Synthesis and Reactions of 3-(Nosyloxy)-2-keto Esters

Article abstract of DOI:10.1021/jo962206h

A series of 3-(nosyloxy)-2-keto esters 7a-j were prepared from the corresponding α-keto esters by conversion to the trimethylsilyl enol ether and reaction with p-nitrobenzenesulfonyl peroxide. Conversion of these materials to 1,2,3-trifunctionalized compounds is described, and comparison of their properties with isomeric 2-(nosyloxy)-3-keto esters is discussed.

Full text of DOI:10.1021/jo962206h

2458
J . Org. Chem. 1997, 62, 2458-2465
Syn th esis a n d Rea ction s of 3-(Nosyloxy)-2-k eto Ester s
Robert V. Hoffman,* M. Catherine J ohnson, and J ohn F. Okonya
Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces, New Mexico 88003-0001
Received November 26, 1996X
A series of 3-(nosyloxy)-2-keto esters 7a -j were prepared from the corresponding R-keto esters by
conversion to the trimethylsilyl enol ether and reaction with p-nitrobenzenesulfonyl peroxide.
Conversion of these materials to 1,2,3-trifunctionalized compounds is described, and comparison
of their properties with isomeric 2-(nosyloxy)-3-keto esters is discussed.
Sch em e 1
In tr od u ction
The feasibility and efficiency of selectively transform-
ing polyfunctional compounds by using differential re-
activity to distinguish the functional groups (instead of
differential protecting groups) has been a major emphasis
in our recent work.1 By independent and orthogonal
manipulation of each position of a polyfunctional com-
pound, densely functionalized products can be produced
without the need for differential protection schemes.
Much greater atom economy, decreased numbers of steps,
and, hence, higher yields result.
In this regard, 2-(nosyloxy)-3-keto esters 12 are excel-
lent precursors for the preparation of a variety of densely
functionalized products. They have been transformed
effectively into 1,2,3-tricarbonyl esters 23 and 1,2,3-
tricarbonyl amides 3, which are functional components
of FK-506 and related compounds.4 Reduction of the
ketone function of 1 can be carried out diastereoselec-
tively to give 3-hydroxy-2-(nosyloxy) esters 4 in high
yields.5 Intramolecular cyclization of 4 yields glycidic
esters 5. Alternatively, the nosylate can be replaced by
azide to give 3-hydroxy-2-azido esters 6, which serves as
a diastereoselective synthesis of 3-hydroxy-2-amino esters
after reduction (Scheme 1).
Sch em e 2
tion sequences of 7 could lead to glycidic esters,9 azirid-
inyl esters,10a and 2,3-diamino esters,6 among others.
Herein, we describe methodology for the preparation
of 3-(nosyloxy)-2-keto esters 7 from 2-keto esters and
report some aspects of their elaboration into other 1,2,3-
trifunctionalized compounds.
On the basis of the synthetic versatility of 1, it was
envisioned that 3-(nosyloxy)-2-keto esters 7 would also
be an attractive functional array for the preparation of
1,2,3-trifunctional compounds. Replacement of the nosy-
loxy group by amine equivalent nucleophiles would lead
to 3-amino-2-keto acid derivatives 8 found in cyclothe-
onamide B6 and other proteinase inhibitors of recent
interest.7 Subsequent reduction of the ketone would give
3-amino-2-hydroxy esters 9 (Scheme 2).
Resu lts
P r ep a r a t ion of â-(Nosyloxy)-r-k et o E st er s. The
reaction of p-nitrobenzenesulfonyl peroxide (pNBSP) with
enol derivatives provides a direct method for the forma-
tion of R-(nosyloxy) ketones.1 This approach was applied
to the synthesis of 3-(nosyloxy)-2-keto esters 7 by con-
verting a series of R-keto esters 10a -i to the correspond-
ing TMS ethers, which were reacted with pNBSP to give
7 (Scheme 3).
Slow addition of a triethylamine solution to a mixture
of R-keto esters 10a -d ,h -j and trimethylsilyl chloride
in THF produced TMS enol ethers 11a -d ,h -j in good
yields (50-89%).11 Silyl enol ethers 11a -d ,h -j were
This functional grouping is found in the side chain of
paclitaxel and has been the focus of a great deal of syn-
thetic attention recently.8 Other substitution and reduc-
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) Hoffman, R. V. Tetrahedron 1991, 47, 1109.
(2) Hoffman, R. V.; Wilson, A. L.; Kim, H.-O. J . Org. Chem. 1990,
55, 1267.
(3) Hoffman, R. V.; Kim, H.-O.; Wilson, A. L. J . Org. Chem. 1990,
55, 2820.
(4) Hoffman, R. V.; Huizenga, D. J . Org. Chem. 1991, 56, 6435.
(5) Hoffman, R. V.; Kim, H.-O. J . Org. Chem. 1991, 56, 6759.
(6) Wipf, P.; Kim, H.-Y. Tetrahedron Lett. 1992, 33, 4275.
(7) (a) Angelastro, M. R.; Mehdi, S.; Burkhart, J . P.; Peet, N. P.;
Bey, P. J . Med. Chem. 1990, 33, 11. (b) Angelastro, M. R.; Peet, N. P.;
Bey, P. J . Org. Chem. 1989, 54, 3913. (c) Ocain, T. D.; Rich, D. H. J .
Med. Chem. 1992, 35, 451. (d) Burkhart, J . P.; Peet, N. P.; Bey, P.
Tetrahedron Lett. 1990, 31, 1385.
(8) Reviews: (a) Rowinsky, E. K.; Cazenave, L. A.; Donehower, R.
C. J . Natl. Cancer Inst. 1990, 82, 1247. (b) Borman, S. Chem. Eng.
News 1991, 69(35), 11. (c) Kingston, D. G. I.; Molinero, A. A.; Rimoldi,
J . M. Prog. Chem. Org. Nat. Prod. 1993, 61, 1.
(9) See, for example: Mori, K.; Takikawa, H. Tetrahedron 1991, 47,
2163 and references therein.
(10) (a) Legters, J .; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 1. (b) Pearson, W. H.; Hines, J . V. J . Org. Chem. 1989,
54, 4235.
(11) Creary, X.; Inocencio, P. A.; Underiner, T. L.; Kostromin, R. J .
Org. Chem. 1985, 50, 1932.
S0022-3263(96)02206-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis and Reactions of 3-(Nosyloxy)-2-keto Esters
J . Org. Chem., Vol. 62, No. 8, 1997 2459
Ta ble 1. Hyd r a tion of
3-[(p-Nitr oben zen esu lfon yl)oxy]-2-k eto Ester s 7a -g in
Aceton e-d 6
Sch em e 3
substrate
time (min)
hydration (%)
7a
7b
7c
7d
7e
7f
15
30
240
120
20
99
96
86
84
60a
0b
7g
45
97
a
Decomposition products accompany the hydration product.
Only decomposition is detected.
b
the fastest, while the more hindered examples 7e,f show
very little hydration, even after prolonged storage. The
NMR spectra of the crude products revealed that small
amounts of the gem-diols were present in the isolated
products. As expected, the least hindered examples 7a -
c,h -j had greater diol contents (10-24%) than the more
hindered examples 7d -g (0-9%). This trend is consis-
tent with the known influence of steric factors on hydra-
tion equilibria.14
Sch em e 4
Since hydration could preclude other carbonyl addition
reactions, it was of interest to characterize the hydration
equilibrium. This was done for 7a -g by dissolving each
in dry acetone-d6, adding a few drops of D2O, and
monitoring the formation of the diol by NMR. The data
collected in Table 1 reveal that 7a -d ,g are converted
nearly completely to the gem-diol, whereas tertiary
nosyloxy ketones 7e,f are much less prone to hydration
and instead decompose to complex product mixtures,
presumably by ionization processes since 12 was detected
in the decomposition products of 7f (eq 1).
found to be stable to hydrolytic workup and silica gel
chromatography. The same procedure was not successful
for keto esters 10e,f, which have a tertiary carbon at the
â-position. This was attributed to reduced acidity of the
â-proton, and thus, a stronger base was needed to
produce the enolate.
Potassium hydride was found to convert 10e,f to their
enolates, which could be trapped with TMSCl to give silyl
enol ethers 11e,f in 71% and 72% yields, respectively.12
Silyl enol ethers 11e,f were sensitive to hydrolysis and,
thus, could not be isolated by aqueous workup or purified
by simple silica gel chromatography but were successfully
carried on as crude products that contained about 10%
of the starting keto ester.
