Unusual reactivity of cis-2-benzoyl-1-benzyl-3-phenylaziridine with p-nucleophiles - Ring opening vs. the Abramov reaction

Article abstract of DOI:10.1039/a909521g

Thermal (80 °C) addition of dimethyl phosphite to cis-2-benzoyl-1-benzyl-3-phenylaziridine occurred exclusively at C(3) with concomitant cleavage of the C(2)-C(3) bond. The carbonyl group in the aminoketone produced under these conditions was reduced with hydrogen over Pearlman's catalyst with low (20%) diastereoselectivity, while good (80%) de was observed in the NaBH₄ reduction as a result of the 1,4-asymmetric induction. The products of the Abramov reaction of the title compound were obtained (de 92%) when CsF was used as catalyst.

Full text of DOI:10.1039/a909521g

View Article Online / Journal Homepage / Table of Contents for this issue
Unusual reactivity of cis-2-benzoyl-1-benzyl-3-phenylaziridine
with P-nucleophiles—ring opening vs. the Abramov reaction
Andrzej E. Wróblewski,*a Waldemar Maniukiewiczb and Wiesława Karolczaka
1
a Institute of Chemistry, Faculty of Pharmacy, Medical University of Łódz´, 90-151 Łódz´,
Muszyn´skiego 1, Poland
b Institute of General and Ecological Chemistry, Technical University of Łódz´, 90-924 Łódz´,
˙
Zwirki 36, Poland
Received (in Cambridge, UK) 2nd December 1999, Accepted 3rd March 2000
Thermal (80 ЊC) addition of dimethyl phosphite to cis-2-benzoyl-1-benzyl-3-phenylaziridine occurred exclusively
at C(3) with concomitant cleavage of the C(2)–C(3) bond. The carbonyl group in the aminoketone produced under
these conditions was reduced with hydrogen over Pearlman’s catalyst with low (20%) diastereoselectivity, while
good (80%) de was observed in the NaBH4 reduction as a result of the 1,4-asymmetric induction. The products
of the Abramov reaction of the title compound were obtained (de 92%) when CsF was used as catalyst.
Introduction
There is a growing interest in the synthesis of amino-
flavonoids1–6 as well as aminochalcones.7,8 In our ongoing
programme directed towards the synthesis of biologically active
phosphonate analogs having amino and hydroxy groups9 we
turned our attention to aminohydroxyphosphonate derivatives
of flavonoids. In model studies we have recently elaborated the
chemistry of β,γ-epoxy-α-hydroxyphosphonates 1 derived from
chalcone epoxide.10 These epoxides would have been considered
as useful precursors to γ-amino-α,β-dihydroxyphosphonates 2
(Scheme 1) if they had been stable in the presence of amines.11
Scheme 2 Reagents and conditions: (a) (MeO)2P(O)H (3), benzene,
80 ЊC.
tallization and was identified as the tertiary amine 5 (Scheme 2).
1
From H NMR and IR spectra the presence of the benzoyl
group was evident. The definitive structural assignments in 5
were based on the detailed analysis of the 13C NMR spectra
including the attached proton test (apt) experiment. Three-
bond C–P couplings were found for two methylene carbons, and
a large one-bond C–P coupling was noticed for the C–H car-
bon. These data clearly differentiate the tertiary amine 5 from
the isomeric phosphonate 6, which would have been formed
Scheme 1 Retrosynthetic approach to 2.
Attempts at opening the oxirane ring in 1 with azides led to
impure γ-azidophosphonates in low yields.12 For this reason we
selected another model compound containing the chalcone
skeleton and found that addition of dimethyl phosphite (3) to
trans-2-benzyl-1-(tert-butoxycarbonyl)-3-phenylaziridine gave
exclusively rearranged enol phosphate in good yield.11 cis-2-
Benzoyl-1-benzyl-3-phenylaziridine (4)13,14 was chosen as the
next model compound and herein we wish to describe its
reactivity with dimethyl phosphite.
