Preparation of α-phosphono lactams via electrophilic phosphorus reagents: An application in the synthesis of lactam-based farnesyl transferase inhibitors

Article abstract of DOI:10.1021/jo020119l

Conversion of N-alkyl lactams to the corresponding α-phosphono lactams has been investigated through procedures that involve formation of the lactam enolate and reaction with a phosphorus electrophile. With N-octylpyrrolidinone, the enolate could be trapped efficiently on oxygen by reaction with diethyl phosphorochloridate, and the resulting vinyl phosphate rearranges smoothly to the desired phosphonate upon treatment with additional LDA. Attempts to apply the same protocol to N-farnesyl lactams met with limited success. Studies with an isolated α-phosphono N-farnesyl lactam have shown that the farnesyl group is not stable to the excess of strong base required for rearrangement of a vinyl phosphate. However, a series of N-farnesyl lactams and imides was converted to the desired phosphonates through formation of the lactam enolate, reaction with diethyl phosphorochloridite, and subsequent oxidation of the phosphorus intermediate to the P(V) state.

Full text of DOI:10.1021/jo020119l

P r ep a r a tion of r-P h osp h on o La cta m s via Electr op h ilic
P h osp h or u s Rea gen ts: An Ap p lica tion in th e Syn th esis of
La cta m -Ba sed F a r n esyl Tr a n sfer a se In h ibitor s
Yanming Du and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
david-wiemer@uiowa.edu
Received February 21, 2002
Conversion of N-alkyl lactams to the corresponding R-phosphono lactams has been investigated
through procedures that involve formation of the lactam enolate and reaction with a phosphorus
electrophile. With N-octylpyrrolidinone, the enolate could be trapped efficiently on oxygen by reaction
with diethyl phosphorochloridate, and the resulting vinyl phosphate rearranges smoothly to the
desired phosphonate upon treatment with additional LDA. Attempts to apply the same protocol to
N-farnesyl lactams met with limited success. Studies with an isolated R-phosphono N-farnesyl
lactam have shown that the farnesyl group is not stable to the excess of strong base required for
rearrangement of a vinyl phosphate. However, a series of N-farnesyl lactams and imides was
converted to the desired phosphonates through formation of the lactam enolate, reaction with diethyl
phosphorochloridite, and subsequent oxidation of the phosphorus intermediate to the P(V) state.
R-Phosphono lactams and amides are widely used
as synthetic reagents, particularly in the Horner-
Wadsworth-Emmons (HWE) reaction.1 They also attract
interest for their potential biological activity because they
can serve as surrogates for diphosphate esters and
carbamyl phosphate groups, which are important meta-
bolic intermediates.2 Formal replacement of a P-O bond
with a P-C bond is considered to increase metabolic
stability.3 For this reason, various R-phosphono amides
have been prepared and tested as inhibitors of farnesyl
protein transferase (FPTase)2a or geranylgeranyl protein
transferase,4 as a transition-state analogue for aspartate
transcarbamylase,5 and for their toxicity to herpes vi-
ruses.6
gen-bonding potential, and a hydrophobic group are
important for their activities.8 For these reasons, the
R-phosphono lactam structure was of new interest to us.
On one hand, such structures would employ an R-phospho-
no amide group to mimic the pyrophosphate group, and
on the other hand, incorporation of a ring structure would
fix part of the molecular geometry and serve as a
template to carry other functional groups.
R-Phosphono lactams can be synthesized from a variety
of precursors. Most frequently they have been prepared
from (diethoxyphosphinyl)acetic acid derivatives through
intramolecular amidation to form a lactam ring.9 The
Arbuzov reaction, in which an R-halolactam is treated
with a trialkyl phosphite, also has been used quite
often.10 Both copper(I)-mediated coupling11 and rhodium-
(II)-catalyzed C-H insertion12 have been reported as well.
With our interest in the design and synthesis of
FPTase inhibitors,7 we were particularly interested in
defining a new bioisoteric replacement for the diphos-
phate moiety of farnesyl pyrophosphate. FPTase is a zinc
metalloenzyme, and it has been shown in some inhibitor
design studies that compounds with zinc ligands, hydro-
(8) Hunt, J . T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.;
Cho, Y.; Chong, S.; Chao, S.; Gullo-Brown, J .; Guo, P.; Kim, S. H.; Lee,
F. Y.; Leftheris, K.; Miller, A.; Mitt, T.; Patel, M.; Penhallow, B. A.;
Ricca, C.; Rose, W. C.; Schmidt, R.; Slusarchyk, W. A.; Vite, G.; Manne,
V. J . Med. Chem. 2000, 43, 3587-3595.
(1) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(2) (a) Patel, D. V.; Schmidt, R. J .; Biller, S. A.; Gordon, E. M.;
Robinson, S. S.; Manne, V. J . Med. Chem. 1995, 38, 2906-2921. (b)
Coutrot, Ph.; Grison, C.; Charbonnier-Gerardin, C. Tetrahedron 1992,
43, 9841-9868.
(9) (a) Soufiane, T.; Hedi, Z. Phosphorus, Sulfur, Silicon Relat. Elem.
1998, 134, 493-502. (b) Chiefar, J .; Galanopoulos, S.; J anowski, W.
K.; Kerr, D. I. B.; Prager, R. H. Aust. J . Chem. 1987, 40, 1511-1518.
(c) Baumann, T.; Buchholz, B.; Stamm, H. Synthesis 1995, 44-46. (d)
Khokhlov, P. S.; Kashemirov, B. A.; Mikityuk, A. D.; Chimishkyan, A.
L.; Strepikheev, Yu. A. J . Gen. Chem. USSR (Engl. Transl.) 1984, 54,
2414-2415. (e) Giambastini, G.; Pacin, B.; Porcelloni, M.; Poli, G. J .
Org. Chem. 1998, 63, 804-807. (f) Khokhlov, P. S.; Kashemirov, B.
A.; Mikityuk, A. D.; Strepikheev, Yu. A. J . Gen. Chem. USSR (Engl.
Transl.) 1983, 53, 1936-1937.
(10) (a) For N,N-dimethylglycine anhydride, cf.: Burger, K.; Heis-
tracher, E.; Simmerl, R.; Eggersdorfer, M. Z. Naturforsch., B 1992,
47, 424-433. (b) Chai, C. L. L.; King, A. R. J . Chem. Res., Miniprint
1997, 11, 2347-2357. (c) For imides, cf: Meanwell, N. A.; Roth, H. R.;
Smith, E. C. R.; Wedding, D. L.; Wright, J . J . K. J . Org. Chem. 1991,
56, 6897-6904. For other R-halo lactams, cf.: (d) Schickli, C. P.;
Seebach, D. Liebigs Ann. Chem. 1991, 7, 655-668. (e) Worley, J . W.;
Ratts, K. W.; Cammack, K. L. J . Org. Chem. 1975, 40, 1731-1734.
(3) Fields, S. C. Tetrahedron 1999, 55, 12237-12273.
(4) Macchia, M.; J annitti, N.; Gervasi, G.; Danesi, R. J . Med. Chem.
1996, 39, 1352-1356.
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C. J . Med. Chem. 1985, 28, 1555-1558.
(6) J ennings, L. J .; Macchia, M.; Parkin, A. J . Chem. Soc., Perkin
Trans. 1 1992, 2197-2202.
(7) (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. (c)
Cermak, D. M.; Du, Y.; Wiemer, D. F. J . Org. Chem. 1999, 64, 388-
393. (d) Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl, R. J . Bioorg.
Med. Chem. 2000, 8, 2729-2737.
10.1021/jo020119l CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002
J . Org. Chem. 2002, 67, 5709-5717
5709

Du and Wiemer
SCHEME 1
SCHEME 2
However, for our purposes it appeared more efficient to
begin with the core lactam structure and add farnesyl
and phosphonyl groups in turn. However, there are fewer
known methods that proceed directly from a lactam to
an R-phosphono lactam.13
For some years we have been interested in the rear-
rangement of vinyl phosphates to phosphonates (Scheme
1).14 When the cyclic ketone 1 or the lactone 2 was treated
with LDA and the resulting enolate was trapped by
reaction with diethyl phosphorochloridate, a vinyl phos-
phate (3 or 4) was formed in good yield. Upon exposure
to LDA, these vinyl phosphates rearrange through an
intramolecular migration of the diethyl phosphoryl group
from oxygen to the R-carbon to provide the keto phos-
phonate 5 and the R-phosphono lactone 6, respectively.
