Temporary phosphate tethers: A metathesis strategy to differentiated polyol subunits

Article abstract of DOI:10.1021/ol0602809

Studies probing reactivity and selectivity of cross metathesis (CM) with an exocyclic olefin in a P-chiral bicyclo[4.3.1]phosphate triester are described. Studies have revealed a Type III CM reactivity pattern for the exocyclic olefin within this phosphat

Full text of DOI:10.1021/ol0602809

Supporting Information
Temporary Phosphate Tethers:
A Metathesis Strategy to Differentiated Polyol
Subunits
Joshua D. Waetzig and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive,
Lawrence, KS 66045-7582 phanson@KU.edu
Table of Contents
General Experimental Methods: S2
Experimental Section and Characterization Data: S3-S11
NMR Spectra for New Compounds: S12-S39

General Experimental Methods
All air and moisture sensitive reactions were carried out in flame- or oven-dried glassware
under argon atmosphere using standard gastight syringes, cannulaes, and septa. Stirring was
achieved with oven-dried magnetic stir bars. Et2O, toluene, THF and CH2Cl2 were purified
by passage through the Solv-Tek purification system employing activated Al2O3 (Grubbs,
R.H.; Rosen, R.K.; Timmers, F.J.; Organometallics 1996, 15, 1518-1520). Et3N was
purified by passage over basic alumina and stored over KOH. Butyl Lithium was purchased
from Aldrich and titrated prior to use. Grubb’s first and second-generation as well as the
Hoveyda-Grubb’s olefin metathesis catalysts were acquired from Materia and used without
further purification. Glycidol ether was acquired from Daiso Co., Ltd., Fine Chemical
Department and used without further purifiction. Flash column chromatography was performed
with Merck silica gel (EM-9385-9, 230-400 mesh). Thin layer chromatography was
performed on silica gel 60F254 plates (EM-5717, Merck). Deuterated solvents were
purchased from Cambridge Isotope Isotope laboratories. 1H, 13C and 31P NMR spectra were
recorded on a Bruker DRX-400 spectrometer operating at 400 MHz, 100 MHz, and 162
MHz respectively; or a Bruker Avance operating at 500 MHz and 125 MHz respectively.
High-resolution mass spectrometry (HRMS) and FAB spectra were obtained on a VG
Instrument ZAB double-focusing mass spectrometer.

General Procedure for Cross Metathesis of Type I Olefins: A flask or pressure tube containing
5 (20 mg, 0.099 mmol) was charged with CH2Cl2 (2 mL) that had been degassed 15 minutes with
argon. The Type I olefin partner (1.1 equiv. relative to compound 5) followed by Hoveyda-
Grubbs II catalyst (6.2 mg, 0.009 mmol) were added and the reaction mixture was refluxed for 3-
6 hours. Upon completion (monitored by TLC) the reaction was cooled to rt and concentrated
under reduced pressure.
2,9,10-Trioxa-1-phosphabicyclo[4.3.1]dec-4-ene, 8-E-(3-hydroxy-propenyl)-, 1-oxide,
(1R,6R, 8R) : 9
O
P
HO
O
O
O
Purification via flash chromatography (9:1 EtOAc/MeOH) supplied 19 mg (86% yield) of 9 as a
1
viscous oil. [∝]D -78.83 (c = 0.60, CH2Cl2); IR (neat) 3402, 2923, 2358, 1286, 1064, 973 cm-1; H
NMR (500 MHz, CDCl3) δ 5.92-6.03 (m, 2H), 5.72 (ddd, JHH = 15.48, 3.81, 1.52 Hz, 1H), 5.55
(ddd, JHH = 11.83, 3.63, 2.74 Hz, 1H), 5.10-5.19 (m, 1H), 5.01 (dd, JHH = 11.78, 5.58 Hz, 1H),
4.91-4.98 (m, 1H), 4.38 (ddd, J = 27.78, 14.79, 6.71 Hz, 1H), 4.14 (d, JHH = 4.32 Hz, 2H), 2.20
(ddd, JHH = 18.28, 12.16, 6.21 Hz, 1H), 1.73 (d, JHH = 14.70 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 133.6, 130.1, 128.5, 127.2 (d, JCP = 10.3 Hz), 77.6, 76.4 (d, JCP = 6.1 Hz), 63.5 (d, JCP =
6.4 Hz), 62.5, 35.6 (d, JCP = 5.7 Hz); 31P NMR (162 MHz, CDCl3) δ -2.70; Exact Mass: calculate
for C9H13O5P (M+Na)+ 255.0398; found 255.0403 (ESI)
2,9,10-Trioxa-1-phosphabicyclo[4.3.1]dec-4-ene, 8-E-[3-[(tert-butyl)dimethylsilyl]]oxy-
propenyl)-, 1-oxide, (1R,6R,8R) : 10
O
TBSO
P
O
O
O
Purification via flash chromatography (1:1 Hexane/EtOAc) supplied 29 mg (87% yield) of 10 as a
1
oil. [∝]D -44.20 (c = 0.24, CH2Cl2); IR (neat) 2954, 2927, 2856, 2348, 1299, 1068 cm-1; H NMR
(500 MHz, CDCl3) δ 5.98 (dddd, JHH = 11.98, 6.62, 2.83, 2.81 Hz, 1H), 5.88 (dddd, JHH = 15.45,
8.20. 4.10, 1.58 Hz, 1H), 5.67-5.71 (m, 1H), 5.63 (ddd, JHH = 11.82, 3.80, 2.76 Hz, 1H), 5.18-5.25
(m, 1H), 5.00 (dd, JHH = 11.49, 5.44 Hz, 1H), 4.95 (m, 1H), 4.37 (ddd, J = 27.73, 14.77, 6.71 Hz,
1H), 4.13 (t, JHH = 1.94 Hz, 2H), 2.19 (ddd, JHH = 18.23, 12.08, 6.21 Hz, 1H), 1.70-1.74 (m, 1H),
0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 133.1, 129.7, 128.4, 125.8 (d, JCP = 10.0

