e
[(S)-15] was obtained from (S)-14 in 89% yield as described
for (R)-15, mp 96-97 °C. [R]D295 +0.93° (c 1.00, ethyl acetate).
1H NMR (270 MHz, CDCl3): δ 8.51 (s, br, 1H), 7.78-7.06 (m,
8H), 6.21 (s, 1H), 4.16 (m, 1H), 4.00 (m, 2H), 2.97 (m, 2H),
2.44 (s, 3H). 13C NMR (67.9 MHz, CDCl3): δ 145.1, 136.0,
133.9, 132.1, 129.8, 128.0, 127.7, 121.3, 119.7, 119.5, 110.5,
101.2, 72.4, 68.9, 31.2, 21.4. MS (CI, NH3): m/e 346 (MH+, 6.0),
174 (100).
(R)-3-Hyd r oxy-4-(2-in d olyl)bu tyr on itr ile (5b). To a so-
lution of LiCN (0.5 M in DMF, 30 mL) were added (R)-15 (5.6
g, 16.2 mmol) and sodium cyanide (1.5 g, 30.6 mmol). The
reaction mixture was stirred for 1 h at 100 °C, cooled to room
temperature, poured into 80 mL of ice water, and extracted
with ethyl acetate. The combined extracts were washed with
saturated sodium bicarbonate and brine, dried over anhydrous
sodium sulfate, and evaporated to yield a deep red oil. This
oil was purified by flash chromatography (hexane/ethyl acetate
2:3) to give 2.4 g (74%) of light yellow solid 5b.
(S)-1-ter t-Bu t yld im et h ylsilyloxy-3-(in d ol-2-yl)-2-p r o-
p a n ol (5d ). To a solution of (S)-14 (1.3 g, 6.8 mmol) in dry
dichloromethane (30 mL) containing triethylamine (1.1 mL,
7.9 mmol) were added a solution of TBDMSCl (1.16 g, 7.7
mmol) in dichloromethane (5 mL) and DMAP (34.2 mg, 0.28
mmol) at 0 °C. The mixture was allowed to warm to room
temperature and stirred for 5 h. Triethylammonium chloride
was filtered off and washed with dichloromethane. The filtrate
was washed with brine, dried over anhydrous sodium sulfate,
and evaporated to give a light red oil. Purification by flash
chromatography (ethyl acetate) afforded 1.57 g (74%) of an
amber oil 5d . [R]D295 +25.42° (c 1.150, ethyl acetate). 1H NMR
(270 MHz, CDCl3): δ 8.74 (br. s, 1H), 7.55-7.06 (m, 4H), 6.24
(s, 1H), 3.99 (m, 1H), 3.65, 3.49 (m, 2H), 2.92(m, 2H), 2.74 (d,
J ) 3.4 Hz, 1H), 0.91 (s, 9H), 0.085 (s, 6H). 13C NMR (67.9
MHz, CDCl3): δ 136.3, 136.2, 128.4, 121.2, 119.8, 119.5, 110.6,
100.7, 71.7, 66.5, 31.5, 25.9, 18.3, -5.24, -5.27. MS (FAB,
NBA): m/e 306 (MH+, 22.0). HRMS (FAB, glycerol): m/e calcd
for C17H28NO2Si [MH+] 306.18893, found 306.18895.
The chiralty of 5b was analyzed by HPLC (Varian Vista
5500) with Chiralcel OD column (4.6 mm × 250 mm) with 1.5
mL/min flow rate of hexane/ethanol (9:1) and was 91% ee.