Interestingly, the use of KH with 10c failed to give silyl
enol ether 11c.13 Thus, two different procedures are
required for the preparation of silyl enol ethers from
R-keto esters. When the â-position is unbranched, TEA/
TMSCl is the method of choice, and when the â-position
is branched, then KH/ TMSCl can be used successfully.
The geometry of 11a -f,h -j could not be assigned, even
by NOE.
These results defined a protocol for studying the
reactions of 7a -j. The extent of hydration was assayed
by NMR, and if necessary, the keto ester was dehydrated
by refluxing in toluene to effect azeotropic removal of
water. In practice, it was found that stored samples of
7b required dehydration virtually every time they were
used, while samples of 7a ,c-g rarely required dehydra-
tion. Moreover, the data clearly establish that solvents
must be dry so as to prevent hydration from competing
with other carbonyl addition reactions. On the other
hand, the data suggest that, as expected, the carbonyl
group of 7 is quite electrophilic and easily hydrated15 and
might have a useful pattern of reactivity.
Silyl enol ethers 11a -f,h -j reacted smoothly with
pNBSP to give 3-(nosyloxy)-2-keto esters 7a -f,h -j in
good yields (59-88%). The keto esters were purified by
recrystallization or chromatography and could be stored
for extended periods at 0 °C. Keto ester 10g contained
an appreciable amount of its enol tautomer; thus, it could
be reacted directly with pNBSP in the presence of zinc
chloride to give 7g in 67% yield.
Nosylates 7a -j undergo slow hydration to the gem-
diol upon storage. This process could be reversed by
heating to reflux in toluene (azeotropic distillation)
(Scheme 4). The less hindered nosylates 7a ,b hydrate
Rea ction s of â-(Nosyloxy)-r-k eto Ester s
One attractive mode for the manipulation of 3-(nosy-
loxy)-2-keto esters is a reduction-substitution sequence.
Reduction of the carbonyl group of 7 was first examined
(12) (a) Brown, C. A. J . Org. Chem. 1974, 39, 3913; (b) Ibid. 1324.
(c) Brown, C. A. J . Am. Chem. Soc. 1973, 95, 982.
(13) Treatment of 10c with KH led only to aldol dimer i in 80% yield.
(14) Guthrie, J . P. Can. J . Chem. 1975, 53, 898.
(15) The hydration of electrophilic ketones has been of recent
interest. (a) Krois, D.; Langer, E.; Lehner, H. Tetrahedron 1980, 36,
1345. (b) Ocain, T. D.; Rich, D. H. J . Med. Chem. 1992, 35, 451. (c)
Yuan, W.; Munoz, B.; Wong, C.-H. J . Med. Chem. 1993, 36, 211. (d)
Peet, N. P.; Burkhart, J . P.; Angelastro, M. R.; Giroux, E. L.; Mehdi,
S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J . Med. Chem. 1990, 33,
394. (e) Gelb, M. H.; Svaren, J . P.; Abeles, R. H. Biochemistry 1985,
24, 1813. (f) Parisi, M. F.; Abeles, R. H. Biochemistry 1992, 31, 9429.

2460 J . Org. Chem., Vol. 62, No. 8, 1997
Hoffman et al.
When the nosylate is tertiary or benzylic (7d -g), only
decomposition products are observed. Moreover, subse-
quent displacement reactions of the reduced products by
even weakly basic nucleophiles yielded glycidic esters.
Thus, treatment of 13b with sodium azide in DMSO20
failed to produce azido alcohol 15b but rather gave
glycidic ester 14b in 93% yield (eq 3). The facile closure
of 13b suggested that a reduction-substitution sequence
for the manipulation of 3-(nosyloxy)-2-keto esters was
unlikely to be a viable route to 1,2,3-trifunctional dis-
placement products.
F igu r e 1.
as a method to access 2-hydroxy-3-(nosyloxy) esters 13.
Subsequent substitution for the nosylate group would
give 2,3-disubstituted esters. Reaction of 7b with sodium
borohydride in absolute ethanol, used in the reduction
of 2-(nosyloxy)-3-keto esters,5 led only to polymeric
products. Change to a mixed solvent system of THF:
MeOH (99:1) at -78 °C produced hydroxy product 13b
in good yield (84%). Nosylates 7a ,c gave lower yields,
and the products in all cases were difficult to purify.
An alternate mode of manipulation of 3-(nosyloxy)-2-
keto esters is a substitution-reduction sequence wherein
a nosylate substitution is followed by a reduction of the
ketone group, if necessary. The substitution of 3-(nosy-
loxy)-2-keto esters 7 by amine nucleophiles was examined
first because the reaction of amines with simple R-(nosy-
loxy) ketones is known to proceed smoothly to give
R-amino ketones.21 Reaction of 7b with either benzyl-
amine or pyrrolidine gave only complex product mixtures.
Reaction of 7b with morpholine in dry acetonitrile at 0
°C gave adduct 16b in 81% crude yield (eq 4). While the
Reduction of 7a -d proceeded smoothly using sodium
triacetoxyborohydride16 in THF at room temperature.
Good yields of reduction products 13a -d that were easy
to isolate and purify were obtained (eq 2). Only a single
diastereomer of 13b,c was produced, but 13d was pro-
duced as a nearly equimolar mixture of diastereomers.
Nosyloxy ketones 7e-g, which have tertiary or benzylic
nosylates, appear to undergo reduction, but the products
subsequently decompose.17
crude product was fairly pure (>90%), attempts to further
purify the material led to extensive decomposition.
Moreover, reaction of 7a and 7j with morpholine under
the same conditions gave only complex mixtures.
It appeared that the basicity of amine nucleophiles
could be a major contributor to the extensive decomposi-
tion observed in the reactions of 7 with amines. This
supposition was bolstered by the observation that 7b and
7d underwent rapid decomposition when treated with the
non-nucleophilic base DBU.22 To circumvent this base
sensitivity, the less basic, amine equivalent nucleophile
azide appeared promising.
As a test case, the reaction of 7b with sodium azide in
acetone was examined since this reagent had been used
as a mild and effective way to produce R-azido ketones
from R-(nosyloxy) ketones.23 The reaction of 7b with
sodium azide in acetone yielded gem diol 17b as the only
isolable product. Apparently, water present in the
solvent added to the carbonyl group faster than azide
displaced the nosylate group. It was further found that
substitution for the nosylate group in 17b is extremely
slow (no reaction after several days), probably because
the hydrated nosylate 17b is structurally analogous to a
neopentyl nosylate (eq 5).
Assignment of the stereochemistry of 13b,c was ac-
complished by closure to the glycidic esters 14b,c by
treatment with potassium carbonate in absolute etha-
nol.18 The chemical shift and coupling constant of the
C-2 protons of 14b and 14c were consistent with the
chemical shifts and coupling constants of other cis-
glycidic esters (Figure 1).5,19 NOE experiments confirmed
the structure assignment. The exclusive formation of the
cis-glycidic ester requires that reduction of 7b,c occurs
stereospecifically to give syn-hydroxy nosylates 13b,c.
The reduction of 3-(nosyloxy)-2-keto esters 7a -g is
somewhat problematic, in that the reduction succeeded
only for secondary (7a -c) or deactivated (7d ) nosylates.
(16) (a) Turnbull, M. D.; Hatter, G.; Ledgerwood, D. E. Tetrahedron
Lett. 1984, 25, 5449. (b) Saksena, A. K.; Mangiaracina, P. Tetrahedron
Lett. 1983, 24, 273. (c) Gribble, G. W.; Ferguson, D. C. J . Chem. Soc.,
Chem. Commun. 1975, 535.
(17) In the case of 7f, reduction product ii was isolated from the
reaction mixture.
(18) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56, 2869.
(19) For other examples of cis-trans assignments of glycidic esters
by NMR see: (a) Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett.
1986, 27, 5397. (b) Petit, Y.; Sanner, C.; Larcheveque, M. Synthesis
1988, 538. (c) Abel-Magid, A.; Pridgen, L. N.; Eggleton, D. S.; Lantos,
I. J . Am. Chem. Soc. 1986, 108, 4595. (d) Denis, J .-M.; Correa, A.
Greene, A. E. J . Org. Chem. 1990, 55, 1957. (e) Denis, J .-M.; Greene,
A. E.; Serra, A. A.; Luche, M.-J . J . Org. Chem. 1986, 51, 46. (f) Caldwell,
C. G.; Bondy, S. S. Synthesis 1990, 34.
(20) These conditions had been used previously to convert 2-(nosy-
loxy)-3-hydroxy esters to 2-azido-3-hydroxy esters in good yield.5
(21) Hoffman, R. V.; J ankowski, B. C.; Carr, C. S.; Duesler, E. N. J .