We postulated that an N-alkyl lactam might undergo a
similar rearrangement to afford an R-phosphono lactam.
To test the viability of a rearrangement in an N-alkyl
lactam, commercially available n-octylpyrrolidinone (7)
was selected. After treatment with LDA and subsequent
addition of diethyl phosphorochloridate, the 31P NMR
spectrum of the reaction mixture showed the presence
of the vinyl phosphate 8 and the R-phosphono lactam
anion 9 in a 3:1 ratio. Without isolation, this mixture was
exposed to additional LDA to give the R-phosphono
lactam 10 as the only product after standard workup
(Scheme 2).
18-crown-6, followed by reaction with farnesyl bromide
(11) to give the N-farnesyl lactams 21-24 in good yields
(Table 1).
When these reaction conditions were applied to lactams
17-20, none of the desired products were formed. In the
case of compound 17, farnesyl tert-butyl ether was formed
as the only product, suggesting that a stronger base and/
or more polar solvent would be needed to make the
nitrogen anion more nucleophilic.16 When compound 17
was treated with NaH and farnesyl bromide in DMF, the
desired product 25 was obtained in 80% yield.
With the first imide, compound 18, attempted reaction
with potassium tert-butoxide and farnesyl bromide gave
only recovered imide. When this reaction was conducted
in DMF with K2CO3 and 18-crown-6 at elevated temper-
ature, the desired product 26 was formed in just 16%
yield. This low yield may result from diminished negative
charge on nitrogen due to the more extensive delocaliza-
tion. However, this delocalization also contributes to
increased acidity of the parent imide, which made it
possible to employ a Mitsunobu reaction.17 Under general
Mitsunobu conditions, farnesol (12) reacted with succin-
imide (18) to afford the desired product 26 in 85% yield.
Through similar reactions, the imide derivatives 27 and
28 were synthesized in moderate to good yields from
imides 19 and 20.
With this series of N-farnesyl compounds in hand,
attention was turned to their use in the synthesis of the
corresponding phosphonates. Given the successful rear-
rangement of the vinyl phosphate 8, the same approach
was applied to lactams 22 and 23 with HMPA added to
aid in formation of the vinyl phosphate14b as well as to
serve as an internal standard for monitoring the reaction
process by 31P NMR. On the basis of the NMR analysis,
the vinyl phosphates 29 and 30 were formed in ratios of
0.26:1 and 0.60:1 relative to the HMPA (Scheme 3), which
Encouraged by the success of this model reaction,
preparation of a series of N-farnesyl lactams with dif-
ferent ring sizes and functional groups became the next
goal. It has been well documented that alkylation of a
primary amide can be realized by reaction of a nitrogen
anion with an electrophile such as farnesyl bromide (11)
or an activated derivative of farnesol (12), and many
lactams (e.g., 13-20) appropriate for this reaction are
readily available (Table 1).15 Thus, lactams 13-16 were
treated with potassium tert-butoxide in the presence of
(11) Minami, T.; Isonaka, T.; Okada, Y.; Ichikawa, J . J . Org. Chem.
1993, 58, 7009-7015.
(12) Okada, Y.; Minami, T.; Miyamoto, M.; Otaguro, T.; Sawasaki,
S.; Ichikawa, J . Heteroat. Chem. 1995, 6, 195-210.
(13) (a) Tay, M. K.; About-J audet, E.; Collignon, N.; Savignac, P.
Tetrahedron 1989, 45, 4415-4430. (b) During the course of this work,
Myers and Mechelke reported the synthesis of polyhydroxylated
pyrrolidines through reaction of a lactam enolate with diethyl phos-
phorohloridite, air oxidation, and an HWE reaction in situ with an
assumed phosphonate intermediate: Mechelke, M. F.; Meyers, A. I.
Tetrahedron Lett. 2000, 41, 9377-9381.
(16) (a) Williams, R. M.; Armstrong R. W.; Maruyama, L. K.; Dung,
J . S.; Anderson, O. P. J . Am. Chem. Soc. 1985, 107, 3246-3253. (b)
J iang, H.; Newcombe, N.; Sutton, P.; Lin, Q. H.; Mullbacher, A.;
Waring, P. Aust. J . Chem. 1993, 46, 1743-1754.
(14) (a) Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F. J . Org.
Chem. 1987, 52, 4185-4190. (b) J ackson, J . A.; Hammond, G. B.;
Wiemer, D. F. J . Org. Chem. 1989, 54, 4750-4754. (c) Wiemer, D. F.
Tetrahedron 1997, 53, 16609-16644.
(17) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127-164. (c) Tsunoda, T.; Yamamiya, Y.;
Ito, S. Tetrahedron Lett. 1993, 34, 1639-1642. (d) Martin, S. F.; Chen,
H.; Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A.
S. Tetrahedron 1996, 52, 7251-7264.
(15) Luh, T.; Fung, S. H. Synth. Commun. 1979, 9, 757-763.
5710 J . Org. Chem., Vol. 67, No. 16, 2002

Preparation of R-Phosphono Lactams
TABLE 1. Syn th esis of N-F a r n esyl La cta m s
SCHEME 3
SCHEME 4
consumption of the vinyl phosphates on the basis of 31P
NMR and formation of the phosphonates 31 and 32 albeit
in low yields.
TLC analysis of the reaction mixtures indicated that
olefins were formed in the second step of every trial. This
suggests that intermediates 29 and 30 and/or products
31 and 32 were not stable under the strongly basic
reaction conditions. To test this possibility, compound 32
was treated with 2.2 equiv of LDA under the typical
reaction conditions (Scheme 4). In this experiment,
compound 32 was recovered in only 16% yield, together
with 25% of the parent R-phosphono lactam 33. These
results supported the conclusion that compound 32 is not
are not as high as observed with the corresponding
lactone substrates.14b Separate treatment of each of these
reaction mixtures with additional LDA (2.2 equiv) led to
J . Org. Chem, Vol. 67, No. 16, 2002 5711

Du and Wiemer
TABLE 2. Syn th esis of r-P h osp h on o N-F a r n esyl
La cta m s
SCHEME 5
SCHEME 6
stable in LDA solution, and this instability was time
dependent. Abstraction of an allylic proton from the
farnesyl group, followed by loss of an amide anion, would
explain this decomposition and still be consistent with
the observation of a successful rearrangement with the
n-octyl lactam 7, which carries only a saturated alkyl
group. Unfortunately, this view suggested that successful
rearrangements would be difficult with the other N-
farnesyl lactams of Table 1.
Conditions used by others to prepare phosphono lac-
tams through the lactam enolate also were examined
with some of these substrates, and met with limited
success. For example, according to conditions reported
by Collignon and Savignac,13a compounds 22 and 23 were
treated first with 2.2 equiv of LDA and the reactions were
quenched by addition of diethyl phosphorochloridate
(Scheme 5). With the five-membered ring lactam 22, this
reaction gave phosphonate 31 in 61% yield. With the six-
membered ring lactam 23, however, the yield was low
and addition of HMPA did not result in improved yield.
Treatment of lactam 22 with LDA, LiCl, and diethyl
phosphorochloridate under conditions parallel to those
reported by Meyers18 for alkylation of amide enolates did
give the desired phosphonate, but only in 30% yield along
with recovered starting material (Scheme 5).
Over the past few years, a different strategy has been
developed for the synthesis of â-keto phosphonates19a and
R-phosphono lactones19 that involves reaction of an
enolate with diethyl phosphorochloridite followed by
oxidation to provide the desired phosphonate products 5
and 6 (Scheme 6) rather than direct use of a P(V) reagent.
Because the P(III) procedure requires only enough base
to make the enolate, it became attractive to explore this
methodology with these N-farnesyl lactams. In the initial
trials, after formation of the enolates through reaction
of compounds 22 and 23 with strong base, treatment with
(EtO)2PCl, and air oxidation, the desired phosphonates
20
were obtained in ∼40% yield. When H2O2 was used for
oxidation of the P(III) intermediate, purification was
simplified, the yields were significantly improved, and
phosphonates 31 and 32 were obtained in 75% and 60%
yield (Table 2). Azetidinone 21 was converted to phos-
phonate 34 in modest yield by this strategy, but com-
pounds 24 and 28 gave the corresponding phosphonates
35 and 36 in good yields. With compound 24, only one
phosphonate regioisomer was observed even though there
(18) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am.
Chem. Soc. 1994, 116, 9361-9362. (b) Ruck, K. Angew. Chem., Int.
