Synthetic Elaboration of the Side Chain of (R)-2,2-Dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine: A New Regio- And Stereoselective Strategy to δ-Functionalized β-Amino Alcohols

Article abstract of DOI:10.1021/jo970619s

An investigation of the reactivity of ethynyloxazolidine 2 is presented. Functionalization at the acetylenic position has been found to occur very easily using the mild Sonogashira conditions. Addition of tributyltin cuprate 1 provided the corresponding stannylated (E)-ethenyloxazolidine 3, a new chiral building block which has been reacted with electrophiles under Pd catalysis. The reaction sequence occurred without racemization and showed an easy and mild procedure for the regio- and stereoselective synthesis of unsaturated amino alcohols.

Full text of DOI:10.1021/jo970619s

J . Org. Chem. 1997, 62, 6187-6192
6187
Syn th etic Ela bor a tion of th e Sid e Ch a in of
(R)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-eth yn yloxa zolid in e: A
New Regio- a n d Ster eoselective Str a tegy to δ-F u n ction a lized
â-Am in o Alcoh ols
Gianna Reginato,* Alessandro Mordini, and Massimo Caracciolo
Dipartimento di Chimica Organica “U. Schiff”, Centro CNR Composti Eterociclici, via G. Capponi 9,
I-50121 Firenze, Italy
Received April 7, 1997X
An investigation of the reactivity of ethynyloxazolidine 2 is presented. Functionalization at the
acetylenic position has been found to occur very easily using the mild Sonogashira conditions.
Addition of tributyltin cuprate 1 provided the corresponding stannylated (E)-ethenyloxazolidine 3,
a new chiral building block which has been reacted with electrophiles under Pd catalysis. The
reaction sequence occurred without racemization and showed an easy and mild procedure for the
regio- and stereoselective synthesis of unsaturated amino alcohols.
Sch em e 1
In tr od u ction
Addition of (tributylstannyl)cuprate 11 to substituted
alkynes is a very powerful method for preparing geo-
metrically defined trisubstituted alkenes.2 The utility of
this tin-based “dimetallic reagent”, besides its high
chemoselectivity, lies in the generation, after addition on
terminal alkynes, of two stereo- and regiodefined vinyl
organometallics which can be reacted stepwise with
different electrophiles. Being interested in investigating
the synthetic utility of this type of reaction,3 we directed
our efforts toward finding new simple acetylenic sub-
strates, focusing our attention particularly on the syn-
thesis of some new, highly functionalized unsaturated
nitrogen compounds.4,5 For example, we showed that
t-Boc-protected chiral propargylic amines can be consid-
ered as very useful reagents for stannylcuprate addition.6
These compounds, which were easily obtained with high
enantiomeric purity from naturally occurring amino
acids, reacted selectively with 1 to afford the correspond-
ing 2-substituted γ-stannylated allylic amines. Coupling
these stannylated amines with electrophiles under Pd
catalysis provided a new mild and stereocontrolled
procedure to chiral γ-substituted (E)-allylic amines, a
class of compounds which proved to be useful intermedi-
ates in the synthesis of conformationally restricted pep-
tide isosters.7
2 as a useful substrate to synthesize vinylstannane 3
through stannylcupration. Because such oxazolidine
moieties are widely employed as synthetic equivalents
of R-amino acids,8 compound 3 could be an interesting
intermediate to be used in the stereoselective synthesis
of nonnatural amino acids.
The first synthesis of compound 2, using naturally
occurring serine as the chiral starting material, was
recently reported by Meffre.9 Its use as a direct precursor
to optically active alkynylglycine derivatives was shown.
We recently published10 an alternative procedure to
compound 2, based on a modification11 of the well-known
Corey and Fuchs12 aldehyde-to-alkyne omologation
method, and pointed out the possibility to achieve a new
class of substituted alkynes through different pathways.
Here we report the full experimental details on the
synthesis of compound 2 and related γ-functionalized
derivatives. Its reactivity with (tributylstannyl)cuprate
is also studied with the aim of preparing stannyl oxazo-
lidine 3. The potentiality of 3 as a chiral building block
for the synthesis of δ-substituted â-amino alcohols will
also be exploited.
Attempting to extend this methodology toward more
functionalized systems, we envisaged ethynyloxazolidine
* Corresponding author: phone, +39 55 2757609; fAX, +39 55
2476964; e-mail, reginato@cesce.fi.cnr.it.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D. C.
Tetrahedron Lett. 1989, 30, 2065.
(2) Lipshutz, B. H. In Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press:
Oxford, 1955; Vol. 12, pp 59-125.
(3) Ricci, A.; Reginato, G.; Degl'Innocenti, A.; Seconi, G. Pure Appl.
Chem. 1992, 64, 439.
(4) Capella, L.; Degl'Innocenti, A.; Mordini, A.; Reginato, G.; Ricci,
A.; Seconi, G. Synthesis 1991, 1201.
(5) Reginato, G.; Capperucci, A.; Degl’Innocenti, A.; Mordini, A.;
Pecchi, S. Tetrahedron 1995, 51, 2129.
(8) (a) Williams, R. M. Synthesis of Optically Active R-Aminoacids;
Pergamon Press: New York, 1989; Vol. 7. (b) Muller, M.; Mann, A.;
Taddei, M. Tetrahedron Lett. 1993, 34, 3289.
(6) Reginato, G.; Mordini, A.; Messina, F.; Degl’Innocenti, A.; Poli,
G. Tetrahedron 1996, 52, 10985.
(9) Meffre, P.; Gauzy, L.; Perdigues, C.; Desanges-Leveque, F.;
Branquet, E.; Durand, P.; Le Goffic, F. Tetrahedron Lett. 1995, 36,
877.
(10) Reginato, G.; Mordini, A.; Degl'Innocenti, A.; Caracciolo, M.
