α-phosphono lactone analogues of farnesyl pyrophosphate: An asymmetric synthesis via ring-closing metathesis

Article abstract of DOI:10.1021/jo0202233

An α-phosphono lactone derivative of farnesol has been prepared, in both racemic and nonracemic forms, to provide a new type of farnesyl pyrophosphate analogue. Attempted preparation of the racemic α-phosphono lactone through rearrangement of a vinyl phosphate derived from the parent lactone resulted in both rearrangement and lactone ring opening, revealing that the farnesyl lactone was not stable to the excess of strong base required for the rearrangement. A procedure for C-P bond formation based on generation of the lactone enolate, reaction with a P(III) reagent, and oxidation was successful in providing the racemic α-phosphono lactone, in part, because only 1 equiv of strong base was required. The same strategy for phosphonate synthesis then was applied to the nonracemic farnesyl lactone, prepared through a sequence including allylation of farnesal with a nonracemic borane reagent, reaction of the product alcohol with acryloyl chloride, and formation of an unsaturated lactone through ring-closing metathesis. A similar strategy gave the corresponding racemic α-phosphono lactam through a six-step sequence from farnesal.

Full text of DOI:10.1021/jo0202233

r-P h osp h on o La cton e An a logu es of F a r n esyl P yr op h osp h a te: An
Asym m etr ic Syn th esis via Rin g-Closin g Meta th esis
Yanming Du and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
david-wiemer@uiowa.edu
Received April 2, 2002
An R-phosphono lactone derivative of farnesol has been prepared, in both racemic and nonracemic
forms, to provide a new type of farnesyl pyrophosphate analogue. Attempted preparation of the
racemic R-phosphono lactone through rearrangement of a vinyl phosphate derived from the parent
lactone resulted in both rearrangement and lactone ring opening, revealing that the farnesyl lactone
was not stable to the excess of strong base required for the rearrangement. A procedure for C-P
bond formation based on generation of the lactone enolate, reaction with a P(III) reagent, and
oxidation was successful in providing the racemic R-phosphono lactone, in part, because only 1
equiv of strong base was required. The same strategy for phosphonate synthesis then was applied
to the nonracemic farnesyl lactone, prepared through a sequence including allylation of farnesal
with a nonracemic borane reagent, reaction of the product alcohol with acryloyl chloride, and
formation of an unsaturated lactone through ring-closing metathesis. A similar strategy gave the
corresponding racemic R-phosphono lactam through a six-step sequence from farnesal.
In tr od u ction
built on farnesyl chains to obtain potential inhibitors of
squalene synthase.10 Although a number of R-phosphono
lactones have been reported, the biological activity of this
class of pyrophosphate analogues remains unexplored.
Our interest in the design and synthesis of FPTase
inhibitors11 has prompted an effort to discover different
replacements for the diphosphate moiety of farnesyl
pyrophosphate (1). One such target compound would be
a phosphonic acid such as compound 2a , which presum-
ably could be derived from the more familiar diethyl
phosphonate 3a . Compound 2a would employ the R-phos-
phono lactone to mimic a pyrophosphate group, not just
in position and polarity but possibly also as a potential
leaving group for enzyme-catalyzed nucleophilic displace-
ment.12 If such enzymatic reactions were observed, the
carbon chain of the lactone ring would then serve as a
tether to keep the “leaving group” connected. Compounds
that could function in this manner might serve as useful
probes of both the FPTase mechanism and the impact of
attaching modified farnesyl groups to various proteins.13
In contrast to lactone 2a , the corresponding lactam 2b
R-Phosphono esters and lactones are widely used
as synthetic reagents, particularly in the Horner-
Wadsworth-Emmons reaction.1 However, a second mo-
tive for study of such compounds derives from their
similarity to pyrophosphate esters, compounds which are
common intermediates in metabolism.2 Formal replace-
ment of a phosphate P-O bond with a phosphonate P-C
bond is considered to increase metabolic stability while
maintaining a structural display similar to that of the
phosphate ester.3 Therefore, R-phosphono acetates have
been prepared and tested as inhibitors of a variety of
enzymes, including farnesyl protein transferase (FPTase),4
biotin carboxylase,5 aspartate carbamoyltransferase,6
DNA polymerase,7 and squalene synthase.8
Ring systems are often incorporated in molecular
design to restrict conformations and/or to serve as a
platform for incorporation of other functional groups.9 For
example, cyclobutanones and cyclopropanes have been
(1) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-
927. (b) Lee, K.; J ackson, J . A.; Wiemer, D. F. J . Org. Chem. 1993, 58,
5967-5971.
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A.; Nakano, T.; Buser, H.-P.; Hatano, M.; Tada, S.; Hayakawa, K. J .
Am. Chem. Soc. 1995, 117, 4411-4412. (b) Cannon, J . G. Pharmacology
for Chemists; American Chemical Society: Washington, DC, and
Oxford University Press: New York and Oxford, 1999.
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60, 941-945 and references therein. (b) De Montellano, P. R. O.;
Castillo, R. Tetrahedron Lett. 1976, 17, 4115-4118.
(11) (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. M.; Wiemer, D. F. J . Org. Chem. 1999, 64,
4750-4754. (d) Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl, R. J .
Bioorg. Med. Chem. 2000, 8, 2729-2737.
(12) (a) Node, M.; Nishide, K.; Ochiai, M.; Fuji, K.; Fujita, E. J . Org.
Chem. 1981, 46, 5163-5166. (b) Black, D. K. J . Chem. Soc. 1966,
1123-1127.
(2) For reviews: (a) Davini, E.; Di Leo, C.; Norelli, F.; Zappelli, P.
J . Biotechnol. 1993, 28, 321-338. (b) Eriksson, B.; Oeberg, B. Dev.
Mol. Virol. 1984, 4, 127-142.
(3) Fields, S. C. Tetrahedron 1999, 55, 12237-12273.
(4) Patel, D. V.; Schmidt, R. J .; Biller, S. A.; Gordon, E. M.; Robinson,
S. S.; Manne, V. J . Med. Chem. 1995, 38, 2906-2921.
(5) Blanchard, C. Z.; Amspacher, D.; Strongin, R.; Waldrop, G. L.
Biochem. Biophys. Res. Commun. 1999, 266, 466-471.
(6) Burns, B. P.; Mendz, G. L.; Hazell, S. L. J . Bacteriol. 1998, 180,
5574-5579.
(7) Mao, J . C.; Robishaw, E. E. Biochemistry 1975, 14, 5475-5479.
(8) (a) Ortiz De Montellano, P. R.; Wei, J . S.; Castillo, R.; Hsu, C.
K.; Boparai, A. J . Med. Chem. 1977, 20, 243-249. (b) Biller, S. A.;
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10.1021/jo0202233 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002
J . Org. Chem. 2002, 67, 5701-5708
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Du and Wiemer
SCHEME 1
would be expected to have much greater metabolic
stability, which might be of value as a control in biological
investigations. Again, it is reasonable to assume that the
lactam 2b could be derived from the phosphonate ester
3b, so the initial goal became preparation of the phos-
phonate esters 3a and 3b.