Org. Chem. 1986, 51, 130.
(22) Upon treatment with DBU in acetonitrile, both 15b and 15d
turn dark and evolve gas bubbles within 10 min at room temperature.
(23) Patonay, T.; Hoffman, R. V. J . Org. Chem. 1995, 60, 2368.

Synthesis and Reactions of 3-(Nosyloxy)-2-keto Esters
J . Org. Chem., Vol. 62, No. 8, 1997 2461
Sch em e 5
If the acetone solvent was thoroughly dried, reaction
of 7b with sodium azide gave keto azide 18b in 77% yield
(eq 6). Since 18b is somewhat unstable, the 7 h reaction
form the silyl enol ether in good yields (Scheme 5).
Moreover, the two protocols are not interchangeable. Use
of KH with the unbranched R-keto esters gives what
appears to be condensation products between the enolate
and the electrophilic ketone. Use of TEA with the
branched-chain R-keto esters gives no reaction whatso-
ever, probably due to the steric congestion around the
methine proton, which prevents close approach by the
TEA. Nevertheless, it is possible to convert most R-keto
esters to silyl enol ethers, and these react normally with
pNBSP to give 7.
On the basis of the exceptional synthetic versatility of
2-(nosyloxy)-3-keto esters 1, it was predicted that their
3-(nosyloxy)-2-keto ester regioisomers 7 would also be
very useful for the preparation of 1,2,3-trifunctionalized
compounds. The interchange of the ketone and nosylate
groups in 7 changes the reactivity patterns significantly
from those of 1 and illustrates the sensitivity of chemical
reactivity to a polyfunctional environment.
time represents a compromise between the extent of
conversion to product and decomposition of the product.
A reaction time of 4 h gives only 53% conversion, whereas
a reaction time of 11 h gives complete loss of starting
material but evidence of decomposition products. Nev-
ertheless, 18b can be used as a synthetic intermediate
without further purification.
Treatment of 18b with sodium borohydride produced
a mixture of azido alcohols syn- and anti-19b (eq 7). The
There are two striking reactivity differences between
7 and 1. Because the ketone group of 7 is sandwiched
between the ester and nosylate groups, it is much more
electrophilic than the ketone group of 1. For example,
the ketone group of 7 hydrates readily and completely
in the presence of water. Furthermore, a very mild
reducing agent, sodium triacetoxyborohydride, is re-
quired to reduce the ketone group of 7 cleanlyssodium
borohydride is too reactive and/or basic. (In contrast, the
hydration of the ketone in 1 has never been observed,
and reduction of 1 proceeds very smoothly with sodium
borohydride.) The extreme reactivity of the ketone group
in 7 is a vexing problem since spontaneous hydration can
thwart carbonyl addition reactions and convert the
trigonal ketone group to a tetrahedral center that ef-
fectively blocks displacement reactions of the nosylate
group.
major isomer had a multiplet (1H) at δ 3.72-3.79 and a
doublet at δ 4.11 (J ) 2 Hz, 1H). These absorptions have
previously been assigned to the syn isomer of 19b;10b thus,
the reduction of 18b occurs with syn diastereoselectivity.
The signals were not sufficiently resolved to determine
the diastereomeric ratio nor could the diastereomers be
separated. The mixture was converted to the carbethoxy
derivatives syn- and anti-20b with ethyl chloroformate
(eq 8). The diastereomers were not separable, but the
1H NMR of the mixture clearly showed distinct doublets
for the C-2 protons at δ 4.89 (major) and δ 5.10 (minor)
in a ratio of 76:24; thus, the reduction of 18b occurs with
a 76:24 syn-diastereoselectivity. Because of the instabil-
ity of 18b and the low diastereoselectivity of its reduction,
the substitution-reduction route to 1,2,3-trifunctional-
ized compounds from 7 is not especially promising.
On the other hand, the nosylate group of 7 is not
sandwiched between the ester and ketone groups as it is
in 1, and it thus functions much more effectively as a
leaving group in eliminations. Consequently, the choice
of nucleophiles for displacement reactions is limited to
those that are good nucleophiles but very mild bases.
Moreover, reduction of the ketone group of 7 is viable
only when the â-carbon is unbranched; hence, the result-
ing secondary nosyloxy alcohol 13 does not decompose
rapidly.
Discu ssion
R-Keto esters 10, the precursors to 7, have significantly
lower enol content than â-keto esters, and they must be
converted to enol derivatives for successful reaction with
pNBSP. Silyl enol ethers serve this purpose well, but it
was found that two different protocols are needed to
convert 10 to their corresponding silyl enol ethers. If the
â-carbon of 10 is a nonbranched methylene group, then
TEA/TMSCl gives the silyl enol ether very effectively. If
the â-carbon is branched then KH/TMSCl is required to
Thus, many of the reactions that make 1 such a
versatile intermediate are unsuitable for manipulating

2462 J . Org. Chem., Vol. 62, No. 8, 1997
Hoffman et al.
Eth yl 3-Ca r beth oxy-3-m eth yl-1-(tr im eth ylsiloxy)p r o-
p en oa te, 11d . By the same procedure, 10d (2.95 g, 15.0
mmol) was reacted with TMSCl (2.2 mL, 1.88 g, 17.0 mmol)
and TEA (2.90 mL, 2.11 g, 21.0 mmol). Purification by
Kugelrohr distillation (0.05-0.06 mmHg) afforded a clear
liquid (3.53 g) that contained 11d (3.00 g, 74% yield) as a
nearly equimolar mixture of E and Z isomers and a small
amount of unreacted diethyl oxalpropionate (0.53g, 2.6 mmol).
11d : 1H NMR (CDCl3) δ 0.26 (s, 9H), 1.28 (t, J ) 7.2 Hz, 3H),
1.34 (t, J ) 7.2 Hz, 3H), 1.84 (s, 3H), 4.18 (q, J ) 7.2 Hz, 2H),
4.25 (q, J ) 7.2 Hz, 2H); 13C NMR (CDCl3) δ 0.7, 12.5, 14.3,
14.5, 61.0, 61.9, 115.4, 148.6, 165.6, 168.6; IR (neat) 1735, 1719,
1638 cm-1. The mixture was used in the next step.
Eth yl 2-[(Tr im eth ylsilyl)oxy]-2-bu ten oa te, 11h . By the
same procedure, 10h (3.77 g, 29.0 mmol) was reacted with
TMSCl (4.36 mL, 3.73 g, 34.3 mmol) and TEA (5.76 mL, 4.18
g, 41.3 mmol). The crude silyl enol ether 11h was obtained
as a yellow oil (5.90 g, 100%, 76% purity). This material
contained some of the starting ketone and was used in the
next step without further purification: 1H NMR (CDCl3) δ 0.23
(s, 9H), 1.31 (t, J ) 7.5 Hz, 3H), 1.71 (d, J ) 7.5 Hz, 3H), 4.20
(q, J ) 7.5 Hz, 2H), 6.15 (q, J ) 7.5 Hz, 1H).
Eth yl 5-Meth yl-2-[(tr im eth ylsilyl)oxy]-2-h exen oate, 11i.
By the same procedure, 10j 71% purity (7.00 g, 29.0 mmol)
was reacted with TMSCl (4.36 mL, 3.73 g, 34.3 mmol) and TEA
(5.76 mL, 4.18 g, 41.3 mmol). The crude silyl enol ether 11j
was obtained as yellow oil (9.12 g, 100%, 75% purity). This
material was used in the next step without further purifica-
tion: 1H NMR (CDCl3) δ 0.22 (s, 9H), 0.93 (d, J ) 6.6 Hz, 6H),
1.34 (t, J ) 7.0 Hz, 3H), 1.68 (m, 1H), 2.08 (t, J ) 7.2 Hz, 2H),
4.24 (q, J ) 7.1 Hz, 2H), 6.10 (t, J ) 7.5 Hz, 1H).
Eth yl 4-Meth yl-2-[(tr im eth ylsilyl)oxy]-2-p en ten oa te,
11j. By the same procedure, 10i (4.58 g, 29.0 mmol) was
reacted with TMSCl (4.36 mL, 3.73 g, 34.3 mmol) and TEA
(5.76 mL, 4.18 g, 41.3 mmol) for 24 h. The crude silyl enol
ether 11i was obtained as yellow oil (6.23 g, 67%, 67% purity).
