Synthesis of nonracemic dimethyl α-(hydroxyfarnesyl)phosphonates via oxidation of dimethyl farnesylphosphonate with (camphorsulfonyl)oxaziridines

Article abstract of DOI:10.1021/jo980984z

Several strategies for synthesis of nonracemic dimethyl α- (hydroxyfarnesyl)phosphonate and the parent phosphonic acid have been explored. Separation of diastereomeric derivatives prepared by esterification of racemic α-hydroxy phosphonate with (S)-(+)-O-methylmandelic acid was possible, and these diastereomers could be assigned absolute stereochemistry on the basis of literature precedent. However, hydrolysis to the α-hydroxy phosphonic acid was accompanied by extensive isomerization. Addition of a nonracemic phosphonamidite to farnesal also gave nonracemic material, but again hydrolysis was problematic. Oxidation of dimethyl farnesylphosphonate anion with nonracemic (camphorsulfonyl)oxaziridines was shown to be regio- and stereoselective for formation of the α-hydroxy phosphonate. Enantiomeric excess of ~70% ee was established by conversion of the oxidation products to their (S)-(+)-O-methylmandelate derivatives. Although hydrolysis of these methyl esters was accompanied by extensive racemization, both enantiomers of α-(hydroxyfarnesyl)phosphonic acid were obtained in low ee by this strategy.

Full text of DOI:10.1021/jo980984z

3
88
J . Org. Chem. 1999, 64, 388-393
Syn th esis of Non r a cem ic Dim eth yl
r-(Hyd r oxyfa r n esyl)p h osp h on a tes via Oxid a tion of Dim eth yl
F a r n esylp h osp h on a te w ith (Ca m p h or su lfon yl)oxa zir id in es
Diana M. Cermak, Yanming Du, and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52245
Received May 22, 1998
Several strategies for synthesis of nonracemic dimethyl R-(hydroxyfarnesyl)phosphonate and the
parent phosphonic acid have been explored. Separation of diastereomeric derivatives prepared by
esterification of racemic R-hydroxy phosphonate with (S)-(+)-O-methylmandelic acid was possible,
and these diastereomers could be assigned absolute stereochemistry on the basis of literature
precedent. However, hydrolysis to the R-hydroxy phosphonic acid was accompanied by extensive
isomerization. Addition of a nonracemic phosphonamidite to farnesal also gave nonracemic material,
but again hydrolysis was problematic. Oxidation of dimethyl farnesylphosphonate anion with
nonracemic (camphorsulfonyl)oxaziridines was shown to be regio- and stereoselective for formation
of the R-hydroxy phosphonate. Enantiomeric excess of ∼70% ee was established by conversion of
the oxidation products to their (S)-(+)-O-methylmandelate derivatives. Although hydrolysis of these
methyl esters was accompanied by extensive racemization, both enantiomers of R-(hydroxyfarnesyl)-
phosphonic acid were obtained in low ee by this strategy.
Various R-hydroxy phosphonates have activity as1
racemic R-allylic heterosubstituted methylphosphonates
and phosphonamidates have been developed which pro-
vide access to some nonracemic R-hydroxy phospho-
inhibitors of a diverse group of enzymes, including renin,
2
enolpyruvylshikimate-3-phosphate (EPSP) synthase, far-
3
4
11
nesyl protein transferase (FPTase), and HIV protease.
nates. Although each of these strategies has proven
Some of the active R-hydroxy phosphonates have been
studied only in racemic form, even though the absolute
configuration at the R position of substituted phosphonic
acids has been shown to influence their biological proper-
successful with specific substrates, a completely general
procedure for synthesis of nonracemic R-hydroxy phos-
phonates has not yet been developed.
An R-hydroxy phosphonate of particular interest to our
5
12
ties in some cases. A number of strategies have been
studies of RAS farnesylation is R-(hydroxyfarnesyl)-
reported for preparation of nonracemic R-hydroxy phos-
phonates.6 The more prominent of these synthetic
methods include addition of nonracemic phosphorus
reagents to aldehydes7 or use of chiral catalysts8 to
control absolute stereochemistry when achiral phospho-
rus reagents are used. Enantioselective reductions of
phosphonic acid (1), a compound which in its racemic
9
R-keto phosphonates and enzymatic resolution of race-
mic mixtures of R-hydroxy phosphonates1 also have been
0
reported. Finally, [2, 3]-Wittig rearrangements of non-
form has been shown to inhibit FPTase with an IC50 of
(
1) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
990, 31, 5587-5590. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.
Tetrahedron Lett. 1990, 31, 5591-5594.
2) Sikorski, J . A.; Miller, M. J .; Braccolino, D. S.; Cleary, D. G.;
3
3
0 nmol. Given the widespread knowledge of the impor-
1
1
3
tance of stereochemistry to biological activity, it was
somewhat surprising that racemic R-(hydroxyfarnesyl)-
phosphonic acid was used in all reported studies on the
effect of this compound on FPTase. Thus, preparation of
the individual enantiomers of compound 1 became our
objective. After examination of several well-precedented
strategies failed to provide the target enantiomers,
(
Corey, S. D.; Font, J . L.; Gruys, K. J .; Han C. Y.; Lin, K. C.; Pansegrau,
P. D.; Ream, J . E.; Schnur, D.; Shah, A.; Walker, M. C. Phosphorus,
Sulfur, Silicon Relat. Elem. 1993, 76, 375-378.
(
3) Pompliano, D. L.; Rands, E.; Schaber, M. D.; Mosser, S. D.;
Anthony, N. J .; Gibbs, J . B. Biochemistry 1992, 31, 3800-3807.
4) Stowasser, B.; Budt, K. H.; Li, J . Q.; Peyman, A.; Ruppert, D.
Tetrahedron Lett. 1992, 33, 6625-6628.
