Diastereoselective vinyl phosphate/β-keto phosphonate rearrangements

Article abstract of DOI:10.1021/jo9518157

Several nonracemic diols and amino alcohols have been tested for their utility as chiral auxiliaries in vinyl phosphate/β-keto phosphonate rearrangements. When (2R,4R)- or (2S,4S)-pentane-2,4-diol were employed, the diastereomeric β-keto phosphonates obtained from three prochiral cyclohexanones gave separate resonances in their respective ³¹P NMR spectra, allowing estimation of diastereomeric excess (de) via straightforward integration. A crystalline enol form of the β-keto phosphonate was obtained from one ketone (4-(1,1-(ethylenedioxy)ethyl)-4-methylcyclohexanone, 10), which allowed determination of its absolute stereochemistry by X-ray diffraction analysis. When LTMP was used to induce rearrangement of vinyl phosphates derived from ketone 10 and (2R,4R)-or (2S,4S)-pentane-2,4-diol, a de of 2.5:1 was obtained. In addition, de values of 2.0:1 and 1.4:1 were obtained with parallel rearrangements of 4-isopropyl- and 4-methylcyclohexanone, suggesting that this sequence may be more generally applicable to preparation of nonracemic materials from prochiral cyclohexanones.

Full text of DOI:10.1021/jo9518157

4040
J . Org. Chem. 1996, 61, 4040-4045
Dia ster eoselective Vin yl P h osp h a te/â-Keto P h osp h on a te
Rea r r a n gem en ts
J ianguo An, J effrey M. Wilson, Yi-Zhong An, and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
Received October 6, 1995X
Several nonracemic diols and amino alcohols have been tested for their utility as chiral auxiliaries
in vinyl phosphate/â-keto phosphonate rearrangements. When (2R,4R)- or (2S,4S)-pentane-2,4-
diol were employed, the diastereomeric â-keto phosphonates obtained from three prochiral
cyclohexanones gave separate resonances in their respective 31P NMR spectra, allowing estimation
of diastereomeric excess (de) via straightforward integration. A crystalline enol form of the â-keto
phosphonate was obtained from one ketone (4-(1,1-(ethylenedioxy)ethyl)-4-methylcyclohexanone,
10), which allowed determination of its absolute stereochemistry by X-ray diffraction analysis. When
LTMP was used to induce rearrangement of vinyl phosphates derived from ketone 10 and (2R,4R)-
or (2S,4S)-pentane-2,4-diol, a de of 2.5:1 was obtained. In addition, de values of 2.0:1 and 1.4:1
were obtained with parallel rearrangements of 4-isopropyl- and 4-methylcyclohexanone, suggesting
that this sequence may be more generally applicable to preparation of nonracemic materials from
prochiral cyclohexanones.
For some years we have studied the base-induced
rearrangements of vinyl phosphates to the corresponding
â-keto phosphonates.1 The earliest of these investiga-
tions established the viability of this reaction for five-
and six-membered ring ketones, as well as specific
bicyclic bridged and fused-ring systems,1-3 and delineated
some aspects of the reaction sequence involved. These
findings have allowed application of this rearrangement
in natural product synthesis4 and have provided conve-
nient access to a variety of novel compounds that have
found use in other studies of â-keto phosphonate
reactivity.5-7 Still broader application of this methodol-
ogy would be encouraged by procedures establishing
stereocontrolled rearrangements.
As shown in Figure 1, the vinyl phosphate rearrange-
ment offers an intriguing possibility for diastereoselection
when prochiral ketones are paired with phosphoryl
substituents containing stereogenic centers. For ex-
ample, the reaction of LDA with a cyclohexanone bearing
two different substituents at the C-4 position affords a
racemic mixture of enolates. Subsequent reaction of
these enolates with a nonracemic dialkyl phosphoro-
chloridate provides a mixture of diastereomeric vinyl
phosphates. Upon reaction with additional LDA, both
vinyl phosphate diastereomers converge to a single
intermediate in cases where the rearrangement involves
a delocalized anion. When carbon-phosphorus bond
formation takes place, it must occur at either the pro-R
or the pro-S position of the allyl system, again affording
a mixture of diastereomers. Because the transition states
F igu r e 1. Stereochemistry of the vinyl phosphate/â-keto
phosphonate rearrangement.(a) Rearrangement induced by
treatment with LDA. (b) Crystalline material obtained from
reaction a. (c) Rearrangement induced by treatment with
LTMP.
leading to the two rearrangement products are them-
selves diastereomeric, some level of diastereoselectivity
may be attainable under properly chosen conditions.
In an earlier paper,8 we reported examination of a
series of nonracemic phosphate esters in the vinyl
phosphate rearrangement. Of the chiral auxiliaries
surveyed at that time, the best results were observed
with rearrangement of vinyl phosphates incorporating
(S)-2-methylbutyl esters. However, while that investiga-
tion established the viability of the general idea, only a
modest diastereomeric excess (de) was observed with
4-methylcyclohexanone and more highly substituted cy-
clohexanones gave mixtures wherein the de and absolute
stereochemistry could not be readily established. In this
report, studies of a new series of chiral auxiliaries are
described, along with new strategies for establishing both
the de and the absolute stereochemistry of some re-
arrangement products.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) (a) Hammond, G. B.; Calogeropoulou, T.; Wiemer, D. F. Tetra-
hedron Lett. 1986, 4265-4268. (b) Calogeropoulou, T.; Hammond, G.
B.; Wiemer, D. F. J . Org. Chem. 1987, 52, 4185-4190.
(2) Gloer, K. B.; Calogeropoulou, T.; J ackson, J . A.; Wiemer, D. F.
J . Org. Chem. 1990, 55, 2842-2846.
(3) An, Y. Z.; Wiemer, D. F. J . Org. Chem. 1992, 57, 317-321.
(4) Lee, K.; J ackson, J . A.; Wiemer, D. F. J . Org. Chem. 1993, 58,
5967-5971.
(5) Ruder, S. M.; Kulkarni, V. R. J . Org. Chem. 1995, 60, 3084-
3091.
For this study, the phosphorochloridates shown in
Table 1 were examined. In each case, the phosphorus
atom was incorporated in a cyclic system, based on the
premise that stricter control of the conformations avail-
(6) Vedejs, E.; Garcia-Rivas, J . A. J . Org. Chem. 1994, 59, 6517-
6518.