SCHEME 2
R-Phosphono lactones have been prepared from a
variety of precursors. For example, they can be made
from phosphono acetate derivatives through condensation
or radical reaction to form a lactone ring14 or via the
Arbuzov reaction of an R-halo lactone and a trialkyl
phosphite.15 However, preparation of R-phosphono lac-
tones containing the farnesyl chain (e.g., 3a ) might best
be approached from the parent lactone 4 through either
of two methodologies for C-P bond formation via an
intermediate enolate.16 For example, when lactone 5 was
treated with LDA and the resulting enolate was trapped
by reaction with diethyl phosphorochloridate, the vinyl
phosphate 6 was formed. Upon exposure to LDA, this
vinyl phosphate undergoes an intramolecular rearrange-
ment to provide the R-phosphono lactone 7. Alternatively,
the lactone enolate can be trapped on carbon by reaction
with diethyl phosphorochloridite, followed by oxidation
of the P(III) intermediate 8 to give the R-phosphono
lactone 7 (Scheme 1). To extend the potential scope of
these procedures and to obtain access to the desired
R-phosphono lactone derivatives of farnesol, direct phos-
phorylation strategies were incorporated in the planned
synthesis of the R-phosphono δ-lactone 3a . Assuming
either or both of these strategies would afford the desired
phosphonate, the initial synthetic target would be the
δ-lactone 4.
(10),17 reaction with the zinc reagent 11 under Knockel’s
condition afforded the δ-hydroxy ester 12.18 Attempts to
convert this ester into the corresponding lactone through
an acid-catalyzed intramolecular transesterification were
unsuccessful. However, cyclization was accomplished
after hydrolysis of the ester to the acid and intramolecu-
lar condensation with EDC and DMAP.
Conversion of lactone 4 into the desired phosphonate
3a was first attempted through a vinyl phosphate-
phosphonate rearrangement, and 31P NMR was used to
monitor the reaction. When δ-lactone 4 was treated with
LDA and the resulting enolate was trapped by reaction
with diethyl phosphorochloridate (Scheme 3), a chemical
shift of -6 ppm clearly revealed formation of vinyl
phosphate 13. Upon exposure of this vinyl phosphate to
LDA (2.2 equiv) in situ, a phosphonate obviously was
formed, as shown by a chemical shift of +25 ppm.
Resu lts a n d Discu ssion s
1
Racemic δ-lactone 4 was prepared from commercially
available farnesol (9) as illustrated in Scheme 2. After
oxidation of farnesol (9) with MnO2 to provide farnesal
However, the H and 13C NMR spectra did not support
assignment of this phosphonate as the desired rear-
rangement product 3a . Instead, interpretation of 1H,
(13) (a) Chehade, K. A. H.; Andres, D. A.; Morimoto, H.; Spielmann,
H. P. J . Org. Chem. 2000, 65, 3027-3033. (b) Gibbs, B. S.; Zahn, T. J .;
Mu, Y.; Sebolt-Leopold, J . S.; Gibbs, R. A. J . Med. Chem. 1999, 42,
3800-3808.
(14) (a) Haigh, D. Tetrahedron 1994, 50, 3177-3194. (b) Toke, L.;
J aszay, Z. M.; Petnehazy, I.; Clementis, G.; Vereczkey, G. D.; Kovesdi,
I.; Rockenbauer, A.; Kovats, K. Tetrahedron 1995, 51, 9167-9178.
(15) Buchel, K. H.; Rochling, H.; Korte, F. J ustus Liebigs Ann. Chem.
1965, 685, 10.
(16) (a) J ackson, J . A.; Hammond, G. B.; Wiemer, D. F. J . Org. Chem.
1989, 54, 4750-4754. (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.; Wiemer, D. F. J . Org. Chem. 1991, 56, 5556-
5560.
(17) Xiao, X. Y.; Prestwich, G. D. Synth. Commun. 1990, 20, 3125-
3130.
(18) Yeh, M. Ch. P.; Chen, H. G.; Knochel, P. Org. Synth. 1991, 70,
195-203.
5702 J . Org. Chem., Vol. 67, No. 16, 2002

R-Phosphono Lactone Analogues of Farnesyl Pyrophosphate
SCHEME 3
SCHEME 4
DEPT, 13C, and COSY NMR experiments showed that
one allylic methyl group in the farnesyl chain had been
converted into a terminal methylene group. Ultimately,
this compound was assigned as the R-phosphono acid 14,
a lactone ring-opened product. This result suggested that
the presence of excess strong base may be problematic;
that is, abstraction of an allylic proton and elimination
of the carboxylate would provide this elimination product.
Because rearrangement of the vinyl phosphate also had
occurred, two reactions must be involved in this process,
a vinyl phosphate-phosphonate rearrangement and a
lactone ring opening, but the sequence of these reactions
was not immediately clear (Scheme 3). It is possible that
the sequence starts with abstraction of the vinyl proton
of the vinyl phosphate followed by rearrangement, but
this would probably require loss of the equivalent of a
dianion during the subsequent elimination process. Al-
ternatively, if the elimination takes place first, it would
generate an anion where significant charge density could
be placed on the R carbon, and this might induce a vinyl
phosphate-phosphonate rearrangement. In this context,
it is significant that rearrangement of vinyl phosphates
derived from acyclic esters has substantial precedent.16a
Results from the attempted vinyl phosphate rear-
rangements demonstrated that the farnesyl lactone 4
does not tolerate an excess of strong base well. Therefore,
application of the phosphonate synthesis based on use
of a P(III) electrophile became attractive because this
strategy requires use of just 1 equiv of strong base. When
δ-lactone 4 was treated with 1.1 equiv of LDA and the
resulting enolate was trapped by reaction with diethyl
phosphorochloridite followed by oxidation, phosphonate
3a was obtained in good yield (Scheme 3). The product
from this sequence was a mixture of diastereomers, in
part because of the earlier decision to employ racemic
lactone 4, and attempts to separate the diastereomers
to two racemates by column chromatography were un-
successful. Thus, this study of racemic lactone 4 estab-
lished a procedure for conversion of the lactone into an
R-phosphono lactone, but further studies of the activity
of these compounds would benefit from a route to
nonracemic preparations of lactone 4.
cyclic structures.19 We have found that metathesis of
acrylate esters derived from different terpene aldehydes
could afford lactones in good yields and with excellent
regioselectivities.20 Because a nonracemic alcohol might
be readily obtained from farnesal through use of a borane
reagent,21 it was envisioned that nonracemic δ-lactone 4
could be synthesized by RCM.
To explore this strategy, Brown’s (+)-B-allyldiiso-
pinocamphenylborane (15) was prepared from commer-
cially available (+)-B-chlorodiisopinocamphenylborane
and allylmagnesium bromide.21 Allylboration of farnesal
(10) with this reagent provided nonracemic alcohol 16
(Scheme 4). The stereochemistry of this addition initially
was assigned by analogy to the general pattern and
assuming a six membered ring transition state. Esteri-
fication of compound 16 with acryloyl chloride readily
provided the acrylate 17, which was transformed smoothly
into the unsaturated lactone 18 through a metathesis
reaction.
