D-mannitol as the chiral source for the EPC synthesis of both enantiomers of 3-ethoxycarbonyl-4-hydroxy-2-isoxazolines and highly functionalized tricyclic systems

Article abstract of DOI:10.1021/jo980941i

The EPC preparation of both enantiomers of cis- and trans 5-substituted 4-hydroxy-2-isoxazoline 2-oxides has been achieved in an enantiodivergent fashion starting from D-mannitol through the application of the tandem nitroaldol-cyclization reaction to enantiomerically pure α- mesyloxyaldehydes. These stereochemically labile aldehydes have been generated in situ and reacted under very mild domino conditions. Enantiomeric purity of the products has been assessed by ¹H NMR and HPLC analyses of the corresponding Mosher's esters. The enantiomerically pure 4-hydroxy-2- isoxazoline 2-oxides have been employed as pivotal intermediates for the EPC preparation of the corresponding deoxygenated derivatives and highly functionalized tricyclic systems (HFTS) 1, useful for the preparation of 2- aminopolyols and α,α-disubstituted polyhydroxy amino acids.

Full text of DOI:10.1021/jo980941i

J . Org. Chem. 1998, 63, 8235-8246
8235
D-Ma n n itol a s th e Ch ir a l Sou r ce for th e EP C Syn th esis of Both
En a n tiom er s of 3-Eth oxyca r bon yl-4-h yd r oxy-2-isoxa zolin es a n d
High ly F u n ction a lized Tr icyclic System s
Emanuela Marotta, Marco Baravelli,1 Luigi Maini,1 Paolo Righi, and Goffredo Rosini*
Dipartimento di Chimica Organica “A. Mangini” dell’Universita`sViale Risorgimento, 4,
I-40136 Bologna, Italy
Received May 19, 1998
The EPC preparation of both enantiomers of cis- and trans 5-substituted 4-hydroxy-2-isoxazoline
2-oxides has been achieved in an enantiodivergent fashion starting from D-mannitol through the
application of the tandem nitroaldol-cyclization reaction to enantiomerically pure R-mesyloxyal-
dehydes. These stereochemically labile aldehydes have been generated in situ and reacted under
1
very mild domino conditions. Enantiomeric purity of the products has been assessed by H NMR
and HPLC analyses of the corresponding Mosher’s esters. The enantiomerically pure 4-hydroxy-
2-isoxazoline 2-oxides have been employed as pivotal intermediates for the EPC preparation of the
corresponding deoxygenated derivatives and highly functionalized tricyclic systems (HFTS) 1, useful
for the preparation of 2-aminopolyols and R,R-disubstituted polyhydroxy amino acids.
Sch em e 1
In tr od u ction
A major challenge in contemporary organic synthesis
is to devise methods and strategies for the rapid and
economic preparation of enantiomerically pure complex
molecules from simple starting materials. In fact, despite
the fact that the synthesis of complex molecules seems
to be a relatively advanced and successful science, most
synthetic problems have not been solved in a practical
fashion, and yet, there is a need for improving the
efficiency. The control of the regio- and stereochemistry
in the synthesis of linear structures containing many
chirality centers and several hydroxy or amino groups
on adjacent carbon atoms is of particular interest. Many
research groups have oriented their efforts to develop
practical methods to prepare these kind of compounds
in a predictable way,2 eventually for commercial produc-
tion.
Along these lines, we have recently developed a new
methodology3 for rapid assembly of stereochemically
defined and functionally rich tricyclic systems such as 1
(Scheme 1). The easy conversion of 1 into the polyhy-
droxylated amino acid derivatives 2 through simple
manipulations makes these compounds important inter-
mediates in our synthetic strategy based on the “folding
and unfolding approach”.
in our group. The first tandem sequence consists of a
nitroaldol (Henry) reaction4-7 of a substrate (3) having
two different and contiguous electrophilic centers, such
as R-bromoaldehydes8 or R,â-epoxyaldehydes,9 with an
activated nitromethane able to act twice as a nucleophile,
for instance ethyl nitroacetate (4), followed by a ring
closure to generate 5-substituted cis- and trans-3-ethoxy-
carbonyl-4-hydroxy-2-isoxazoline 2-oxides (6). (Scheme
2).
The vinylsilicon derivatization of the newly formed
4-hydroxyl group of 6 is followed by a spontaneous
intramolecular 1,3-dipolar cycloaddition to generate a
new class of highly functionalized tricyclic structures 1
(HFTS)10 in almost quantitative yields and in regio- and
stereospecific fashion3 (Scheme 3). The preparation of
these fused triheteroatomic tricyclic compounds has
(4) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265-1268.
Rosini, G. The Henry (Nitroaldol) Reaction. In Comprehensive Organic
Synthesis; Trost, B. M., Heathcock, C. H., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p 321 and references therein.
(5) For an excellent review on the lanthanum-catalysed asymmetric
Henry reaction, see: Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1236-1256.
(6) Studies concerning ab initio models for the nitroaldol (Henry)
reaction were reported recently, see: Lecea, B.; Arrieta, A.; Morao, I.;
Cossio, F. Chem.sEur. J . 1997, 3, 20-28.
(7) For reviews on the versatility of nitro compounds in organic
synthesis, see: (a) Nitro Compounds, Recent Advances in Synthesis
and Chemistry; Fever, H., Nielsen, A. T., Eds.; VCH: Weinheim, 1990.
(b) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423. (c) Rosini,
G.; Ballini, R. Synthesis 1988, 833. (d) Seebach, D.; Colvin, E. W.;
Leher, F.; Weller, T. Chimia 1979, 33, 1-18.
(8) Rosini, G.; Marotta, E.; Righi, P.; Seerden, J .-P. J . Org. Chem.
1991, 56, 6258-6260.
(9) Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. J . Org. Chem. 1990,
55, 781-783.
The synthesis of the tricyclic system (1) has been
achieved by two consecutive tandem sequences developed
* Corresponding author. Phone: +39 51 644 3640. Fax: +39 51
644 3654. E-mail: rosini@ms.fci.unibo.it.
(1) Taken in part from the Tesi di Laurea of L. Maini (March 1997)
and M. Baravelli (March 1998) at the Universita` di Bologna, Facolta`
di Chimica Industriale.
(2) For a review on biologically active aminopolyols or hydroxylated
amino acids, see: Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998,
1075-1091. For some other examples, see: (a) Hatakeyama, S.;
Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto, T.; Yamada,
H.; Nishizawa, M. Tetrahedron Lett. 1997, 38, 7887-7890. (b) Koba-
yashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett
1997, 301-303. (c) Kobayashi, S.; Hayashi, T.; Iwamoto, S.; Furuta,
T.; Matsumura, M. Synlett 1996, 672-674. (d) Mori, K.; Otaka, K.
Tetrahedron Lett. 1994, 35, 9207-9210.
(3) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J . Am. Chem.
Soc. 1996, 118, 9446-9447.
10.1021/jo980941i CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8236 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
Sch em e 2
Sch em e 4
Sch em e 3
corresponding 4-hydroxy-2-isoxazoline 2-oxides in high
yields and under mild reaction conditions with a trans/
cis ratio of 1:1. The same study showed that aldehydes
bearing acetoxy, benzoyloxy, chloroacetoxy, trichloroac-
etoxy, or a trifluoroacetoxy group on the R-carbon gave
only the nitroaldol reaction; the corresponding nitroal-
kanols 5 were isolated, and no product arising from the
ring closure was observed.
Scheme 4 shows the pivotal role that cis and trans
5-substituted 3-ethoxycarbonyl-4-hydroxy-2-isoxazoline
2-oxides (6) play in the global synthetic project. In fact,
these compounds can be considered as key intermediates
both for the preparation of the tricyclic derivatives 1,
which can be unfolded to obtain the target linear prod-
ucts, as well as for the preparation of linear 2-aminopo-
lyols or polyhydroxylated R-amino acid derivatives by
deoxygenation, followed by stereoselective reduction of
the CdN14 and the reductive cleavage of the heteroatomic
ring.15
recently been accomplished in consecutive and domino
conditions11 starting, in some cases, from nonracemic
aldehydes.
