Efficient Synthesis of β,γ-Dehydrovaline

Full text of DOI:10.1021/jo990916s

7670
J . Org. Chem. 1999, 64, 7670-7674
Ch a r t 1
Efficien t Syn th esis of â,γ-Deh yd r ova lin e
Thomas F. Woiwode and Thomas J . Wandless*
Department of Chemistry, Stanford University,
Stanford, California 94305-5080
Received J une 4, 1999
Unnatural amino acids continue to be the targets of
much synthetic interest.1 In particular, â,γ-unsaturated
amino acids have been the subject of many synthetic
studies because of their interesting biological activity and
due to the inherent challenges that are associated with
developing efficient synthetic routes to these sensitive
compounds. Vinylglycine, the parent compound of this
family, has been isolated from mushrooms2 and is
postulated to be an intermediate in the enzymatic
conversion of homoserine to threonine3 and R-keto-
butyrate.4 Several â,γ-unsaturated amino acids have been
shown to be irreversible inhibitors of pyridoxal phosphate-
dependent enzymes and have found use as herbicides and
fungicides.5 In addition, â,γ-unsaturated amino acids are
of interest because of their unique conformational prop-
erties. The majority of the synthetic efforts toward â,γ-
unsaturated amino acids have been directed specifically
toward vinylglycine, with few reports describing routes
to â,γ-dehydrovaline or other â,γ-unsaturated amino
acids. Our laboratory studies antimitotic natural products
that bind to microtubules, and we are presently pursuing
the total synthesis of phomopsin A (Chart 1). These
studies have resulted in new methods to prepare hin-
dered alkyl aryl ethers and R,â-unsaturated amino acids.6
As part of our effort, we required an efficient route to
â,γ-dehydrovaline or an appropriately functionalized
precursor that could be incorporated into the macrocycle
and unveiled at the appropriate time.
derivatives,9a,b reduction of alkynyl glycine derivatives,9c
and Heck coupling approaches.9d However, none of these
methods readily lend themselves to the synthesis of â,γ-
dehydrovaline.
Two asymmetric syntheses of â,γ-dehydrovaline have
been reported to date. The approach utilized by Baldwin
et al. entails deconjugation of an R,â-dehydrovaline
derivative followed by enzymatic resolution to separate
the racemic mixture of enantiomers.10 We initially chose
to pursue the second approach reported by Schollkopf,
which involves the formation of the bis-lactim ether from
glycine and D-valine followed by hydroxyalkylation with
acetone and subsequent dehydration.11 In practice, this
approach provides a mixture of both R,â-dehydrovaline
and â,γ-dehydrovaline. Despite optimization, we achieved
as our best result a 3:2 ratio of the two products with
the desired unconjugated isomer as the minor component.
A more general method to synthesize the desired amino
acid was necessary. Of the numerous methods to syn-
thesize derivatives of R-amino acids, the methodology
developed by Evans and co-workers is particularly at-
tractive because of its proven utility in numerous ap-
plications.12 The most straightforward approach would
involve adding the chiral auxiliary to 3-methyl-3-butenoic
acid and performing an asymmetric electrophilic amina-
tion. However, this transformation is known to generate
a mixture of R- and γ-amination products.13 We were also
aware of the propensity for â,γ-unsaturated alkenes to
migrate into conjugation, so we chose to develop a
strategy in which an alkene precursor would be incor-
porated into the macrocycle precursor and transformed
into the desired alkene later in the synthesis.
Many of the reported syntheses of vinylglycine involve
oxidative degradation of suitably modified, optically pure
R-amino acids (e.g., L-methionine, L-glutamic acid, and
L-homoserine);7 however, these methods are not ap-
plicable to the synthesis of â,γ-dehydrovaline. More
general strategies to prepare â,γ-unsaturated amino acids
have been reported,8 including olefination of serine
Working with a masked alkene would provide maxi-
mum flexibility, which is valuable in the context of a
multistep synthesis. Phenylselenide functional groups are
labile toward oxidative conditions but are generally stable
toward a variety of other conditions, and this robust
character makes them particularly attractive for use in
the synthesis of complex molecules.14 Elimination of the
* To whom correspondence should be addressed. Phone: (650) 723-
4005. Fax: (650) 725-0259. E-mail: wandless@chem.stanford.edu.
(1) Williams, R. M. Synthesis of optically active R-amino acids;
Oxford; New York: Pergamon Press: 1989.
(2) Dardenne, G.; Casimir, J .; Marlier, M.; Larsen, P. O. Phytochem-
istry 1974, 13, 1897.
(3) Flavin, M.; Slaughter, C. J . Biol. Chem. 1960, 235, 1112.