Several methods have been employed to establish the
enantiomeric excess of nonracemic alcohols, including
preparation of diastereomeric derivatives through reac-
22
tion with a chiral reagent or use of HPLC with chiral
(19) (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013-3043.
(b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (c)
Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115,
9856-9857. (d) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res.
1995, 28, 446-452. (e) Schwab, P. E.; Grubbs, R. H.; Ziller, J . W. J .
Am. Chem. Soc. 1996, 118, 100-110. (f) Armstrong, S. K. J . Chem.
Soc., Perkin Trans. 1 1998, 371-388. (g) Hanson, P. R.; Stoianova, D.
S. Tetrahedron Lett. 1998, 39, 3939-3942.
(20) Du, Y.; Wiemer, D. F. Tetrahedron Lett. 2001, 42, 6069-6072.
(21) (a) Brown, H. C.; J adhav, P. K. J . Am. Chem. Soc. 1983, 105,
2092-2093. (b) Ramachandran, P. V.; Chen, G. M.; Brown, H. C.
Tetrahedron Lett. 1997, 38, 2417-2420.
(22) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
Ring-closing metathesis (RCM) has become a well-
established strategy for construction of a wide range of
J . Org. Chem, Vol. 67, No. 16, 2002 5703

Du and Wiemer
SCHEME 5
SCHEME 6
columns.23 In this case, alcohol 16 was esterified to a
mandelic acid derivative to prepare diastereomers. When
racemic O-methylmandelic acid was used,24 methoxy
groups in the two diastereomers showed two separate 1H
NMR resonances in a 1:1 ratio. When the S-(+) acid 19
was used (Scheme 5), the ratio observed for the product
ester 20 was 12:1, corresponding to an 85% ee for
compound 16. Furthermore, the 1H NMR spectra of these
compounds supported the initial assignment of the R
stereochemistry to the major product of the allylboration
reaction. In particular, with the ester derived from
alcohol 16 and the S-(+) acid, resonances for the meth-
ylene group of the allyl unit and the adjacent vinylic
hydrogen were shifted significantly upfield (from δ 5.66
to 5.46 and from δ 2.36 to 2.22, respectively) relative to
the corresponding resonances observed when the non-
racemic alcohol 16 was esterified with the racemic acid.
According to the standard model based on extended
Newman projections,24 these shifts support assignment
of the R stereochemistry to the predominant enantiomer
of compound 16.
In theory, the conjugated lactone 18 could be converted
into the desired phosphonate either by conjugate addition
of hydride and trapping the intermediate enolate on
carbon through reaction with diethyl phosphorochloridite
followed by oxidation or through stepwise conjugate
reduction to give the saturated lactone followed by
enolate formation, reaction with the P(III) reagent, and
oxidation. Unfortunately, attempts to apply the poten-
tially more efficient first route through reaction with
Stryker’s catalyst25 or CuMe-HMPA-DIBAL26 were
unsuccessful. With respect to the second route, several
reduction systems were tested, first with the racemic
material (4) and then with nonracemic material (Scheme
6). Upon attempted reduction with Mg-MeOH27 or with
NaBH4-CuCl,28 mixtures were obtained and the ring-
opened product 21 was formed, perhaps because of
generation of methoxide during the course of the reac-
tions. Successful reduction was effected upon treatment
with CuMe-HMPA-DIBAL. While this appears to be
the first report of conjugate reduction of a lactone under
these conditions, they have been used widely for the
reduction of conjugated ketones.26
Finally, phosphorylation of the nonracemic lactone 22
was accomplished through formation of the enolate and
reaction with diethyl phosphorochloridite as described
above. In this case, oxidation with H2O2 instead of air
appeared to facilitate separation. Two diastereomers of
the product 23 were obtained, presumably differing in
configuration at the R carbon, and separation of these
diastereomers by chromatography on silica gel columns
was not readily accomplished. However, it is possible that
the separated diastereomers would equilibrate given the
acidity of the remaining R hydrogen, so the separation
was not pursued.
An R-phosphono lactam analogous to compound 3a also
could be viewed as a farnesyl pyrophosphate analogue,
albeit one where displacement would be less likely, so
an extension of this approach to preparation of the
(23) Chiral Separation by Liquid Chromatography; Satinder, A., Ed.;
ACS Symposium Series 471; American Chemical Society: Washington,
DC, 1991.
(24) (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) Marshall,
J . A.; Adams, N. D. J . Org. Chem. 2002, 67, 733-740.
(25) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J . M. J . Am.
Chem. Soc. 1988, 110, 291-293. (b) Tao, C. L.; Donaldson, W. A. J .
Org. Chem. 1993, 58, 2134-2143.
(26) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T.
J . Org. Chem. 1986, 51, 537-540.
(27) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett.
1987, 28, 5287-5290.
(28) Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. J . Org.
Chem. 1989, 54, 5308-5313.
5704 J . Org. Chem., Vol. 67, No. 16, 2002

R-Phosphono Lactone Analogues of Farnesyl Pyrophosphate
SCHEME 7
corresponding lactam was attempted. To avoid an unfa-
vorable impact of a secondary amide group on the
metathesis process,29 a p-methoxybenzyl (PMB) group
was incorporated as a protecting group (Scheme 7).
Condensation of farnesal (10) with p-methoxybenzy-
lamine afforded the desired imine 24, and this intermedi-
ate was treated with allylmagnesium bromide without
isolation to give the secondary amine 25. Through a
sequence parallel to that used in preparation of lactone
18,20 including reaction with acryloyl chloride to give the
amide 26 and subsequent metathesis with Grubbs cata-
lyst, the conjugated δ-lactam 27 was obtained in good
yield. Conjugate reduction proved to be more straight-
forward than that with the corresponding lactone 18, and
compound 27 was reduced with Mg-MeOH at room
temperature to provide the saturated lactam 28 in good
yield. Phosphorylation through formation of the enolate,
reaction with diethyl phosphorochloridite, and oxidation
with H2O2 gave the desired phosphonate 29 as a mixture
of diastereomers. In contrast to the difficulty encountered
with the separation of the R-phosphono lactone 23, this
mixture could be separated by column chromatography
into two racemic pairs. An attempt to remove the PMB
group through reaction with CAN was not successful, but
it is possible that more forceful conditions or other
strategies30 for this cleavage may yet afford the parent
lactam.
from farnesal with very good regioselectivity, and condi-
tions for regioselective reduction of the metathesis prod-
ucts have been found. Further studies on the biological
activities of the parent phosphonic acids derived from
these new phosphonates will be reported in due course.
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. Lithium chloride was dried at 120 °C in vacuo (0.05
mmHg) overnight before use. 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 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. All 31P NMR chemical shifts
are reported in ppm relative to 85% H3PO4 (external standard).
High resolution and electron-spray mass spectra were obtained
at the University of Iowa Mass Spectrometry Facility. Elemen-
tal analyses were performed by Atlantic Microlab, Inc. (Nor-
cross, GA).