Ed. Engl. 1995, 34, 433-435.
(19) (a) Lee, K.; Wiemer, D. F. J . Org. Chem. 1991, 56, 5556-5560.
(b) Boeckman, R. K., J r.; Kamenecka, T. M.; Nelson, S. G.; Pruit, J .
R.; Barta, T. E. Tetrahedron Lett. 1991, 32, 2581-2584. (c) Lee, K.;
J ackson, J . A.; Wiemer, D. F. J . Org. Chem. 1993, 58, 5967-5971.
(20) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434-9453.
5712 J . Org. Chem., Vol. 67, No. 16, 2002

Preparation of R-Phosphono Lactams
SCHEME 7
may be two sites for proton abstraction. The regiochem-
istry of phosphonate 35 was supported by extensive NMR
experiments. In particular, in an HMBC experiment the
imine methyl hydrogens were correlated to C5, and C5
could be unambiguously assigned as a methylene group
1
on the basis of H NMR and HMQC data.
It was also noteworthy that bisphosphonates were
formed in some of these reactions, even though they were
observed in generally small amounts. The structures of
the bisphosphonates were established unambiguously by
NMR. Especially informative were the triplets observed
as a result of P-C coupling in the 13C NMR spectra,
where the direct C-P attachment resulted in a large J
(∼150 Hz) and the adjacent carbonyl carbons displayed
much smaller J values (∼6-7 Hz). With the five-
membered lactam 22, the bisphosphonate 37 was always
a minor product, and with the N-farnesyl â-lactam 21,
the bisphosphonate 38 was a minor product (6%) when
HMPA was used as a cosolvent. In the absence of HMPA,
the mono- and bisphosphonates 34 and 38 were obtained
in similar yields (24% and 19%, respectively). When these
conditions were applied to lactam 24, a small amount of
the bisphosphonate 39 was obtained.
Preliminary studies with compounds 26 and 27 under
the conditions described above were disappointing. Com-
plex mixtures were obtained with monophosphonates
isolated in low yields. Efforts to optimize the reaction
conditions with these substrates included replacing LDA
with other bases, changing the sequence of reagent
addition, and varying the temperature for enolate forma-
tion. For compound 26, the best yield of compound 40
(71%) was obtained through use of a slight deficiency of
LHMDS (0.99 equiv) at -100 °C with inverse addition.
For compound 27 when 0.99 equiv of LHMDS was used
with inverse addition, and enolate formation was con-
ducted at -78 °C, the desired phosphonate 41 was formed
in 70% yield. With compound 25, no reaction was
observed at -100 °C, and at -10 °C, a complex mixture
was formed and phosphonate 42 was isolated in just 25%
yield. The yield was finally improved to 62% when
enolate formation was carried out at -40 °C. These
findings suggest that general statements about optimum
reaction conditions must be made with great care, but
that reasonable yields of the R-phosphono lactams have
been obtained in all of the cases examined thus far.
Finally, the new N-farnesyl lactam 43 was prepared
to probe the differences between the procedures for
phosphonate synthesis based on the P(V) reagent. In
contrast to the results described above for compound 22
(Scheme 5), when lactam 43 was treated with 2.2 equiv
of LDA and then diethyl phosphorochloridate, there was
no evidence for phosphonate formation in the 31P NMR
spectrum of the reaction mixture. This may support the
view that phosphonate formation requires formation of
a vinyl phosphate anion, which of course is prevented
by the presence of the methyl substituent in compound
43. In any event, the phosphonate 44 was obtained
through the P(III) approach in 67% yield (Scheme 7),
demonstrating that the enolate can be formed under
these conditions and that even highly substituted phos-
phonates may be accessible via this strategy.
with electrophilic phosphorus reagents. The farnesyl
group does not tolerate well the strongly basic conditions
necessary to bring about a vinyl phosphate-phosphonate
rearrangement. However, a number of N-farnesyl lac-
tams and imides have been converted to the correspond-
ing phosphonates through reaction of the enolate with
diethyl phosphorochloridite and subsequent oxidation.
This finding is especially of interest for phosphorylation
of compounds which contain base labile groups or bear a
substituent at the R position.
Exp er im en ta l Section
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium/benzophenone immediately prior to use, while dichlo-
romethane was freshly distilled from calcium hydride. HMPA
was distilled over CaH2 under vacuum and stored under argon
until used. All nonaqueous reactions were conducted in oven-
dried glassware, under an atmosphere of argon, and with
magnetic stirring. Flash chromatography was carried out on
silica gel with a 40 µm average particle diameter. NMR spectra
were recorded at 600, 400, or 300 MHz for 1H with CDCl3 as
solvent and (CH3)4Si (1H and 13C) as internal standard unless
otherwise noted. The 31P NMR chemical shifts are reported
in parts per million relative to that of 85% H3PO4 (external
standard). High-resolution and electron-spray mass spectra
were obtained at the University of Iowa Mass Spectrometry
Facility. Elemental analyses were performed by Atlantic
Microlab, Inc. (Norcross, GA).
1-n -Octyl-3-(dieth oxyph osph in yl)-2-pyr r olidin on e (10).
To a solution of LDA [3.77 mmol, prepared in situ from
diisopropylamine (0.56 mL) and n-BuLi (1.46 mL, 2.58 M in
hexane)] in anhydrous THF (15 mL) at -78 °C was added
dropwise via cannula a solution of 1-n-octyl-2-pyrrolidinone
(676 mg, 3.43 mmol) in THF (2 mL). After 30 min, HMPA (0.71
mL, 4.11 mmol) and diethyl phosphorochloridate (0.59 mL,
4.11 mmol) were added sequentially, and the resulting mixture
was allowed to warm to room temperature over the course of
30 min. After the reaction mixture was cooled to -78 °C, a
solution of LDA (1.1 equiv in 15 mL of THF) was added via
cannula, and the reaction mixture was allowed to warm to
room temperature over 2 h. The reaction was quenched by slow
addition of a solution of acetic acid in diethyl ether (1 M, 4.4
equiv), and the resulting mixture was filtered through a pad
of Florisil. Final purification by column chromatography (silica
gel, from EtOAc to EtOAc/CH3CN, 1:1) afforded compound 10
(776 mg, 68%) as a clear oil: 1H NMR (300 MHz) δ 4.33-4.10
(m, 4H), 3.51 (q, J ) 8.3 Hz, 1H), 3.39-3.18 (m, 3H), 2.94 (ddd,
J HP ) 21.7 Hz, J ) 10.1, 5.3 Hz, 1H), 2.50-2.20 (m, 2H), 1.58-
1.43 (m, 2H), 1.39-1.19 (m, 16H), 0.92-0.83 (m, 3H); 13C NMR
(75 MHz) δ 169.0 (d, J CP ) 3.6 Hz), 63.0 (d, J CP ) 7.0 Hz),
62.2 (d, J CP ) 6.1 Hz), 45.8 (d, J CP ) 4.0 Hz), 43.0, 41.2 (d, J CP
In conclusion, these studies have shown that it is
possible to prepare a variety of R-phosphono lactams and
imides through reaction of the corresponding enolates
) 142.5 Hz), 31.8, 29.2, 29.2, 27.2, 26.7, 22.6, 20.5 (d, J CP
)
P
3.6 Hz), 16.5 (d, J CP ) 5.5 Hz), 16.4 (d, J CP ) 5.0 Hz), 14.0; 31
J . Org. Chem, Vol. 67, No. 16, 2002 5713

Du and Wiemer
NMR (121 MHz) 25.3 ppm. Anal. Calcd for C16H32NO4P: C,
57.64; H, 9.67; N, 4.20. Found: C, 57.59; H, 9.85; N, 4.28.