Tetrahedron Lett. 1995, 36, 8275.
(11) Grandjean, D.; Pale, P.; Chuche, J . Tetrahedron Lett. 1994, 35,
3529.
(12) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 12, 3769.
(7) (a) Thompson, W. J .; Tucker, T. J .; Schwering, J . E.; Barnes, J .
L. Tetrahedron Lett. 1990, 32, 6819. (b) Kempf, D. J .; Wang, X. C.;
Spanton, S. G. Int. J . Pept. Protein Res. 1991, 38, 237. (c) Bol, K. M.;
Liskamp, R. M. J . Tetrahedron 1992, 48, 6425. (d) J enmalm, A.; Berts,
W.; Li, Y. L.; Luthman, K.; Csoregh, I.; Hacksell, U. J . Org. Chem.
1994, 59, 1139.
S0022-3263(97)00619-1 CCC: $14.00 © 1997 American Chemical Society

6188 J . Org. Chem., Vol. 62, No. 18, 1997
Reginato et al.
Sch em e 2
Sch em e 3
Sch em e 4
Resu lts a n d Discu ssion
Syn th esis of Com p ou n d 2 a n d Its Der iva tives.
Compound 2 was prepared using naturally occurring
serine as the chiral starting material. The amino acid
was transformed into the corresponding aldehyde 4
following the well-known procedure described by Gar-
ner.13 The recently proposed reduction-oxidation se-
quence14,15 can be alternatively followed to obtain good
yields of the desired aldehyde which can be directly used,
for our purposes, without any further purification. The
synthesis of 5 has been described using the Corey-Fuchs
conditions.16 The modified procedure we used, in the
presence of Et3N at low temperature,11 provided an
efficient transformation to 5 which was easily isolated
in 79% yield.
found to be clearly distinguishable and showed no
contamination from racemized material.
We then examined the possibility of introducing new
functional groups to the terminal position of the lateral
chain of the oxazolidine ring. Three different pathways
were considered as outlined in Scheme 3.
Intermediate 5 was quantitatively dehydrohalogenated
in the presence of sodium bis(hexamethyldisilylamide)
(NAHMDS) to the corresponding (bromoethynyl)oxazo-
lidine derivative 7a . Conversion into 2 was accomplished
simply by treating with 2 equiv of BuLi at -78 °C.12 The
whole reaction sequence from 4 to 2 could also be
performed without isolation of 5 in 74% yield after
purification. Variable amounts of enamine 6a were
always formed in this transformation. The same result
was also observed17 when compound 2 was treated with
BuLi. However, using our conditions, this byproduct was
present in very small amounts (lower than 10%) and
became predominant only when a large excess of base
was used for prolonged reaction times.
The enantiomeric purity of compound 2 was estab-
lished by 1H-NMR analysis of the diastereomeric Mosher
amides.18 These were prepared by reaction of both (R)-
(-)- and (S)-(+)-R-methoxy-R-(trifluoromethyl)phenylace-
tic acid chloride (MTPACl) with the amino alcohol
obtained by deprotection of 2 with Amberlist in MeOH/
H2O at room temperature. The two diastereomers were
In the first two cases, a direct introduction of substit-
uents on the triple bond was considered in order to obtain
the corresponding ethynyloxazolidine derivatives 7 or 8.
Alternatively, the synthesis of (E)-ethenyloxazolidine
derivatives 9 was accomplished through the correspond-
ing γ-stannylated intermediate 3, via a palladium-
catalyzed Stille coupling.19
It was already shown that the introduction of new
functional groups at the terminal position in propargyl
aminic systems can be easily achieved through metala-
tion and further reaction with electrophiles.20 The same
approach was successfully applied in the alkylation and
silylation of compound 2;17 therefore, we tried to extend
this procedure to a wider series of electrophiles. Unfor-
tunately, as shown in Scheme 4, discouraging results
were obtained. When acetyl chloride was used, for
example, the desired product 7b was formed only in low
yield. Conversely, with more reactive electrophiles like
methyl chloroformate or methoxymethyl chloride, the
starting material was completely transformed to 7c,d ;
however, in both cases variable amounts of byproducts
6c,d were recovered.
(13) Garner, P.; Park, J . M. Org. Synth. 1991, 70, 18.
(14) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem. 1995, 60,
8074.
(15) Roush, W. R.; Hunt, J . A. J . Org. Chem. 1995, 60, 798.
(16) Chung, J . Y. L.; Wasicak, J . T. Tetrahedron Lett. 1990, 31,
3957.
In order to circumvent this problem, we decided to turn
to a milder procedure, taking into consideration the
(17) Meffre, P.; Gauzy, L.; Branquet, E.; Durand, P.; LeGoffic, F.
Tetrahedron 1996, 52, 11215.
(18) Dole, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(19) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(20) Corriu, R. J . P.; Huynh, V.; Moreau, J . J . E. Tetrahedron Lett.
1984, 25, 1887.

New Strategy to δ-Functionalized â-Amino Alcohols
J . Org. Chem., Vol. 62, No. 18, 1997 6189
Sch em e 5
Sch em e 7
Sch em e 6
of the crude mixture. The 19.4 Hz coupling we measured
for the vinyl protons in the 1H-NMR spectrum was in
good agreement for the assigned E-geometry of 3.4
As we have previously mentioned, the main feature of
this reaction is that it can provide,4 through the bis-
metallic intermediate adduct 10, an efficient entry to the
stepwise â,γ-substitution of the lateral chain. This was
demonstrated by reacting 3 with several electrophiles
which resulted in a new series of γ-substituted (E)-
ethenyloxazolidines (9a -e). Iododestannylation was per-
formed first, and iodo derivative 9a was obtained selec-
tively with high yield. Aryl and vinyl halides as well as
anisoyl chloride and cinnamyl acetate were then used
following the well-known Pd-catalyzed procedure de-
scribed by Stille.19 Experimental details and results are
reported in Scheme 7.