Hz), 76.0 (d, JCP = 6.3 Hz), 63.0 (d, JCP = 6.4 Hz), 62.5, 35.3 (d, JCP = 6.3 Hz), 25.9, 18.4, -5.31, -
5.29; 31P NMR (162 MHz, CDCl3) δ -2.75; Exact Mass: calculate for C15H27O5PSi (M+Na)+
369.1263; found 369.1263 (ESI)
Boc-Protected Allyl Amine derived Bicyclo[4.3.1]phosphate Triester: 11
O
BocNH
P
O
O
O
Purification via flash chromatography (1:1 Hexane/EtOAc) supplied 22 mg (69% yield) of 11 as a
1
oil. [∝]D -49.37 (c = 0.16, CH2Cl2); IR (neat) 3330, 2962, 2358, 1712, 1515, 1292 cm-1; H NMR
(500 MHz, CDCl3) δ 5.98-6.02 (m, 1H), 5.81 (app dt, JHH = 15.33, 5.28 Hz, 1H), 5.59 (dd, JHH
=
15.47, 5.06 Hz, 1H), 5.53 (app dt, JHH = 10.91, 3.24 Hz, 1H), 5.13 (app d, J = 24.48 Hz, 1H), 4.90-
5.01 (m, 2H), 4.40 (ddd, J = 28.75, 14.79, 6.72 Hz, 1H), 3.71 (s, 2H), 2.17 (ddd, JHH = 18.41,
12.32, 6.26 Hz, 1H), 1.71 (d, JHH = 14.53, 1H) 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.7,
130.9, 129.6, 128.2, 127.9 (d, JCP = 9.6 Hz), 76.9, 75.8 (d, JCP = 6.1 Hz), 63.0 (d, JCP = 6.3 Hz),
41.6, 35.1 (d, JCP = 6.0 Hz), 29.7, 28.4; 31P NMR (162 MHz, CDCl3) δ -2.96; Exact Mass:
calculate for C14H22NO6P (M+H)+ 332.1263; found 332.1277 (ESI)
2,9,10-Trioxa-1-phosphabicyclo[4.3.1]dec-4-ene, 8-E-[3-(dimethyl-phosphate)-propenyl]-, 1-
oxide, (1R,6R, 8R): 12
O
(MeO)2PO
O
P
O
O
O
Purification via flash chromatography (9:1 EtOAc/MeOH) supplied 27 mg (80% yield) of 12 as a
oil. [∝]D -48.3 (c = 0.48, CH2Cl2); IR (neat) 2956, 2358, 1296 1037, 955 cm-1; 1H NMR (500
MHz, CDCl3) trans isomer δ 5.98-6.03 (m, 1H), 5.94 (app dt, JHH = 15.47, 5.27 Hz, 1H), 5.78 (dd,
JHH = 15.48, 3.49 Hz, 1H), 5.55 (app dt, JHH = 11.81, 3.68 Hz, 1H), 5.15 (d, JHH = 24.30 Hz, 1H),
5.00-5.06 (m, 1H), 4.91-4.99 (m, 1H), 4.51 (dd, J = 7.80, 4.66 Hz, 2H), 4.33 (ddd, J = 27.74,
14.77, 6.66 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.17 (app ddd, JHH = 18.31, 12.35, 6.11 Hz, 1H),
1.75 (app d, JHH = 14.17 Hz, 1H); 13C NMR (125 MHz, CDCl3) trans isomer δ 130.0 (d, JCP = 10.3
Hz), 129.5, 128.3, 127.4 (d, JCP = 6.6 Hz), 77.0, 76.9, 75.1 (d, JCP = 6.0 Hz), 66.5 (d, JCP = 5.2 Hz),
54.5, 54.4, 35.0 (d, JCP = 5.8 Hz); 31P NMR (162 MHz, CDCl3) trans isomer δ 2.66, -3.04; cis

