Synthesis and bioactivity of novel bisphosphonate derivatives

Article abstract of DOI:10.3987/COM-07-11246

Synthesis of novel bis-(2,10-dimethyl-4,8-di-t-butyl-12H-6-oxidodibenzo[d,g][1,3,2]dioxaphosphocin -6-yl)2/3/4-substituted phenyl/heteroarylmethanes were accomplished by Pudovic reaction. Addition of an equimolar quantities of 2,2′-methylene-bis(6-tert-bu

Full text of DOI:10.3987/COM-07-11246

HETEROCYCLES, Vol. 75, No. 3, 2008
611
HETEROCYCLES, Vol. 75, No. 3, 2008, pp. 611 - 618. © The Japan Institute of Heterocyclic Chemistry
Received, 18th October, 2007, Accepted, 5th December, 2007, Published online, 11th December, 2007. COM-07-11246
SYNTHESIS AND BIOACTIVITY OF NOVEL BISPHOSPHONATE
DERIVATIVES
B. Hari Babu,a G. Syam Prasad,a M. F. Stephen Babu,a
Pallamreddy Haranath,a S. Hemadri Reddy,b and C. Naga Raju*a
aDepartment of Chemistry, Sri Venkateswara University, Tirupati-517502, India
bDepartment of Biotechnology, Sri Venkateswara University, Tirupati, India
E-mail: naga_raju04@yahoo.co.in
Abstract – Synthesis of novel bis-(2,10-dimethyl-4,8-di-t-butyl-12H-6-oxido-
dibenzo[d,g][1,3,2]dioxaphosphocin -6-yl)2/3/4-substituted phenyl / heteroaryl-
methanes were accomplished by Pudovic reaction. Addition of an equimolar
quantities of 2,2′-methylene-bis(6-tert-butyl-4-methylphenol) 1 and EtOH to
PCl3 afforded cyclic condensation product. This on reaction with respective
aldehydes followed by treatment with phosphorus(III) monochloride of 1,
corresponding bisphosphonate intermediates were formed which on subsequent
stirring at reflux temperature rearranged from P(III) to P(V) state.
INTRODUCTION
Bisphosphonates, carbon analogues of pyrophosphate, strongly chelate metal ions and adsorb to bone.1
They have been used to treat osteoporosis2 and as radio imaging agents3 and have reduced metastases in
breast cancer.4 Bisphosphonates as anticancer drugs is receiving further attention following the reports
that clodronate exhibited antimetastatic activity in cancer patients, decreasing the tumor burden in the
bone.5 Even simple carbonyl bisphosphonates are reported to inhibit HIV-1 replication in vitro.6
Another interesting use is in nuclear medicine as ligands for radiometals as bone-seeking diagnostic and
therapeutic agents. Nugent et al7 synthesised a few pyrazoline bisphosphonate esters and studied their
anti-inflammatory and antiarthritic activity. Bisphosphonates find application in the prevention and
treatment of bone metastases in breast cancer.8 Oldfield et al9 synthesised nitrogen containing
bisphosphonates and tested for their activity in inhibiting the growth of three human cell lines, and found
the most active species being a tetrakispivaloylmethyl (POM) ester, having an (average) IC50 of 6.8 µM.
The most potent bisphosphonates are found10 in the series containing a heteroaromatic moiety (with at
least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit.
Zoledronic acid10 is the most potent derivative and it has an ED50 of 0.07 mg/kg. However, full potential

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HETEROCYCLES, Vol. 75, No. 3, 2008
of bisphosphonates in chemotherapy is yet to be exploited and it remains to be work of the future.10-11 In
view of the above reports, we have synthesized new bisphosphonates and studied their antimicrobial
activity.
RESULTS AND DISCUSSION
Synthesis of novel bis-(2,10-dimethyl-4,8-di-t-butyl-12H-6-oxidodibenzo [d,g] [1,3,2] dioxaphosphocin-
6-yl) 2/3/4-substituted phenyl / heteroaryl methanes (6a-j) were accomplished by Pudovic reaction.
