Photochemical Ring Expansion of α-Alkoxycyclobutanones to 2-Acetoxy-5-alkoxytetrahydrofurans: Nucleophilic Reactions at the 2-Position

Article abstract of DOI:10.1021/jo980429x

Photolysis of cyclobutanones in the presence of acetic acid produced 2-acetoxy-5-alkoxytetrahydro-furans regiospecifically and with retention of configuration at the migrating α-position. The acetoxy group was replaced by nucleophiles such as allylsilane, trimethylsilyl azide, diethylaluminum cyanide, and silylated thymine in the presence of Lewis acids.

Full text of DOI:10.1021/jo980429x

J . Org. Chem. 1998, 63, 5173-5178
5173
P h otoch em ica l Rin g Exp a n sion of r-Alk oxycyclobu ta n on es to
2-Acetoxy-5-a lk oxytetr a h yd r ofu r a n s: Nu cleop h ilic Rea ction s a t
th e 2-P osition
Gisela Umbricht, Melissa D. Hellman, and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received March 9, 1998
Photolysis of cyclobutanones in the presence of acetic acid produced 2-acetoxy-5-alkoxytetrahydro-
furans regiospecifically and with retention of configuration at the migrating R-position. The acetoxy
group was replaced by nucleophiles such as allylsilane, trimethylsilyl azide, diethylaluminum
cyanide, and silylated thymine in the presence of Lewis acids.
In tr od u ction
carbene complexes for use in organic synthesis.7 Among
the processes developed was the efficient synthesis of
optically active cyclobutanones (eq 2),8 potential sub-
strates for the photochemical ring expansion discussed
above. Below are reported the results of studies of the
process, as well as reactions of the resulting cyclic ketals.
The photochemical ring expansion of strained ketones
to oxacarbenes with subsequent trapping by protic nu-
cleophiles of the type X-H was originally reported with
the cyclocamphone ring system1 but was soon extended
to cyclobutanones and cyclopentanones.2 The mechanism
(eq 1)3 is thought to involve photochemical R-cleavage of
the cyclobutanone to the diradical with subsequent
expansion to the oxacarbene and irreversible trapping
by protic nucleophiles. R-Substitution favors ring expan-
sion over decarbonylation and cleavage pathways. Ring
expansion toward the more substituted R-position is also
favored. With radical-stabilizing R-substituents, forma-
tion of the oxacarbene is thought to be reversible.
Notwithstanding the intermediacy of a diradical, stereo-
genic centers in the R-position retain stereochemistry on
forming the oxacarbene-derived product, while the ox-
acarbene center is trapped with little or no stereoselec-
tivity.
Resu lts a n d Discu ssion
To assess the feasibility of utilizing the photolytic ring
expansion of cyclobutanones with R-alkoxycyclobutanones,
the model reaction in eq 3 was carried out. As expected,
insertion into the R-position bearing the alkoxy group was
observed exclusively, while a 1:1 mixture of diastereoi-
somers at the anomeric carbon was obtained.
In addition to its mechanistic interest, the photochemi-
cal ring expansion of cyclobutanones has been used to
synthesize dioxabicyclic [n.3.0] ring systems by intramo-
lecular3 and intermolecular4 trapping of the oxacarbene
by alcohols. Trapping with imides and imidazoles pro-
duced cyclic R-amino acetals,5 while use of purine and
pyrimidine bases led to dideoxynucleosides.6 (In these
latter two cases, mixtures of diastereoisomers at the
anomeric position were obtained.)
The reactivity of optically active cyclobutanone 2 was
next addressed (eq 4). Photolysis of 2 in the presence of
methanol and carboxylic acids resulted in fair to good
yields of functionalized tetrahydrofurans as mixtures of
epimers at the ketal (anomeric) carbon, while the use of
dimethyl malonate led to decomposition. Photolysis of
2 in the presence of phenylacetylene resulted in no
reaction after 24 h, with recovery of starting material
without racemization of the R-position. In contrast,
photolysis of 2 in the presence of water led to an excellent
yield of ketoaldehyde 4 from ring opening of the lactol
Research in these laboratories has centered on the
development of photochemical reactions of chromium
(1) Yates, P.; Kilmurry, L. J . Am. Chem. Soc. 1966, 88, 1563.
(2) (a) Morton, D. R.; Lee-Ruff, E.; Southam, R. M.; Turro, N. J . J .
Am. Chem. Soc. 1970, 92, 4349. (b) Morton, D. R.; Turro, N. J . J . Am.
Chem. Soc. 1973, 95, 3947.
(3) Pirrung, M. C.; Chang, V. K.; De Amicis, C. V. J . Am. Chem.
Soc. 1989, 111, 5824 and references therein.
(4) Mittra, A.; Biswas, S.; Venkateswaran, R. V. J . Org. Chem. 1993,
58, 7913.
(5) Hayes, I. E. E.; J andrisits, L.; Lee-Ruff, E. Can. J . Chem. 1989,
67, 2057.
(6) (a) Lee-Ruff, E.; Wan, W.-Q.; J iang, J .-L. J . Org. Chem. 1994,
59, 2114. (b) Lee-Ruff, E.; Xi, F.-d.; Qie, J . H. J . Org. Chem. 1996, 61,
1547.
(7) For a recent review, see: Hegedus, L. S. Tetrahedron 1997, 53,
4105.
(8) Hegedus, L. S.; Bates, R. W.; So¨derberg, B. C. J . Am. Chem. Soc.
1991, 113, 923.
S0022-3263(98)00429-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/25/1998

5174 J . Org. Chem., Vol. 63, No. 15, 1998
Umbricht et al.
within 20 h. (This same compound was obtained from
the DIBALH reduction of the Baeyer-Villiger lactone of
2 via the same lactol.) These last two examples confirm
that the cyclobutanone-to-oxacarbene conversion is re-
versible and stereospecific in this system. Attempts to
trap the oxacarbene with adenine or N-benzyladenine
resulted in very low yields of the desired product,
primarily because of the low solubility of these nucleo-
philes.
potentially reactive. The R-acetoxy group was expected
to be more reactive than the R′-alkoxy group, and this
proved to be the case. Treatment of 6b with a number
of nucleophiles in the presence of Lewis acids resulted
in clean replacement of the R-acetoxy group without
competitive reaction at the R-ethoxy position (eq 7).
Unfortunately, the two resident chiral centers had no
influence on the stereochemistry of this process, and all
products, with the exception of that from thymine (9d ),
were obtained as a 1:1 mixture of diastereoisomers.