(2C), 142.5 (2C), 135.6 (2C), 131.4 (2C), 124.3 (2C), 123.5 (2C),
116.9 (2C), 48.9 (2C), 42.8 (2C), 39.7 (2C), 39.6 (2C), 26.7 (2C),
26.3 (2C), 25.7 (2C), 17.7 (2C), 16.4 (2C), 16.0 (2C). Anal. Calcd
for C34H54N2O2: C, 78.11; H, 10.41; N, 5.36. Found: C, 77.93;
H, 10.49; N, 5.33.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-2-
a zetid in on e (21). Gen er a l P r oced u r e for th e P r ep a r a tion
of N-F a r n esyl La cta m s 21-24. A mixture of 2-azetidinone
(13; 142 mg, 2.00 mmol), potassium tert-butoxide (380 mg, 3.20
mmol), and 18-crown-6 (53 mg, 0.20 mmol) in ether (20 mL)
was stirred at room temperature for 45 min and then cooled
in an ice bath. Farnesyl bromide (11; 0.81 mL, 3.00 mmol) was
added dropwise, and the mixture was stirred at room temper-
ature for 16 h. The mixture was filtered through a pad of
Celite, the filtrate was concentrated in vacuo, and the resulting
oil was purified by flash chromatography (1:1 hexanes:EtOAc)
to give 280 mg (52%) of compound 21 as a clear oil: 1H NMR
(400 MHz) δ 5.17 (tq, J ) 7.2, 1.2 Hz, 1H), 5.12-5.05 (m, 2H),
3.81 (d, J ) 7.2 Hz, 2H), 3.16 (t, J ) 4.0 Hz, 2H), 2.89 (t, J )
4.0 Hz, 2H), 2.15-1.94 (m, 8H), 1.70-1.66 (m, 6H), 1.60 (s,
6H); 13C NMR (75 MHz) δ 167.2, 141.0, 135.5, 131.4, 124.2,
123.6, 117.2, 39.7, 39.5, 39.4, 38.2, 36.5, 26.7, 26.2, 25.7, 17.7,
16.2, 16.0; HRMS (ES) m/z calcd for C18H30NO (M+ + H)
276.2327, found 276.2343.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-2-
p yr r olid in on e (22). According to the general procedure,
2-pyrrolidinone (14; 500 mg, 5.87 mmol) was treated with
farnesyl bromide to afford compound 22 (1.46 g, 86%) as a clear
oil: 1H NMR (400 MHz) δ 5.16-5.05 (m, 3H), 3.86 (d, J ) 7.2
Hz, 2H), 3.28 (t, J ) 7.1 Hz, 2H), 2.35 (t, J ) 8.2 Hz, 2H),
2.14-1.93 (m, 10H), 1.66 (s, 6H), 1.57 (s, 6H); 13C NMR (100
MHz) δ 174.4, 140.4, 135.3, 131.3, 124.2, 123.7, 118.5, 46.4,
40.0, 39.7, 39.5, 31.0, 26.7, 26.2, 25.7, 17.7, 17.6, 16.2, 16.0.
Anal. Calcd for C19H31NO‚0.5H2O: C, 76.46; H, 10.81; N, 4.69.
Found: C, 76.32; H, 10.55; N, 4.73.
1-(3′,7′,11′-Tr im eth yl-2′(E),6′(E),10′-dodecatr ien yl)-2-pip-
er id in on e (23). According to the general procedure, 2-piperi-
dinone (15; 1.00 g, 10.09 mmol) was treated with farnesyl
bromide to afford lactam 23 (2.31 g, 76%) as a clear oil: 1H
NMR (400 MHz) δ 5.17-5.05 (m, 3H), 4.02 (d, J ) 7.0 Hz,
2H), 3.24-3.17 (m, 2H), 2.41-2.34 (m, 2H), 2.14-1.92 (m, 8H),
1.81-1.74 (m, 4H), 1.68 (s, 6H), 1.60 (s, 6H); 13C NMR (100
MHz) δ 169.3, 139.8, 135.3, 131.3, 124.3, 123.8, 119.5, 46.9,
44.0, 39.7, 39.6, 32.4, 26.8, 26.3, 25.7, 23.3, 21.5, 17.7, 16.2,
16.0. Anal. Calcd for C20H33NO: C, 79.15; H, 10.96; N, 4.62.
Found: C, 79.24; H, 10.96; N, 4.71.
2-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-6-
m eth yl-4,5-d ih yd r o-3(2H)-p yr id a zin on e (24). According to
the general procedure, 4,5-dihydro-3(2H)-pyridazinone mono-
hydrate (16; 260 mg, 2.00 mmol) was treated with farnesyl
bromide to afford lactam 24 (550 mg, 87%) as a clear oil: 1H
NMR (400 MHz) δ 5.26 (tq, J ) 6.5, 1.2 Hz, 1H), 5.13-5.05
(m, 2H), 4.32 (d, J ) 6.6 Hz, 2H), 2.49-2.39 (m, 4H), 2.13-
1.93 (m, 11H), 1.73 (m, 3H), 1.68 (d, J ) 0.9 Hz, 3H), 1.60 (s,
3H), 1.59 (d, J ) 1.0 Hz, 3H); 13C NMR (75 MHz) δ 164.6,
153.1, 139.1, 135.1, 131.3, 124.4, 124.0, 119.5, 46.1, 39.7, 39.6,
26.9, 26.7, 26.4 (2C), 25.7, 23.2, 17.7, 16.5, 16.0. Anal. Calcd
for C20H32N2O: C, 75.90; H, 10.19; N, 8.85. Found: C, 75.90;
H, 10.23; N, 8.84.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of N-
F a r n esyl Im id es 26-28. Syn th esis of 1-(3′,7′,11′-Tr im eth -
yl-2′(E),6′(E),10′-dodecatr ien yl)-2,5-pyr r olidin edion e (26).
To a solution of succinimide (18; 190 mg, 1.88 mmol), PPh3
(640 mg, 2.44 mmol), and farnesol (12; 500 mg, 2.25 mmol) in
THF (10 mL) was added dropwise at 0 °C diethyl azodicar-
boxylate (0.38 mL, 2.44 mmol). The mixture was stirred at
room temperature for 24 h, and then concentrated in vacuo.
The residue was triturated with hexanes, and the organic
extracts were concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(hexanes/EtOAc, from 1:0 to 7:3) to give compound 26 (494
mg, 85%): 1H NMR (300 MHz) δ 5.25-5.00 (m, 3H), 4.10 (d,
J ) 7.3 Hz, 2H), 2.69 (s, 4H), 2.15-1.85 (m, 8H), 1.78 (d, J )
0.7 Hz, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H); 13C NMR
(75 MHz) δ 176.9 (2C), 141.0, 135.4, 131.3, 124.3, 123.6, 117.2,
39.7, 39.5, 36.7, 28.2 (2C), 26.7, 26.2, 25.7, 17.7, 16.4, 16.0.
Anal. Calcd for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found:
C, 74.92; H, 9.69; N, 4.58.
1-(3′,7′,11′-Tr im eth yl-2′(E),6′(E),10′-d od eca tr ien yl)-2,6-
p ip er id in ed ion e (27). According to the procedure described
above for compound 26, 2,6-piperidinedione (19; 430 mg, 3.75
mmol) was treated with farnesol and the product was purified
by flash chromatography on silica gel (CH2Cl2) to give com-
pound 27 (690 mg, 57%) as a clear oil: 1H NMR (400 MHz) δ
5.12-5.00 (m, 3H), 4.34 (d, J ) 6.9 Hz, 2H), 2.61 (t, J ) 6.6
Hz, 4H), 2.08-1.85 (m, 10H), 1.74 (s, 3H), 1.65 (d, J ) 1.0 Hz,
3H), 1.57 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz) δ 172.3
(2C), 139.8, 135.1, 131.3, 124.3, 123.8, 118.8, 39.7, 39.6, 37.7,
32.9 (2C), 26.7, 26.3, 25.7, 17.7, 17.2, 16.3, 16.0. Anal. Calcd
for C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.68;
H, 9.94; N, 4.55.
1-Meth yl-3-(3′,7′,11′-tr im eth yl-2′(E),6′(E),10′-d od eca tr i-
en yl)-2,4-im id a zolid in e d ion e (28). According to the pro-
cedure described above for compound 26, 1-methyl-2,4-
imidazolidinedione (20; 1.00 g, 8.77 mmol) was treated with
farnesol and the product was purified by flash chromatography
on silica gel (hexanes/EtOAc, from 9:1 to 5:5) to afford
compound 28 (1.60 g, 75%) as a clear oil: 1H NMR (400 MHz)
δ 5.25-5.18 (m, 1H), 5.11-5.03 (m, 2H), 4.10 (d, J ) 7.1 Hz,
2H), 3.83 (s, 2H), 2.99 (s, 3H), 2.12-1.92 (m, 8H), 1.78 (s, 3H),
1.68 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz) δ
169.5, 156.8, 140.8, 135.3, 131.3, 124.3, 123.7, 117.6, 51.8, 39.7,
39.5, 36.8, 29.6, 26.7, 26.2, 25.7, 17.7, 16.4, 16.0; HRMS (ES)
m/z calcd for C19H31N2O2 (M+ + H) 319.2386, found 319.2397.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d ieth oxyp h osp h in yl)-2-p yr r olid in on e (31). Syn th esis of
P h osp h on a te 31 via Vin yl P h osp h a te-P h osp h on a te Re-
a r r a n gem en t. To a solution of LDA (1.1 equiv) in anhydrous
THF (10 mL) at -78 °C was added dropwise via cannula a
solution of lactam 22 (940 mg, 3.26 mmol, 1.0 equiv) in THF
(2 mL). After 30 min, HMPA (0.68 mL, 1.20 equiv) and diethyl
phosphorochloridate (0.56 mL, 1.20 equiv) were added in
sequence, and the resulting mixture was allowed to warm to
room temperature over the course of 30 min. After the reaction
mixture was cooled to -78 °C, a solution of LDA (2.2 equiv)
in THF (15 mL) was added via cannula, and the reaction
mixture was allowed to warm to room temperature over 2 h.