Compound 5b (2.0 g) was dissolved in chloroform (2 mL), and
the solvent was slowly evaporated at room temperature in
atmosphere. After a week, crystals were formed and filtered
off, mp 92-93 °C. The filtrate was collected and dried under
In d olyl-oxa za p h osp h or in e (7b). A dried 5-mL round-
bottomed flask containing 1 mL of dry THF was flushed with
argon and sealed with a septum, and then PCl3 (44 µL, 0.5
mmol) was introduced via a microsyringe. The flask was cooled
to -78 °C, and a solution of 5b (100 mg, 0.5 mmol) in THF (1
mL) containing triethylamine (0.3 mL, 2.2 mmol) was added
via a syringe. The reaction mixture was stirred for 30 min at
-78 °C, and then warmed to 0 °C for 1 h. The flask was cooled
to -78 °C again, and a solution of 5-O′-TBDMS-thymidine (178
mg, 0.5 mmol) in THF (0.5 mL) was added via a syringe. The
reaction mixture was stirred at -78 °C for 30 min, and then
the solution was warmed to room temperature. Triethylam-
monium chloride was filtered off and washed with CH2Cl2. The
filtrate was concentrated and purified with TLC chromatog-
raphy (CH2Cl2/CH3CN 1:5) to afford 94 mg (32%) of white solid
indolyl-oxazaphosphorine 7b, mp 85-86 °C. Two diastereo-
isomers of 7b were obtained in a ratio of 30:1 as established
by 31P NMR. 31P NMR (202.3 MHz, CDCl3): δ 120.78 (96.8%),
vacuum to give 0.5 g of a light amber oil 5b in 96% ee. [R]D
295
-8.67° (c 0.565, ethyl acetate). 1H NMR (500 MHz, CDCl3): δ
8.37 (s, br, 1H), 7.5-7.0 (m, 4H), 6.32 (s, 1H), 4.22 (m, 1H),
3.05, 2.96 (m, 2H), 2.67 (s, br. 1H), 2.49 (m, 2H). 13C NMR
(125.7 MHz, CDCl3): δ 136.1, 133.3, 128.0, 121.7, 119.9, 119.8,
110.6, 101.8, 117.2, 67.2, 34.7, 25.0. MS (EI): m/e 200 (M+•
,
48.5), 130 (100). HRMS (FAB, glycerol): m/e calcd for C12H13N2O
[MH+] 201.10278, found 201.10285.
(S)-3-Hyd r oxy-4-(2-in d olyl)bu tyr on itr ile [(S)-5b]. By
the same procedure as described for 5b, (S)-5b was obtained
from (S)-15 in 64% yield. After crystallization in chloroform
for 2 weeks, a red oil (S)-15 in 96% ee was obtained from the
mother liquor (optical rotation could not be detected because
1
120.65 (3.2%). H NMR (500 MHz, CDCl3): δ 8.35 (s, br, 1H),
7.39 (s, 1H), 7.57-7.17 (m, 4H), 6.42 (s, 1H), 6.32 (dd, J ) 8.8,
5.0 Hz, 1H), 4.80 (m, 1H), 4.52 (m, 1H), 4.02 (m, 1H), 3.65,
3.23 (m, 2H), 3.40, 3.25 (m, 2H), 2.91, 2.82 (m, 2H), 2.38, 2.04
(m, 2H), 1.87 (s, 3H), 0.85 (s, 9H), -0.004 (ss, 6H). 13C NMR
(125.7 MHz, CDCl3): δ 163.3, 149.9, 137.6, 137.5, 134.9, 133.3,
129.4 (d, J ) 1.8 Hz), 122.5, 121.6, 120.4, 115.6, 110.8, 110.2
(d, J ) 11.0 Hz), 104.2, 85.7 (d, J ) 2.7 Hz), 84.4, 74.4 (d, J )
6.4 Hz), 69.4 (d, J ) 7.2 Hz), 62.6, 39.9 (d, J ) 1.8 Hz), 30.6
(d, J ) 4.6 Hz), 25.6, 25.4 (d, J ) 2.6 Hz), 18.0, 12.2, -5.6,
-5.9. MS (FAB, NBA): m/e 585 (MH+, 19.7). HRMS (FAB,
glycerol): m/e calcd for C28H38N4O6PSi [MH+] 585.22982, found
585.22985.