5) (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wakisaka, K.; Haga,
(
(
14
further elaboration of a strategy involving stereocon-
S.; Sugi, H.; Tanigawa, K.; Suzuki, Y.; Fukawa, K.; Irino, O.; Saita,
O.; Yamabe, S. Heterocycles 1981, 16, 1205-1242. (b) Atherton, F. R.;
Hall, M. J .; Hassall, C. H.; Lambert, R. W.; Lloyd, W. J .; Ringrose, P.
S. Antimicrob. Agents Chemother. 1979, 15, 696-705.
(
(
(11) (a) Denmark, S. E.; Miller, P. C. Tetrahedron Lett. 1995, 36,
6631-6634. (b) Gulea-Purcarescu, M.; About-J audet, E.; Collignon, N.
Tetrahedron Lett. 1995, 36, 6635-6638.
6) Wiemer, D. F. Tetrahedron 1997, 53, 16609-16644.
7) Blazis, V. J .; Koeller, K. J .; Spilling, C. D. J . Org. Chem. 1995,
(12) (a) Hohl, R. J .; Lewis, K.; Cermak, D. M.; Wiemer, D. F. Lipids
1998, 33, 39-46. (b) Holstein, S. A.; Cermak, D. M.; Wiemer, D. F.;
Lewis, K.; Hohl, R. J . Bioorg. Med. Chem. 1998, 6, 687-694.
(13) (a) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.;
Hu, H. J . Org. Chem. 1996, 61, 4572-4581. (b) Stinson, S. C. Chem.
Eng. News Oct. 9, 1995, 95, 44-74.
6
0, 931-940.
(
8) (a) Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J . Org.
Chem. 1996, 61, 2926-2927. (b) Smaardijk, A. A.; Noorda, S.; van
Bolhuis, F.; Wynberg, H. Tetrahedron Lett. 1985, 26, 493-496.
(
(
9) Gajda, T. Tetrahedron: Asymmetry 1994, 5, 1965-1972.
10) (a) Li, Y.-F.; Hammerschmidt, F. Tetrahedron: Asymmetry
(14) (a) Pogatchnik, D. M.; Wiemer, D. F. Tetrahedron Lett. 1997,
38, 3495-3498. (b) Pogatchnik, D. M., Ph.D. Thesis, University of Iowa,
1997.
1
993, 4, 109-120. (b) Drescher, M.; Hammerschmidt, F.; Kahlig, H.
Synthesis 1995, 1267.
1
0.1021/jo980984z CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/05/1999

Dimethyl R-(Hydroxyfarnesyl)phosphonates
J . Org. Chem., Vol. 64, No. 2, 1999 389
Ta ble 1. 1H NMR Sh ifts of Ra cem ic Dim eth yl
r-(Hyd r oxyfa r n esyl)P h osp h on a te (2) a n d th e
Cor r esp on d in g O-Meth ylm a n d ela tes (4) a n d (5)
trolled oxidation of alkyl phosphonate anions was pur-
sued. The results of these efforts form the basis of this
article.
less polar
more polar
O-methylmandelate O-methylmandelate
Resu lts a n d Discu ssion
R-hydroxy
phosphonate
(2) δ
(4)
(5)
Racemic R-(hydroxyfarnesyl)phosphonic acid (1) can be
prepared easily via addition of dimethyl phosphite anion
to farnesal and subsequent hydrolysis of the methyl
esters, as first reported by Pompliano and co-workers.3
The individual enantiomers of the product would be
available through separation of diastereomeric ester
derivatives and subsequent hydrolysis. In 1994, the use
of O-methylmandelate esters15 for determination of enan-
tiomeric purity and absolute configuration of several
R-hydroxy phosphonates was reported by Spilling and co-
workers.16 They also noted that the resulting diastereo-
mers could be separated by chromatography and that the
absolute configuration of the R-carbon could be assigned
1H
δ
∆δa
δ
∆δa
CH3O
CH3O′
C(2)-H
3.82
3.80
5.34
3.54
3.38
5.30
0.28
0.42
0.04
3.74
3.71
5.00
0.08
0.11
0.34
a
The ∆δ refers to the difference in chemical shift between the
parent alcohol and each mandelate derivative.
literature precedent.16a The separation of the resonances
for the two methoxy signals also increased from 0.02 ppm
in the parent alcohol (2) to 0.16 ppm in the less polar
isomer. In the spectrum of the more polar isomer (5), the
phosphonate methoxy signals were shifted slightly up-
field of the parent alcohol (∼0.1 ppm) but were still well
downfield of the less polar isomer (∼0.2 to 0.3 ppm). The
resonances for the C-2 hydrogen of the farnesyl chains
were shifted in the opposite sense. In the more polar
isomer, the resonance for this vinylic hydrogen was
shifted upfield at δ 5.00-5.15, overlaid with resonances
from the other vinylic hydrogens. In the less polar isomer,
the C-2 vinylic hydrogen was shifted downfield to δ 5.25-
1
through H NMR methods once both diastereomers were
in hand. To explore an extension of this method, racemic
phosphonate 2 was treated with (S)-(+)-O-methylman-
delic acid (3) and the carbodiimide EDC17 to provide
O-methylmandelate diastereomers 4 and 5. These dia-
5
.33, quite distinctly downfield of the other vinylic
3
1
resonances. Finally, the P NMR data displayed trends
similar to those observed with the methoxy resonances.
The less polar isomer had an upfield 31P NMR resonance
at 21.5 ppm, whereas the more polar isomer was observed
downfield at 21.9 ppm.
On the basis of shifts observed in the H and 31P NMR
spectra of diastereomers 4 and 5, the absolute stereo-
chemistry of the R-carbon could be assigned. These
chemical shift differences can be traced to deshielding
effects of the phenyl group which differ in the two
1
1
5,16a
diastereomers. By analogy with previous assignments,
which have been confirmed by a diffraction analysis of
one phosphonate,1 the less polar diastereomer derived
from dimethyl R-(hydroxyfarnesyl)phosphonate (2) and
6a
(
(
S)-(+)-O-methylmandelic acid (3) was assigned as the
R,S)-diastereomer 4, and the more polar compound was
assigned as the (S,S)-diastereomer 5.