Sonogashira21 copper-palladium-catalyzed coupling of
terminal alkynes with aromatic halides. This reaction
is known22 to be efficient, high yielding, and tolerant of
a wide range of functional groups which might allow us
to insert on the lateral chain consisting of a large variety
of differently substituted aromatic rings. This could be
very useful, for example, if our sequence had to be
employed to investigate structure-activity relationships
within a series of compounds. Our results are reported
in Scheme 5.
We attempted this simple procedure with three differ-
ent electrophiles. In all cases a clean reaction was
observed and the corresponding coupled products 8a -c
were isolated after chromatography with satisfactory
yields.
In each case the reaction proceeded with retention of
configuration with respect to the vinyl-tin bond, as
1
confirmed by H-NMR analysis, and the corresponding
cross-coupled products were obtained and isolated in good
yields. Since stannylcupration and Stille coupling condi-
tions have already proved6,23 not to alter the enantiomeric
excesses in chiral compounds, we can conclude that this
mild method can be widely used for obtaining chiral
ethenyloxazolidines with a predictable E-geometry.
Cleavage of the oxazolidine ring was tested on com-
pounds 9b,d . The best reaction conditions were found
using PTSA in wet methanol at room temperature.
Amino alcohols 12b,d were obtained in satisfactory
yields. Conveniently deprotection can be carried out
avoiding purification of oxazolidine 9 as we proved in the
case of 9b, from which 12b was obtained in 71% overall
yield from 3.
Sta n n ylcu p r a tion of 2 a n d Som e Syn th etic Ap -
p lica tion s of Vin ylsta n n a n e 3. (Tributylstannyl)cy-
anocuprate 11 was found to add efficiently to compound
2 at low temperature, affording the corresponding γ-stan-
nylated (E)-ethenyloxazolidine 3 in a regio- and stereo-
selective manner. Remarkably, the opposite regioisomer
1
11 was not detected as determined by H-NMR analysis
Amino alcohols of type 12 are of interest as unnatural
(not coded) amino acids precursors. A limitation to their
use results in the lack of oxidative methods compatible
with the presence of unsaturations on the backbone. It
(21) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(22) Campbell, I. B. In Organocopper Chemistry. A Practical Ap-
proach; Taylor, R. J . K., Ed.; Oxford University Press: New York, 1994;
pp 217-235.
(23) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 59, 3213.

6190 J . Org. Chem., Vol. 62, No. 18, 1997
Reginato et al.
when possible. Mass spectra were obtained at a 70 eV
ionization potential and are reported in the form m/ z (inten-
sity relative to base ) 100). Organotin fragments are given
for 120Sn. Polarimetric measurements were performed in
CHCl3 solution at λ ) 589 nm, and the temperature is specified
case by case. IR spectra were recorded in CCl4 solution.
Ma ter ia ls. Garner aldehyde 4 was prepared according to
the literature.13 Starting materials are commercially available
unless otherwise stated. All commercial reagents were used
without further purification except TMSCl which was distilled
over quinoline. THF was dried by distillation over sodium
benzophenone ketyl. CH2Cl2 was purified by the standard
procedure, dried over CaCl2, and stored over 4-Å molecular
sieves. Toluene was distilled over sodium wire and stored over
4-Å molecular sieves. DMF was distilled over CaCl2 and stored
over 4-Å molecular sieves. Petroleum ether, unless specified,
is the 40-70 °C boiling fraction.
Sch em e 8
Sch em e 9
(R)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-(2,2-d ibr o-
m oeth en yl)oxa zolid in e (5). CBr4 (5.98 g, 18.0 mmol) was
dissolved in CH2Cl2 (120 mL) and cooled at -20 °C. A solution
of PPh3 (4.67 g, 17.8 mmol) in CH2Cl2 (250 mL) was added,
and the mixture was stirred for 30 min and then cooled to -60
°C. A solution of 4 (2.12 g, 9.0 mmol) and Et3N (12.5 g, 8.9
mmol) in CH2Cl2 (100 mL) was added, and the mixture was
kept at -60 °C for 30 min, then warmed at rt, and stirred
overnight. The solution was diluted with pentane and filtered,
the solvent evaporated, and the crude residue chromato-
graphed on SiO2 (CH2Cl2), affording 2.73 g (79%) of (R)-516 as
a white solid: mp 55-56 °C; 1H-NMR (300 MHz, 50 °C) δ 6.46
(d, J ) 8.1 Hz, 1H), 4.59-4.44 (m, 1H), 4.10 (dd, J ) 6.6, 9.3
Hz, 1H), 3.78 (dd, J ) 9.3, 2.7 Hz, 1H), 1.60 (s, 3H), 1.52 (s,
3H), 1.48 (s, 9H); 13C-NMR (50.3 MHz) δ 151.7, 138.5, 94.5,
89.9, 80.4, 67.3, 59.5, 28.5, 26.3, 23.9; MS m/ z 312/314/316
(10/19/10), 57 (100); [R]20D ) +18 (c 0.94, CHCl3). Anal. Calcd
for C12H19NO3Br2: C, 37.43; H, 4.97; N, 3.64. Found: C, 37.87;
H, 5.04; N, 3.67.
was already shown,24 for example, that aromatic alcohol
12b can not be oxidized to the corresponding vinylglycine
derivative. Nevertheless, we thought that amino alcohols
12 could be interesting substrates for the preparation of
saturated amino acids, as we proved in the case of 12b.