Sp -In d olyl-oxa za p h osp h or in e (7Sb). By the same pro-
cedure as described for 7b, white solid (S)-5b was obtained
from (S)-5b in 21% yield after purification by flash chroma-
tography (CH2Cl2/CH3CN 1:10), mp 93-94 °C. Two diastereo-
isomers of indolyl-oxazaphosphorine 7Sb were obtained in a
1
of the deep color). H NMR (270 MHz, CDCl3): δ 8.42 (s, br,
1H), 7.0-7.5 (m, 4H), 6.30 (d, J ) 1.48 Hz, 1H), 4.20 (m, 1H),
3.01 (m, 2H), 2.47, 2.49 (m, 2H). 13C NMR (67.9 MHz, CDCl3):
δ 136.56, 133.58, 128.55, 121.94, 120.16, 120.06, 110.74,
102.12, 117.12, 67.55, 35.10, 25.28. MS (EI): 200 (M+•, 59.6),
130 (100.0).
(S)-3-In d ol-2-yl-1-isop r op yla m in o-2-p r op a n ol (16). To
a pressure vessel were added 2.94 g of (S)-15 and 10 mL of
isopropylamine. The mixture was stirred overnight at 110 °C.
Evaporation of the solvent afforded an amber oil, which was
purified by flash chromatography (acetone/triethylamine 10:
1) to give 1.6 g (81%) of a sticky oil 16. [R]D -8.13° (c 0.75,
295
ethyl acetate). 1H NMR (270 MHz, CDCl3): δ 9.01 (s, br, 1H),
7.0-7.5 (m, 4H), 6.23 (s, 1H), 3.89 (m, 1H), 2.72-3.03 (m, 5H),
2.44, 2.59 (m, 2H), 1.05 (d, J ) 6.18 Hz, 6H). 13C NMR (67.9
MHz, CDCl3): δ 136.6, 136.2, 128.4, 121.1, 119.8, 119.4, 110.7,

8096 J . Org. Chem., Vol. 64, No. 22, 1999
Wang and J ust
ratio of 6:1 as established by 31P NMR. 31P NMR (202.3 MHz,
CDCl3): δ 120.53 (85.3%), 120.72 (14.7%). The following NMR
spectra were assigned for the major isomer. 1H NMR (500
MHz, CDCl3): δ 9.20 (s, br, 1H), 7.42 (s, 1H), 7.57-7.17 (m,
4H), 6.42 (s, 1H), 6.34 (dd, J ) 8.8, 5.0 Hz, 1H), 4.82 (m, 1H),
4.47 (m, 1H), 3.94 (m, 1H), 3.76, 3.66 (m, 2H), 3.40-3.24 (m,
2H), 2.91 (m, 2H), 2.41, 2.01 (m, 2H), 1.89 (s, 3H), 0.88 (s, 9H),
0.066 (ss, 6H). 13C NMR (67.9 MHz, CDCl3): δ 163.66, 150.41,
138.11, 137.87, 135.14, 133.60, 129.67, 122.78, 121.86, 120.75,
116.13, 111.18, 110.51 (d, J ) 10.8 Hz), 104.41, 86.41 (d, J )
4.1 Hz), 84.81, 75.49 (d, J ) 12.9 Hz), 70.71 (d, J ) 8.2 Hz),
63.15, 39.82, 30.88 (d, J ) 5.7 Hz), 25.96, 25.66, 18.36, 12.55,
-5.30, -5.41. MS (FAB, NBA): 557 (M - HCN, 44.5).
In d olyl-oxa za p h osp h or in e (7Sc). By the same procedure
as described for 7b, 42 mg (58%) of 7Sc was obtained from 5c
(30 mg, 0.11 mmol). Two diastereoisomers of 7Sc were
obtained in a ratio of 6.8:1 as established by 31P NMR. 31P
NMR (202.3 MHz, CDCl3): δ 120.76 (12.8%), 120.68 (87.2%).
1H NMR (500 MHz, CDCl3): δ 8.16 (s, br, 1H), 7.39 (s, 1H),
7.54-7.17 (m, 4H), 6.35 (m, 2H), 4.74 (m, 1H), 4.46 (m, 1H),
4.10 (m, 2H), 3.89, 3.47 (m, 3H), 3.11 (m, 1H), 2.4, 1.9 (m, 2H),
2.17 (s, 3H), 1.86 (s, 3H), 1.24 (m, 6H), 0.87 (s, 9H), 0.035 (ss,
6H).