isomer δ 2.74, 2.89; Exact Mass: calculate for C11H18O8P2 (M+Na)+ 363.0375; found 363.0386
(ESI)
General Procedure for Cross Metathesis of Type II Olefins: A flask or pressure tube
containing 5 (20 mg, 0.099 mmol) was charged with CH2Cl2 (2 mL) that had been degassed 15
minutes with argon. The Type II olefin partner (4-5 equiv. relative to compound 5) followed by
Hoveyda-Grubbs II catalyst (6.2 mg, 0.009 mmol) were added and the reaction mixture was
refluxed for 3-6 hours. Upon completion (monitored by TLC) the reaction was cooled to rt and
concentrated under reduced pressure.
2,9,10-Trioxa-1-phosphabicyclo[4.3.1]dec-4-ene, 8-E-[3-(oxo)-butenyl]-, 1-oxide, (1R,6R,
8R): 8
O
P
O
O
O
O
Purification via flash chromatography (9:1 EtOAc/MeOH) supplied 18 mg (75% yield) of 8 as a
1
oil. [∝]D -56.7 (c = 0.33, CH2Cl2); IR (neat) 2958, 2362, 1701, 1677, 1275, 973 cm-1; H NMR
(500 MHz, CDCl3) δ 6.61 (app dt, JHH = 20.34, 3.53Hz, 1H), 6.50 (dd, JHH = 15.71, 1.66 Hz, 1H),
6.12 (ddd, JHH = 11.87, 3.81, 2.75 Hz, 1H), 5.57 (dddd, JHH = 11.83, 6.62, 2.79, 2.40 Hz, 1H),
5.20-5.24 (m, 1H), 5.14-5.19 (m, 1H), 4.94-5.00 (m, 1H), 4.35 (ddd, J = 27.97, 14.85, 6.71 Hz,
1H), 2.22 (s, 3H), 2.13-2.23 (m, 1H), 1.82 (app dd, JHH = 14.62, 1.46 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 197.2, 140.4 (d, JCP = 10.4 Hz), 129.9, 129.2, 128.7, 76.9 (d, JCP = 5.7 Hz), 74.2
(d, JCP = 5.9 Hz), 63.2 (d, JCP = 6.3 Hz), 34.5 (d, JCP = 6.0 Hz), 28.67; 31P NMR (162 MHz, CDCl3)
δ -3.39; Exact Mass: calculate for C10H13O5P (M+Na)+ 267.0398; found 267.0409 (ESI)
Methyl acrylate derived Bicyclo[4.3.1]phosphate Triester: 14
O
O
P
O
O
O
MeO
Purification via flash chromatography (1:2 Hexane/EtOAc) supplied 20 mg (78% yield) of 14 as a
1
oil. [∝]D -42.75 (c = 0.40, CH2Cl2); IR (neat) 2954, 2852, 1724, 1300, 973 cm-1; H NMR (500
MHz, CDCl3) δ 6.87 (app dt, JHH = 15.55, 3.73 Hz, 1H), 6.27 (dd, JHH = 15.54, 1.85 Hz, 1H), 6.12

