Some properties of cyclic phosphoramidites and their phosphites: Phosphitylation, ester exchange, and hydrolysis

Article abstract of DOI:10.3987/COM-99-S89

Phosphorylation of diols using sterically bulky cyclic phosphoramidites was performed in a good selectivity. Their phosphite derivatives underwent tetrazole-catalyzed hydrolysis and transesterification. The reaction was shown to proceed via a phosphorane intermediate by NMR analysis.

Full text of DOI:10.3987/COM-99-S89

HETEROCYCLES, Vol. 52, No. 2, 2000, pp. 799 – 810, Received, 7th May, 1999
SOME PROPERTIES OF CYCLIC PHOSPHORAMIDITES
AND THEIR PHOSPHITES: PHOSPHITYLATION, ESTER EXCHANGE,
#
AND HYDROLYSIS
ꢀ
Yutaka Watanabe* and Shin-ich Maehara
Department of Applied Chemistry, Faculty of Engineering, Ehime University,
Matsuyama 790-8577, Japan
Abstract
Phosphorylation of diols using sterically bulky cyclic
phosphoramidites was performed in a good selectivity. Their phosphite derivatives
underwent tetrazole-catalyzed hydrolysis and transesterification. The reaction was
shown to proceed via a phosphorane intermediate by NMR analysis.
Various phosphoramidites have been utilized for phosphorylation of alcohols mainly in nucleotide and
1
phospholipid chemistry. However, their and related cyclic derivatives have rarely attracted attention for
2, 3
study on synthesis and reactivity,
although there have been a number of reports on structure analysis of
5
4
cyclic phosphorus compounds. We released xylylene N,N-diethylphosphoramidite (XEPA) as a ꢀ
6
powerful phosphitylating reagent for phosphorylation of polyols such as inositol derivatives. In contrast to
the methodology, so called exhaustive phosphorylation, selective phosphorylation strategy is also a
synthetically useful tool. In order to develop such a method, XEPA was modified to produce a sterically
hindered derivative. During this study, we found phosphorous triesters (phosphites) were activated even by ꢀ
a weak acid, 1H-tetrazole (pKa 4.89), resulting in hydrolysis and ester exchange in the presence of water ꢀ
7
and an alcohol respectively. In this paper, we describe the selective phosphorylation ability of the cyclic
phosphoramidites and ester exchange and hydrolysis of their phosphite versions.
RESULTS AND DISCUSSION
Synthesis of cyclic phosphoramides and phosphorylation
O
O
O
O
O
O
P-NEt
P NEt
P NEt
2
2
2
XEPA
1 (dl and meso)
2
Dimethyl and tetramethyl phosphoramidites (1) and (2) were first candidates for modified XEPA
derivatives bearing substituents at the benzylic positions. The former (1) was shown to be usable for
phosphorylation, however, selective reaction towards a primary vs secondary alcohol did not proceed
#This paper is dedicated to Professor Teruaki Mukaiyama on the occasion of his 73rd birthday.

and also diastereomeric products were troublesome. Since more hindered 2 could not be prepared, several
analogous alicyclic phosphoramidites (5) and (6) including six- and five-membered rings as well as seven
were synthesized according to the following equation (eq. 1):
H O
O H
(CH )
O
O
+
(Et N) P
2 3
(CH )
(eq. 1)
P NEt
2 n
2
2 n
3
(a: n=2, b: n=1, c: n=0)
4
5
Et
Et
O
P NEt
2
O
Et Et
6
R'
R'
R'
R'
O
O
O
O
(CH )
(CH )
5, 6
+
ROH
P O R
P
(eq. 2)
2 n
2 n
O R
Tetrazole
mCPBA
O
R' R'
7 (R'=Me), 8 (R'=Et)
R' R'
9 (R'=Me), 10 (R'=Et)
Table 1. Phosphorylation using phosphoramidites
Yield, %
*
*
9a 9a
1
9b 9b
1
9c 9c
1
10a 10a
ROH
OH 11
2
2
2
1
2
Ph
Ph
86
93
76
84
12
91
96
88
78
86
50
OH
11 + 12
91
87
#
#
#
#
(82/18)
(73/27)
(66/34)
(86/14)
*1.4 Equiv of pyridine based on alcohol employed was added.
#
Ratio of primary ester/secondary ester.
The reactivity of phosphoramidites (5) thus obtained was first evaluated by phosphorylation of simple
alcohols. They were first treated with 3-phenylpropyl alcohol (PPrOH, 11) or dl-1-phenyl-1-pentyl alcohol
(12) in the presence of 1H-tetrazole to form phosphites (7) and (8), which were then oxidized with m-
chloroperbenzoic acid (mCPBA) to give phosphates (9) and (10) in good yields (Table 1). Although their
reactivity was lower than that of XEPA and other common acyclic phosphitylating reagents such as ꢀ
dibenzyl and dimethyl phosphoramidite, phosphorylation yields were generally as high as those for the ꢀ
latter amidite reagents. It is interesting to note that five-membered ring products (9c) were so fairly stable
that they were isolate by a preparative silica gel TLC, whereas five-membered cyclic phosphates are
8
generally known to be quite unstable.