Thus, allylsilane, trimethylsilyl azide, and diethylalu-
minum cyanide all coupled in good yield, while vinylsi-
lanes and silylenol ethers of ketones failed to react at
all. The formation of a low yield of a single epimer of
thymine product 9d suggests that only one epimer of 6b
underwent coupling and the other decomposed during
workup.
Chiral racemic cyclobutanone 5, having the more
easily-deprotected diphenyloxazolidinone moiety, was
next examined. It showed similar reactivity to cyclobu-
tanone 2, although the ratios of isomers at the anomeric
carbon were uniformly 1:1 with this substrate (eq 5).
The two epimers of 9b as well as those of 9c were
separable, and the stereochemistry of those of 9b was
assigned on the basis of HETCOR and NOE NMR
studies. In contrast, the stereochemistry of the epimers
of 9c could not be assigned on the basis of the same
measurements, nor could they be assigned by comparison
to those of 9b. Similarly, the stereochemistry of 9d (a
Again, the use of diethyl malonate led to decomposi-
tion, phenylacetylene failed to react, the use of 9-benzy-
ladenine resulted in low (<20%) yields, and water almost
quantitatively cleaved the product to give the ketoalde-
hyde corresponding to 4. Finally, ring expansion of
chiral, optically active cyclobutanone 7 (a potential
precursor to 4′-disubstituted nucleoside analogs) with
acetic acid trapping was also efficient (eq 6).
1
single epimer on the basis of the H NMR spectrum of
the crude reaction mixture after quenching with water
and filtration to remove aluminum salts) could not be
confidently assigned on the basis of comparison of 1H and
13C NMR spectra with those of the epimers of 9b.
In contrast to 6b, compound 8 underwent acetate
replacement reactions in lower yields, and the resulting
products 10a -c were considerably less stable, decompos-
ing on standing over the course of hours or days. In
addition, they proved very difficult to purify, and assign-
ment of structures was based primarily on comparison
of spectra with 9a -d . The reason for this difference in
stability is unknown.
Tetrahydrofurans 6b and 8 are interesting substrates
for Vorbru¨ggen-type9 couplings at the positions R to the
ring oxygen in that both the 2 and 4 positions are
In summary, photolysis of chiral cyclobutanones in the
presence of nucleophiles resulted in efficient ring expan-
(9) Niedballa, U.; Vorbru¨ggen, H. J . Org. Chem. 1974, 39, 3654.

Ring Expansion of R-Alkoxycyclobutanones
J . Org. Chem., Vol. 63, No. 15, 1998 5175
epimer B as clear oils after chromatography on silica gel
(hexane/ethyl acetate 4:1). The product consisted of a 3:1
mixture of two epimers at C-1′, as determined by integration
of the corresponding acetal proton signals and methoxy proton
sion to tetrahydrofurans, with retention of configuration
of all resident stereocenters, but with no stereoselectivity
at the newly formed stereogenic center. Acetic acid was
the most efficient nucleophile, and the resulting 2-ac-
etoxytetrahydrofurans underwent efficient but nonste-
reoselective Lewis acid-catalyzed replacement of the
acetate by a variety of nucleophiles. Since the oxazoli-
dinone moiety in all of the new compounds can readily
be removed by catalytic hydrogenolysis, to give the free
NH2 group,10 this chemistry offers routes to amino-
substituted tetrahydrofurans and nucleoside analogs.
1
signals in the crude 1H NMR. Ep im er A: H NMR (C6D6) δ
0.97 (t, 3H, J ) 7.2 Hz), 1.32-1.80 (m, 6H), 2.00-2.09 (m, 1H),
2.21 (ddd, 1H, J ) 5.1, 7.8, 13.0 Hz), 3.14 (s, 3H), 3.16 (s, 3H),
3.41 (dd, 1H, J ) 2.5, 8.5 Hz), 3.83 (t, 1H, J ) 8.4 Hz), 4.31
(dd, 1H, J ) 2.5, 8.3 Hz), 4.64 (t, 1H, J ) 5.6 Hz), 4.98 (d, 1H,
J ) 6.5 Hz), 6.88-6.98 (m, 5H); 13C NMR (C6D6) δ 14.0, 23.4,
25.5, 30.4, 34.8, 48.2, 55.9, 58.2, 59.8, 70.3, 106.0, 111.9, 126.1,
128.7, 129.2, 141.9, 158.0; IR (film) ν 2959 m, 1755s, 1721s,
1459m, 1412m, 1383w, 1211m, 1121m, 1069m cm-1; TLC
(hexane/ethyl acetate 1:1) Rf ) 0.55; HRMS ((m + 1)/z) calcd
for C19H28NO5 350.1967, found: 350.1976.
Exp er im en ta l Section
1
Ep im er B: H NMR δ 0.93 (t, 3H, J ) 7.0 Hz), 1.22-1.67
Gen er a l P r oced u r es. Photoreactions to produce cyclobu-
tanones were carried out using a 450 W Hanovia 7825
medium-pressure mercury vapor lamp immersed in a Pyrex
well and Pyrex tubes or Ace pressure tubes equipped with a
pressure head capable of withstanding 150 psi. All NMR data
were obtained in CDCl3 filtered through basic alumina im-
mediately before use. Unless otherwise noted, the spectra
were obtained at 300 MHz for protons and 75 MHz for carbon.
The following compounds were prepared according to literature
methods: [(ethoxy)(methyl)carbene]pentacarbonylchromium-
(0),11 [(benzyloxymethyl)(ethoxy)carbene]pentacarbonylchromium-
(0),12 and syn-4,5-diphenyl-3-vinyl-2-oxazolidinone.13
Gen er a l P r oced u r e for Rin g-Exp a n sion Rea ction s.
The cyclobutanone and the nucleophile were placed in a 12 ×
100 mm oven-dried Pyrex test tube. The test tube was flushed
with argon and capped with a rubber septum. Degassed
dichloromethane or tetrahydrofuran was added with a syringe.
The tube was then irradiated at 0 °C until TLC showed no
cyclobutanone remaining, typically 3-4 days. The contents
of the test tube were then poured into a separatory funnel,
and the test tube was rinsed with additional dichloromethane.
The combined organic layers were washed with water, dried
over MgSO4, and concentrated by rotary evaporation. The
residue was separated by column chromatography. In some
cases, radial chromatography was used to separate epimers.
The anomeric ratio was determined by integration of the
appropriate anomeric proton NMR signals of the crude prod-
uct.