The reaction then was quenched by slow addition of a solution
of acetic acid in diethyl ether (1 M, 32.6 mL, 10 equiv), and
the resulting mixture was filtered through a pad of Florisil.
Final purification by column chromatography (silica gel, from
EtOAc to EtOAc/CH3CN, 1:1) afforded phosphonate 31 (10%).
1,4-Bis(3′,7′,11′-tr im eth yl-2′(E),6′(E),10′-d od eca tr ien yl)-
2,5-p ip er a zin ed ion e (25). NaH (140 mg, 3.62 mmol, 60% in
mineral oil) was added to a stirred solution of 2,5-piperazinedi-
one (17; 190 mg, 1.66 mmol) in DMF (5 mL) at room
temperature, and the mixture was stirred at this temperature
for 30 min. Farnesyl bromide (1.00 mL, 3.69 mmol) was added
dropwise via syringe over 10 min. The resulting mixture was
allowed to stir for 4 h at room temperature, poured into satd
NH4Cl (5 mL), and thoroughly extracted with diethyl ether.
The combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (hexanes/EtOAc, from 9:1 to 1:1)
to give compound 25 (700 mg, 80%) as a white solid: 1H NMR
(300 MHz) δ 5.17-5.03 (m, 6H), 4.04 (d, J ) 7.5 Hz, 4H), 3.90
(s, 4H), 2.15-1.91 (m, 16H), 1.71 (s, 3H), 1.71 (s, 3H), 1.68 (s,
3H), 1.68 (s, 3H), 1.60 (s, 12H); 13C NMR (75 MHz) δ 163.1
Syn th esis of P h osp h on a te 31 via Meth od B. To a
solution of LDA (2.2 equiv) in THF (26 mL) at -78 °C was
added dropwise via cannula a stirred solution of lactam 22
(1.30 g, 4.49 mmol, 1.0 equiv) in THF (4 mL). The mixture
5714 J . Org. Chem., Vol. 67, No. 16, 2002

Preparation of R-Phosphono Lactams
was stirred at this temperature for 30 min and then at room
temperature for 5 min, and then cooled back to -78 °C. After
diethyl phosphorochloridate (0.74 mL, 1.15 equiv) was added
dropwise via syringe, the resulting mixture was allowed to
warm to room temperature over 2 h. The reaction was
quenched by slow addition of a solution of acetic acid in diethyl
ether (1 M, 15 equiv), and the resulting mixture was filtered
through a pad of Florisil. Final purification by column chro-
matography (silica gel, from EtOAc to EtOAc/CH3CN, 1:1)
afforded phosphonate 31 (1.17 g, 61%).
Syn th esis of P h osp h on a te 31 via Meth od C. To a
suspension of lithium chloride (870 mg, 20.52 mmol, 6 equiv;
dried at 150 °C and 0.1 mmHg for 4 h prior to use) in THF (5
mL) was added diisopropylamine (0.55 mL, 3.93 mmol). The
resulting suspension was cooled to -78 °C, and a solution of
n-butyllithium in hexanes (2.58 M, 1.43 mL, 3.69 mmol) was
added via syringe. After this mixture was stirred at this
temperature for 10 min, it was stirred at 0 °C for 5 min, and
then cooled to -78 °C. A solution of lactam 22 (0.99 g, 3.42
mmol) in THF (10 mL) was added to the reaction mixture via
cannula. The mixture was stirred at -78 °C for 1 h, at 0 °C
for 15 min, and at room temperature for 5 min. After the
resulting mixture was cooled to 0 °C, diethyl phosphorochlo-
ridate was added. The mixture was stirred overnight and then
quenched by addition of acetic acid in diethyl ether (1 M, 10
mL, 10 equiv), and the resulting mixture was filtered through
a pad of Florisil. Final purification by column chromatography
(silica gel, from EtOAc to EtOAc/CH3CN, 1:1) afforded phos-
phonate 31 (430 mg, 30%).
Gen er a l P r oced u r e for P h osp h on a te Syn th esis via
P (III) Electr op h iles. Syn th esis of P h osp h on a te 31. A
solution of lactam 22 (310 mg, 1.07 mmol, 1.0 equiv) in diethyl
ether (2 mL) was added dropwise via cannula to a stirred
solution of LDA [1.1 equiv, prepared in situ from diisopropyl-
amine (0.16 mL, 1.18 mmol) and n-butyllithium in hexanes
(2.50 M, 0.47 mL, 1.18 mmol)] in anhydrous diethyl ether (5
mL) at -78 °C. After 60 min, HMPA (0.21 mL, 0.23 mmol)
and diethyl phosphorochloridite (0.18 mL, 0.23 mmol) were
added in turn, and the resulting mixture was allowed to warm
to 0 °C over the course of 2 h. The reaction was quenched by
slow addition of hydrogen peroxide (30%, 1.21 mL, 10 equiv),
and the resulting mixture was stirred vigorously at this
temperature for 10 min. The organic phase was separated,
washed with brine, and dried (MgSO4). After concentration,
final purification by column chromatography on silica gel (from
EtOAc to 1:1 EtOAc/CH3CN) afforded phosphonate 31 (340 mg,
75%) as the major product and then (EtOAc/MeOH, 8:2) a
minor product (37; 70 mg, 12%) as a clear oil.
Da ta for th e Ma jor P r od u ct 31: 1H NMR (600 MHz) δ
5.11 (tq, J ) 6.0, 1.2 Hz, 1H), 5.09-5.04 (m, 2H), 4.28-4.13
(m, 4H), 3.95 (dd, J ) 14.8, 7.2 Hz, 1H), 3.84 (dd, J ) 14.8,
7.2 Hz, 1H), 3.41 (m, 1H), 3.27 (tdd, J ) 9.4, 4.4, 2.0 Hz, 1H),
2.93 (ddd, J HP ) 21.8 Hz, J ) 10.2, 5.4 Hz, 1H), 2.41-2.21 (m,
2H), 2.01-1.93 (m, 8H), 1.67 (s, 6H), 1.59 (s, 3H), 1.58 (s, 3H),
1.36-1.31 (m, 6H); 13C NMR (100 MHz) δ 168.7 (d, J CP ) 3.8
Hz), 140.9, 135.4, 131.3, 124.2, 123.6, 118.0, 62.9 (d, J CP ) 6.6
Hz), 62.2 (d, J CP ) 6.4 Hz), 45.1 (d, J CP ) 4.1 Hz), 41.1(d, J CP
) 4.1 Hz), 17.7, 16.5 (d, J CP ) 2.2 Hz, 2C), 16.4 (d, J CP ) 2.0
Hz, 2C), 16.2, 16.0; 31P NMR (121 MHz) 19.9 ppm. Anal. Calcd
for C27H49NO7P2: C, 57.74; H, 8.79; N, 2.49. Found: C, 57.50;
H, 8.93; N, 2.46.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d iet h oxyp h osp h in yl)-2-p ip er id in on e (32). According to
the general procedure described for compound 31, compound
23 (324 mg, 1.07 mmol) was treated with LDA, diethyl
phosphorochloridite, and H2O2 to obtain phosphonate 32 (280
mg, 60%) as a clear oil: 1H NMR (400 MHz) δ 5.14 (t, J ) 6.8
Hz, 1H), 5.11-5.05 (m, 2H), 4.30-4.10 (m, 5H), 3.94 (dd, J )
14.6, 7.2 Hz, 1H), 3.32-3.16 (m, 2H), 2.98 (dt, J HP ) 26.7 Hz,
J ) 6.7 Hz, 1H), 2.22-1.93 (m, 11H), 1.76-1.64 (m, 7H), 1.60
(s, 3H), 1.59 (s, 3H), 1.34 (t, J ) 7.4 Hz, 3H), 1.33 (t, J ) 7.3,
3H); 13C NMR (100 MHz) δ 164.4 (d, J CP ) 5.0 Hz), 140.2,
135.3, 131.3, 124.3, 123.8, 119.1, 63.0 (d, J CP ) 6.9 Hz), 61.9
(d, J CP ) 7.2 Hz), 46.7, 44.6, 41.8 (d, J CP ) 137.8 Hz), 39.7,
39.6, 26.7, 26.4, 25.7, 23.3(d, J CP ) 5.0 Hz), 21.6 (d, J CP ) 8.0
Hz), 17.7, 16.5(d, J CP ) 6.1 Hz), 16.4 (d, J CP ) 6.0 Hz), 16.2,
16.0; 31P NMR (121 MHz) 25.7 ppm. Anal. Calcd for C24H42
-
NO4P‚0.5H2O: C, 64.26; H, 9.66; N, 3.12. Found: C, 64.53; H,
9.59; N, 3.19.