Reaction of equimolar amounts of both alcohols with 5 or 6 at 0 ˚C proceeded in good selectivity, resulting
in the predominant formation of primary esters (9 ) and (10 ). Selectivity decreased with the ring size of
1
1
reagents from seven to five. Methyl and ethyl substituents on the seven-membered ring did not affect the

selectivity, however, morpholino version instead of diethylamino one decreased selectivity in some extent.
On the basis of these results, some substrates (13-15) bearing two hydroxyl groups in the same molecules
were treated with 5a and phosphoric esters of higher reactive equatorial and primary alcohols were obtained
accompanied with a small amount of diphosphates. Thus, completely selective phosphorylation could not
be realized.
OH
2
HO
BzO
6
PMB
HO
O
N
OH
OBz
BzO
BzO
O
N
MeO
CH3(CH2)5 CH (CH2)11OH
O
OH
13
6-P: 77%
2,6-P : 2%
14
5'-P: 75%
3',5'-P2: 6%
15
1-P: 69%
1,12-P : 10%
2
2
Deprotection of 9a was accomplished by the reaction with bromotrimethylsilane, combination of
1
chlorotrimethylsilane and NaI, or diluted HCl to afford 3-phenylpropyl phosphate in 95% yield.
TMS-Br
O
O
O
Ph(CH ) OP(O)O H
2 3
P
2
O(CH ) Ph
2 3
9a
1
Hydrolysis of cyclic phosphites (7)
O
1. H O
2
O
Tetrazole
5
+ 11
7
+ (CH )
+
(eq. 3)
9
P
11
2 n
H
CH Cl
2
2
2. mCPBA
O
16
Table 2. Hydrolysis of phosphites (7)
#
Yield (%)
9
16
11
7a
7b
7c
44
(0 ˚C: 74%)
18
29
45
*
*
47
(0 ˚C: 79%)
33
-
6
(0 ˚C: 9%)
82
*
#Isolated yield by preparative TLC.
*Other products were not isolated.
Treatment of cyclic phosphites (7), derived in situ from amidites (5) and PPrOH (11), with water for 1 h at
an ambient temperature followed by oxidation with mCPBA, which was done to isolate P(III) compound(s)
without decomposition, yielded hydrolysis products (16) and the alcohol (11) to a fairly extent along with

phosphorylation product (9), while the reaction at 0 ˚C furnished phosphorylation products (9)
predominantly (eq. 3 and Table 2). The yield of H-phosphonates (16) was expected to be comparable with
that of alcohol (11) recovered, however, their isolation yields were decreased because of their instability on
9
silica gel. Especially, five-membered ring phosphonate (16c) was not isolated. It should be noted that, as
suggested based on the sum of yields of 9b and 11, hydrolysis occurred at the exocyclic position almost
exclusively and also a remaining phosphorus-containing product was phosphorylation one (9b). In the case
of 5a, one more product, presumably a ring-cleavage derivative was formed, resulting in decrease of the
amount of alcohol compared with results in the case of 5b and 5c as expected from the ester exchange
experiments described below. Since, in independent experiments, hydrolysis of phosphites (7) was not
10
observed in the absence of tetrazole and diethylammonium tetrazolide which is generated during the
phosphitylation, the former weak acid catalyst and even the less acidic latter became apparent to accelerate
11, 12
the hydrolysis.
Thus, hydrolysis of phosphite is assumed to take place by protonation on the
phosphorus atom.
Hydrolysis of the five-membered phosphite (5c) was faster than that of others. However, the ring size of 5
did not influenced enormously their hydrolytic reactivity, while five-membered ring phosphates are known
8
to be much more reactive than six- and seven-membered cyclic phosphates as well as acyclic esters.
Ester exchange reaction of phosphites
R'OH
ROH
+
P H
H
(RO) P
3
(RO)
P
OR' (eq. 3)
(RO) P
(RO)
3
3
2
OR'
Tetrazole
Tetrazole
18
19
17'
17
In order to understand the hydrolysis process described above and a catalytic ability of tetrazole in the
reaction of a phosphites with nucleophiles, the reaction with an alcohol instead of water was then explored.
Thus, equimolar amounts of a phosphite, alcohol, and tetrazole were stirred in CH Cl for 22 h at ambient
2 2
temperature (around 27 ˚C), and then the mixture was treated with mCPBA to isolate P(III) products ꢀ
without decomposition by transforming to P(V) derivatives. Six- and five-membered cyclic phosphites (7b)
and (7c) were converted in the presence of benzyl alcohol to the corresponding 3-phenylpropyl and benzyl
phosphoric triesters resulting from ester exchange without any other side-reaction (run 3, 5 in Table 3) as
31
P NMR spectroscopy of the reaction of 7b with PPrOH (11) in the presence of tetrazole in CDCl
3
showed only one peak at 128.12 ppm due to 7b even after 3 days.