Catalytic hydrogenation to saturated 13 was performed,
and subsequent oxidation using J ones’ conditions af-
forded t-Boc-homophenylalanine (14) with good optical
purity [R]25 ) +4.9 (c 0.9, EtOH) [lit.25 [R]D ) +5.9 (c
D
1.4, EtOH)].
(S)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-(2,2-d ibr o-
m oeth en yl)oxa zolid in e (5). (R)-4 (123 mg, 0.5 mmol) was
reacted to afford 154 mg (83%) of (S)-5: [R]20 ) -19 (c 0.92,
Con clu sion s
D
CHCl3).
We have developed a novel procedure for the prepara-
tion of ethynyloxazolidine 2 and investigated some
synthetic elaborations on the lateral chain which deliv-
ered the final products in essentially enantiomerically
pure form. In particular, vinylstannane 3 has been
highlighted as an interesting building block which,
hopefully, can be used in the synthesis of molecules of
biological and pharmaceutical interest.
(R)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-eth yn ylox-
a zolid in e (2). A solution of 5 (1.03 g, 2.7 mmol) in THF (20
mL) was cooled at -78 °C, and BuLi (3.4 mL, 5.4 mmol) was
added dropwise. After 30 min the mixture was heated to -15
°C, stirred for a further 15 min, and then quenched with NaOH
(0.01 M). After extraction, drying, and evaporation of the
solvent, 614 mg of crude material was obtained which, after
flash chromatography (CH2Cl2), afforded 482 mg (79%) of 2
as a colorless oil and 26 mg (5%) of 6a . (R)-2:10 [R]20D ) -73.5
(c ) 1.01, CHCl3) [lit.17 [R]20 ) -96.5 (c 1.23, CHCl3)]. 6a :
D
Exp er im en ta l Section
1H-NMR (200 MHz) δ 6.00 (bs, 1H), 5.78 (s, 1H), 5.01 (s, 1H),
2.85 (s, 1H), 1.45 (s, 9H); 13C-NMR (50.3 MHz) δ 152.2, 123.0,
106.3, 80.8, 80.2, 75.4, 28.2; MS m/z 167 (2), 57 (100); IR (film)
3310.
Gen er a l. All reactions were carried out under a positive
pressure of dry nitrogen. Ethereal extracts were dried with
Na2SO4. The temperature of dry ice-ether baths is indicated
as -100 °C, that of dry ice-ethanol as -78 °C, and that of
ice-NaCl as -15 °C. Reactions were monitored by TLC on
SiO2; detection was made using a KMnO4 basic solution. Flash
column chromatography26 was performed using glass columns
(10-50 mm wide) and SiO2 (230-400 mesh). 1H-NMR spectra
were recorded at 200 or 300 MHz. 13C-NMR spectra were
recorded at 50.3 MHz. Chemical shifts were determined
relative to the residual solvent peak (CHCl3, δ 7.26 for 1H-
NMR; CHCl3, δ 77.0 for 13C-NMR). Coupling constants (J ) are
reported in Hz. Multiplicities are indicated as s (singlet), d
(doublet), t (triplet), q (quartet), dd (doublet of a doublet), m
(multiplet), bs (broad singlet), bt (broad triplet), and bq (broad
quartet). For those compounds which are present as slowly
interconverting rotamers, NMR experiments were performed
at 50 °C and signals of the averaged spectrum are reported
(S)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-eth yn ylox-
a zolid in e (2). (R)-Dibromide 5 (97 mg, 0.25 mmol) was
reacted to afford 47 mg (58%) of (S)-2: [R]20 ) +75 (c 1.03,
D
CHCl3).
Syn th esis of th e Mosh er ’s Ester s of Dep r otected 2.
Compound 2 (104 mg, 0.5 mmol) was dissolved in MeOH/H2O
(10/1, 3 mL) together with 600 mg of Amberlist IR-120 (PLUS)
and stirred at rt for 20 h. After filtration the resin was washed
several times with MeOH. Evaporation of MeOH afforded 79
mg of crude material. After chromatography (petroleum ether/
ethyl acetate: 3/1) 56 mg (65%) of (R)-2a 10,17 was recovered:
[R]22 ) -32.5 (c 1.20, CHCl3) [lit.17 [R]20 ) -43 (c 1.08,
D
D
CHCl3)].
Anhydrous pyridine (0.300 mL), CCl4 (0.500 mL), and (S)-
MTPA chloride (50 mg, 0.20 mmol) were mixed together and
reacted at rt for 1 h with 25 mg (0.1 mmol) of (R)-2a . After
workup the residue was analyzed by 1H-NMR and showed the
presence of the 1S,2R-derivative with ee > 95%. The reaction
was repeated with (R)-MTPA chloride affording the 1R,2R-
diastereomer with ee > 95%. The two diastereoisomers were
purified by chromatography (petroleum ether/ethyl acetate:
3/1).
(24) Beaulieau, P. L.; Duceppe, J . S.; J ohnson, C. J . Org. Chem.
1991, 56, 4196.
(25) J ackson, R. F. W.; Wishart, N.; Wood, A.; J ames, K.; Wythes,
M. J . J . Org. Chem. 1992, 57, 3397.
(26) Still, W. C.; Kahn, M. K.; Mitra, A. J . Org. Chem. 1978, 43,
293.

New Strategy to δ-Functionalized â-Amino Alcohols
J . Org. Chem., Vol. 62, No. 18, 1997 6191
(1S ,2R )-2-[(t er t -Bu t oxyca r b on yl)a m in o]b u t -3-yn yl
1-m et h oxy-1-(t r iflu or om et h yl)p h en yla cet a t e: 1H-NMR
(200 MHz) δ 3.59 (q, J ) 1.6 Hz, 3H); MS m/z 189 (100), 57
(63); ee > 95%.
