Syntheses and Reactions of Optically Active α-Aminoallenylstannanes

Article abstract of DOI:10.1021/jo0302861

Lithiation/stannylation of optically active N-propargyloxazolidinones produced optically active α-oxazolidinonylallenylstannanes. Reaction of these with aldehydes in the presence of BF₃·OEt₂ produced β-hydroxypropargylamines with hig

Full text of DOI:10.1021/jo0302861

Syn th eses a n d Rea ction s of Op tica lly Active
r-Am in oa llen ylsta n n a n es
Peter B. D. Ranslow, Louis S. Hegedus,* and Cristobal de los Rios
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
hegedus@lamar.colostate.edu
Received September 8, 2003
Lithiation/stannylation of optically active N-propargyloxazolidinones produced optically active
R-oxazolidinonylallenylstannanes. Reaction of these with aldehydes in the presence of BF3‚OEt2
produced â-hydroxypropargylamines with high syn diastereoselectivity and ee. These were converted
to γ-hydroxy-â-amino acids by oxidative cleavage of the alkyne.
In tr od u ction
Group 6 heteroatom-stabilized metal (Cr, Mo, W)
carbene complexes undergo M-H insertion reactions
with group 4 metal (Si, Ge, Sn) hydrides to give the
corresponding R-heteroatom group 4 metal species (eq 1).6
Carbene complexes having R-chiral centers on the alkyl
side chain undergo this reaction with good to excellent
Chiral allenylstannanes have been extensively devel-
oped, primarily by Marshall,1 for stereoselective aldol
reactions wherein both the relative (syn/anti) and abso-
lute (R/S) stereochemistries can be controlled. They
undergo reactions with aldehydes in the presence of
Lewis acids (BF3‚OEt2, MgBr2‚OEt2) via a SE2′ process
to produce homopropargylic alcohols. The absolute ster-
eochemical outcome of this reaction is dependent on both
the substrate and Lewis acid used but has been shown
to proceed with high absolute stereoselectivity in a
number of cases.1 The relative (syn/anti) stereochemistry
is also dependent on the substrate and Lewis acid used;
however, in simple cases, selectivity for the formation of
syn-homopropargylic alcohols has been observed. With
chiral R-alkoxyaldehydes, double diastereoselection is
operable, and the syn/anti ratios depend both on the
absolute configuration of the allene and on the Lewis
acid.
diastereoselectivity,7 as do carbene complexes having
chiral oxazolidinones8 or imidazolidinones9 as the het-
eroatom substituent. Alkenyl- and alkynylcarbene com-
plexes produce allyl- and propargylstannanes,10 respec-
tively, although allenylstannanes result when the alkyne
substituents are relatively unhindered.
In contrast, chiral propargylstannanes are rarely stud-
ied, primarily because of their propensity to rearrange
to the corresponding allenylstannane.2 Those that are
known undergo reactions with aldehydes in the presence
of tetra- or trichlorotin or boron promoters to give
homopropargylic alcohols, via the allenylmetal interme-
diate.3 In contrast, terminal propargylstannanes under-
went reactions with aldehydes in the presence of Ti(IV)-
(S)BINOL to give optically active allenyl alcohols.4
Optically active propargylstannanes could be isolated
from the reaction of optically active allenyltitanium
species with trialkyltin chlorides via a syn SE2′ mecha-
nism.5 They also rearrange to the allenylstannane under
mild conditions.
R-Heteroatom propargylstannanes are rare, although
an R-methoxypropargylstannane has been made and was
shown to react with aldehydes in the presence of butyltin
trichloride to give anti-1,2-diols.3a R-Aminopropargylcop-
per species alkylated aldehydes with high anti selectivity,
producing R-aminopropargylic alcohols.11 Propargylstan-
nanes having a chiral oxazolidinone R to tin (potentially
accessible from the carbenechromium complex chemistry
(6) (a) Fischer, E. O.; Do¨tz, K. H. J . Organomet. Chem. 1972, 36,
C4. (b) Connor, J . A.; Day, J . P.; Turner, R. M. J . Chem. Soc., Dalton
Trans. 1976, 108. (c) Connor, J . A.; Day, J . P.; Turner, R. N. J . Chem.
Soc., Dalton Trans. 1976, 283.
(7) Nakamura, E.; Tanaka, K.; Aoki, S. J . Am. Chem. Soc. 1992,
114, 9715.
(8) (a) Masters, J . J . Ph.D. Dissertation, Colorado State University,
Fort Collins, CO, 1993. (b) Dubuisson, C. Ph.D. Dissertation, Colorado
State University, Fort Collins, CO, 1996.
(9) (a) Parisi, M.; Solo, A.; Wulff, W. D.; Guzei, I. A.; Rheingold, A.
L. Organometallics 1998, 17, 3696. (b) Powers, T. S.; Wulff, W. D.;
Quinn, J .; Shi, Y.; J iang, W.; Shung, R.; Parisi, M.; Rahm, A.; J iang,
X. W.; Yap, G. P. A.; Rheingold, A. L. J . Organomet. Chem. 2001, 617-
618, 182-208.
(1) For a review, see: Marshall, J . A. Chem. Rev. 1996, 96, 31-47.
(2) Marshall, J . A.; Perkins, J . J . Org. Chem. 1994, 59, 3509-3511.
(3) (a) Savall, B. M.; Powell, N. A.; Roush, W. R. Org. Lett. 2001, 3,
3057-3060. (b) Carter, R. G.; Weldon, D. J . Org. Lett. 2000, 2, 3913-
3916. (c) Kadota, I.; Hatakeyama, D.; Seki, K.; Yamamoto, Y. Tetra-
hedron Lett. 1996, 37, 3059-3062.
(4) Yu, C.-M.; Yoon, S.-K.; Lee, S.-J .; Lee, J .-Y.; Kim, S.-S. Chem.
Commun. 1998, 2749-2750.
(5) Okamoto, S.; Matsuda, S.-i.; An, D. K.; Sato, F. Tetrahedron Lett.
2001, 42, 6323-6326.
(10) (a) Merlic, C. A.; Albaneze, J . Tetrahedron Lett. 1995, 36, 1007.
(b) Merlic, C. A.; Albaneze, J . Tetrahedron Lett. 1995, 36, 1011.
(11) Bernaud, F.; Vrancken, E.; Mangeney, P. Org. Lett. 2003, 5,
2567.
10.1021/jo0302861 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/12/2003
J . Org. Chem. 2004, 69, 105-111
105

Ranslow et al.
SCHEME 1
SCHEME 2
described above) could provide routes to the optically
active 1,2-amino alcohols by similar reaction chemistry.
Studies addressing this issue are detailed below.
SCHEME 3
Resu lts a n d Discu ssion
Syn th esis of P r op a r gylsta n n a n es a n d Allen yl-
sta n n a n es. The initial approach to optically active
R-aminoalkynylstannanes involved the tin hydride cleav-
age of chiral (oxazolidinone)(alkynyl)carbenechromium
complexes discussed above.9 The requisite carbene com-
plex 2 was synthesized by the reaction of (methoxy)-
(trimethysilylethynyl)carbenechromium complex 1 with
(R)-2-amino-2-phenylethanol to give aminocarbene com-
plex 2.9b Deprotonation of the amino alcohol with 2 equiv
of n-butyllithium followed by treatment with phosgene
produced the desired oxazolidinone carbene complex 3
(Scheme 1). Although formed in good yield, the complex
was rather unstable and decomposed on purification,
handling, and storage. To minimize this, the THF solu-
tion of freshly prepared 3 was concentrated under
reduced pressure, taken up in hexane, and directly
treated with tributyltin hydride to produce the desired
R-oxazolidinonylpropargylstannane 4 in 40% yield. The
material was a single diastereoisomer according to the
1H NMR spectrum of the crude reaction mixture, but its
configuration was unknown (Scheme 1). Because this
approach proved to be inefficient, an alternate route was
sought.