P h otolysis of 2-Meth oxy-2,3,3,4-tetr a m eth ylcyclobu -
ta n on e in th e P r esen ce of Im id a zole To P r od u ce Tet-
r a h yd r ofu r a n 1 (eq 3). Photolysis (40 h) of the cyclobu-
tanone (49 mg, 0.31 mmol) and imidazole (22 mg, 0.32 mmol)
in 2 mL of THF at -5 °C (degassed) gave 44 mg (63%) of a
clear oil after chromatography on silica gel (diethyl ether with
increasing amount of methanol to 8%). The product consisted
of a 1:1 mixture of two epimers at C-1′, determined by
integration of the corresponding acetal protons and methoxy
protons: 1H NMR δ 0.58 (d, 3H, J ) 7.5 Hz), 0.87 (s, 3H), 0.89
(s, 3H), 0.91 (d, 3H, J ) 7.2 Hz), 0.98 (s, 3H), 1.00 (s, 3H),
1.26 (s, 3H), 1.36 (s, 3H), 2.66 (quintet, 1H, J ) 7.8 Hz), 2.76
(dq, 1H, J ) 9, 7.2 Hz), 3.20 (s, 3H), 3.29 (s, 3H), 5.32 (d, 1H,
J ) 8.7 Hz), 5.77 (d, 1H, J ) 8.4 Hz), 6.92-7.01 (m, 4H), 7.54-
7.57 (m, 2H); 13C NMR δ 8.5, 9.8, 14.8, 14.9, 18.7, 20.1, 21.8,
44.9, 46.2, 46.8, 47.9, 48.6, 48.9, 53.3, 87.9, 91.1, 110.2, 111.2,
117.3, 128.9, 129.7, 135.7 136.8; IR (film) ν 2966, 1491, 1459,
1379 cm-1; HRMS ((m + 1)/z) calcd for C12H21N2O2 225.1603,
found 225.1614.
(m, 5H), 1.81-1.89 (m, 2H), 2.27 (ddd, 1H, J ) 6.6, 9.1, 15
Hz) 3.21 (s, 3H), 3.29 (s, 3H), 4.00 (dd, 1H, J ) 1.2, 8.3 Hz),
4.48-4.54 (m, 2H), 4.86 (dd, 1H, J ) 2.3, 6.6 Hz), 5.02 (d, 1H,
J ) 6.8 Hz), 7.18-7.38 (m, 5H); 13C NMR (acetone D6) δ 14.2,
23.6, 25.8, 32.1, 33.5, 48.5, 55.9, 57.0, 58.9, 72.0, 104.7, 111.9,
126.8, 128.7, 129.6, 143.4, 158.0; TLC (hexane/ethyl acetate
1:1) Rf ) 0.58.
(b) Rea ction w ith P r op ion ic Acid To Give 3b. Pho-
tolysis (2.5 days) of 2 (37 mg, 0.12 mmol) and propionic acid
(distilled, 0.1 mL, 1.3 mmol) in 5 mL of THF (degassed) gave
31 mg (66%) of a 2:1 mixture of epimers as a clear oil after
chromatography on silica gel (hexane/ethyl acetate 4:1) (mix-
ture of two diastereomers, minor indicated with superscript
M): 1H NMR δ 0.88-0.92 (m, 3H), 1.02-1.08 (m, 3H), 1.20-
1.45 (m, 6H), 1.68-1.76 (m, 1H), 1.99-2.09 (m, 1H), 2.15-
2.27 (m, 3H + 0.5H), 2.49-2.51 (m, 0.5H), 3.13 (s, 3H), 3.20
(s, 3H), 4.02 (dd, 1H, J ) 1.2, 8.4 Hz), 4.08 (dd, 1H, J ) 2.4,
8.6 Hz), 4.51 (t, 1H, J ) 8.5 Hz), 4.57 (dd, 1H, J ) 2.2, 9.1
Hz), 4.70 (d, 1H, J ) 7.7 Hz), 4.75 (dd, 1H, J ) 2.2, 8.4 Hz),
4.96 (d, 1H, J ) 7.1 Hz), 5.87 (dd, 1H, J ) 5.0, 6.5 Hz), 6.01
(dd, 1H, J ) 2.5, 7.1 Hz), 7.19-7.41 (m, 5H); 13C NMR δ 8.6,
13.6, 13.7M, 22.8, 24.6, 24.9, 27.5, 29.1, 30.0, 32.3, 33.8, 48.4,
48.6M, 56.6, 57.9, 58.0, 59.2, 70.9, 71.4M, 96.0M, 96.8, 112.1M,
112.5, 125.6, 126.0, 129.1, 129.3, 129.5, 140.7, 141.1, 158.1,
158.4M, 172.9M, 173.7; IR (film) ν 2944m, 2878, 1747s, 1455w,
1411m, 1378w, 1318w, 1208m, 1170m, 1071m, 1054m, 972m,
890w, 758w, 714w cm-1; TLC (hexane/ethyl acetate 2:1) Rf )
0.33, HRMS ((m + 1)/z) calcd for C21H30NO6 392.2073, found
392.2053.
(c) Rea ction w ith P iva lic Acid To Give 3c. Photolysis
(3.5 days) of 2 (40 mg, 0.13 mmol) and pivalic acid (distilled,
0.15 mL, 1.3 mmol) in 5 mL of THF (degassed) gave 15 mg of
epimer A, 9 mg of a mixture of both epimers, and 5 mg of not
completely clean epimer B (overall yield 55%) (∼3:1 mixture
of epimers) as clear oils after chromatography on silica gel
(hexane/ethyl acetate 4:1).
Ep im er A: 1H NMR δ 0.85-0.93 (m, 3H), 1.11 (s, 9H), 1.22-
1.42 (m, 6H), 1.74 (dd, 1H, J ) 6.6, 14.9 Hz), 2.02-2.06 (m,
1H), 2.22 (ddd, 1H, J ) 5.0, 8.0, 14.8 Hz), 3.16 (s, 3H), 4.07
(dd, 1H, J ) 2.3, 8.6 Hz), 4.51 (t, 1H, J ) 8.5 Hz), 4.69 (d, 1H,
J ) 7.9 Hz), 4.75 (dd, 1H, J ) 2.2, 8.4 Hz), 5.84 (dd, 1H, J )
5.1, 6.4 Hz), 7.28-7.42 (m, 5H); 13C NMR δ 13.7, 22.9, 25.0,
27.0, 29.1, 34.1, 38.6, 48.6, 58.0, 59.3, 71.0, 97.3, 112.6, 126.0,
129.3, 129.6, 140.7, 158.1, 177.7; IR (film) ν 2960m, 2873w,
1745s, 1459m, 1414m, 1210m, 1148m, 1056m, 975m, 893w,
826w, 760w, 716w, 702w cm-1; TLC (hexane/ethyl acetate 2:1)
Rf ) 0.40; [R]D ) -68.5° (c ) 0.93, CH2Cl2); mp 135-137 °C.