(1R ,2R )-2-[(t er t -Bu t oxyca r b on yl)a m in o]b u t -3-yn yl
1-m eth oxy-1-(tr iflu or om eth yl)ph en ylacetate: 1H-NMR (200
MHz) δ 3.56 (q, J ) 1.4 Hz, 3H); MS m/z 189 (100), 57 (98); ee
> 95%.
(R)-2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-4-[(p -n it r o-
p h en yl)eth yn yl]oxa zolid in e (8a ). 4-Nitroiodobenzene (44
mg, 0.2 mmol) was stirred with a solution of 2 (46 mg, 0.2
mmol) in Et2NH (2 mL) at rt for 4 h. After workup 76 mg of
crude material was obtained. Purification (petroleum ether/
ethyl acetate: 5/1) afforded 41 mg (67%) of 8a as a yellow,
low-melting solid: 1H-NMR (200 MHz) δ 8.16 (bd, J ) 8.6 Hz,
2H), 7.54 (bd, J ) 8.6 Hz, 2H), 4.93-4.73 (m, 1H), 4.14-4.09
(m, 2H), 1.66 (s, 3H), 1.53 (s, 3H), 1.50 (s, 9H); 13C-NMR δ
(50.3 MHz) δ 151.3, 147.1, 132.4, 129.7, 123.5, 94.6, 93.6, 80.3,
(R)-2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-4-(b r om o-
eth yn yl)oxa zolid in e (7a ). A solution of 5 (387 mg, 1.0 mmol)
in THF (10 mL) was cooled at -100 °C. A THF solution (1 M)
of NaHMDS (1.00 mL, 1.00 mmol) was added dropwise. The
mixture was stirred for 45 min and then hydrolyzed at low
temperature with aqueous NaOH (0.01 M). The organic layer
was extracted with ether, washed with brine, and dried. After
evaporation of the solvent 313 mg of crude material was
obtained; 100 mg of the residue was purified by bulb-to-bulb
distillation (90 °C, 0.75 mBar) to afford 87 mg (87%) of pure
7a as a colorless oil: 1H-NMR (300 MHz) δ 4.64-4.42 (m, 1H),
4.01-3.99 (m, 2H), 1.61 (s, 3H), 1.48 (s, 9H + 3H); 13C-NMR
(75.45 MHz) δ 151.5, 94.5, 80.5, 78.8, 68.4, 67.3, 49.4, 28.5,
77.2, 68.5, 49.1, 28.4, 26.0, 24.3; MS m/z 290 (4), 57 (100); [R]20
D
) -149 (c 1.03, CHCl3). Anal. Calcd for C18H22N2O5: C, 62.42;
H, 6.40; N, 8.09. Found: C, 62.47; H, 6.38; N, 8.17.
(R )-2,2-D i m e t h y l-3-(t er t -b u t o x y c a r b o n y l)-4-[(p -
for m ylp h en yl)eth yn yl]oxa zolid in e (8b). 4-Bromobenzal-
dehyde (54 mg, 0.3 mmol) was stirred with a solution of 2 (67
mg, 0.3 mmol) in Et3N (2 mL) for 2 h at 50 °C. After workup
108 mg of crude material was obtained. Purification (petro-
leum ether/ethyl acetate: 5/1) afforded 56 mg (59%) of 8b: 1H-
NMR (200 MHz) δ 9.99 (s, 1H), 7.81 (bd, J ) 8.0 Hz, 2H), 7.57
(bd, J ) 8.0 Hz, 2H), 4.91-4.69 (m, 1H), 4.14-4.07 (m, 2H),
1.66 (s, 3H), 1.53 (s, 3H), 1.50 (s, 9H); 13C-NMR (50.3 MHz) δ
191.4, 151.5, 135.4, 132.2, 129.4, 129.1, 94.1, 92.3, 81.2, 80.3,
25.7, 24.4; MS m/z 288/290 (3/3), 57 (100); [R]20 ) -103 (c
D
1.09, CHCl3). Anal. Calcd for C12H18NO3Br: C, 47.38; H, 5.96;
N, 4.60. Found: C, 47.23; H, 6.01; N, 4.64.
68.6, 49.1, 28.4, 25.9, 24.4; MS m/z 273 (7), 57 (100); [R]22
)
D
-185 (c 1.44, CHCl3). Anal. Calcd for C19H23NO4: C, 69.28;
Meta la tion of 2 a n d Rea ction w ith Electr op h iles:
Gen er a l P r oced u r e. A THF solution of 2 was cooled at -78
°C. BuLi (1 equiv) was added, and the mixture was stirred
for 30 min. The appropriate electrophile was then added and
the reaction progress monitored by TLC. After the reaction
was complete, the reaction mixture was diluted with ether,
hydrolyzed with NaOH (0.01 M), then extracted, washed with
brine, and dried.
H, 7.04; N, 4.25. Found: C, 69.37; H, 7.08; N, 4.29.