(7) Clarke, R.; Gahagan, M.; Mackie, R. K.; Foster, D. F.; Cole-
Hamilton, D. J .; Nicol, M.; Montford, A. W. J . Chem. Soc., Dalton
Trans. 1995, 1221-1226.
(8) An, Y. Z.; An, J . G.; Wiemer, D. F. J . Org. Chem. 1994, 59, 8197-
8202.
S0022-3263(95)01815-9 CCC: $12.00 © 1996 American Chemical Society

Diastereoselective Vinyl Phosphate Rearrangements
J . Org. Chem., Vol. 61, No. 12, 1996 4041
Ta ble 1. Ch ir a l Au xilia r ies for th e Vin yl P h osp h a te/
Reaction of ketone 10 with LDA cleanly gave the
expected racemic enolate, and that enolate reacted
smoothly with the phosphoryl chlorides 2, 4, 6, and 8 to
afford the desired vinyl phosphates. Attempted re-
arrangement of the binaphthol-derived vinyl phosphate
11 was not successful under the standard rearrangement
conditions.1 At this time it is not clear whether the
difficulty lies in formation of the requisite anion or
whether the anion was formed and simply failed to
proceed to C-P bond formation under these conditions.
In any event, only the parent vinyl phosphate 11 was
recovered after the usual acidic workup.
â-Keto P h osp h on a te Rea r r a n gem en t
The vinyl phosphates derived from ketone 10 and the
pentanediol phosphorochloridates 4 and 6 proved much
more interesting than those from binaphthol. Vinyl
phosphate 12 was formed in about 80% yield from
reaction of ketone 10 with LDA and the phosphorochlo-
ridate 4. When treated with LDA, this vinyl phosphate
rearranged as expected, forming the diastereomeric
â-keto phosphonates 13 and 14 in yields of 40-50%.
Analysis of the de of this reaction was possible, albeit
not immediately obvious, by direct inspection of the 31P
NMR spectrum of the reaction mixture. The spectrum
contains six resonances, three (23.3, 19.4, and 18.9 ppm)
representing the 5R series (corresponding to C-4 of the
original ketone) with the phosphoryl group in enolic, 1S,
and 1R positions and three (23.4, 19.2, and 19.1 ppm)
attributable to the 5S series in the enol, 1R, and 1S
forms. If the spectrum is obtained under basic condi-
tions, such that only the anions of the â-keto phosphon-
ates are present, only two resonances are observed (30.1
and 29.9 ppm). Although integration of these resonances
did not show appreciable de from this rearrangement
with LDA, the pentanediol auxiliary was the first we
have observed to result in distinguishable 31P resonances
for the rearrangement products (Figure 2) and thus the
first to allow an approximate determination of de by 31P
NMR.
able to the chiral auxiliary might be reflected in a more
diastereoselective rearrangement. The three phosphate
esters (2, 4, and 6) were prepared through reaction of
POCl3 with commercially available binaphthol (1)9 or
(2R,4R)- (3) or 2S,4S-pentane-2,4-diol (5).10 One phos-
phoramide (8) was prepared from POCl3 and the amino
alcohol N-methylleucenol (7),11 but attempted prepara-
tion of a bicyclic reagent from the related amino alcohol
(S)-(+)-2-pyrrolidinemethanol (9) was not successful
under the same reaction conditions, perhaps due to a
higher degree of strain.
The prochiral ketone selected for initial study was the
cyclohexanone 10, available via a short sequence from
acrylonitrile.12 On the one hand, this ketone presents a
well-defined conformation if the assumption is made that
the steric demands of the acetal moiety approximate
those of a tert-butyl group. At the same time, the acetal
functionality was likely to be compatible with the condi-
tions required for formation of the vinyl phosphate and
for the subsequent rearrangement3 and yet allow further
modification of this substituent to obtain more varied C-4
groups once a rearrangement had been achieved.13
A second advantage of the pentane-2,4-diol auxiliary
became apparent when it proved possible to separate the
diastereomeric series by a simple crystallization. When
the product was crystallized from a mixture of ether and
methanol, the crystalline material obtained showed only
a single resonance in its 31P NMR spectrum, if the
spectrum was recorded immediately after dissolution of
the crystals. The single peak corresponds in chemical
(9) Both binaphthol enantiomers are commercially available from
Aldrich Chemical Co. Previous applications of binaphthyl phosphoro-
chloridates include ref 7 and the following: (a) Gong, B.; Chen, W.;
Hu, B. J . Org. Chem. 1991, 56, 423-425. (b) Kato, N. J . Am. Chem.
Soc. 1990, 112, 254-257. (c) Kyba, E. P.; Gokel, G. W.; de J ong, F.;
Koga, K.; Sousa, L. R.; Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram,
D. J . J . Org. Chem. 1977, 42, 4173-4184. (d) J acques, J .; Fouquey,
C.; Vitterbo, R. Tetrahedron Lett. 1971, 4617-4620.
(10) Gordillo, B.; Eliel, E. L. J . Am. Chem. Soc. 1991, 113, 2172-
2177 and references therein.
(11) Hiroshi, T.; Suzuki, Y. Chem. Pharm. Bull. 1983, 31, 4295-
4299.
(12) Vig, O. P.; Sharma, S. D.; Bari, S. S.; Lal, M. Indian J . Chem.
1976, 14B, 932-933.
(13) The further elaboration of phosphonates 14 and 16 will be the
subject of a later report.

4042 J . Org. Chem., Vol. 61, No. 12, 1996
An et al.
The immediate goal was to establish the de values of
the rearrangements conducted with ketone 10 and other
chiral auxiliaries, which would be possible through
comparisons of optical rotations if all the varied phos-
phonates could be converted to a common derivative in
which C-5 was the only stereogenic center. One obvious
embodiment of this strategy is to employ a Horner-
Wadsworth-Emmons condensation for removal of the
chiral auxiliaries and conversion of C-2 to an sp2 center.
Condensation of the R,R,R phosphonate 14 with acet-
aldehyde gave the enone 18 as a single olefin isomer, but
surprisingly the product had [R]D ) 0°. Because it was
extremely unlikely that racemization had occurred under
the condensation conditions and the starting phosphonate
was known to have the 5R stereochemistry from the
diffraction analysis, other wavelengths were examined.