The main aspects concerning the chemio-, regio-,
ambido-, and stereoselectivity of each step have been
considered in previous communications.3,8,9 In particular,
it is important to stress that only the first step of the
overall process, the nitroaldol (Henry) reaction, is ste-
reoselective, while all the successive steps occur ste-
reospecifically. We therefore explored the possibility of
preparing the target compounds in nonracemic form by
the use of optically active aldehydes of type 3. We chose
R-hydroxyaldehydes because of their easy availability
from cheap starting materials by many multigram meth-
ods12,13 that afford, in most cases, both enantiomerically
pure forms. In addition, the hydroxy group can be
activated by reaction with acid chlorides for its nucleo-
philic displacement.
This paper reports the results obtained in preparing
nonracemic chiral cis and trans 5-substituted 3-ethoxy-
carbonyl-4-hydroxy-2-isoxazoline 2-oxides (6) and their
separation and conversion into the corresponding deoxy-
genated forms (9) and tricyclic compounds (1).
Resu lts a n d Discu ssion
A preliminary screening study1 revealed that only
R-mesyloxyaldehydes and R-tosyloxyaldehydes afford the
The approach we used to prepare chiral nonracemic
2-sulfonyloxyaldehydes is depicted in Scheme 5. It is
known that both D-mannitol diepoxide 10 and L-iditol
diepoxide 11 can be prepared from D-mannitol and that
they can be used as convenient chiral building blocks to
prepare, respectively, suitably O-derivatized (2R)- and
(2S)-2-hydroxyaldehydes in an enantiodivergent fashion.
(10) We found that one of the possible IUPAC names of tricyclic
compounds of type 1 is ethyl 2,2-dimethyltetrahydro-2H,6bH-1,4,5-
trioxa-4a-aza-2-silacyclopenta[cd]pentalene-6b-carboxylate. (ACD/ IU-
PAC Name, version 3.00; Advanced Chemistry Development, Inc.:
Toronto, Nov. 1997.) We suggest the use of the acronym HFTS in place
of this awkward IUPAC name.
(11) Marotta, E.; Righi, P.; Rosini, G. Tetrahedron Lett. 1998, 39,
1041-1044.
(12) Among the classical procedures for the EPC synthesis of
2-hydroxy aldehydes, see: (a) Eliel, E. L.; Morris-Natschke, S. J . Am.
Chem. Soc. 1984, 106, 2937-2942. (b) Lynch, J . E.; Eliel, E. L. J . Am.
Chem. Soc. 1984, 106, 2943-2948. (c) Frye, St. V.; Eliel, E. L. J . Org.
Chem. 1985, 50, 3402-3404. (d) Eliel, E. L. in Asymmetric Synthesis-
Stereodifferentiating Addition Reactions; Morrison, J . D., Ed.; Academic
Press Inc.: Orlando, FL; Vol. 2. (e) Whitesell, J . K.; Bhattacharya, A.;
Henke, K. J . Chem. Soc., Chem. Commun. 1982, 988-989. (f) Whitesell,
J . K.; Bhattacharya, A.; Aguilar, D. A.; Henke, K. J . Chem. Soc., Chem.
Commun. 1982, 989-990. (g) Mukaiyama, T. Tetrahedron 1981, 37,
4111. (h) O’Brien, P.; Warren, S. Tetrahedron Lett. 1995, 36, 2681-
2684 and literature therein cited. (i) Dondoni, A.; Fantin, G.; Fogagnolo,
M.; Medici, A.; Pedrini, P. J . Org. Chem. 1989, 54, 693-702. (j)
Dondoni, A. Pure Appl. Chem. 1990, 62, 643-652. (k) Dondoni, A.;
Marra, A.; Perrone, D. J . Org. Chem. 1993, 58, 275-277. (l) Dondoni,
A.; Merino, P. Org. Synth. 1993, 72, 21-31. (m) Kirshning, A.; Dra¨ger,
G.; J ung, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 253-255. All these
procedures are potentially useful for the preparation of optically active
2-mesyloxy or 2-tosyloxy aldelhydes if the hydrolysis of the correspond-
ing acetals or aminals does not compromise the chemical and/or
stereochemical integrity of the products.
(13) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: New York, 1983. 2-Hydroxy aldehydes, O-
protected 2-hydroxy aldehydes, as well as 2-mesyloxy and 2-tosyloxy-
aldehydes may be obtained by reduction of the methyl or ethyl esters
of 2-hydroxy acid derivatives with DIBAH: Coppola, G. M.; Schuster,
H. F. R-Hydroxy Acids in Enantioselective Syntheses; VCH: Weinheim,
1997. Ho, T.-L. Enantioselective Synthesis: Natural Products from
Chiral Terpenes; J ohn Wiley & Sons: New York, 1992. Coppola, G.
M.; Schuster, H. F. Asymmetric Synthesis: Construction of Chiral
Molecules using Amino Acids; J ohn Wiley & Sons: New York, 1987.
(14) LiAlH4 is reported to reduce 4-hydroxy-2-isoxazolines to ami-
nopolyols by introduction of the hydride ion syn to the C4 hydroxyl
group and anti when this has been protected with a group bulky
enough: J a¨ger, V.; Schwab, W.; Buss, V. Angew. Chem., Int. Ed. Engl.
1981, 20, 601-603.
(15) J a¨ger et al. have shown 4-hydroxy-2-isoxazolines are versatile
intermediates for the synthesis of amino sugars and other biologically
important molecules, see: (a) J a¨ger, V.; Schone, R. Tetrahedron 1984,
40, 2199-2210. (b) J a¨ger, V.; Mu¨ller, I.; Schohe, R.; Frey, M.; Ehrler,
R.; Ha¨fele, B.; Schro¨ter, D. Lect. Heter. Chem. 1985, 6, 79-98 and
references therein.

D-Mannitol as Chiral Source for EPC Synthesis
J . Org. Chem., Vol. 63, No. 23, 1998 8237
Ta ble 1. Yield s of th e F or m a tion of 6
Sch em e 5
R
yield (%)
a
b
c
d
e
n-Pr
n-Bu
3-butenyl
cyclohexyl
93
86
90
quant
95
(2S)-2-methylbutyl
Sch em e 7
Sch em e 6
Sch em e 8
Thus, D-mannitol was converted into the diepoxide 10
through a simple sequence of well-known reactions.16,17
The regiospecific opening of this diepoxide was performed
by means of alkylmagnesium bromides in the presence
of cuprous bromide-dimethyl sulfide18 (Scheme 6). The
reaction of 10 with a variety of organocopper compounds
allowed us to prepare symmetric alkylated diols 12,
which were successively converted into the corresponding
bismethanesulfonate derivatives 13, which upon depro-
tection afforded the diols 14.
The symmetry of the starting material is preserved
during the chemical transformations and, as a conse-
quence, the oxidative cleavage of compounds 14 led to 2
equiv of identical enantiopure (2R)-2-methanesulfony-
loxyaldehydes 15. Moreover, 15 can be generated in the
presence of ethyl nitroacetate (4) and imidazole, working
in domino conditions, without any need to isolate or even
manipulate the stereochemically labile19 aldehyde (Scheme
7). After 6-10 h of reaction at room temperature and a
simple workup, the mixtures of cis- and trans-4-hydroxy-
2-isoxazoline 2-oxides 6 were isolated from the other
reaction products and small amounts of unreacted start-
ing materials by flash column chromatography (Table 1).