24:1 as established by 31P NMR. 31P NMR (202.3 MHz,
CDCl3): δ 66.31 ppm (96%), 65.73 (4%). H NMR (500 MHz,
1
CDCl3): δ 9.16 (s, br, 1H), 9.13 (s, br, 1H), 8.60 (s, br, 1H),
7.63-7.05 (m, 16H), 6.33 (s, 1H), 6.27 (m, 1H), 6.17 (dd, J )
9.0, 5.0 Hz, 1H), 4.91 (m, 2H), 4.30 (m, 1H), 4.10 (m, 1H), 3.88
(m, 1H), 3.79 (m, 2H), 3.54, 3.45 (m, 2H), 3.19 (m, 2H), 2.65
(m, 2H), 2.28 (m, 2H), 2.01 (m, 1H), 1.89 (s, 3H), 1.86 (s, 3H),
1.87 (m, 1H), 1.06 (s, 9H), 0.88 (s, 9H), 0.068 (ss, 6H). 13C NMR
(67.9 MHz, CDCl3): δ 163.82, 163.71, 150.35, 150.27, 136.33,
136.10, 135.79, 134.85, 132.96, 132.81, 131.61, 130.30, 128.33,
128.13, 128.06, 122.20, 120.24, 115.85, 111.36 (d, J ) 7.7 Hz),
110.94, 102.61, 86.32, 85.49 (d, J ) 6.2 Hz), 85.13 (d, J ) 8.2
Hz), 84.60, 80.75 (d, J ) 4.6 Hz), 77.29, 74.23 (d, J ) 5.1 Hz),
73.06, 67.86 (d, J ) 6.7 Hz), 63.16, 39.92, 38.92 (d, J ) 4.1
Hz), 33.57 (d, J ) 4.6 Hz), 31.00, 26.90, 25.96, 23.65 (d, J )
4.6 Hz), 19.06, 18.34, 12.58 (d, J ) 4.6 Hz), -5.33, -5.41. MS
(FAB, NBA): 1097 (MH+, 11.1), 759 (5.4), 377 (28.1), 339
(51.7), 182 (100).
P h osp h or oth ioa te Tr iester (9Sd ). By the same procedure
as described for 9b, 18 mg (70%) of 9Sd was obtained from
7Sd (15 mg, 0.022 mmol). Triester 9Sd was directly used in
the next step to test the removal of silyloxyl chiral auxiliary
in the presence of TBAF. 31P NMR (109.4 MHz, CDCl3): δ
69.10 ppm.
In d olyl-oxa za p h osp h or in e (7Sd ). By the same procedure
as described for 7b, 15 mg (22%) of white solid 7Sd was
obtained from 5d (60 mg, 0.20 mmol), mp 70-71 °C. Two
diastereoisomers of 7Sd were obtained in a ratio of 14:1 as
Dith ym id in yl P h osp h or oth ioa te (Sp -10). To a solution
of 9b (60 mg, 0.056 mmol) in methanol (1 mL) was added 20
mL of aqueous ammonia (28%). The solution was stirred at
50 °C for 30 min, neutralized with HCl (6 N), and extracted
with ethyl acetate. The combined extracts were dried over
anhydrous sodium sulfate. The solvent was evaporated, and
the residue was purified by flash chromatography (acetone/
triethylamine 10:1) to give 32 mg (58%) of Sp-10 which existed
as a triethylammonium salt. 31P NMR (202.3 MHz, CD3OD):
established by 31P NMR. 31P NMR (202.3 MHz, CDCl3):
δ
1
121.02 (6.8%), 120.64 (93.2%). H NMR (500 MHz, CDCl3): δ
8.30 (s, br, 1H), 7.38 (d, J ) 1.5 Hz), 7.54-7.13 (m, 4H), 6.36
(m, 2H), 4.75 (m, 1H), 4.42 (m, 1H), 3.87 (m, 2H), 3.80 (m,
1H), 3.72 (m, 1H), 3.16 (m, 3H), 2.29 (m, 1H), 1.89 (m, 1H),
1.85 (d, J ) 1.0 Hz, 3H), 0.90, 0.84 (ss, 18H), 0.097(ss, 12H).