5-H yd r oxy-7,11,15-t r im et h yl-6E,10E,14-h exa d eca t r i-
en oic Acid Eth yl Ester (12). A suspension of activated zinc
dust (980 mg, 15.1 mmol) in THF (1 mL) was treated with
1,2-dibromoethane (42 µL, 0.49 mmol) and then heated gently
until boiling was observed. The zinc suspension was stirred a
few minutes and heated again, and this process was repeated
three times. Chlorotrimethylsilane (30 µL, 0.26 mmol) in THF
(0.5 mL) was added dropwise into the suspension. After 15
min, the reaction mixture was warmed to 30 °C and ethyl-4-
iodobutyrate31 (3.08 g, 12.7 mmol) in THF (7 mL) was added
dropwise over 20 min. After the addition was complete, the
reaction mixture was stirred for 4 h at 40 °C to dissolve most
of the zinc dust and give a clear solution of the zinc reagent.
This preparation was added to a stirred solution of CuCN/
2LiCl, prepared in situ by dissolving CuCN (1.02 g, 11.36
mmol) and LiCl (960 mg, 22.7 mmol) in THF (8 mL) at rt, at
-40 °C via cannula. The resulting solution was allowed to
These studies have shown that it is possible to prepare
an R-phosphono lactone through reaction of the corre-
sponding enolate with an electrophilic phosphorus(III)
reagent, even in a case where the vinyl phosphate-
phosphonate rearrangement is complicated by a compet-
ing elimination. A parallel set of reactions has been used
to prepare an analogous R-phosphono lactam. In addition,
metathesis can be used to build a nonracemic lactone
(29) (a) Rutjes, F. P. J . T.; Schoemaker, H. E. Tetrahedron Lett. 1997,
38, 677-680. (b) Creighton, C. J .; Reitz, A. B. Organic Lett. 2001, 3,
893-895.
(30) For example, through reaction with TFA: Chen, P.; Barrish,
J . C.; Iwanowicz, E.; Lin, J .; Bednarz, M. S.; Chen, B. C. Tetrahedron
Lett. 2001, 42, 4293-4296.
(31) Bergmann, E. D.; Yaroslavsky, S. Tetrahedron 1960, 11, 154-
157.
J . Org. Chem, Vol. 67, No. 16, 2002 5705

Du and Wiemer
warm to 0 °C over 1 h to complete the transmetalation and
then cooled to -78 °C. Boron trifluoride etherate (4.32 mL,
34.0 mmol) was added dropwise, and the reaction mixture was
allowed to warm to -30 °C, stirred for 30 min at this
temperature, and then cooled to -78 °C. Farnesal17 (10, 2.00
g, 9.08 mmol) in THF (2 mL) was added slowly via cannula.
The reaction mixture was allowed to warm to -30 °C over 1
h, stirred at this temperature for 15 h, and then stirred for 30
min at 0 °C. After the solution was diluted with ethyl acetate
(100 mL), it was treated with saturated NH4Cl. The mixture
was filtered, and the organic layer was separated. The aqueous
layer was extracted with ethyl acetate, and the combined
organic solution was washed with 10% sodium thiosulfate (10
mL), saturated NH4Cl, and brine, and finally dried over
MgSO4. After concentration in vacuo, purification of the
residue by flash column chromatography over silica (hexanes/
EtOAc 8:2) yielded compound 12 (2.34 g, 76%): 1H NMR (400
MHz) δ 5.17 (dm, J ) 8.6 Hz, 1H), 5.13-5.05 (m, 2H), 4.37
(dt, J ) 8.7, 6.2 Hz, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 2.32 (t, J )
7.2 Hz, 2H), 2.16-1.94 (m, 8H), 1.75-1.40 (m, 16H), 1.25 (t, J
) 7.2 Hz, 3H); 13C NMR (100 MHz) δ 173.6, 138.9, 135.4, 131.3,
127.6, 124.3, 123.7, 68.2, 60.2, 39.7, 39.6, 37.0, 34.2, 26.7, 26.3,
25.7, 21.0, 17.7, 16.6, 16.0, 14.2. Anal. Calcd for C21H36O3: C,
74.95; H, 10.78. Found: C, 75.12; H, 10.74.
J CP ) 6.4 Hz), 63.1 (d, J CP ) 6.8 Hz), 45.1 (d, J CP ) 130.7 Hz),
39.8, 32.3, 31.4 (d, J CP ) 15.2 Hz), 26.9, 26.8, 26.8, 25.8, 17.8,
16.4 (d, J CP ) 6.6 Hz, 2C), 16.2; 31P NMR +24.5 ppm. HRMS
(ES) m/z: calcd for (M + Na)+ C23H39O5NaP, 449.2433; found,
449.2448.
r-(Dieth oxyp h osp h in yl)-6-(2′,6′,10′-tr im eth yl-1′E,5′E,9′-
u n d eca t r ien yl)t et r a h yd r op yr a n -2-on e (3). A solution of
lactone 4 (200 mg, 0.69 mmol) in ether (1 mL) was added
dropwise via cannula to a stirred solution of LDA (1.1 equiv),
prepared in situ from diisopropylamine (0.11 mL, 0.76 mmol)
and n-butyllithium in hexanes (2.50 M, 0.30 mL, 0.76 mmol),
in anhyd ether (2.5 mL) at -78 °C. After 60 min, HMPA (0.13
mL, 0.76 mmol) and diethyl phosphorochloridite (0.11 mL, 0.76
mmol) were added sequentially, 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 acetic acid in ether (1 M, 4
mL), and the resulting mixture was filtered through a pad of
Celite. After concentration, the residue was stirred open to the
air at rt overnight. Final purification by column chromatog-
raphy (silica gel, gradient elution from hexanes/EtOAc 1:1 to
EtOAc) afforded phosphonate 3 (190 mg, 62%) as a clear oil
consisting of a mixture of diastereomers: 1H NMR (400 MHz)
δ 5.31-5.19 (m, 3H), 5.12-5.02 (m, 5H), 4.30-4.14 (m, 8H),
3.19-3.06 (m, 2H), 2.42-2.16 (m, 4H), 2.16-1.80 (m, 20 H),
1.72 (d, J ) 1.0 Hz, 3H), 1.70 (d, J ) 1.5 Hz, 3H), 1.68 (s, 3H),
1.68 (s, 3H), 1.60 (s, 12H), 1.39-1.32 (m, 12H); 31P NMR +23.2,
22.6 ppm.