On the other hand, the tetrazole-catalyzed reaction of seven-membered 7a with PPrOH (11) proceeded
differently to afford bis(3-phenylpropyl) hydrophosphonate as a major product (63% yield) along with 4%
of phosphoric triester and 36% of 2,2,5,5-tetramethyltetrahydrofuran (run 1). Analogous seven-membered
phosphites (20) and (21), however, gave only ester exchange products (run 6, 7) as 7b and 7c. A simple
acyclic tributyl phosphite (22) was also smoothly transesterified resulting in the formation of three
phosphoric triesters (run 8). Therefore, structural feature of 7a, that is, tertiary ester changed the pathway
dramatically. It is interesting to compare the result of the cyclic di-tertiary ester (7a) with that of an acyclic
analogue, di-tert-butyl 3-phenylpropyl phosphite (23) (run 9). In the absence of PPrOH (11), 23
decomposed on treatment with tetrazole within 3 h at room temperature to form tert-butyl 3-phenylpropyl

hydrophosphonate quantitatively, and even in the presence of the alcohol, transesterification product was ꢀ
not observed. The results can be explained in terms of protonation on the phosphorus atom in 23 with
tetrazole and spontaneous formation of trimethylcarbocation, resulting in the formation of the H-
phosphonate. In contrast, 7a did not decompose on treatment with tetrazole in the absence of an alcohol for
2 h at room temperature and then for 2 h under refluxing in CH Cl .
2 2
Table 3. Tetrazole-catalyzed reaction of phosphites in the presence of an alcohol
a
Products and yields
Run
Phosphite
Alcohol
O
O
O
O
H
O
Ph(CH2)3O
P
P
1
7a
24
O(CH2)3Ph
Ph(CH2)3O
b
36%
4%
63%
R = Ph(CH2)3: 85%
2
3
7b
7b
24
25
O
O
P
R = Ph(CH ) : 41%
2 3
24: 46%, 25: 49%
24: 46%, 25: 48%
O
OR
R = PhCH2: 30%
4
5
7c
7c
24
25
R = Ph(CH2)3: 69%
O
O
P
R = Ph(CH2)3: 42%
R = PhCH2: 15%
O
OR
O
O
O
O
OH
6
P-O(CH2)3Ph
24
P
P[O(CH2)3Ph]2
[Ph(CH2)3O]3P(O)
O
O
O(CH2)3Ph
O
20
55%
4%
14%
O
O
O
O
R = Ph(CH2)3: 34%
24: 34%, 25: 42%
P
P O(CH2)3Ph
7
8
25
24
OR R = PhCH2: 28%
O
21
(n-BuO)3P
22
(n-BuO)3P(O): 21%
(n-BuO)2P(O)-O(CH2)3Ph: 36%
n-BuOP(O)[O(CH2)3Ph]2: 16%
O
O
P
Ph(CH2)3O
O
P-O(CH2)3Ph
9
24
O
H
quant. (rt, 3 h without alcohol)
85%
23
a
b
24=Ph(CH ) OH, 25=PhCH OH. GLC analysis
2 3
2
11
The transesterification of trialkyl phosphites was reported to be catalyzed by acids such as phosphoric
13
14
14
acid, diethyl hydrophosphonate, aluminum chloride, and protonated phosphonium salt intermediates
14
were postulated.
15
Alkylation of p-toluenesulfonic acid with phosphites via phosphonium salts was also
reported. Protonated species, phosphonium salts derived from phosphites with strong acids such as ꢀ
16
17
18
100% sulfuric acid, FSO H, and HCl were detected by NMR study. To our knowledge, however,
3
there is no report on direct observation of the intermediate in the transesterification of phosphites. We
propose that a phosphorane such as 19 is a key intermediate in transesterification of phosphites (eq. 3)
19
based on direct observation of hydrophosphorane (26) by NMR spectroscopy.
When the reaction of 7c with PPrOH (11) in the presence of tetrazole in CDCl was monitored by
31
P
3
NMR spectroscopy, the spectrum exhibited doublet of quintets as a minor peak due to the coupling with
the proton on the phosphorus (J = 666.5 Hz) and two alcoholic methylene (J=18.7 Hz) at -24.95 ppm

O
O
N P
O
O
P
O
O
P
H
O R
H
O(CH ) Ph
H
O
O
O P
2 3
N
O(CH ) Ph
2 3
OPh
H
26
29
27
28
MeOH
O
O
O
H
OMe
(eq. 4)
P NMe
O
P OMe
2
O
P
O
OMe
31
30
(80% H PO as external standard), indicating the existence of hydrophosphorane (26).ꢀIts concentration
4
3
during the reaction was kept constantly from 10 min to more than 2 days under anhydrous conditions,
suggesting that 26 exists in an equilibrium reaction. This signal was not observed in a spectrum of a
mixture of 7c and tetrazole. Boisdon et al. observed hydrophosphorane (31) (ꢀ -26 ppm) in an NMR ꢀꢀꢀ
p
20
study of the reaction of phosphoramidite (30) with methanol (eq. 4). As a special case, transesterification
of o-phenylene 8-quinolyl phosphite with phenol was reported to proceed via hydrophosphorane (27) ꢀ
21
31
which was observed by P NMR. Novel bicyclo phosphoramidites were demonstrated to react with
alcohols to yield the hydrophosphoranes (28) which transesterified with other alcohols without any
22
7
catalyst. Intramolecular adduct (29) between a carboxyl group and phosphine was also reported. A
pentacoordinate intermediate like 26 was not detected in the cases of 7a, 7b, and 22 by the same analysis.
These differences are mainly attributed that phosphorane containing a five-membered ring is more stable
23
than cyclic and acyclic ones.
From these facts, it is reasonable to consider that the tetrazole-catalyzed
ester exchange reaction of phosphites proceeds by way of 32 and 33 (Scheme 1).