Addition of an equimolar amount of 2,2′-methylene-bis (6-tert-butyl-4-methylphenol) (1) and EtOH to
PCl3 in toluene afforded cyclic condensation product 2. It is a better procedure to get cyclic hydrogen
phosphonates (2) when compared to the method of reaction of 1 directly with PCl3 followed by addition
of water in which acid-catalyzed reversible reaction occurs giving back the starting compounds.12
Phosphonate 2, was treated with respective aldehydes 3a-j to get corresponding (2,10-dimethyl-4,8
-di-t-butyl-12H-6-oxidodibenzo [d,g] [1,3,2] dioxaphosphocin- 6-yl) 2/3/4 substituted phenyl / heteroaryl
methanols (4a-j) (Pudovic reaction). Reaction of 4a-j with 6-chloro-2,10-dimethyl-4,8-di-t-butyl
-12H-dibenzo[d,g] [1,3,2] dioxaphosphocin (5), which was prepared by reacting 1 with PCl3 in N2
atmosphere corresponding bisphosphonate intermediates were obtained. These on subsequent stirring at
reflux temperature for about 6 hrs rearranged from
P(III) to P(V) state12-13 and afforded
bis(2,10-dimethyl-4,8-di-t-butyl-12H-6-oxidodibenzo[d,g][1,3,2]dioxaphosphocin-6-yl) 2/3/4 substituted
phenyl / heteroaryl methanes (6a-j).
But
Me
3'
O
3
But
Me
4'
Me
CH2
But
5
O
But
But
Cl P
2
4
But
Me
Me
Me
2'
1'
5'
O 4a'
O
4a
H
C
R
1
OH
But
O
O
RCHO
3a-j
O
O
P
O
Me
12a'
12' CH2
O
P H
12a
H
5
i
12 CH2
6
P
CH2
CH2
P C OH
R
CH2
6'
ii
11a'
7'O7a'
11a
reflux
11'
10'
11
OH
O
But
O7
O
But
7a
8 But
10
But
Me
Me
8'
Me
But
Me
Me
9'
9
6a-j
1
2
4a-j
i) PCl3, EtOH
ii) toluene, Et3N
R
Compd.
h
R
R
Compd.
e
Compd.
a
-CCl3
3''-NO2-C6H4
4''-HO-C6H4
4''-MeO-C6H4
O
S
4''-Me-C6H4
b
c
f
g
i
4''-Cl-C6H4
4''-Br-C6H4
j
N
d
The structures of all the compounds are confirmed by elemental analysis, multi NMR and FAB mass
spectrometry. The compounds 6a-j were obtained as isomeric products. Their separation could not be
effected by fractional crystallization. A few carbon NMR signals were split into two signals due to the
presence of diastereoisomers in the sample.14 The presence of two forms in the solution state is further
evidenced by the presence of two phosphorus chemical shifts in the 31P NMR spectra of all the

HETEROCYCLES, Vol. 75, No. 3, 2008
613
synthesized compounds 6a-j.
All the title compounds showed IR absorption bands15-17 in the region 1276-1262 (P=O), 769-761
(P-Caliph), 1219-1201 [O-C of P-O-C(aromatic)] and 956-931 [P-O of P-O-C(aromatic)] cm-1.In the 31P-NMR, all
31
the compounds 6a-j exhibited two distinct P chemical shifts for the two phosphorus (Pα and Pβ) atoms
present in them. This indicates their high magnitude of non-equivalence which might be arising due to
their existence in two different isomers because of the restricted rotation between them.18-19
The aromatic protons of the title compounds showed multiplets at δ 7.82-6.08. The bridged methyne
(P-CH-P) proton resonated as a triplet due to coupling with phosphorous20 in the region 3.61-3.66 ppm (t,
J
P-C-H=14.5-14.7 Hz). The chemical shifts of other protons are observed in the expected regions for the
13
compounds 6a-j. Interpretation of the C NMR data was based on additivity rules, computed chemical
shifts of starting compound 1, carbon couplings with phosphorus and intensity of signals. The oxygen
bearing C(4a) & C(7a) and C(4a′) & C(7a′) resonated as doublets in the downfield region at δ 149.98 –
149.61 (2JPOC = 5.3-6.9 Hz). The chemical shifts of the bridged C(11a) & C(12a) and C(11a′) & C(12a′)
appeared as low intensity signals at δ 126.25-125.26.21 The bulky t-butyl groups attached to C(4) & C(8)
and C(4′) & C(8′) showed signals in the region δ 136.79-136.40. The singlet at δ 131.86-130.85 is
assigned to C(2) & C(10) and C(2′) & C(10′). The signals in the regions δ 20.96-20.94 and 31.27-30.53
were ascribed to methyl carbons [-C(CH3)] and t-butyl group [-C(CH3)3] attached to C-2 & 10 / C-2′ &
10′ and C-4 & 8 / C-4′ & 8′ respectively. The bridged chiral carbon in these compounds gave the signal
in the region δ 48.25-44.76.20 Mass spectral data for 6b, 6g and 6i were recorded. All the three
compounds exhibited M+1 and M+• ions in their mass spectra. Multinuclear NMR and mass spectral data
conclusively confirm the structures of 6a- j.