6-(2′,6′,10′-Tr im eth yl-1′E,5′E,9′-u n d eca tr ien yl)tetr a h y-
d r op yr a n -2-on e (4). To a stirred solution of compound 12
(1.00 g, 2.98 mmol) in THF (6 mL) at 0 °C was added 1 N LiOH
(6.00 mL, 6.00 mmol). The mixture was stirred at this
temperature for 30 min, then diluted with 20 mL of water,
and washed with ether. The aqueous phase was separated,
acidified with 1 N HCl to pH 3, and then extracted with ethyl
acetate. The combined extracts were washed with brine and
dried over MgSO4. After evaporation of the solvent, a clear
liquid was obtained which was dissolved in CH2Cl2 (30 mL)
and cooled to 0 °C. 1-(3-Dimethylamino)propyl-3-ethylcarbo-
diimide hydrogen chloride (EDC, 860 mg, 4.47 mmol) and
(dimethylamino)pyridine (DMAP, 180 mg, 1.49 mmol) were
added successively. After the reaction was stirred for 10 min
at this temperature, the mixture was stirred for 16 h at rt
and then concentrated in vacuo. The residue was treated with
ether and filtered through a pad of Celite. After evaporation
of solvent, the residue was purified by flash column chroma-
tography (hexanes/EtOAc 8:2) to furnish compound 4 (710 mg,
83%): 1H NMR (400 MHz) δ 5.26 (dq, J ) 8.6, 1.3 Hz, 1H),
5.13-5.00 (m, 3H), 2.65-2.41 (m, 2H), 2.16-1.81 (m, 12H),
1.71 (d, J ) 1.3 Hz, 3H), 1.68 (d, J ) 0.9 Hz, 3H), 1.60 (s, 6H);
13C NMR δ 171.7, 141.5, 135.6, 131.4, 124.3, 123.5, 123.0, 77.4,
39.7, 39.4, 29.5, 28.6, 26.7, 26.2, 25.7, 18.6, 17.7, 16.8, 16.0.
HRMS (ES) m/z: calcd for (M + H)+ C19H31O2, 291.2324; found,
291.2310.
6,10,14-Tr im eth yl-1,5E,9E,13-p en ta d eca tetr a en -(4R)-4-
ol (16). To a stirred suspension of (+)-B-chlorodiisopinocam-
pheylborane (3.16 g, 9.88 mmol) in ether (30 mL) was added
allylmagnesium bromide in ether (1 M, 9.00 mL, 9.00 mmol)
dropwise at -78 °C. The mixture was allowed to warm to rt
over the course of 4 h and then stirred for another 2 h. The
resulting cloudy white suspension was cooled to -100 °C and
treated with farnesal (10, 1.66 g, 7.53 mmol) in THF (15 mL).
After the reaction was stirred for 4 h at this temperature, the
mixture was treated with methanol (1 mL) and allowed to
warm to rt. After NaOH (3 N, 7.24 mL) and H2O2 (30%, 2.98
mL) were added, the resulting mixture was heated at reflux
for 1 h. The organic phase was separated and washed with
water (5 mL) and brine (5 mL) and then dried over MgSO4.
After concentration in vacuo, purification of the residue by
flash chromatography on silica gel (hexanes to hexanes/EtOAc
9:1) afforded the alcohol 16 as a clear oil (1.55 g, 78%): [R]22
D
) -8.4 (c 1.15, EtOH); both H and 13C NMR spectra matched
1
those of racemic 16.32
2-P r op en oic Acid , 3,7,11-Tr im eth yl-(1R)-1-(2-p r op en -
yl)-2E,6E,10-d od eca tr ien yl Ester (17). To a solution of
alcohol 16 (1.00 g, 3.81 mmol) and triethylamine (1.59 mL,
11.4 mmol) in THF (25 mL) at 0 °C was added acryloyl chloride
(0.62 mL, 7.62 mmol) dropwise. The resulting mixture was
stirred at rt overnight and then treated with saturated NH4-
Cl (15 mL). Extraction with ether, concentration of the
combined extracts in vacuo, and purification by flash chroma-
tography on silica gel (hexanes/EtOAc from 1:0 to 9:1) afforded
acrylate ester 17 (690 mg, 57%): [R]25D ) +15.6 (c 1.41, CHCl3);
1H NMR (400 MHz) δ 6.37 (dd, J ) 17.4, 1.4 Hz, 1H), 6.09
(dd, J ) 17.3, 10.6 Hz, 1H), 5.78 (dd, J ) 10.3, 1.6 Hz, 1H),
5.80-5.67 (m, 1H), 5.62 (dt, J ) 9.0, 6.6 Hz, 1H), 5.19-5.14
(m, 1H), 5.12-5.02 (m, 4H), 2.47-2.30 (m, 2H), 2.15-1.93 (m,
8H), 1.74 (d, J ) 1.4 Hz, 3H), 1.68 (d, J ) 1.0 Hz, 3H), 1.61-
1.58 (m, 6H); 13C NMR (100 MHz) δ 165.6, 140.9, 135.4, 133.4,
131.3, 130.2, 129.0, 124.3, 123.6, 122.8, 117.7, 70.9, 39.7, 39.5,
39.5, 26.7, 26.2, 25.7, 17.7, 16.9, 16.0. Anal. Calcd for
2-(Dieth oxyp h osp h in yl)-7-m eth ylen yl-11,15-d im eth yl-
5E,10E,14-h exa d eca tr ien oic Acid (14). To a solution of LDA
(1.10 mmol) in anhyd THF (3 mL) at -78 °C was added
dropwise via cannula a solution of lactone 4 (290 mg, 1.00
mmol) in THF (2 mL). After 30 min, HMPA (0.20 mL, 1.15
mmol) and diethyl phosphorochloridate (0.17 mL, 1.15 mmol)
were added sequentially, and the resulting mixture was
allowed to warm to rt over the course of 30 min. After the
reaction mixture was cooled to -78 °C, a solution of LDA (2.2
equiv) in THF (3 mL) was added via cannula, and the reaction
mixture was allowed to warm to rt over 2 h. The reaction was
quenched by slow addition of a solution of acetic acid in ether
(1 M, 15 mL), and the resulting mixture was filtered through
a pad of Florisil. Final purification by column chromatography
(silica gel, from EtOAc to EtOAc/AcOH 95:5) afforded com-
pound 14 (290 mg, 68%): 1H NMR (300 MHz) δ 11.74 (br s,
1H), 6.08 (d, J ) 15.8 Hz, 1H), 5.64 (dt, J ) 15.7, 6.6 Hz, 1H),
5.75-5.55 (m, 2H), 4.90 (s, 1H), 4.88 (s, 1H), 4.35-4.05 (m,
4H), 3.01 (ddd, J HP ) 23.1, J ) 10.2, 3.7 Hz, 1H), 2.36-1.79
(m, 12H), 1.68 (s, 3H), 1.60 (s, 6H), 1.34 (t, J ) 7.0 Hz, 3H),
1.33 (t, J ) 7.0 Hz, 3H); 13C NMR δ 171.2 (d, J CP ) 4.0 Hz),
145.7, 135.4, 133.9, 131.3, 127.6, 124.5, 124.2, 114.2, 63.7 (d,
C
21H32O2: C, 79.70; H, 10.19. Found: C, 79.90; H, 10.21.
(6R)-6-(2,6,10-Tr im eth yl-1E,5E,9-u n d eca tr ien yl)-5,6-d i-
h yd r o-2H-p yr a n -2-on e (18). To a solution of compound 17
(380 mg, 1.23 mmol) in CH2Cl2 (125 mL) at reflux was added
dropwise a solution of Grubbs’ ruthenium catalyst (100 mg,
(32) Mechelke, M. M. Ph.D. Thesis, University of Iowa, Iowa City,
IA, 1999.