Once the diastereomers were identified, hydrolysis of
the mandelate and phosphonate esters would afford the
desired enantiomers 6 and 7. Cleavage of mandelate
esters from R-hydroxy carboxylic acids has been ac-
complished through transesterification with methanol
and potassium carbonate to obtain the free alcohol
without racemization.1 However, when these conditions
were applied with mandelates 4 and 5, all isolated
material had undergone isomerization. Transesterifica-
tion also was attempted by treatment with a Lewis acid
and isopropyl alcohol, as previously applied to some
carboxylic acids,18 but in our case, only decomposition was
observed.
Because hydrolysis of the mandelate esters proved
problematic, an alternative method for synthesis of
nonracemic R-(hydroxyfarnesyl)phosphonic acid (1) was
examined. The reported addition of a nonracemic phos-
phonamidite to cinnamaldehyde was one of the few
strategies known to give 1,2-addition to a conjugated
stereomers were cleanly separated by column chroma-
tography into the less polar isomer and the more polar
5a
isomer.
Comparison of the 1H and 31P NMR spectra of diaster-
eomers 4 and 5 revealed a number of significant differ-
1
ences (Table 1). In the H NMR spectrum of the less polar
isomer (4), the hydrogens of the phosphonate methoxy
groups showed an upfield shift of ∼0.3 to 0.4 ppm relative
to the parent R-hydroxy phosphonate, in accord with the
(15) (a) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370-2374. (b) Galinis,
D. L.; Wiemer, D. F. J . Org. Chem. 1993, 58, 7804-7807.
(
16) (a) Kozlowski, J . K.; Rath, N. P.; Spilling, C. D. Tetrahedron
1
1
995, 51, 6385-6396. (b) Rath, N. P.; Spilling, C. D. Tetrahedron Lett.
994, 35, 227-230.
(17) (a) Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993,
3
4, 7685-7688. (b) Sheehan, J . C.; Cruickshank, P. A.; Boshart, G. L.
(18) Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zuger, M. Synthesis 1982, 138-141.
J . Org. Chem. 1961, 26, 2525-2528.

3
90 J . Org. Chem., Vol. 64, No. 2, 1999
Cermak et al.
aldehyde, producing an allylic R-hydroxy phosphonamide
Stereocontrolled oxidations have been obtained with
nonracemic (camphorsulfonyl)oxaziridine (15) and 8,8-
7
23
in good yield with good diastereoselectivity. The result-
ing phosphonamide was then converted to the corre-
sponding phosphonic acid by acid-catalyzed hydrolysis.
To examine this approach, the desired N,N′-neopentyl-
substituted phosphonamidite19 (10) was prepared by a
disubstituted derivatives such as the dichloro compound
2
4
16, and these reagents are readily prepared in large
quantities.2 We have found that several benzyl phos-
phonates (e.g., 17a -d ) undergo enantioselective hy-
droxylation upon treatment of the corresponding anions
with nonracemic oxaziridines, giving the corresponding
R-hydroxyphosphonates 18a -d in reasonable yields and
ee’s.14 Although a parallel reaction can be readily envi-
5
7
variation of the literature synthesis. Thus, (1R,2R)-
trans-diaminocyclohexane20 (8) underwent condensation
with 2 equiv of pivaloyl chloride to give the expected
diamide (9), followed by reduction with borane-THF
complex21 to provide the N,N′-bisneopentyl derivative 10
in virtually quantitative yield. Compared to the reported
reductive amination of diamine 8 with trimethylacetal-
dehyde (83% yield),19 amide formation and subsequent
reduction required one additional step, but compound 10
was produced in greater purity and somewhat better
yield through the two-step sequence.
After diamine 10 was converted to phosphonamidite
1
9
1
1 under standard conditions, treatment with base and
trans,trans-farnesal (12) provided phosphonamides 13
and 14 in 58% yield, as a 10.6:1 ratio of diastereomers
on the basis of inspection of the 31P NMR spectrum of
the product. Although complete separation of the dia-
sioned for conversion of a farnesyl phosphonate to its
R-hydroxy derivative, this application would have to
address an issue of R versus γ reactivity that is not likely
to complicate oxidations of benzyl phosphonates.
Dimethyl farnesylphosphonate (19), readily prepared
by an Arbuzov reaction of farnesyl bromide and trimethyl
phosphite,26 was treated with base and an oxaziridine
under various conditions to gauge the extent of regio- and
enantioselectivity possible in oxidation of an allylic
phosphonate (Table 2). In all cases, oxidation was favored
at the R position, as definitively established by compari-
son of the reaction product with racemic 1 prepared by
addition of dimethyl phosphite to farnesal.1 Nonracemic
products also were produced in all cases, but both low
yields and low rotations were observed with the oxaziri-
dine (+)-15. Even though the yields were still modest,
the dichloro oxaziridine (+)-16 resulted in product with
2a
significantly higher optical rotation, parallel to reports
on oxidation of enolates,2
4,25,27
as well as our previous
stereomeric products was not readily achieved by chro-
matography, diastereomeric ratios as high as 52:1 were
1
4
study with benzyl phosphonate hydroxylation. As ex-
pected, an enantiomeric product of almost equal rotation
was obtained when the (-)-enantiomer of reagent 16 was
employed in the oxidation of the dimethyl farnesylphos-
phonate anion. However, because there is no previous
description of the enantiomers 20 and 21, the enantio-
obtained. Assuming that the stereochemistry of this
addition follows literature precedents,7 the (R,R,S)-
diastereomer would be the major product when the (R,R)-
diamide is employed. Unfortunately, attempted hydrol-
ysis of the phosphonamides by reaction with 4 M HCl in
dioxane resulted only in decomposition. Thus, we were
encouraged to develop a new approach to synthesis of the
nonracemic R-(hydroxyfarnesyl)phosphonic acids.
(22) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919-934 and
references therein.
(
23) (a) Davis, F. A.; Sheppard, A. C.; Chen, B.-C.; Haque, M. S. J .