(dddd, JHH = 11.89, 6.61, 2.81, 2.40 Hz, 1H), 5.66 (ddd, JHH = 11.86, 3.83, 2.66 Hz, 1H), 5.28-
5.32 (m, 1H), 5.22-5.28 (m, 1H), 5.03-5.09 (m, 1H), 4.44 (ddd, J = 27.93, 14.84, 6.71 Hz, 1H),
3.79 (s, 3H), 2.25 (ddd, JHH = 18.35, 12.28, 6.23 Hz, 1H), 1.90 (app dd, JHH = 14.66, 1.25 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 166.2, 142.6 (d, JCP = 10.3 Hz), 129.2, 128.7, 122.1, 76.8, 74.1 (d,
JCP = 5.8 Hz), 52.0, 34.4 (d, JCP = 5.9 Hz) 29.7; 31P NMR (162 MHz, CDCl3) δ -3.36; Exact Mass:
calculate for C10H13O6P (M+H)+ 261.0528; found 261.0533 (ESI)
t-Butyl acrylate derived Bicyclo[4.3.1]phosphate Triester: 15
t-BuO
O
O
P
O
O
O
Purification via flash chromatography (1.5:1 Hexane/EtOAc) supplied 3 mg of the minor cis-15
isomer of methyl acrylate derived bicyclic phosphate as a oil. The trans isomer was inseparable
from starting material (5:1 E/Z). [∝]D -65.50 (c = 0.20, CH2Cl2); IR (neat) 3010, 2923, 1710,
1
1301, 1242, 1159, 973 cm-1; H NMR (500 MHz, CDCl3) δ 6.21 (dd, JHH = 11.66, 6.68 Hz, 1H),
6.04-4.14 (m, 2H), 5.77 (dd, JHH = 11.67, 1.06 Hz, 1H), 5.72 (ddd, JHH = 11.90, 3.86, 2.67 Hz,
1H), 5.16-5.27 (m, 1H), 4.98-5.08 (m, 1H), 4.44 (ddd, J = 27.95, 14.62, 6.78 Hz, 1H), 2.14-2.24
13
(m, 1H), 2.06 (ddd, JHH = 14.38, 3.87, 2.38 Hz, 1H), 1.48 (s, 9H); C NMR (100 MHz, CDCl3) δ
164.5, 144.5 (d, JCP = 12.5 Hz), 129.8, 128.0, 122.7, 81.2, 74.3 (d, JCP = 5.0 Hz), 63.1, 33.4 (d, JCP
= 6.3 Hz) 29.7, 28.1; 31P NMR (162 MHz, CDCl3) δ -3.33 trans, -3.29 cis; Exact Mass: calculate
for C13H19O6P (M+Na)+ 325.0817; found 325.0825 (ESI)
2,9,10-Trioxa-1-phosphabicyclo[4.3.1]dec-4-ene, 8-E-[3-(oxo)-propenyl]-, 1-oxide, (1R,6R,
8R): 16
O
O
P
O
O
O
H
Purification via flash chromatography (9:1 EtOAc/MeOH) supplied 18 mg (78% yield) of 16 as a
oil. [∝]D -34.4 (c = 0.45, CH2Cl2); IR (neat) 3150, 2930, 1698, 1300, 975 cm-1; 1H NMR (500
MHz, CDCl3) δ 9.93 (d, JHH = 7.44 Hz, 1H), 6.76 (ddd, JHH = 15.73, 3.93, 3.13 Hz, 1H), 6.47
(ddd, JHH = 16.33, 7.42, 1.64 Hz, 1H), 6.12-6.18 (m, 1H), 5.68 (ddd, JHH = 11.88, 3.88, 2.67 Hz,
1H), 5.36 (ddd, J = 12.30, 3.81, 1.82 Hz, 1H), 5.26-5.33 (m, 1H), 5.04-5.11 (m, 1H), 4.46 (ddd, J