ANTIMICROBIAL ACTIVITY
The compounds 6a-j were screened at two different concentrations (25, 75 µg / disc) for their antifungal
activity on Aspergillus niger and Fusarium solani, Nystatin (25 µg / disc) is used as standard according to
disc-diffusion method.22 The fungal cultures were grown on potato dextrose broth at 25 °C for 3 hours
and finally spore suspension was adjusted to 106 spores/ disc. Their antibacterial activity was evaluated
against Staphylococcus aureus and Escherichia coli (105 cell / mL) on nutrient agar plates at 37 °C for 24
hours.23 Ciprofloxacin is used as standard antibiotic. The title compounds were potent against tested
bacteria. The compounds showed promising antibacterial activity against the bacteria when compared
with that of standard, whereas their antifungal activity is moderate. It is interesting to observe that the
nitrogen containing analogues 6e and 6j possess significant antibacterial activity (Table 1).

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Table 1: Antibacterial and antifungal activitiesa of compounds 6a-j in terms of zone of inhibition (mm)
Bacteria
Fungi
Compd.
Staphylococcus
aureus(µg/disc)
Escherichia coli
Aspergillus
niger(µg/disc)
Fusarium solani
(µg/disc)
(µg/disc)
25
5
2
3
-
75
6
3
5
3
9
5
3
5
7
9
8
-
25
3
-
75
5
3
5
-
25
3
-
75
5
2
4
-
25
4
3
5
-
75
6a
5
-
6b
6c
5
2
4
3
-
5
2
4
2
-
4
-
6d
6e
5
4
-
7
5
2
5
6
8
6
-
5
3
2
2
3
5
-
4
5
-
6
-
6f
6g
-
6h
6i
3
3
6
-
4
3
5
-
3
2
4
-
5
3
4
-
3
5
6
-
6j
Ciprofloxacin
Nystatin
-
-
-
6
-
4
a concentrations expressed in ppm, ‘-’ indicates no activity.
In summary, we have adopted an effective and simple route for the synthesis of novel bisphosphonates,
whose structures were supported by elemental and spectral analyses. The reaction can be performed
smoothly in dry toluene in the presence of a base and the products are relatively easy to isolate and purify.
EXPERIMENTAL
The melting points were determined on a Mel-Temp apparatus and were uncorrected. Elemental
analyses were performed by the Central Drug Research Institute, Lucknow, India. All IR spectra were
1
13
31
recorded as KBr pellets on a Perkin-Elmer 1430 unit, H, C and P NMR spectra were recorded on
1
AMX 400 MHz spectrometer, operating at 400 MHz for H, 100 MHz for 13C and 161.9 MHz for 31P as
13
solutions in CDCl3 and the chemical shifts were referenced to TMS (1H & C) and 85% H3PO4 (31P).
2,2′-methylene-bis (6-tert-butyl-4-methyl) phenol (1) was procured from Aldrich chemical company,
USA.
Synthesis of Bis (2,10-dimethyl-4,8-di-t-butyl-12H-6-oxidodibenzo[d,g] [1,3,2] dioxaphosphocin-6-yl)-
4-methylphenylmethane (6b).
It is obtained in 4 steps. In step 1,2,2′-methylene-bis(6-tert-butyl-4-methylphenol )(1, 0.68 g, 0.002

HETEROCYCLES, Vol. 75, No. 3, 2008
615
mol) was dissolved in 25 mL of dry toluene and to this EtOH (0.09 g, 0.002 mol) was added. The mixture
was cooled to 5-10 °C. To this PCl3 (0.27 g, 0.002 mol) was added dropwise taken in 10 mL of dry
toluene. The reaction flask was cooled extremely so that the temperature did not rise above 25 °C. The
reaction mixture was stirred at 25 °C for 4 h. Finally the reaction mixture was warmed on the steam bath
to complete the removal of the by-products, 2,2′-methylene-bis(6-tert-butyl-4-methyl) hydrogen
phosphonate (2) was obtained after removal of toluene at reduced pressure as white crystalline solid, mp
155-157 °C.