13C NMR (125.7 MHz, CDCl3): δ 163.25, 149.82, 137.78,
137.66, 135.62, 134.98, 129.63, 122.04, 121.28, 120.22, 110.75,
110.20 (d, J ) 10.9 Hz), 103.38, 86.23, 84.47, 75.68 (d, J ) 7.4
Hz), 73.79 (d, J ) 10.0 Hz), 66.08, 62.70, 39.71, 29.52, 28.45
(d, J ) 5.5 Hz), 28.02, 25.71, 18.21 (d, J ) 11.9 Hz), 12.28,
-5.45, -5.56, -5.69. MS (FAB, NBA): 690 (MH+, 2.76), 689
(M+, 6.21).
1
δ 58.98 ppm. H NMR (500 MHz, CDCl3): δ 7.76 (d, J ) 1.0
Hz, 1H), 7.56-7.31 (m, 10H), 7.48 (d, J ) 1.0 Hz, 1H), 6.39
(dd, J ) 9.2, 5.0 Hz, 1H), 6.05 (dd, J ) 8.8, 5.0 Hz, 1H), 4.88
(m, 1H), 4.47 (m, 1H), 3.98 (m, 1H), 3.95 (m, 1H), 3.74, 3.50
(m, 2H), 3.67 (m, 2H), 2.86, 1.10 (q, t, N(CH2CH3)3), 2.28 (m,
1H), 2.00 (m, 3H), 1.83 (d, J ) 1.0 Hz, 3H), 1.76 (d, J ) 1,0
Hz, 3H), 0.98 (s, 9H), 0.80 (s, 9H), 0.009 (ss, 6H). 13C NMR
(125.7 MHz, CD3OD): δ 166.3, 166.2, 152.4, 151.9, 138.0,
137.2, 136.8, 136.8, 134.3, 134.2, 131.1, 131.0, 129.0, 128.9,
112.2, 111.0, 88.0 (d, J ) 9.1 Hz), 87.6 (d, J ) 4.6 Hz), 86.3,
86.1, 77.9 (d, J ) 5.5 Hz), 76.3, 66.4 (d, J ) 6.4 Hz), 64.8, 47.4
(NEt3), 41.3, 40.5 (d, J ) 4.5 Hz), 27.2, 26.4, 19.6, 19.1, 12.6,
12.5, 9.7 (NEt3), -5.22, -5.28. MS (FAB, NBA): m/e 937
(MNa+).
P h osp h or ot h ioa t e Tr iest er (9b ). To a round-bottomed
flask was added 7b (80 mg, 0.137 mmol) and 3′-O-TBDPS-
thymidine (50 mg, 0.104 mmol). The flask was flushed with
argon and sealed with a septum. Dry THF (0.5 mL) was
introduced followed by DBU (40 µL, 0.268 mmol) via a syringe.