= 27.99, 14.87, 6.71 Hz, 1H), 2.33 (ddd, JHH = 18.36, 12.23, 2.10 Hz, 1H), 1.95 (ddd, JHH = 14.53,
13
3.35, 2.10 Hz, 1H); C NMR (125 MHz, CDCl3) δ 192.1, 149.8 (d, JCP = 10.8 Hz), 132.1, 129.1,
31
128.9, 76.7, 74.0 (d, JCP = 5.7 Hz), 63.2 (d, JCP = 6.3 Hz), 34.2 (d, JCP = 6.0 Hz); P NMR (162
MHz, CDCl3) δ -3.65; Exact Mass: calculate for C9H11O5P (M+H)+ 231.0422; found 231.0447
(ESI)
(R)-1-(Benzyloxy)buten-2-ol derived Bicyclo[4.3.1]phosphate Triester: 17
O
P
O
O
BnO
O
HO
Purification via flash chromatography (1:2 Hexane/EtOAc) supplied 25 mg (72% yield) of 17 as a
1
oil. [∝]D -45.00 (c = 0.60, CH2Cl2); IR (neat) 3404, 2923, 2854, 1272, 1114 cm-1; H NMR (500
MHz, CDCl3) δ 7.22-7.33 (m, 5H), 5.94-6.01 (m, 1H), 5.75-5.85 (m, 2H), 5.53 (ddd, JHH = 11.85,
3.84, 2.61 Hz, 1H), 5.13 (app d, J = 24.47 Hz, 1H), 4.91-5.02 (m, 2H), 4.50 (s, 2H), 4.33 (m,
1H), 4.31 (ddd, J = 27.78, 14.79, 6.71 Hz, 1H), 3.48 (dd, JHH = 9.56, 3.30 Hz, 1H), 3.27 (dd, JHH
9.56, 7.95 Hz, 1H), 2.47 (s, 1H), 2.16 (ddd, JHH = 18.21, 12.05, 6.19 Hz, 1H), 1.72 (dd, JHH
14.71, 1.16 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 137.6, 131.6, 129.6, 128.5, 128.3 (d, JCP =
=
=
10.1 Hz), 128.2, 128.0, 127.9, 77.0, 75.6 (d, JCP = 6.1 Hz), 73.7, 73.5, 70.2, 63.0 (d, JCP = 6.3 Hz),
35.2 (d, JCP = 5.7 Hz); 31P NMR (162 MHz, CDCl3) δ -2.88
(2Z,4R,6R,7E,9R)-10-(benzyloxy)deca-2,7-diene-1,4,6,9-tetraol: 18
OH
OH OH
OBn
HO
o
17 (0.033 g, 0.090 mmol) was taken up in THF (2.0 mL) and lowered to 0 C. LiAlH4 (17 mg,
0.45 mmol) was slowly added. Upon complete addition of LiAlH4, the reaction was warmed to rt
and stirred for one hour. The reaction was quenched under non-aqueous conditions (0.017 mL
H2O slowly, 0.017 mL 15% NaOH slowly, and 0.051 mL H2O). Salts were filtered and washed
(5x with ether) and reaction was concentrated. The concentrated reaction mixture was purified by
flash chromotagraphy (9:1 EtOAc) to supply 23 mg of 18 (70% yield) as an oil. [∝]D -24.28 (c =
1
0.034, CH2Cl2); IR (neat) 3404, 2923, 2856, 1452, 1272, 1110 cm-1; H NMR (500 MHz, CDCl3)
δ 7.29-7.39 (m, 5H), 5.85 (dd, JHH = 15.29, 5.23 Hz, 1H), 5.54-5.76 (m, 3H), 4.68-4.77 (m, 1H),
4.56 (s, 2H), 4.33-4.44 (m, 2H), 4.24 (dd, JHH = 12.52, 6.56 Hz, 1H), 4.02-4.10 (m, 1H), 3.51

(dd, JHH = 9.50, 3.19 Hz, 1H), 3.38 (app t, JHH = 7.98 Hz, 1H), 3.13-3.33 (broad s, 4H), 1.75-1.85
(m, 1H), 1.68-1.71 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 137.7, 134.6, 134.6, 130.2, 128.9,
128.5, 128.0, 127.9, 74.0, 73.4, 70.7, 69.8, 65.7, 58.7, 42.6; Exact Mass: calculate for C17H24O5
(M+NH4)+ 326.1968; found 326.1942 (FAB)
Second Generation Bicyclic Phosphate: 19
O
P
O
O
O
A flask was charged with diol 1 (0.60 g, 4.69 mmol), NEt3 (1.444 g, 14.3 mmol), and DMAP
o
(0.057 g, 0.47 mmol) in DCM (23 mL). The solution was cooled to 0 C, and freshly distilled
POCl3 (0.789 g, 5.16 mmol) was added dropwise. After 25 minutes stirring in the ice bath, 20 mL
of ether was added, and the salts filtered off. The concentrated reaction mixture was purified by
flash chromotagraphy (1:1 Hexane/EtOAc) to supply 0.682 g (70% yield) of the (3R,5R)-
phosphate monochloride as a clear oil. A solution of 2-methylbut-3-en-2-ol (0.310 g, 3.60 mmol)
o
in THF (18.0 mL) was cooled to -30 C. BuLi (2.47 M, 3.60 mmol) was slowly added, followed
by one hour of stirring. A solution of phosphate monochloride (0.682 g, 3.27 mmol) in THF (6.0
mL) was slowly cannulated into the reaction vessel containing the alkoxide. The reaction was
+
stirred at rt for 24 hours and was quenched with 1 mL of NH4 Cl- (sat’d aq) and diluted with 20
ml distilled water. The separated aqueous layer was extracted EtOAc (3x), and the combined
-
organic layers were washed with Na+HCO3 (sat’d aq.), brine, and dried (Na2SO4). A flask
containing triene phosphate was charged with CH2Cl2 (360 mL) that had been degassed 15
minutes with argon. Grubbs Second Generation catalyst was added (122 mg, 0.144 mmol) and the
reaction mixture was refluxed for 3-3.5 hours. Upon completion (monitored by TLC) the reaction
was cooled to rt and concentrated under reduced pressure. Purification via flash chromatography
(1:1 Hexanes/EtOAc) supplied 377 mg (50% yield over two steps) of the 19. [∝]D -93.20 (c =
1
0.72, CH2Cl2); IR (neat) 3197, 2933, 2383, 1384, 1299, 999 cm-1; H NMR (500 MHz, CDCl3) δ
5.83-5.94 (m, 1H), 5.87 (dd, JHH = 12.17, 1.37 Hz, 1H), 5.45 (d, JHH = 16.46 Hz, 1H), 5.42 (dd, JHH
= 12.31, 4.71 Hz, 1H), 5.27 (d, JHH = 10.63 Hz, 1H), 5.14 (ddd, J = 24.56, 5.91, 4.63 Hz, 1H),
4.99 (ddd, J = 11.85, 3.40, 1.54 Hz, 1H), 2.20 (ddd, JHH = 18.22, 12.06, 6.20 Hz, 1H), 1.84 (s,
13
3H), 1.79 (app dd, JHH = 14.58, 1.19 Hz, 1H), 1.52 (d, JHP = 2.59 Hz, 3H); C NMR (125 MHz,
CDCl3) δ 137.9, 135.0 (d, JCP = 10.4 Hz), 125.6, 117.1 (d, JCP = 1.1 Hz), 80.9 (d, JCP = 7.6 Hz),
75.9 (d, JCP = 6.5 Hz), 75.8 (d, JCP = 6.0 Hz), 34.6 (d, JCP = 5.8 Hz), 31.5 (d, JCP = 12.2 Hz), 28.7;