(4) Posner, B. I.; Flavin, M. J . Biol. Chem. 1972, 247, 6402.
(5) (a) Soper, T. S.; Manning, J . M.; Marcotte, P. A.; Walsh, C. T. J .
Biol. Chem. 1977, 252, 1571. (b) Rando, R. R. Acc. Chem. Res. 1975, 8,
281.
(6) (a) Woiwode, T. F.; Rose, C.; Wandless, T. J . J . Org. Chem. 1998,
63, 9594-9596. (b) Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J . J .
Am. Chem. Soc. 1999, 121, 6100-6101.
(7) From L-methionine: (a) Afzali-Ardakani, A.; Rapaport, H. J . Org.
Chem. 1980, 45, 4817. Ffrom L-homoserine: (b) Itaya, T.; Shimizu, S.;
Nakagawa, S.; Morisue, M. Chem. Pharm. Bull. 1994, 42, 1927. (c)
Pellicciari, R.; Natalini, B.; Marinozzi, M. Synth. Commun. 1988, 18,
1715. From L-glutamate: (d) Hannesian, S.; Sahoo, S. P. Tetrahedron
Lett. 1984, 25, 1425. (e) Barton, D. H. R.; Crich, D.; Herve, Y.; Potier,
P.; Thierry, J . Tetrahedron 1985, 41, 4347.
(9) (a) Beaulieu, P. L.; Duceppe, J . S.; J ohnson, C. J . Org. Chem.
1991, 56, 4196. (b) Sasaki, N. A.; Hashimoto, C.; Pauly, R. Tetrahedron
Lett. 1989, 30, 1943. (c) Williams, R. M.; Zhai, W. Tetrahedron 1988,
44, 5425. (d) Crisp, G. T.; Glink, P. T. Tetrahedron 1992, 48, 3541.
(10) Baldwin, J . E.; Haber, S. B.; Hoskins, C.; Kruse, L. I. J . Org.
Chem. 1977, 42, 1239.
(11) (a) Schollkopf, U.; Groth, U. Angew. Chem., Int. Ed. Engl. 1981,
20, 977. (b) Schollkopf, U.; Groth, U.; Gull, M.-R.; Nozulak, J . Liebigs.
Ann. Chem. 1983, 1133.
(12) (a) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J .
Am. Chem. Soc. 1990, 112, 4011. (b) Evans, D. A.; Britton, T. C. J .
Am. Chem. Soc. 1987, 109, 6881.
(13) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J . F.
Tetrahedron 1988, 44, 5525.
(8) Havlicek, L.; Hanus, J . Collect. Czech. Chem. Commun. 1991,
56, 1365.
(14) (a) Reich, H. J . Acc. Chem. Res. 1979, 12, 22. (b) Reich, H. J .;
Wollowitz, S. Org. React. 1993, 44, 1.
10.1021/jo990916s CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

Notes
J . Org. Chem., Vol. 64, No. 20, 1999 7671
Sch em e 1
Sch em e 2
selenoxide functional group is a mild and useful method
to prepare alkenes with good control of regioselectivity.15
Berkowitz and co-workers have used this strategy to
synthesize racemic R-vinylamino acids, suggesting that
this strategy would be effective in our case as well.16
Lactone 1 was synthesized from citraconic anhydride
as reported (Scheme 1).17 Nucleophilic opening of lactone
1 was best accomplished by first reducing diphenyldi-
selenide with sodium borohydride in a solution of de-
gassed DMF. Lactone 1 was then added as a solution in
degassed DMF, and the resulting reaction was heated
to 120 °C for 4 h. Subsequent isolation provided the
desired carboxylic acid (2) in moderate yield. Berkowitz
and co-workers noted that using sodium trimethoxyboro-
hydride as the reducing agent gave superior results as
it avoided the competing reduction of the lactone.16 In
our hands, use of sodium trimethoxyborohydride resulted
in very slow reduction of diphenyldiselenide and inferior
yields of the desired product as compared with sodium
borohydride.
Condensation of the chiral auxiliary was accomplished
following the procedure of Evans to provide oxazolidinone
3.13 As Evans and co-workers have noted, the azide
transfer is a capricious reaction that is very sensitive to
experimental conditions.12b In accord with their observa-
tions, this transformation was most successful when
quenched with acetic acid at -78 °C after 3 min, followed
by addition of potassium acetate and allowing the reac-
tion to slowly warm from -78 °C to room temperature
overnight. This protocol provided the desired R-azido
carboxylic acid derivative 4 with >95% diastereoselec-
tivity.