5706 J . Org. Chem., Vol. 67, No. 16, 2002

R-Phosphono Lactone Analogues of Farnesyl Pyrophosphate
0.12 mmol) in CH2Cl2 (5 mL) over the course of 30 min. The
resulting mixture was stirred under reflux for 2 h and allowed
to cool to rt, and then, DMSO (0.44 mL) was added. After the
resulting mixture was stirred at rt for 18 h, concentration in
vacuo and purification of the residue by flash chromatography
with excess H2O2 (30%) at -10 °C for 10 min. The organic
phase was separated, washed with brine, and dried over
MgSO4. After concentration in vacuo, final purification by
column chromatography (silica gel, hexanes/EtOAc 1:1 to
EtOAc) gave phosphonate 23 (270 mg, 52%) as a clear oil: 1H
NMR and 31P NMR spectra were consistent with those of
compound 3; 13C NMR δ 166.9 (d, J CP ) 4.2 Hz), 166.7 (d, J CP
) 4.4 Hz), 142.4, 141.9, 135.6, 135.6, 131.4 (2C), 124.3 (2C),
123.5, 123.4, 122.5, 122.4, 78.0, 77.5, 63.6 (d, J CP ) 6.9 Hz),
on silica gel (hexanes/EtOAc 8:2) yielded lactone 18 (318 mg,
1
92%): [R]32 ) +34.0 (c 1.54, CHCl3); H NMR (400 MHz) δ
D
6.88 (ddd, J ) 9.8, 5.3, 3.2 Hz, 1H), 6.04 (ddd, J ) 9.8, 2.0, 1.4
Hz, 1H), 5.36 (dq, J ) 8.6, 1.2 Hz, 1H), 5.16 (ddd, J ) 9.9, 8.6,
5.2 Hz, 1H), 5.12-5.05 (m, 2H), 2.46-2.30 (m, 2H), 2.17-1.94
(m, 8H), 1.73 (d, J ) 1.3 Hz, 3H), 1.68 (d, J ) 0.8 Hz, 3H),
1.60 (s, 6H); 13C NMR (100 MHz) δ 164.5, 144.9, 142.8, 135.7,
131.4, 124.3, 123.4, 121.8, 121.7, 74.9, 39.7, 39.4, 30.0, 26.7,
26.1, 25.7, 17.7, 16.9, 16.0. HRMS (ES) m/z: calcd for (M +
Na)+ C19H28O2Na, 311.1987; found, 311.1983.
63.3 (d, J CP ) 6.9 Hz), 62.7 (d, J CP ) 7.6 Hz), 62.6 (d, J CP
)
6.9 Hz), 39.8 (d, J CP ) 135.9 Hz), 39.7 (2C), 39.4, 39.4, 39.3 (d,
J CP ) 138.2 Hz), 28.3 (d, J CP ) 7.4 Hz), 26.7 (2C), 26.7 (d, J CP
) 5.4 Hz), 26.2, 26.1, 25.7 (2C), 20.8 (d, J CP ) 4.5 Hz), 20.7 (d,
J CP ) 4.5 Hz), 17.7 (s, 2C), 16.9, 16.8, 16.4 (d, J CP ) 6.4 Hz),
16.4 (d, J CP ) 6.0 Hz), 16.4 (d, J CP ) 6.4 Hz), 16.4 (d, J CP
)
6.0 Hz), 16.0 (2C). HRMS (ES) m/z: calcd for (M + H)+
(S)-Meth oxyp h en yla cetic Acid , 3,7,11-Tr im eth yl-(1R)-
1-(2-p r op en yl)-2E,6E,10-d od eca tr ien yl Ester (20). To a
mixture of alcohol 16 (76 mg, 0.29 mmol), EDC (83 mg, 0.44
mmol), and DMAP (18 mg, 0.15 mmol) in THF (5 mL) was
added (S)-methoxyphenylacetic acid (19, 63 mg, 0.38 mmol),
and the mixture was stirred at rt. After 28 h, ether (20 mL)
was added and the resulting mixture was filtered and washed
with brine. The organic phase was dried over MgSO4, filtered,
and concentrated to provide a clear oil. Purification by flash
column chromatography (hexanes/EtOAc 95:5) gave compound
20 (113 mg, 95%): 1H NMR (600 MHz, relaxation delay 30 s)
δ 7.45-7.39 (m, 2H), 7.37-7.28 (m, 3H), 5.58 (dt, J ) 9.0, 6.5
Hz, 1H), 5.51-5.39 (m, 1H), 5.17-4.98 (m, 3H), 4.88-4.84 (m,
1H), 4.84-4.81 (m, 1H), 4.71 (s, 1H), 3.39 (s, 3H), 2.29-2.14
(m, 2H), 2.12-1.90 (m, 8H), 1.70-1.67 (m, 6H), 1.60 (s, 3H),
1.59 (s, 3H); 13C NMR (100 MHz) δ 170.0, 141.6, 136.5, 135.4,
132.8, 131.3, 128.6, 128.5 (2C), 127.3 (2C), 124.3, 123.6, 122.4,
117.7, 82.6, 71.5, 57.2, 39.7, 39.5, 39.2, 26.7, 26.2, 25.7, 17.7,
16.9, 16.0. HRMS (ES) m/z: calcd for (M + Na)+ C27H38O3Na,
433.2719; found, 433.2733.
5-H yd r oxy-7,11,15-t r im et h yl-6E,10E,14-h exa d eca t r i-
en oic Acid Meth yl Ester (21). Lactone 4 (200 mg, 0.69
mmol) in anhyd MeOH (6 mL) was added to stirred magne-
sium turnings (170 mg, 7.08 mmol). The mixture was stirred
at rt for 3 h until disappearance of the UV spot for the starting
material was noted upon TLC analysis. A solution of AcOH in
ether (1 N, 25 mL) was added to quench the reaction, and ether
(15 mL) was used to dilute the mixture. After filtration, the
organic solution was concentrated in vacuo. Final purification
by column chromatography (silica gel, hexanes/EtOAc 8:2)
gave ester 21 (50 mg, 22%) as a clear oil: 1H NMR (300 MHz)
δ 5.16 (d, J ) 9.0 Hz, 1H), 5.13-5.04 (m, 2H), 4.36 (dt, J )
8.8, 6.3 Hz, 1H), 3.66 (s, 3H), 2.34 (t, J ) 7.1 Hz, 2H), 2.16-
1.91 (m, 8H), 1.76-1.40 (m, 4H), 1.68 (s, 6H), 1.59 (s, 6H).
HRMS (EI) m/z: calcd for (M - H2O)+ C20H32O2, 304.2402;
found, 304.2400.
C
23H40O5P, 427.2613; found, 427.2610.