R-Alkoxypropargylstannanes have been prepared by R
metalation of propargyl ethers followed by the reaction
with tributyltin chloride.3a Propargyloxazolidinone 5
could be prepared by literature methods either from
propargyl bromide and the anion of the oxazolidinone,
followed by the silylation of the terminal alkyne, or by
the reaction of the anion of the oxazolidinone with
(trimethylsilyl)propargyl bromide. The attempted pro-
pargylic stannylation under the reported3a conditions
(t-BuLi, ZnCl2, Bu3SnCl) gave a complex mixture of
products. Omission of the zinc chloride and addition of
TMEDA produced a mixture of a single propargylstan-
nane, identical to that obtained from tin hydride cleavage
of carbenechromium complex 3, along with two diaste-
reoisomeric allenylstannanes (Scheme 2). When the
solvent was changed to ether, a slightly higher yield of 4
was obtained along with smaller amounts of allenylstan-
nanes.
2, was obtained in excellent yield. The configuration of
the allenylstannane was tentatively assigned as S based
on the assumption that transmetalation from magnesium
to tin occurred by an anti-SE2′ process1 from the less
sterically congested chelated organomagnesium complex
(Scheme 3). With both propargylstannane 4 and allenyl-
stannane 6a in hand, Lewis acid catalyzed reactions with
aldehydes were examined.
Reaction of propargylstannane 4 with aldehydes under
conditions reported for the corresponding R-alkoxypro-
pargylstannane3a (BuSnCl3, CH2Cl2, -78 °C) did not lead
to the expected homopropargylic alcohol but rather to the
allenylcarbinol as a single diastereoisomer (Scheme 4).
The relative and absolute stereochemistries of 7b were
determined by single-crystal X-ray diffraction. Tin(IV)-
catalyzed reactions of propargylstannanes are thought
to proceed by transmetalation by an anti-SE2′ process to
produce the more stable allenylstannane,2 which then
reacts with aldehydes by once again an anti-SE2′ mech-
anism to give homopropargyl alcohols. In the case of 4,
either the reaction proceeds by a different mechanism
or the initially formed allenylstannane rearranges to the
propargylstannane which can by stabilized by chelation
to the oxazolidinone carbonyl group. This then reacts by
an anti-SE2′ process to give the observed allenylcarbinol
(Scheme 4).
Because of both the relatively low yields of propargyl-
stannane 4 and the unexpected production of allenyl-
carbinols rather than homopropargyl alcohols, the reac-
tion of allenylstannane 6a with aldehydes was next
examined. Reaction of 6a with benzaldehyde under the
conditions of Scheme 4 resulted in extensive decomposi-
tion of the allenylstannane. Using stannous chloride12 in
place of trichlorobutylstannane resulted in 71% yield of
In an attempt to increase the yield of 4, magnesium
bromide etherate was added prior to the addition of
tributyltin chloride. A single allenylstannane, corre-
sponding to the major allenylstannane obtained in Scheme
(12) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J . A.; Nkansah, N.
T. Org. Lett. 1999, 1, 2145.
106 J . Org. Chem., Vol. 69, No. 1, 2004

Optically Active R-Aminoallenylstannane
SCHEME 4
SCHEME 5a
TABLE 1. Rea ction s of 6a w ith RCHO (Sch em e 5)
a
Reported yields are for pure, isolated material; diastereose-
lectivity estimated from 1H NMR spectra of the crude reaction
mixtures.
a 2:1 mixture of diastereoisomeric homopropargyl alco-
hols 8a and 9a (Scheme 5). The relative and absolute
stereochemistry was determined by single-crystal X-ray
diffraction. The use of conditions developed specifically
for the condensation of allenylstannanes with aldehydes
(2.5 equiv of BF3‚OEt2, CH2Cl2, -78 °C)13 produced the
desired homopropargyl alcohol in high yield with greater
than 95:5 diastereoselectivity based on the 1H NMR
spectrum of the crude material.
The reaction proved to be general for a range of
aldehydes (Table 1). Aromatic, straight- and branched-
chain aliphatic, and R,â-unsaturated aldehydes all un-
derwent the reaction in high yield and diastereoselectiv-
ity. In contrast, the electron-rich formylimidazole was
unreactive.
The reaction was relatively insensitive to R chirality
in the aldehyde partner with both S and R enantiomeric
aldehydes, R ) CH3CH(OBn), giving almost exclusively
the same syn disposition of the newly formed homopro-
pargyl alcohol center and oxazolidinone in products 8f
and 8g. Neither acetophenone nor the N-tosylimine of
benzaldehyde underwent BF3‚OEt-catalyzed condensa-
tion with 6a . Only decomposition of the tin reagent was
observed, suggesting that this process will be restricted
to aldehydes.
a
Reported yields are for isolated, purified single diastereoiso-
mers. Estimated from the 1H NMR spectrum of the crude
b
reaction mixture. c Stereochemistry determined by single-crystal
X-ray diffraction.
SCHEME 6
centers. Terminal alkynes are readily converted to ter-
minal carboxylic acids by a hydroboration/oxidation
sequence,16 making these homopropargyl alcohols sources
of the γ-hydroxy-â-amino acid functional group array.
Although the monophenyloxazolidinone used above
was an effective chiral auxiliary, conversion to the free
amino group would require harsh hydrolysis or reduction
conditions incompatible with sensitive functionality,
limiting its use in the synthesis. In contrast, the diphen-
yloxazolidinone12 is easily cleaved by mild hydrogenoly-
sis.17 Conversion of propargyldiphenyloxazolidinone 5′ to
protected amino ester 12 proceeded in good yield and with
high stereoselectivity (Scheme 7). Reductive cleavage of
oxazolidinone proceeded in good yield with 12a (R ) Ph).
The stereochemical outcome of the condensation of 6a
with aldehydes is consistent with the Felkin-Ahn transi-
tion-state model developed by Marshall et al.1,14 for BF3‚
OEt2-catalyzed reactions of aldehydes with allenylstan-
nanes (Scheme 6). This requires the aldehyde to approach
from the face opposite the tributyltin group with the large
oxazolidinone anti to the large R group of the aldehyde.
Con ver sion of Hom op r op a r gyl Alcoh ols to γ-Hy-
d r oxy-â-a m in o Acid s. The ability to generate syn-amino
alcohols with high diastereo- and enantioselectivity,
coupled with the absence of double diastereoselectivity
with R-chiral aldehydes as substrates, makes this meth-
odology applicable to the synthesis of a variety of biologi-
cally active compounds having adjacent contiguous chiral
(15) Marshall, J . A.; Wang, X.-J . J . Org. Chem. 1991, 56, 3211.
(16) Alemany, C.; Bach, J .; Farra`s, J .; Garcia, J . Org. Lett. 1999, 1,
1831.
(13) Yasuda, M.; Sugawa, Y.; Yamamoto, A.; Shibata, I.; Baba, A.
Tetrahedron Lett. 1996, 37, 5951.
(14) Marshall, J . A.; Yanik, M. M. J . Org. Chem. 2001, 66, 1373.
(17) Masters, J . J .; Hegedus, L. S. J . Org. Chem. 1993, 58, 4547.