When an [R]365 ) +187° was observed, it became clear
that the D-line rotation for compound 18 simply happens
to be near 0°. For confirmation of this conclusion,
crystalline S,S,S diastereomer 16 also was treated with
acetaldehyde under typical Horner-Wadsworth-
Emmons conditions to obtain the enantiomeric enone 19.
This enone also has [R]D ) 0° and [R]365 ) -182°.
F igu r e 2. 31P NMR resonances for the enol isomers obtained
from rearrangements of vinyl phosphate 15. (a) Rearrange-
ment induced by treatment with LDA. (b) Crystalline material
obtained from reaction a. (c) Rearrangement induced by
treatment with LTMP.
shift to one of the enol resonances observed in the initial
product mixture. On allowing the product to stand in
CDCl3, equilibration occurs such that a mixture of the
1R and 1S isomers accompanies the enol form.
The fortuitous formation of crystalline material allowed
determination of absolute stereochemistry by single-
crystal diffraction analysis.14 The known absolute stereo-
chemistry of the starting pentanediol allowed facile
determination of the C-5 stereochemistry of the enol.
Thus it was established that use of (2R,4R)-pentane-2,4-
diol resulted in formation of a crystalline enol with R,R,R
stereochemistry (14).
In a series of parallel experiments, the phosphorochlo-
ridate 6 derived from (2S,4S)-pentane-2,4-diol was al-
lowed to react with the enolate of ketone 10, and the
resulting vinyl phosphate 15 was treated with LDA to
induce rearrangement to the â-keto phosphonates 16 and
17. Once again, six resonances were observed in the
initial product mixture, and crystallization gave only the
enol form of the S,S,S isomer 16. With access to both
C-5 stereoisomers, it was possible to probe various
aspects of this rearrangement in ways hitherto not
possible.
The enolate of ketone 10 was then treated with
phosphorochloridate 8, and the resulting vinyl phosphate
20 was treated with LDA to obtain the â-keto phos-
phonate 21. In contrast to phosphonates 13/14 and 16/
17, compound 21 showed only two resonances in its 31P
NMR spectrum. Furthermore, while condensation with
acetaldehyde proceeded under standard conditions, the
resulting enone (18/19) was clearly racemic ([R]365 ) 0°).
A similar situation prevailed with the vinyl phosphate
23 prepared from ketone 10 and bis((S)-2-methylbutyl)
phosphorochloridate (22).8 In this series, the overall yield
for formation of the vinyl phosphate and its subsequent
rearrangement to â-keto phosphonate was quite good
(54%) and condensation with acetaldehyde also was
smooth. Unfortunately, an [R]365 ) +2-9° for the product
indicated minimal diastereoselectivity for the rearrange-
ment.
(14) Capron, M. A.; An, J .; Swenson, D. C.; Wiemer, D. F. Acta
Crystallogr. 1995, C51, 479-482.

Diastereoselective Vinyl Phosphate Rearrangements
J . Org. Chem., Vol. 61, No. 12, 1996 4043
Because use of these different auxiliaries did not
materially improve the diastereoselectivity, and because
it was now possible to establish de through 31P NMR data
in the pentane-2,4-diol series, we examined the impact
of other conditions on the diastereoselectivity of the
rearrangement of vinyl phosphate 12. To induce re-
arrangement, the vinyl phosphates usually have been
treated with excess LDA but because these conditions
gave no de with compound 12, other bases were exam-
ined. When a mixture of LDA and lithium 2,6-dimethyl-
piperidide (LDMP), or when 2 equiv of LDMP, was used
to effect rearrangement, the S,S,S and S,S,R diastereo-
mer series were obtained in essentially a 1:1 ratio.
However, when the more hindered base lithium 2,2,6,6-
tetramethylpiperidide (LTMP) was employed, analysis of
the 31P NMR spectrum of the mixture indicated that the
S,S,S series was formed in a 2.5:1 preference over the
S,S,R series (Figure 2). Given that crystallization can
be employed to obtain the enol form of the S,S,S dia-
stereomer, this was an important step in making dia-
stereoselective rearrangements a more attractive process.
Our final goal was to begin testing other ketones for
the generality of diastereoselective rearrangements with
the 2,4-pentane-2,4-diol auxiliary. Reaction of 4-isopro-
pylcyclohexanone (25) with LDA and phosphorochloridate
6 gave the expected vinyl phosphate 26, and subsequent
reaction of 26 with LTMP resulted in rearrangement to
corresponding â-keto phosphonates 27. In the 31P NMR
spectrum of the reaction mixture, six resonances repre-
senting the three isomers of each C-5 diastereomeric
series were observed in a ratio indicating that this
rearrangement had proceeded with a de of about 2:1.
Another example of this diastereoselective rearrange-
ment was observed with 4-methylcyclohexanone (28).
Again in this series, six resonances were observed in the
31P NMR spectrum of the final product mixture when
LTMP was employed to induce rearrangement, corre-
sponding to the 1R, 1S, and enol isomers of each C-5
stereochemistry. Integration of these resonances indi-
cated that this rearrangement proceeded with a de of ca.
1.4:1. Unfortunately, the products of the latter two
reactions were obtained as oils, precluding direct use of
crystallography for determination of the C-5 stereochem-
istry in these cases.
further work will be necessary to establish the range of
this process and to allow prediction of the major dia-
stereomer, it seems clear that diastereoselective vinyl
phosphate/â-keto phosphonate rearrangements have po-
tential for preparation of nonracemic synthetic interme-
diates from prochiral ketones.
Exp er im en ta l Section
All reaction solvents were distilled immediately prior to use.
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none, while benzene, triethylamine, and diisopropylamine
were distilled from CaH2. All reactions were conducted in
oven-dried glassware, under an atmosphere of nitrogen, and
with magnetic stirring. Flash chromatography was carried out
on Baker silica gel with 40 µm average particle diameter.
Melting points are uncorrected. Optical rotations were meas-
ured with a Perkin-Elmer Model 141 automatic polarimeter.