3-(Dieth oxyp h osp h in yl)-2-p ip er id in on e (33). A solution
of R-phosphono lactam 32 (367 mg, 0.83 mmol) in THF (2 mL)
was added dropwise via cannula to a stirred solution of LDA
[2.2 equiv, prepared in situ from diisopropylamine (0.27 mL,
1.92 mmol) and n-butyllithium in hexanes (2.44 M, 0.75 mL,
1.84 mmol)] in anhydrous THF (5 mL) at -78 °C. The resulting
mixture was allowed to warm to room temperature over the
course of 2 h, and stirred for another 22 h at this temperature.
The reaction was quenched by slow addition of a solution of
acetic acid in diethyl ether (1 M, 20 mL, 24 equiv), and the
resulting mixture was filtered through a pad of Florisil.
Purification of this mixture by column chromatography (silica
gel, first with hexanes/EtOAc, 1:1) gave recovered compound
32 (60 mg, 16%). Continued gradient elution (from EtOAc to
EtOAc/MeOH, 6:4) afforded the defarnesylated R-phosphono
lactam 33 (50 mg, 25%): 1H NMR (300 MHz) δ 6.91 (br, 1H),
4.32-4.07 (m, 4H), 3.45-3.24 (m, 2H), 2.95 (dt, J ) 27, 6.7
Hz, 1H), 2.28-1.97 (m, 3H), 1.81-1.62 (m, 1H), 1.34 (t, J )
7.1 Hz, 3H), 1.34 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz) δ
167.2 (d, J CP ) 4.6 Hz), 62.8 (d, J CP ) 6.4 Hz), 61.9 (d, J CP
)
7.2 Hz), 42.0, 41.0 (d, J CP ) 137.2 Hz), 22.6 (d, J CP ) 4.5 Hz),
20.7 (d, J CP ) 7.2 Hz), 16.3 (d, J CP ) 6.4 Hz), 16.2 (d, J CP
)
6.2 Hz); 31P NMR (121 MHz) 26.3 ppm; HRMS (ES) m/z calcd
for C9H19NO4P (M+ + H) 236.1052, found 236.1060.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d ieth oxyp h osp h in yl)-2-a zetid in on e (34). According to the
general procedure for compound 31, azetidinone 21 (365 mg,
1.32 mmol) was treated with LDA, diethyl phosphorochloridite,
and H2O2 to afford phosphonate 34 as the major product (151
mg, 28%) and bisphosphonate 38 as the minor product (46 mg,
6%).
Da ta for th e Ma jor P r od u ct 34: 1H NMR (300 MHz) δ
5.21-5.13 (m, 1H), 5.13-5.04 (m, 2H), 4.33-4.09 (m, 4H), 3.85
(d, J ) 7.2 Hz, 2H), 3.63-3.52 (m, 1H), 3.40-3.33 (m, 2H),
2.18-1.92 (m, 8H), 1.68 (s, 3H), 1.68 (s, 3H), 1.60 (s, 6H), 1.39-
1.31 (m, 6H); 13C NMR (75 MHz) δ 161.4 (d, J CP ) 7.2 Hz),
142.0, 135.6, 131.4, 124.2, 123.5, 116.5, 62.8 (d, J CP ) 6.4 Hz),
) 143.8 Hz), 40.0, 39.7, 39.5, 26.7, 26.3, 25.7, 20.3 (d, J CP
)
4.4 Hz), 17.6, 16.4 (d, J CP ) 6.6 Hz), 16.4 (d, J CP ) 5.9 Hz),
16.2, 16.0; 31P NMR (121 MHz) 25.0 ppm. Anal. Calcd for
62.5 (d, J CP ) 6.4 Hz), 46.7 (d, J CP ) 147.9 Hz), 39.8 (d, J CP
)
C
23H40NO4P‚0.5H2O: C, 63.57; H, 9.51; N, 3.22. Found: C,
1.2 Hz), 39.7, 39.6 (d, J CP ) 3.6 Hz), 39.5, 26.7, 26.3, 25.7, 17.7,
16.4 (d, J CP ) 6.0 Hz, 2C), 16.3, 16.0; 31P NMR (121 MHz) 21.0
ppm; HRMS (ES) m/z calcd for C22H39NO4P (M+ + H) 412.2617,
found 412.2624.
63.44; H, 9.29; N, 3.29.
Da ta for th e Min or P r od u ct 1-(3′,7′,11′-Tr im eth yl-2′-
(E),6′(E),10′-d od eca tr ien yl)-3,3-bis(d ieth oxyp h osp h in yl)-
2-p yr r olid in on e (37): 1H NMR (300 MHz) δ 5.17-5.03 (m,
3H), 4.38-4.15 (m, 8H), 3.92 (d, J ) 7.1 Hz, 2H), 3.37 (t, J )
7.0 Hz, 2H), 2.63 (tt, J HP ) 17.5 Hz, J ) 6.9 Hz, 2H), 2.14-
1.91 (m, 8H), 1.68 (s, 6H), 1.60 (s, 3H), 1.59 (s, 3H), 1.34 (t, J
) 7.1 Hz, 12H); 13C NMR (75 MHz) δ 166.2 (t, J CP ) 4.6 Hz),
141.1, 135.4, 131.4, 124.3, 123.7, 117.9, 63.7 (d, J CP ) 6.5 Hz,
2C), 63.4 (d, J CP ) 7.0 Hz, 2C), 52.6 (t, J CP ) 135.6 Hz), 44.5
(t, J CP ) 3.9 Hz), 40.9, 39.7, 39.6, 26.7, 26.4, 25.7, 24.9 (t, J CP
Da ta for th e Min or P r od u ct 1-(3′,7′,11′-Tr im eth yl-2′-
(E),6′(E),10′-d od eca tr ien yl)-3,3-bis(d ieth oxyp h osp h in yl)-
2-a zetid in on e (38): 1H NMR (400 MHz) δ 5.17 (tq, J ) 7.2,
1.2 Hz, 1H), 5.12-5.03 (m, 2H), 4.35-4.10 (m, 8H), 3.88 (d, J
) 7.2 Hz, 2H), 3.53 (t, J HP ) 7.6 Hz, 2H), 2.16-1.93 (m, 8H),
1.68 (s, 6H), 1.60 (s, 6H), 1.36 (t, J HP ) 7.1 Hz, 6H), 1.35 (t,
J HP ) 7.1 Hz, 6H); 13C NMR (100 MHz) δ 158.5 (t, J CP ) 7.2
Hz), 142.2, 135.6, 131.4, 124.3, 123.5, 116.2, 63.6 (m, 2C), 63.6
J . Org. Chem, Vol. 67, No. 16, 2002 5715

Du and Wiemer
(m, 2C), 57.9 (t, J CP ) 136.8 Hz), 43.0 (t, J CP ) 3.7 Hz), 40.2,
39.7, 39.6, 26.7, 26.4, 25.7, 17.7, 16.4 (m, 2C), 16.4 (m, 2C),
16.3, 16.0; 31P NMR (121 MHz) 15.9 ppm; HRMS (ES) m/z calcd
for C26H47NO7NaP2 (M+ + Na) 570.2726, found 570.2746.