This material contained some starting ketone and was used
in the next step without further purification: 1H NMR (CDCl3)
δ 0.22 (s, 9H), 1.03 (d, J ) 6.5 Hz, 6H), 1.32 (t, J ) 7.2 Hz,
3H), 1.65-1.77 (m, 1H), 4.20 (q, J ) 7.2 Hz, 2H), 5.90 (d, J )
10.0 Hz, 1H).
7. It is clear from the above results that the electrophi-
licity of the ketone group dominates the chemistry of 7,
and thus, useful transformations of 7 will have to involve
carbonyl addition by nonbasic reagents as the first step
of the sequence.
Exp er im en ta l Section
Most chemicals were purchased from Aldrich Chemical Co.
and used as received. p-Nitrobenzenesulfonyl chloride was
purchased from Fluka Chemical Co. and recrystallized from
chloroform and hexane. THF was distilled from sodium
benzophenone ketyl. Acetone was distilled after being stirred
overnight over CaSO4. Acetonitrile, ether, and TEA were dried
with CaH2 and distilled. TMSCl was distilled from magnesium
turnings. All other solvents were HPLC-grade solvents.
Melting points are uncorrected. Thin-layer chromatography
was performed on silica gel 60 F254 plates and visualized by
UV irradiation and/or iodine. Analytical HPLC was performed
with the indicated solvent systems and flow rates on a 21.4
mm i.d. × 25 cm L Dynamax 60A silica gel column. Flash
chromatography was performed using silica gel 60 PF254
containing gypsum. Radial chromatography was performed
on a radial chromatograph (Harrison) using 1-mm and 2-mm
plates of silica gel 60 PF254 containing gypsum. Elemental
analyses were carried out by M-H-W Laboratories, Phoenix,
AZ.
R-Keto esters 10a ,b,d ,e were available commercially, and
10c,24 10f,25 10g,26 and 10h -j27 were prepared by a literature
procedure. pNBSP was prepared by the literature method.28
Eth yl 2-[(Tr im eth ylsilyl)oxy]p r op en oa te, 11a .11 TEA
(5.85 mL, 4.25 g, 42.0 mmol) in THF (40 mL) was added
dropwise to a mixture of methyl pyruvate, 10a (3.17 g, 31.1
mmol), and TMSCl (4.4 mL, 3.77 g, 35.0 mmol) in THF (60
mL) under N2. After 3.5 h (TLC monitoring, EtOAc:hexane,
1:4), pentane (75 mL) was added, and the reaction mixture
was filtered. The filtrate was washed with water (2 × 50 mL)
and with brine (1 × 50 mL), dried (MgSO4), and evaporated
to give 11a as a clear liquid (3.63 g, 67%) that was used
without further purification: 1H NMR (CDCl3) δ 0.24 (s, 9H),
3.77 (s, 3H), 4.88 (s, 1H), 5.51 (s, 1H); 13C NMR (CDCl3) δ 0.3,
Eth yl 3-Meth yl-2-[(tr im eth ylsilyl)oxy]-2-bu ten oate, 11e.
KH (35% by weight, 1.32 g, 0.46 g actual, 11.5 mmol) was
washed with pentane (3 × 5 mL) under N2. Dry THF (25 mL)
was added, and the flask was cooled to 0 °C. Keto ester 10e
(1.55 g, 10.8 mmol) was syringed into the flask, and the
reaction was stirred for 30 min. TMSCl (3.0 mL, 2.57 g, 24
mmol) in THF (15 mL) was added dropwise. After 2.5 h,
pentane (50 mL) was added, and the reaction mixture was
filtered and evaporated to dryness under vacuum (60 mmHg).
Kugelrohr distillation of the residue (0.05-0.06 mmHg) af-
forded a clear liquid (1.81 g) that was a mixture of 11e (1.64
g, 71% yield) and 10e (0.17 g, 1.2 mmol). 11e: 1H NMR
(CDCl3) δ 0.19 (s, 9H), 1.33 (t, J ) 7.2 Hz, 3H), 1.80 (s , 3H),
2.06 (s, 3H), 4.21 (q, J ) 7.2 Hz, 2H); 13C NMR (CDCl3) δ 0.4,
14.3, 19.7, 20.6, 60.4, 130.6, 135.8, 165.2; IR (neat) 1717, 1637
52.4, 104.3, 147.4, 165.2; IR (neat) 2956, 1735, 1627cm-1
.
Eth yl 3-P h en yl-2-[(tr im eth ylsilyl)oxy]-2-bu ten oate, 11b.
By the same procedure, 10b (3.98 g, 19.0 mmol) was reacted
with TMSCl (2.9 mL, 2.48 g, 23.0 mmol) and TEA (3.75 mL,
2.72 g, 27.0 mmol). The crude product was separated by radial
chromatography (EtOAc:hexane, 1:9) to afford 4.84 g (89%) of
11b: 1H NMR (CDCl3) δ 0.25 (s, 9H), 1.29 (t, J ) 7.2 Hz, 3H),
3.51 (d, J ) 7.4 Hz, 2H), 4.20 (q, J ) 7.2 Hz, 2H), 6.22 (t, J )
7.4 Hz, 1H), 7.19-7.21 (m, 3H), 7.29-7.27 (m, 2H); 13C NMR
(CDCl3) δ 0.6, 14.2, 32.0, 61.0, 121.3, 126.2, 128.5, 128.5, 139.7,
141.0, 164.8; IR (neat) 3028, 1722, 1645, 1603 cm-1
.
Eth yl 2-[(Tr im eth ylsilyl)oxy]-2-octen oa te, 11c. By the
same procedure, 10c (3.59 g, 19.0 mmol) was reacted with
TMSCl (2.9 mL, 2.48 g, 23.0 mmol) and TEA (3.75 mL, 2.72 g,
27.0 mmol). The crude product was separated by radial
chromatography using a solvent gradient (EtOAc:hexane 2:98
to 1:9) to afford 2.46 g (49%) of 11c: 1H NMR (CDCl3) δ 0.22
(s, 9H, 0.90 (t, J ) 6.8 Hz, 3H), 1.31 (t, J ) 7.2 Hz, 3H), 1.41
(t, J ) 7.2 Hz, 2H), 1.29-1.43 (m, 4H), 2.15 (dt, J ) 7.2, J )
7.6 Hz, 2H), 4.21 (q, J ) 7.2 Hz, 2H), 6.07 (t, J ) 7.6 Hz, 1H);
13C NMR (CDCl3) δ 0.6, 14.2, 14.4, 22.7, 26.0, 28.6, 31.9, 61.0,
cm-1
.
Eth yl 3-Cycloh exyl-2-[(tr im eth ylsilyl)oxy]p r op en oa te,
11f. By the same procedure, KH (35% by weight, 0.83 g, 0.29
g actual, 7.2 mmol) and 10f (1.14 g, 6.2 mmol) were reacted
and quenched with TMSCl (1.5 mL, 1.28 g, 12.0 mmol).
Kugelrohr distillation of the crude product (0.05-0.06 mmHg)
afforded 11f (1.15 g, 72%) that was not completely pure. It
was used without further purification: 1H NMR (CDCl3) δ 0.18
(s, 9H), 1.33 (t, J ) 7.2 Hz, 3H), 1.57 (m, 6H), 2.28 (m, 2H),
2.64 (m, 2H), 4.20 (q, J ) 7.2 Hz, 2H); 13C NMR (CDCl3) δ 0.5,
14.5, 26.7, 27.7, 28.3, 29.3, 29.4, 60.6, 133.3, 137.2, 165.8; IR
123.9, 140.8, 165.2; IR (neat) 1721, 1647 cm-1
.
(24) Rambaud, M.; Bakasse, M.; Duguay, G.; Villieras, J . Synthesis
1988, 564.
(25) Akiyama, Y.; Kawasaki, T.; Sakamoto, M. Chem. Lett. 1983,
1231.
(26) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553.
(27) (a) Weinstock, L. M.; Currie, R. B.; Lovell, A. V. Synth.
Commun. 1981, 11, 943. (b) Melillo, D. G.; Larsen, R. D.; Mathre, D.
J .; Shukis, W. F.; Wood, A. W.; Colleluori, J . R. J . Org. Chem. 1987,
52, 5143. (c) Creary, X. J . Org. Chem. 1987, 52, 5026.