NMR spectra (1H at 300 MHz and 13C at 75 MHz) were
recorded with CDCl3 as solvent and (CH3)4Si (1H) or CDCl3
(13C, 77.0 ppm) as internal standards. 31P NMR chemical
shifts are reported in ppm relative to 85% H3PO4 (external
standard). Both low- and high-resolution mass spectra were
obtained at an ionization potential of 70 eV. High-resolution
mass spectra were obtained at the University of Iowa Mass
Spectrometry Facility or at the Midwest Center for Mass
Spectrometry, Lincoln, NB. Elemental analyses were per-
formed by Atlantic Microlab, Inc. (Norcross, GA).
1,1′-Bin a p h th yl-2,2′-d iyl P h osp h or och lor id a te (2).7,9
Phosphorus oxychloride (766 mg, 5.0 mmol in 10 mL benzene)
was added slowly to a solution of 1,1′-bi-2-naphthol (143 mg,
5.0 mmol) and triethylamine (2.0 g, 20 mmol) in benzene (40
mL) at rt, and a white precipitate was formed immediately.
After 15 h, the reaction mixture was filtered through Celite
and the filtrate was concentrated in vacuo. Purification of the
residue by flash column chromatography (90% hexanes, 10%
ethyl acetate) gave compound 2 (1.43 g, 78%): 1H NMR δ 8.08
(d, J ) 8.9 Hz, 1), 8.07 (d, J ) 8.9 Hz, 1), 7.99 (d, J ) 8.2 Hz,
1), 7.97 (d, J ) 8.2 Hz, 1), 7.63 (dd, J ) 8.9, 0.9 Hz, 1), 7.56-
7.50 (m, 3), 7.42-7.30 (m, 4); 31P NMR 11.5; 13C NMR δ 132.1,
131.8, 131.6, 128.6, 127.2, 127.1, 127.0, 126.3, 120.3, 119.9 (d,
J CP ) 4.1 Hz).
(4R,6R)- or (4S,6S)-(+)-2-Ch lor o-4,6-d im et h yl-2-oxo-
1,3,2-d ioxa p h osp h or in a n e (4 or 6). According to the pro-
cedure described for the preparation of compound 2, (2R,4R)-
or (2S,4S)-pentane-2,4-diol (5.0 g, 50 mmol), triethylamine
(20.2 g, 200 mmol), benzene (250 mL), and phosphorus
oxychloride (7.7 g, 50 mmol) were added sequentially to a
reaction flask. After filtration of the reaction mixture and
concentration of the filtrate in vacuo, compound 4 (8.5 g, 96%),
or compound 6, was obtained through flash column chroma-
tography (hexanes 35%, ethyl acetate 65%). For compound 4:
[R]D ) +43° (CHCl3, c ) 3.7); 1H NMR δ 5.03-4.86 (m, 2),
2.24-2.14 (m, 1), 2.00 (dd, J ) 14.9, 2.9 Hz, 1), 1.61 (d, J )
6.8 Hz, 3), 1.50 (dd, J ) 6.3, 2.6 Hz, 3); 31P NMR -4.2; 13C
NMR δ 78.5 (d, J CP ) 8.7 Hz), 74.5 (d, J CP ) 7.4 Hz), 36.7 (d,
J CP ) 8.0 Hz), 21.5 (d, J CP ) 9.3 Hz), 20.0; EIMS m/ z (rel
intensity) 187 (M+ + 2, 1), 185 (M+, 3), 147 (30), 145 (90), 119
(23), 117 (70), 68 (100), 45 (48). For compound 6 [R]D ) -45°
(CHCl3, c ) 1.0), but all other spectral data were identical to
that for compound 4.
(4S )-N -m e t h yl-4-isob u t yl-2-ch lor o-1,3,2-oxa za p h os-
p h olid in -2-on e (8). According to the procedure described for
compound 2, compound 711 (4.01 g, 30.6 mmol), triethylamine
(15.5 g, 153 mmol), benzene (100 mL), and phosphorus
oxychloride (4.7 g, 31 mmol) were added sequentially to a
reaction flask. After standard workup, compound 8 (4.01 g,
62%) was obtained through flash column chromatography
(hexanes 10%, ethyl acetate 90%): [R]D ) +61° (CHCl3, c )
2.3); 1H NMR δ 4.50-4.41 (m, 1), 4.09-4.00 (m, 1), 3.41-3.31
(m, 1), 2.65 (d, J HP ) 14.4 Hz, 3), 1.70-1.53 (m, 2), 1.48-1.36
(m, 1), 0.97 (d, J ) 6.4 Hz, 3), 0.94 (d, J ) 6.0 Hz, 3); 31P NMR
In conclusion, examination of several additional chiral
auxiliaries in the vinyl phosphate/â-keto phosphonate
rearrangement has led to recognition of the special utility
of 2,4-pentane-2,4-diol derivatives. The â-keto phos-
phonates that include this auxiliary have given rise to
distinct signals in their 31P NMR spectra, allowing ready
estimates of de. In one case, a rearrangement product
crystallized readily in the enol form, allowing determi-
nation of absolute stereochemistry via single-crystal
diffraction analysis. Finally, this information has al-
lowed the discovery of rearrangement conditions that
produce de values that range from 1.4:1 to 2.5:1. While
27.3; 13C NMR δ 70.5, 55.8 (d, J CP ) 14.0 Hz), 40.3 (d, J CP
)
10.0 Hz), 28.6 (d, J CP ) 4 Hz), 23.9, 23.3, 21.5; EIMS m/ z (rel
intensity) 213 (M+ +2, 0.8), 211 (M+, 2.4), 196 (0.3), 156 (61),

4044 J . Org. Chem., Vol. 61, No. 12, 1996
An et al.
154 (100), 118 (14), 42 (16); HRMS calcd for C7H15NO2P35Cl
211.0529, found 211.0514; calcd for C7H15NO2P37Cl 213.0499,
found 213.0497.
The mother liquors from the crystallization were enriched
in the 5S diastereomer: 31P NMR (CDCl3) 23.4, 19.2, 19.1;
(CH3OH/NaOMe) 29.9.
Cyclic (1S,3S)-1,3-Dim eth yltr im eth ylen e 4-Meth yl-4-
(2-m eth yl-1,3-d ioxola n -2-yl)-1-cycloh exen yl P h osp h a te
(15). Vinyl phosphates 15 were prepared from ketone 10 (9.11
g, 46 mmol) and phosphorochloridate 6 (8.49 g, 46 mmol) in a
fashion exactly parallel to preparation of vinyl phosphates 12
(87% yield).