In step 2,4-methylbenzaldehyde (3b, 0.12 g, 0.001 mol) and trietylamine (0.50 g, 0.005 mol) in dry toluene
was added at 5-8 °C to 2 (0.38 g, 0.001 mol) in toluene and mixture was stirred for 4 h to get
2,10-dimethyl-4,8-di-t-butyl-12H-6-oxidodibenzo[d,g][1,3,2]dioxaphosphocin-6-yl)-4-methylphenylmethanol
(4b). In step 3, compound 1 was treated with PCl3 in toluene under nitrogen atmosphere in the presence
of triethylamine to get 5.
In step 4, to the cold (5-7 °C) solution of 4b (0.50 g, 0.001 mol) and triethylamine (0.1 g, 0.001 mol)
taken in a new reaction flask in toluene, 5 (0.38 g, 0.001 mol) was added. Temperature was slowly raised
to 50°C and stirring was continued for 6 h and then at refluxing temperature for 6 more h. Triethylamine
hydrochloride was separated by filtration and the solvent from the filtrate was removed under reduced
pressure. The residue was recrystallised from EtOH to afford the title compound 6b. The title compounds
6a and 6c-j were prepared by adopting the same procedure.
Physical, Analytical and Spectral Data for the Compounds 6a-j
6a ;Yield 73%, mp 112-114 °C (EtOH). IR (KBr): νmax 1276 (P=O), 1219, 934 P-O-C(aromatic) 768 (P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.38-7.25 (m, 8H,
Ar-H), 4.39-4.43 (m, 4H, 2x-CH2-), 3.62-3.65(t, J=14.7 Hz, 1H, P-CH-P), 2.25 (s, 12H, CH3), 1.39 (s,
36H, C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ: 129.4 (C-1&11/ C-1’&C11’), 131.9 (C-2&10/ C-2’&10’),
127.1 (C-3&9/ C-3’&9’), 136.4 (d, J=4.2 Hz, C-4&8/ C-4’&8’), 149.9 (d, J=6.3 Hz, C-4a&7a/ C-4a’&
7a’), 126.3 (d, J=4.2 Hz, C-11a&12a/ C-11a’&12a’), 32.1 (-CH2-12&12’), 20.9 ((CH3), 2,10/2’,10’) 34.6
(t-C(CH3)3, 4,8/4’8’), 30.5 (t-C(CH3)3, 4,8/4’8’) , 48.3 (P-CH-P) 106.8 (-CCl3). Anal. Calcd for
C48H61O6P2Cl3: C 63.89; H 6.76. Found: C 63.85; H 6.79 %.
6b ;Yield 71%, mp 118-120 °C (EtOH). IR (KBr): νmax 1262 (P=O), 1201, 956 P-O-C(aromatic) 768 (P-C)
1
31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.36-7.24 (m, 12H, Ar-H),
4.39- 4.58 (m, 4H, 2x-CH2-), 3.61-3.65 (t, J=14.7 Hz, 1H, P-CH-P), 2.28 (s, 12H, CH3), 1.37 (s, 36H,
C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ: 129.4 (C-1&11/ C-1’&11’), 130.9 (C-2&10/ C-2’& 10’), 127.7
(C-3&9/ -3’&9’), 136.5(d, J=4.1 Hz, C-4&8/ C-4’&8’), 149.9 (d, J=6.9 Hz, C-4a&7a/ C-4a’& 7a’), 125.3

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(d, J=4.2 Hz, C-11a&12a/ C-11a’&12a’), 32.0 (-CH2-12&12’), 20.9 ((CH3), 2,10/2’,10’) 34.6 (t-C(CH3)3,
4,8/4’8’), 31.3(t-C(CH3)3, 4,8/4’8’), 46.1 (P-CH-P), 126.3 (C-1”), 129.6(C-2”&6”), 131.9 (C-3”&5”),
140.7(C-4”), 29.9(4”-CH3) FAB-MS, m/z (%): 875 (M+• + 1, 16), 874 (M+•, 14), 845 (19), 790 (23),
774(41), 725 (11), 664 (5), 660 (4), 609 (4), 562 (8), 387 (100), 340 (53), 331 (12), 275 (28), 265 (8), 223
(6),77 (48), 161 (27), 136 (21), 105 (11), 91 (9). Anal. Calcd for C54H68O6P2: C 74.14;H 7.78. Found: C
74.07;H 7.74 %.