This reaction mixture was shaken at room temperature for
10 min and passed though a short silica gel column to remove
DBU, and the column was eluted with CH3CN. The solvent
was evaporated to afford light yellow solid. This solid was
redissolved in dry CH2Cl2 (2 mL), and Beaucage’s reagent (35
mg, 0.175 mmol) was added. After 5 min, evaporation of the
solvent followed by flash chromatography (dichloromethane/
acetone 5:1) afforded 84 mg (74%) of light yellow solid
phosphorothioate triester 9b, mp 113-114 °C. 31P NMR (202.3
MHz, CDCl3): δ 66.55 ppm. 1H NMR (500 MHz, CDCl3): δ
10.21 (s, br, 1H), 9.56 (s, br, 1H), 9.14 (s, br, 1H), 7.62-6.92
(m, 16 H), 6.35 (m, 1H), 6.28 (s, 1H), 6.06 (dd, J ) 9.0, 5.5 Hz,
1H), 4.88 (m, 1H), 4.82 (m, 2H), 4.32 (m, 1H), 4.06 (m, 1H),
3.93 (m, 1H), 3.88 (m, 1H), 3.71 (m, 2H), 3.63 (m, 1H), 3.21
(m, 2H), 2.61 (m, 2H), 2.29, 1.95 (m, 2H), 1.90 (s, 3H), 1.88 (s,
3H), 1.82, 1.40 (m, 2H), 1.06 (s, 9H), 0.88 (s, 9H), 0.063 (ss,
6H). 13C NMR (125.7 MHz, CDCl3): δ 164.13, 164.09, 150.70,
150.35, 135.82, 135.65, 135.54, 134.65, 132.75, 132.51, 131.97,
130.12 (d, J ) 3.6 Hz), 128.32, 127.93, 127.89, 121.45, 119.76,
119.56, 115.63, 111.22 (d, J ) 2.7 Hz), 110.80, 101.26, 85.24
(d, J ) 8.1 Hz), 84.94, 84.76 (d, J ) 9.1 Hz), 84.44, 80.32, 74.02
(d, J ) 4.6 Hz), 72.55, 67.22 (d, J ) 5.5 Hz), 63.02, 39.89, 38.16,
33.18 (d, J ) 6.4 Hz), 26.67, 25.75, 23.45, 18.81, 18.12, 12.41
(d, J ) 7.2 Hz), -5.5, -5.6. HRMS (FAB, NBA/CsI): m/e calcd
for C54H69N6O11Si2PSCs [MCs+] 1229.30755, found 1229.30710.
P h osp h or oth ioa te Tr iester (9Sb). By the same procedure
as described for 9b, 388 mg (68%) of white solid 9Sb was
obtained from the reaction of 7Sb (307 mg, 0.526 mmol) and
3′-O-TBDPS-thymidine (253 mg, 0.526 mmol), mp 116-117
°C. Two diastereoisomers of 9Sb were obtained in a ratio of
P h osp h or oth ioa te (Sp -11). A solution of TBAF (1.0 M in
DMF, 4 mL) containing dimer Sp-10 (20 mg, 0.017 mmol) was
stirred at room temperature for 1 h. The solvent was evapo-
rated under vacuum, and the residue was purified by flash
chromatography (acetone/triethylamine 1:1) to give 15 mg
(95%) of Sp-11, which existed as a tetrabutylammonium salt.
31P NMR (202.3 MHz): δ 58.76 ppm (CD3OD), 55.45 ppm
(D2O). 1H NMR (500 MHz, CD3OD): δ 7.80 (d, J ) 1.0 Hz,
1H), 7.78 (d, J ) 1.5 Hz), 6.29 (dd, J ) 8.0, 6.0 Hz, 1H), 6.22
(dd, J ) 8.0, 6.0 Hz, 1H), 4.98 (m, 1H), 4.45 (m, 1H), 4.12 (m,
1H), 4.09, 3.98 (m, 2H), 3.98 (m, 1H), 3.74 (m, 2H), 3.17, 1.59,
1.35, 0.94 (NBu4+), 2.40 (m, 1H), 2.20 (m, 2H), 2.12 (m, 1H),
1.89 (d, J ) 1.0 Hz, 3H), 1.80 (d, J ) 1.0 Hz, 3H). 13C NMR
(125.7 MHz, CD3OD): δ 166.4, 166.3, 152.4, 152.2, 138.08,
138.06, 112.0, 111.5, 87.6 (d, J ) 5.5 Hz), 87.3 (d, J ) 10.0),
86.1, 86.0, 77.0 (d, J ) 5.5 Hz), 72.8, 66.6 (d, J ) 5.4 Hz), 62.7,
59.39 (t, NBu4+), 40.7, 40.0 (d, J ) 4.5 Hz), 24.69 (NBu4+),
20.61 (NBu4+), 13.85 (NBu4+), 12.6, 12.3. HRMS (FAB): m/e
calcd for C20H27N4O11PSNa [MNa+] 585.10323, found 585.10340.