To verify if the stereochemical integrity of the starting
material was preserved, we made the Mosher’s ester
analysis of the mixture of products (4RS,5R)-6a . First,
racemic 6a was prepared from the corresponding racemic
bromoaldehyde, which gave the products in a trans/cis
5:1 ratio. These racemic and isomeric substrates were
converted into the Mosher’s esters (Scheme 8) and the
1H NMR spectrum was recorded focusing on the proton
attached to C4, which appears as a doublet since it
couples only with the proton on C5.
The analysis of the spectrum (Figure 1a) revealed that
all four stereoisomers are distinguishable by this method.
The doublets of the pair of diastereoisomers derived from
two enantiomers of the cis-isoxazoline 2-oxide have larger
coupling constants (J ) 5.8 Hz and J ) 5.8 Hz) and are
in the 6.7 ppm region, while the doublets deriving from
the two enantiomers of the trans isomers are in the 6.3
ppm region with a smaller coupling constant (J ) 1.4 Hz
and J ) 1.4 Hz).
Next, the 2-isoxazoline 2-oxides 6a , prepared from the
pure enantiomer 14, were converted into the correspond-
ing Mosher’s esters (4RS,5S,2′S)-16 (Scheme 9).
(16) Le Merrer, Y.; Dure´ault, A.; Greck, C.; Micos-Lauguin, D.;
Gravier, G.; Depazay, J . C. Heterocycles 1987, 25, 541-548.
(17) (a) Le Merrer, Y.; Gravier-Pelletier, C.; Micos-Lauguin, D.;
Mestre, F.; Dure´ault, A.; Depazay, J . C. J . Org. Chem. 1989, 54, 2409-
2416. (b) Tranchpain, I.; Le Berre, F.; Dure´ault, A.; Le Merrer, Y.;
Depazay, J . C. Tetrahedron 1989, 45, 2057-2065. (c) Allevi, P.;
Anastasia, M.; Ciuffreda, P.; Sanvito, A. M. Tetrahedron: Asymmetry
1994, 5, 927-934.
1
From the H NMR spectra (Figure 1b), we could verify
that in this case only one enantiomer for both the cis-
and trans-isoxazolines was seen, confirming that the
isoxazoline 2-oxides obtained from 14 were enantiomeri-
cally pure and that the intramolecular cyclization oc-
curred stereospecifically with the complete inversion of
the original chirality.
(18) House, H. O.; Chu, C. Y.; Wilkins, J . M.; Umen, M. J . Org.
Chem. 1975, 40, 1460-1469.
(19) Morpain, C.; Tisserand, M. J . Chem. Soc., Perkin Trans. 1 1979,
1379-1383.

8238 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
Sch em e 9
4R configuration to the two isomers that showed an
upfield shift of the C5 H and C1′ H2 signals.21 This
assignment confirmed that the isoxazoline ring closure
occurs with complete inversion of the configuration of the
chiral center of the starting aldehyde. Finally, the
enantiomeric excesses of the isoxazolines 6a were deter-
mined also by HPLC analysis of the Mosher’s esters 16
and were found to be in the range of 98.0-99.2%.22
It is noteworthy that this synthesis employs only 1
equiv of sodium periodate to generate 2 equiv of products
without any loss of the carbon atoms of the starting
mannitol. Both of the three-carbon fragments from
D-mannitol were embedded into the structure of 2-acti-
vated aldehydes, preserving the chirality of C2 and C5
of the intermediate diepoxide 10. Moreover, the possibil-
ity of using the mesyl group for the activation of the
R-hydroxy aldehyde, in place of the tosyl group, reduces
the waste production. All these achievements greatly
contribute to increasing the atom economy of the overall
process. An additional advantage of the synthesis is that
the antipodal enantiomer of the target compounds 6 can
be obtained by using the diastereoisomeric diepoxyacetal
11 as a chiral template in lieu of 10.
Sep a r a tion of Cis- a n d Tr a n s Isom er s of 5-Alk yl-
4-h yd r oxy-2-isoxa zolin e 2-Oxid es. Any attempt to
separate the cis- and trans-isomers of the 5-substituted
4-hydroxy-2-isoxazoline 2-oxides 6a -e was unsuccessful.
To achieve a good and practical separation of the enan-
tiopure cis- and trans-6a -e, we performed a simple
derivatization of the hydroxyl group on C4 with tert-
butyldiphenylsilyl chloride (TBDPSCl) in dichloromethane
in the presence of triethylamine and a catalytic amount
of (dimethylamino)pyridine (DMAP). (Scheme 11).
The derivatization of cis- and trans-6 occurred with
different rates as reported in Table 2. While the trans
isomers reacted faster to give the protected compounds
20, the cis isomers reacted much more slowly and after
24 h of reaction at room temperature remained mainly
unprotected. In addition, the tert-butyldiphenylsilyl
F igu r e 1.
To further confirm this important result, the enanti-
omers of the isoxazolines 6a were prepared from the
diepoxyacetal 11, by the same procedure used for the
diastereoisomer 10 and previously depicted in Scheme 6
1
(Scheme 10). Again, the H NMR analysis of the Mosh-
er’s esters (Figure 1c) confirmed the enantiomeric purity
of the isoxazolines; this time the other two signals for
the C4 H were observed.
Each pair of the diastereomeric Mosher’s esters 16 was
separated and for each one the H NMR spectrum was
recorded again as a single pure diastereoisomer. The
differences in the chemical shifts observed in the spectra
allowed us to assign the absolute configuration to both
chiral centers of all four stereoisomeric 2-isoxazoline
2-oxides 6a , according to Mosher’s method for the eluci-
dation of the structure of secondary alcohols.20 In
particular, it was possible to assign the 4S configuration
to the two isomers that showed an upfield shift of the
signals relative to the ethyl group of the ester and the
1
(20) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J . Org. Chem. 1973, 38,
2143. For a more recent application with high-field FT NMR, see:
Ohtani, I.; J usumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem. Soc.
1991, 113, 4092-4096.
(21) For a more detailed discussion see the Supporting Information.
(22) For more details and actual chromatograms, see the Experi-
mental Section and Supporting Information.

D-Mannitol as Chiral Source for EPC Synthesis
J . Org. Chem., Vol. 63, No. 23, 1998 8239
Sch em e 10
Sch em e 11
Ta ble 2. Yield s of Isola ted Com p on en ts of th e Rea ction Mixtu r es a fter Der iva tiza tion
trans/cis ratio
(4R,5S-trans)-20
(4S,5S-cis)-20
(4S,5S-cis)-6
R
of starting 6
(%)
(%)
(%)
a
b
c
d
e
n-Pr
n-Bu
3-butenyl
cyclohexyl
43/57
44/56
42/58
48/52
44/56
33
34
39
48
39
19
25
15
14
17
36
33
43
36
39
(2S)-2-methylbutyl
derivatives of the trans isomers were eluted first in flash
column chromatography (SiO2, petroleum ether/diethyl
ether 4:1) and were well differentiated from the cis
isomers. Finally, the unreacted compounds cis-6 were
recovered by elution with diethyl ether or ethyl acetate.
The deprotection of the separated enantiopure trans- and
cis-4-tert-butyldiphenylsilyl derivatives 20 was performed
by treatment with tetra-n-butylammonium fluoride
(TBAF) in THF, which gave the enantiopure 4-hydroxy-
2-isoxazoline 2-oxides 6 in fairly good yields.