O
O
(CH2)n
P OR
Tet.
(CH2)n
P OR'
O
O
Tet.
O
R'OH
ROH
O
O
(CH2)n
O P
OR'
O
H
H
+
P
+
P
(CH2)n
(CH2)n
H
OR
OR'
OR
O
32
33
OH
O
H
+
O
+
O P
H
+
P
H
OR
OR'
P
O
O
OR
OR
34
36
35
O
P
O
RO
R'O
+
H
Tet.=1H-tetrazole
37
Scheme 1. Mechanism of the tetrazole-catalyzed reactions

A mechanistic feature of the reaction of 7a is decomposition of the seven-membered ring with the formation
of tetramethyltetrahydrofuran. Its process seems to involve the formation of 36 led from 33. Another
pathway including 34 and 35 is at least not important, because 7a was not decomposed by treatment with
tetrazole without an alcohol. Analogous reaction was reported in which phosphorane (38) decomposed via
24
39 at room temperature, forming oxirane and triethyl phosphate (eq. 5). We could not detect the same
oxirane in the reaction of 9c whereas a trace of bis(3-phenylpropyl) hydrophosphonate was observed by
NMR analysis.
O
O
H O
OEt
P OEt
OEt
+
OEt
P OEt
OEt
(eq. 5)
(EtO) P(O) +
3
O
O
39
38
Finally, we would like to warn a possibility that phosphitylation using a phosphoramidite in the presence of
tetrazole induces decomposition of the resultant phosphite by the excess of the catalyst and the alcohol, and
25
26
by a prolonged reaction time. Indeed, glycosyl phosphites and a phosphite of a tertiary alcohol was
converted to the N-alkylation products by replacement of the hydroxyl groups with tetrazole.
EXPERIMENTAL
31
All NMR spectra were taken in CDCl . In the case of P NMR, 85% H PO (ꢀ=0.0) was used as an
3
3
4
external standard. Extracts obtained after work-up were dried over MgSO or Na SO . All compounds
4
2
4
isolated were oily except for 1,3,4,5-Tetra-O-benzoyl-myo-inositol 6-(4,4,7,7-tetramethylbutylene
phosphate).
2-Diethylamino-4,4,7,7-tetramethyl-1,3,2-dioxaphosphepane (5a). A mixture of 2,5-dimethyl-2,5-
hexanediol (10.0 g, 68.4 mmol) and tris(diethylamino)phosphine (22.6 mL, 82.1 mmol) was ꢀꢀꢀ
heated at 100 ˚C for 2 h and distilled under reduced pressure to give 5a (10.1 g, 60%): bp 51 ˚C/0.4 ꢀ
1
mmHg; H NMR (90 MHz) ꢀ 1.03 (6H, t, J=8.0 Hz), 1.19 (6H, s), 1.37 (6H, s), 1.77 (4H, br), 3.01 ꢀꢀ
31
(4H, dq, J=12.0 and 8.0 Hz); P NMR (109 MHz) ꢀ 137.23; Anal. Calcd for C H NO P: C, 58.28; ꢀ
12 26
2
H, 10.60; N, 5.66. Found: C, 57.97; H, 10.65; N, 5.87.
2-Diethylamino-4,4,6,6-tetramethyl-1,3,2-dioxaphosphane (5b). According to the procedure ꢀꢀꢀ
1
for 5a, 5b was obtained (100 ˚C, 3 h, 66%): bp 53-54 ˚C/0.09 mmHg; H NMR (90 MHz) ꢀ 1.00 (6H, t,
31
J=8.0 Hz), 1.25 (6H, s), 1.40 (6H, s), 1.65 (2H, br), 3.40 (4H, dq, J=12.0 and 8.0 Hz); P NMR (109
MHz) ꢀ 137.99; Anal. Calcd for C H NO P: C, 56.63; H, 10.37; N, 6.00. Found: C, 56.60; H,
11 24
2
10.35; N, 6.23.
2-Diethylamino-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane (5c). 5c was similarly prepared ꢀꢀ
1
(100 ˚C, 2 h, 73%): bp 65-68 ˚C/1.5 mmHg; H NMR (90 MHz) ꢀ 1.10 (6H, t, J=8.0 Hz), 1.25 (6H, s),
31
1.31 (6H, s), 3.12 (4H, dq, J=12.0 and 8.0 Hz); P NMR (109 MHz) ꢀ 145.84; Anal. Calcd for
C H NO P: C, 54.78; H, 10.11; N, 6.39. Found: C, 54.66; H, 10.16; N, 6.73.
10 22
2

2-Diethylamino-4,4,7,7-tetraethyl-1,3,2-dioxaphosphepane (6). A mixture of 3,6-diethyl-3,6-
octanediol (5.0 g, 24.7 mmol) and tris(diethylamino)phosphine (8.84 mL, 32.1 mmol) was heated at 130 ꢀ
˚C for 5 h. Distillation and subsequent flash column chromatography (AcOEt/Hexane, 1:10 including 1% of
1
Et N) gave 6: bp 95-100 ˚C/0.4 mmHg; H NMR (270 MHz) ꢀ 0.75 (12H, t, J=7.3 Hz), 0.95 (6H, s), ꢀ
3
31
1.49 (8H, s), 1.83 (4H, br), 2.90 (4H, dq, J=11.7 and 7.3 Hz); P NMR (109 MHz) ꢀ 136.13; Anal. ꢀ
Calcd for C H NO P: C, 63.34; H, 11.29; N, 4.62. Found: C, 63.37; H, 11.21; N, 4.56.