31P NMR (162 MHz, CDCl3) δ -6.86; Exact Mass: calculate for C10H15O4P (M+H)+ 231.0786;
found 231.0793 (ESI)
Homoallyl Alcohol Derived Second Generation Bicyclic Phosphate: 20
O
P
O
O
HO
O
A flask or pressure tube containing 19 (20 mg, 0.087 mmol) was charged with CH2Cl2 (2 mL) that
had been degassed 15 minutes with argon. Homo-allyl alcohol (12.5 mg, 0.173 mmol) followed
by Hoveyda-Grubbs II catalyst (6.2 mg, 0.009 mmol) was added and the reaction mixture was
refluxed for 3-6 hours. Upon completion (monitored by TLC) the reaction was cooled to rt and
concentrated under reduced pressure. Purification via flash chromatography (9:1 EtOAc/MeOH)
supplied 17 mg (71% yield) of 20 as an oil. [∝]D -99.33 (c = 0.30, CH2Cl2); IR (neat) 3404, 2923,
1
1384, 1288, 1271, 1002 cm-1; H NMR (500 MHz, CDCl3) δ 5.83 (dd, JHH = 15.13, 6.94 Hz, 1H),
5.77 (dd, JHH = 12.33, 1.58 Hz, 1H), 5.56 (ddd, JHH = 15.13, 5.67, 0.63 Hz, 1H), 5.32 (dd, JHH
=
12.31, 4.59 Hz, 1H), 4.98-5.08 (m, 1H), 4.90 (q, J = 11.66, 5.67 Hz, 1H), 3.63 (t, JHH = 6.86 Hz,
2H), 2.27 (q, JHH = 12.59, 6.20 Hz, 2H), 2.17 (ddd, JHH = 18.97, 11.95, 6.30 Hz, 1H), 1.75 (s, 3H),
1.68 (ddd, JHH = 14.50, 3.21, 2.20 Hz, 1H), 1.44 (d, JHP = 2.47 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 137.9, 130.5, 129.8 (d, JCP = 10.1 Hz), 125.6, 80.9 (d, JCP = 7.7 Hz), 75.9 (d, JCP = 6.4
31
Hz), 75.8 (d, JCP = 5.9 Hz), 61.6, 35.4, 34.9 (d, JCP = 5.8 Hz), 31.5 (d, JCP = 12.3 Hz), 28.7; P
NMR (162 MHz, CDCl3) δ -6.89; Exact Mass: calculate for C12H19O5P (M+H)+ 275.1048; found
275.1059 (ESI)
Partial Hydrogenation Alcohol-derived Second Generation Phosphate: 21
O
P
O
O
HO
O
CH2Cl2 (14 mL) was added to a flask containing the 20 (0.019 g, 0.069 mmol). Grubbs second
generation catalyst (0.06 g, 0.007 mmol) was added along with Et3N (0.004 g, 0.03 mmol). The
solution was then canulated into a H2 Parr bomb apparatus. The solution was purged with H2 and
o
the bomb sealed. The mixture was heated at 37 C and 300 psi H2 for 2 hours. Concentration
under reduced pressure and purification of the mixture via flash chromatography (9:1