(R)-2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-4-(b en zoyl-
eth yn yl)oxa zolid in e (8c). Benzoyl chloride (34 mg, 0.2
mmol) was stirred with a solution of 2 (46 mg, 0.2 mmol) in
Et3N (1 mL) for 17 h at rt. After workup 76 mg of crude
material was obtained. Purification (petroleum ether/ethyl
acetate: 4/1) afforded 47 mg (70%) of 8c: 1H-NMR (200 MHz)
δ 8.20-8.08 (m, 2H), 7.75-7.38 (m, 3H), 4.93-4.75 (m, 1H),
4.20-4.11 (m, 2H), 1.69 (s, 3H), 1.50 (s, 9H + 3H); 13C-NMR
(50.3 MHz) δ 177.5, 151.1, 136.5, 134.5, 130.5, 128.8, 94.8, 92.7,
81.0, 79.8, 68.0, 48.7, 28.3, 26.0, 24.2; MS m/z 314 (2), 105
(R)-Met h yl [(2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-
oxazolidin -4-yl]pr opyn oate (7c). Freshly distilled ClCOOMe
(61 mg, 0.6 mmol) was reacted with 2 (108 mg, 0.5 mmol) in
THF (5 mL) and stirred at -78 °C for 1 h. The reaction
mixture was allowed to warm up to rt and then stirred for 1
h. After workup 153 mg of crude material was obtained. 1H-
NMR analysis showed the presence of compounds 7c and 6c
in a 80/20 ratio. Flash chromatography (petroleum ether/ethyl
acetate: 3/1) afforded 61 mg (46%) of 7c and 12 mg (8%) of
6c. 7c: 1H-NMR (300 MHz, 50 °C) δ 4.67-4.58 (m, 1H), 4.14-
3.99 (m, 2H), 3.79 (s, 3H), 1.61 (s, 3H), 1.49 (s, 3H + 9H); 13C-
NMR (75.45 MHz) δ 153.7, 151.0, 94.8, 86.0, 80.9, 73.7, 67.7,
52.7, 48.3, 28.3, 25.8, 24.2; MS m/z 268 (3), 57 (100); IR (KBr)
(100); [R]23 ) -111 (c 0.97, CHCl3). Anal. Calcd for
D
C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.21; H,
6.95; N, 4.30.
(R,E)-2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-4-[(2-t r i-
bu tylsta n n yl)eth en -1-yl]oxa zolid in e (3). (Tributylstan-
nyl)cuprate was prepared according to the literature.1
A
solution of 2 (794 mg, 3.5 mmol) in THF (10 mL) was added,
and the reaction mixture was stirred at -78 °C for 1 h. The
reaction mixture was diluted with ether and hydrolyzed with
ammonium buffer. Evaporation of the solvent afforded 2.863
g of crude material which was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate: 15/1); 1.342 g (74%) of 3
was obtained as a colorless oil: 1H-NMR (200 MHz) δ 6.06
(bd, J ) 19.4 Hz, 1H), 5.90 (dd, J ) 19.4, 5.4 Hz, 1H), 4.41-
4.28 (m, 1H), 4.02 (dd, J ) 8.4, 6.6 Hz, 1H), 3.76 (dd, J ) 8.4,
2.4 Hz, 1H), 1.62-1.18 (m, 12H + 6H + 9H), 0.88 (t, J ) 7.4
Hz, 15H); 13C-NMR (50.3 MHz) δ 151.9, 146.7, 128.9, 93.9,
79.4, 68.3, 62.3, 29.1, 28.4, 27.2, 26.5, 23.8, 13.7, 9.4; MS m/z
1709; [R]20 ) -105 (c 1.10, CHCl3). Anal. Calcd for
D
C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C, 59.26; H,
7.40; N, 4.97. 6c: 1H-NMR (200 MHz) δ 5.94 (d, J ) 0.6 Hz,
1H), 5.70 (d, J ) 0.6 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 1.51
(s, 9H); 13C-NMR (75.45 MHz) δ 153.6, 152.3, 149.5, 129.0,
124.6, 84.3, 81.8, 78.4, 54.1, 52.9, 27.8; MS m/z 268 (0.5), 57
(100).
(R)-2,2-Dim eth yl-3-(ter t-bu toxycar bon yl)-4-(3-m eth oxy-
1-p r op yn yl)oxa zolid in e (7d ). Chloromethyl methyl ether
(23 mg, 0.3 mmol) was reacted with 2 (52 mg, 0.2 mmol) in
THF (3 mL). The reaction mixture was warmed up to -15 °C
and stirred for 3 h. After workup 89 mg of crude material
was obtained. 1H-NMR analysis showed the presence of
compounds 7d and 6d in a 70/30 ratio. 7d and 6d were not
separable by chromatography. 7d : 1H-NMR (200 MHz) δ
4.68-4.50 (m, 1H), 4.13-4.08 (m, 2H), 4.05-3.97 (m, 2H), 3.36
(s, 3H), 1.62 (s, 3H), 1.48 (s, 9H + 3H); 13C-NMR (50.3 MHz)
δ 151.5, 94.3, 85.4, 80.3, 68.7, 59.9, 57.3, 55.8, 48.5, 28.4, 25.9,
24.3; MS m/z 254 (8), 57 (100). 6d : 1H-NMR (200 MHz) δ 5.48
(s, 1H), 5.43 (s, 1H), 4.87 (s, 2H), 4.21 (s, 2H), 3.38 (s, 3H),
3.35 (s, 3H), 1.48 (s, 9H); 13C-NMR (50.3 MHz) δ 153.7, 128.6,
119.4, 83.9, 83.2, 81.5, 79.6, 60.1, 57.7, 55.8, 28.1; MS m/z 199
(5), 57 (100).
460 (9), 57 (100); [R]19 ) -44 (c 1.19, CHCl3).
D
(R,E)-2,2-Dim et h yl-3-(ter t-b u t oxyca r b on yl)-4-(2-iod o-
eth en -1-yl)oxa zolid in e (9a ). A solution of 3 (302 mg, 0.6
mmol) in CHCl3 (2 mL) was reacted with I2 (150 mg, 0.6 mmol)
for 3 h at rt. After solvent evaporation, 193 mg of crude
product was obtained. Purification by flash chromatography
(petroleum ether/ethyl acetate: 8/1) afforded 112 mg (54%) of
9a : 1H-NMR (300 MHz, 50 °C) δ 6.50 (dd, J ) 14.4, 7.6 Hz,
1H), 6.75 (bd, J ) 14.4 Hz, 1H), 4.38-4.21 (m, 1H), 3.99 (dd,
J ) 8.8, 6.0 Hz, 1H), 3.75 (dd, J ) 8.8, 2.1 Hz, 1H), 1.59 (s,
3H), 1.49 (s, 3H), 1.45 (s, 9H); 13C-NMR (50.3 MHz) δ 151.7,
144.3, 94.1, 80.1, 78.1, 67.1, 61.3, 28.4, 26.5, 23.6; MS m/z 338
(2), 282 (19), 57 (100); [R]22 ) -75.3 (c 1.9, CHCl3).