Results and discussion
In order to add 3 to the carbonyl group of the aziridine 4 several
catalysts have been tried, but most of them led to the formation
of complex reaction mixtures usually containing significant
amounts of the unreacted 4. The best result was obtained when
an equimolar mixture of 3 and 4 was refluxed in benzene in the
presence of 1 equiv. of NEt3. The 31P NMR spectrum of the
crude product showed one major resonance at 25.70 ppm
accompanied by several minor ones at 29.81, 28.70 and 26.42
as a result of the N–C(3) bond cleavage. Later, we found that
the synthesis of 5 was accomplished from 3 and 4 in refluxing
benzene without triethylamine.
The formation of the P–C bond in 5 can be rationalized
in the following way. At elevated temperatures the C(2)–C(3)
bond in the aziridine 4 is cleaved to give an azomethine ylide
(Scheme 2).15–17 Thermal [2 ϩ 3] cycloadditions of similar
᎐
ylides to C᎐C and various C᎐X (X = C, S, O, N) bonds have
᎐
᎐
1
ppm, while the H NMR spectrum and TLC analysis proved
that all starting aziridine was used up. The addition product
was isolated by chromatography on silica gel followed by crys-
been studied in detail.17 The addition of dimethyl phosphite to
the electrophilic center of the ylide followed by the transfer of a
proton to the enolate leads to the aminoketone 5. Under these
DOI: 10.1039/a909521g
J. Chem. Soc., Perkin Trans. 1, 2000, 1433–1437
This journal is © The Royal Society of Chemistry 2000
1433

View Article Online
Scheme 3 Reagents and conditions: (a) NaBH4, MeOH, rt; (b) H2, Pd(OH)2–C, MeOH.
conditions only racemic 5 is produced because both faces of the
31P NMR chemical shifts (23.15 and 22.46 ppm) for 10a and
10b, respectively, and that both compounds have very similar
polarities.
azomethine carbon are equally accessible. The stereochemistry
of 4 has no influence on the structure of the addition product
5 because only one azomethine ylide is formed from both the
cis- and trans-isomers.
In order to gather further evidence for the formation of 10b,
attempts at equilibrating pure 10a to a mixture of 10a and
10b were proposed. However, it has recently been shown that
in the presence of basic catalysts the structurally related
β,γ-epoxy-α-hydroxyphosphonates 1 did not only undergo the
retro-Abramov reaction, but they also rearranged to enol
phosphates, and were partially demethylated when triethyl-
amine was used.11 Based on these results DBU and CsF were
Sodium borohydride reduction of the carbonyl group in 5
afforded a 9:1 mixture of inseparable aminoalcohols 7a and
7b, respectively (Scheme 3). On the other hand, hydrogenation
of 5 over Pearlman’s catalyst gave a 6:4 mixture of amino-
alcohols 8a and 8b, which also could not be separated. The
same aminoalcohols, but in a 9:1 ratio, were produced by
hydrogenolysis of 7a and 7b over Pd(OH)2–C. To assign the
relative stereochemistry in the major product of the boro-
hydride reduction, a 9:1 mixture of 7a and 7b was esterified
with p-nitrobenzoyl chloride. The p-nitrobenzoate 9a of the
major diastereoisomer was isolated by column chromatography
followed by crystallization and formed crystals suitable for
X-ray structural studies (vide infra).
Low diastereoselectivity in the catalytic reduction of the
carbonyl group in 5 (de ca. 20%) contrasts with significant (de
80%) excess of 7a over 7b, when NaBH4 was used. We suggest
that in the borohydride reduction the diastereoselectivity was
induced by the center of chirality at the C α to the phosphoryl
group (1,4-asymmetric induction). Fig. 1 shows the preferred
conformation of 5 coordinated to Naϩ which leaves the re face
of the carbonyl group in (R)-5 open to hydride addition. In
this conformation three phenyl groups attain interaction-free
spatial arrangement.
selected as catalysts for the equilibration of 10a. The 1H and 31
P
NMR monitoring of an equimolar mixture of 10a and DBU at
room temperature revealed the retro-Abramov reaction as a
single equilibration pathway. After 2 h, ca. 50% of 10a was
transformed into the starting aziridine 4 and a series of decom-
position products produced from dimethyl phosphite, and after
48 h only traces of 10a remained in the mixture. The 31P NMR
signal of minor diastereoisomeric phosphonate 10b was never
detected. When 10a was treated with 200 mol% of CsF at room
temperature for 24 h, a mixture of 10a (23%) and the aziridine 4
1
(77%) was obtained as judged from the H NMR spectrum.