(d, J ) 7.1 Hz, 2H), 3.27 (ddd, J HP ) 23.5 Hz, J ) 9.5, 4.7 Hz,
1H), 3.06-2.86 (m, 2H), 2.10-1.92 (m, 8H), 1.77 (d, J ) 1.1
Hz, 3H), 1.68 (d, J ) 1.0 Hz, 3H), 1.60 (s, 3H), 1.58 (s, 3H),
1.40-1.29 (m, 6H); 13C NMR (100 MHz) δ 174.9 (d, J CP ) 6.1
Hz), 172.0 (d, J CP ) 5.5 Hz), 141.7, 135.6, 131.5, 124.5, 123.8,
117.0, 63.8 (d, J CP ) 6.6 Hz), 63.4 (d, J CP ) 6.6 Hz), 40.6, 39.9,
39.6 (d, J CP ) 142.7 Hz), 37.5, 30.9 (d, J CP ) 3.8 Hz), 26.9,
26.5, 25.9, 17.9, 16.6, 16.6 (d, J CP ) 5.6 Hz, 2C), 16.2; 31P NMR
(121 MHz) 20.6 ppm. Anal. Calcd for C23H38NO5P: C, 62.85;
H, 8.71; N, 3.19. Found: C, 62.81; H, 8.76; N, 3.15.
2-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d ieth oxyp h osp h in yl)-6-m eth yl-4,5-d ih yd r o-3(2H)-p yr i-
d a zin on e (35). According to the general procedure described
for compound 31, compound 24 (300 mg, 0.94 mmol) was
treated with LDA, diethyl phosphorochloridite, and H2O2 to
obtain phosphonate 35 (340 mg, 79%) as a clear oil: 1H NMR
(400 MHz) δ 5.30-5.22 (m, 1H), 5.13-5.04 (m, 2H), 4.39 (dd,
J ) 14.8, 6.6 Hz, 1H), 4.29 (dd, J ) 14.9, 6.4 Hz, 1H), 4.22-
4.08 (m, 4H), 3.02 (ddd, J HP ) 24.1 Hz, J ) 8.4, 5.2 Hz, 1H),
2.90-2.63 (m, 2H), 2.13-1.93 (m, 11H), 1.72 (s, 3H), 1.68 (d,
J ) 1.1 Hz, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.35 (t, J ) 7.3 Hz,
3H), 1.31 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz) δ 160.0 (d,
J CP ) 4.4 Hz), 151.8 (d, J CP ) 5.6 Hz), 139.4, 135.2, 131.3,
124.3, 123.9, 119.1, 63.0 (d, J CP ) 6.9 Hz), 62.8 (d, J CP ) 6.5
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d ieth oxyp h osp h in yl)-2,6-p ip er id in ed ion e (41). To a solu-
tion of lactam 27 (280 mg, 0.88 mmol) in diethyl ether (9 mL)
at -78 °C was added dropwise LHMDS (1.0 M, 0.87 mL, 0.87
mmol, 0.99 equiv). After the solution was stirred at this
temperature for 40 min, HMPA (0.15 mL, 0.88 mmol, 1.00
equiv) and diethyl phosphorochloridite (0.13 mL, 0.87 mmol,
0.99 equiv) were added sequentially, and the resulting mixture
was allowed to warm to 0 °C over the course of 4 h. The
reaction was quenched by slow addition of hydrogen peroxide
(30%, 1.00 mL, 8.82 mmol, 10 equiv), and the resulting mixture
was stirred vigorously at this temperature for 10 min. The
organic phase was separated, washed with brine, and dried
(MgSO4). After concentration, final purification by column
chromatography (silica gel, EtOAc) afforded phosphonate 41
(280 mg, 71%) as a clear oil along with small amounts of
starting material (55 mg, or 87% yield of compound 41 based
on recovered starting material): 1H NMR (400 MHz) δ 5.15-
5.03 (m, 3H), 4.40 (d, J ) 6.9 Hz, 2H), 4.24-4.12 (m, 4H), 3.21
(dt, J HP ) 25.8 Hz, J ) 5.0 Hz, 1H), 3.04-2.91 (m, 1H), 2.64
(dt, J ) 17.7, 5.2 Hz, 1H), 2.37-2.11 (m, 2H), 2.10-1.91 (m,
8H), 1.76 (d, J ) 1.0 Hz, 3H), 1.68 (d, J ) 1.0 Hz, 3H), 1.60 (s,
3H), 1.58 (s, 3H), 1.40-1.29 (m, 6H); 13C NMR (100 MHz) δ
171.5, 167.9 (d, J CP ) 4.5 Hz), 140.0, 135.2, 131.3, 124.3, 123.8,
118.5, 63.2 (d, J CP ) 7.0 Hz), 63.0 (d, J CP ) 6.6 Hz), 42.2 (d,
J CP ) 134.7 Hz), 39.7, 39.6, 38.3, 30.5 (d, J CP ) 5.5 Hz), 26.7,
26.4, 25.7, 18.6 (d, J CP ) 4.9 Hz), 17.7, 16.4, 16.4 (d, J CP ) 6.1
Hz, 2C), 16.0; 31P NMR (121 MHz) 21.6 ppm. Anal. Calcd for
Hz), 46.6, 39.7, 39.6, 37.2 (d, J CP ) 136.8 Hz), 27.7 (d, J CP
)
5.2 Hz), 26.7, 26.4, 25.7, 23.2, 17.7, 16.5, 16.4 (d, J CP ) 3.8
Hz), 16.3 (d, J CP ) 3.8 Hz), 16.0; 31P NMR (121 MHz) 22.6
ppm; HRMS (ES) m/z calcd for
453.2882, found 453.2880.
C
24H42N2O4P (M+ + H)
Da ta for th e Min or P r od u ct 2-(3′,7′,11′-Tr im eth yl-2′-
(E), 6′(E),10′-d od eca tr ien yl)-3,3-bis(d ieth oxyp h osp h in yl)-
6-m eth yl-4,5-d ih yd r o-3(2H)-p yr id a zin on e (39): yield 30
mg, 5%; clear oil; 1H NMR (400 MHz) δ 5.32-5.23 (m, 1H),
5.15-5.04 (m, 2H), 4.34 (d, J ) 6.6 Hz, 2H), 4.43-4.10 (m,
8H), 3.05 (t, J HP ) 17.6 Hz, 2H), 2.12-1.93 (m, 11H), 1.71 (s,
3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.32 (t, J ) 7.1 Hz,
12H); 13C NMR (100 MHz) δ 158.0 (t, J CP ) 5.6 Hz), 150.9 (t,
J CP ) 7.2 Hz), 139.3, 135.2, 131.3, 124.4, 124.0, 119.1, 64.2
(m, 2C), 63.8 (m, 2C), 48.6 (t, J CP ) 131.6 Hz), 47.2, 39.7, 39.7,
32.0 (t, J CP ) 5.1 Hz), 26.8, 26.5, 25.7, 23.0, 17.7, 16.6, 16.4
(m, 2C), 16.4 (m, 2C), 16.0; 31P NMR (121 MHz) 18.5 ppm;
HRMS (ES) m/z calcd for C28H51N2O7P2 (M+ + H) 589.3169,
found 589.3172.
1-Meth yl-3-(3′,7′,11′-tr im eth yl-2′(E),6′(E),10′-d od eca tr i-
en yl)-5-(dieth oxyph osph in yl)-2,4-im idazolidin edion e (36).
According to the general procedure described for compound
31, compound 28 (360 mg, 1.13 mmol) was treated with LDA,
diethyl phosphorochloridite, and H2O2 to obtain phosphonate
36 (350 mg, 68%) as a clear oil: 1H NMR (400 MHz) δ 5.28
(tq, J ) 7.0, 1.2 Hz, 1H), 5.19-5.11 (m, 2H), 4.38-4.23 (m,
4H), 4.23 (d, J HP ) 13.9 Hz, 1H), 4.18 (d, J ) 7.1 Hz, 2H), 3.20
(s, 3H), 2.19-1.98 (m, 8H), 1.85 (s, 3H), 1.75 (d, J ) 0.8 Hz,
3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.47 (t, J ) 7.1 Hz, 3H), 1.38 (t,
J ) 7.1 Hz); 13C NMR (100 MHz) δ 166.2 (d, J CP ) 4.4 Hz),
156.6 (d, J CP ) 5.7 Hz), 141.3, 135.4, 131.3, 124.3, 123.7, 117.2,
C
24H40NO5P: C, 63.56; H, 8.89; Found: C, 63.30; H, 8.94.