16 34
2
Representative procedure for phosphorylation. A mixture of PPrOH (11) (54 mg, 0.40 mmol), ꢀꢀꢀ
5a (108 mg, 0.44 mmol), and 1H-tetrazole (31 mg, 0.44 mmol) in CH Cl (1.5 mL) was stirred for 1 h at
2 2
rt, and after being cooled to -78 ˚C, treated with mCPBA (6 mg, 0.56 mmol). The solution was stirred at rt
for an additional 30 min and AcOEt was added. The resulting solution was washed successively with a ꢀ
10% aq. Na SO solution, saturated NaHCO solution, and brine, dried and evaporated. The residue was
2
3
3
subjected to flash column chromatography on silica gel eluting with AcOEt and hexane (1:1) to give 9a
1
(111 mg, 86%). Selective phosphorylation experiments were carried out at 0 ˚C.
1
4,4,7,7-Tetramethyl-2-oxo-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphepane (9a ).
1
H
NMR (270 MHz) ꢀ 1.41 (6H, d, J=1.22 Hz), 1.54 (6H, s), 1.92-2.06 (6H, complex), 2.72 (2H, t, J=6.4 ꢀ
31
Hz), 4.05 (2H, dt, J=6.4 and 6.4 Hz), 7.15-7.35 (5H, complex); P NMR (109 MHz) ꢀ -5.06; Anal.
.
Calcd for C H O P 1/2H O: C, 59.81; H, 8.16. Found: C, 60.08; H, 8.00.
16 25 4
2
1
4,4,7,7-Tetramethyl-2-oxo-2-(1-phenylpentyloxy)-1,3,2-dioxaphosphepane (9a ).
2
H ꢀꢀꢀ
NMR (90 MHz) ꢀ 0.91 (3H, t, J=6.5 Hz), 1.07-1.60 (18H, complex), 1.92 (4H, br s), 5.25 (1H, dt, ꢀꢀ
31
J=7.4 and 6.5 Hz), 7.28 (5H, complex);
P NMR (109 MHz) ꢀ -5.69; Anal. Calcd for
.
C H O P 1/5H O: C, 63.74; H, 8.84. Found: C, 63.74; H, 8.64.
19 31 4
2
1
4,4,7,7-Tetramethyl-2-oxo-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphane (9b ).
1
H NMR
(270 MHz) ꢀ 1.49 (6H, s), 1.56 (6H, s), 2.02 (2H, complex), 2.72 (2H, t, J=7.6 Hz), 4.09 (2H, dt,
31
J=7.6 and 6.4 Hz), 7.15-7.35 (5H, complex); P NMR (109 MHz) ꢀ -6.99.
4,4,7,7-Tetramethyl-2-oxo-2-(1-phenylpentyloxy)-1,3,2-dioxaphosphane (9b ).
1
H NMR
2
(90 MHz) ꢀ 0.85 (3H, t, J=5.8 Hz), 1.25-1.50 (18H, complex), 1.92 (2H, s), 5.28 (1H, dt, J=6.7 and ꢀꢀ
31
.
5.8 Hz), 7.22 (5H, complex); P NMR (109 MHz) ꢀ -7.94; Anal. Calcd for C H O P 1/2H O: C,
18 29 4
2
61.88; H, 8.65. Found: C, 62.04; H, 8.46.
4,4,7,7-Tetramethyl-2-oxo-2-(3-phenylpropyloxy)-1,3,2-dioxaphospholane (9c ).
1
H ꢀꢀꢀ
1
NMR (90 MHz) ꢀ 1.43 (6H, s), 1.49 (6H, s), 2.01 (2H, complex), 2.70 (2H, t, J=7.3 Hz), 4.10 (2H, dt,
31
J=7.3 and 7.4 Hz), 7.13 (5H, complex); P NMR (109 MHz) ꢀ 12.60.
4,4,7,7-Tetramethyl-2-oxo-2-(1-phenylpentyloxy)-1,3,2-dioxaphospholane (9c ).
1
H
2
NMR (90 MHz) ꢀ 0.81 (3H, t, J=8.0 Hz), 1.00-1.45 (6H, br), 1.32 (12H, s), 4.50 (1H, m), 7.16 (5H,
31
complex); P NMR (109 MHz) ꢀ 12.60; Anal. Calcd for C H O P: C, 62.57; H, 8.34. Found: C,
17 27 4
62.44; H, 8.34.
4,4,7,7-Tetraethyl-2-oxo-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphepane (10a ).
1
H ꢀꢀꢀ
1
NMR (90 MHz) ꢀ 0.88 (12H, t, J=6.1 Hz), 1.50-2.20 (14H, complex), 2.68 (2H, t, J=6.1 Hz), 3.97 ꢀꢀ
31
(2H, dt, J=6.1 and 6.1 Hz), 7.08 (5H, complex); P NMR (109 MHz) ꢀ -6.12

1
4,4,7,7-Tetraethyl-2-oxo-2-(1-phenylpentyloxy)-1,3,2-dioxaphosphepane (10a ).