4-(1,1′-(E t h y le n e d i o x y )e t h y l)-4-m e t h y lc y c lo h e x -
a n on e (10). Ketone 10 was prepared from acrylonitrile
according to a literature procedure.12 For 10: 1H NMR δ 4.03-
3.86 (m, 4), 2.45-2.27 (m, 4), 2.05-1.94 (m, 2), 1.75-1.66 (m,
2), 1.28 (s, 3), 1.21 (s, 3); 13C NMR δ 212.3, 113.4, 64.7 (2),
40.4, 36.9 (2), 30.7 (2), 18.9, 18.8.
Cyclic (1S,3S)-1,3-Dim eth yltr im eth ylen e [(5S)-5-Meth -
yl-5-(2-m eth yl-1,3-d ioxola n -2-yl)-2-oxocycloh exyl] p h os-
p h on a te (16) a n d th e 5R Dia ster eom er 17. In a manner
parallel to preparation of compounds 13 and 14, vinyl phos-
phates 15 (0.80 g, 2.3 mmol in 10 mL THF) were added slowly
to a solution of LDA (2.5 mmol) and LTMP (2.5 mmol) in 40
mL THF. Standard workup and final purification by flash
column chromatography (95% ethyl acetate, 5% methanol)
gave equal amounts of the expected products, the S,S,S and
S,S,R diastereomers (0.38 g, 47%). Crystallization from ether/
methanol (9:1) afforded compound 16 as white crystalline
needles: mp ) 163 °C, [R]D ) -19.2° (CHCl3, c ) 0.96). Both
NMR (1H,31P, and 13C) and mass spectral data were identical
to that obtained for the opposite enantiomer, compound 14.
The mother liquors were enriched in the S,S,R diastereomer
17, as seen previously with compounds 13 and 14.
1,1′-Bi-2-n a p h th yl 4-Meth yl-4-(2-m eth yl-1,3-d ioxola n -
2-yl)-1-cycloh exen yl P h osp h a te (11). According to the
procedure described below for compound 12, ketone 10 (0.48
g, 2.5 mmol in 4 mL THF) was added to an LDA solution (0.33
mmol in 30 mL THF) and phosphorochloridate 2 (0.93 g, 2.54
mmol in 6 mL THF) was then added. Standard workup as
described below and purification by flash column chromatog-
raphy (50% hexanes, 50% ethyl acetate) gave vinyl phosphates
11 (0.28 g, 21%) as an oil: 1H NMR δ 8.08 (d, J ) 8.9 Hz, 1),
8.07 (d, J ) 8.9 Hz, 1), 8.0 (d, J ) 8.2 Hz, 1), 7.9 (d, J ) 8.2
Hz, 1), 7.6 (d, J ) 8.9 Hz, 1), 7.5-7.2 (m, 7), 5.6 (br, 1), 3.98-
3.82 (m, 4), 2.42-2.20 (br, 3), 1.92-1.70 (br, 2), 1.65-1.55 (br,
1), 1.31 (s, 3), 1.05 (s, 3); 31P NMR -2.2, -2.4; 13C NMR δ 147.5
(d, J CP ) 5.0 Hz), 147.3, 146.5, 146.3 (d, J CP ) 5.0 Hz), 146.2,
146.1, 132.1, 131.8, 131.6, 131.4, 131.0, 128.4, 128.3, 128.2,
127.1, 126.9, 126.7, 125.7, 121.4, 120.6, 120.1, 113.7, 110.4,
65.0, 64.8, 39.8, 31.5, 30.4, 27.3, 18.9, 18.2; HRMS calcd for
(4R)-2(E)-Eth yliden e-4-m eth yl-4-(2-m eth yl-1,3-dioxolan -
2-yl)cycloh exa n on e (18). A mixture of â-keto phosphonate
14 (0.13 g, 0.38 mmol), potassium carbonate (51 mg, 0.45
mmol), and acetaldehyde (167 mg, 3.8 mmol) in 1,4-dioxane
(10 mL) and water (2 drops) was stirred at rt for 15 h.15 The
resulting solution was concentrated in vacuo, and the residue
was purified by flash column chromatography (80% hexanes,
20% ethyl acetate) to give enone 18 (33 mg, 40%) as a light
oil: [R]365 ) +187° (CHCl3, c ) 0.8); 1H NMR δ 6.78-6.71 (m,
1), 4.03-3.78 (m, 4), 2.58-2.32 (m, 4), 2.08-1.98 (m, 1), 1.74
C
31H29O6P 528.1702, found 528.1677.
Cyclic (1R,3R)-1,3-Dim eth yltr im eth ylen e 4-Meth yl-4-
(2-m eth yl-1,3-d ioxola n -2-yl)-1-cycloh exen yl P h osp h a te
(12). Compound 10 (1.00 g, 5.0 mmol) in THF (5 mL) was
added slowly to an LDA solution (5.0 mmol in 20 mL THF) at
-78 °C. After 1 h, phosphorochloridate 4 (0.70 g, 3.8 mmol in
5 mL THF) was added, and the reaction was allowed to warm
to rt slowly. After 4 h at rt, the reaction was quenched by
addition of saturated aqueous NH4Cl. The aqueous layer was
extracted twice with ether (50 mL), and the combined organic
extracts were dried over Na2SO4 and then concentrated in
vacuo. Final purification of the residue by flash column
chromatography (100% ethyl acetate) gave the vinyl phosphate
12 as a mixture of diastereomers (3.06 g, 80%): 1H NMR δ
5.40 (br, 1), 4.87-4.74 (m, 2), 4.00-3.82 (m, 4), 2.34-2.24 (br,
3), 2.11-2.02 (br, 1), 1.88-1.69 (m, 3), 1.49 (d, J ) 6.7 Hz, 3),
1.44 (dd, J ) 6.3, 2.1 Hz, 3), 1.25 (s, 3), 1.00 (s, 3); 31P NMR
-12.33, -12.43; 13C NMR δ 146.0 (d, J CP ) 8.0 Hz), 113.2,
108.56 (d, J CP ) 5.7 Hz) and 108.33 (d, J CP ) 5.3 Hz) (two
diastereomers), 74.8 (d, J CP ) 7.3 Hz), 72.6 (d, J CP ) 6.5 Hz),
64.8, 64.6, 39.6, 37.2 (d, J CP ) 7.2 Hz), 30.2, 27.1, 24.6, 21.6
(d, J CP ) 8.2 Hz), 20.3, 18.7, 17.9; EIMS m/ z (rel intensity)
346 (M+, 1), 331 (1.6), 302 (1), 284 (1), 259 (4), 215 (3), 99 (13),
87 (100), 43 (19); HRMS calcd for C16H27O6P 346.1545, found
346.1568.