A well-known strategy for introduction of the hydroxyl
Am. Chem. Soc. 1990, 112, 6679-6690. (b) Davis, F. A.; Haque, M. S.;
Ulatowski, T. G.; Towson, J . C. J . Org. Chem. 1986, 51, 2402-2404.
(24) Davis, F. A.; Weismiller, M. C. J . Org. Chem. 1990, 55, 3715-
group at an activated methylene position is based on
reaction of oxaziridines with the corresponding enolate.22
3
717.
(
25) (a) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R.
(
19) Koeller, K. J . Ph.D. Thesis, University of Missouri-St. Louis,
994.
20) (1R,2R)-1,2-Diaminocyclohexane was obtained by resolution of
()-trans-1,2-diaminocyclohexane (Aldrich): (a) Hollis, L. S.; Doran,
S. L.; Amundsen, A. R.; Stern, E. W. Inorg. Synth. 1990, 27, 283-286.
b) Larrow, J . F.; J acobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C.
M. J . Org. Chem. 1994, 59, 1939-1942.
21) Denmark, S. E.; Chen, C.-T. J . Am. Chem. Soc. 1995, 117,
1879-11897.
T.; Chen, B.-C. J . Org. Chem. 1992, 57, 7274-7285. (b) Mergelsberg,
I.; Gala, D.; Scherer, D.; DiBenedetto, D.; Tanner, M. Tetrahedron Lett.
1992, 33, 161-164.
1
(
(
(26) Patel, D. V.; Gordon, E. M.; Schmidt, R. J .; Weller, H. N.; Young,
M. G.; Zahler, R.; Barbacid, M.; Carboni, J . M.; Gullo-Brown, J . L.;
Hinihan, L.; Ricca, C.; Robinson, S.; Seizinger, B.; R.; Tuomari, A. V.;
Manne, V. J . Med. Chem. 1995, 38, 435-442.
(
(
(27) Gala, D.; DiBenedetto, D. J .; Mergelsberg, I.; Kugelman, M.
Tetrahedron Lett. 1996, 37, 8117-8120.
1

Dimethyl R-(Hydroxyfarnesyl)phosphonates
J . Org. Chem., Vol. 64, No. 2, 1999 391
Ta ble 2. Oxid a tion of Dim eth yl F a r n esylp h osp h on a te
w ith (Ca m p h or su lfon yl)oxa zir id in es
be assigned via preparation of the (S)-O-methylmande-
late derivatives and detailed analysis of their NMR
spectra. Enantiomeric excesses of about 70% were ob-
served in these oxidations, which may be sufficient to
probe the importance of this stereocenter to the biological
activity of the enantiomeric phosphonate esters. How-
ever, hydrolysis of these dimethyl esters was accompa-
nied by partial racemization, giving phosphonic acids of
low optical activity. If the ee obtained during oxidation
of the dimethyl phosphonate is not to be sacrificed during
conversion to the phosphonic acid, investigation of ester
groups that can be cleaved without racemization will be
required.
Exp er im en ta l Section
Tetrahydrofuran (THF) was distilled from sodium/ben-
zophenone immediately prior to use. All nonaqueous reactions
were conducted in oven-dried glassware, under an atmosphere
of nitrogen or argon, and with magnetic stirring. Flash
chromatography was carried out on Baker silica gel with 40
µm average particle diameter. Melting points are uncorrected.
entry
base
T (°C)
15/16
% yield
opt. rot.
1
2
3
4
5
6
7
n-BuLi
n-BuLi
LDA
NaHMDS
LDA
-75
-75
-70
-90
-75
-75
-90
(+)-15
(+)-15
(+)-15
(+)-16
(+)-16
(-)-16
(-)-16
50
52
67
51
50
46
35
-10.5
-8.1
-9.9
-26.4
-22.1
+24.4
+19.9
1
13
NMR spectra ( H at 300 MHz and C at 75 MHz) were
LDA
NaHMDS
1
recorded with CDCl
3
as solvent and (CH
3 4 3
) Si ( H) or CDCl
1
1
3
(
C, 77.0 ppm) as internal standards, unless otherwise noted.
P NMR chemical shifts are reported in ppm relative to 85%
PO (external standard). Both low- and high-resolution mass
3
meric excess could not be established directly from the
optical rotations.
H
3
4
spectra were obtained at an ionization potential of 70 eV; only
selected ions are reported here. Elemental analyses were
performed by Atlantic Microlab, Inc. (Norcross, GA).
Diastereomeric excess was readily established by con-
version of these reaction products to their (S)-O-meth-
ylmandelate derivatives 4 and 5 and integration of the
(
1R,2E,6E)-1-(Dim eth oxyp h osp h in yl)-3,7,11-tr im eth yl-
2,6,10-d od eca tr ien yl (S)-Meth oxyp h en yla ceta te (4) a n d
1S,2E,6E)-1-(Dim et h oxyp h osp h in yl)-3,7,11-t r im et h yl-
,6,10-d od eca tr ien yl (S)-Meth oxyp h en yla ceta te (5). To a
mixture of R-hydroxyphosphonate 2 (865 mg, 2.62 mmol), EDC
2.51 g, 13.1 mmol), and DMAP (1.77 g, 14.5 mmol) in CH Cl
3
1
P NMR spectrum. On the basis of this analysis, the
(
2
sample with the strongest negative rotation (entry 4,
Table 2) was found to be a 6.2:1 ratio of the (S,S)- and
(
R,S)-diastereomers, indicating an ee of approximately
2%. By a parallel analysis, the sample of largest positive
rotation (entry 6) was found to give a 1:5.3 ratio of the
S,S)- and (R,S)-diastereomers, consistent with an ee of
ca. 68%.