Ep im er B: 1H NMR δ 0.89-0.93 (m, 3H), 1.12 (s, 9H), 1.23-
1.63 (m, 6H), 1.75-1.83 (m, 1H), 1.88-1.98 (m, 1H), 2.36-
2.46 (m, 1H), 3.22 (s, 3H), 4.06 (dd, 1H, J ) 1.7, 8.3 Hz), 4.55
(t, 1H, J ) 7.7 Hz), 4.93 (d, 1H, J ) 6.2 Hz), 6.01 (dd, 1H, J )
3.7, 6.9 Hz), 7.21-7.40 (m, 5H); TLC (hexane/ethyl acetate 2:1)
Rf ) 0.36.
P h otolysis of Cyclobu ta n on e 2. (a ) With Meth a n ol To
Give 3a . Photolysis (22 h) of 2 (51 mg, 0.16 mmol) and
methanol (distilled over sodium, 2 mL) in 8 mL of THF
(degassed) gave 20 mg (36%) of epimer A and 22 mg (39%) of
(10) Lander, P. A.; Hegedus, L. S. J . Am. Chem. Soc. 1994, 116,
8126.
(11) Darensbourg, M. Y.; Darensbourg, D. J . Inorg. Chem. 1970, 9,
32.
(12) Reed, A. D.; Hegedus, L. S. Organometallics 1997, 16, 2313.
(13) (a) Montgomery, J .; Wieber, G. M.; Hegedus, L. S. J . Am. Chem.
Soc. 1990, 112, 6255. (b) Akiba, T.; Tamura, O.; Terashima, S. Org.
Synth. 1997, 75, 45.
Rea ction w ith Wa ter To Give 4. Photolysis (2 days) of 2
(51 mg, 0.16 mmol) and water (2 mL) in 17 mL of THF
(degassed) gave 48 mg (>90%) of a clear oil after chromatog-
raphy on silica gel (hexane/ethyl acetate 1:1): 1H NMR δ 0.82
(t, 3H, J ) 7.5 Hz), 1.16-1.26 (m, 2H), 1.37-1.50 (m, 2H),
2.20-2.31 (m, 1H) 2.44-2.55 (m, 1H), 2.74 (dd, 1H, J ) 6.6,

5176 J . Org. Chem., Vol. 63, No. 15, 1998
Umbricht et al.
18.6 Hz), 3.10 (dd, 1H, J ) 6.3, 18.6 Hz), 4.27 (t, 1H, J ) 6.3
Hz), 4.34 (dd, 1H, J ) 7.2, 8.9 Hz), 4.65 (t, 1H, J ) 8.9 Hz),
4.83 (dd, 1H, J ) 7.2, 8.9 Hz), 7.39-7.46 (m, 5H), 9.64 (s, 1H);
13C NMR δ 13.7, 22.0, 25.4, 38.7, 41.8, 56.4, 60.2, 70.3, 128.0,
129.4, 129.7, 137.4, 157.1, 199.1, 205.3; IR (film) ν 2958m,
1754s, 1721s, 1411s, 1361m, 1224m, 1171m, 1115m, 1086m,
1034m, 766m cm-1; TLC (hexane/ethyl acetate 1:1) Rf ) 0.33;
[R]D ) +23.8 (c ) 0.011, CH2Cl2); HRMS ((m + 1)/z) calcd for
74%) as a 1.1:1 mixture of anomers: 1H NMR δ 1.05 (t, 3 ×
0.5H, J ) 6.9 Hz), 1.14 (t, 3 × 0.5H, J ) 6.9 Hz), 1.60 (s, 3 ×
0.5H), 1.68 (s, 3 × 0.5H), 2.04-2.09 (m, 2H), 2.51 (ddd, 1 ×
0.5H, J ) 6.1, 9.0, 15.7 Hz), 2.81 (ddd, 1 × 0.5H, J ) 7.8, 8.0,
14.9 Hz), 3.20-3.31 (m, 1 × 0.5H), 3.46-3.72 (m, 2H + 1 ×
0.5H), 4.64 (dd, 1 × 0.5H, J ) 7.8, 9.0 Hz), 4.75 (dd, 1 × 0.5H,
J ) 1.2, 8.0 Hz), 5.34 (d, 1 × 0.5H, J ) 7.5 Hz), 5.44 (d, 1 ×
0.5H, J ) 7.5 Hz), 5.91-5.98 (m, 1H), 6.07-6.14 (m, 1H), 6.90-
7.18 (m, 10H), 7.61 (s, 1 × 0.5H), 7.68 (s, 1 × 0.5H); 13C NMR
δ 15.0, 15.5, 17.3, 18.1, 33.2, 34.3, 57.2, 57.4, 60.4, 61.8, 63.4,
64.4, 80.7, 80.8, 84.1, 85.8, 109.8, 110.7, 116.4, 117.1, 126.0,
126.9, 127.1, 127.8, 127.9, 128.1, 128.4, 128.5, 128.6, 128.9,
129.8, 130.0, 133.2, 135.1, 135.3, 135.9, 136.5, 158.1, 158.3.
Anal. Calcd for C25H27N3O4: C, 69.27; H, 6.28; N, 9.69.
Found: C, 69.23; H, 6.53; N, 9.43.
C
17H21NO4 303.1471, found 303.1480.
(()-Cyclobu ta n on e 5. [(Ethoxy)(methyl)carbene]pentac-
arbonylchromium(0) (1.00 g, 3.80 mmol) and racemic syn-4,5-
diphenyl-3-vinyl-2-oxazolidinone (0.50 g, 1.90 mmol) were
placed in an Ace pressure tube. Dichloromethane (25 mL) was
added, and the tube was sealed with a pressure head. The
contents were degassed with three freeze-pump-thaw cycles.