(d, J ) 8.7 Hz, 3), 1.70-1.61 (m, 1), 1.31 (s, 3), 1.05 (s, 3); 13
C
NMR δ 200.9, 135.7, 134.7, 113.7, 65.0, 64.8, 41.0, 35.7, 32.3,
28.8, 20.8, 19.0, 13.4; EIMS m/ z (rel intensity) 224 (M+, 0.1),
209 (2.3), 179 (0.4), 87 (100), 67 (4), 53 (6), 43 (35); HRMS
calcd for C13H20O3 224.1412, found 224.1424.
(4S)-2(E)-Eth yliden e-4-m eth yl-4-(2-m eth yl-1,3-dioxolan -
2-yl)cycloh exa n on e (19). In a manner identical to that
described for preparation of compound 18, phosphonate 16 (106
mg, 0.31 mmol) was treated with potassium carbonate (51 mg,
3.1 mmol) and acetaldehyde in wet dioxane to afford compound
19 (40 mg, 58%) as a light oil: [R]365 ) -182° (CHCl3, c ) 0.7).
1H and 13C NMR and mass spectral data were identical to
those found for the corresponding (+)-enantiomer 18. Anal.
Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.43; H,
9.07.
2-[(4-Me t h y l-4-(2-m e t h y l-1,3-d io x o la n -2-y l)c y c lo -
h exen yl)oxy]-N-m eth yl-4-(4S)-isobu tyl-1,3,2-oxa za p h os-
p h olid in -2-on e (20). According to the procedure described
for compound 12, ketone 10 (1.0 g, 5.0 mmol in 5 mL THF)
was added to an LDA solution (5.0 mmol in 30 mL THF),
followed by addition of phosphorochloridate 8 (0.85 g, 4.0
mmol). Standard workup and purification by flash column
chromatography (100% ethyl acetate) afforded vinyl phos-
phates 20 (1.02 g, 68%) as a mixture of diastereomers: 1H
NMR δ 5.34 (br, 1), 4.37-4.28 (m, 1), 4.00-3.85 (m, 5), 3.42-
3.37 (m, 1), 2.65 (d, J HP ) 10.5 Hz, 3), 2.35-2.20 (m, 3), 1.83-
1.53 (m, 5), 1.41-1.28 (m, 1), 1.25 (s, 3), 1.00 (s, 3), 0.95 (d, J
) 6.3 Hz, 3), 0.91 (d, J ) 6.3, 3); 31P NMR 17.6, 17.4; 13C NMR
δ 146.6 (d, J CP ) 5.0 Hz) and 146.5 (d, J CP ) 5.0 Hz) (for two
diastereomers), 113.4, 109.2 (d, J CP ) 5.7 Hz), 69.7, 64.9, 64.7,
56.6 (d, J CP ) 13.6 Hz), 40.6 (d, J CP ) 6.9 Hz), 39.8, 30.4, 28.7,
24.8 (d, J CP ) 6.4 Hz), 24.3, 23.6, 21.7, 18.8, 18.1; EIMS m/ z
(rel intensity) 373 (M+, 0.6), 358 (0.8), 311 (2), 286 (2.1), 254
(0.5), 194 (13), 136 (11), 87 (100), 43 (19); HRMS calcd for
C18H32NO5P 373.2018, found 373.2011.
Cyclic (1R,3R)-1,3-Dim eth yltr im eth ylen e [(5R)-5-Meth -
yl-5-(2-m eth yl-1,3-d ioxola n -2-yl)-2-oxocycloh exyl] p h os-
p h on a te (14) a n d th e 5S Dia ster eom er 13. Compound 12
(2.59 g, 7.5 mmol in 10 mL THF) was added dropwise to an
LDA solution (16.4 mmol in 80 mL THF) at -78 °C. The
reaction mixture then was allowed to warm to rt, and after 5
h at rt, the reaction was quenched by addition of saturated
aqueous NH4Cl. The aqueous layer was extracted with ether
(3 × 40 mL), the combined organic extracts were dried over
Na2SO4, and this solution was concentrated in vacuo. Final
purification by flash column chromatography (95% ethyl
acetate, 5% methanol) gave equal amounts of two diastereo-
mers, the R,R,R and R,R,S isomers (1.05 g, 41%). Crystal-
lization from ether/methanol (9:1) afforded compound 14 as
white crystalline needles: mp ) 163 °C; [R]D ) +17.3° (CHCl3,
1
c ) 1.0); H NMR δ 10.91 (s, 1), 4.90-4.85 (m, 1), 4.70-4.60
(m, 1), 4.03-3.84 (m, 4), 2.28-2.22 (m, 3), 1.94-1.87 (m, 2),
1.82-1.68 (m, 2), 1.62-1.48 (m, 1), 1.57 (d, J ) 6.7 Hz, 3),
1.38 (dd, J ) 6.2, 1.5 Hz, 3), 1.28 (s, 3), 0.99 (s, 3); 31P NMR
(CDCl3) 23.3, 19.4, 18.9 (enol form, trans, and cis); (CH3OH/
NaOMe) 30.1; EIMS m/ z (rel intensity) 346 (M+, 1), 331 (1),
301 (8), 259 (10), 233 (8), 113 (9), 87 (100); HRMS calcd for
C16H27O6P 346.1545, found 346.1552. Anal. Calcd for
C16H27O6P: C, 55.48; H, 7.86. Found: C, 55.49; H, 7.90.
2-[5-Meth yl-5-(2-m eth yl-1,3-d ioxola n -2-yl)-2-oxocyclo-
h exyl]-N-m eth yl-4(S)-isobu tyl-1,3,2-oxa za p h osp h olid in -
2-on e (21). According to the procedure described for phos-
(15) Mouloungui, Z.; Delmas, M.; Gaset, A. Synth. Commun. 1984,
14, 701-705.