2
H ꢀꢀꢀ
NMR (90 MHz) ꢀ 0.50-0.97 (15H, complex), 1.07-2.00 (18H, complex), 5.09 (1H, dt, J=6.4 and 6.4 ꢀꢀ
31
Hz), 7.11 (5H, complex); P NMR (109 MHz) ꢀ -5.41.
1,3,4,5-Tetra-O-benzoyl-myo-inositol 6-(4,4,7,7-tetramethylbutylene phosphate). rt, 3 h
1
then reflux, 1 h for phosphitylation: mp 194-195 ˚C (from AcOEt); H NMR (270 MHz) ꢀ 0.86 (3H, s),
0.91 (3H, s), 0.94 (3H, s), 1.05 (3H, s), 1.63 and 1.74 (ABq, J=14.3 Hz), 4.66 (1H, br), 5.44-5.57 ꢀꢀ
31
(3H, complex), 5.80 (1H, t, J=9.5 Hz), 6.27 (1H, t, J=9.5 Hz), 7.26-8.27 (20H, complex); P NMR
(109 MHz) ꢀ -4.99; Anal. Calcd for C H O P: C, 64.12; H, 5.51. Found: C, 64.08; H, 5.51.
34 43 12
3-N-( p-Methoxybenzyl)-2'-O-methyluridine 5'-(4,4,7,7-tetramethylbutylene phosphate).
1
3.3 Equiv. of pyridine based on the alcohol was additionally used to promote the reaction (rt, 3 h). H ꢀ
NMR (270 MHz) ꢀ 1.39 (3H, d, J=1.5 Hz), 1.40 (3H, s), 1.53 (6H, s), 2.02 (4H, m), 3.60 (3H, s), 3.72 ꢀ
(1H, dd, J=5.2 and 2.1 Hz), 3.76 (3H, s), 4.06 (1H, dt, J=7.3 and 2.1 Hz), 4.18 (1H, dd, J=7.3 and 5.2 ꢀ
Hz), 4.26 and 4.37 (2H, dddx2, J=12.5, 6.4, and 2.1 Hz), 4.97 and 5.09 (ABq, J=13.7 Hz), 5.74 (1H, ꢀꢀꢀ
d, J=7.9 Hz), 5.93 (1H, d, J=2.1 Hz), 6.81 (2H, d, J=8.8 Hz), 7.42 (2H, d, J=8.8 Hz), 7.71 (1H, d, ꢀꢀ
31
J=7.9 Hz); P NMR (109 MHz) ꢀ -4.59; Anal. Calcd for C H N O P: C, 54.93; H, 6.56; N, 4.93.
26 37 2 10
Found: C, 54.98; H, 6.63; N, 5.06.
1
1,12-Octadecanediol 1-(4,4,7,7-tetramethylbutylene phosphate). 0 ˚C, 6.5 h: H NMR (270 ꢀꢀ
MHz) ꢀ 0.88 (3H, t, J=4.6 Hz), 1.41 (6H, s), 1.53 (6H, s), 1.27-1.67 (30H, complex), 1.95 (4H, m), ꢀꢀ
31
3.58 (1H, br), 4.02 (2H, q J=6.7 Hz); P NMR (109 MHz) ꢀ -5.31; Anal. Calcd for C H O P: C,
26 53 5
65.51; H, 11.21. Found: C, 65.62; H, 11.25.
Hydrolysis experiment (typical). A solution of phosphoramidite (5a) (91.7 mg, 0.37 mmol), PPrOH
(45.9 mg, 0.34 mmol), and tetrazole (28.3 mg, 0.40 mmol) in CH Cl (1 mL) was stirred at ambient
2 2
temperature for 2 h and water (18 mg, 1.00 mmol) was added. The mixture was vigorously stirred for 1 h
and cooled to -78 ˚C. After addition of mCPBA (87.2 mg, 0.51 mmol), the mixture was stirred at ambient
temperature for 30 min and AcOEt was added. The organic solution was washed with 10% Na SO
2
3
solution, sat. NaHCO solution, and brine, dried and evaporated. The residue was subjected to PTLC
3
(AcOEt/CH Cl , 1:4) to give 9a (48.9 mg, 44%), 16a (13.1 mg, 18%), and PPrOH (13.1 mg, 29%). In a
2 2
similar manner, 5b and 5c were treated.
Synthesis of hydrophosphonate 16 (typical). A mixture of phosphoramidite 5a (121 mg, 0.49 ꢀꢀ
mmol), tetrazole (134 mg, 0.49 mmol), water (44 mg, 2.46 mmol), and CH Cl (5 mL) was stirred for 1 h ꢀ
2 2
at rt, and volatile materials were evaporated. The residue was extracted with ether (84 mg) and the soluble
fraction was subjected to a bulb to bulb distillation to afford 16a (31 mg, 33%).
2-Hydro-4,4,7,7-tetramethyl-1,3,2-dioxaphosphepane (16a): R 0.3 (AcOEt/CH Cl , 1:4); bp
2 2
f
1
110 ˚C (bath temp.)/0.4 mmHg; H NMR (90 MHz) ꢀ 1.30 (6H, s), 1.43 (6H, s), 1.89 (4H, br), 6.59
31
-1
(1H, d, J=705.6 Hz); P NMR (109 MHz) ꢀ 1.58; IR (neat) 2430 cm ; Anal. Calcd for
C8H17O3P•3/4H2O: C, 46.71; H, 9.06. Found: C, 46.43; H, 8.72.