J . Org. Chem, Vol. 69, No. 1, 2004 107

Ranslow et al.
SCHEME 7a
in toluene, 0.5 mmol). The reaction was stirred for an ad-
ditional 20 min at -78 °C, then warmed to room temperature,
and stirred a final 15 min. The solvent was removed under
reduced pressure at 0 °C with stirring. To ensure that no
phosgene remained in the removed solvent, it was trapped
through a tube of potassium hydroxide. Once the reaction had
been sufficiently concentrated, hexane (3 mL) was added. The
reaction was placed under a carbon monoxide atmosphere,
cooled to 0 °C, and Hunig’s base (2 drops) and tributyltin
hydride (123 µL, 0.46 mmol) were added. After stirring for 30
min, the reaction was again concentrated and purified by flash
column chromatography on silica gel, eluting with 5% diethyl
ether in hexane, to give propargylstannane 4 (0.10 g, 40%) as
a pale yellow oil.
1H NMR δ: 7.42 (m, 3H), 7.30 (m, 2H), 5.05 (t, J ) 8.4 Hz,
1H), 4.63 (t, J ) 8.7 Hz, 1H), 4.09 (t, J ) 8.4 Hz, 1H), 3.15 (s,
1H), 1.52 (m, 6H), 1.30 (m, 6H), 1.04 (m, 6H), 0.89 (t, J ) 7.2
Hz, 9H), 0.15 (s, 9H). 13C NMR (75 MHz) δ: 159.1, 137.9, 129.4,
129.2, 127.6, 105.0, 69.6, 60.7, 31.2, 29.2, 27.6, 14.0, 12.9, 0.4.
Gen er a l P r oced u r e for th e Syn th esis of (Tr im eth yl-
silyl)p r op a r gyloxa zold in on es 5 a n d 5′. (Tr im eth ylsilyl)-
p r op a r gyloxa zolid in on e 5. To a stirred solution of propar-
gyloxazolidinone (1.24 g, 6.20 mmol) in THF (30 mL, 0.2 M)
cooled to -78 °C was added lithium hexamethyldisilazane (1.0
M in THF, 6.8 mmol). After stirring for 5 min at -78 °C,
trimethylsilyl chloride (875 µL, 6.9 mmol) was added. After
stirring an additional 10 min, the reaction was quenched by
the addition of a saturated ammonium chloride solution (15
mL) at -78 °C and allowed to warm to room temperature.
Once the mixture had warmed to room temperature, water (5
mL) and diethyl ether (60 mL) were added, and the organic
layer was separated. The aqueous layer was again extracted
with diethyl ether (60 mL), and the combined organic layer
was dried over magnesium sulfate, filtered, and concentrated
under reduced pressure to afford the crude reaction product.
Purification via flash column chromatography with silica gel,
eluting with 5:1 hexane/ethyl acetate, gave (trimethylsilyl)-
propargyloxazolidinone 5 (1.41 g, 83%) as a white solid.
a
Reported yields are for isolated, purified single diastereoiso-
mers. Diastereoisomeric ratios were determined by 1H NMR
spectroscopy of the crude reaction mixture.
In contrast, 12c (R ) CH3CHCOBn) produced an insepa-
rable mixture of products arising from the competitive
cleavage of the O-benzyl group followed by cyclization of
a mixture (by infrared spectroscopy) of lactones. Com-
i
pound 12b (R ) Pr) cleaved without complication, but
the product amino ester was volatile and difficult to
isolate. Conversion to the more tractable lactone amine
hydrochloride led to a fair yield of 14.
Mp: 64-66 °C. [R] 22 -166 (c 1.1, CHCl3). IR ν (thin film):
D
1761 cm-1 (CO). H NMR δ: 7.42 (m, 3 H), 7.31 (m, 2H), 4.96
1
(t, J ) 8.4 Hz, 1 H), 4.67 (t, J ) 8.7 Hz, 1H), 4.42 (d, J ) 17.4
Hz, 1H), 4.17 (t, J ) 7.5 Hz, 1H), 3.44 (d, J ) 17.7 Hz, 1H),
0.17 (s, 9H). 13C NMR (75 MHz) δ: 157.9, 137.1, 129.5, 129.4,
127.5, 98.2, 90.7, 70.1, 59.3, 33.3, 0.0. Elem anal. Calcd for
In summary, an efficient, highly stereoselective syn-
thesis of R-aminoallenylstannanes has been developed.
These underwent reactions with aldehydes that had high
syn diastereoselectivity and high enantioselectivity.
C
15H19NO2Si: C, 65.90; H, 7.00; N, 5.12. Found: C, 65.08; H,
6.96; N, 5.03.
(Tr im eth ylsilyl)p r op a r gyloxa zolid in on e 5′. Following
the above procedure, using propargyloxazolidinone (350 mg,
1.26 mmol), lithium hexamethyldisilazane (1.0 M, 1.39 mmol),
and trimethylsilyl chloride (192 µL, 1.51 mmol) in THF (6.3
mL, 0.2 M) led to the isolation of (trimethylsilyl)propargyl-
oxazolidinone 5′ (388.6 mg, 88%) as a white solid.
Mp: 122-123 °C. IR ν (thin film): 1760 cm-1 (CO). 1H NMR
δ: 7.18 (m, 6 H), 6.98 (m, 2H), 6.86 (m, 2H), 5.91 (d, J ) 8.4
Hz, 1H), 5.25 (d, J ) 8.4 Hz, 1H), 4.56 (d, J ) 17.7 Hz, 1H),
3.53 (d, J ) 17.7 Hz, 1H), 0.17 (s, 9H). 13C NMR (75 MHz) δ:
157.9, 134.8, 133.6, 128.7, 128.6, 128.2, 128.1, 128.0, 126.2,
Exp er im en ta l Section
Syn th esis of [(Tr im eth ylsilyl)pr opar gyl]am in ocar ben e
Com p lex 2. To a stirred solution of [(trimethylsilyl)propargyl]-
methoxycarbene complex 19b (1.0 g, 3.0 mmol) in THF (10 mL)
at -78 °C was added (R)-2-amino-2-phenylethanol (0.46 g, 3.3
mmol) in one portion. The reaction was stirred at -78 °C for
1 h, then warmed to room temperature, and stirred an
additional 2.5 h. The reaction mixture was then filtered
through a plug of 1:1 silica/Celite, rinsed thoroughly with THF
(20 mL), and concentrated under reduced pressure to give the
crude reaction product as a deep orange oil. Purification via
flash column chromatography with silica gel, eluting with 3:1
hexanes/ethyl acetate, gave [(trimethylsilyl)propargyl]ami-
nocarbene complex 2 (1.17 g, 89%) as a deep orange, viscous
oil contaminated with a small amount of ethyl acetate. This
compound was used without further purification.
98.5, 90.6, 79.8, 64.2, 33.9, 0.0. Elem anal. Calcd for C21H23
-
NO2Si: C, 72.17; H, 6.63; N, 4.01. Found: C, 71.83; H, 6.58;
N, 3.95.