Deoxygen a tion of 2-Isoxa zolin es 2-Oxid e 6. In
addition to opening an efficient route for the separation
of the isomers (6), the derivatization with TBDPSCl was
useful to accomplish the deoxygenation reaction to gener-
ate the corresponding enantiopure cis- and trans-4-
hydroxy-2-isoxazolines 9. Some selected examples illus-
trating the viability of this procedure are shown in
Scheme 12.
with trimethyl phosphite at 100 °C for half an hour. The
deprotection promoted by the fluoride anion gave enan-
tiopure (4R,5S)- and (4S,5S)-5-alkyl-4-hydroxy-2-isox-
azolines 9. It is necessary to stress that the sequence
takes place without epimerization and/or decomposition
of substrates and that the same deoxygenation step failed
when the unprotected substrates were used. To the best
of our knowledge, this is the first general route to obtain
enantiomerically pure cis- and trans-3-ethoxycarbonyl-
5-alkyl-4-hydroxy-2-isoxazolines.23 The previously de-
scribed procedures for the synthesis of optically active
4-hydroxy-2-isoxazolines are all based on the general
methodology first depicted by J a¨ger et al.24 for racemic
compounds by which the hydroxylation of C4 was achieved
(23) For methods that yield optically active 4-hydroxy-2-isoxazolines,
see: (a) Liu, J .; Eddings, A.; Wallace, R. H. Tetrahedron Lett. 1997,
38, 6795-6798. (b) Wade, P. A.; Shah, S. S.; Govindarajian, J . Org.
Chem. 1994, 59, 7199-7200. (c) Davis, F. A.; Kumar, A.; Reddy, R. E.;
Chen, B.; Wade, P. A.; Shah, S. W. J . Org. Chem. 1993, 58, 7591-
7593. (d) Panek, J . S.; Beresis, R. T. J . Am. Chem. Soc. 1993, 115,
7898-7899.
Compounds trans- and cis-20a ,c,e were easily con-
verted into the deoxygenated derivatives when treated

8240 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
Sch em e 12
Ta ble 3. Yield s of th e Tr icycliza tion Rea ction s
starting material
(4R,5S-trans)-6a
product
yield (%)
(2aR,6S,6aS,6bR)-6-exo-1a
(2aR,6S,6aS,6bR)-6-endo-1a
93
93
85
89
76
73
81
83
(4S,5S-cis)-6a
(4R,5S-trans)- and (4S,5S-cis)-6b
(4R,5S-trans)-6c and (4S,5S-cis)-6c
(4R,5S-trans)-6d
(4S,5S-cis)-6d
(4R,5S-trans)-6e
(2aR,6S,6aS,6bR)-6-exo-1b and (2aR,6S,6aS,6bR)-6-endo-1b
(2aR,6S,6aS,6bR)-6-exo-1c and (2aR,6S,6aS,6bR)-6-endo-1c
(2aR,6S,6aS,6bR)-6-exo-1d
(2aR,6S,6aS,6bR)-6-endo-1d
(2aR,6S,6aS,6bR)-6-exo-1e
(4S,5S-cis)-6e
(2aR,6S,6aS,6bR)-6-endo-1e
through (a) the generation of azaenolate anions of 5-alkyl-
2-isoxazolines at very low temperature, (b) selective
enolate treatment with borates, and (c) subsequent
oxidative workup. The asymmetric hydroxylation per-
formed by Davis and Wade et al.23b with chiral N-
sulfonyloxyaziridines gave low yields and low ee of only
the trans-4-hydroxy-2-isoxazolines. The procedure de-
veloped by Wallace23a stems from the utilization of
vinylboronic esters derivatized with an optically active
sultam in a cascade of (a) nitrile oxide cycloaddition, (b)
oxidative cleavage of the intermediate boronic ester and,
finally, (c) hydrolysis of the amide. However, notwith-
standing the higher yields and better ee, both of these
procedures are restricted to the preparation of the trans
isomers only.
Sch em e 13
P r ep a r a tion of En a n tiom er ica lly P u r e High ly
F u n ction a lized Tr icyclic System s (HF TS). The syn-
thesis of enantiomerically pure endo- and exo-6-alkyl-
HFTS (1) was accomplished through the utilization of the
same conditions we developed for the racemic com-
pounds.3 The trans-3-ethoxycarbonyl-5-alkyl-4-hydroxy-
2-isoxazoline 2-oxides (6) furnished exclusively the 6-exo-
alkyl-HFTS 1 and the cis isomers gave the 6-endo-1. In
general, the endo and exo diastereoisomers can be easily
separated and purified by flash column chromatography
with silica gel. This methodology made it possible to
perform the tricyclization reaction directly with the
mixtures of cis- and trans- 4-hydroxy-2-isoxazoline 2-ox-
ides 6, maintaining the same diastereoisomeric ratio
(Scheme 13, Table 3).
2-methanesulfonyloxy aldehydes and allows one to quickly
achieve the molecular complexity associated with the
target structures 9 and 1, useful intermediates for the
preparation of linear 2-amino polyols and polyhydroxy-
lated 2-amino acids by practical “unfolding” sequences.2,3,8
The optically active 2-activated aldehydes are available
in both enantiomeric forms by chirality transfer25 from
D-mannitol by two enantiodivergent synthetic sequences.
The general procedures here depicted are particularly
attractive and efficient since they utilize enantiopure
2-activated aldehydes and their conversion into the
corresponding enantiopure target compounds 6, and then
9 and 1, through a sequence of stereospecific reactions,
except the nitroaldol reaction. The criteria of selectivity
and atom economy have been the guidelines for our
efforts in achieving practicality in the procedures we have
developed.
Con clu sion s
In this paper, we have shown a general and efficient
procedure to prepare enantiomerically pure 3-ethoxycar-
bonyl-5-alkyl-4-hydroxy-2-isoxazoline 2-oxides (6) and
their conversion into the deoxygenated forms 9 and the
highly functionalized tricyclic systems 1.
Exp er im en ta l Section
Gen er a l. Proton and 13C NMR were recorded at 300.08
MHz and at 75.46 MHz, respectively, in CDCl3 at 20 °C with
either tetramethylsilane (0.00 ppm) or chloroform (7.26 ppm
for 1H NMR, 77.00 for 13C NMR) as the internal standard.
The “folding” sequence we have devised and developed
highly implements the chirality of enantiomerically pure
(25) (a) J oullie, M. M.; Wang, P. C.; Semple, J . E. J . Am. Chem.
Soc. 1980, 102, 887-889. (b) Lopez, J . C.; Fraser-Reid, B. J . Chem.
Soc., Chem. Commun. 1997, 2251-2257.
(24) Schwab, W.; J ager, V. Angew. Chem., Int. Ed. Engl. 1981, 20,
603-605.

D-Mannitol as Chiral Source for EPC Synthesis
J . Org. Chem., Vol. 63, No. 23, 1998 8241
Solvents were reagent grade and used as received; anhydrous
solvents were prepared according to standard methodologies.
Melting points are uncorrected. Unless otherwise stated, the
solution of the crude product obtained at the end of each
workup procedure was dried over magnesium sulfate, filtered,
and evaporated under reduced pressure. All chromatographic
separations were performed with flash column chromatogra-
phy using Silica gel Merck 60 (70-230 mesh ASTM). Diep-
oxides 10 and 11 were prepared according to ref 16.
Bisa lk yla tion of Diep oxid e 10. A three-necked round-
bottomed flask with a internal stirring and equipped with a
thermometer, addition funnel, and reflux cooler was kept
under a positive pressure of nitrogen. The flask was charged
with magnesium turnings (2.05 equiv), which were barely
covered with anhydrous diethyl ether, and a catalytic amount
of 1,2-dibromoethane (10 µL) was added. Stirring was started
very slowly, and the mixture was heated to reflux for about
chloride (1.25 equiv) was slowly added via a syringe. The flask
was stoppered and kept in a refrigerator at 4 °C overnight.