EtOAc/MeOH) supplied 15 mg of the 21 (76% yield) as a oil. [∝]D -68.90 (c = 0.14, CH2Cl2); IR
1
(neat) 3407, 2927, 2854, 1384, 1290, 1271, 1095, 1002 cm-1; H NMR (500 MHz, CDCl3) δ 5.73
(dd, JHH = 10.30, 1.89 Hz, 1H), 5.28 (dd, JHH = 12.29, 4.73 Hz, 1H), 4.96-5.02 (m, 1H), 4.38-4.45
(m, 1H), 3.57 (t, JHH = 6.30, 2H), 2.08 (ddd, JHH = 17.97, 11.98, 5.99 Hz, 1H), 1.73 (s, 3H), 1.40-
13
173 (m, 7H), 1.41 (d, JHP = 2.51 Hz, 3H); C NMR (125 MHz, CDCl3) δ 137.4, 125.5, 80.4 (d,
JCP = 7.5 Hz), 75.9 (d, JCP = 3.8 Hz), 75.8 (d, JCP = 3.8 Hz), 62.3, 35.1 (d, JCP = 8.8 Hz), 34.0 (d, JCP
31
= 6.3 Hz), 31.9, 31.2 (d, JCP = 12.5 Hz), 28.3, 20.7; P NMR (162 MHz, CDCl3) δ -6.37; Exact
Mass: calculate for C12H21O5P (M+H)+ 277.1205; found 277.1213 (ESI)
PMB-Protected Alcohol derived Second Generation Phosphate: 22
O
P
OPMB
O
O
O
The PMB-imidate was prepared via previous method (Organ, M. G.; Wang, J. J. Org. Chem.
2002, 67, 7847-7851). The crude PMB-imidate (86 mg, 0.306 mmol) was dissolved in CH2Cl2
(1.0 mL) at rt and 21 (28 mg, 0.102 mmol) and PPTS (3 mg, 0.0119 mmol) were added. The
mixture was stirred for 22 h during which time a white solid formed. After washing with
saturated NaHCO3 and brine, the solution was dried over anhydrous Na2SO4 and subsequently
filtered. Concentration under reduced pressure and purification of the mixture via flash
chromatography (1:1 EtOAc/MeOH) supplied 37 mg of the 22 (94% yield) as an oil. [∝]D -65.70
1
(c = 0.525, CH2Cl2); IR (neat) 2931, 2858, 1612, 1512 1367, 1290, 1271, 1095, 1000 cm-1; H
NMR (500 MHz, CDCl3) δ 7.26 (app d, JHH = 6.49 Hz, 2H), δ 6.87 (app d, JHH = 8.61 Hz, 2H), δ
5.81 (dd, JHH = 12.32, 1.74 Hz, 1H), 5.35 (dd, JHH = 12.33, 4.51 Hz, 1H), 5.08 (app dt, J = 24.56,
5.19 Hz, 1H), 4.45-4.53 (m, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.43 (t, JHH = 6.15 Hz, 2H), 2.13
(ddd, JHH = 18.11, 11.91, 6.31 Hz, 1H), 1.81 (s, 3H), 1.45-179 (m, 7H), 1.49 (d, JHP = 6.00 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 136.6, 129.5, 128.3, 124.8, 112.8, 79.7 (d, JCP = 7.7
Hz), 75.2 (d, JCP = 3.1 Hz), 75.1 (d, JCP = 2.7 Hz), 71.6, 68.7, 54.3, 34.5 (d, JCP = 9.3 Hz), 33.3 (d,
JCP = 5.9 Hz), 30.5 (d, JCP = 12.1 Hz), 28.3, 27.6, 20.4; 31P NMR (162 MHz, CDCl3) δ -6.34;
Exact Mass: calculate for C20H29O6P (M+H)+ 397.1780; found 397.1782 (ESI)
(4S,5R,7S)-11-(4-methoxybenzyloxy)-2,4-dimethylundec-2-ene-5,7-diol: 23
OPMB
OH OH