tions.18 Reduction of the azide using tin dichloride in
p-dioxane and water was ultimately successful. The
nascent amine was protected in situ as the tert-butyl
carbamate during the alkaline workup.19 This procedure
produced the desired Boc-protected amino acid 6, which
was subsequently used to prepare the macrocycle precur-
sor 9 shown in Scheme 2.22
We began to investigate reaction conditions to perform
the desired selenoxide elimination.15 A variety of oxidants
have been used to oxidize the selenide to the selenoxide
including hydrogen peroxide, tert-butyl hydroperoxide,
ozone, m-CPBA, and sodium periodate.20 As a model
system, we converted Boc-protected amino acid 6 into the
methyl ester followed by treatment with hydrogen per-
oxide and pyridine in CCl4. Oxidation of the selenide to
the selenoxide proceeded cleanly within 2 h, but the
subsequent elimination to the alkene required heating
the reaction to 40 °C for 12 h to provide the desired â,γ-
unsaturated amino acid in 75% yield.
The major side product arose from the electrophilic
addition of benzeneselenenic acid, produced during the
course of the reaction, to the nascent alkene in the
desired product. Butyl vinyl ether was added to the
reaction in order to trap the benzeneselenenic acid that
is formed, but this tactic did not improve the yield.21 We
chose to postpone further optimization studies until the
fully functionalized macrocycle precursor was available.
Subjecting the fully functionalized macrocycle precur-
sor 922 to the same conditions (hydrogen peroxide, pyri-
(18) Hydrogenation conditions: PtO2/H2, Pd(OH)2/H2, 10%Pd/C/H2,
and Raney Ni/H2. Staudinger conditions: Ph3P/H2O and Me3P/H2O.
(19) Maiti, S. N.; Singh, M. P.; Micetich, R. G. Tetrahedron Lett.
1986, 27, 1423.
(20) Reich, H. J .; Renga, J . M.; Reich, I. L. J . Am. Chem. Soc. 1975,
97, 5434.
(21) We did isolate R-phenylselenylacetaldehyde, showing that butyl
vinyl ether did react with benzeneselenenic acid.
(22) Compound 9 was prepared as follows:
Hydrolytic removal of the auxiliary proceeded quickly
and efficiently to provide carboxylic acid 5. Subsequent
reduction of the azide was unsuccessful using either
catalytic hydrogenation or Staudinger reduction condi-
(15) (a) Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron
Lett. 1973, 1979. (b) Reich, H. J .; Wollowitz, S.; Trend, J . E.; Chow,
F.; Wendelborn, D. F. J . Org. Chem. 1978, 43, 1697. (c) Thornberry,
N. A.; Bull, H. G.; Taub, D.; Greenlee, W. J .; Patchett, A. A.; Cordes,
A. H. J . Am. Chem. Soc. 1987, 109, 7543.
(16) Pederson, M. L.; Berkowitz, D. B. J . Org. Chem. 1993, 58, 6966.
(17) (a) Schulz, S. Liebigs Ann. Chem. 1992, 829. (b) Kayser, M. M.;
Morand, P. Can. J . Chem. 1980, 58, 2484.

7672 J . Org. Chem., Vol. 64, No. 20, 1999
Notes
silica gel (30% Et2O in hexanes to 60% Et2O in hexanes) provided
6.09 g (60% yield) of the desired product 2 as a pale yellow
liquid: 1H NMR (500 MHz, CDCl3) δ 7.54-7.52 (m, 2H), 7.30-
7.25 (m, 3H), 3.02-2.92 (m, 2H), 2.68-2.62 (m, 1H), 2.34-2.26
(m, 2H), 1.13 (d, J ) 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
178.9, 132.6, 130.3, 129.1, 126.9, 40.6, 35.2, 30.8, 20.1; IR (neat)
3057, 2962, 1705. Anal. Calcd for C11H14O2Se: C, 51.37; H, 5.49.
Found: C, 51.37; H, 5.48.
dine, CCl4) gave rise to a disappointing 25% isolated yield
of the desired alkene product 10 (Scheme 2). To optimize
this transformation, we used anhydrous tert-butyl hy-
droperoxide as the oxidant, and we added a variety of
compounds to trap benzeneselenenic acid including
2-octene, 1-methyl-1-cyclohexene, diethylamine, and tri-
ethylamine. These studies provided dramatically im-
proved yields of 10, with the combination of tert-butyl
hydroperoxide and diethylamine proving to be most
efficient. Oxidation of 9 with tert-butyl hydroperoxide
requires 8 equiv of oxidant in practice and is significantly
slower relative to hydrogen peroxide. Nevertheless, tert-
butyl hydroperoxide does accomplish the clean oxidation
of the selenide to the selenoxide at which point addition
of diethylamine, dilution with CCl4, and heating to 50
°C for 10 h provides the desired R,â-unsaturated alkene
10 in 87% isolated yield (Scheme 2).