2-Hydro-4,4,6,6-tetramethyl-1,3,2-dioxaphosphane (16b). R 0.2 (AcOEt/Hexane, 2:1); bp
f
1
110 ˚C (bath temp.)/0.5 mmHg; H NMR (90 MHz) ꢀ 1.48 (6H, s), 1.52 (6H, s), 1.65 (2H, br), 1.91 ꢀꢀ

31
and 2.10 (2H, ABq, J=13.7 Hz), 6.94 (1H, d, J=694.8 Hz); P NMR (109 MHz) ꢀ -3.14; IR (neat) ꢀ
-1
2430 cm ; Anal. Calcd for C H O P 1/5H O: C, 46.25; H, 8.54. Found: C, 46.31; H, 8.39.
7 15 3
.
2
2-Hydro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane (16c): bp 115-120 ˚C (bath temp.)/0.3 ꢀmmHg;
31
1
H NMR (90 MHz) ꢀ 1.40 (6H, s), 1.51 (6H, s), 7.25 (1H, d, J=706.5 Hz); P NMR (109 MHz) ꢀ 17.37.
Tetrazole-catalyzed reaction (Typical). Phosphite (5a), which was prepared as described above was
isolated in 88% by flash column chromatography (AcOEt/hexane containing 1% Et N, 1:14). A mixture of
3
5a (384.7 mg, 1.24 mmol), PPrOH (168.8 mg, 1.24 mmol), and tetrazole (86.8 mg, 1.24 mmol) in ꢀ
CH Cl (2 mL) was stirred for 22 h at rt. The solution was subjected to GLC analysis to measure the
2 2
quantity of 2,2,5,5-tetramethylhydrofuran (36%). The mixture was then cooled to -78 ˚C and after addition
of mCPBA (213.9 mg, 1,24 mmol), the solution was stirred for 30 min at rt. After a usual work-up
procedure as above (hydrolysis experiment), bis(3-pheylpropyl) hydrophosphonate (132 mg, 63%) and
9a (7.8 mg, 4%) were isolated by PTLC (Et O/hexane, 3:1).
1
2
1
4,4,7,7-Tetramethyl-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphepane (7a).
H
NMR
(90 ꢀꢀꢀ
MHz) ꢀ 1.42 (12H, s), 1.87 (4H, br), 1.93 (2H, m), 2.70 (2H, t, J=7.4 Hz), 3.82 (2H, dt, J=9.0 and 7.4 Hz),
31
7.20 (5H, br); P NMR (109 MHz) ꢀ 135.3.
1
4,4,7,7-Tetramethyl-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphane
(7b).
H
NMR
(270 ꢀꢀꢀ
MHz) ꢀ 1.41 (6H, s), 1.43 (6H, s), 1.48 (1H, d, J=22 Hz), 1.61 (1H, d, J=22 Hz), 1.95 (2H, m), 2.71 ꢀꢀ
31
(2H, t, J=7.6 Hz), 3.78 (2H, dt, J=8.2 and 6.4 Hz), 7.25 (5H, complex); P NMR (109 MHz) ꢀ ꢀꢀ
128.10.
4,4,7,7-Tetramethyl-2-(3-phenylpropyloxy)-1,3,2-dioxaphospholane
1
(7c).
H
NMR
(90 ꢀꢀꢀ
MHz) ꢀ 1.25 (6H, s), 1.38 (6H, s), 1.90 (2H, m), 2.67 (2H, t, J=7.3 Hz), 3.85 (2H, dt, J=10.4 and 6.1 ꢀꢀ
31
Hz), 7.17 (1H, t, J=7.0 Hz), 7.18 (2H, d, J=7.0 Hz), 7.27 (2H, t, J=7.0 Hz); P NMR (109 MHz) ꢀ ꢀ
148.20.
1
3-Phenylpropyl o-xylylene phosphite (21): H NMR (90 MHz) ꢀ 2.05 (2H, m), 2.77 (2H, t, ꢀꢀ
J=6.4 Hz), 3.94 (2H, dt, J=7.4 and 6.4 Hz), 4.57 (2H, dd, J=13.0 and 8.9 Hz), 5.67 (2H, dd, J=13.0
and 9.4 Hz), 7.22 (9H, complex).
1
Di-t-butyl 3-phenylpropyl phosphite (23): H NMR (90 MHz) ꢀ 1.41 (18H, s), 1.91 (2H, m), ꢀꢀ
2.69 (2H, t, J=6.2 Hz), 3.80 (2H, q, J=6.2 Hz), 7.20 (5H, complex).
2-(3-Phenylpropyloxy)-1,3,2-dioxaphosphepane (20) prepared from the corresponding amidite and ꢀ
PPrOH was used after chromatographic purification and TLC analysis. 2-Diethylamino-1,3,2-
1
dioxaphosphepane: bp 120-130 ˚C (bath temp.)/5 mmHg; H NMR (90 MHz) ꢀ 1.00 (6H, t, J=8.5 Hz),
31
1.70 (4H, m), 3.12 (4H, dq, J=10.8 and 8.5 Hz), 3.90 (4H, m); P NMR (109 MHz) ꢀ 131.42.