To obtain the desired enantiomers of R-(hydroxyfar-
(
2
2
7
(25 mL) was added (S)-acid 3 (544 mg, 3.27 mmol) and the
mixture was stirred at room temperature. After 28 h of
stirring, hexanes (50 mL) were added, and the solution was
(
extracted with 1 M HCl (3 × 50 mL), saturated NaHCO
3
(2 ×
5
0 mL), and brine (50 mL). The organic phase was dried over
4
MgSO , filtered, and concentrated to provide a yellow oil.
nesyl)phosphonic acid (1), samples of the phosphonate
esters 20 and 21 were treated with TMSBr and collidine,
followed by hydrolysis with aqueous acid to obtain the
phosphonic acids 6 and 7. Hydrolysis of ester 20 gave
the (S)-acid 7 in low yield but in optically active form
Purification by flash column chromatography (70:30 ethyl
acetate/hexanes) gave a total yield of 969 mg (77%) including
fractions of pure (R,S)-ester 4 and (S,S)-ester 5, each as a clear
oil.
(
R,S)-ester 4, less polar isomer: 459 mg; [R]25
D
+59.9° (c )
1
1
1
3
3
3
.0, CHCl
3
); H NMR δ 7.28-7.49 (m, 5H), 5.92 (dd, J ) 11.5,
(
[R]
reaction of ester 21 gave the nonracemic R-acid 6, also
in nonracemic form ([R] ) +5.7° (c ) 0.55, MeOH)). To
D
) -4.6° (c ) 0.55, MeOH)), whereas the parallel
0 Hz, 1H), 5.25-5.34 (m, 1H), 5.03-5.14 (m, 2H), 4.80 (s, 1H),
.54 (d, J ) 10.6 Hz, 3H), 3.38 (d, J ) 10.6 Hz, 3H), 3.38 (s,
H), 1.93-2.17 (m, 8H), 1.79 (dd, J ) 3.0, 1.4 Hz, 3H), 1.67 (s,
D
establish the stereochemical fidelity of the hydrolysis, a
sample of the acid 7 was converted back to the methyl
ester 20 by reaction with diazomethane. Unfortunately,
the methyl ester obtained this way had a rotation
significantly lower than the material from which it was
obtained (-3.3° versus -21.5°), suggesting that substan-
tial racemization had occurred during hydrolysis. Further
reaction of this ester with (S)-O-methylmandelic acid and
13
H), 1.59 (s, 6H); C NMR δ 168.8 (d, J CP ) 7.4 Hz), 145.8 (d,
J CP ) 13.1 Hz), 135.4, 135.1, 130.7, 128.3, 128.1 (2C), 127.0
(2C), 123.8, 122.9, 114.7 (d, J CP ) 3.1 Hz), 81.8, 66.0 (d, J CP
)
173.9 Hz), 56.7, 52.8 (d, J CP ) 2.8 Hz), 52.7 (d, J CP ) 2.2 Hz),
3
1
9.2, 39.2 (d, J CP ) 1.5 Hz), 26.4, 25.6 (d, J CP ) 2.1 Hz), 25.2,
7.2, 16.7 (d, J CP ) 1.2 Hz), 15.5; 31P NMR δ 21.5. Anal. Calcd
for C26
39 6
H O P: C, 65.24; H, 8.22. Found: C, 65.33; H, 8.21.
2
5
(
S,S)-ester 5, more polar isomer: [R]
3
D
+17.4° (c ) 1.0,
1
CHCl
); H NMR δ 7.28-7.48 (m, 5H), 5.93 (dd, J ) 11.6, 9.8
integration of the diastereomer resonances in the 31
P
Hz, 1H), 4.99-5.16 (m, 3H), 4.84 (s, 1H), 3.74 (d, J ) 10.7 Hz,
3
8H), 1.69 (s, 6H), 1.60 (s, 3H), 1.56 (s, 3H); C NMR δ 169.4
NMR spectrum indicated that the low rotation corre-
sponds to ∼8% ee.
H), 3.71 (d, J ) 10.7 Hz, 3H), 3.43 (s, 3H), 1.85-2.10 (m,
1
3
(
1
8
d, J CP ) 6.4 Hz), 146.5 (d, J CP ) 13.5 Hz), 135.7, 135.6, 131.3,
These studies have shown that both enantiomers of
dimethyl R-(hydroxyfarnesyl)phosphonate can be pre-
pared by oxidation of the parent dimethyl farnesylphos-
phonate with a nonracemic oxaziridine. The oxidation
proved to be R selective in this case, although whether
that is a general phenomenon with allylic phosphonates
will require further study. The absolute stereochemistry
and enantiomeric excess of the oxidation products can
28.7, 128.5 (2C), 127.1 (2C), 124.2, 123.2, 114.7 (d, J CP ) 3.0),
2.4, 66.4, (d, J CP ) 174.2), 57.4, 53.5 (d, J CP ) 3.7 Hz), 53.4
(
1
1
d, J CP ) 2.4 Hz), 39.6, 39.5, 26.6, 26.1, 25.7 (d, J CP ) 2.4 Hz),
31
-1
7.6, 17.1, 15.9; P NMR δ 21.9; IR (thin film, cm ) 1752,
260, 1040. Anal. Calcd for C26 P‚0.5 H O: C, 64.05; H,
H
39
O
6
2
8.27. Found: C, 64.47; H, 8.16.
N,N′-[(1R,2R)-1,2-Cycloh exylen e]b is(p iva la m id e) (9).
2
0
To a stirred solution of (1R,2R)-1,2-diaminocyclohexane (8,

3
92 J . Org. Chem., Vol. 64, No. 2, 1999
Cermak et al.