The pressure tube was flushed three times with 65 psi of CO,
charged with 65 psi CO, and irradiated overnight at room
temperature. The solvent was removed by rotary evaporation,
and the Cr(CO)6 was recovered by sublimation at reduced
pressure. The remaining solid was purified by flash chroma-
tography (3:1:1 hexanes/EtOAc/CH2Cl2, SiO2) to give a single
diastereomer (0.49 g, 72%) of cyclobutanone as a white solid:
(()-Ketoa ld eh yd e Der ived fr om Cyclobu ta n on e 5. (()-
Cyclobutanone (115 mg, 0.31 mmol) and distilled water (1 mL)
were dissolved in THF in a test tube. Argon was bubbled
through the reaction for 20 min. The test tube was then
irradiated as above. MgSO4 was added to the solution, which
was then filtered through Celite. The tube was rinsed three
times with CH2Cl2, and the combined organic layers were
concentrated by rotary evaporation. Flash chromatography
(SiO2; 2:1:1 hexanes/CH2Cl2/EtOAc) gave the white solid
product in nearly quantitative yield (105 mg): 1H NMR δ 2.25
(s, 3H), 2.76 (dd, 1H, J ) 6.0, 18.6 Hz), 3.00 (ddd, 1H, J ) 0.7,
6.3, 18.6 Hz), 4.52 (t, 1H, J ) 6.3 Hz), 5.09 (d, 1H, J ) 8.4
Hz), 5.90 (d, 1H, J ) 8.4 Hz), 6.80-7.15 (m, 10H), 9.49 (s, 1H);
13C NMR δ 27.1, 42.1, 57.3, 64.4, 80.3, 125.8, 127.8, 127.9,
128.2, 128.3, 128.4, 128.8, 128.9, 134.1, 134.3, 157.8, 198.5,
203.1.
1
mp 179-181 °C; H NMR δ 1.14 (t, 3H, J ) 6.9 Hz), 1.51 (s,
3H), 2.55 (dd, 1H, J ) 10.3, 18.1 Hz), 2.92 (dd, 1H, J ) 9.2,
18.0 Hz), 3.54 (m, 2H), 4.53 (t, 1H, J ) 9.6 Hz), 5.06 (d, 1H, J
) 7.5 Hz), 5.88 (d, 1H, J ) 7.5 Hz), 6.81-7.08 (m, 10H); 13C
NMR δ 15.6, 43.3, 48.8, 60.7, 66.0, 80.2, 95.5, 126.1, 127.2,
128.0, 128.2, 128.6, 128.7, 133.6, 158.2, 206.4. Anal. Calcd
for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.14;
H, 6.39; N, 3.83.
(()-Meth a n ol Ad d u ct 6a . (()-Cyclobutanone (118 mg,
0.32 mmol) and methanol (1.5 mL) were used. The crude
reaction mixture was concentrated without washing, and the
residue was further dried under reduced pressure before
chromatography. A proton NMR spectrum of the crude
product showed both epimers present in a 1:1 ratio, but flash
chromatography (SiO2; 1:1 hexanes/EtOAc) followed by radial
chromatography (10:1 hexanes/EtOAc) resulted in isolation of
only one epimer (59 mg, 46%) as a white solid: 1H NMR δ
1.13 (t, 3H, J ) 7.0 Hz), 1.54 (s, 3H), 2.32 (ddd, 1H, J ) 6.6,
8.6, 15.1 Hz), 3.31 (s, 3H), 3.51-3.61 (m, 2H), 4.48 (dd, 1H, J
) 2.0, 9.0 Hz), 4.86 (dd, 1H, J ) 2.1, 6.6 Hz), 5.24 (d, 1H, J )
7.2 Hz), 5.81 (d, 1H, J ) 7.2 Hz), 6.90-7.10 (m, 11H); 13C NMR
δ 15.6, 18.6, 32.5, 56.1, 57.0, 58.5, 63.7, 81.2, 105.0, 110.2,
126.0, 126.2, 127.7, 127.8, 128.1, 128.4, 133.7, 136.5, 158.8.
Anal. Calcd for C23H27NO5: C, 69.50; H, 6.85; N, 3.52.
Found: C, 69.56; H, 6.92; N, 3.63.
(()-Acetic Acid Ad d u ct 6b. (()-Cyclobutanone (300 mg,
0.82 mmol) and acetic acid (0.2 mL, 3.4 mmol) were used,
equally divided between two test tubes. The reaction mixture
was washed with NaHCO3 (saturated aqueous) and dried over
Na2SO4, and after concentration the product was further dried
under reduced pressure to yield a white foam (310 mg, 89%).
The crude product, a 1.1:1 mixture of anomers, was not further
purified as it was not stable to chromatography on SiO2: 1H
NMR δ 1.13 (t, 3 × 0.5H, J ) 7.1 Hz), 1.14 (t, 3 × 0.5H, J )
7.1Hz), 1.56 (s, 3 × 0.5H), 1.58 (s, 3 × 0.5H), 1.97 (s, 3 × 0.5H),
1.98 (s, 3 × 0.5H), 2.25-2.35 (m, 2 × 0.5H), 2.53-2.63 (m, 2
× 0.5H), 3.48-3.64 (m, 2H), 4.59 (dd, 1 × 0.5H, J ) 1.1, 9.1
Hz), 4.72 (dd, 1 × 0.5H, J ) 1.1, 8.2 Hz), 4.91 (d, 1 × 0.5H, J
) 7.6 Hz), 5.14 (d, 1 × 0.5H, J ) 7.2 Hz), 5.81 (m, 1H), 5.96
(dd, 1 × 0.5H, J ) 5.1, 6.5 Hz), 6.05 (dd, 1 × 0.5H, J ) 2.0, 6.8
Hz), 6.85-7.23 (m, 10H); 13C NMR δ 15.2, 15.4, 17.3, 17.8, 21.0,
21.1, 32.2, 33.1, 57.0, 57.2, 58.6, 61.0, 63.0, 63.4, 80.8, 81.3,
96.9, 97.0, 110.7, 110.9, 125.8, 125.9, 126.1, 126.3, 126.4, 126.5,
126.6, 126.7, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.8,
133.3, 133.4, 136.0, 136.1, 158.2, 158.6, 169.1, 170.1; IR ν 1752
cm-1. The product was not sufficiently stable for elemental
analysis and was used without further purification.