Again, the formation of 10b was not observed.
The aziridine phosphonate 10a was found to be almost
completely unreactive towards hydrogen in the presence of
Pd(OH)2–C and appeared unstable in Pd–C catalyzed hydro-
genolysis under pressure in methanol. The cleavage of the P–C
bond was the major transformation observed as judged from
the 31P NMR spectra of the crude product and 4 was isolated in
69% yield after column chromatography. Due to the instability
of 10a we turned to X-ray structural analysis in order to estab-
lish the configuration of this compound.
The molecular structures of 9a and 10a are shown in Figs. 2
and 3, respectively. The atomic parameters for non-H atoms are
available as Electronic Supplementary Information.† In both
structures the P atom adopts a distorted tetrahedral configur-
ation; the bond angles around the P atom are in the range
101.1(1)–116.8(1)Њ for 9a and 101.6(1)–116.1(1)Њ for 10a. The
mean P–O bond lengths [1.563(2) Å for 9a and 1.568(2) Å for
Fig. 1 The preferred conformation of 5.
Finally, we succeeded in the addition of dimethyl phosphite
to the carbonyl group of the aziridine 4 (Scheme 4). This was
10a], the P᎐O bond lengths [1.458(3) Å for 9a and 1.454(2) Å
᎐
for 10a] and P–C bond lengths [1.800(4) Å for 9a and 1.836(2)
Å for 10a] correspond well with those found in the Cambridge
Structural Database.18 The C2N ring in 10a shows the character-
istic behavior of analogous substituted aziridines where the
presence of a heteroatom is coupled with the high strain of the
three-membered ring and the actual geometry is the result of
several effects due to each substituent. The C(2)–C(4) bond
3
3
of 1.500(3) Å is shorter than the normal single Csp –Csp bond,
but is longer than the mean value of 1.484(3) Å retrieved from
the Cambridge Crystallographic Database for saturated C2N
rings.19 As expected the ring nitrogen is pyramidal, lying
0.656(2) Å out of the plane defined by the three atoms bonded
to it. The interesting point of note is the intramolecular hydro-
gen bond observed between the nitrogen of the aziridine ring
Scheme 4 Reagents and conditions: (a) CsF, CH2Cl2, rt, 2 h.
achieved using CsF as a catalyst, but in order to obtain pure
products the reaction time had to be shortened to 2 h. After
recovery of the unreacted 4 by column chromatography (45%),
a mixture of 10a containing its C(1) epimer 10b (4%) was
isolated in 16% yield. Pure diastereoisomer 10a was obtained by
crystallization. Although we were unable to separate pure 10b,
the formation of this phosphonate was concluded from the
† Structure factors can be obtained from the author (W. M.). Aniso-
tropic displacement parameters and hydrogen atom parameters have
been deposited at Cambridge Crystallographic Data Centre. CCDC
reference number 207/407. See http://www.rsc.org/suppdata/p1/a9/
a909521g for crystallographic files in .cif format.
1434
J. Chem. Soc., Perkin Trans. 1, 2000, 1433–1437

View Article Online
Fig. 5 Stereochemical model of the addition to cis-4.
Hz. The respective dihedral angles calculated from the molecu-
lar structure are 174 and 32Њ, in agreement with values obtained
using the known 3J(P–C) and 3J(P–H) vs. dihedral angle
relationships.20,21
In the antiperiplanar conformation of 10a the phenyl rings
(Ph–C–P and Ph–CH–N) are positioned almost parallel to each
other and for this reason shielding of the respective aromatic
protons would be expected. 2D (1H–1H and 1H–13C) NMR
correlations showed that resonances of Ph–CH–N are signifi-
cantly shifted upfield (ortho 6.59 ppm, meta 6.89 ppm, para
6.97 ppm), while signals of Ph–C–P form a poorly separated
multiplet at 7.1–7.3 ppm.