The solution was carefully poured onto a 3:1 mixture of 10%
HCl and crushed ice and extracted several times with ethyl
acetate. The organic layer was subsequently washed with a
saturated solution of CuSO4 and brine, and the crude product
was used without further purification.
a . (5R,6S,7S,8R)-6,7-O-Isop r op ylid en e-5,8-d i-O-m eth -
a n esu lfon yl-5,6,7,8-d od eca n etetr a ol (13a ). The reaction
was performed on 7.81 mmol of 12a . Quantitative yield of a
clear oil. 1H NMR (CDCl3) δ 0.92 (t, 6), 1.20-1.65 (m, 14),
1.80 (m, 4), 3.10 (s, 6), 4.29 (m, 2), 4.77 (m, 2) ppm. 13C NMR
(CDCl3) δ 111.4, 82.2, 79.3, 39.3, 30.8, 27.5, 27.1, 22.9, 14.4
ppm. [R]25 ) +28.70 (c 0.99, CHCl3). Anal. Calcd for
D
C
17H34O8S2: C, 47.42; H, 7.96. Found: C, 47.53; H, 8.01.
b. (6R,7S,8S,9R)-7,8-O-Isop r op ylid en e-6,9-d i-O-m eth -
a n su lfon yl-6,7,8,9-tetr a d eca n etetr a ol (13b). The reaction
was performed on 3.31 mmol of 12b. Quantitative yield of a
clear oil. 1H NMR (CDCl3) δ 0.90 (t, 6), 1.20-1.65 (m, 18),
1.82 (m, 2), 3.10 (s, 6), 4.15 (m, 2), 4.75 (m, 2) ppm. 13C NMR
(CDCl3) δ 111.4, 82.1, 79.3, 39.3, 31.9, 31.0, 27.5, 24.6, 22.8,
15 min until spontaneous gas evolution was observed.
A
solution of the corresponding alkyl bromide in anhydrous
diethyl ether (2 M, 2 equiv) was added dropwise at room
temperature, and the mixture was kept stirring until most of
the magnesium was consumed. The dark solution was then
cooled to -50 °C, and a catalytic amount of CuBr‚SMe2 (0.5
equiv) was added to the mixture that was kept stirring for
another 2 h. After that, a solution of the diepoxide 10 in
anhydrous THF (0.33 M, 1 equiv) was added dropwise to the
mixture. The cooling bath was removed, and the temperature
was allowed to reach the ambient value in about 30 min. The
mixture was quenched by the careful addition of a saturated
solution of NH4Cl and extracted several times with ethyl
acetate. The crude product was purified by flash chromatog-
raphy.
14.4 ppm. [R]30 ) +25.3 (c 1.00, CHCl3). Anal. Calcd for
D
C
19H38O8S2: C, 49.76; H, 8.35. Found: C, 49.61; H, 8.30.
c. (6R,7S,8S,9R)-7,8-O-Isop r op ylid en e-6,9-d i-O-(m eth -
a n esu lfon yl)tetr a d eca n e-1,13-d ien e-6,7,8,9-tetr a ol (13c).
The reaction was performed on 3.02 mmol of 12c. Yield 90%
of a clear oil. 1H NMR (CDCl3) δ 1.30-1.95 (m, 14), 2.10 (m,
4), 3.10 (s, 6), 4.16 (m, 2), 4.75 (m, 2), 5.00 (m, 4), 5.80 (m, 2)
ppm. 13C NMR (CDCl3) δ 138.3, 115.7, 111.5, 81.8, 79.4, 39.3,
33.7, 30.4, 27.5, 24.1 ppm. [R]27 ) +24.70 (c 1.12, CHCl3).
D
Anal. Calcd for C19H34O8S2: C, 50.20; H, 7.54. Found: C,
50.35; H, 7.59.
a . (5R,6R,7R,8R)-6,7-O-Isop r op ylid en e-5,6,7,8-d od e-
ca n etetr a ol (12a ). The reaction was performed on 10.8 mmol
of 10. Yield 79% of a white solid. mp 36-38 °C. 1H NMR
(CDCl3) δ 0.9 (t, 6), 1.20-1.65 (m, 16), 1.80 (m, 2), 3.45-3.70
(m, 4), 4.36 (m, 2) ppm. 13C NMR (CDCl3) δ 108.7, 83.8, 73.6,
d. (2R,3S,4S,5R)-1,6-Dicycloh exyl-3,4-O-Isopr opyliden e-
2,5-d i-O-(m et h a n esu lfon yl)-2,3,4,5-h exa n et et r a ol (13d ).
The reaction was performed on 1.86 mmol of 12d . Quantita-
tive yield of a clear oil. 1H NMR (CDCl3) δ 0.75-2.00 (m, 32),
3.10 (s, 6), 4.15 (m, 2), 4.88 (m, 2) ppm. 13C NMR (CDCl3) δ
111.4, 79.7, 39.4, 38.5, 34.5, 33.5, 32.8, 27.5, 26.8, 26.6, 26.3
34.4, 27.8, 27.4, 23.2, 14.5 ppm. [R]26 ) +26.81 (c 0.99,
D
CHCl3). Anal. Calcd for C15H30O4: C, 65.66; H, 11.02.
Found: C, 65.52 H, 11.08.
ppm. [R]29 ) +53.67 (c 1.02, CHCl3). Anal. Calcd for
D
C
23H42O8S2: C, 54.09; H, 8.29. Found: C, 53.91; H, 8.34.
b. (6R,7R,8R,9R)-7,8-O-Isop r op ylid en e-6,7,8,9-tetr a d e-
ca n etetr a ol (12b). The reaction was performed on 5 mmol
of 10. Yield 75% of a white solid. mp 41-44 °C. 1H NMR
(CDCl3) δ 0.90 (t, 6), 1.20-1.65 (m, 20), 1.80 (m, 2), 3.55 (bs,
2), 3.65 (m, 2), 4.35 (m, 2) ppm. 13C NMR (CDCl3) δ 108.7,
e. (3S,6R,7S,8S,9R,12S)-7,8-O-Isopr opyliden e-3,12-dim -
eth yl-6,9-d i-O-(m eth a n esu lfon yl)-6,7,8,9-tetr a d eca n etet-
r a ol (13e). The reaction was performed on 5.94 mmol of 12e.
Quantitative yield of a clear oil. 1H NMR (CDCl3) δ 0.85 (m,
12), 1.05-1.55 (m, 16), 1.80 (m, 4), 3.12 (s, 6), 4.17 (dd, 2),
4.72 (m, 2) ppm. 13C NMR (CDCl3) δ 111.6, 82.5, 79.3, 39.3,
83.3, 73.2, 34.2, 31.9, 26.9, 24.9, 14.1 ppm. [R]33 ) +25.43 (c
D
0.93, CHCl3). Anal. Calcd for C17H34O4: C, 67.51; H, 11.33.
Found: C, 67.58; H, 11.29.
34.6, 31.5, 29.8, 28.6, 27.6, 19.3, 11.8 ppm. [R]25 ) +31.29 (c
D
1.08, CHCl3). Anal. Calcd for C21H42O8S2: C, 51.83; H, 8.70.
Found: C, 51.99; H, 8.77.
c. (6R,7R,8R,9R)-7,8-O-Isop r op ylid en etetr a d eca n e-1,-
13-d ien -6,7,8,9-tetr a ol (12c). The reaction was performed
on 8.06 mmol of 10. Yield 95% of a clear oil. 1H NMR (CDCl3)
δ 1.20-1.95 (m, 14), 2.10 (m, 4), 3.55 (m, 4), 4.40 (m, 2), 5.00
(m, 4), 5.80 (m, 2) ppm. 13C NMR (CDCl3) δ 139.0, 115.0, 109.3,
Hyd r olysis of Aceta ls 13. Concentrated hydrochloric acid
(ca. 10 equiv) was added dropwise to a stirred solution of the
starting acetal 13 in acetic acid (0.1 M). During the addition,
the solution turned deep-blue, and after 1 h of being stirred
at room temperature, the reaction was diluted with water and
extracted several times with ethyl acetate. The combined
organic layers were subsequently washed with saturated
sodium carbonate and brine. The crude product was used
without further purifications.