P r ep a r a tion of P r op a r gylsta n n a n e 4 fr om P r op a r gyl-
oxa zolid in on e 5. To a stirred mixture of (trimethylsilyl)-
propargyloxazolidinone 5 (100 mg, 0.37 mmol) and TMEDA
(275 µL, 1.83 mmol) in diethyl ether (3.6 mL) at -78 °C was
added n-butyllithium (1.54 M, 0.40 mmol). The reaction
mixture was stirred for 1 h at -78 °C, during which an orange
color developed. At this time, tributyltin chloride (99 µL, 0.37
mmol) was added, and the reaction was stirred a final 30 min
at -78 °C. The reaction was quenched by the addition of a
10% aq ammonium chloride solution (5 mL) and allowed to
warm to room temperature. Diethyl ether (40 mL) was added,
and the aqueous layer was separated. The organic layer was
1H NMR δ: 9.50 (m, 1H), 7.38 (m, 3H), 7.29 (m, 2H), 5.36
(p, J ) 4.2 Hz, 1H), 4.13 (m, 1H), 4.05 (m, 1H), 1.72 (t, J ) 5.7
Hz, 1H), 0.20 (s, 9H).
Syn th esis of P r op a r gylsta n n a n e 4 fr om [(Tr im eth yl-
silyl)p r op a r gyl]a m in oca r ben e Com p lex 2. To a stirred
solution of carbene complex 2 (0.20 g, 0.46 mmol) in THF (3
mL) at -78 °C was slowly added n-butyllithium (1.6 M in
hexane, 0.94 mmol). The reaction was stirred at -78 °C for
45 min followed by the addition of a phosgene solution (1.9 M
108 J . Org. Chem., Vol. 69, No. 1, 2004

Optically Active R-Aminoallenylstannane
washed with brine (5 mL), dried with magnesium sulfate,
filtered, and concentrated under reduced pressure to give the
crude reaction product. Purification via flash column chroma-
tography with silica gel, eluting with 9:1 hexane/diethyl ether,
gave compound 4 (106.9 mg, 52%) as a clear oil. Spectroscopic
data matched that reported above. The later fractions contain
a mixture of diastereomeric allenylstannanes 6, which con-
stitute the bulk of the remaining material.
129.4, 129.3, 128.7, 128.6, 128.3, 127.6, 127.4, 126.6, 126.4,
117.0, 93.9, 75.7, 74.3, 70.6, 70.5, 60.6, 59.9, 0.0, -0.4. Elem
anal. Calcd for C22H25NO3Si: C, 69.62; H, 6.64; N, 3.69.
Found: C, 69.57; H, 6.68; N, 3.58.
Allen ylca r bin ol 7b. This compound was prepared by the
general method described above, using isobutyraldehyde,
which gave allenylcarbinol 7b (27.1 mg, 66%) as a white
crystalline solid.
Mp: 116-117 °C. [R] 22 -184 (c 1.4, CHCl3). IR ν (thin
Syn t h esis of Allen ylst a n n a n es 6a a n d 10 fr om (Tr i-
m eth ylsilyl)p r op a r gyloxa zolid in on e 5 a n d 5′. Allen yl-
st a n n a n e 6a . To a stirred solution of (trimethylsilyl)-
propargyloxazolidinone 5 (1.0 g, 3.66 mmol) and TMEDA (550
µL, 3.66 mmol) in THF (36 mL) cooled to -78 °C was added
n-butyllithium (1.48 M in hexane, 4.03 mmol). The mixture
was stirred for 45 min at -78 °C, during which an orange color
developed, then magnesium(II) bromide (0.12 M in THF, 4.03
mmol) was added, and the reaction was stirred an additional
15 min. Tributyltin chloride (990 µL, 3.66 mmol) was added,
and the reaction was stirred a final 30 min at -78 °C. The
reaction was quenched by the addition of a saturated aq
sodium bicarbonate solution (25 mL) at -78 °C, allowed to
warm to room temperature, and extracted with diethyl ether
(200 mL). The organic layer was dried with magnesium sulfate,
filtered, and concentrated under pressure to give the crude
reaction product. Purification via silica flash chromatography
with silica gel, eluting with 4:1 hexane/diethyl ether, gave
allenylstannane 6a (1.60 g, 80%) as a white wax of >95% de
(determined by comparison of the tin satelites of the major
diastereomer to the minor peak of the allenyl proton in the
1H NMR spectrum).
1H NMR (400 MHz) δ: 7.36 (m, 3H), 7.23 (m, 2H), 6.23 (s,
1H), 4.66 (m, 2H), 4.04 (dd, J 1 ) 4.5 Hz, J 2 ) 7.8 Hz, 1H),
1.28 (m, 12H), 0.89 (t, J ) 7.2 Hz, 9H), 0.66 (m, 6H), 0.09 (s,
9H). 13C NMR (75 MHz) δ: 202.2, 155.8, 140.0, 129.4, 128.8,
126.5, 102.9, 84.9, 70.8, 60.3, 29.1, 28.1, 27.8, 27.5, 13.9, 10.8,
0.0.
Allen ylsta n n a n e 10. This compound was made by the
procedure described above, using (trimethylsilyl)propargylox-
azolidinone 5′, which gave allenylstannane 10 (2.55 g, 70%)
as an off-white oil of >95% de (determined by comparison of
the tin satelites of the major diastereomer to the minor peak
of the allenyl proton in the 1H NMR spectrum).
D
film): 3487 (OH), 1748 cm-1 (CO). H NMR δ: 7.41 (m, 3H),
1
7.25 (m, 2H), 6.65 (d, J ) 1.8 Hz, 1H), 4.83 (dd, J 1 ) 6.6 Hz,
J 2 ) 9.0 Hz, 1H), 4.72 (t, J ) 8.7 Hz, 1H), 4.09 (dd, J 1 ) 6.3
Hz, J 2 ) 8.4 Hz, 1H), 3.08 (bs, 1H), 1.64 (m, 1H), 0.66 (d, J )
6.6 Hz, 6H), 0.12 (s, 9H). 13C NMR (75 MHz) δ: 199.2, 155.6,
138.4, 129.4, 129.0, 126.6, 116.4, 92.9, 79.6, 70.6, 59.8, 32.8,
28.1, 27.1, 19.8, 17.7, 17.2, 13.8, 0.0. The absolute configuration
of this product was determined by single-crystal X-ray analysis
(see the Supporting Information).
Tin (II) Ch lor id e P r om oted Con d en sa tion of Allen yl-
sta n n a n e 6a w ith Ben za ld eh yd e. Syn th esis of Dia ster e-
om er ic Hom op r op a r gylic Alcoh ols 8a a n d 9a . To a stirred
solution of allenylstannane 6a (500 mg, 0.89 mmol) and
benzaldehyde (91 µL, 0.89 mmol) cooled to 0 °C was added
tin(II) chloride (169 mg, 0.89 mmol) in one portion. The
reaction was stirred at 0 °C for 4 h and then allowed to slowly
warm to room temperature overnight. The reaction was
quenched by pouring in 10% aq ammonium chloride (25 mL)
and diluted with diethyl ether (100 mL). The organic layer
was separated, washed with brine, dried with magnesium
sulfate, filtered, and concentrated under reduced pressure to
give the crude reaction product. NMR spectroscopy of the crude
reaction mixture showed an approximate 2:1 mixture of the
diastereomeric products. Purification via flash column chro-
matography with silica gel, eluting with 3:1 hexane/ethyl
acetate, gave homopropargylic alcohol 8a (156.7 mg, 46%) and
homopropargylic alcohol 9a (89.9 mg, 27%) both as white
solids.