High diastereoselectivity of the addition of dimethyl phos-
phite to cis-4 can be rationalized by shielding the si-face of
the carbonyl group by Ph–CH–N (Fig. 5). In this conform-
ation oxygen and nitrogen atoms are chelated by Csϩ on the
surface of solid caesium fluoride, while the electronegative sub-
stituent (N) is placed on the opposite side to the approaching
nucleophile (the Ahn model).22,23
Fig. 2 The molecular structure of 9a with the atom labelling scheme.
Displacement ellipsoids are shown at the 50% probability level and H
atoms are shown as circles of an arbitrary radius.
In conclusion, we have demonstrated that in the presence of
CsF at room temperature dimethyl phosphite adds preferen-
tially (de 92%) to the re-face of the carbonyl group of cis-4.
Thermal addition (80 ЊC) leads, however, to the cleavage of
the C(2)–C(3) bond in the aziridine ring and formation of the
aminoketone 5 in excellent yield.
Experimental
The general experimental procedures and instrumentation were
described earlier.10 2D (1H–1H and 1H–13C) NMR spectra were
obtained on Varian Mercury-300 and Bruker DPX (250 MHz)
spectrometers, respectively.
cis-2-Benzoyl-3-phenyl-1-(phenylmethyl)aziridine 4
Fig. 3 The molecular structure of 10a with the atom labelling scheme.
Displacement ellipsoids are shown at the 50% probability level and H
atoms are shown as circles of an arbitrary radius.
To a cooled (ϩ10 ЊC) solution of dibromochalcone (9.2 g, 0.025
mol) in benzene (25 ml), benzylamine (8.2 ml, 0.075 mol) in
benzene (10 ml) was added dropwise over 1 h and the reaction
mixture was left at room temperature for 20 h. The precipitate
was filtered off, washed with benzene and discarded. The benz-
ene solution was washed with water (3 × 20 ml), dried (MgSO4)
and concentrated to leave a white solid, which was suspended in
petroleum ether (100 ml). After filtration the aziridine 4 (2.80 g,
35%) was obtained as a white amorphous solid, mp 106–107 ЊC
(lit.,13 mp 108 ЊC); νmax (KBr)/cmϪ1 1681, 1598, 1495; δH (100
MHz, CDCl3) 7.9–7.8 (m, 2H, o-C6H5CO), 7.5–7.1 (m, 13H,
C6H5), 4.02 and 3.81 (AB, 2H, J 14.0, CH2), 3.39 and 3.31 (AB,
2H, J 7.0, HC-CH).
Addition of dimethyl phosphite to the aziridine 4
Fig. 4 The preferred conformation of 10a in CDCl3.
a. In refluxing benzene in the presence of NEt3. A solution of
the aziridine 4 (1.56 g, 5.00 mmol), dimethyl phosphite (0.55 g,
5.00 mmol) and NEt3 (0.69 ml, 5.00 mmol) in benzene (5 ml)
was refluxed for 4 h. Volatiles were evaporated, the residue was
dissolved in CH2Cl2 (10 ml), washed with water (3 × 10 ml) and
dried (MgSO4). After removal of solvents the crude product
was subjected to column chromatography on silica gel with
chloroform–methanol (100:1, v/v). The appropriate fractions
and the hydroxy group [O ؒ ؒ ؒ N = 2.644(3) Å, Є O–H ؒ ؒ ؒ
N = 131Њ]. In addition, the crystal packing in both structures
is governed by some intermolecular interactions of the type
C–H ؒ ؒ ؒ O.