Diastereoselective Vinyl Phosphate Rearrangements
J . Org. Chem., Vol. 61, No. 12, 1996 4045
phonate 14, compound 20 (0.93 g, 2.5 mmol in 5 mL THF) was
added to an LDA solution (5.5 mmol in 30 mL THF). Standard
workup and final purification by flash column chromatography
(100% ethyl acetate) gave phosphonates 21 (0.35 g, 37%) as a
mixture of diastereomers: 1H NMR δ 11.17 (d, J HP ) 1.3 Hz,
1) and 11.13 (d, J HP ) 1.3 Hz, 1) (for two diastereomers), 4.07-
3.84 (m, 5), 3.41-3.37 (m, 1), 2.61(d, J HP ) 9.9 Hz, 3) and 2.58
(d, J HP ) 9.7 Hz, 3) (for two diastereomers), 2.34-2.20 (m, 2),
2.05-2.03 (br, 1), 1.76-1.56 (m, 5), 1.45-1.36 (m, 1), 1.26 (s,
3), 1.01 (s, 3) and 1.00 (s, 3) (for two diastereomers), 0.95 (d,
J ) 6.3 Hz, 3), 0.92 (d, J ) 6.3 Hz, 3) and 0.91 (d, J ) 6.3 Hz,
3) (for two diastereomers); 31P NMR 45.9, 45.6; 13C NMR δ
170.4 (d, J CP ) 4.9 Hz) and 170.3 (d, J CP ) 4.9 Hz) (for two
isomers), 113.2 and 113.1 (for two isomers), 85.7 (d, J CP ) 163.7
Hz), 71.1 and 70.8 (two isomers), 58.4 (d, J CP ) 11.5 Hz) and
58.22 (d, J CP ) 11.2 Hz) (for two isomers), 40.90 (d, J CP ) 11.3
Hz) and 40.2 (d, J CP ) 9.7 Hz) (for two isomers), 37.0, 28.9 (d,
J CP ) 6.1 Hz) and 28.8 (d, J CP ) 8.0 Hz) (for two isomers),
27.8 (d, J CP ) 8.4 Hz) and 27.6 (d, J CP ) 7.7 Hz) (for two
isomers), 26.44, 26.3 and 26.1 (for two isomers), 24.7, 23.6,
21.7, 18.7, 17.9 and 17.7 (for two isomers); EIMS m/ z (rel
intensity) 373 (M+, 3), 358 (1), 330 (6), 328 (16), 286 (8), 254
(3), 188 (4), 87 (100), 43 (31); HRMS calcd for C18H32NO5P
373.2018, found 373.2016.
Cyclic (1S,3S)-1,3-Dim eth yltr im eth ylen e (5-Isop r op yl-
2-oxocycloh exyl)p h osp h on a te (27). 4-Isopropylcyclohex-
anone (25) (700 mg, 5.0 mmol) was added slowly to an LDA
solution (5 mmol in 10 mL THF) at 0 °C. After 15 min,
phosphorochloridate 6 (923 mg, 5.0 mmol) was added, and the
reaction was allowed to warm slowly to rt. After 4 h at rt,
the reaction was quenched by addition of saturated aqueous
NH4Cl. The aqueous layer was extracted three times with
ether (30 mL), and the combined organic extracts were dried
over Na2SO4 and concentrated in vacuo. Vinyl phosphates 26
were utilized for rearrangement without further purification:
31P NMR -13.1, -13.1.
Compound 26 (1.44 g, 5.0 mmol) was added dropwise to an
LTMP solution (12.5 mmol in 50 mL of THF) at -78 °C. The
reaction mixture was then allowed to warm slowly to rt. After
1 h at rt, the reaction was quenched by addition of saturated
aqueous NH4Cl. The aqueous layer was extracted three times
with ether (30 mL), and the combined organic extracts were
dried over Na2SO4 and concentrated in vacuo. Final purifica-
tion of the residue by flash column chromatography (90% ethyl
acetate, 10% methanol) gave an oil identified as a mixture of
diastereomers 27 (533 mg, 37% overall from ketone 25): 1H
NMR δ 10.87 (s, enol tautomer), 4.93-4.73 (m, 1), 4.72-4.51
(m, 1), 3.12-2.98 (m, 1), 2.97-2.67 (m, ketone tautomer),
2.53-2.30 (m, 2), 2.28-2.21 (m, 1), 2.20-1.70 (m, 5), 1.69-
1.23 (m, 9), 0.97-0.84 (m, 7); 31P NMR 23.1, 23.1, 18.7, 18.5,
18.4, 17.6. Anal. Calcd for C14H25O4P: C, 58.32; H, 8.74.
Found: C, 58.46; H, 8.76.
Condensation with acetaldehyde, as described for phos-
phonate 14, gave a mixture of compounds 18 and 19 in 40%
yield; a measured [R]365 ) 0° indicated that no de was obtained
in this rearrangement.
Bis[(S)-2-m eth ylbu tyl] 4-Meth yl-4-(2-m eth yl-1,3-d iox-
ola n -2-yl)-1-cycloh exen yl P h osp h a te (23). According to
the procedure described for compounds 12, ketone 10 (2.18 g,
11 mmol in 10 mL THF) was added to an LDA solution (13
mmol in 50 mL THF) at -78 °C, followed by addition of bis-
[(S)-(-)-2-methylbutyl] phosphorochloridate (2.80 g, 11 mmol).8
Flash column chromatography (hexanes 80%, ethyl acetate
20%) gave vinyl phosphates 23 (3.61 g, 78%) as a mixture of
two diastereomers: 1H NMR δ 5.41-5.38 (m, 1), 3.99-3.83
(m, 8), 2.36-2.06 (m, 3), 1.89-1.64 (m, 4), 1.62-1.40 (m, 3),
1.29-1.12 (m, 2), 1.25 (s, 3), 1.00 (s, 3), 0.95 (d, J ) 6.6 Hz, 6),
0.91 (t, J ) 7.3 Hz, 6); 31P NMR -4.6; 13C NMR δ 146.2 (d, J CP
) 8.7 Hz), 113.4, 108.9 (d, J CP ) 5.3 Hz), 72.3, 72.2, 64.9 (d,
J CP ) 11.6 Hz), 39.8, 35.3 (d, J CP ) 7.1 Hz), 30.4, 27.3, 25.3,
24.5, 18.8, 18.1, 15.8, 11.0; EIMS m/ z (rel intensity) 418 (M+,
1), 403 (1), 331 (1), 261 (1), 234 (2), 216 (11), 180 (5), 135 (7),
118 (10), 99 (29), 87 (100), 77 (6), 55 (12); HRMS calcd for
C21H39O6P 418.2484, found 418.2481.