Oxidation of the methyl ester of compound 6 using tert-
butyl hydroperoxide proved to be efficient as well, provid-
ing Boc-isodehydrovaline methyl ester 7 in 93% isolated
yield (Scheme 1). The enantiomeric purity of the synthetic
material was assessed by hydrogenation of 7 to 8 followed
by comparison to authentic Boc-valine methyl ester.23
Optical rotation measurements indicate that the syn-
thetic material was produced in 95% enantiomeric excess.
The phenylselenide functional group is an excellent
synthon for a carbon-carbon double bond, and this report
demonstrates its utility in the context of complex natural
product synthesis. Unnatural amino acids that contain
unsaturation possess unique conformational and reactiv-
ity properties, and methods that improve access to these
compounds will likely lead to new functional molecules.
The variety of conditions that are tolerated by the
phenylselenide indicate that amino acids that contain
this functional group will also be amenable to solid-phase
synthetic techniques.
3-(R,S)-4-(S)-4-Ben zyl-3-[3-m et h yl-4-(p h en ylselen o)b u -
ta n oyl]-1,3-oxa zolid in -2-on e (3). Following the general pro-
cedure of Evans et al.,13 triethylamine (4.15 mL, 30.0 mmol, 1.3
equiv) and pivaloyl chloride (3.14 mL, 25.4 mmol, 1.1 equiv) were
added to a flame-dried 250-mL round-bottom flask charged with
50 mL of THF under an argon atmosphere and cooled to -78
°C. A solution of 2 in 5 mL of THF was added dropwise and
then warmed to 0 °C once addition was complete. After 1 h at 0
°C, the solution was recooled to -78 °C. In the meantime, (S)-
4-benzyl-2-oxazolidinone (4.50 g, 25.4 mmol, 1.1 equiv) and
triphenylmethane (6 mg) were added to a flame-dried 100-mL
flask, placed under argon, dissolved in 50 mL of distilled THF,
and cooled to -40 °C. n-Butyllithium (15.9 mL of 1.6 M solution
in hexanes, 25.4 mmol, 1.1 equiv) was added dropwise, producing
a bright orange color upon completion of the addition. This
solution was cooled to -78 °C and added via cannula to the
solution of the mixed anhydride that was formed in situ. The
flask in which the lithiated oxazolidinone was generated was
rinsed with 5 mL of THF and added via cannula to the mixed
anhydride solution. The reaction was stirred at -78 °C for 30
min and then warmed to room temperature for 3 h, at which
point it was diluted with 150 mL of CH2Cl2 and washed with
100 mL of pH 7-phosphate buffer. The aqueous layer was
extracted with CH2Cl2 three times. The CH2Cl2 layers were
combined, dried over MgSO4, concentrated, and purified over
silica gel (15% EtOAc in hexanes to 25% EtOAc in hexanes),
which yielded 6.68 g (70% yield) of 3 as a white solid, which is
a mixture of diastereomers: 1H NMR (500 MHz, CDCl3) δ 7.57-
7.54 (m, 4H), 7.38-7.34 (m, 4H), 7.32-7.20 (m, 12H), 4.69-4.64
(m, 1H), 4.61-4.56 (m, 1H), 4.21-4.14 (m, 4H), 3.31-3.26 (m,
2H), 3.23-3.14 (m, 2H), 3.11-3.05 (m, 3H), 3.00-2.91 (m, 3H),
2.75-2.71 (m, 2H), 2.50-2.42 (m, 2H), 1.17 (d, J ) 5.5-6.5 Hz,
3H), 1.16 (d, J ) 5.5-6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.94, 171.90, 153.34, 153.29, 135.23, 132.72, 132.56, 129.37,
129.04, 128.94, 127.40, 127.32, 126.77, 126.72, 66.16, 66.09,
55.12, 55.08, 41.84, 41.56, 37.90, 35.47, 35.41, 30.35, 30.11, 20.30;
IR (neat) 2961, 1780, 1698; HRMS calcd for C21H23NO3Se (M +
Na) 440.0741, found (FAB, M + Na) 440.0756. Anal. Calcd for
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were measured
in CDCl3 using the solvent resonance as an internal standard
(7.26 ppm for 1H and 77.0 for 13C). Mass spectral data were
obtained at the Scripps Research Institute Mass Spectrometry
Facility. THF was distilled over sodium metal under an atmo-
sphere of argon. All glassware was evacuated, flame-dried, and
flushed with argon prior to use. Commercially available com-
pounds were used without further purification. Chromatography
was performed using 230-400 mesh silica gel and HPLC-grade
solvents. TLC plates were stained with either ceric ammonium
molybdate, potassium permanganate or ninhydrin solutions.