The O–H ؒ ؒ ؒ N hydrogen bond also stabilizes the conform-
ation of 10a in a chloroform solution (Fig. 4). This conclusion
3
3
is supported by values of J(P–C) = 11.8 Hz and J(P–H) = 6.3
J. Chem. Soc., Perkin Trans. 1, 2000, 1433–1437
1435

View Article Online
were collected and recrystallized from ethanol to give dimethyl
N-benzyl-N-(2-oxo-2-phenylethyl)amino-1-phenylmethylphos-
phonate (5) (0.99 g, 49%) as colorless crystals, mp 101–102 ЊC
(Found: C, 67.93; H, 6.26; N, 3.29. C24H26NO4P requires C,
68.07; H, 6.19; N, 3.30%); νmax (KBr)/cmϪ1 1689, 1598, 1581,
1493, 1456, 1230, 1058, 1036; δH (250 MHz, CDCl3) 7.92–7.84
(m, 2H, o-C6H5CO), 7.62–7.25 (m, 13H, C6H5), 4.81 (d, 1H,
J 17.3, HCH), 4.41 (d, 1H, J 23.0, HCP), 4.08 (dd, 1H, J 13.3
and 1.6, HCH), 3.75 (d, 3H, J 10.7, CH3OPOCH3), 3.72 (d, 1H,
J 17.2, HCH), 3.50 (d, 1H, J 13.4, HCH), 3.39 (d, 3H, J 10.5,
CH3OPOCH3); δC (62.9 MHz, CDCl3) 198.33, 138.45 (d, J 0.4),
136.15, 133.04, 132.37 (d, J 2.9), 130.69 (d, J 8.5), 129.34,
128.51, 128.42, 128.38 (d, J 1.5), 128.33, 128.10, 127.38, 60.84
(d, J 159.8), 56.78 (d, J 5.0), 56.02 (d, J 11.5), 53.58 (d, J 7.2),
52.87 (d, J 7.0); δP (101.26 MHz, CDCl3) 25.70.
Preparation of the p-nitrobenzoate derivative of 7a
Standard p-nitrobenzoylation of a 9:1 mixture of 7a and 7b
afforded a mixture of p-nitrobenzoates 9a (δP 25.38) and 9b
(δP 26.20) in 83% yield after chromatography on silica gel.
Recrystallization from AcOEt–hexanes gave pure 9a, mp
128–130 ЊC (Found: C, 64.57; H, 5.29; N, 4.84. C31H31N2O7P
requires C, 64.80; H, 5.43; N, 4.87%); νmax (KBr)/cmϪ1 1711,
1530, 1350, 1277; δH (250 MHz, CDCl3) 8.31 (s, 4H, C6H4),
7.50–7.25 (m, 15H, Ph), 6.25 (dd, 1H, J 9.9 and 2.7, HCO), 4.32
(dd, 1H, J 13.8 and 2.8, HCH), 4.08 (d, 1H, J 25.0, HCP),
3.98 (dd, 1H, J 13.8 and 9.9, HCH), 3.47 (d, 3H, J 10.8,
CH3OPOCH3), 3.40 (d, 3H, J 10.5, CH3OPOCH3), 3.39 (d, 1H,
J 14.0, HCH), 2.70 (dd, 1H, J 14.0 and 2.9, HCH); δP (101.26
MHz, CDCl3) 25.38.
Hydrogenation of the aminoketone 5 over Pd(OH)2–C
b. In refluxing benzene. A solution of the aziridine 4 (313 mg,
1.00 mmol) and dimethyl phosphite (0.091 ml, 1.00 mmol)
in benzene (3 ml) was refluxed for 4 h. After evaporation of
benzene, the residue was dissolved in CH2Cl2 (10 ml), washed
with water (3 × 10 ml), dried over MgSO4 and concentrated.
Purification on silica gel column afforded 5 (0.380 g, 90%) as
a colorless solid.