6c ; Yield 81%, mp 151-153 °C (EtOH). IR (KBr): νmax 1276 (P=O), 1218, 931 P-O-C(aromatic) 769 (P-C)
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, 1H NMR (CDCl3, 400 MHz) δ: 6.31-7.18 (m, 12, Ar-H),
4.32-4.41 (m, 4H, 2x-CH2-), 3.61-3.64 (t, J=14.7 Hz, 1H, P-CH-P), 2.25 (s, 12H, CH3), 1.33 (s, 36H,
(CH3)3 ). Anal. Calcd for C53H61O6P2Cl: C 71.10; H 7.26. Found: C 71.07; H 7.22 %.
6d ; Yield 76%, mp 139-141 °C (EtOH). IR (KBr): νmax 1270(P=O), 1211, 943 P-O-C(aromatic) 763 (P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.37-7.38 (m, 12H,
Ar-H), 4.38- 4.41 (m, 4H, 2x-CH2-), 3.61-3.65 t, J=14.7 Hz, 1H, P-CH-P), 2.28 (s, 12H, CH3), 1.38 (s,
36H, C(CH3)3). Anal. Calcd for C53H65O6P2Br: C 67.73; H 6.92. Found: C 67.69; H 6.89 %.
6e ; Yield 77%, mp 115-117 °C (EtOH). IR (KBr): νmax 1276 (P=O), 1219, 934 P-O-C(aromatic) 768 (P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.38-7.66 (m, 12H,
Ar-H), 4.39-4.43 (m, 4H, 2x-CH2-), 3.62-3.66 (t, J=14.7 Hz, 1H, P-CH-P), 2.29 (s, 12H, CH3), 1.39 (s,
13
36H, C(CH3)3); C NMR (CDCl3, 100 MHz) δ: 128.3 (C-1&11/ C-1’&11’), 131.7 (C-2&10/ C-2’&10’),
127.8 (C-3&9/ C-3’&9’), 135.6 (d, J=4.8 Hz, C-4&8/ C-4’&8’), 149.6 (d, J=6.3 Hz, C-4a&7a/ C-4a’&
7a’), 125.3 (d, J=4.2 Hz, C-11a&12a/ C-11a’&12a’), 31.3(-CH2-12&12’), 20.3 ((CH3), 2,10/2’,10’)
34.6(t-C(CH3)3, 4,8/4’8’),30.5 (t-C(CH3)3, 4,8/4’8’) 44.8 (P-CH-P), 126.8(C-1”),129.6(C-2”), 142.6
(C-3”), 128.7(C-4”), 129.4 (C-5”), 136.6(C-6”). Anal. Calcd for C53H65NO8P2: C 70.27; H 7.18; N 1.54.
Found: C 70.23; H 7.15; N 1.51 %.
6f ; Yield 73%, mp 124-126 °C (EtOH). IR (KBr): νmax 1273(P=O), 1207, 933 P-O-C(aromatic) 761 (P-C)
31
1
cm-1, P NMR (CDCl3, 161.9 MHz) δ: 4.88, H NMR (CDCl3, 400 MHz) δ: 6.37-7.24 (m, 12H, Ar-H),
4.38-4.43 (m, 4H, 2x-CH2-), 3.61-3.65 (t, J=14.7 Hz, 1H, P-CH-P), 2.25 (s, 12H, CH3), 1.37 (s, 36H,
C(CH3)3). Anal. Calcd for C53H66O7P2: C 72.60; H 7.53. Found: C 72.54; H 7.48 %.