(28) Dannley, R. L.; Gagen, J . E.; Stewart, O. J . J . Org. Chem. 1970,
35, 3076.
(neat) 1716, 1630 cm-1
.
Met h yl 3-[(p -n it r ob en zen esu lfon yl)oxy]-2-oxop r op i-
on a te, 7a . pNBSP (0.61 g, 1.5 mmol) was added to a cooled
solution (0 °C) of 11a (0.41 g, 2.4 mmol) in EtOAc (40 mL).
The mixture was stirred for 4 h at 0 °C and placed in the
refrigerator overnight. The pale yellow solution was washed
with cold water (2 × 25 mL) and brine (1 × 25 mL). The
organic layer was dried (MgSO4) and evaporated until 10 mL
of liquid remained. Hexane was added until the solution

Synthesis and Reactions of 3-(Nosyloxy)-2-keto Esters
J . Org. Chem., Vol. 62, No. 8, 1997 2463
became cloudy, and it was evaporated to afford a pale yellow
solid. Recrystallization from EtOAc:hexane gave 7a as a pale
yellow solid (0.375 g, 82%): mp 118-120 °C dec; 1H NMR
(CDCl3) δ 3.92 (s, 3H), 5.34 (s, 2H), 8.18 and 8.43 (AA′BB′, J
) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 53.7, 71.2, 124.5, 129.5,
141.5, 151.1, 158.9, 183.8; IR (KBr) 3110, 1764, 1609, 1529
cm-1. Anal. Calcd for C10H9NO8S: C, 39.61; H, 2.99; N, 4.62.
Found: C, 39.76; H, 2.75; N, 4.42.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxo-4-p h en -
ylbu ta n oa te, 7b, was prepared by the same procedure from
11b (0.60g, 2.2 mmol) and pNBSP (0.66 g, 1.6 mmol). Recrys-
tallization from EtOAc:hexane afforded a white solid (0.55 g,
81%): mp 104-105 °C; 1H NMR (CDCl3) δ 1.40 (t, J ) 7.2 Hz,
3H), 3.00 (dd, J ) 10.0, 14.2 Hz, 1H), 3.27 (dd, J ) 3.6, 14.2
Hz, 1H), 4.37 (q, J ) 7.2 Hz, 2H), 5.63 (dd, J ) 3.6, 10.0 Hz,
1H), 7.05-7.07 (m, 2H), 7.14-7.21 (m, 3H), 7.75 and 8.16
(AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 12.9, 36.1, 62.4,
81.6, 123.2, 126.5, 127.8, 127.9, 128.3, 132.9, 139.9, 149.5,
158.5, 186.3; IR (KBr) 3027, 1766, 1724, 1603, 1531 cm-1. Anal.
Calcd for C18H17NO8S: C, 53.07; H, 4.21; N, 3.44. Found: C,
52.88; H, 4.40; N, 3.24.
7.5 Hz, 1H), 8.15 and 8.43 (AA′BB′, J ) 10.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 17.1, 63.4, 78.2, 124.4, 129.2, 141.8,
150.9, 159.4, 187.9; IR (neat, hydrate) 3490, 1822, 1735, 1609,
. Anal. Calcd for C12H13NO8S‚0.8H2O: C, 41.69;
H, 4.26; N, 4.05. Found: C, 41.72; H, 4.62; N, 4.25.
1537 cm-1
Eth yl 5-m eth yl-3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxo-
h exa n oa te, 7i, was prepared by the same procedure from 11i
(1.44 g, 75% purity, 4.4 mmol) and pNBSP (1.32 g, 3.20 mmol).
Trituration of the crude product with EtOAc:hexane afforded
1
a white solid (0.950 g, 80%): mp 47-49 °C; H NMR (CDCl3)
δ 0.91 (d, J ) 7.7 Hz, 3H), 0.94 (d, J ) 7.0 Hz, 3H), 1.39 (t, J
) 7.0 Hz, 3H), 1.67-1.79 (m, 3H,), 4.36 (q, J ) 7.0 Hz, 2H),
5.72 (dd, J ) 9.5, 3.3 Hz, 1H), 8.17 and 8.41 (AA′BB′, J ) 8.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 20.8, 23.0, 24.6,
39.2, 63.3, 80.5, 124.4, 129.4, 141.7, 150.9, 159.2, 188.1; IR
(KBr, hydrate) 3305, 1716, 1609, 1537 cm-1. Anal. Calcd for
C15H19NO8S: C, 48.25; H, 5.13; N, 3.75. Found: C, 48.25; H,
4.89; N, 3.63.
Eth yl 4-m eth yl-3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxo-
p en ta n oa te, 7j, was prepared by the same procedure from
11j (1.51 g, 67% purity, 4.4 mmol) and pNBSP (1.32 g, 3.20
mmol). Trituration of the crude product with EtOAc:hexane
afforded a clear yellow oil (0.930 g, 81%): 1H NMR (CDCl3) δ
0.87 (d, J ) 6.9 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H), 1.38 (t, J )
7.1 Hz, 3H), 2.40 (m, 1H), 4.36 (q, J ) 7.1 Hz, 2H), 5.53 (d, J
) 4.3 Hz, 1H), 8.15 and 8.42 (AA′BB′, J ) 9.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 13.8, 16.3, 18.8, 30.1, 63.3, 85.6,
124.4, 129.4, 141.6, 150.9, 159.8, 188.2; IR (neat) 1750, 1732,
1609, 1537 cm-1. Anal. Calcd for C14H17NO8S: C, 46.79; H,
4.77; N, 3.90. Found: C, 46.80; H, 4.76; N, 3.97.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-3-p h en yl-2-oxo-
p r op ion a te, 7g. A mixture of dry zinc chloride (0.21 g, 1.5
mmol) and pNBSP (0.60 g, 1.5 mmol) in EtOAc (50 mL) was
stirred at 0 °C until the solution turned clear (20 min). Ethyl
3-phenylpyruvate, 10g (0.37 g, 1.9 mmol), was added, and the
mixture was stirred for 4 h at 0 °C and placed in the
refrigerator overnight. The solution was worked up as above
and evaporated to dryness after addition of hexane to afford
an orange solid. Recrystallization from EtOAc/hexane gave a
yellow solid (0.39 g, 67%): mp 105-107 °C; 1H NMR (CDCl3)
δ 1.26 (t, J ) 7.2 Hz, 3H), 4.22 (dq, J ) 7.2, 10.6 Hz, 1H), 4.27
(dq, J ) 7.2, 10.6 Hz, 1H), 6.71 (s, 1H), 7.26-7.37 (m, 5H),
8.00 and 8.28 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ
13.8, 63.3, 83.2, 124.2, 129.1, 129.2, 129.29, 129.33, 130.7,
142.3, 150.7, 159.0, 184.3; IR (KBr) 3109, 1752, 1740, 1609,
1538 cm-1. Anal. Calcd for C17H15NO8S: C, 51.91; H, 3.84;
N, 3.56. Found: C, 51.96; H, 4.00; N, 3.50.
Hyd r a tion Stu d ies of 3-[(p-Nitr oben zen esu lfon yl)oxy]-
2-k eto Ester s 7a -g. A sample of 7 (usually 50 mg) was
dissolved in dry acetone-d6, and a drop of D2O was added. The
NMR spectrum was recorded at regular intervals until no
further changes in the spectrum were observed. The hydration
of 7 was evident by the disappearance of NMR peaks from the
keto form and appearance of new peaks from the hydrate.
Hydration of the carbonyl group typically caused the chemical
shift of the R-protons to move upfield by about 1 ppm. In
addition, the 13C chemical shift of the ketone carbon disap-
peared and a new signal for the gem diol carbon grew in at δ
90-95.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxoocta n oa te,
7c, was prepared by the same procedure from 11c (0.50 g, 1.9
mmol) and pNBSP (0.65 g, 1.6 mmol). The yellow oil was
separated by radial chromatography using a solvent gradient
of EtOAc:hexane (1:4 to 1:1) to give 7c as a pale yellow oil
(0.55 g, 88%): 1H NMR (CDCl3) δ 0.85 (t, J ) 6.4 Hz, 3H),
1.26 (m, 4H), 1.25-1.27 (m, 2H), 1.38 (t, J ) 7.2 Hz, 3H), 1.78-
1.87 (m, 1H), 1.91-2.00 (m, 1H), 4.36 (q, J ) 7.2 Hz, 2H), 5.65
(dd, J ) 4.0, 8.4 Hz, 1H), 8.15 and 8.42 (AA′BB′, J ) 8.8 Hz,
4H); 13C NMR (CDCl3) δ 13.8, 13.9, 22.2, 24.4, 30.78, 30.81,
63.3, 81.9, 124.4, 129.4, 141.8, 150.9, 159.5, 188.0; IR (neat)
3109, 1756, 1731, 1608, 1535 cm-1. Anal. Calcd for C16H21
-
NO8S: C, 49.61; H, 5.46; N, 3.62. Found: C, 49.48; H, 5.59;
N, 3.59.