A suspension of 5 (105 mg, 0.25 mmol), anhydrous CH3OH
(1 ml) and Pd(OH)2–C (20 mg) was stirred under atmospheric
pressure of H2 (balloon) at room temperature for 24 h. The
catalyst was removed on Celite, and the solution was concen-
trated to leave a 6:4 mixture of 8a and 8b quantitatively as a
colorless oil (Found: C, 60.73; H, 6.76; N, 4.07. C17H22NO4P
requires: C, 60.89; H, 6.61; N, 4.18%); νmax (neat)/cmϪ1 3366,
1493, 1454, 1233, 1028; δH (250 MHz, CDCl3) 8a 7.4–7.1 (m,
10H, C6H5), 4.76 (dd, 1H, J 8.6 and 3.8, HCO), 4.10 (d, 1H,
J 20.9, HCP), 3.74 (d, 3H, J 10.6, CH3OPOCH3), 3.51 (d, 3H,
J 10.5, CH3OPOCH3), 2.76 (dAB, 1H, J 12.3 and 4.1, HCH),
2.69 (dAB, 1H, J 12.3 and 8.9, HCH), 8b 7.4–7.1 (m, 10H), 4.66
(dd, 1H, J 8.7 and 3.5, HCO), 4.02 (d, 1H, J 20.6, HCP), 3.73
(d, 3H, J 10.6, CH3OPOCH3), 3.50 (d, 3H, J 10.5, CH3-
OPOCH3), 2.86 (dd, 1H, J 12.2 and 3.6, HCH), 2.60 (dd, 1H,
J 12.2 and 8.8, HCH); δC (62.9 MHz, CDCl3) 8a 142.18, 135.12
(d, J 2.8), 128.58 (d, J 2.5), 128.30 (d, J 6.2), 128.18, 128.08 (d,
J 3.0), 127.36, 125.72, 71.51, 59.65 (d, J 154.8), 54.88 (d, J 15.8),
53.44 (d, J 7.0), 8b 142.29, 135.46 (d, J 3.3), 128.54 (d, J 2.6),
128.25 (d, J 6.3), 128.30, 128.04 (d, J 3.0), 127.40, 125.75, 72.65,
60.92 (d, J 153.6), 55.85 (d, J 15.6), 53.55 (d, J 6.6); δP (101.26
MHz, CDCl3) 8a 26.25, 8b 26.12.
c. In the presence of CsF. A mixture of the aziridine 4 (1.55 g,
4.95 mmol), dimethyl phosphite (0.458 ml, 5.00 mmol) and CsF
(1.51 g, 10.0 mmol) containing CH2Cl2 (1 ml) was stirred at
room temperature for 2 h. The fluoride was filtered off and
washed with CH2Cl2 (10 ml). The organic solution was washed
with water (3 × 10 ml), dried over MgSO4 and concentrated.
The crude product was chromatographed on silica gel with
chloroform–methanol (200:1, v/v) to give unreacted 4 (0.701 g,
45%) and phosphonates 10a and 10b (0.339 g, 16%) as a white
solid. Recrystallization of this material from AcOEt–hexanes
gave 10a, mp 134–136 ЊC (Found: C, 68.20; H, 6.56; N, 3.43.
C24H26NO4P requires C, 68.07; H, 6.19; N, 3.30%); νmax (KBr)/
cmϪ1 3284, 1496, 1449, 1240, 1056, 1020; δH (250 MHz, CDCl3)
7.50–7.42 (m, 2H), 7.42–7.32 (m, 3H), 7.32–7.25 (m, 2H), 7.22–
7.10 (m, 3H), 7.05–6.85 (m, 3H), 6.59 (d, 2H, J 7.3, aromatic
protons), 4.41 (d, 1H, J 13.0, HCH), 3.97 (br s, 1H, OH),
3.74 (d, 3H, J 10.1, CH3OPOCH3), 3.51 (d, 1H, J 13.0, HCH),
3.44 (d, 3H, J 10.1, CH3OPOCH3), 3.08 (dd, 1H, J 6.5 and
6.3, H-2), 2.96 (d, 1H, J 6.5, H-3); δC (62.9 MHz, CDCl3)
137.70, 137.60 (d, J 2.6), 134.62, 128.91, 128.56, 127.63, 127.60,
127.51 (d, J 2.8), 127.28, 127.18 (d, J 3.2), 126.39, 125.75 (d,
J 4.5), 72.49 (d, J 164.0), 62.94, 54.51 (d, J 7.5), 53.88 (d, J 8.1),
47.78 (d, J 5.7), 44.98 (d, J 11.8); δP (101.26 MHz, CDCl3)
23.15.
1H and 31P NMR monitoring of the reaction of 10a and DBU
To a solution of 10a (0.021 g, 0.050 mmol) in chloroform-d
(0.7 ml) DBU (0.015 g, 0.050 mmol) was injected. The progress
of the reaction was monitored by 31P NMR after 0.5 and
1 h, and by 1H and 31P NMR after 2 and 48 h.