Cyclobu ta n on e 7. [(Benzyloxymethyl)(ethoxy)carbene]-
pentacarbonylchromium(0) (1 equiv) and syn-4,5-diphenyl-3-
vinyl-2-oxazolidinone (2 equiv) were combined in a pressure
tube under argon. Degassed dichloromethane (enough to
dissolve all solids) was added via cannula, and the tube was
sealed with a pressure head. The apparatus was flushed three
times with 65 psi of CO, charged with 65 psi of CO, and
irradiated at -35 °C until clear, typically 4-7 days. The
solvent was removed by rotary evaporation, and the Cr(CO)6
was recovered by sublimation at reduced pressure. The
remaining solid was purified by flash chromatography (SiO2,
9:1 hexanes/EtOAc to remove excess ene-carbamate followed
by 3:1 hexanes/EtOAc) to give the product. If racemic ene-
carbamate was used, the resulting racemic cyclobutanone
could be recrystallized (hexanes/EtOAc) to give a white solid,
mp 156-158 °C, and yields were typically 50-60%. If enan-
tiomerically pure ene-carbamate was used, the cyclobutanone
was a clear oil and yields were typically 30-40%: 1H NMR δ
1.35 (t, 3H, J ) 7.3 Hz), 2.42 (dd, 1H, J ) 10.6, 18.2 Hz), 2.68
(dd, 1H, J ) 9.8, 18.2 Hz), 3.66-3.80 (m, 2H), 3.84 (d, 1H, J
) 9.2 Hz), 4.05 (d, 1H, J ) 9.2 Hz), 4.53 (d, 1H, J ) 11.2 Hz),
4.67 (d, 1H, J ) 11.2 Hz), 4.78 (t, 1H, J ) 10.2 Hz), 5.02 (d,
1H, J ) 7.7 Hz), 5.58 (d, 1H, J ) 7.7 Hz), 6.45-7.46 (m, 15H);
13C NMR δ 15.7, 46.1, 48.0, 61.7, 64.8, 69.1, 74.4, 80.4, 97.7,
125.9, 126.8, 127.7, 127.8, 127.9, 128.0, 128.1, 128.3, 128.4,
128.8, 133.6, 135.5, 137.2, 158.5, 206.4; [R]D for product derived
from (+)-ene-carbamate ) 42.4° (c ) 1, CH2Cl2).
Rin g Exp a n sion of Cyclobu ta n on e 7. The ring-expan-
sion procedure for the model system was used. Cyclobutanone
7 (154 mg, 0.33 mmol) and acetic acid (0.06 mL, 1.0 mmol)
were converted to 132 mg (76%) of tetrahydrofuran 8 as a 1.2:1
mixture of anomers. This clear oil was used without further
purification: 1H NMR δ 1.10-1.21 (m, 3H), 1.68-1.90 (m, 1H
+ 1H × 0.5), 1.92 (s, 3H × 0.5), 1.94 (s, 3H × 0.5), 2.22-2.43
(m, 1H × 0.5), 3.45-4.05 (m, 2H), 4.45-5.02 (m, 5H + 1H ×
0.5), 5.26 (dd, 1H × 0.5, J ) 7.3, 12.8 Hz), 6.02 (dd, 1H × 0.5,
J ) 2.9, 5.6 Hz), 6.13 (dd, 1H × 0.5, J ) 2.9, 5.6 Hz), 6.46-
6.51 (m, 1H × 0.5), 6.85-7.46 (m, 15H); 13C NMR δ 15.3, 15.5,
32.1, 34.0, 56.9, 57.3, 63.3, 63.4, 68.4, 69.2, 74.5, 74.6, 80.4,
80.8, 96.2, 96.8, 109.9, 110.1, 125.9, 126.1, 127.5, 127.6, 127.7,
127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6,
128.7, 128.8, 133.6, 133.7, 136.2, 136.5, 137.4, 137.7, 158.3,
(()-Im id a zole Ad d u ct 6c. (()-Cyclobutanone (115 mg,
0.31 mmol) and imidazole (63 mg, 0.93 mmol) were used. The
crude reaction mixture was concentrated without washing.
Chromatography (SiO2; 1:1 hexanes/EtOAc to remove any less
polar materials, followed by 19:1 CH2Cl2/MeOH to elute the
product) gave the pure imidazole adduct (yellow solid, 101 mg,

Ring Expansion of R-Alkoxycyclobutanones
J . Org. Chem., Vol. 63, No. 15, 1998 5177
158.6, 169.2, 170.0. The product was not sufficiently stable
for elemental analysis and was used without further purifica-
tion.
Ep im er A: 1H NMR δ 1.23 (t, 3H, J ) 7.0 Hz), 1.59 (s, 3H),
1.81-1.89 (m, 1H), 2.01-2.14 (m, 1H), 3.59 (q, 2H, J ) 7.0
Hz), 4.47 (dd, 1H, J ) 2.4, 9.4 Hz), 4.62 (dd, 1H, J ) 8.1, 12.1
Hz), 5.31 (d, 1H, J ) 7.4 Hz), 5.82 (d, 1H, J ) 7.6 Hz), 6.92-
7.09 (m, 10H); 13C NMR δ 15.8, 19.6, 31.6, 57.0, 58.8, 62.7,
63.7, 80.9, 107.5, 118.2, 126.1, 127.0, 127.9, 128.0, 128.4, 128.5,
133.6, 136.1, 158.3.
R ep r esen t a t ive Su b st it u t ion R ea ct ion P r oced u r e:
Azid e Su bstitu tion P r od u cts 9b. A 25 mL round-bottomed
flask was charged with (()-acetate 6b (120 mg, 0.28 mmol),
TMSN3 (0.12 mL, 0.90 mmol), 15 mL of dichloromethane, and
a stir bar. The reaction vessel was chilled in an ice bath for
10 minutes, and Me2AlCl (1.0 M in hexanes; 0.90 mL, 0.90
mmol) was added. The reaction was allowed to stir and slowly
warm to room temperature overnight. After 15 h, the reaction
was quenched by adding saturated NaHCO3 solution. The
reaction mixture was filtered through Celite to remove the
aluminum salts, and the layers were separated. The aqueous
layer was extracted with dichloromethane (2 × 15 mL). The
combined organic layers were washed with distilled water (1
× 15 mL) and brine (1 × 15 mL), dried over MgSO4, and
concentrated by rotary evaporation. Flash chromatography
(SiO2, 3:1 hexanes/EtOAc) removed any polar impurities and
gave 105 mg of a clear oil, a 1:1 mixture of anomers. The
anomers were separated by radial chromatography (12:1
hexanes/EtOAc) to give 45 mg of epimer A, 43 mg of epimer
B, and an additional 5 mg of mixed epimers, for a total of 93
mg (0.22 mmol, 81%). Assignments were made by HETCOR
measurements, and the epimers were subsequently identi-
fied by NOE difference experiments. Anal. Calcd for
C22H24N4O4: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.83; H,
6.00; N, 13.89.
Ep im er B: 1H NMR δ 1.20 (t, 3H, J ) 7.0 Hz), 1.58 (s, 3H),
1.92 (dd, 1H, J ) 8.5, 14.4 Hz), 2.60 (ddd, 1H, J ) 7.1, 8.0,
14.1 Hz), 3.55-3.70 (m, 2H), 4.25 (dd, 1H, J ) 7.2, 8.5 Hz),
4.72 (d, 1H, J ) 8.1 Hz), 4.83 (d, 1H, J ) 7.8 Hz), 5.78 (d, 1H,
J ) 7.8 Hz), 6.92-7.12 (m, 10H); 13C NMR δ 14.8, 16.4, 32.8,
57.6, 60.6, 63.0, 63.8, 80.6, 110.8, 119.2, 125.9, 128.0, 128.1,
128.7, 129.0, 133.3, 135.8, 158.0.