6g ; Yield 68%, mp 109-111 °C (EtOH). IR (KBr): νmax 1269 (P=O), 1213, 940 P-O-C(aromatic) 765 (P-C)
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.941H NMR (CDCl3, 400 MHz) δ: 6.38-7.26 (m, 12H,

HETEROCYCLES, Vol. 75, No. 3, 2008
617
Ar-H), 4.39-4.43 (m, 4H, 2x-CH2-), 3.62-3.66 (t, J=14.7 Hz, 1H, P-CH-P), 2.29 (s, 12H, CH3), 1.39 (s,
36H, C(CH3)3); FAB-MS m/z (%):906 (M+•+1, 28), 905 (M+•, 21), 845 (5), 844 (3), 774 (97), 727 (18),
725 (16), 708 (9), 595 (2), 572 (3), 562 (16), 516 (38), 488 (42), 460 (9), 387 (99), 386 (51), 340 (100),
339 (33), 275 (41), 265 (12), 223 (16), 177 (97), 161 (67), 102 (69), 91 (11). Anal. Calcd for C54H68O7P2:
C 72.80; H 7.64; Found: C 72.85; H 7.59 %.
6h ; Yield 63%, mp 120-122 °C (EtOH). IR (KBr): νmax 1271 (P=O), 1215, 941 P-O-C(aromatic) 764(P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.08-7.82 (m, 11H,
Ar-H), 4.32-4.39 (m, 4H, 2x-CH2-), 3.63-3.66 (t, J=14.7 Hz, 1H, P-CH-P), 2.17 (s, 12H, CH3), 1.45 (s,
36H, C(CH3)3). Anal. Calcd for C51H64O7P2: C 72.00; H 7.52. Found: C 72.06; H 7.48 %.
6i ; Yield 65%, mp 134-136 °C (EtOH). IR (KBr): νmax 1276 (P=O), 1218, 934 P-O-C(aromatic) 769 (P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.38-7.25 (m, 11H,
Ar-H), 4.39-4.43 (m, 4H, 2x-CH2-), 3.62-3.65 (t, J=14.7 Hz, 1H, P-CH-P), 2.29 (s, 12H, CH3), 1.39 (s,
36H, C(CH3)3); FAB-MS m/z (%): 867 (M+• +1, 23), 866 (M+•, 21), 845 (4), 808 (4), 774 (23), 727 (6),
658 (3), 562 (6), 387 (100), 340 (57), 331 (13), 275 (21), 239 (7), 223 (9), 177 (43), 161 (23), 154 (21),
136 (18), 105 (11), 91 (9). Anal. Calcd for C51H64O6P2S: C 70.66; H 7.39. Found: C 70.63 H 7.44 %.
6j ; Yield 74%, mp 129-131 °C (EtOH). IR (KBr): νmax 1274 (P=O), 1219, 934 P-O-C(aromatic) 769 (P-C)
1
cm-1, 31P NMR (CDCl3, 161.9 MHz) δ: 0.77, 4.94, H NMR (CDCl3, 400 MHz) δ: 6.38-7.26 (m, 12H,
Ar-H), 4.37-4.40 (m, 4H, 2x-CH2-), 3.61-3.65 (t, J=14.7 Hz, 1H, P-CH-P), 2.28 (s, 12H, CH3), 1.38 (s,
13
36H, C(CH3)3); C NMR (CDCl3, 100 MHz) δ: 129.4 (C-1&11/ C-1’&11’), 131.9 (C-2&10/ C-2’&10’),
127.1 (C-3&9/ C-3’&9’), 136.7 (d, J=3.8, Hz, C-4&8/ C-4’&8’), 149.6(d, J=5.3 Hz, C-4a&7a/
C-4a’&7a’), 126.3 (d, J=4.2 Hz, C-11a&12a/ C-11a’&12a’), 31.1 (-CH2-12&12’), 20.9 ((CH3),
2,10/2’,10’) 34.6 (t-C(CH3)3, 4,8/4’8’), 30.5 (t-C(CH3)3, 4,8/4’,8’),46.3 (P-CH-P), 181.7(C-2”&6”),
128.7(C-3”&5”), 178.6(C-4”). Anal. Calcd for C52H65NO6P2: C 72.47; H 7.54; N 1.62. Found: C 72.50; H
7.49; N 1.58 %.
ACKNOWLEDGEMENTS
The authors express thanks to the director of Central Drug Research Institute, Lucknow and Sophisticated
Instrumentation Facility, IISc, Bangalore for the elemental analyses and spectral data.
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