CsF-catalyzed transformation of 10a
A suspension of 10a (0.070 g, 0.165 mmol) and CsF (0.050 g,
0.33 mmol) in CH2Cl2 (2 ml) was stirred at room temperature
for 24 h. After removal of CsF by filtration, the organic solu-
tion was washed with water (3 × 4 ml), dried and concentrated
NaBH4 reduction of 5
A solution of the aminoketone 5 (211 mg, 0.50 mmol) in
methanol (1 ml) was cooled to 0 ЊC and NaBH4 (19 mg, 0.50
mmol) was added portionwise. After 1 h at room temperature,
water (0.1 ml) was injected and CH2Cl2 (10 ml) was added. The
solution was dried over MgSO4 and concentrated to leave a
crude product (221 mg, 104%). Filtration through a pad of
silica gel gave a solid (212 mg, 100%) identified as a 9:1 mixture
of 7a and 7b, mp 80–82 ЊC; νmax (KBr)/cmϪ1 3371, 1491, 1451,
1221, 1031; δH (250 MHz, CDCl3) 7a 7.50–7.15 (m, 15H), 4.80
(dd, 1H, J 10.6 and 2.7, H-C-OH), 4.29 (br s, 1H, OH), 4.24 (d,
1H, J 26.9, HCP), 4.17 (dd, 1H, J 13.7 and 2.7, HCH), 3.83 (d,
3H, J 10.8, CH3OPOCH3), 3.50 (d, 3H, J 10.5, CH3OPOCH3),
3.46 (dd, 1H, J 13.4 and 10.7, HCH), 3.38 (d, 1H, J 13.4,
HCH), 2.54 (dd, 1H, J 13.4 and 2.8, HCH); δC (62.9 MHz,
CDCl3) 7a 142.12, 137.98, 131.29 (d, J 5.3), 130.62 (d, J 8.8),
129.04, 128.53, 128.42, 128.38, 128.19, 127.50, 127.30, 125.69,
70.30, 60.09 (d, J 165.0), 59.49 (d, J 3.5), 55.72 (d, J 14.0), 53.17
(d, J 7.0), 53.07 (d, J 7.3); δP (101.26 MHz, CDCl3) 7a 26.46, 7b
27.25.
1
to leave a colorless oil (40 mg) which was analyzed by H and
31P NMR spectroscopy.
Hydrogenation of a 9:1 mixture of 7a and 7b over Pd(OH)2–C
A mixture of 7a and 7b (105 mg, 0.25 mmol) was hydrogenated
as described above to give a 9:1 mixture of 8a and 8b (84 mg,
100%).
X-Ray determination
Common to both determinations: KM4 diffractometer
equipped with graphite-monochromatized Cu-Kα. The struc-
tures were solved by direct methods using the SHELXS
program24 and refined on F 2 values by full-matrix least squares
using the SHELXL program25 from the SHELX-97 package.
All non-H atoms were refined anisotropically while H atoms
were introduced at the calculated positions and refined using a
1436
J. Chem. Soc., Perkin Trans. 1, 2000, 1433–1437

View Article Online
6 T. Akama, Y. Shida, T. Sugaya, H. Ishida, K. Gomi and M. Kasai,
J. Med. Chem., 1996, 39, 3461.
riding model, each with an isotropic displacement parameter
equal to 1.2 times Ueq of the neighboring heavier atom.
7 S. F. Nielsen, S. B. Christensen, G. Cruciani, A. Kharazmi and
T. Liljefors, J. Med. Chem., 1998, 41, 4819.
8 J. R. Dimmock, N. M. Kandepu, M. Hetherington, J. W. Quail,
U. Pugazhenthi, A. M. Sudom, M. Chamankhah, P. Rose, E. Pass,
T. M. Allen, S. Halleran, J. Szydlowski, B. Mutus, M. Tannous,
E. K. Manavathu, T. G. Myers, E. De Clercq and J. Balzarini,
J. Med. Chem., 1998, 41, 1014.
Compound 9a. Crystal data. C31H31N2O7P, Mr = 574.55,
¯
triclinic, P1, a = 9.479(2), b = 10.342(1), c = 15.374(2) Å, α =
94.17(1), β = 99.43(2), χ = 91.32(2)Њ, V = 1481.9(4) Å3, Z = 2,
Dx = 1.288 g cmϪ3, T = 293 K, λ (Cu-Kα) = 1.54178 Å, µ = 1.2
mmϪ1, F(000) = 604, final R = 0.0546 for 3381 observed reflec-
tions [Fo > 4σ(Fo)].†
9 A. E. Wróblewski and D. G. Piotrowska, Tetrahedron, 1998, 54,
8123.