83.7, 73.5, 34.2, 27.4, 24.9 ppm. [R]27 ) +25.86 (c 1.14,
D
CHCl3). Anal. Calcd for C17H30O4: C, 68.42; H, 10.13.
Found: C, 68.53; H, 10.20.
d. (2R,3R,4R,5R)-1,6-Dicycloh exyl-3,4-O-isopr opiliden e-
2,3,4,5-h exa n etetr a ol (12d ). The reaction was performed on
1.61 mmol of 10. Yield 63% of a white waxy solid. 1H NMR
(CDCl3) δ 0.75-1.90 (m, 30), 3.70 (m, 4), 4.05 (m, 2) ppm. 13C
NMR (CDCl3) δ 109.3, 83.9, 70.9, 42.3, 35.1, 33.9, 32.7, 27.5,
a. (5R,6S,7S,8R)-5,8-Di-O-m eth an esu lfon yl-5,6,7,8-dode-
ca n etetr a ol (14a ). The reaction was performed on 7.81 mmol
of 13a . Yield 82% of a white solid. mp 64-66 °C. 1H NMR
(CDCl3) δ 0.92 (t, 6), 1.20-1.60 (m, 8), 1.85 (m, 4), 3.12 (s, 8),
3.88 (d, 2), 4.72 (dt, 2) ppm. 13C NMR δ 82.1, 69.5, 38.5, 30.8,
27.1, 26.9, 26.6 ppm. [R]30 ) +37.38 (c 1.00, CHCl3). Anal.
D
Calcd for C21H38O4: C, 71.14; H, 10.80. Found: C, 71.03; H,
10.78.
26.6, 22.5, 13.9 ppm. [R]26 ) -3.65 (c 0.99, CHCl3). Anal.
D
e. (3S,6R,7R,8R,9R,12S)-7,8-O-Isop r op ylid en e-3,12-
d im eth yl-6,7,8,9-tetr a d eca n etetr a ol (12e). The reaction
was performed on 6.77 mmol of 10. Yield 80% of a white solid.
mp 54-57 °C. 1H NMR (CDCl3) δ 0.90 (m, 12), 1.00-1.55 (m,
18), 1.75 (m, 2), 3.52 (m, 2), 3.65 (dt, 2), 4.15 (d, 2) ppm. 13C
NMR (CDCl3) δ 109.2, 83.7, 73.9, 35.0, 32.4, 32.2, 30.1, 27.4,
19.5, 11.9 ppm. [R]22D ) +35.36 (c 1.03, CHCl3). Anal. Calcd
for C19H38O4: C, 69.05; H, 11.59. Found: C, 69.12; H, 11.63.
Bism esyla tion of Diols 12. To a solution of the starting
diol 12 in dry pyridine (0.3 M, 1 equiv) was added DMAP (0.1
equiv). The solution was cooled to 0 °C, and methanesulfonyl
Calcd for C14H30O8S2: C, 43.06; H, 7.74. Found: C, 42.90; H,
7.78.
b. (6R,7S,8S,9R)-6,9-Di-O-m eth a n esu lfon yl-6,7,8,9-tet-
r a d eca n etetr a ol (14b). The reaction was performed on 3.27
mmol of 13b. Quantitative yield of a greenish oil. 1H NMR
(CDCl3) δ 0.90 (t, 6), 1.20-1.60 (m, 12), 1.85 (m, 4), 2.90 (bs,
2), 3.10 (s, 6), 3.88 (d, 2), 4.66 (ddd, 2) ppm. 13C NMR (CDCl3)
δ 82.0, 69.5, 38.5, 31.6, 31.1, 24.2, 22.4, 14.0 ppm. [R]31
)
D
-0.86 (c 1.12, CHCl3). Anal. Calcd for C16H34O8S2: C, 45.91;
H, 8.19. Found: C, 46.10; H, 8.15.

8242 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
c. (6R,7S,8S,9R)-6,9-Di-O-(m eth a n esu lfon yl)tetr a d e-
ca n e-1,13-d ien e-6,7,8,9-tetr a ol (14c). The reaction was
performed on 1.03 mmol of 13c. Yield 85% of a clear oil. 1H
NMR δ 1.60 (m, 4), 1.85 (m, 4), 2.15 (m, 4), 3.12 (s, 6), 3.22
(bs, 2), 3.85 (d, 2), 4.75 (ddd, 2), 5.00 (m, 4), 5.80 (m, 2) ppm.
13C NMR δ 138.0, 115.2, 81.7, 69.5, 38.5, 33.3, 30.5, 23.7 ppm.
Hyd r olysis of Aceta l 18. The reaction was performed as
described above for acetal 13, in this case on 3.02 mmol of
starting material, obtaining 1.08 g (92% yield) of a waxy white
solid. 1H NMR (CDCl3) δ 0.90 (t, 6), 1.45 (m, 8), 1.60-1.83
(m, 4), 3.07 (s, 2), 3.10 (s, 6), 3.75 (d, 2), 4.83 (m, 2) ppm. 13C
NMR (CDCl3) δ 85.53, 72.78, 39.70, 31.74, 28.10, 23.45, 14.92
[R]28 ) -6.77 (c 1.01, CHCl3). Anal. Calcd for C16H30O8S2:
ppm. [R]24 ) -25.51 (c 1.00, CHCl3). Anal. Calcd for
D
D
C, 46.36; H, 7.29. Found: C, 46.18; H, 7.34.
C
14H30O8S2: C, 43.06; H, 7.74. Found: C, 42.89; H, 7.79.
d . (2R,3S,4S,5R)-1,6-Dicycloh exyl-2,5-d i-O-(m eth a n e-
su lfon yl)-2,3,4,5-h exa n etetr a ol (14d ). The reaction was
performed on 1.86 mmol of 13d . Yield 70% of a white solid.
mp 114-115 °C. 1H NMR δ 0.80-2.00 (m, 26), 3.01 (d, 2),
3.10 (s, 6), 3.88 (dd, 2), 4.82 (dt, 2) ppm. 13C NMR δ 81.2, 70.9,
Dom in o P r ep a r a tion of 2-Isoxa zolin es 2-Oxid es (4RS,-
5R)-6a . The reaction was performed as described above for
the preparation of the (4RS,5S) isomers, in this case on 2.59
mmol of diol 19, obtaining a 92% yield of a clear oil.
P r ep a r a tion a n d An a lysis of Mosh er ’s Ester s of 6a .
The preparation of the Mosher’s esters was performed accord-
ing to Sharpless et al.,26 using (R)-2-methoxy-2-phenyl-3,3,3-
trifuoropropanoyl chloride [(R)-MTPA-Cl, which is obtained
from the corresponding (S) acid]. The reactions were per-
formed on a 0.1 mmol scale for (i) rac-6a obtained from racemic
2-bromohexanal as a 5:1 mixture of the trans and cis isomers,
(ii) (4RS,5S)-6a obtained from 14 as a 1:1 mixture of the trans
and cis isomers, and (iii) (4RS,5R)-6a obtained from 19 as a
1:1 mixture of the trans and cis isomers. 1H NMR analysis in
CDCl3 at 300 MHz focused on the proton on C4 of the
isoxazoline ring (doublet) that is found in the region 6.2-6.8
ppm. After determination of the enantiomeric excess, the
diastereoisomer pairs were separated by column chromatog-
raphy eluting with petroleum ether/diethyl ether ) 4:1.
Alternatively, in each case (i, ii, and iii) trans- and cis-6a
were separated and derivatized with (R)-MTPA-Cl. The crude
mixture of the esters was analyzed by HPLC (column, Lichro-
spher 100 RP-18 (5 µm) 4 mm ID × 250 mm with a 4 mm ID
× 4 mm precolumn (Merck); mobile phase, 80% methanol in
water; flow rate, 1 mL/min; detector, UV 254 nm; sample, An
aliquot of the crude esterification mixture dissolved in the
mobile phase (20 µL). The measured enantiomeric excesses
were always in the range 98.0-99.5%.