8a . Mp: 171-173 °C. [R] 22 -145 (c 1.1, CHCl3). IR (thin
D
film): 3438 (OH), 1731 cm-1 (CO). 1H NMR (400 MHz) δ: 7.32
(m, 8H), 7.14 (m, 2H), 5.11 (t, J ) 5.6 Hz, 1H), 4.88 (t, J ) 8.4
Hz, 1H), 4.54 (t, J ) 8.4 Hz, 1H), 4.39 (d, J ) 6.8 Hz, 1H),
4.05 (dd, J 1 ) 7.6 Hz, J 2 ) 8.4 Hz, 1H), 3.85 (d, J ) 5.6 Hz,
1H), 0.00 (s, 9H). 13C NMR (75 MHz) δ: 159.2, 140.1, 137.5,
129.2, 128.4, 128.3, 127.6, 126.8, 98.8, 92.9, 74.6, 71.2, 60.4,
53.6, -0.2. The absolute configuration of this product was
determined by single-crystal X-ray analysis.
1H NMR (400 MHz) δ: 7.05 (m, 6H), 6.94 (m, 2H), 6.79 (m,
2H), 6.32 (s, 1H), 5.86 (d, J ) 8.1 Hz, 1H), 4.87 (d, J ) 8.1 Hz,
1H), 1.20 (m, 12 H), 0.84 (t, J ) 6.6 Hz, 9H), 0.57 (m, 6H),
0.10 (s, 9H). 13C NMR (75 MHz) δ: 202.5, 155.3, 135.1, 134.4,
128.4, 128.2, 128.1, 128.0, 127.4, 126.5, 102.9, 85.0, 80.5, 65.1,
29.1, 27.7, 27.4, 13.9, 10.7, 0.0.
Min or Dia ster eom er 9a . [R] 22 -86 (c 1.4, CHCl3). 1H
D
NMR (400 MHz) δ: 7.35 (m, 3H), 7.30 (s, 5H), 7.14 (m, 2H),
5.22 (t, J ) 3.9 Hz, 1H), 4.88 (t, J ) 8.4 Hz, 1H), 4.60 (t, J )
8.7 Hz, 1H), 4.16 (d, J ) 4.5 Hz, 1H), 4.09 (t, J ) 7.8 Hz, 1H),
3.92 (d, J ) 3.6 Hz, 1H), 0.09 (s, 9H). Some minor impurities
are visible in this spectrum. The absolute configuration of this
product was determined by single-crystal X-ray analysis (see
the Supporting Information).
Gen er a l Meth od for th e Bu tyltin Tr ich lor id e P r o-
m oted Con d en sa tion of P r op a r gylsta n n a n e 4 w ith Al-
d eh yd es. Syn th esis of Allen ylca r bin ol 7a . To a stirred
solution of (trimethylsilyl)propargylstannane 4 (50 mg, 0.09
mmol) and benzaldehyde (7.5 µL, 0.074 mmol) cooled to -78
°C was added butyltin trichloride (1 M in methylene chloride,
0.09 mmol) dropwise. The resulting solution was stirred,
gradually, over approximately 1 h, allowed to warm to 0 °C,
and stirred at that temperature for a further 30 min. The
reaction was quenched by the addition of dilute aq hydrochloric
acid (0.1 N, 500 µL) and extracted with diethyl ether (4 mL).
The resulting solution was stirred with potassium fluoride/
Celite (100 mg) for 1.5 h, then filtered through a plug of Celite,
and concentrated under reduced pressure to give the crude
reaction product. Purification via flash column chromatogra-
phy with silica, eluting with 5:1 hexane/ethyl acetate, gave
allenylcarbinol 7a (9.5 mg, 34%) as a white crystalline solid.
Gen er a l P r oced u r e for th e Con d en sa tion of Allen yl-
sta n n a n es 6a a n d 10 w ith Ald eh yd es. Syn th esis of
Hom op r op a r gylic Alcoh ol 7a . To a stirred solution of
allenylstannane 6a (100 mg, 0.18 mmol) and benzaldehyde (24
µL, 0.23 mmol) in methylene chloride (900 µL) at -78 °C was
added boron trifluoride diethyl etherate (55 µL, 0.45 mmol).
The reaction was stirred at -78 °C for 2.5-3 h, until no
allenylstannane remained by TLC, then quenched at -78 °C
with saturated sodium bicarbonate (5 mL), and stirred an
additional 15-20 min while warming to room temperature.
The reaction mixture was diluted with diethyl ether (40 mL),
and the organic phase was separated, dried with magnesium
sulfate, filtered, and concentrated under reduced pressure to
give the crude reaction product. The diastereoselectivity of the
reaction was determined to be >95:5. Purification through
silica gel, eluting with 3:1 hexane/ethyl acetate, gave homopro-
pargylic alcohol 7a (64.2 mg, 95%) as a white solid. Also a
small, unweighed portion of the minor diastereomer 8a could
Mp: 112-116 °C. [R] 22 -86 (c 1.4, CHCl3). IR ν (thin
D
film): 3554 (OH), 1754 cm-1 (CO). H NMR δ: 7.46 (m, 3H),
1
7.34 (m, 2H), 7.21 (m, 3H), 6.96 (m, 2H), 6.79 (d, J ) 2.1 Hz,
1H), 4.92 (dd, J 1 ) 6.6 Hz, J 2 ) 9.3 Hz, 1H), 4.76 (t, J ) 9.3
Hz, 1H), 4.62 (dd, J 1 ) 2.7 Hz, J 2 ) 4.5 Hz, 1H), 4.11 (dd,
J 1 ) 6.6 Hz, J 2 ) 8.4 Hz, 1H), 1.29 (d, J ) 4.8 Hz, 1H), -0.10
(s, 9H). 13C NMR (75 MHz) δ: 199.3, 155.7, 142.1, 138.3, 129.6,
J . Org. Chem, Vol. 69, No. 1, 2004 109

Ranslow et al.
be isolated in this way. The spectral data matched that
reported previously.
(m, 7H), 7.29 (m, 3H), 4.95 (t, J ) 8.7 Hz, 1H), 4.80 (d, J ) 9.9
Hz, 1H), 4.64 (d, J ) 12.9 Hz, 1H), 4.62 (t, J ) 8.4 Hz, 1H),
4.44 (d, J ) 11.7 Hz, 1H), 4.11 (t, J ) 8.4 Hz, 1H), 3.87 (q,
J ) 6.3 Hz, 1H), 3.73 (t, J ) 10.2 Hz, 1H), 2.36 (d, J ) 10.5
Hz, 1H), 1.31 (d, J ) 6.3 Hz, 3H), -0.07 (s, 9H). 13C NMR (75
MHz) δ: 159.3, 138.4, 138.0, 129.1, 129.0, 128.6, 128.0, 127.9,
99.8, 92.0, 74.8, 72.7, 71.4, 71.0, 59.0, 49.6, 16.7, -0.2. The
absolute configuration of this product was determined by
single-crystal X-ray analysis (see the Supporting Information).
Hom op r op a r gyl Alcoh ol 8b. This compound was made
according to the general procedure, using isobutyraldehyde,
which gave homopropargylic alcohol 8b (58.6 mg, 95%) as a
white crystalline solid. The diastereoselectivity of the reaction
was determined to be >95:5.