N-[3,7,11-Tr im eth yl-1-(2-p r op en yl)-2E,6E,10-d od eca tr i-
en yl]-4-m et h oxyben zyla m in e (25). To a suspension of
MgSO4 (3.00 g, dried at 130 °C at 0.1 mmHg for 4 h prior to
use) and farnesal (10, 685 mg, 3.11 mmol) in ether (20 mL)
was added 4-methoxybenzylamine (0.44 mL, 3.26 mmol) at 0
°C. The resulting mixture was stirred at this temperature for
2 h and then was filtered and concentrated in vacuo. The
residue was dissolved in THF (15 mL), cooled to -40 °C, and
then treated with allylmagnesium bromide in ether (1 M, 13
mL). The resulting mixture was stirred for 1 h at -40 °C and
then for 2.5 h at -25 °C and then was quenched by addition
of saturated NH4Cl (10 mL). Extraction with ether, concentra-
tion of the combined extracts in vacuo, and purification of the
residue by flash chromatography (CH3CN and then MeOH)
gave the secondary amine 25 (912 mg, 77%): 1H NMR (400
MHz) δ 7.19 (dm, J ) 8.6 Hz, 2H), 6.84 (dm, J ) 8.7 Hz, 2H),
5.80-5.67 (m, 1H), 5.17-4.98 (m, 5H), 3.78 (s, 3H), 3.74 (d, J
) 13.0 Hz, 1H), 3.56 (d, J ) 13.0 Hz, 1H), 3.37 (dt, J ) 9.1,
6.6 Hz, 1H), 2.26-2.02 (m, 8H), 2.01-1.94 (m, 2H), 1.67 (d, J
) 0.9 Hz, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.47 (br
s, 1H); 13C NMR (100 MHz) δ 158.4, 137.4, 135.6, 135.1, 133.0,
131.2, 129.2 (2C), 128.0, 124.3, 124.0, 116.9, 113.7 (2C), 55.2,
54.2, 50.6, 40.7, 39.7 (2C), 26.7, 26.4, 25.7, 17.6, 16.7, 16.0.
Anal. Calcd for C26H39NO: C, 81.84; H, 10.30; N, 3.67. Found:
C, 81.43; H, 10.31; N, 3.74.
N-[4-Meth oxyben zyl]-N-[3,7,11-tr im eth yl-1-(2-pr open yl)-
2E,6E,10-d od eca tr ien yl]-2-p r op en a m id e (26). According to
the procedure described above for compound 17, the secondary
amine 25 (862 mg, 2.26 mmol) was treated with triethylamine
(0.94 mL, 6.78 mmol) and acryloyl chloride (0.37 mL, 4.52
mmol). Standard workup and purification of the resulting oil
by flash chromatography (hexanes/EtOAc from 9:1 to 85:15)
gave amide 26 (790 mg, 81%) as a mixture of rotamers: 1H
NMR (400 MHz, 50 °C) δ 7.09 (br s, 2H), 6.81 (d, J ) 8.6 Hz,
2H), 6.40-6.30 (m, 2H), 5.76-5.50 (br m, 2H), 5.46-5.25 (m,
1H), 5.16-4.93 (m, 5H), 4.48 (br s, 2H), 3.37 (s, 3H), 2.44-
2.28 (br s, 1H), 2.26-2.16 (m, 1H), 2.08-1.88 (m, 8H), 1.67 (d,
(6R)-6-(2′,6′,10′-Tr im eth yl-1′E,5′E,9′-u n d eca tr ien yl)tet-
r a h yd r op yr a n -2-on e (22). To a stirred slurry of CuI (28 mg,
0.15 mmol) in THF (10 mL) at -55 °C was added MeLi (1.4
M, 0.11 mL, 0.16 mmol). After the reaction was stirred for 10
min, the mixture was treated with HMPA (0.39 mL, 2.24
mmol) and DIBAL (1 M in hexanes, 1.64 mL, 1.64 mmol)
sequentially. The resulting mixture was stirred at this tempter-
ature for another 30 min, and then lactone 18 (430 mg, 1.49
mmol) in THF (2 mL) was added via cannula. After the
resulting mixture was stirred at -55 °C for 20 h, HCl (1 N,
1.50 mL) was added and the mixture was extracted with ether.
After standard workup, final purification by column chroma-
tography (silica gel, hexanes/EtOAc 8:2) gave lactone 22 (360
J ) 1.0 Hz, 3H), 1.58 (s, 3H), 1.63 (br s, 3H), 1.55 (s, 3H); 13
C
NMR (100 MHz, 25 °C, for the major rotamer) δ 166.5, 158.6,
141.5, 135.2, 134.9, 131.3, 130.4, 128.5, 128.3, 127.3 (2C),
124.2, 123.8, 122.5, 117.0, 113.8 (2C), 55.2, 51.7, 46.7, 39.7,
39.4, 38.6, 26.7, 26.2, 25.7, 17.7, 17.2, 16.0. Anal. Calcd for
C
29H41NO2: C, 79.95; H, 9.49; N, 3.22. Found: C, 79.83; H,
9.59; N, 3.43.
1-(4-Meth oxyben zyl)-6-(2,6,10-tr im eth yl-1E,5E,9-u n d e-
ca tr ien yl)-5,6-d ih yd r o-2(1H)-p yr id in on e (27). According to
the procedure described above for compound 18, acrylamide
26 (384 mg, 0.88 mmol) in CH2Cl2 (85 mL) was treated with
Grubbs’ ruthenium catalyst (73 mg, 0.088 mmol) for 1 h to
obtain lactam 27 (331 mg, 92%): 1H NMR (600 MHz) δ 7.18
(m, 2H), 6.84 (m, 2H), 6.43 (ddd, J ) 9.8, 5.4, 2.9 Hz, 1H),
6.00 (dd, J ) 9.8, 1.8 Hz, 1H), 5.36 (dd, J ) 9.8, 1.0 Hz, 1H),
5.29 (d, J ) 14.8 Hz, 1H), 5.12-5.04 (m, 2H), 4.12 (ddd, J )
9.7, 7.0, 3.6 Hz, 1H), 3.79 (s, 3H), 3.69 (d, J ) 14.8 Hz, 1H),
2.55 (ddt, J ) 17.8, 6.8, 2.9 Hz, 1H), 2.14 (dt, J ) 17.9, 4.3 Hz,
mg, 84%) as a clear oil: [R]24 ) -48.0 (c 1.82, CHCl3); both
D
1H and 13C NMR spectra matched those of the racemic
compound 4.
r-(Die t h oxyp h osp h in yl)-(6R )-6-(2′,6′,10′-t r im e t h yl-
1′E,5′E,9′-u n d eca tr ien yl)tetr a h yd r op yr a n -2-on e (23). Lac-
tone 22 (358 mg, 1.23 mmol) was treated with LDA and diethyl
phosphorochloridite as described for preparation of compound
3. The resulting intermediate was then oxidized by treatment
J . Org. Chem, Vol. 67, No. 16, 2002 5707

Du and Wiemer
1H), 2.11-1.94 (m, 8H), 1.68 (d, J ) 0.6 Hz, 3H), 1.60 (s, 3H),
1.60 (s, 3H), 1.52 (d, J ) 1.2 Hz, 3H); 13C NMR δ 164.1, 158.7,
138.8, 137.4, 135.4, 131.3, 130.2, 129.2 (2C), 125.0, 124.2,
123.4, 123.1, 113.8 (2C), 55.2, 51.6, 46.1, 39.6, 39.3, 30.5, 26.7,
26.1, 25.6, 17.6, 16.2, 16.0. HRMS (ES) m/z: calcd for (M +
H)+ C27H38NO2, 408.2902; found, 408.2901.