Cyclic (1S,3S)-1,3-Dim eth yltr im eth ylen e (5-Meth yl-2-
oxocycloh exyl)p h osp h on a te (30). According to the proce-
dure described for compound 12, ketone 28 (0.23 g, 2.0 mmol
in 2 mL THF) was added to an LDA solution (2 mmol in 8 mL
THF) at -78 °C, followed by addition of compound 22 (0.37 g,
2 mmol in 2 mL THF). After standard workup, purification
by flash column chromatography (20% hexanes, 80% ethyl
acetate) gave compound 29 (0.39 g, 75%): 1H NMR δ 5.44 (br,
1), 4.86-4.70 (m, 2), 2.35-2.01 (m, 5), 1.85-1.61 (m, 4), 1.49
(d, J ) 6.7 Hz, 3), 1.44 (dd, J ) 6.3, 2.2 Hz, 3), 0.96 (d, J ) 6.6
Hz, 3); 13C NMR δ 147.4 (d, J CP ) 10.6 Hz), 109.6 (d, J CP ) 6.1
Hz), 74.8 (d, J CP ) 7.4 Hz), 72.6 (d, J CP ) 6.9 Hz), 37.5 (d, J CP
) 7.0 Hz), 32.9, 31.8, 30.6, 27.6 (d, J CP ) 9.1 Hz), 21.9 (d, J CP
) 8.4 Hz), 21.0, 20.6; 31P NMR -12.3.
Vinyl phosphate 29 (0.39 g, 1.5 mmol in 3 mL THF) then
was added to an LTMP solution (3.75 mmol in 20 mL THF) at
-78 °C, according to the procedure described for compound
23. After standard workup, purification by flash column
chromatography (100% ethyl acetate) gave compound 30 as a
mixture of diastereomers (0.22 g, 56%): 1H NMR δ 10.87 (enol
tautomer), 4.87-4.83 (m, 1), 4.68-4.55 (m, 1), 3.07-2.91 (m,
1), 2.82-2.71 (m, ketone tautomer), 2.45-2.31 (m, 2), 2.24-
2.10 (m, 1), 2.06-1.89 (m, 3), 1.77-1.60 (m, 1), 1.55-1.30 (m,
1), 1.50-1.40 (m, 6), 1.05-0.95 (m, 3); 31P NMR 23.1 and 22.8
(two isomers of enol forms), 18.5, 18.4, 18.2, and 17.6 (four
isomers of ketone forms); EIMS m/ z (rel intensity) 260 (M+,
19), 232 (12), 192 (26), 177 (33), 165 (39), 150 (89), 109 (83),
69 (91), 41 (100); HRMS calcd for C12H21O4P 260.1177, found
260.1150.
Bis[(S)-2-m eth ylbu tyl] [5-Meth yl-5-(2-m eth yl-1,3-d iox-
ola n -2-yl)-2-oxocycloh exyl] p h osp h on a te (24). According
to the procedure described for 14, compound 23 (1.4 g, 3.3
mmol in 10 mL THF) was added to an LDA solution (7 mmol
in 40 mL THF). Flash column chromatography (80% hexanes,
20% ethyl acetate) gave phosphonate 24 (0.97 g, 69%): [R]D
)
2.40° (CHCl3, c ) 3.5); 1H NMR δ 10.76 (enol tautomer), 4.40-
3.62 (m, 8), 3.35 (ddd, J HP ) 24.5 Hz, J ) 12.5, 5.7 Hz), 3.01
(ddd, J HP ) 23.0 Hz, J ) 13.9, 5.7 Hz), 2.50-2.01 (m, 4), 1.84-
1.48 (m, 6), 1.24-1.13 (m, 2), 1.26 (m, 3), 1.00 (m, 3), 0.97-
0.88 (m, 12); 31P NMR 27.9, 25.1, 24.7; 13C NMR δ 207.4 (d,
J CP ) 6.2 Hz), 206.7 (d, J CP ) 6.9 Hz), 168.5 (d, J CP ) 6.6 Hz),
146.9 (d, J CP ) 8.9 Hz), 113.4, 113.3, 113.2, 108.7, 108,7, 72.4,
72.3, 70.7, 70.6, 69.9, 69.8, 65.0 (d, J CP ) 4.8 Hz), 65.0 (d, J CP
) 5.6 Hz), 64.9 (d, J CP ) 4.0 Hz), 46.6 (d, J CP ) 139.3 Hz),
45.5 (d, J CP ) 143.8 Hz), 41.9, 41.0, 40.9, 40.2, 40.1, 35.6 (d,
J CP ) 7.5 Hz), 35.4 (d, J CP ) 6.8 Hz), 34.4 (d, J CP ) 4.0 Hz),
32.1, 30.9, 29.2, 29.1, 26.7, 26.6, 26.1, 25.9, 25.6, 25.5, 25.4,
25.2, 20.5, 19.1, 19.0, 18.9, 18.8, 18.4, 18.0, 16.1, 16.0, 15.9,
11.1; EIMS m/ z (rel intensity) 418 (M+, 1), 403 (1), 373 (1),
233 (9), 217 (5), 191 (15), 180 (4), 135 (12), 113 (7), 87 (100),
71 (7), 55 (14); HRMS calcd for C21H39O6P 418.2484, found
418.2480. Condensation with acetaldehyde, as described for
compound 14, gave a mixture of compounds 18 and 19 in 67%
yield; a measured [R]365 ) +2-9° (CHCl3, c ) 1.0) indicated a
slight diastereoselectivity for the 5R isomer in this rearrange-
ment.
Ack n ow led gm en ts. We thank the University of
Iowa Center for Biocatalysis and Bioprocessing and NIH
Training Grant GM-08365 for financial support in the
form of a fellowship to J .M.W. Financial support from
the National Institutes of Health (GM-46631) is grate-
fully acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra (9 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9518157