Mp: 167-168 °C. [R] 22 -104 (c 1.7, CHCl3). IR ν (thin
D
film): 3342 (OH), 1714 cm-1 (CO). H NMR δ: 7.38 (m, 5H),
1
5.04 (dd, J 1 ) 6.9 Hz, J 2 ) 8.7 Hz, 1H), 4.65 (t, J ) 8.7 Hz,
1H), 4.43 (d, J ) 7.8 Hz, 1H), 4.16 (dd, J 1 ) 6.9 Hz, J 2 ) 7.5
Hz, 1H), 3.77 (ddd, J 1 ) 5.1 Hz, J 2 ) 7.2 Hz, J 3 ) 12.0 Hz,
1H), 2.36 (d, J ) 6.9 Hz, 1H), 1.96 (m, 1H), 0.94 (dd, J 1 ) 7.2
Hz, J 2 ) 12.6 Hz, 6H), -0.01 (s, 9H). 13C NMR (75 MHz) δ:
159.1, 138.4, 129.1, 129.0, 127.8, 99.9, 92.0, 76.6, 71.1, 59.6,
50.3, 30.0, 20.1, 15.9, -0.1. Elem anal. Calcd for C19H27NO3-
Si: C, 66.05; H, 7.88; N, 4.05. Found: C, 65.94; H, 7.85; N,
4.05.
Hom op r op a r gyl Alcoh ol 8g. This compound was made
according to the general procedure, using (R)-2-benzyloxypro-
panal, which gave homopropargylic alcohol 8g (67.5 mg, 87%)
as a white crystalline solid. The diastereoselectivity of the
reaction was not able to be determined.
Mp: 220-221 °C. [R] 22 -90 (c 1.0, CHCl3). IR ν (thin
D
film): 3347 (OH), 1719 cm-1 (CO). 1H NMR (400 MHz) δ: 7.32
(M, 10 H), 5.00 (dd, J 1 ) 6.9 Hz, J 2 ) 8.7 Hz, 1H), 4.57 (m,
3H), 4.44 (d, J ) 11.7 Hz, 1H), 4.10 (m, 2H), 3.75 (dq, J 1 ) 4.2
Hz, J 2 ) 6.3 Hz, 1H), 2.85 (d, J ) 4.5 Hz, 1H), 1.24 (d, J ) 6.3
Hz, 3H), -0.04 (s, 9H). 13C NMR (75 MHz) δ: 159.0, 138.4,
129.1, 129.0, 128.6, 128.0, 127.9, 99.4, 92.1, 74.9, 73.1, 71.0,
70.8, 59.4, 48.5, 13.9, -0.2. The absolute configuration of this
product was determined by single-crystal X-ray analysis (see
the Supporting Information).
Hom op r op a r gyl Alcoh ol 8c. This compound was made
according to the general procedure, using n-butyraldehyde,
which gave homopropargylic alcohol 8c (56.9 mg, 93%) as a
white crystalline solid. The diastereoselectivity of the reaction
was determined to be >95:5.
Mp: 123-126 °C. [R] 22 -97 (c 1.2, CHCl3). IR ν (thin
D
film): 3494 (OH), 1716 cm-1 (CO). 1H NMR δ: 7.38 (s, 5H),
5.04 (dd, J 1 ) 5.1 Hz, J 2 ) 6.3 Hz, 1H), 4.66 (t, J ) 6.6 Hz,
1H), 4.23 (d, J ) 5.4 Hz, 1H), 4.15 (dd, J 1 ) 5.4 Hz, J 2 ) 6.6
Hz, 1H), 3.99 (dq, J 1 ) 2.4 Hz, J 2 ) 6.6 Hz, 1H), 2.69 (d, J )
4.8 Hz, 1H), 1.62 (m, 2 H), 1.42 (m, 2H), 0.93 (t, J ) 5.4 Hz,
3H), 0.0 (s, 9H). 13C NMR (75 MHz) δ: 159.0, 138.2, 129.2,
127.8, 99.8, 92.2, 72.3, 71.1, 59.9, 52.5, 36.3, 19.0, 14.2, -0.1.
Elem anal. Calcd for C19H27NO3Si: C, 66.05; H, 7.88; N, 4.05.
Found: C, 66.26; H, 8.05; N, 4.20.
Hom op r op a r gyl Alcoh ol 11a . This compound was made
according to the general procedure, using benzaldehyde and
allenylstannane 10, which gave homopropargylic alcohol 11a
(308.5 mg, 85%) as a white crystalline solid. The diastereose-
lectivity of the reaction was determined to be ∼95:5.
Mp: 252-254 °C. [R] 22 -111 (c 0.9, CHCl3). IR ν (thin
D
film): 3434 (OH), 1721 cm-1 (CO). 1H NMR (300 MHz) δ: 7.41
(m, 5H), 7.03 (m, 6H), 6.85 (m, 2H), 6.70 (d, J ) 6.9 Hz, 2H),
5.64 (d, J ) 7.8 Hz, 1H), 5.15 (t, J ) 6.0 Hz, 1H), 5.05 (d, J )
7.8 Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 3.61 (d, J ) 5.7 Hz, 1H),
-0.07 (s, 9H). 13C NMR (75 MHz) δ: 158.9, 139.8, 134.4, 134.2,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 126.9, 126.4, 98.5, 93.9,
81.2, 75.0, 64.7, 53.5, -0.3. Elem anal. Calcd for C28H29NO3-
Si: C, 73.81; H, 6.42; N, 3.07. Found: C, 74.00; H, 6.47; N,
3.18.
Hom op r op a r gyl Alcoh ol 8d . This compound was made
according to the general procedure, using crotonaldehyde,
which gave homopropargylic alcohol 8d (49.4 mg, 80%) as a
white crystalline solid. The diastereoselectivity of the reaction
was determined to be >90:10.
Mp: 179-183 °C. [R] 22 -97 (c 2.2, CHCl3). IR ν (thin
D
film): 3398 (OH), 1747 cm-1 (CO). 1H NMR δ: 7.38 (s, 5H),
5.82 (ddq, J 1 ) 1.2 Hz, J 2 ) 6.6 Hz, J 3 ) 15.3 Hz, 1H), 5.47
(ddd, J 1 ) 1.5 Hz, J 2 ) 6.0 Hz, J 3 ) 15.0 Hz, 1H), 5.02 (dd,
J 1 ) 7.2 Hz, J 2 ) 8.7 Hz, 1H), 4.63 (t, J ) 8.4 Hz, 1H), 4.44 (q,
J ) 6.6 Hz, 1H), 4.30 (d, J ) 6.9 Hz, 1H), 4.14 (dd, J 1 ) 6.9
Hz, J 2 ) 8.4 Hz, 1H), 2.88 (d, J ) 6.3 Hz, 1H), 1.73 (d, J ) 6.6
Hz, 3H), 0.0 (s, 9H). 13C NMR (75 MHz) δ: 159.0, 138.2, 129.6,
129.3, 129.2, 129.1, 127.8, 99.2, 92.6, 73.1, 71.1, 59.9, 52.4, 18.0,
-0.1. Elem anal. Calcd for C19H25NO3Si: C, 66.44; H, 7.34; N,
4.08. Found: C, 66.28; H, 7.13; N, 4.06.
Hom op r op a r gyl Alcoh ol 11b. This compound was made
according to the general procedure, using isobutyraldehyde
and allenylstannane 10, which gave homopropargylic alcohol
11b (295.9 mg, 90%) as a white crystalline solid. The diaste-
reoselectivity of the reaction was determined to be >95:5.