Eth yl 3-Ca r boeth oxy-3-[(p-n itr oben zen esu lfon yl)oxy]-
2-oxobu ta n oa te, 7d , was prepared by the same procedure
from 11d (0.91 g, 3.3 mmol) and pNBSP (0.63 g, 1.6 mmol) as
a pale yellow oil. The oil was dissolved in EtOAc, and hexane
was added until cloudy. A pale yellow oil (0.41 g, 65%) was
collected by decanting the solvent: 1H NMR (CDCl3) δ 1.28 (t,
J ) 7.2 Hz, 3H), 1.36 (t, J ) 7.2 Hz, 3H), 2.00 (s, 3H), 4.30 (q,
2H, J ) 7.2), 4.33-4.39 (m, 2H), 8.16 and 8.42 (AA′BB′, J )
8.8 Hz, 4H); 13C NMR (CDCl3) δ 13.8, 13.9, 21.2, 63.4, 63.5,
88.7, 124.4, 129.2, 143.0, 150.9, 159.6, 165.2, 184.4; IR (neat)
3110, 1759, 1737, 1609, 1537 cm-1. Anal. Calcd for C15H17
-
NO10S: C, 44.67; H, 4.25; N, 3.47. Found: C, 44.82; H, 4.02;
N, 3.41.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxo-3-m eth -
ylbu ta n oa te, 7e, was prepared by the same procedure from
11e (0.36 g, 1.7 mmol) and pNBSP (0.61 g, 1.5 mmol).
Recrystallization from EtOAc:hexane gave of an off-white solid
(0.32g, 61%): mp 66-68 °C dec; 1H NMR (CDCl3) δ 1.38 (t, J
) 7.2 Hz, 3H), 1.83 (s, 6H), 4.36 (q, J ) 7.2 Hz, 2H), 8.14 and
8.41 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 14.0, 25.2,
62.9, 91.8, 124.4, 129.0, 143.5, 150.7, 160.5, 191.5; IR (KBr)
3116, 1739, 1607, 1532 cm-1
. Anal. Calcd for C13H15NO8S:
C, 45.22; H, 4.38; N, 4.06. Found: C, 45.12; H, 4.42; N, 4.11.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxo-3-cyclo-
h exylp r op ion a te, 7f, was prepared by the same procedure
from 11f (0.41 g, 1.6 mmol) and pNBSP (0.61 g, 1.5 mmol).
Recrystallization from EtOAc:hexane gave a white solid (0.34
Hyd r a tion of 7a . After 15 min, the 1H NMR showed 7a
was (99%) hydrated: 1H NMR (acetone-d6) δ 3.72 (s, 3H), 4.28
(s, 2H), 8.24 and 8.54 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR
(acetone-d6) δ 53.2, 73.3, 92.4, 125.4, 130.4, 141.8, 151.8, 170.6.
Hyd r a tion of 7b. After 30 min, the 1H NMR showed 7b
was (96%) hydrated: 1H NMR (acetone-d6) δ 1.32 (t, J ) 7.2
Hz, 3H), 2.92 (dd, J ) 10.2, 14.8 Hz, 1H), 3.23 (dd, J ) 2.0,
14.8 Hz, 1H), 4.13 (d, J ) 4.6 Hz, 2H), 4.21 (dq, J ) 4.6, 7.2
Hz, 2H), 5.29 (dd, J ) 2.0, 10.2 Hz, 1H), 7.07-7.16 (m, 5H),
7.71 and 8.24 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (acetone-d6)
δ 14.1, 35.7, 63.0, 88.3, 94.1, 124.9, 127.3, 129.2, 129.4, 130.3,
137.4, 143.7, 151.0, 170.9.
1
g, 59%): mp 103-105 °C; H NMR (CDCl3) δ 1.26-1.35 (m,
1H), 1.39 (t, J ) 7.2 Hz, 3H), 1.55-1.69 (m, 5H), 1.98 (dt, J )
3.6, 13.2 Hz, 2H), 2.40 (d, J ) 14.0 Hz, 2H), 4.36 (q, J ) 7.2
Hz, 2H), 8.17 and 8.42 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR
(CDCl3) δ 14.0, 20.9, 24.3, 32.8, 62.8, 94.3, 124.3, 129.1, 143.3,
150.7, 160.3, 191.5; IR (KBr) 3104, 1740, 1605, 1538 cm-1
.
Anal. Calcd for C16H19NO8S: C, 49.87; H, 4.97; N, 3.63.
Found: C, 49.92; H, 5.11; N, 3.59.
Eth yl 3-[(p-n itr oben zen esu lfon yl)oxy]-2-oxobu tan oate,
7h , was prepared by the same procedure from 11h (0.89 g,
4.4 mmol) and pNBSP (1.3 g, 3.2 mmol). Trituration of the
crude product with EtOAc:hexane afforded a clear yellow oil
(0.79 g, 75%): 1H NMR (CDCl3) δ 1.38 (t, J ) 7.0 Hz, 3H),
1.62 (d, J ) 7.5 Hz, 3H), 4.35 (q, J ) 7.0 Hz, 2H), 5.77 (q, J )
1
Hyd r a tion of 7c. After 240 min, the H NMR showed 7c
was (86%) hydrated: 1H NMR (acetone-d6) δ 0.86 (t, J ) 6.8
Hz, 3H), 1.23-1.35 (m, 6H), 1.25 (t, J ) 7.2 Hz, 3H), 1.76-
1.88 (m, 2H), 4.10 (dq, J ) 7.2, 10.8 Hz, 1H), 4.19 (dq, J ) 7.2,
10.8 Hz, 1H), 4.98 (dd, J ) 3.6, 9.0 Hz, 1H), 8.21 and 8.47

2464 J . Org. Chem., Vol. 62, No. 8, 1997
Hoffman et al.
(AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (acetone-d6) δ 14.12, 14.15,
22.9, 25.8, 29.7, 31.9, 62.7, 87.4, 94.2, 124.9, 130.0, 144.2, 151.3,
170.9.
Eth yl 3-Ca r beth oxy-3-[(p-n itr oben zen esu lfon yl)oxy]-
2-h yd r oxybu ta n oa te, 13d . By the same procedure, 7d (0.42
g, 1.0 mmol) was reduced with sodium triacetoxyborohydride
(0.25 g, 1.2 mmol) for 18 h at room temperature to give a clear
oil (0.34 g, 81%). Two diastereomers were obtained in a 2:3
ratio that were not separable due to decomposition: 1H NMR
(CDCl3) δ 1.16 (t, J ) 7.2 Hz, 3H), 1.27 (t, J ) 7.2 Hz, 3H),
1.331 (t, J ) 7.2 Hz, 3H), 1.335 (t, J ) 7.2 Hz, 3H), 1.97 (s,
3H), 1.99 (s, 3H), 3.45 (br s, 1H), 4.17 (q, J ) 7.2, 2H), 4.27 (q,
J ) 7.2, 2H), 4.30 (q, J ) 7.2, 2H), 4.31 (q, J ) 7.2, 2H), 4.44
(s, 1H), 8.17 and 8.39 (AA′BB′, J ) 8.8 Hz, 4H), 8.18 and 8.38
(AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 13.9, 14.0, (14.0),
(14.0), 19.3, 20.0, 62.75, 62.80, 62.9, 63.0, 74.6, 75.1, 90.8, 90.9,
124.17, 124.23, 128.9, 129.1, 143.8, 143.9, 150.5, 150.6, 167.7,
168.0, 169.6, 169.9; IR (neat) 3491, 3109, 1745, 1609, 1534
1
Hyd r a tion of 7d . After 120 min, the H NMR showed 7d
was (84%) hydrated: 1H NMR (acetone-d6) δ 1.16 (t, J ) 7.2
Hz, 3H), 1.28 (t, J ) 7.2 Hz, 3H), 1.95 (s, 3H), 4.14-4.20 (m,
2H), 4.26 (q, 2H, J ) 7.2), 8.28 and 8.53 (AA′BB′, J ) 8.8 Hz,
4H); 13C NMR (acetone-d6) δ 14.0, 14.1, 18.2, 63.1, 63.2, 92.2,
95.3, 125.2, 129.7, 144.7, 151.5, 168.5, 170.0.