1,4-Bis(3′,7′,11′-Tr im eth yl-2′(E),6′(E),10′-dodecatr ien yl)-
3-(d ieth oxyp h osp h in yl)-2,5-p ip er a zin ed ion e (42). To a
solution of lactam 25 (404 mg, 0.77 mmol) in diethyl ether (9
mL) at -40 °C was added dropwise LHMDS (1.0 M, 0.76 mL,
0.76 mmol, 0.99 equiv). After the reaction was stirred for 1 h,
the mixture was cooled to -78 °C, HMPA (0.13 mL, 0.77 mmol,
1.00 equiv) and diethyl phosphorochloridite (0.11 mL, 0.76
mmol, 0.99 equiv) were added, and the resulting mixture was
allowed to warm to 0 °C over 4 h. The reaction was quenched
by slow addition of hydrogen peroxide (30%, 0.87 mL, 7.73
mmol, 10 equiv), and the resulting two-phase mixture was
stirred vigorously at this temperature for 10 min. The organic
phase was separated, washed with brine, and dried (MgSO4).
After concentration, final purification by column chromatog-
raphy (silica gel, EtOAc/hexanes, 1:1) afforded phosphonate
42 (307 mg, 62%) as a clear oil, along with small amounts of
starting material (60 mg, or 72% yield of 42 based on recovered
starting material): 1H NMR (300 MHz) δ 5.20-5.00 (m, 6H),
4.79 (dd, J ) 15.0, 4.9 Hz, 1H), 4.31 (d, J HP ) 17.2 Hz, 1H),
4.33-3.88 (m, 7H), 3.78-3.66 (m, 2H), 2.15-1.90 (m, 16H),
1.72 (s, 3H), 1.70 (s, 3H), 1.68 (s, 3H), 1.68 (s, 3H), 1.60 (s,
6H), 1.59 (s, 6H), 1.38 (t, J ) 7.1 Hz, 3H), 1.34 (t, J ) 7.1 Hz,
3H); 13C NMR (75 MHz) δ 164.8, 161.3 (d, J CP ) 1.2 Hz), 143.5,
142.7, 135.8 (s, 2C), 131.5, 131.5, 124.5, 124.5, 123.7 (s, 2C),
117.3, 117.1, 64.1 (d, J CP ) 7.2 Hz), 63.6 (d, J CP ) 7.0 Hz),
57.9 (d, J CP ) 142.0 Hz), 49.7, 43.7, 42.4, 39.9, 39.9 (s, 2C),
39.9, 26.9 (s, 2C), 26.6, 26.5, 25.9 (s, 2C), 17.9 (s, 2C), 16.7 (d,
64.3 (d, J CP ) 6.9 Hz), 63.8 (d, J CP ) 7.1 Hz), 60.1 (d, J CP
)
155.8 Hz), 39.7, 39.5, 37.2, 30.0, 26.7, 26.3, 25.7, 17.7, 16.5 (d,
J CP ) 5.5 Hz), 16.4 (d, J CP ) 5.7 Hz), 16.4, 16.0; 31P NMR (121
MHz) 12.6 ppm. Anal. Calcd for C23H39N2O5P: C, 60.78; H,
8.65; N, 6.16. Found: C, 60.37; H, 8.91; N, 6.18.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
(d ieth oxyp h osp h in yl)-2,5-p yr r olid in ed ion e (40). A solu-
tion of lactam 26 (251 mg, 0.83 mmol) in diethyl ether (9 mL)
at -100 °C was treated with LHDMS (1.0 M, 0.82 mL, 0.82
mmol, 0.99 equiv). After 1 h at this temperature, HMPA (0.14
mL, 0.83 mmol, 1.00 equiv) and diethyl phosphorochloridite
(0.12 mL, 0.82 mmol, 0.99 equiv) were added sequentially, and
the resulting mixture was allowed to warm to 0 °C over the
course of 5 h. The reaction was quenched by slow addition of
hydrogen peroxide (30%, 0.94 mL, 8.26 mmol, 10 equiv), and
the resulting mixture was stirred vigorously at this temper-
ature for 10 min. The organic phase was separated, washed
with brine, and dried (MgSO4). After concentration, final
purification by column chromatography (silica gel, EtOAc)
afforded phosphonate 40 (254 mg, 71%) as a clear oil along
with small amounts of starting material (30 mg, or 79% yield
of compound 40 based on recovered starting material): 1H
NMR (400 MHz) δ 5.19-5.02 (m, 3H), 4.30-4.14 (m, 4H), 4.11
J CP ) 3.4 Hz), 16.6, 16.6 (d, J CP ) 3.6 Hz), 16.5, 16.2, 16.2; 31
P
NMR (121 MHz) 18.0 ppm. Anal. Calcd for C38H63N2O5P: C,
69.27; H, 9.64; N, 4.25. Found: C, 68.88; H, 9.70; N, 4.34.
1-(3′,7′,11′-Tr im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
m eth yl-2-p yr r olid in on e (43). According to the general pro-
cedure for preparation of compound 21, 3-methyl-2-pyrrolid-
5716 J . Org. Chem., Vol. 67, No. 16, 2002

Preparation of R-Phosphono Lactams
inone (592 mg, 5.79 mmol) was treated with farnesyl bromide
to afford lactam 43. Purification by flash chromatography on
silica gel (hexanes/EtOAc, 2:8 to 1:1) gave lactam 43 (1.61 g,
1.74 (m, 9H), 1.68 (s, 6H), 1.59 (s, 6H), 1.44 (d, J HP ) 16.1 Hz,
3H), 1.38-1.28 (m, 6H); 13C NMR (75 MHz) δ 172.2 (d, J CP
2.4 Hz), 140.8, 135.4, 131.4, 124.3, 123.7, 118.2, 63.0 (d, J CP
)
)
1
89%) as a clear oil: H NMR (400 MHz) δ 5.16-5.04 (m, 3H),
6.6 Hz), 62.4 (d, J CP ) 7.2 Hz), 45.5 (d, J CP ) 140.2 Hz), 43.7
(d, J CP ) 2.4 Hz), 40.7, 39.7, 39.6, 29.6 (d, J CP ) 1.7 Hz), 26.7,
26.3, 25.7, 19.6 (d, J CP ) 3.1 Hz), 17.7, 16.5, 16.5 (d, J CP ) 1.1
Hz), 16.2, 16.0; 31P NMR 28.1 ppm; HRMS (ES) m/z calcd for
3.89 (d, J ) 7.2 Hz, 2H), 3.27-3.17 (m, 2H), 2.50-2.39 (m,
1H), 2.20 (dddd, J ) 12.7, 8.5, 6.7, 4.1 Hz, 1H), 2.14-1.92 (m,
8H), 1.68 (s, 6H), 1.64-1.53 (m, 1H), 1.60 (s, 6H), 1.20 (d, J )
7.1 Hz, 3H); 13C NMR (100 MHz) δ 176.8, 140.4, 135.4 131.4,
124.3, 123.7, 118.6, 44.5, 40.2, 39.7, 39.6, 36.8, 27.1, 26.7, 26.3,
C
24H43NO4P (M+ + H) 440.2930, found 440.2944.
25.7, 17.7, 16.4, 16.2, 16.0; HRMS (ES) m/z calcd for C20H34
-
Ack n ow led gm en t. We thank Mr. J ohn Snyder for
NO (M+ + H) 304.2640, found 304.2639.
his assistance with the NMR spectroscopy. Financial
support from the Roy J . Carver Charitable Trust is
gratefully acknowledged.
1-(3′,7′,11′-t r im et h yl-2′(E),6′(E),10′-d od eca t r ien yl)-3-
m eth yl-3-(d ieth oxyp h osp h in yl)-2-p yr r olid in on e (44). Ac-
cording to the general procedure described for compound 31,
compound 43 (444 mg, 1.46 mmol) was treated with LDA,
diethyl phosphorochloridite, and H2O2 to obtain phosphonate
44 (430 mg, 67%) as a clear oil: 1H NMR (300 MHz) δ 5.20-
5.03 (m, 3H), 4.32-4.06 (m, 4H), 3.98 (dd, J ) 14.7, 7.0 Hz,
1H), 3.85 (dd, J ) 14.7, 7.2 Hz, 1H), 3.47-3.32 (m, 1H), 3.27-
3.14 (m, 1H), 2.63 (dddd, J ) 18.1, 13.5, 7.7, 3.0 Hz, 1H), 2.20-
Su p p or tin g In for m a tion Ava ila ble: 1H and/or 13C NMR
spectra for compounds 21, 28, 33, 34, 35, 38, 39, 43, and 44.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O020119L
J . Org. Chem, Vol. 67, No. 16, 2002 5717