Mp: 96-106 °C. [R] 22 -23 (c 0.3, CHCl3). IR ν (thin film):
D
1
3531 (OH), 1725 cm-1 (CO). H NMR (300 MHz) δ: 7.06 (m,
6H), 6.93 (m, 4H), 5.85 (d, J ) 7.5 Hz, 1H), 5.29 (d, J ) 8.1
Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 3.75 (q, J ) 6.0 Hz, 1H),
2.37 (d, J ) 5.7 Hz, 1H), 2.03 (septet, J ) 6.0 Hz, 1H), 1.04 (d,
J ) 6.9 Hz, 3H), 0.99 (d, J ) 6.6 Hz, 3H), -0.1 (s, 9H). 13C
NMR (75 MHz) δ: 158.7, 134.9, 134.3, 128.3, 128.2, 128.1,
128.0, 126.4, 99.7, 92.9, 81.1, 78.1, 64.3, 50.2, 30.1, 20.0, 16.6,
-0.3. Elem anal. Calcd for C25H31NO3Si: C, 71.22; H, 7.41; N,
3.32. Found: C, 71.41; H, 7.24; N, 3.40.
Hom op r op a r gyl Alcoh ol 8e. This compound was made
according to the general procedure, using (S)-2-(tert-butyl-
diphenylsilyloxy)propanal, which gave homopropargylic alcohol
8e (70.8 mg, 68%) as a white crystalline solid. The diastereo-
selectivity of the reaction was determined to be 85:15.
Mp: 197-198 °C. [R] 22 -60 (c 1.3, CHCl3). IR ν (thin
D
film): 3381 (OH), 1705 cm-1 (CO). 1H NMR (400 MHz) δ: 7.68
(m, 4H), 7.42 (m, 5H), 7.36 (m, 6H), 4.94 (t, J ) 8.8 Hz, 1H),
4,90 (d, J ) 10.0 Hz, 1H), 4.63 (t, J ) 8.8 Hz, 1H), 4.26 (q,
J ) 10.4 Hz, 1H), 4.12 (t, J ) 10 Hz, 1H), 3.65 (t, J ) 10.0 Hz,
1H), 2.50 (d, J ) 10.8 Hz, 1H), 1.04 (d, J ) 7.2 Hz, 3H), 1.03
(s, 9H), -0.01 (s, 9H). 13C NMR (75 MHz) δ: 159.5, 138.5,
136.1, 136.0, 134.3, 133.0, 130.1, 129.9, 129.6, 129.0, 128.0,
127.7, 127.5, 99.7, 92.1, 75.2, 71.0, 68.7, 59.0, 49.8, 27.1, 26.9,
21.1, 19.7, 0.1, -0.2. Elem anal. Calcd for C34H43NO4Si: C,
69.70; H, 7.40; N, 2.47. Found: C, 69.80; H, 7.47; N, 2.47.
Hom op r op a r gyl Alcoh ol 8f. This compound was made
according to the general procedure, using (S)-2-benzyloxypro-
panal, which gave homopropargylic alcohol 8f (67.7 mg, 87%)
as a white crystalline solid. The diastereoselectivity of the
reaction was determined to be 92:8.
Hom op r op a r gyl Alcoh ol 11c. This compound was made
according to the general procedure, using (R)-2-benzyloxypro-
panal and allenylstannane 10, which gave homopropargylic
alcohol 11c (245.9 mg, 61%) as a white crystalline solid. The
diastereoselectivity of the reaction was determined to be ∼90:
10.
Mp: 150-152 °C. [R] 22 -38 (c 1.1, CHCl3). IR ν (thin
D
film): 3459 (OH), 1733 cm-1 (CO). 1H NMR (300 MHz) δ: 7.37
(m, 5H), 7.07 (m, 6H), 6.89 (m, 4H), 5.71 (d, J ) 7.5 Hz, 1H),
5.21 (d, J ) 7.8 Hz, 1H), 4.83 (d, J ) 7.2 Hz, 1H), 4.65 (d, J )
11.4 Hz, 1H), 4.50 (d, J ) 11.4 Hz, 1H), 4.05 (m, 1H), 3.81
(quintet, J ) 5.7 Hz, 1H), 2.73 (d, J ) 4.5 Hz, 1H), 1.32 (d,
J ) 6.3 Hz, 3H), -0.12 (s, 9H). 13C NMR (75 MHz) δ: 158.6,
138.3, 135.0, 134.5, 128.7, 128.3, 128.2, 128.1, 128.0, 127.9,
126.4, 99.2, 92.9, 81.0, 74.9, 74.3, 71.0, 64.0, 48.7, 14.3, -0.3.
Elem anal. Calcd for C31H35NO4Si: C, 72.48; H, 6.87; N, 2.73.
Found: C, 72.43; H, 6.78; N, 2.59.
Mp: 110-112 °C. [R] 22 -28 (c 1.4, CHCl3). IR ν (thin
D
film): 3382 (OH), 1713 cm-1 (CO). 1H NMR (400 MHz) δ: 7.37
110 J . Org. Chem., Vol. 69, No. 1, 2004

Optically Active R-Aminoallenylstannane
Hyd r obor a tion /Oxid a tion of (Tr im eth ylsilyl)a lk yn es.
Syn th esis of â-Am in o Ester 12a . To a stirred solution of
cyclohexene (115 µL, 1.1 mmol) in THF (1.1 mL) cooled to
0 °C was added the borane methyl sulfide complex (55 µL, 0.55
mmol). The reaction was warmed to room temperature, stirred
for 1 h, and then recooled to 0 °C. Homopropargylic alcohol
11a (50 mg, 0.11 mmol) in THF (1.1 mL) was added dropwise,
and reaction was again allowed to warm to room temperature
and stirred for 1.5 h (until no 11a was visible by TLC). The
reaction was then quenched by the addition of a saturated
ammonium bicarbonate solution (1.1 mL) followed by the
addition of 30% aq hydrogen peroxide (400 µL). The reaction
was stirred a final 3 h and recooled to 0 °C, and acetic acid
(220 µL) was added. The reaction was stirred overnight and
then extracted with methylene chloride (4 × 5 mL). The
combined organic extracts were dried with magnesium sulfate,
filtered, and concentrated under reduced pressure. The white
residue, thus generated, was redissolved in 4:1 benzene/
methanol (2.2 mL). (Trimethylsilyl)diazomethane (2.0 M in
hexane, 0.22 mmol) was added, and the reaction was allowed
to stir for 30 min and then was concentrated under reduced
pressure to give the crude reaction product. Purification by
flash column chromatography with silica gel, eluting with 95:5
methylene chloride/ethyl acetate, gave â-amino ester 12a (30.6
mg, 64%) as a white solid with some (<1 equiv) dimethyl
sulfone contaminant. The dimethyl sulfone was removed by
sublimation under reduced pressure by heating to approxi-
mately 40 °C, and this compound was used without further
purification.
Celite, rinsing with ethanol (5 mL), and concentrated under
reduced pressure to give the crude reaction mixture. The crude
residue was dissolved in diethyl ether, filtered again through
a pad of Celite to remove any insoluble impurities, and
concentrated again under reduced pressure. The dibenzyl
byproduct was removed by trituration with hexane (4 × 1 mL)
to give γ-hydroxy-â-amino ester 13a (11.2 mg, 78%) as a white
crystalline solid.
Mp: 97-98 °C. [R] 22 -20 (c 0.2, CHCl3). IR ν (thin film):
D
3123 (OH), 1729 cm-1 (CO). 1H NMR (300 MHz) δ: 7.36 (s,
5H), 4.44 (d, J ) 6.0 Hz, 1H), 3.68 (s, 3H), 3.35 (m, 1H), 2.50
(dd, J 1 ) 4.2 Hz, J 2 ) 15.9 Hz, 1H), 2.34 (dd, J 1 ) 9.3 Hz,
J 2 ) 16.2 Hz, 1H), 2.13 (bs, 2H). 13C NMR (75 MHz) δ: 172.8,
141.8, 128.7, 128.1, 126.8, 76.6, 54.6, 51.9, 39.0. Elem anal.