(()-Th ym in e Su bstitu tion P r od u ct 9d . Thymine (283
mg, 2.24 mmol) and N,O-bis(trimethylsilyl)acetamide (1.22
mL, 4.93 mmol) were heated to reflux for 8 h in 1,2-dichloro-
ethane. This mixture was cooled to room temperature and
then placed in an ice bath. (()-Acetate 6b (318 mg, 0.75 mmol)
was added, the reaction was allowed to stir for 5 min at 0 °C,
and Me2AlCl (1.0 M in hexanes, 5.68 mL, 5.68 mmol) was
added. The reaction was allowed to proceed as above. Only
one epimer was detected by proton NMR of the crude product.
Recrystallization (MeOH/H2O or DMSO/H2O) gave off-white
needles of product (165 mg, 45%) as a single epimer: 1H NMR
(DMSO-d6) δ 1.24 (t, 3H, J ) 7.0 Hz), 1.64 (s, 3H), 1.86 (s,
3H), 1.93 (m, 1H), 2.50 (m, 1H), 3.51 (m, 1H), 3.71 (m, 1H),
4.67 (dd, 1H, J ) 0.7, 7.6 Hz), 5.44 (d, 1H, J ) 8.5 Hz), 6.19
(d, 1H, J ) 7.7 Hz), 6.34 (t, 1H, J ) 7.3 Hz), 7.18 (m, 10H),
7.54 (s, 1H), 11.38 (bs, 1H); 13C NMR (DMSO-d6) δ 12.1, 15.0,
17.6, 30.4, 57.1, 60.8, 61.9, 79.7, 83.8, 109.5, 110.5, 126.1, 127.6,
128.1, 128.3, 134.2, 135.9, 136.7, 150.7, 157.5, 163.5; IR ν 3178,
Ep im er A (N3 a n d oxa zolid in on e tr a n s): 1H NMR δ 1.24
(t, 3H, J ) 7.0 Hz), 1.40 (dd, 1H, J ) 7.3, 12.7 Hz), 1.61 (s,
3H), 1.90 (dt, 1H, J ) 6.5, 12.6 Hz), 3.59-3.68 (m, 2H), 4.58
(dd, 1H, J ) 7.2, 12.4 Hz), 5.18 (d, 1H, J ) 6.4 Hz), 5.32 (d,
1H, J ) 7.6 Hz), 5.81 (d, 1H, J ) 7.5 Hz), 6.92-7.23 (m, 10H);
13C NMR δ 15.9, 20.7, 33.9, 56.9, 57.8, 63.8, 80.8, 88.6, 107.7,
126.1, 127.8, 128.1, 128.3, 133.8, 136.3, 158.4; IR ν 2114, 1745
1736 cm-1
. Anal. Calcd for C27H29N3O6: C, 65.98; H, 5.95;
N, 8.55. Anal. Calcd for C27H29N3O6‚0.5H2O: C, 64.79; H,
6.04; N, 8.40. Found: C, 64.90; H, 6.39; N, 8.03.
cm-1
.
Azid e Rep la cem en t P r od u ct 10a . As in the representa-
tive procedure, acetate 8 (170 mg, 0.32 mmol), TMSN3 (0.13
mL, 0.96 mmol), and Me2AlCl (1.0 M in hexanes, 0.96 mL)
were allowed to react. Flash chromatography (SiO2, 3:1
hexanes/EtOAc) followed by radial chromatography gave 84
mg of one epimer of product (51%) as a clear oil that quickly
degraded to a yellow glasslike solid upon standing neat
overnight or in solution for 2 h. Because of its instability,
assignment of structure is based primarily on the similarity
of its 13C spectrum to that of 9b: 1H NMR δ 1.16-1.26 (m,
3H), 1.68-1.77 (m, 1H), 1.81-1.90 (m, 1H), 3.59-4.11 (m, 4H),
4.65 (d, 1H, J ) 3.6 Hz), 4.83-4.92 (m, 2H), 5.22-5.29 (m,
2H), 6.64-6.68 (m, 1H), 6.93-7.46 (m, 15H); 13C NMR δ 15.3,
34.0, 57.6, 63.4, 68.7, 74.5, 80.3, 90.9, 109.8, 125.9, 126.2, 127.0,
127.7, 128.3, 128.7, 133.5, 136.1, 137.3, 158.1; IR ν 2111, 1755
1
Ep im er B (N3 a n d oxa zolid in on e cis): H NMR δ 1.31
(t, 3H, J ) 7.0 Hz), 1.55 (s, 3H), 1.57-1.67 (m, 1H), 1.79-1.88
(m, 1H), 3.58-3.78 (m, 2H), 4.40 (dd, 1H, J ) 8.2, 12.1 Hz),
5.19 (t, 1H, J ) 6.6 Hz), 5.40 (d, 1H, J ) 7.4 Hz), 5.83 (d, 1H,
J ) 7.4 Hz), 6.93-7.06 (m, 10H); 13C NMR δ 15.6, 19.8, 32.6,
57.0, 59.2, 63.7, 81.0, 89.2, 106.8, 126.1, 127.8, 127.9, 128.3,
128.4, 128.5, 128.7, 128.8, 133.8, 136.3, 158.4; IR ν 2108, 1761
cm-1
.
(()-Allyl Su bstitu tion P r od u ct 9a . (()-Acetate 6b (112
mg, 0.26 mmol) and allyltrimethylsilane (0.13 mL, 0.79 mmol)
were dissolved in acetonitrile and chilled in an ice bath;
TMSOTf (one drop) was added and the reaction allowed to
proceed as above. No filtration was required. Flash chroma-
tography (SiO2; 5:1-3:1 hexanes/EtOAc) gave 102 mg (95%)
of a clear oil. This 1:1 mixture of epimers proved insepa-
rable: 1H NMR δ 0.93 (t, 3H × 0.5, J ) 7.0 Hz), 1.18 (t, 3H ×
0.5, J ) 7.0 Hz), 1.44-1.56 (m, 1H), 1.65-1.82 (m, 1H), 1.95-
2.16 (m, 1H), 2.22 (s, 3H × 0.5), 2.26 (s, 3H × 0.5), 2.92-3.14
(m, 2H), 3.27-3.77 (m, 2H), 4.29 (dd, 1H × 0.5, J ) 5.1, 7.8
Hz), 4.64 (dd, 1H × 0.5, J ) 3.3, 9.9 Hz), 4.74-4.81 (m, 2H ×
0.5), 4.91-4.96 (m, 1H × 0.5), 5.12-5.26 (m, 2H), 5.48-5.62
(m, 1H × 0.5), 5.92 (d, 1H × 0.5, J ) 8.4 Hz), 6.04 (d, 1H ×
0.5, J ) 8.4 Hz), 6.87-7.11 (m, 10H); 13C NMR δ 15.1, 15.5,
27.4, 28.4, 33.0, 33.4, 37.7, 38.1, 59.5, 61.1, 63.6, 64.0, 65.0,
75.0, 75.3, 80.7, 80.8, 117.3, 117.7, 125.9, 126.0, 127.7, 127.8,
127.9, 128.1, 128.2, 128.3, 133.5, 134.4, 135.5, 136.6, 158.4,
158.7, 205.4, 206.0. Anal. Calcd for C25H29NO4: C, 73.69; H,
7.17; N, 3.44. Found: C, 73.75; H, 7.03; N, 3.59.