3-Meth yl-4-(ph en ylselen o)bu tan oic Acid (2). Sodium boro-
hydride (2.96 g, 77.8 mmol, 2.0 equiv) was added to a flame-
dried two-neck 500-mL round-bottom flask equipped with a
reflux condenser, stir bar, and septum. The flask was evacuated
and purged with argon. Diphenyl diselenide (9.70 g, 31.1 mmol,
0.8 equiv) was added as a solution in 250 mL of DMF via cannula
under argon and stirred at room temperature for 10 min. The
DMF was rigorously degassed using the freeze-pump-thaw
technique. The yellow diphenyldiselenide solution immediately
cleared upon contact with NaBH4. A solution of (()-3-methyl-
γ-butyrolactone (1)17 (3.89 g, 38.9 mmol, 1.0 equiv) in 10 mL of
degassed DMF was added via syringe. The resultant solution
was heated to 120 °C for 4 h and then cooled to room temper-
ature, diluted with 200 mL ether, and washed with 250 mL of
1 N aqueous HCl. The layers were separated, and the aqueous
layer was extracted with ether twice. The organic layers were
combined, dried over MgSO4, and concentrated. Purification over
C
21H23NO3Se: C, 60.57; H, 5.57; N, 3.36. Found: C, 60.87; H,
5.82; N, 3.34.
2-(S)-3-(R,S)-4(S)-3-[2-Azid o-3-m eth yl-4-(p h en ylselen o)-
bu ta n oyl]-4-ben zyl-1,3-oxa zolid in -2-on e (4). A solution of
KHMDS (34.2 mL of a 0.48 M solution in toluene, 16.4 mmol,
1.1 equiv) was added to a flame-dried 500-mL flask containing
50 mL of THF under argon and cooled to -78 °C. A solution of
3 (6.20 g, 14.9 mmol, 1.0 equiv) in 35 mL of THF cooled to -78
°C was added to the KHMDS solution via cannula, and the
reaction was stirred at -78 °C for 40 min. A solution of trisyl
azide (5.55 g, 17.9 mmol, 1.2 equiv) in 50 mL of THF that was
precooled to -78 °C was added via cannula. This addition
process took approximately 3 min. The reaction was allowed to
stir for an additional 1 min, and then acetic acid (3.80 mL, 67.1
mmol, 4.5 equiv) was added via syringe. The reaction was
allowed to warm slowly from -78 °C, and once it had reached
-30 °C, potassium acetate (4.40 g, 44.7 mmol, 3 equiv) was
added and the reaction was allowed to slowly warm to room
temperature overnight. The reaction solution was filtered over
Celite, rinsed with Et2O, and washed with 0.1 N aqueous HCl.
The layers were separated, and the aqueous layer was extracted
with Et2O three times. The organic layers were combined, dried
over MgSO4, concentrated, and purified over silica gel (4:1
hexanes/CH2Cl2 with 4% Et2O to 4:1 hexanes/CH2Cl2 with 10%
Et2O) to yield 5.46 g of the desired product 4 as a yellow oil
(80%), which is a mixture of diastereomers: 1H NMR (500 MHz,
CDCl3) δ 7.53-7.49 (m, 4H), 7.37-7.19 (m, 16H), 5.28 (d, J )
6.0 Hz, 1H), 5.16 (d, J ) 6.5 Hz, 1H), 4.59-4.53 (m, 2H), 4.21-
4.08 (m, 4H), 3.32-3.27 (m, 2H), 3.22-3.19 (m, 1H), 3.13-3.09
(23) Sugawara, N.; Stevens, E. S.; Bonora, G. M.; Toniolo, C. J . Am.
Chem. Soc. 1980, 102, 7044.

Notes
J . Org. Chem., Vol. 64, No. 20, 1999 7673
(m, 1H), 2.97-2.93 (m, 1H), 2.86-2.81 (m, 2H), 2.78-2.73 (m,
1H) 2.43-2.37 (m, 1H), 2.33-2.27 (m, 1H), 1.18 (d, J ) 6.5 Hz,
3H), 1.15 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
169.49, 169.20, 152.78, 152.57, 134.65, 133.12, 132.56, 130.09,
129.40, 129.38, 129.13, 129.10, 129.04, 127.55, 127.52, 127.21,
126.92, 66.55, 66.49, 64.75, 64.58, 55.53, 55.50, 37.54, 37.48,
36.84, 35.91, 32.36, 30.69, 17.38, 15.44; IR (neat) 2973, 2107,
1781, 1700; HRMS calcd for C21H22N4O3Se (M + Na) 481.0755,
found (FAB, M + Na) 481.0765. Anal. Calcd for C21H22N4O3Se:
C, 55.15, H, 4.85, N, 12.25. Found: C, 55.26; H, 4.76; N, 12.26.