27
Bis(3-phenylpropyl) hydrophosphonate: bp 205 ˚C (bath temp.)/0.4 mmHg (lit.,
186 ˚C/0.2 ꢀ
1
mmHg); H NMR (270 MHz) ꢀ 2.02 (4H, tt, J=7.3 and 6.4 Hz), 2.73 (4H, t, J=7.3 Hz), 4.08 (4H, dt, ꢀ
31
J=7.9 and 6.4 Hz), 6.83 (1H, d, J=694.6 Hz), 7.08-7.18 (10H, complex); P NMR (109 MHz) ꢀ 8.52; ꢀ
-1
IR (neat) 2450 cm .

1
2-Benzyloxy-4,4,7,7-tetramethyl-2-oxo-1,3,2-dioxaphosphane.
H NMR (90 MHz) ꢀ 1.28 ꢀꢀꢀ
31
(6H, s), 1.40 (6H, s), 1.85 (2H, br), 4.93 (2H, d, J=6.7 Hz), 7.20 (5H, complex); P NMR (109 MHz) ꢀꢀ
ꢀ -7.11; Anal. Calcd for C H O P: C, 59.15; H, 7.45. Found: C, 59.44; H, 7.22.
14 21 4
1
2-Oxo-2-(3-phenylpropyloxy)-1,3,2-dioxaphosphepane. H NMR (90 MHz) ꢀ 1.58-2.10 (6H,
31
complex), 2.67 (2H, t, J=6.4 Hz), 3.53-4.30 (6H, complex), 7.18 (5H, complex); P NMR (109 MHz) ꢀꢀ
ꢀ 3.86; Anal. Calcd for C H O P: C, 57.78; H, 7.09. Found: C, 57.11; H, 7.10.
13 19 4
1
4-Hydroxybutyl bis(3-phenylpropyl) phosphate: H NMR (270 MHz) ꢀ 1.59-1.82
(4H, ꢀ
complex), 2.00 (4H, m), 2.72 (4H, t, J=7.3 Hz), 3.67 (2H, t, J=6.1 Hz), 4.05 (4H, q, J=6.4 Hz), 4.09 ꢀꢀ
31
(2H, dt, J=10.1 and 6.1 Hz), 7.12 (10H, complex); P NMR (109 MHz) ꢀ 0.06; IR (neat, cm ) 3450;
-1
.
Anal. Calcd for C H O P 1/2H O: C, 63.60; H, 7.76. Found: C, 63.71; H, 7.70.
22 31 5
2
1
Tri-3-phenylpropyl phosphate: H NMR (90 MHz) ꢀ 2.01 (6H, quint, J=6.4 Hz), 2.70 (6H, t, ꢀ
31
J=6.4 Hz), 4.01 (6H, q, J=6.4 Hz), 7.13 (15H, complex); P NMR (109 MHz) ꢀ 0.00
1
3-Phenylpropyl o-xylylene phosphate: H NMR (90 MHz) ꢀ 1.98 (2H, quint, J=6.9 Hz), 2.67 ꢀꢀ
31
(2H, t, J=6.9 Hz), 4.08 (2H, q, J=6.9 Hz), 5.07 (4H, m), 7.18 (5H, complex); P NMR (109 MHz) ꢀ ꢀ
.
0.74; Anal. Calcd for C H O P 2/3H O: C, 61.81; H, 6.19. Found: C, 61.57; H, 5.79.
17 19 4
2
1
Benzyl o-xylylene phosphate: H NMR (90 MHz) ꢀ 4.89 (6H, complex), 7.10-7.40 (9H, complex);
31
P NMR (109 MHz) ꢀ 0.10.
1
Dibutyl 3-phenylpropyl phosphate: H NMR (90 MHz) ꢀ 0.90 (6H, t, J=6.4 Hz), 1.17-1.87 (8H, ꢀꢀ
31
br), 2.00 (2H, m), 2.70 (2H, t, J=6.4 Hz), 4.01 (6H, q, J=6.4 Hz), 7.16 (5H, complex); P NMR (109
MHz) ꢀ 0.08. The authentic specimen was prepared according to a usual procedure from dibutyl
phosphorochloridate and PPrOH.
1
Butyl bis(3-phenylpropyl) phosphate: H NMR (90 MHz) ꢀ 0.83 (3H, t, J=6.0 Hz), 1.10-1.70 ꢀꢀ
31
(4H, br), 1.89 (4H, m), 2.65 (4H, t, J=6.4 Hz), 3.94 (6H, q, J=6.4 Hz), 7.13 (10H, complex);
P ꢀꢀ
NMR (109 MHz) ꢀ 0.07. The authentic specimen was prepared according to a usual procedure from butyl
phosphorodichloridate and PPrOH.
1
tert-Butyl 3-phenylpropyl hydrophosphonate: H NMR (90 MHz) ꢀ 1.53 (9H, s), 2.01 (2H, m), ꢀ
2.70 (2H, t, J=6.4 Hz), 4.01 (2H, dt, J=8.3 and 6.4 Hz), 6.79 (1H, d, J=680.4 Hz), 7.21 (5H, complex); ꢀ
31
-1
P NMR (109 MHz) ꢀ 9.78; IR (neat) 2430 cm .
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