A thoroughly dried flask was charged with a solution of CuCN.2LiCl in THF (0.342 mL, 1.0 M
o
solution) and lowered to –30 C. Me2Zn in THF (0.171 mL, 2.0 M solution) was slowly added.
o
Upon addition, the mixture was stirred for 30 minutes at –30 C (mossy green color). A solution
of 22 (27 mg, 0.069 mmol) in THF (0.069 mL) was cannulated slowly into the cuprate solution
o
(at –30 C). The reaction was stirred for 3 hrs and quenched with 10% HCl (5 mL, the reaction
was stirred until copper solids dissolved). The two layers were separated, and the aqueous layer
was washed with CH2Cl2 (4x). The combined organic layers were washed with H2O (1x) and
concentrated under reduced pressure to provide the crude phosphonic acid (one product peak by
31P analysis) as an oil. The acid was taken up in methanol and TMSCHN2 was added at rt until the
yellow solution persisted. A drop of acetic acid was added and the solution was evaporated under
o
reduced pressure. The phosphate was taken up in toluene (0.685 mL) and cooled to 0 C. Red-Al
(0.083 mL of 65% solution in toluene) was slowly added. Upon addition of Red-Al, the flask was
+
warmed to rt and stirred for 3 hrs. The reaction was quenched with 3 mL of NH4 Cl- (sat’d, aq.).
The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined
organic layers were washed with brine (1x), dried (Na2SO4), and concentrated under reduced
pressure. Flash chromatography (1:1 EtOAc/hexane) provided 15 mg of 23 (65% yield over three
steps). [∝]D -13.72 (c = 0.510, CH2Cl2); IR (neat) 3392, 2927, 2856, 1612, 1512 1363, 1247,
1
1209, 1097, 1035 cm-1; H NMR (500 MHz, CDCl3) δ 7.26 (app d, JHH = 8.39 Hz, 2H), δ 6.87
(app d, JHH = 8.51 Hz, 2H), δ 4.97 (d, JHH = 9.78 Hz, 1H), 4.42 (s, 2H), 3.90-3.96 (m, 1H), 3.81 (s,
3H), 3.58 (ddd, JHH = 7.94, 7.87, 2.97 Hz, 1H), 3.44 (t, JHH = 6.53 Hz, 2H), 2.80 (broad s, 2H),
2.44-2.51 (m, 1H), 1.76 (s, 3H), 1.67-173 (m, 1H), 1.66 (s, 3H), 1.35-1.65 (m, 9H), 0.92 (d, JHH
=
6.70 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.1, 135.2, 130.7, 129.3, 126.7, 113.8, 73.4, 72.6,
70.0, 69.1, 55.3, 39.0, 38.9, 37.2, 29.8, 26.1, 22.6, 18.4, 17.0; Exact Mass: calculate for C21H34O4
(M+H)+ 351.2535; found 351.2538 (ESI)

Allyl Alcohol derived Bicyclo[4.3.1]phosphate Triester: 9
O
HO
P
O
O
O

O
P
HO
O
O
O

TBS-Protected Allyl Alcohol derived Bicyclo[4.3.1]phosphate Triester: 10
O
TBSO
P
O
O
O

O
P
TBSO
O
O
O

Boc-Protected Allyl Amine derived Bicyclo[4.3.1]phosphate Triester: 11
O
BocNH
P
O
O
O

O
P
BocNH
O
O
O

Allyl Phosphate derived Bicyclo[4.3.1]phosphate Triester: 12
O
(MeO)2PO
O
P
O
O
O

O
O
P
(MeO)2PO
O
O
O

Methyl Vinyl Ketone derived Bicyclo[4.3.1]phosphate Triester: 8
O
P
O
O
O
O

O
P
O
O
O
O

Methyl acrylate derived Bicyclo[4.3.1]phosphate Triester: 14
O
O
P
O
O
O
MeO

O
P
O
O
O
O
MeO

t-Butyl acrylate derived Bicyclo[4.3.1]phosphate Triester: 15
O
t-BuO
O
P
O
O
O

O
t-BuO
O
P
O
O
O

Acrolein derived Bicyclo[4.3.1]phosphate Triester: 16
O
O
P
O
O
O
H

O
P
O
O
O
O
H

(R)-1-(Benzyloxy)buten-2-ol derived Bicyclo[4.3.1]phosphate Triester: 17
O
P
O
O
BnO
O
HO

O
P
O
O
BnO
O
HO

(2Z,4R,6R,7E,9R)-10-(benzyloxy)deca-2,7-diene-1,4,6,9-tetraol: 18
OH
OH
OH
OBn
HO