2-(S)-3-(R,S)-2-Azid o-3-m et h yl-4-(p h en ylselen o)b u t a n -
oic Acid (5). To a solution of 4 (2.68 g, 5.86 mmol, 1.0 equiv) in
44 mL of THF at 0 °C was added a 1.0 M solution of LiOH (14.7
mL, 14.7 mmol, 2.5 equiv) in H2O precooled to 0 °C. The reaction
was stirred for 30 min at 0 °C and then diluted with 75 mL of
CH2Cl2 and washed with 100 mL of brine. The aqueous layer
was extracted with CH2Cl2 three times. The pH of the aqueous
layer was adjusted from pH 14 to pH 2 using a pH 2.4 aqueous
phosphate buffer and 1 N HCl, which caused a white precipitate
to form. The aqueous layer was again extracted with CH2Cl2
four times and temporarily set aside. The initial three CH2Cl2
extracts were combined and washed with 1:1 0.1 N NaOH/brine
twice. At this point, the CH2Cl2 layer was dried over MgSO4,
concentrated, and purified over silica gel (40% EtOAc in hexanes)
to yield 905 mg (87% recovery) of (S)-4-benzyl-2-oxazolidinone.
The NaOH/brine washings were acidified to pH 2, extracted with
CH2Cl2 three times, combined with the above four CH2Cl2
extracts, dried over MgSO4, concentrated, and purified over silica
gel (2% MeOH in CH2Cl2 to 8%MeOH in CH2Cl2) to provide 1.57
g of the desired product 4 as a yellow oil (90%), which is a
mixture of diastereomers: 1H NMR (400 MHz, CDCl3) δ 7.55-
7.43 (m, 4H), 7.30-7.25 (m, 6H), 4.63 (d, J ) 3.2 Hz, 1H), 4.10
(d, J ) 5.6 Hz, 1H), 3.12-3.08 (m, 1H), 2.95-2.81 (m, 3H), 2.32-
2.28 (m, 2H), 1.15 (d, J ) 6.8 Hz, 3H) 1.01 (d, J ) 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 175.69, 174.66, 133.15, 132.89,
129.62, 129.28, 129.20, 129.13, 127.45, 127.26, 66.15, 64.50,
36.32, 36.26, 32.02, 31.02, 16.89, 15.22; IR (neat) 2969, 2111,
1714; HRMS calcd for C11H13N3O2Se (M + Na) 322.0071, found
(FAB, M + Na) 322.0079.
2-(S)-3-(R,S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-m eth yl-
4-(p h en ylselen o)bu ta n oic Acid (6). Tin dichloride (1.9 g, 8.4
mmol, 2.5 equiv) was dissolved in a solution of 20 mL of dioxanes
and 7 mL of H2O in a 50-mL flask. The azide 5 (1.00 g, 3.36
mmol, 1.0 equiv) was added dropwise as a neat liquid, and the
solution was stirred at 0 °C for 1 h before warming to room
temperature and stirring for an additional 3.5 h. At this point,
an additional 760 mg (1.0 equiv) of SnCl2 was added and the
reaction stirred an additional 2.5 h, at which time NaOH was
added as a 2.0 M solution in H2O (23.5 mL, 47.0 mmol, 14 equiv)
followed by Boc anhydride (3.66 g, 16.8 mmol, 5 equiv) and
stirred 1 h at room temperature. The solution was acidified to
approximately pH 2.5 using pH -2.4 phosphate buffer and 1 N
HCl and extracted with EtOAc five times. The organic layers
were combined, dried over MgSO4, concentrated, and purified
over silica gel (1%MeOH in CH2Cl2, to 10%MeOH in CH2Cl2) to
yield 1.11 g of the desired product as a yellow oil (89%), which
is a mixture of diastereomers: 1H NMR (400 MHz, CD3OD) δ
7.52-7.48 (m, 4H), 7.27-7.22 (m, 6H), 4.52 (d, J ) 3.6 Hz, 1H),
4.26 (d, J ) 5.2 Hz, 1H), 3.09-3.05 (m, 1H), 2.96-2.91 (m, 1H),
2.82-2.76 (m, 2H), 2.30-2.20 (m, 1H), 2.20-2.10 (m, 1H), 1.44
(s, 9H), 1.43 (s, 9H), 1.05 (d, J ) 7.2 Hz, 3H), 0.97 (d, J ) 7.2
Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 175.32, 174.89, 158.35,
158.08, 133.85, 133.65, 131.58, 130.18, 128.03, 127.93, 80.62,
80.58, 59.14, 57.84, 37.72, 37.41, 32.95, 32.09, 28.70, 16.86, 15.43;
IR (neat) 3426, 1651; HRMS calcd for C16H23NO4Se (M + Na)
396.0690, found (FAB, M + Na) 396.0679.