D
(R ,E )-2,2-D im e t h y l-3-(t er t -b u t o x y c a r b o n y l)-4-(2-
p h en yleth en -1-yl)oxa zolid in e (9b). A solution of 3 (148 mg,
0.3 mmol) and bromobenzene (65 mg, 0.4 mmol) in toluene (2
mL) was refluxed for 24 h in the presence of Pd(Ph3)4 (10%).
After this time bromobenzene (30 mg, 0.15 mmol) was readded
and the reaction mixture kept under reflux for a further 24 h.
The mixture was filtered through a SiO2 plug, diluted with
ether, and then stirred for 2 h with a saturated KF solution
(10% NH4OH). The organic layer was separated and evapo-
Cou p lin g w it h E lect r op h iles u n d er Son oga sh ir a 21
Con d ition s: Gen er a l P r oced u r e. Compound 2 (0.2 mmol)
was dissolved in the appropriate amine (2 mL). The electro-
phile (0.2 mmol) was then added together with CuI (10%) and
(Ph3P)2PdCl2 (10%) and left to react as specified case by case.
The amine was evaporated. The residue was dissolved with
ether, filtered over SiO2, and, after evaporation of the solvent,
purified by flash chromatography.

6192 J . Org. Chem., Vol. 62, No. 18, 1997
Reginato et al.
rated to afford 138 mg of crude material; 31 mg of the mixture
was purified by TLC (petroleum ether/ethyl acetate: 10/1) and
gave 16 mg (78%) of 9b: 1H-NMR (200 MHz) δ 7.42-7.21 (m,
5H), 6.50 (bd, J ) 15.6 Hz, 1H), 6.16 (dd, J ) 15.6, 8.2 Hz,
1H), 4.62-4.38 (m, 1H), 4.12 (dd, J ) 9.2, 5.8 Hz, 1H), 3.83
(dd, J ) 9.2, 2.2 Hz, 1H), 1.66 (s, 3H), 1.55 (s, 3H), 1.44 (s,
9H); 13C-NMR (50.3 MHz) δ 152.5, 137.2, 132.1, 129.0, 128.1,
126.9, 94.2, 80.1, 68.8, 60.0, 28.9, 27.1, 24.2; MS m/z 303 (1),
247 (59), 189 (100), 57 (97); [R]24D ) -71.3 (c 1.1, CHCl3). Anal.
Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C,
70.97; H, 8.28; N, 4.53.
93.9, 79.7, 68.3, 59.2, 28.5, 26.6, 23.8; MS m/z 273 (21), 91 (50),
57 (100); [R]19 ) -15 (c 0.6, CHCl3).
D
(R,E)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-4-p h en ylb u t -3-
en -1-ol (12b). The crude material (103 mg) obtained from
reaction of 3 with bromobenzene (see above) was dissolved in
MeOH/H2O (90/10, 4 mL) and stirred with a catalytic amount
of PTSA at rt for 48 h. MeOH was evaporated; the residue
was dissolved with ether and washed with brine. After
evaporation of the solvent and chromatography (petroleum
ether/ethyl acetate: 2/1) 41 mg (71% from 3) of 12b was
obtained: 1H-NMR (200 MHz) δ 7.37-7.18 (m, 5H), 6.57 (d, J
) 16.2 Hz, 1H), 6.12 (dd, J ) 16.2, 6.2 Hz, 1H), 5.03 (bd, J )
7.4 Hz, 1H), 4.42-4.27 (m, 1H), 3.77-3.64 (m, 2H), 2.56 (bs,
1H), 1.44 (s, 9H); 13C-NMR (50.3 MHz) δ 156.0, 136.3, 131.8,
128.5, 127.7, 126.7, 126.4, 79.9, 65.4, 54.6, 28.3; MS m/z 248
(R ,E )-2,2-D im e t h y l-3-(t er t -b u t o x y c a r b o n y l)-4-(p -
a n isoyleth en -1-yl)oxa zolid in e (9c). A solution of 3 (86 mg,
0.2 mmol) and anisoyl chloride (34 mg, 0.2 mmol) in CHCl3 (2
mL) was refluxed for 10 h in the presence of Pd(Ph3)ClBz
(10%). After this time the reaction mixture was filtered
through a SiO2 plug. Evaporation of the solvent afforded 98
mg of crude material. Purification by TLC (petroleum ether/
ethyl acetate: 4/1) yielded 36 mg (53%) of 9c: 1H-NMR (300
MHz, 60 °C) δ 7.94 (dt, J ) 8.7, 1.8 Hz, 2H), 7.02-6.80 (bd +
m, 2H + 2H), 4.59-4.47 (m, 1H), 4.13 (dd, J ) 6.4, 9.0 Hz,
1H), 3.90-3.82 (m, 1H), 3.88 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H),
1.46 (s, 9H); MS m/z 305 (19), 246 (36), 202 (20), 135 (51), 77
(11), 232 (15), 84 (100), 57 (97); [R]22 ) -33 (c 1.25, CHCl3).
D
Anal. Calcd for C15H25NO3: C, 68.42; H, 8.42; N, 5.32.
Found: C, 69.17; H, 8.19; N, 5.19.