(()-Cya n id e Su bstitu tion P r od u ct 9c. (()-Acetate 6b
(243 mg, 0.57 mmol) was dissolved in CH2Cl2 and chilled in
an ice bath. Et2AlCN (1.0 M in toluene; 1.71 mL, 1.71 mmol)
was added and the reaction allowed to proceed as above. The
crude product was separated by flash chromatography (SiO2;
1:1 hexanes/EtOAc) to obtain a white foam as a 1:1 mixture
of epimers (175 mg, 78%). The epimers were partially
separable by radial chromatography (12:1 hexanes/EtOAc).
Although NOE experiments were carried out, it was still not
possible to assign the stereochemistry of these epimers: IR ν
2237, 1751 cm-1. Anal. Calcd for C23H24N2O4: C, 70.39; H,
6.16; N, 7.14. Found: C, 70.28; H, 6.41; N, 7.00.
cm-1
.
Cya n id e R ep la cem en t P r od u ct 10b . As in the model
system reaction, 132 mg (0.25 mmol) of acetate 8 was treated
with 0.74 mL of Et2AlCN (1.0 M in toluene). The crude
product (79 mg) was obtained as a white foam consisting of a
2:1:1 mixture of a single epimer of product and each epimer
of starting material. This mixture was partially separated by
radial chromatography to give 15 mg of product (22% based
on recovered starting material) as well as an additional 50 mg
(38%) of pure starting material and 10 mg of a mixture of
product and starting material: 1H NMR δ 1.21-1.27 (m, 3H),
1.93 (ddd, 1H, J ) 2.3, 8.5, 14.0 Hz), 2.47 (ddd, 1H, J ) 7.1,
8.0, 14.0 Hz), 3.60-3.81 (m, 3H), 3.88 (d, 1H, J ) 11.2 Hz),
4.36 (dd, 1H, J ) 7.1, 8.0 Hz), 4.55 (d, 1H, J ) 11.4 Hz), 4.66-
4.76 (m, 1H), 4.91 (dd, 1H, J ) 2.3, 8.0 Hz), 5.00 (d, 1H, J )
7.7 Hz), 6.60-6.64 (m, 1H), 6.92-7.47 (m, 15H); 13C NMR δ
14.9, 32.6, 57.1, 59.1, 63.1, 64.4, 66.3, 74.5, 80.2, 110.0, 118.8,
125.9, 127.7, 127.8, 128.0, 128.3, 128.4, 128.6, 128.8, 128.9,
133.4, 136.1, 137.0, 158.0. Anal. Calcd for C30H30N2O5: C,
72.27; H, 6.06; N, 5.62. Found: C, 72.08; H, 6.14; N, 5.44.
Th ym in e Su bstitu tion P r od u ct 10c. Thymine (27 mg,
0.21 mmol) and N,O-bis(trimethylsilyl)acetamide (0.11 mL,
0.44 mmol) were stirred in 10 mL of acetonitrile for 1 h.
Acetate 8 (75 mg, 0.14 mmol) was dissolved in a minimum
amount of acetonitrile and added to the silylated thymine

5178 J . Org. Chem., Vol. 63, No. 15, 1998
Umbricht et al.
mixture. The reaction was cooled in an ice bath for 15 min,
and 0.85 mL of Me2AlCl (1.0 M in hexanes) was added. The
reaction was allowed to stir and warm to rt overnight.
Rochelle’s salt (15 mL of a saturated aqueous solution) was
slowly added to quench the reaction and the biphasic mixture
stirred for 1 h. The quenched reaction was transferred to a
separatory funnel, 10 mL each of ethyl acetate and distilled
water were added, and the layers were separated. The
aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with distilled H2O (2 ×
10 mL) and brine (1 × 10 mL), dried over MgSO4, and
evaporated to give 100 mg of a gummy yellow solid. Flash
chromatography (SiO2, 2% MeOH in CH2Cl2) yielded 48 mg of
d6) after 15.5 h, the following peaks could be seen: δ 11.5, 15.7,
54.9, 62.5, 67.4, 73.0, 106.7, 126.0, 127.6, 128.1, 128.3, 150.0;
HRMS ((m + 1)/z) calcd for C34H35N3O7Na 620.2373, found
620.2362.
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631. M.D.H.
thanks the Department of Education for a fellowship.
a gummy white solid (57%).
A
1H NMR spectrum of this
material showed the product to be present as a 1:1 mixture of
epimers, but further attempts at purification by chromatog-
raphy and crystallization failed: 1H NMR (DMSO-d6) δ 0.85-
1.27 (m, 3H), 1.70-2.22 (m, 3H), 3.37-4.14 (m, obscured by
water), 4.47-4.85 (m, 3H), 4.99 (dd, 1 × 0.5H, J ) 8.4, 12.0
Hz), 5.11 (d, 1 × 0.5H, J ) 7.5 Hz), 5.18 (d, 1 × 0.5H, J ) 7.5
Hz), 5.50 (d, 1 × 0.5H, J ) 7.8 Hz), 5.64 (d, 1 × 0.5H, J ) 7.5
Hz), 5.86 (d, 1 × 0.5H, J ) 6.6 Hz), 5.91 (d, 1 × 0.5H, J ) 7.5
Hz), 5.96-6.23 (m, 3H), 6.46 (dd, 1 × 0.5H, J ) 3.0, 9.5 Hz),
6.82-7.69 (m, 15H), 11.21-11.34 (bm, 1H); 13C NMR (DMSO-
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 1, 3a -c, 4, 6b, 8, 9b-d , 10a -c
and HRMS for compound 10c (42 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.
J O980429X