Dith ym id in yl p h osp h or oth ioa te (Rp -10) was obtained
from 9Sb in 80% yield as described for Sp-10. 31P NMR (202.3
MHz, CD3OD): δ 59.07 ppm. The minor isomer could not be
1
identified from its 31P NMR. H NMR (500 MHz, CD3OD): δ
7.69 (d, J ) 1.0 Hz, 1H), 7.49-7.24 (m, 10H), 7.44 (d, J ) 1.0
Hz, 1H), 6.32 (dd, J ) 9.0, 5.5 Hz, 1H), 6.02 (dd, J ) 8.5, 5.5
Hz, 1H), 4.83 (m, 1H), 4.40 (m, 1H), 4.05 (m, 1H), 3.92 (m,
1H), 3.72 (m, 2H), 3.45 (m, 1H), 2.84, 1.04 (q, t, NEt3), 2.07
(m, 2H), 1.92 (m, 1H), 1.80 (m, 1H), 1.76 (br), 1.71 (d, J ) 1.0

Chiral Indolyl-oxazaphosphorines
J . Org. Chem., Vol. 64, No. 22, 1999 8097
Hz, 3H), 0.91 (s, 9H), 0.75 (s, 9H), -0.041 (ss, 6H). 13C NMR
(125.7 MHz, CD3OD): δ 166.36, 166.21, 152.44, 151.96, 138.03,
137.11, 136.86, 136.81, 134.36, 134.26, 131.19, 131.13, 129.07,
129.00, 112.13, 111.26, 88.11, 88.06, 88.04 (d, J ) 1.7 Hz),
86.29, 88.24, 78.53 (d, J ) 4.6 Hz), 76.20, 66.47 (d, J ) 5.5
Hz), 64.90, 47.45 (NEt3), 41.57, 40.43 (d, J ) 4.6 Hz), 27.39,
26.51, 22.08, 19.74, 19.20, 12.72, 12.67, 9.68 (NEt3), -5.08,
-5.16.
5.5 Hz) 87.49, 87.42, 86.20, 86.08, 77.49 (d, J ) 5.5 Hz), 72.94,
66.35 (d, J ) 6.4 Hz), 62.83, 59.44 (t, NBu4+), 40.87, 39.88 (d,
J ) 4.5 Hz), 24.70 (NBu4+), 20.62 (NBu4+), 13.87 (NBu4+),
12.61, 12.40.
Ack n ow led gm en t. We wish to thank the Natural
Science and Engineering Research Council of Canada
and ISIS Pharmaceuticals, Carlsbad, CA, for the gener-
ous financial support. J .-C. Wang thanks McGill Uni-
versity for Clifford C. F. Wong Graduate McGill Major
Fellowship.
P h osp h or oth ioa te (Rp -11) was obtained from Rp-10 in
78% yield as described for Sp-11. Two diastereomers of Rp-
and Sp-11 were observed from its 31P NMR in a ratio of around
24:1. 31P NMR (202.3 MHz, CD3OD): δ 58.92 ppm (Rp-11,
1
96%), 58.99 ppm (Sp-11, 4%). H NMR (500 MHz, CD3OD): δ
7.85 (d, J ) 1.0 Hz, 1H), 7.80 (d, J ) 1.0 Hz, 1H,), 6.29 (dd, J
) 8.0, 6.0 Hz, 1H), 6.22 (dd, J ) 8.2, 5.5 Hz, 1H), 5.00 (m,
1H), 4.45 (m, 1H), 4.15 (m, 1H), 4.06 (m, 2H), 3.98 (m, 1H),
3.77 (m, 2H), 3.17, 1.59, 1.35, 0.95 (NBu4+), 2.40 (m, 1H), 2.20
(m, 2H), 2.14 (m, 1H), 1.91 (d, J ) 1.0 Hz, 3H), 1.81 (d, J )
1.0 Hz, 3H). 13C NMR (125.7 MHz, CD3OD): δ 166.43, 166.28,
152.39, 152.21, 138.12, 138.03, 112.00, 111.48, 87.85 (d, J )
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for all compounts in the Experimental Section
and 31P NMR spectra for compounds 7a , 7b, 9a , 9b, 10, and
11. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O990242L