2
.00 g, 17.5 mmol) and DMAP (4.49 g, 36.8 mmol) in benzene
allowed to warm to -40 °C in a liquid nitrogen/acetonitrile
bath. After 20 min at -40 °C, the reaction mixture was again
cooled to -95 °C for 5 min and then added to a solution of
oxaziridine (+)-16 (367 mg, 1.23 mmol) in THF (12 mL) via
cannula. The reaction mixture was allowed to stir at -75 °C
(
45 mL) at 0 °C was added trimethylacetyl chloride (4.55 mL,
6.9 mmol) in benzene (22 mL) via cannula over 30 min. After
the mixture warmed to room temperature and was stirred for
9 h, water (125 mL) was added and the solution was extracted
with ether (3 × 100 mL). The organic fractions were combined,
washed with saturated NH Cl (100 mL), dried over MgSO
and concentrated in vacuo to give diamide 9 as a white solid
3
1
4
for 3 h, quenched by addition of saturated NH Cl (20 mL), and
4
4
,
allowed to warm to room temperature. Water (10 mL) was
added, the resulting solution was extracted with ethyl acetate
(3 × 25 mL), and the combined organic layers were dried over
(4.86 g, 98%). A sample suitable for elemental analysis was
2
5
purified by sublimation: mp 243-245 °C; [R]
1
D
+48.1° (c )
4
MgSO and finally concentrated to give a white solid. Final
1
.0, CHCl
3
); H NMR (C
6
D
6
) δ 6.10-6.24 (br s, 2H), 3.56-3.71
purification by flash column chromatography (gradient of 15:
85 acetone/chloroform to 30:70 acetone/chloroform) gave phos-
phonate 18a as a white crystalline solid (113 mg, 70%, 93%
(m, 2H), 2.00-2.11 (m, 2H), 1.68-1.82 (m, 2H), 1.17-1.42 (m,
4
2
9
H), 1.15 (s, 18H); 13C NMR (C
7.5, 24.7. Anal. Calcd for C16
.92. Found: C, 67.81; H, 10.58; N, 10.11.
1R,2R)-N,N′-Bis(2,2-dim eth ylpr opyl)-1,2-cycloh exan edi-
6
D
6
) δ 179.1, 53.6, 38.4, 32.3,
: C, 68.03; H, 10.71; N,
8
b
29
1
H
30
N
2
O
2
ee): mp 100-102 °C, lit. 100-101 °C; [R]
D
-43° (c ) 1.0,
acetone), lit.8b [R]
20
-46° (c ) 1.0, acetone); H NMR and
NMR were identical to literature data;
13
C
D
8
a 31
P NMR δ 24.3.
(
1
9
a m in e (10). To a solution of diamide 9 (1.29 g, 4.57 mmol)
in THF (18 mL) at 0 °C was added BH -THF (18.4 mL, 1 M
Dim eth yl (S)-Hydr oxy-(p-n itr oph en yl)m eth ylph osph o-
n a te (18b).8a According to the procedure described for prepa-
3
2
9
in THF, 18.4 mmol). The reaction was stirred at 0 °C for 20
min and then allowed to warm to room temperature. After 3
days of stirring, the reaction mixture was cooled to 0 °C, and
water (10 mL) was added slowly until evolution of gas ceased.
The mixture was acidified by addition of 6 M HCl to pH 2,
and the resulting solution was stirred for 12 h. The solution
was then made basic by addition of KOH pellets at 0 °C to pH
ration of phosphonate 18a , phosphonate 17b (184 mg, 0.75
mmol) was treated with NaHMDS (1.13 mL, 1 M in hexanes,
1.13 mmol) and oxaziridine (+)-16 (449 mg, 1.51 mmol).
Standard workup and final purification by flash column
chromatography (gradient of 20:80 acetone/chloroform to 30:
70 acetone/chloroform) gave phosphonate 18b as a white solid
8
a
25
(106 mg, 54%, 80% ee): mp 119-120 °C, lit. 119 °C; [R]
D
22
1
2. Ether (10 mL) was added, the resulting organic layer was
-54.2° (c ) 1.0, CHCl
3
), lit.8a [R]
D
3
-69.2° (c ) 1.0, CHCl );
1
H NMR and C NMR were identical to literature data; 31P
13
8a
separated, and the aqueous layer was continuously extracted
with ether for 24 h. The combined organic layers were dried
NMR δ 22.5.
over MgSO
4
, filtered, and concentrated in vacuo to afford
Dim et h yl (S)-h yd r oxy-(p -ch lor op h en yl)m et h ylp h os-
1
9
1
8a
diamine 10 as a clear oil (1.16 g, 100%): H NMR δ 2.56 (d,
J ) 11.1 Hz, 2H), 2.10 (d, J ) 11.1 Hz, 2H), 2.02-2.14 (m,
p h on a te (18c). According to the procedure described for
3
0
preparation of phosphonate 18a , phosphonate 17c (184 mg,
0.75 mmol) was treated with NaHMDS (1.15 mL, 1 M in
hexanes, 1.15 mmol) and oxaziridine (+)-16 (450 mg, 1.51
mmol). Standard workup and final purification by flash column
chromatography (gradient of 20:80 acetone/chloroform to 30:
4
2
3
H), 1.63-1.76 (m, 2H), 1.42-1.56 (br s, 2H), 1.16-1.27 (m,
13
H), 0.87-1.04 (m, 2H), 0.91 (s, 18H); C NMR δ 63.1, 59.8,
2.0, 31.5, 27.7, 25.1.
2
-(1′-Hyd r oxy-3′,7′,11′-tr im eth yl-(2′E,6′E,10′E)-2′,6′,10′-
7
(
0 acetone/chloroform) gave phosphonate 18c as a white solid
d od eca tr ien yl)-2,3,3a ,4,5,6,7,7a -octa h yd r o-1,3-bis(2,2-d i-
8
a
26
143 mg, 76%, 87% ee): mp 68-69 °C, lit. 69 °C; [R]
D
-51.4°
m eth ylpr opyl)-1H-1,3,2-ben zodiazaph osph ole 2-Oxide (13/
8
a
25
1
4). A solution of phosphonamidite 1119 (1.25 g, 4.15 mmol)
(c ) 1.0, CHCl ), lit. [R]
3
D
-59.2° (c ) 1.0, CHCl ); H NMR
3
1
and 13C NMR were identical to literature data;
3.6.