39.0, 38.9, 34.6, 33.8, 32.8, 26.8, 26.7, 26.4 ppm. [R]28
)
D
+34.67 (c 1.01, CHCl3). Anal. Calcd for C20H38O8S2: C, 51.04;
H, 8.14. Found: C, 51.18; H, 8.15.
e. (3S,6R,7S,8S,9R,12S)-3,12-Dim eth yl-6,9-d i-O-(m eth -
a n esu lfon yl)-6,7,8,9-tetr a d eca n etetr a ol (14e). The reac-
tion was performed on 5.94 mmol of 13e. Yield 98% of a clear
oil. 1H NMR δ 0.90 (m, 12), 1.10-1.62 (m, 10), 1.85 (m, 4),
3.10 (s, 8), 3.88 (d, 2), 4.66 (ddd, 2) ppm. 13C NMR δ 82.4,
69.4, 38.5, 34.2, 31.1, 29.4, 28.6, 18.9, 11.4 ppm. [R]27D ) +0.60
(c 1.07, CHCl3). Anal. Calcd for C18H38O8S2: C, 48.41; H, 8.58.
Found: C, 48.20; H, 8.53.
Dom in o P r ep a r a tion of 2-Isoxa zolin es 2-Oxid es (4RS,-
5S)-6. A 1 M aqueous solution of sodium periodate (1 equiv)
was added to a stirred solution of the diol 14 in ethanol (0.1
M, 1 equiv). Imidazole (1.1 equiv) and ethyl nitroacetate (1
equiv) were immediately added, and the mixture was kept
stirring at room temperature until the reaction was complete.
The mixture was filtered over a glass sintered filter, and the
solution was concentrated in vacuo. The residue was taken
up with a 10% solution of sodium carbonate and extracted
several times with ethyl acetate. The combined organic layers
were washed with brine, and the crude product was obtained
as a mixture of (4S,5S) and (4R,5S) diastereoisomers. Some-
times, the products required purification by flash chromatog-
raphy. For the spectroscopical characterization of the single
diastereoisomers, see below.
a . (4RS,5S)-5-Bu t yl-3-et h oxyca r b on yl-4-h yd r oxy-2-
isoxa zolin e 2-Oxid e (6a ). The reaction was performed on
6.41 mmol of diol 14a . No chromatographic purification was
needed. Yield 93% of a clear oil.
b. (4RS,5S)-3-Eth oxyca r bon yl-5-p en tyl-4-h yd r oxy-2-
isoxa zolin e 2-Oxid e (6b). The reaction was performed on
3.28 mmol of diol 14b. Yield 86% of a clear oil.
c. (4RS,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-(4-p en te-
n yl)-2-isoxa zolin e 2-Oxid e (6c). The reaction was per-
formed on 0.87 mmol of diol 14c. No chromatographic
purification was needed. Yield 90% of a clear oil.
d . (4RS,5S)-5-Cycloh exylm eth yl-3-eth oxyca r bon yl-4-
h yd r oxy-2-isoxa zolin e 2-Oxid e (6d ). The reaction was
performed on 1.25 mmol of diol 14d . No chromatographic
purification was needed. Quantitative yield of a clear oil.
e. (4RS,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-[(3S)-3-m e-
th ylp en tyl]-2-isoxa zolin e 2-Oxid e (6e). The reaction was
performed on 5.04 mmol of diol 14e. No chromatographic
purification was needed. Yield 95% of a clear oil.
a. (4R,5S)-5-Bu tyl-3-eth oxycar bon yl-4-[(2S)-2-m eth oxy-
2-ph en yl-3,3,3-tr iflu or opr opan oyloxy]-2-isoxazolin e 2-Ox-
id e [(4R,5S,2′S)-tr a n s-16]. 1H NMR δ 0.93 (t, 3), 1.30 (t, 3),
1.35-1.55 (m, 4), 1.83 (dt, 2), 3.56 (s, 3), 4,30 (q, 2), 4.40 (dt,
1), 6.36 (d, 1), 7.35-7.45 (m, 3), 7,36-7,55 (m, 2) ppm. 13C
NMR δ 166.06, 157.88, 131.52, 130.02, 128.66, 127.01, 124.97,
121.14, 106.09, 82.02, 79.78, 62.17, 55.65, 31.66, 26.47, 22.19,
14.04, 13.73 ppm.
b. (4S,5S)-5-Bu tyl-3-eth oxycar bon yl-4-[(2S)-2-m eth oxy-
2-ph en yl-3,3,3-tr iflu or opr opan oyloxy]-2-isoxazolin e 2-Ox-
id e [(4S,5S,2′S)-cis-16]. 1H NMR δ 0.88 (t, 3), 1.24 (t, 3),
1.30-1.50 (m, 4), 1.55-1.80 (m, 2), 3.44 (s, 3), 4.24 (q, 2), 4.76
(dt, 1), 6.69 (d, 1), 7.35-7.45 (m, 3), 7.50-7.60 (m, 2) ppm. 13
C
NMR δ 165.69, 157.61, 130.81, 130.02, 128.66, 127.62, 125.05,
121.22, 108.54, 80.16, 75.59, 62.02, 55.28, 27.52, 26.42, 22.28,
13.97, 13.65 ppm.
c. (4S,5R)-5-Bu tyl-3-eth oxycar bon yl-4-[(2S)-2-m eth oxy-
2-ph en yl-3,3,3-tr iflu or opr opan oyloxy]-2-isoxazolin e 2-Ox-
id e [(4S,5R,2′S)-tr a n s-16]. 1H NMR δ 0.95 (t, 3), 1.18 (t, 3),
1.30-1.60 (m, 4), 1.65-1.95 (m, 2), 3.53 (s, 3), 4.22 (q, 2), 4.56
(dt, 1), 6.28 (d, 1), 7.30-7.60 (m, 5) ppm. 13C NMR δ 166.40,
157.95, 131.51, 130.35, 129.48, 128.96, 128.56, 127.68, 126.27,
120.52, 106.46, 82.55, 80.52, 62.38, 56.83, 31.97, 26.88, 22.58,
14.27, 14.09, 12.46, 12.27 ppm.
d . (4R,5R)-5-Bu tyl-3-eth oxyca r bon yl-4-[(2S)-2-m eth -
oxy-2-p h e n yl-3,3,3-t r iflu or op r op a n oyloxy]-2-isoxa zo-
lin e 2-Oxid e [(4R,5R,2′S)-cis-16]. 1H NMR δ 0.85 (t, 3), 1.28
(t, 3), 1.30-1.50 (m, 6), 3.55 (s, 3), 4.28 (q, 2), 4.73 (dt, 1), 6.71
(d, 1), 7.35-7.45 (m, 3), 7.50-7.65 (m, 2) ppm. 13C NMR δ
165.63, 157.83, 131.59, 129.97, 128.51, 127.10, 125.05, 121.21,
108.57, 80.41, 62.19, 55.73, 27.61, 26.15, 22.23, 13.99, 13.70
ppm.
Bisa lk yla tion of Diep oxid e 11. The reaction was per-
formed as described above for diepoxide 10 on 4.14 mmol of
starting material 11, obtaining 0.84 g (74% yield) of a clear
oil. 1H NMR (CDCl3) δ 0.91 (t, 6), 1.20-1.65 (m, 12), 1.41 (s,
6), 2.10 (d, 2), 3.50 (m, 2), 3.93 (dd, 2) ppm. 13C NMR (CDCl3)
δ 110.1, 80.94, 71.08, 35.55, 28.96, 28.30, 23.61, 15.00 ppm.
[R]28 ) +8.58 (c 1.00, CHCl3). Anal. Calcd for C15H30O4: C,
D
65.66; H, 11.02. Found: C, 65.80 H, 10.94.