29a : 1H NMR (400 MHz) δ 7.16 (dm, J ) 8.6 Hz, 2H), 6.83
(dm, J ) 8.8 Hz, 2H), 5.42 (d, J ) 14.8 Hz, 1H), 5.13 (dd, J )
9.6, 1.2 Hz, 1H), 5.12-5.06 (m, 2H), 4.36-4.12 (m, 4H), 4.02
(dt, J ) 9.3, 5.1 Hz, 1H), 3.78 (s, 3H), 3.69 (d, J ) 14.9 Hz,
1H), 3.06 (dt, J HP ) 26.5 Hz, J ) 5.4 Hz, 1H), 2.22-1.94 (m,
11H), 1.67 (d, J ) 0.8 Hz, 3H), 1.61 (d, J ) 0.6 Hz, 3H), 1.58-
1.50 (m, 1H), 1.60 (s, 3H), 1.46 (d, J ) 1.3 Hz, 3H), 1.37 (t, J
) 7.1 Hz, 3H), 1.34 (t, J ) 7.1 Hz, 3H); 13C NMR δ 165.2 (d,
J CP ) 5.7 Hz), 158.7, 139.0, 135.6, 131.4, 129.4, 129.1 (2C),
124.9, 124.2, 123.5, 113.8 (2C), 62.8 (d, J CP ) 5.7 Hz), 62.1 (d,
J CP ) 6.9 Hz), 55.2, 53.4, 46.4, 41.8 (d, J CP ) 135.2 Hz), 39.8,
39.5, 27.7 (d, J CP ) 7.1 Hz), 26.7, 26.1, 25.7, 20.2 (d, J CP ) 4.6
Hz), 17.7, 16.5 (d, J CP ) 6.1 Hz), 16.4 (d, J CP ) 6.0 Hz), 16.2,
16.1; 31P NMR +26.1 ppm.
1-(4-Meth oxyph en ylm eth yl)-6-(2,6,10-tr im eth yl-1E,5E,9-
u n d eca tr ien yl)p ip er id in -2-on e (28). Lactam 27 (289 mg,
0.71 mmol) in anhyd MeOH (7 mL) was added to stirred
magnesium turnings (170 mg, 7.08 mmol). The resulting
mixture was stirred at rt for 100 min until disappearance of
starting material was noted on TLC analysis. After HCl (1 N,
10 mL) was added to quench the reaction, ether was used to
extract the aqueous solution. The combined organic solution
was washed with saturated NaHCO3 and then with brine and
finally dried over MgSO4. Standard workup and final purifica-
tion by column chromatography (silica gel, hexanes/EtOAc 7:3)
gave the lactam 28 (252 mg, 86%) as a clear oil: 1H NMR (300
MHz) δ 7.13 (m, 2H), 6.82 (m, 2H), 5.34 (d, J ) 14.6 Hz, 1H),
5.16 (dq, J ) 9.4, 1.2 Hz, 1H), 5.13-5.03 (m, 2H), 4.07-3.92
(m, 1H), 3.79 (s, 3H), 3.60 (d, J ) 14.4 Hz, 1H), 2.47 (t, J )
6.5 Hz, 2H), 2.20-1.55 (m, 12H), 1.68 (d, J ) 0.9 Hz, 3H), 1.62
29b: 1H NMR (400 MHz) δ 7.14 (dm, J ) 8.6 Hz, 2H), 6.82
(dm, J ) 8.7 Hz, 2H), 5.28 (d, J ) 14.4 Hz, 1H), 5.29-5.24 (m,
1H), 5.12-5.06 (m, 2H), 4.36-4.14 (m, 4H), 4.02 (dt, J ) 9.4,
5.3 Hz, 1H), 3.78 (s, 3H), 3.75 (dd, J ) 14.6, 1.6 Hz, 1H), 3.08
(dt, J HP ) 26.8 Hz, J ) 7.5 Hz, 1H), 2.34-1.70 (m, 12H), 1.67
(d, J ) 0.4 Hz, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.53 (d, J ) 1.3
Hz, 3H), 1.36 (t, J ) 7.0 Hz, 3H), 1.36 (t, J ) 7.0 Hz, 3H); 13
C
NMR δ 165.1 (d, J CP ) 4.9 Hz), 158.8, 138.9, 135.5, 131.4,
129.7, 129.5 (2C), 125.0, 124.3, 123.6, 113.8 (2C), 62.9 (d, J CP
) 6.7 Hz), 62.0 (d, J CP ) 6.6 Hz), 55.2, 53.6, 47.0, 41.9 (d, J CP
) 138.5 Hz), 39.8, 39.5, 28.2 (d, J CP ) 9.4 Hz), 26.8, 26.3, 25.7,
20.4 (d, J CP ) 4.2 Hz), 17.7, 16.5 (d, J CP ) 6.2 Hz), 16.4 (d, J CP
) 6.3 Hz), 16.2, 16.1; 31P NMR +25.6 ppm.
(d, J ) 0.9 Hz, 3H), 1.59 (s, 3H), 1.51 (d, J ) 1.3 Hz, 3H); 13
C
NMR (75 MHz) δ 170.0, 158.7, 138.4, 135.5, 131.4, 130.0, 129.4
(2C), 125.6, 124.2, 123.6, 113.8 (2C), 55.2, 53.4, 46.2, 39.8, 39.5,
32.6, 29.9, 26.7, 26.1, 25.7, 18.4, 17.7, 16.2, 16.1. HRMS (ES)
m/z: calcd for (M + H)+ C27H40NO2, 410.3059; found, 410.3046.
r-(Dieth oxyp h osp h in yl)-1-(4-m eth oxyp h en ylm eth yl)-
6-(2,6,10-t r im et h yl-1E,5E,9-u n d eca t r ien yl)p ip er id in -2-
on e (29). According to the procedure described above for
preparation of compound 23, lactam 28 (217 mg, 0.53 mmol)
was treated with LDA (1.1 equiv), with diethyl phosphoro-
chloridite, and then with H2O2. Standard workup and purifica-
tion by column chromatography (silica gel, hexanes/EtOAc 1:1
to EtOAc) gave phosphonate 29 (184 mg, 64%) as a clear oil
consisting of a 1:1 mixture of diastereomers along with some
recovered compound 28 (0.03 g or 74% yield based on recovered
starting material). Anal. Calcd for C31H48NO5P: C, 68.23; H,
8.87; N, 2.57. Found: C, 67.97; H, 8.91; N, 2.62.
Ack n ow led gm en t. We thank Professor Raymond J .
Hohl (University of Iowa, Departments of Internal
Medicine and Pharmacology) for his helpful discussions
and Mr. J ohn Snyder (University of Iowa) for his
assistance with NMR spectroscopy. Financial support
from the Roy J . Carver Charitable Trust is gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H and/or 13C NMR
spectra for compounds 4, 14, 18, 20, 21, 23, 27, and 28. This
material is available free of charge via the Internet at
http://pubs.acs.org.
A second column chromatography experiment gave the two
individual diastereomers as the less polar compound 29a and
the more polar compound 29b on TLC (EtOAc).
J O0202233
5708 J . Org. Chem., Vol. 67, No. 16, 2002