Dim eth yl (S)-Hyd r oxy-(p-m eth oxyp h en yl)m eth ylph os-
p h on a te (18d ).8a According to the procedure described for
8a 31
P NMR δ
in THF (15 mL) was cooled to -60 °C, and n-BuLi (4.40 mL,
.94 M in hexanes, 4.14 mmol) was added. After 2 h of stirring
at -60 °C, trans,trans-farnesal (12, 732 mg, 3.32 mmol) in THF
18 mL) was added dropwise via cannula over 1 h. After 2.5 h
of stirring at -60 °C, the reaction mixture was quenched by
addition of saturated aqueous NH Cl (5 mL) and allowed to
2
0
(
3
1
preparation of phosphonate 18a , phosphonate 17d (173 mg,
0.75 mmol) was treated with NaHMDS (1.15 mL, 1 M in
hexanes, 1.15 mmol) and oxaziridine (+)-16 (449 mg, 1.51
mmol). Standard workup and final purification by flash column
chromatography (gradient of 20:80 acetone/chloroform to 30:
70 acetone/chloroform) gave phosphonate 18d as a white solid
4
warm to room temperature slowly. Chloroform (100 mL) was
added, and the mixture was extracted with water (2 × 80 mL).
2 4
The organic phase was dried over Na SO and concentrated
3
1
in vacuo to afford the crude product. A P NMR spectrum of
this material indicated a ratio of diastereomers of 10.6:1 (δ
8
a
26
(112 mg, 60%, 81% ee): mp 69-70 °C, lit. 70 °C; [R]
D
-40.0°
(c ) 1.0, CHCl
3
), lit.8a [R]
25
D
3
-59.2° (c ) 1.0, CHCl ); H NMR
1
4
7
1.0:40.5). Purification by flash column chromatography (30:
0 ethyl acetate/hexane) gave compounds 13/14 as a clear oil
and 13C NMR were identical to literature data;
24.4.
8a 31
P NMR δ
in a 52:1 mixture of diastereomers (996 mg, 58%). For the
major diastereomer: H NMR δ 5.30-5.39 (m, 1H), 5.05-5.20
1
Dim eth yl[3,7,11-Tr im eth yl-(E,E)-2,6,10-d od eca tr ien yl]-
p h osp h on a te (19).26 A solution of farnesyl bromide (2.51 g,
8.80 mmol) and trimethyl phosphite (2.4 mL, 20.4 mmol) was
heated to reflux. After 12 h of heating at reflux, the reaction
mixture was allowed to cool to room temperature, and all
volatiles were removed in vacuo. The remaining orange oil was
purified by flash column chromatography (20:80 acetone/
chloroform) to afford phosphonate 19 as a clear, colorless oil
(
m, 2H), 4.82 (dd, J ) 9.5, 6.7 Hz, 1H), 3.29 (dd, J ) 14.5,
1
2.0 Hz, 1H), 3.21 (dd, J ) 16.6, 14.7 Hz, 1H), 3.15-3.50 (br
s, 1H), 2.70-2.91 (m, 2H), 2.50 (dd, J ) 14.7, 3.8 Hz, 1H), 2.46
d, J ) 14.5 Hz, 1H), 1.88-2.19 (m, 10H), 1.73-1.84 (m, 2H),
.75 (dd, J ) 3.4, 1.1 Hz, 3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.60
s, 3H), 1.15-1.35 (m, 4H), 0.97 (s, 9H), 0.93 (s, 9H); 13C NMR
(
1
(
δ 141.4 (d, J CP ) 12.8 Hz), 135.6, 131.3, 124.2, 123.6, 119.8 (d,
J
1
CP ) 4.3 Hz), 68.1 (d, J CP ) 123.3 Hz), 65.5 (d, J CP ) 7.3 Hz),
5.2 (d, J CP ) 6.7 Hz), 56.1 (d, J CP ) 1.2 Hz), 54.3 (d, J CP
.0 Hz), 40.1 (d, J CP ) 1.8 Hz), 39.7, 32.8, 31.9, 30.7, 30.6, 30.3,
0.2, 28.7 (3C), 28.4 (3C), 26.7, 25.6, 24.8, 24.3, 17.6, 15.9; 31
(2.74 g, 99%): H NMR δ 5.13-5.24 (m, 1H), 5.04-5.14 (m,
6
3
3
)
2H), 3.73 (d, J ) 10.7 Hz, 6H), 2.58 (dd, J HP ) 22.0, 7.8 Hz,
2H), 1.92-2.15 (m, 8H), 1.67 (s, 3H), 1.66 (s, 3H), 1.60 (s, 6H);
13
P
C NMR δ 140.0 (d, J CP ) 14.0 Hz), 134.9, 130.8, 124.0, 123.4,
+
NMR δ 40.9; HR FAB MS calcd for C31
43.4055; found 543.4067.
Dim et h yl (S)-H yd r oxy-(p h en yl)m et h ylp h osp h on a t e
H
57NO
2
PNa (M + Na)
111.8 (d, J CP ) 11.0 Hz), 52.1 (d, J CP ) 6.7 Hz), 39.4, 39.3 (d,
5
J
1
CP ) 3.1 Hz), 26.4, 26.1, 25.3, 25.1 (d, J CP ) 135.5 Hz), 17.3,
5.9, 15.6; 31P NMR δ 31.2; IR (thin film, cm ) 1660, 1260,
-1
8
b,10a
28
1044.
(
18a ).
To a mixture of phosphonate 17a (150 mg, 0.75
mmol) in THF (12 mL) at -95 °C was added NaHMDS (980
µL, 1 M in hexanes, 0.98 mmol). After the golden yellow
solution was stirred for 5 min, the reaction mixture was
(
29) (a) Li, T.; Hilton, S.; J anda, K. D. J . Am. Chem. Soc. 1995, 117,
2123-2127. (b) Gordon, J .; Sheldon, T. J .; Bradley, D. D. C.; Burn, P.
L. J . Mater. Chem. 1996, 6, 1253-1258.
(
30) Arient, J . Collect. Czech. Chem. Commun. 1981, 46, 101-106.
(28) Kawashima, T.; Ishii, T.; Inamoto, N. Bull. Chem. Soc. J pn.