10 A. E. Wróblewski and W. Karolczak, Pol. J. Chem., 1998, 72,
Compound 10a. Crystal data. C24H26NO4P, Mr = 423.43,
orthorhombic, P212121, a = 6.116(1), b = 16.340(2), c =
1160.
11 A. E. Wróblewski and W. Karolczak, Pol. J. Chem., 1999, 73,
1191.
12 A. E. Wróblewski and W. Karolczak, unpublished observations.
13 N. H. Cromwell and R. A. Wankel, J. Am. Chem. Soc., 1949, 71,
711.
14 V. D. Orlov, F. G. Yaremenko and V. F. Lavrushin, Khim.
Geterotsikl. Soedin., 1980, 16, 1489.
22.124(4) Å, V = 2211.0(6) Å3, Z = 4, Dx = 1.272 g cmϪ3
,
T = 293 K, λ (Cu-Kα) = 1.54178 Å, µ = 1.3 mmϪ1, F(000) = 896,
final R = 0.0350 for 2283 observed reflections [Fo > 4σ(Fo)]. An
absorption correction based on ψ-scan was applied.26 †
15 A. Padwa, L. Hamilton and L. Norling, J. Org. Chem., 1966, 31,
1244.
16 P. Tarburton, C. A. Kingsbury, A. E. Sopchik and N. H. Cromwell,
J. Org. Chem., 1978, 43, 1350.
17 J. W. Lown, J. P. Moser and R. Westwood, Can. J. Chem., 1969, 47,
4335, and references cited therein.
18 F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen
and R. Taylor, J. Chem. Soc., Perkin Trans. 2, 1987, S1.
19 F. H. Allen, Tetrahedron, 1982, 38, 2843.
20 J.-R. Neeser, J. M. J. Tronchet and E. J. Charollais, Can. J. Chem.,
1983, 61, 2112.
21 C. Benezra, J. Am. Chem. Soc., 1973, 95, 6890.
22 N. T. Anh, Fortschr. Chem. Forsch., 1980, 88, 145.
23 N. T. Anh, F. Maurel and J.-M. Lefour, New J. Chem., 1995, 19,
353.
Acknowledgements
Financial support from the Medical University of Łódz´ (503-
302-4) is gratefully acknowledged. We thank Mrs Jolanta
Płocka for her skilled experimental contributions and Miss
Dorota G. Piotrowska for discussion of 2D NMR data.
References
1 S. Mahboobi and H. Pongratz, Synth. Commun., 1999, 29, 1645.
2 J. Ferte, J.-M. Kühnel, G. Chapnis, Y. Rolland, G. Lewin and M. A.
Schwaller, J. Med. Chem., 1999, 42, 478.
3 P. Traxler, J. Green, H. Mett, U. Sequin and P. Furet, J. Med.
Chem., 1999, 42, 1018.
4 T. Akama, H. Ishida, U. Kimura, K. Gami and H. Saito, J. Med.
Chem., 1998, 41, 2056.
5 T. Akama, H. Ishida, Y. Shida, U. Kimura, K. Gomi, H. Saito,
E. Fuse, S. Kobayashi, N. Yoda and M. Kasai, J. Med. Chem., 1997,
40, 1894.
24 G. M. Sheldrick, SHELXS-97. Program for the Refinement of
Crystal Structures, University of Göttingen, Germany, 1997.
25 G. M. Sheldrick, SHELXL-97. Program for the Refinement of
Crystal Structures, University of Göttingen, Germany, 1997.
26 KUMA KM-4 Manual, Wrocław, 1996.
J. Chem. Soc., Perkin Trans. 1, 2000, 1433–1437
1437