Hyd r a tion of 7e. After 60 min, the 1H NMR showed 7e
was (71%) hydrated; however, what appeared to be an elimi-
nation product and other unidentified side products began to
grow in after 15 min: 1H NMR (acetone-d6) δ 1.22 (t, J ) 7.2
Hz, 3H), 1.72 (s, 6H), 4.21 (q, J ) 7.2 Hz, 2H), 8.21 and 8.50
(AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (acetone-d6) δ 14.2, 22.4,
62.9, 96.1, 97.2, 125.3, 129.6, 145.8, 151.4, 171.4.
cm-1
.
1
cis-Eth yl 4-P h en yl-2,3-oxir a n ebu ta n oa te 14b. Anhy-
drous potassium carbonate (0.31 g, 2.26 mmol) was added to
a solution of 13b (0.26 g, 0.64 mmol) in absolute ethanol (8
mL). The reaction was stirred for 24 h at room temperature.
Ether (45 mL) was added, and the organic layer was washed
with water (40 mL). The aqueous phase was washed with
ether (2 × 30 mL). The combined organic layers were washed
with brine (25 mL), dried (MgSO4), and evaporated to dryness
to afford a pale yellow oil (0.11 g, 85%). The crude product
was purified by Kugelrohr distillation to afford a pale yellow
oil (0.10 g, 77%): 1H NMR (CDCl3) δ 1.32 (t, J ) 7.2 Hz, 3H),
2.90 (dd, J ) 6.4, 14.8 Hz, 1H), 3.11 (dd, J ) 6.0, 14.8 Hz,
1H), 3.39 (dt, J ) 4.8, 6.4 Hz, 1H), 3.57 (d, J ) 4.8 Hz, 1H),
4.30 (q, J ) 7.2 Hz, 2H), 7.21-7.34 (m, 5H); 13C NMR (CDCl3)
δ 14.3, 33.8, 52.8, 57.7, 61.6, 126.9, 128.7, 128.9, 136.6, 168.3;
Hyd r a tion of 7f. After 48 h, the H NMR showed 7f had
decomposed, the major product being identified as elimination
product 12: 1H NMR (acetone-d6) δ 1.33 (t, J ) 7.2 Hz, 3H),
1.67 (t, J ) 2.8 Hz, 4H), 2.20 (br s, 2H), 2.35 (br s, 2H), 4.33
(q, J ) 7.2 Hz), 2H, 6.99 (t, J ) 3.6 Hz, 1H); 13C NMR (acetone-
d6) δ 14.3, 22.18, 22.20, 22.6, 27.2, 62.6, 136.6, 150.6, 166.1,
189.8.
Hyd r a tion of 7g. After 45 min, the 1H NMR showed 7g
was (97%) hydrated: 1H NMR (acetone-d6) δ 1.28 (t, J ) 7.2
Hz, 3H), 4.18 (q, J ) 7.2 Hz, 2H), 5.81 (s, 1H), 7.13-7.22 (m,
3H), 7.33 (d, J ) 7.2 Hz, 2H), 7.92 and 8.25 (AA′BB′, J ) 8.8
Hz, 4H); 13C NMR (acetone-d6) δ 14.2, 62.9, 86.6, 94.5, 124.9,
128.3, 129.6, 130.2, 130.5, 133.2, 143.4, 151.3, 170.8.
Meth yl 3-[(p-Nitr oben zen esu lfon yl)oxy]-2-h ydr oxypr o-
p ion a te, 13a . Sodium triacetoxyborohydride (0.32 g, 1.5
mmol) was added to a solution of 7a (0.41 g, 1.4 mmol) in THF
(40 mL) at 0 °C, and the mixture was stirred for 18 h at room
temperature. EtOAc (40 mL) was added, and the reaction
mixture was washed with water (3 × 40 mL) and brine (1 ×
40 mL). The aqueous layers were extracted with EtOAc, and
the combined organic layers were dried (MgSO4), passed
through a 1.5 cm pad of silica gel, and evaporated to give a
yellow oil. Recrystallization from EtOAc/hexane afforded 13a
as a yellow solid (0.25 g, 61%): mp 80-82 °C; 1H NMR (CDCl3)
δ 3.83 (s, 3H), 4.40 (t, J ) 2.8 Hz, 1H), 4.44 (d, J ) 2.8 Hz,
2H), 8.12 and 8.41 (AA′BB′, J ) 8.4 Hz, 4H); 13C NMR (CDCl3)
δ 53.4, 69.0, 71.4, 124.4, 129.4, 141.4, 150.9, 171.1; IR (KBr)
IR (neat) 1749, 1605 cm-1
.
Oxirane 14b was obtained in 93% yield when a solution of
syn-13b in DMSO was treated with sodium azide (2 equiv) at
room temperature for 23 h.
cis-Eth yl 2,3-Oxir a n eocta n oa te, 14c, was prepared by
the same procedure from 13c (0.20 g, 0.51 mmol) to afford a
yellow oil (0.043 g, 45%): 1H NMR (CDCl3) δ 0.89 (t, J ) 6.8
Hz, 3H), 1.31 (t, J ) 7.2 Hz, 3H), 1.50-1.75 (m, 8H), 3.17 (dt,
J ) 4.8, 5.8 Hz, 1H), 3.51 (d, J ) 4.8 Hz, 1H), 4.26 (dq, J )
2.0, 7.2 Hz, 2H); 13C NMR (CDCl3) δ 13.9, 14.2, 22.5, 25.8, 27.2,
31.4, 62.9, 57.7, 61.4, 168.4; IR (neat) 1753 cm-1
.
Eth yl 3-Mor ph olin o-2-oxo-4-ph en ylbu tan oate, 16b. De-
hydration of 7b (0.30 g, 0.74 mmol) was effected by refluxing
in toluene to effect azeotropic removal of water. After removal
of the toluene and dissolution in acetonitrile (50 mL) at 0 °C,
morpholine (0.13 mL, 0.13 g, 1.5 mmol) was added, and the
reaction mixture was stirred for 4.5 h at 0 °C. CH2Cl2 (50 mL)
was added, and the organic layers were washed with cold
water (2 × 25 mL) and with cold brine (1 × 25 mL). The
combined aqueous extracts were combined and washed with
CH2Cl2 (1 × 50 mL). The combined organic phases were dried
(MgSO4) and evaporated to afford a yellow oil. The crude
product was dissolved in CH2Cl2 and filtered through cotton
to remove morpholine salts, and hexane was added until
cloudy. A small additional amount of precipitate was collected,
and the filtrate was evaporated to yield 16b (0.17 g, 81%): 1H
NMR (CDCl3) δ 1.32 (t, J ) 6.8 Hz, 3H), 2.62 (t, J ) 4.2 Hz,
4H), 2.89 (dd, J ) 5.6, 13.8 Hz, 1H), 3.05 (dd, J ) 8.6, 13.8
Hz, 1H), 3.56-3.64 (m, 4H), 4.16 (dd, J ) 5.6, 8.6 Hz, 1H),
4.28 (q, J ) 6.8 Hz, 2H), 7.21-7.27 (m, 5H); 13C NMR (CDCl3)
δ 13.1, 28.6, 48.5, 61.0, 66.3, 68.7, 125.4, 127.6, 128.3, 137.1,
162.8, 190.6; IR (neat) 1744, 1728, 1604 cm-1. Product 16b
was not sufficiently stable to obtain elemental analysis.
Eth yl 3-Azid o-2-oxo-4-p h en ylbu ta n oa te, 18b. Sodium
azide (0.124 g, 1.91 mmol) was added to 7b (0.39 g, 0.96 mmol)
that was dehydrated by refluxing in toluene and dissolved in
dry acetone (30 mL). The reaction was stirred for 7 h at 0 °C.