(31) Crenshaw, M. D.; Zimmer, H. J . Org. Chem. 1983, 48, 2782-
2784.
1
987, 60, 1831-1837.

Dimethyl R-(Hydroxyfarnesyl)phosphonates
-)-(S)-Dim eth yl [1-Hyd r oxy-3,7,11-tr im eth yl-(2E,6E)-
J . Org. Chem., Vol. 64, No. 2, 1999 393
(
concentrated to give a yellow solid. Final purification by flash
column chromatography (gradient of 20:80 acetone/chloroform
to 30:70 acetone/chloroform) gave phosphonate 20 as a clear
2
,6,10-d od eca tr ien yl]p h osp h on a te (20). To a mixture of
phosphonate 19 (473 mg, 1.50 mmol) in THF (12 mL) at -90
C was added NaHMDS (2.25 mL, 1 M in hexanes, 2.25 mmol).
°
oil (227 mg, 46%): [R]25
D
3
+24.4° (c ) 1.0, CHCl ); all spectra
After the orange-brown solution was stirred at this tempera-
ture for 5 min, the reaction mixture was allowed to warm to
were identical to those of racemic phosphonate 2.
Formation of the (S)-(+)-O-methylmandelic acid derivatives
(4/5) confirmed the stereochemistry of the product as R in a
5.3:1 ratio of diastereomers, corresponding to 68% ee.
(+)-(R)-[1-Hyd r oxy-3,7,11-tr im eth yl-(E,E)-2,6,10-d od ec-
a tr ien yl]p h osp h on ic Acid (6). According to the published
-
-
5
40 °C in a liquid nitrogen/acetonitrile bath. After 20 min at
40 °C, the reaction mixture was again cooled to -90 °C for
min and then added dropwise to a solution of oxaziridine
(
+)-16 (896 mg, 3.01 mmol) in THF (12 mL) via cannula. The
reaction mixture was allowed to stir at -90 °C for 1 h,
quenched by addition of saturated NH Cl (20 mL), and allowed
3
procedure, phosphonate 20 (118 mg, 0.36 mmol) was treated
4
with trimethylsilyl bromide (200 µL, 1.51 mmol) and 2,4,6-
collidine (200 µL, 1.51 mmol) in dichloromethane (6 mL) to
obtain the corresponding phosphonic acid 6 (27 mg, 25%):
to warm to room temperature. Water (10 mL) was added, the
resulting solution was extracted with ethyl acetate (3 × 30
mL), and the combined organic layers were dried over MgSO
4
[R]25
+5.7° (c ) 0.55, MeOH); all spectra were identical to
D
and finally concentrated to give a yellow solid. Final purifica-
tion by flash column chromatography (gradient of 20:80
acetone/chloroform to 30:70 acetone/chloroform) gave phos-
those of racemic phosphonate 1.
(-)-(S)-[1-Hyd r oxy-3,7,11-tr im eth yl-(E,E)-2,6,10-d od ec-
a tr ien yl]p h osp h on ic Acid (7). According to the published
procedure, phosphonate 19 (116 mg, 0.35 mmol) was treated
2
5
3
phonate 20 as a clear oil (251 mg, 51%): [R]
.0, CHCl ); all spectra were identical to those of racemic
phosphonate; IR (thin film, cm ) 3359 (br), 1664, 1633, 1234,
034.
Formation of the (S)-(+)-O-methylmandelic acid derivatives
4/5) confirmed the stereochemistry of the product as S in a
D
-26.4° (c )
1
3
with trimethylsilyl bromide (200 µL, 1.51 mmol) and 2,4,6-
collidine (200 µL, 1.51 mmol) in dichloromethane (6 mL) to
obtain the corresponding phosphonic acid 7 (37 mg, 35%):
-
1
1
[R]25
-4.6° (c ) 0.55, MeOH); all spectra were identical to
3
D
-1
(
those of racemic phosphonate 1; IR (Nujol, cm ) 3180 (br),
1152.
6
.2:1 ratio of diastereomers, corresponding to a 72% ee.
+)-(R)-Dim et h yl [1-H yd r oxy-3,7,11-t r im et h yl-(E,E)-
,6,10-d od eca tr ien yl]p h osp h on a te (21). To a mixture of
(
To establish the ee, excess diazomethane in ether was added
2
5
2
dropwise to a solution of acid 7 (30 mg, 0.1 mmol, [R]
D
-3.8°)
phosphonate 18 (472 mg, 1.50 mmol) in THF (8 mL) at -75
C was added a solution of LDA [made by adding of n-BuLi
2.00 mL, 1.18 M in hexanes, 2.36 mmol) to a solution of
diisopropylamine (320 µL, 2.28 mmol) in THF (8 mL) at 0 °C,
stirring for 15 min, and cooling to -75 °C for 5 min] via
cannula. After the yellow solution was stirred at this temper-
ature for 15 min, the reaction mixture was added dropwise to
a solution of oxaziridine (-)-16 (899 mg, 3.02 mmol) in THF
in methanol (3 mL) until the color persisted for 5 min. The
reaction was quenched by addition of acetic acid. Standard
workup and purification by column chromatography gave ester
°
(
20 (30 mg, 92%, [R]25
-3.34°). Esterification of this R-hydroxy
D
phosphonate with (S)-O-methylmandelic acid as described
above and integration of the 31P NMR spectrum of the product
indicated material of ∼8% de.
(
8 mL) at -75 °C via cannula. The reaction mixture was
allowed to stir at -75 °C for 1 h, quenched by addition of
saturated NH Cl chloride (20 mL), and allowed to warm to
Ack n ow led gm en t. Financial support from the Roy
J . Carver Charitable Trust, the Leukemia Society of
America, and the National Institutes of Health is
gratefully acknowledged.
4
room temperature. Water (10 mL) was added, the resulting
solution was extracted with ethyl acetate (3 × 30 mL), and
the combined organic layers were dried over MgSO
4
and finally
J O980984Z