Calcd for C11H15NO3‚0.5H2O: C, 60.54; H, 7.39; N, 6.42.
Found: C, 60.27; H, 6.94; N, 6.17.
Syn th esis of â-Am in o-γ-bu tyr ola cton e Hyd r och lor id e
Sa lt 14. A stirred solution of γ-hydroxy-â-amino ester 12b (50
mg, 0.126 mmol) in THF (6.3 mL) under argon was added to
10% palladium on carbon (53.2 mg, 0.05 mmol). The reaction
mixture was flushed with hydrogen gas for 15 s and then
stirred under a balloon of hydrogen for 24 h. The reaction was
filtered through a pad of Celite, rinsing with THF (10 mL),
and concentrated under reduced pressure to give the crude
reaction mixture, in which γ-hydroxy-â-amino ester 13b was
clearly visible in the 1H NMR spectrum. This crude residue
was dissolved in diethyl ether, filtered again through a pad of
Celite to remove any insoluble impurities into a small round-
bottomed flask, and concentrated again under reduced pres-
sure. Water (2 mL) was then added, and the suspension was
gently heated and swirled for approximately 2-3 min. The
suspension was filtered through a plug of cotton, and the
filtrate was extracted with methylene chloride (5 × 5 mL) and
dried with sodium sulfate. The residue on the cotton filter and
in the round-bottomed flask were dissolved in methylene
chloride, dried with sodium sulfate, combined with the dried
methylene chloride layer from the extraction, and concentrated
under reduced pressure to approximately a 5 mL volume.
Excess hydrochloric acid (saturated in diethyl ether, 250 µL)
was added, and the solution was allowed to stand for 1-2 min
and then was concentrated to dryness under reduced pressure.
The dibenzyl byproduct was removed by trituration with
hexane (4 × 1 mL), and the remaining solid was recrystallized
from ethanol/hexane (3 crops total) to give â-amino-γ-butyro-
lactone hydrochloride salt 14 (14.2 mg, 63%) as a white,
cottony solid.
1
IR ν (thin film): 3467 (OH), 1735 cm-1 (CO). H NMR (300
MHz) δ: 7.30 (m, 5H), 7.05 (m, 4H), 6.91 (m, 2H), 6.80 (m,
2H), 6.41 (bs, 2H), 5.71 (d, J ) 8.4 Hz, 1H), 5.21 (d, J ) 8.4
Hz, 1H), 4.99 (t, J ) 7.5 Hz, 1H), 4.64 (d, J ) 8.4 Hz, 1H),
3.99 (q, J ) 6.0 Hz, 1H), 3.67 (s, 3H), 2.86 (dd, J 1 ) 7.5 Hz,
J 2 ) 16.8 Hz, 1H), 2.77 (dd, J 1 ) 5.7 Hz, J 2 ) 16.8 Hz, 1H).
13C NMR (75 MHz) δ: 172.0, 159.9, 141.3, 134.6, 133.7, 128.7,
128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 126.6, 126.1, 81.0, 75.2,
66.2, 57.4, 52.2, 34.4. HRMS (FAB+) (M + H) m/z: calcd for
C
26H27NO5, 432.1811; found, 432.1804.
Syn th esis of γ-Hyd r oxy Ester 12b. This compound was
made according to the general procedure, using 11c, which
gave γ-hydroxy ester 12c (35.5 mg, 63%) as a white solid.
[a] 22 +31 (c 0.4, CHCl3). IR (thin film): 3468 (OH), 1747
D
(CO), 1719 cm-1 (CO). 1H NMR (300 MHz) δ: 7.09 (m, 6H),
7.00 (m, 4H), 5.90 (d, J ) 8.4 Hz, 1H), 5.32 (d, J ) 8.1 Hz,
1H), 4.19 (dt, J 1 ) 4.5 Hz, J 2 ) 7.2 Hz, 1H), 3.64 (s, 3H), 3.36
(dt, J 1 ) 3.3 Hz, J 2 ) 4.5 Hz, 1H), 3.17 (d, J ) 7.2 Hz, 1H),
2.68 (dd, J 1 ) 7.8 Hz, J 2 ) 16.2 Hz, 1H), 2.49 (dd, J 1 ) 6.3 Hz,
J 2 ) 16.5 Hz, 1H), 1.72 (sextet, J ) 6.6 Hz, 1H), 0.97 (d, J )
6.6 Hz, 3H), 0.69 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz) δ:
172.2, 158.9, 135.8, 134.6, 128.7, 128.4, 128.1, 127.9, 126.0,
80.9, 78.4, 65.9, 53.6, 52.1, 35.9, 31.1, 19.6, 18.4. HRMS (FAB+)
(M + H) m/z: calcd for C23H28NO5, 398.1967; found, 398.1959.
Syn th esis of â-Am in o Ester 12c. This compound was
made by the procedure described above, using 11c, which gave
â-amino ester 12c (88.4 mg, 62%) as a white solid.
Mp: 228-230 °C. IR ν (thin film): 2918 (NH3+), 1770 cm-1
1
(CO). H NMR (300 MHz, methanol-d4) δ: 4.26 (m, 2H), 3.25
(dd, J 1 ) 6.1 Hz, J 2 ) 18.3 Hz, 1H), 2.62 (d, J ) 18.3 Hz, 1H),
1.92 (d septets, J 1 ) 6.0 Hz, J 2 ) 4.2 Hz, 1H), 1.19 (d, J ) 6.0
Hz, 3H), 1.03 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz) δ: 174.8,
87.4, 51.4, 36.8, 28.7, 20.4, 18.1. Elem anal. Calcd for C7H14
-
ClNO3: C, 46.80; H, 7.86; N, 7.80. Found: C, 47.03; H, 7.65;
N, 7.73.
Ack n ow led gm en t. Support for this research under
Grant GM26178 from the National Institutes of Health
is gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation Grant GM 49631.
1
IR ν (thin film): 3416 (OH), 1740 cm-1 (CO). H NMR (300
MHz) δ: 7.25 (m, 5H), 7.06 (m, 6H), 6.93 (m, 4H), 5.74 (d, J )
8.1 Hz, 1H), 5.28 (d, J ) 7.8 Hz, 1H), 4.44 (d, J ) 11.4 Hz,
1H), 4.39 (m, 1H), 3.94 (d, J ) 10.8 Hz, 1H), 3.80 (d, J ) 6.6
Hz, 1H), 3.71 (q, J ) 3.6 Hz, 1H), 3.61 (s, 3H), 3.53 (t, J ) 6.3
Hz, 1H), 2.79 (dd, J 1 ) 7.5 Hz, J 2 ) 16.8 Hz, 1H), 2.51 (dd,
J 1 ) 6.0 Hz, J 2 ) 17.1 Hz, 1H), 1.31 (d, J ) 5.7 Hz, 3H).
Syn t h esis of γ-Hyd r oxy-â-a m in o E st er 13a . A stirred
solution of â-amino ester 12a (29.8 mg, 0.069 mmol) in ethanol
(7.0 mL) under argon was added to 10% palladium on carbon
(15 mg, 0.014 mmol). The reaction mixture was flushed with
hydrogen gas for 15 s and then stirred under a balloon of
hydrogen for 17 h. The reaction was filtered through a pad of
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectrum
of 3; 1H and 13C NMR spectra of 6a , 7b, 8a , 8f, 8g, 10, 9a ,
12a , 12b, and 13a ; X-ray structural data for 7b, 8a , 8f, 8g,
and 9a . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0302861
J . Org. Chem, Vol. 69, No. 1, 2004 111