Water (50 mL) was added, and the aqueous layer was washed
with EtOAc (3 × 50 mL). The combined organic layers were
dried (MgSO4) and evaporated to give a dark yellow oil (0.183
g, 77%). Due to the instability of the product, no further
purification was attempted: 1H NMR (CDCl3) δ 1.37 (t, J )
7.2 Hz, 3H), 2.96 (dd, J ) 8.8, 13.8 Hz, 1H), 3.23 (dd, J ) 5.2,
13.8 Hz, 1H), 4.33 (q, J ) 7.2 Hz, 2H), 4.76 (dd, J ) 5.2, 8.8
Hz, 1H), 7.25-7.34 (m, 5H); 13C NMR (CDCl3) δ 13.9, 36.3,
3514, 3118, 1735, 1610, 1543 cm-1. Anal. Calcd for C10H11
-
NO8S: C, 39.35; H, 3.63; N, 4.59. Found: C, 39.51; H, 3.75;
N, 4.58.
E t h yl 3-[(p -Nit r ob en zen esu lfon yl)oxy]-2-h yd r oxy-4-
p h en ylbu ta n oa te, 13b. By the same procedure, 7b (0.35 g,
0.86 mmol) was reacted with sodium triacetoxyborohydride
(0.21 g, 0.99 mmol) at room temperature for 11 h to give a
yellow oil. Recrystallization from EtOAc/hexane afforded 13b
1
as a pale, yellow solid (0.27 g, 77%): mp 73-74 °C; H NMR
(CDCl3) δ 1.32 (t, J ) 7.2 Hz, 3H), 3.05 (dd, J ) 7.4, 13.8 Hz,
1H), 3.16 (dd, J ) 7.4, 13.8 Hz, 1H), 4.19 (dq, J ) 7.2, 10.6
Hz, 1H), 4.21 (dd, J ) 2.2, 4.2 Hz, 1H), 4.27 (dq, J ) 7.2, 10.6
Hz, 1H), 5.23 (ddd, J ) 2.2, 7.4, J ) 7.4 Hz, 1H), 7.16-7.22
(m, 5H), 7.83 and 8.24 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR
(CDCl3) δ 14.0, 37.3, 62.9, 70.7, 84.2, 124.2, 127.3, 128.82,
128.84, 129.6, 135.0, 142.2, 150.5, 171.4; IR (KBr) 3491, 3129,
3001, 1743, 1608, 1527 cm-1
. Anal. Calcd for C18H19NO8S:
C, 52.81; H, 4.68; N, 3.42. Found: C, 52.90; H, 4.69; N, 3.38.
Eth yl 3-[(p-Nitr oben zen esu lfon yl)oxy]-2-h yd r oxy-4-oc-
ta n oa te, 13c. By the same procedure, 7c (0.33 g, 0.85 mmol)
was reduced with sodium triacetoxyborohydride (0.20 g, 0.94
mmol) overnight at room temperature to give an orange oil.
Purification by radial chromatography (EtOAc:hexane, 1:4)
gave 13c as a yellow oil (0.23 g, 70%): 1H NMR (CDCl3) δ 0.87
(t, J ) 6.4 Hz, 3H), 1.27-1.35 (m, 6H), 1.33 (t, J ) 7.2 Hz,
3H), 1.72-1.81 (m, 1H), 1.82-1.91 (m, 1H), 2.99 (br s, 1H),
4.19 (dq, J ) 7.2, 10.6 Hz, 1H), 4.26 (d, J ) 2.0 Hz, 1H), 4.29
(dq, J ) 7.2, 10.6 Hz, 1H), 5.06 (ddd, J ) 2.0, 7.4, 7.4 Hz, 1H),
8.09 and 8.39 (AA′BB′, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ
13.9, 14.0, 22.4, 24.8, 31.0, 31.3, 62.8, 71.2, 83.7, 124.3, 129.1,
142.7, 150.7, 171.6; IR (neat) 3493, 3109, 1742, 1608, 1535
cm-1. Anal. Calcd for C16H23NO8S: C, 49.35; H, 5.95; N, 3.60.
Found: C, 49.15; H, 5.91; N, 3.47.

Synthesis and Reactions of 3-(Nosyloxy)-2-keto Esters
63.2, 65.5, 127.4, 128.9, 129.3, 135.4, 160.4, 189.8; IR (neat)
J . Org. Chem., Vol. 62, No. 8, 1997 2465
(2:3). A yellow oil (0.15 g, 68%), which consisted of a mixture
of diastereomers, syn and anti (76:24), was collected. The
NMR spectra of each isomer could be extracted from the
spectrum of the mixture. syn -20b (major isomer): 1H NMR
(400 MHz, CDCl3) δ 1.28 (t, J ) 7.2 Hz, 3H), 3.01 (dd, J ) 7.4,
13.4 Hz, 1H), 3.08 (dd, J ) 8.0, 13.4 Hz, 1H), 4.02 (dt, J ) 2.8,
7.4 Hz, 1H), 4.16-4.31 (m, 2H), 4.89 (d, J ) 2.8 Hz, 1H), 7.21-
7.35 (m, 5H); 13C NMR (400 MHz, CDCl3) δ 14.1, 14.2, 36.4,
62.2, 62.6, 65.0, 75.5, 127.4, 129.0, 129.1, 135.9, 154.3, 167.5;
IR (neat) 2115, 1751, 1604, cm-1. a n ti-20b (minor isomer):
1H NMR (400 MHz, CDCl3) δ 1.37 (t, J ) 7.2 Hz, 3H), 2.99 (d,
J ) 7.4 Hz, 2H, 4.02 (dt, J ) 2.8, 7.4 Hz, 1H), 4.16-4.31 (m,
2H), 5.10 (d, J ) 3.2 Hz, 1H), 7.21-7.35 (m, 5H); 13C NMR
(400 MHz, CDCl3) δ 14.1, 14.2, 36.0, 62.1, 63.2, 65.0, 76.4,
127.1, 128.7, 129.3, 136.3, 154.1, 166.9.
2119, 1732, 1605 cm-1
.
Eth yl 3-Azid o-2-h yd r oxy-4-p h en ylbu ta n oa te, 19b. So-
dium borohydride (0.093 g, 2.5 mmol) was slowly added to a
cold (-78 °C) mixture of THF:methanol (20 mL:0.5 mL). Ethyl
3-azido-2-oxo-4-phenylbutanoate, 18b (0.21 g, 0.85 mmol), in
THF (25 mL) was added, and the mixture was allowed to stir
at -78 °C for 30 min. Water (50 mL) was added, and the pH
was adjusted to neutrality with aqueous HCl. The aqueous
layer was extracted with EtOAc (3 × 50 mL), and the combined
organic layers were dried (MgSO4) and evaporated to give a
yellow oil (0.19 g, 90%). The crude product was dissolved in
CH2Cl2, leaving an insoluble, white solid that was filtered. The
filtrate was evaporated to give a yellow oil (0.17 g, 81%): 1H
NMR (CDCl3) major isomer δ 1.28 (t, J ) 7.2 Hz, 3H), 3.12 (d,
J ) 7.8 Hz, 2H), 3.72-3.79 (m, 1H), 4.11 (d, J ) 2.0 Hz, 1H),
4.25 (dq, J ) 3.6, 7.2 Hz, 1H), 4.29 (dq, J ) 3.6, 7.2 Hz, 1H),
7.24-7.39 (m, 5H); 13C NMR (CDCl3) δ 13.1, 35.2, 61.4, 63.3,
70.5, 126.0, 127.8, 128.4, 135.7, 171.7; IR (neat) 3446, 3236,
Ack n ow led gm en t. This work was supported in part
by the National Science Foundation (CHE 9004980 and
CHE9520431). MCJ was the recipient of a Graduate
Fellowship from the Air Force Graduate Fellowship
Program.
2112, 1739, 1604 cm-1
. The product was a mixture of syn-
and anti-19b which could not be separated.
Eth yl 3-Azid o-2-ca r beth oxy-4-p h en ylbu ta n oa te, 20b.
Ethyl chloroformate (0.33 mL, 0.37 g, 3.5 mmol), pyridine
(0.075 mL, 0.073 g, 0.93 mmol), and DMAP (0.013 g, 0.11
mmol) in CH2Cl2 (15 mL) were stirred at 0 °C for 15 min. Azido
alcohol 19b (0.17 g, 0.68 mmol) in CH2Cl2 (15 mL) was added,
and the reaction was stirred for 5 h at room temperature. The
reaction mixture was washed with water (2 × 30 mL), dried
(MgSO4), and filtered through a 1.5 cm pad of silica gel. After
evaporation, a yellow oil (0.17 g, 78%) remained. The crude
product was purified by preparative TLC using EtOAc:hexane
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
11a -f, 13d , 18b, and 20b and 13C spectra of 14b,c, 16b, and
19b (13 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 O962206H