hexanes to 30% Et2O in hexanes), yielding 1.0 g of the desired
methyl ester of 6 as a light yellow oil (95%), which is a mixture
of diastereomers: 1H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m,
4H), 7.29-7.25 (m, 6H), 5.10-5.05 (m, 2H), 4.69-4.67 (m, 1H),
4.44-4.41 (m, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.01-2.96 (m,2H),
2.76-2.67 (m, 2H), 2.31-2.21 (m, 1H), 2.21-2.15 (m, 1H), 1.45
(s, 9H), 1.44 (s, 9H), 1.07 (d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.56, 172.15, 155.67,
155.39, 132.88, 132.75, 130.32, 130.12, 129.07, 127.06, 126.94,
80.03, 57.64, 56.59, 52.36, 52.17, 37.42, 36.93, 32.13, 31.15, 28.27,
16.60, 15.04; IR (neat) 3349, 2975, 1747, 1714; HRMS calcd for
C17H25NO4Se (M + Na) 410.0846, found (FAB, M + Na)
410.0832. Anal. Calcd for C17H25NO4Se: C, 52.85;, H, 6.52; N,
3.63. Found: C, 52.73; H, 6.49; N, 3.63.
2-(S)-Meth yl 2-[(ter t-Bu toxyca r bon yl)a m in o]-3-m eth yl-
3-bu ten oa te (7). To a solution of the methyl ester of 6 (30.0
mg, 0.078 mmol, 1.0 equiv) in 800 µL of distilled CCl4 was added
pyridine (13 µL, 0.16 mmol, 2.0 equiv, distilled over CaH2)
followed by tert-butyl hydroperoxide (47 µL of a 5 M solution in
anhydrous decane, 0.23 mmol, 3.0 equiv). This solution was
stirred at room temperature under an argon atmosphere for 3
h before an additional 78 µL of tert-butyl hydroperoxide (5 M in
anhydrous decane, 0.39 mmol, 5.0 equiv) was added, and the
reaction was allowed to stir for an additional 10 h at room
temperature under argon. At this point, 1.6 mL of distilled CCl4
was added followed by diethylamine (32 µL, 0.31 mmol, 4.0
equiv, distilled over CaH2), and the solution was heated to 50
°C for 4 h. The reaction solution was cooled, solid sodium sulfite
(98 mg, 0.78 mmol, 10 equiv) was added, and the mixture was
stirred vigorously for 5 min and then diluted with CH2Cl2 and
washed with saturated aqueous NaHCO3. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
three times. The organic layers were combined, dried over
Na2SO4, concentrated, and purified over silica gel (5% Et2O in
hexanes to 15% Et2O in hexanes) to yield 17 mg of the desired
product 7 as a clear oil (93%): 1H NMR (400 MHz, CDCl3) δ
5.33 (m, 1H), 5.06 (s, 1H), 5.01 (s, 1H), 4.76 (d, J ) 7.6 Hz, 1H),
3.76 (s, 3H), 1.77 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) ? 171.35, 154.86, 140.36, 114.86, 80.02, 58.93, 52.58,
28.29, 19.35; IR (neat) 3378, 2979, 1746, 1715; HRMS calcd for
C11H19NO4 (M + Na) 252.1212, found (FAB, M + Na) 252.1219.
2-(S)-Meth yl 2-[(ter t-Bu toxyca r bon yl)a m in o]-3-m eth yl-
bu ta n oa te. (8) A heterogeneous mixture of 7 (14 mg, 0.061
mmol) and 2 mg of 10% Pd/C in 1.0 mL of EtOAc was stirred
under a balloon of H2 for 3 h at room temperature. The solution
was filtered over Celite to remove the catalyst, rinsed with Et2O,
and concentrated to yield 10 mg (71%) of the desired amino acid
8 as a clear oil: 1H NMR (500 MHz, CDCl3) δ 5.02 (d, J ) 8.0
Hz, 1H), 4.22 (dd, J ) 9.0, 4.5 Hz, 1H), 3.73 (s, 3H), 2.12 (m,
1H), 1.44 (s, 9h), 0.95 (d, J ) 6.5 Hz, 3H), 0.88 (d, J ) 6.5 Hz,
3H); [R]23 -20.0° (c 1.0, CH3OH) (lit.23 [R]21 -21.2° (c 1.1,
D
D
CH3OH)).