(R,E,E)-2-[(ter t-Bu toxyca r bon yl)a m in o]-7-p h en yl-3,6-
h ep ta d ien -1-ol (12d ). A solution of 9d (40 mg, 0.1 mmol) in
MeOH/H2O (90/10, 4 mL) was stirred with a catalytic amount
of PTSA at rt for 72 h. After the workup 33 mg of crude
material was obtained. Purification by TLC (petroleum ether/
ethyl acetate: 5/1) afforded 22 mg (62%) of 12d : 1H-NMR (300
MHz) δ 7.33-7.20 (m, 5H), 6.40 (d, J ) 16.2 Hz, 1H), 6.18 (dt,
J ) 16.2, 6.2 Hz, 1H), 5.79 (dtd, J ) 15.2, 6.2, 1.4 Hz, 1H),
5.46 (dtd, J ) 15.2, 1.0, 1.4 Hz, 1H), 3.77-3.64 (m, 2H), 2.56
(bs, 1H), 1.44 (s, 9H); 13C-NMR (50.3 MHz) δ 156.0, 136.3,
131.8, 128.5, 127.7, 126.7, 126.4, 79.9, 65.4, 54.6, 28.3; MS m/z
(21), 57 (100); [R]22 ) +33 (c 0.9, CHCl3).
D
(R,E,E)-2,2-Dim eth yl-3-(ter t-bu toxycar bon yl)-4-(5-ph en -
yl-1,4-p en ta d ien -1-yl)oxa zolid in e (9d ). A solution of 3 (208
mg, 0.4 mmol) and cinnamyl acetate (73 mg, 0.4 mmol) in DMF
(2 mL) was stirred in the presence of Pd2(dba)3 (10%) and LiCl
(52 mg) for 24 h at rt. The reaction mixture was diluted with
ether and then stirred with a saturated KF solution (10%
NH4OH). The organic layer was separated and washed with
brine. Evaporation of the solvent afforded 233 mg of crude
material which was purified by flash chromatography (petro-
leum ether/ethyl acetate: 5/1) to give 77 mg (56%) of 9d : 1H-
NMR (300 MHz) δ 7.36-7.13 (m, 5H), 6.38 (d, J ) 15.9 Hz,
1H), 6.16 (dt, J ) 15.9, 6.6 Hz, 1H), 5.77-5.52 (m, 1H), 5.48
(dd, J ) 7.6, 15.5 Hz, 1H), 4.42-4.18 (m, 1H), 4.00 (dd, J )
8.7, 6.6 Hz, 1H), 3.71 (dd, J ) 8.7, 2.3 Hz, 1H), 2.95-2.88 (m,
2H), 1.58 (s, 3H), 1.48 (s, 3H), 1.41 (s, 9H); 13C-NMR (50.3
MHz) δ 152.0, 137.6, 130.9, 130.4, 130.0, 128.5, 128.2, 127.0,
126.0, 93.7, 79.6, 68.4, 59.1, 35.4, 28.5, 26.9, 23.9; MS m/z 287
272 (19), 144 (77), 57 (100); [R]23 ) -8.22 (c 0.9, CHCl3).
D
(R,E)-2-[(ter t-Bu toxyca r bon yl)a m in o]-4-p h en ylbu ta n -
1-ol (13). 12b (35 mg, 0.1 mmol) was dissolved in ethanol
(95%, 1 mL) and hydrogenated (H2, 1 atm) overnight over
catalytical Pd on carbon. After filtration over SiO2 and
evaporation of the solvent, 32 mg (91%) of pure 13 was
obtained: 1H-NMR (200 MHz) δ 7.33-7.15 (m, 5H), 4.66 (bs,
1H), 3.72-3.54 (m, 2H + 1H), 2.81-2.58 (m, 2H), 2.35 (bs,
1H), 1.88-1.55 (m, 2H), 1.46 (s, 9H); 13C-NMR (50.3 MHz) δ
156.5, 141.5, 128.4, 128.3, 126.0, 79.7, 65.9, 52.6, 33.3, 32.4,
28.4; MS m/ z 234 (6), 91 (88), 57 (100); [R]19 ) +4.5 (c 1.1,
D
CHCl3).
(2), 144 (77), 57 (100); [R]18 ) -11.5 (c 0.8, CHCl3).
D
(R,E,E)-2,2-Dim eth yl-3-(ter t-bu toxycar bon yl)-4-(4-ph en -
yl-1,3-bu ta d ien -1-yl)oxa zolid in e (9e). A solution of 3 (77
mg, 0.15 mmol) and trans-â-iodostyrene (47 mg, 0.2 mmol) in
DMF (2 mL) was stirred in the presence of Pd2(CH3CN)2 (10%)
for 15 h at rt. DMF was removed under vacuum; 103 mg of
crude material was obtained which was purified by TLC
(petroleum ether/ethyl acetate: 10/1) to give 31 mg (62%) of
9e: 1H-NMR (200 MHz) δ 7.42-7.18 (m, 5H), 6.75 (dd, J )
15.6, 10.2 Hz, 1H), 6.50 (d, J ) 15.6 Hz, 1H), 6.42-6.18 (m,
1H), 5.83-4.62 (bdd, J ) 15.8, 8.1 Hz, 1H), 4.51-4.24 (m, 1H),
4.06 (dd, J ) 5.8, 8.8 Hz, 1H), 3.76 (dd, J ) 8.8, 2.6 Hz, 1H),
1.62 (s, 3H), 1.51 (s, 3H), 1.45 (s, 9H); 13C-NMR (50.3 MHz) δ
151.9, 137.2, 132.6, 132.5, 132.0, 128.6, 128.2, 127.5, 126.3,
Ack n ow led gm en t. We are grateful to Prof. Maur-
izio Taddei for helpful discussions and critical reading
of the paper. Financial support by the Consiglio Na-
zionale delle Ricerche, Rome, is much appreciated.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR spectra of
compounds 3, 9a ,d ,e, 12d , and 13 (6 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS. See any current masthead page for
ordering information.
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