Meth yl 2-(S)-Azido-3-(3-[2-(S)-((2-(S)-[(ter t-bu toxycar bon -
yl)am in o]-3-m eth yl-3-bu ten oyl)am in o]-1-(R)-eth yl-3-(m eth -
oxym et h oxy)-1-m et h ylp r op oxy]-4-[[ter t-b u t yl(d im et h yl)-
silyl]oxy]p h en yl)-3-(S)-[[ter t-bu tyl(d im eth yl)silyl]oxy]p r o-
p a n oa te. (10) To a solution of 9 (152 mg, 0.153 mmol, 1.0 equiv)
in 1.5 mL of distilled CCl4 was added pyridine (25.0 µL, 0.306
mmol, 2.0 equiv, freshly distilled over CaH2) followed by tert-
butyl hydroperoxide (92 µL of a 5 M solution in anhydrous
decane, 0.46 mmol, 3.0 equiv) and the mixture stirred at room
temperature under an argon atmosphere. After 3 h, an ad-
ditional 154 µL of tert-butyl hydroperoxide (5 M solution in
anhydrous decane, 0.77 mmol, 5.0 equiv) was added and the
mixture stirred an additional 10 h at room temperature under
argon. At this time, 3.0 mL of distilled CCl4 was added followed
by diethylamine (79 µL, 0.77 mmol, 5 equiv, freshly distilled over
CaH2) and the mixutre heated to 50 °C for 10 h. The reaction
solution was cooled, solid Na2SO4 (193 mg, 1.53 mmol, 10 equiv)
was added, and the mixture was stirred vigorously for 5 min.
The reaction solution was diluted with CH2Cl2 and washed with
saturated aqueous NaHCO3. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 three times. The
organic layers were combined, dried over Na2SO4, concentrated,
and purified over silica gel (30% Et2O in hexanes to 35% Et2O
in hexanes) to yield 106 mg of the desired product 10 as a clear
oil (83%): 1H NMR (500 MHz, CDCl3) δ 6.96-6.94 (m, 2H), 6.84
2-(S)-3-(R,S)-Meth yl 2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
m eth yl-4-(p h en ylselen o)bu ta n oa te. A solution of 6 (1.02 g,
2.74 mmol, 1.0 equiv) in 20 mL of Et2O was treated with CH2N2
generated by decomposing Diazald (1.17 g, 5.48 mmol, 2.0 equiv)
in a solution of KOH (307 mg, 5.48 mmol, 2.0 equiv) in 450 mL
of EtOH and 50 mL of Et2O and bubbling the generated CH2N2
gas into the Et2O solution using fire-polished glass tubing. When
TLC showed complete consumption of the starting material (2
h), argon gas was bubbled through the Et2O solution for 30 min,
and then the ether was removed under reduced pressure and
the resulting residue was purified over silica gel (20% Et2O in

7674 J . Org. Chem., Vol. 64, No. 20, 1999
Notes
(d, J ) 6.0 Hz, 1H), 6.27 (d, J ) 9.5 Hz, 1H), 5.80 (d, J ) 4.5 Hz,
1H), 5.20 (s, 1H), 5.05 (s, 1H), 4.83 (d, J ) 8.0 Hz, 1H), 4.67-
4.64 (m, 1H), 4.65 (d, J ) 6.5 Hz, 1H), 4.58 (d, J ) 6.5 Hz, 1H),
4.45-4.39 (m, 1H), 3.97-3.94 (m, 1H), 3.94 (d, J ) 7.5 Hz, 1H),
3.77 (s, 3H), 3.77-3.74 (m, 1H),3.35 (s, 3H), 1.87-1.81 (m, 1H),
1.71 (s, 3H), 1.69-1.63 (m, 1H), 1.44 (s, 9H), 1.24 (s, 3H), 0.96
(s, 9H), 0.86 (t, J ) 7.0 Hz, 3H), 0.83 (s, 9H), 0.24 (s, 3H), 0.23
(s, 3H), 0.02 (s, 3H), -0.20 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.75, 155.83, 150.53, 145.71, 143.39, 133.54, 125.16, 123.46,
121.69, 116.73, 97.04, 86.41, 80.27, 75.69, 69.15, 67.49, 61.49,
56.01, 54.40, 53.16, 42.98, 31.73, 29.07, 26.70, 26.23, 21.56, 19.36,
18.65, 9.92, -3.03, -3.92, -4.69; IR (neat) 3330, 2932, 2112,
1755, 1719, 1682; HRMS calcd for C40H71N5O10Si2 (M + Cs)
970.3794, found (FAB, M + Cs) 970.3768.
Ack n ow led gm en t. Support has been provided by
the NIH (CA-77317), the Beckman Foundation, and
Pharmacia & Upjohn. For predoctoral fellowships,
T.F.W. acknowledges the NSF and the ACS Division of
Organic Chemistry (sponsored by Hoechst Marion
Roussel).
J O990916S