Bism esyla tion of Diol 17. The reaction was performed
as described above for diol 12, in this case on 3.02 mmol of
starting material obtaining 1.12 g (87% yield) of a clear oil.
1H NMR (CDCl3) δ 0.90 (t, 6), 1.41 (m, 14), 1.71-1.95 (m, 4),
3.10 (s, 6), 4.12 (s, 2H), 4.75 (t, 2) ppm. 13C NMR (CDCl3) δ
110.2, 80.40, 77.57, 39.31, 31.98, 27.85, 27.37, 22.83, 14.31
P r otection of 2-Isoxa zolin es 2-Oxid es 6. To a stirred
solution of the starting 2-isoxazoline 2-oxide (6) in dichlo-
romethane (0.5 M, 1 equiv) was added triethylamine (1.1
ppm. [R]28 ) -10.03 (c 0.97, CHCl3). Anal. Calcd for
D
(26) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
C
17H34O8S2: C, 47.42; H, 7.96. Found: C, 47.55; H, 8.02.

D-Mannitol as Chiral Source for EPC Synthesis
J . Org. Chem., Vol. 63, No. 23, 1998 8243
equiv), DMAP (0.3 equiv), and tert-butyldiphenylsilyl chloride
(1.1 equiv). The mixture was kept stirring at room tempera-
ture for 24 h, and then it was partitioned between saturated
NH4Cl and dichloromethane. The aqueous layer was extracted
3 times with dichloromethane, and the products were sepa-
rated by flash chromatography eluting with petroleum ether/
diethyl ether, 4:1, for the protected derivatives 20 and then
with diethyl ether alone for unreacted cis-6.
7.70 (m, 4) ppm. 13C NMR δ 159.2, 136.3-128.2, 111.1, 83.1,
79.8, 62.0, 39.2, 34.0, 33.7, 32.6, 27.0, 26.7, 26.4, 26.3, 19.8,
14.5 ppm. [R]25 ) -27.98 (c 1.02, CHCl3). Anal. Calcd
D
C
29H39NO5Si: C, 68.34; H, 7.71; N, 2.75. Found: C, 68.21; H,
7.72; N, 2.78.
(4S,5S)-4-(t-Bu tyldiph en ylsilyloxy)-5-cycloh exylm eth yl-
3-eth oxyca r bon yl-2-isoxa zolin e 2-Oxid e (cis-20d ). Yield
14% of a white solid. mp 140-142 °C. 1H NMR δ 0.85 (t, 3),
1.05 (s, 9), 1.20 (m, 6), 1.70 (m, 6), 2.00 (m, 1), 3.25 (dq, 1),
3.82 (dq, 1), 4.45 (ddd, 1), 5.15 (d, 1), 7.30-7.90 (m, 10) ppm.
13C NMR δ 158.6, 136.5-128.0, 113.7, 81.6, 75.1, 61.6, 34.6,
34.5, 34.0, 33.4, 27.3, 26.8, 26.6, 20.2, 14.0 ppm. [R]23D ) -7.89
(c 0.95, CHCl3). Anal. Calcd C29H39NO5Si: C, 68.34; H, 7.71;
N, 2.75. Found: C, 68.39; H, 7.68; N, 2.74.
a . P r otection of 6a . The reaction was performed on 11.9
mmol. Overall yield 88%.
a.1. (4R,5S)-5-Bu tyl-4-(t-bu tyldiph en ylsilyloxy)-3-eth ox-
yca r bon yl-2-isoxa zolin e 2-Oxid e (tr a n s-20a ). Yield 33%
of a white solid. mp 58-60 °C. 1H NMR δ 0.67 (t, 3), 0.80-
1.40 (m, 16), 4.01 (dq, 1), 4.24 (dq, 1), 4.29 (ddd, 1), 5.06 (d, 1),
7.40 (m, 6), 7.70 (m, 4), 13C NMR δ 159.2, 136.3-128.3, 111.1,
85.2, 79.3, 62.1, 31.5, 27.1, 27.0, 22.6, 19.7, 14.4, 14.2 ppm.
e. P r otection of 6e. The reaction was performed on 9.81
mmol. Overall yield 95%.
[R]27 ) -42.64 (c 1.00, CHCl3). Anal. Calcd for C27H37NO5-
D
e.1. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r -
bon yl-5-[(3S)-3-m eth ylpen tyl]-2-isoxazolin e 2-Oxide (tr a n s-
20e). Yield 39% of a clear oil. 1H NMR δ 0.68 (d, 3), 0.75 (t,
3), 0.80-1.40 (m, 19), 4.02 (dq, 1), 4.14-4.32 (m, 2), 5.07 (d,
1), 7.40 (m, 6), 7.70 (m, 4) ppm. 13C NMR δ 159.2, 136.3-
128.3, 111.1, 85.6, 79.3, 62.0, 34.4, 31.5, 29.6, 29.5, 27.2, 19.7,
Si: C, 67.05; H, 7.71; N, 2.90. Found: C, 67.20; H, 7.76; N,
2.87.
a.2. (4S,5S)-5-Bu tyl-4-(t-bu tyldiph en ylsilyloxy)-3-eth ox-
yca r bon yl-2-isoxa zolin e 2-Oxid e (cis-20a ). Yield 19% of
a white solid. mp 90-92 °C. 1H NMR δ 0.86 (t, 3), 0.92 (t, 3),
1.05 (s, 9), 1.40 (m, 4), 1.90 (m, 1), 2.10 (m, 1), 3.26 (dq, 1),
3.87 (dq, 1), 4.40 (ddd, 1), 5.20 (d, 1), 7.90-7.30 (m, 10) ppm.
13C NMR δ 158.1, 136.0-127.6, 113.2, 83.2, 74.3, 61.1, 27.6,
19.3, 14.4, 11.7 ppm. [R]23 ) -35.87 (c 1.01, CHCl3). Anal-
D
.Calcd C28H39NO5Si: C, 67.57; H, 7.90; N, 2.81. Found: C,
67.48; H, 7.90; N, 2.82.
26.8, 26.3, 22.5, 19.7, 14.0, 13.6 ppm. [R]27 ) +6.61 (c 0.98,
D
(4S,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r bon yl-
5-[(3S)-3-m eth ylp en tyl]-2-isoxa zolin e 2-Oxid e (cis-20e).
Yield 17% of a white solid. mp 100-101 °C. 1H NMR δ 0.80
(m, 9), 1.05 (s, 9), 1.10-1.50 (m, 5), 1.85 (m, 2), 3.32 (dq, 1),
3.85 (dq, 1), 4.34 (ddd, 1), 5.18 (d, 1), 7.30-7.90 (m, 10) ppm.
13C NMR δ 158.6, 136.4-128.1, 113.7, 84.1, 74.7, 61.5, 34.7,
32.6, 29.6, 27.2, 25.0, 20.2, 19.5, 14.0, 11.7 ppm. [R]26D ) +0.60
(c 1.00, CHCl3). Anal. Calcd C28H39NO5Si: C, 67.57; H, 7.90;
N, 2.81. Found: C, 67.65; H, 7.93; N, 2.79.
Dep r otection of Silyl Eth er s 20. A flask fitted with a
calcium chloride tube was charged with a solution of the
starting ether 20 in anhydrous THF (0.2 M, 1 equiv). To the
stirred solution was added a solution of tetrabutylammonium
fluoride in THF (1 M, 2 equiv). After 30 min, the reaction
was quenched by the addition of a saturated solution of NH4-
Cl. The aqueous layer was extracted several times with
dichloromethane. The crude product was purified by filtration
over a 5 cm pad of silica gel eluting with ethyl acetate/
petroleum ether, 4:1.
a . (4R,5S)-5-Bu tyl-3-eth oxyca r bon yl-4-h yd r oxy-2-isox-
a zolin e 2-Oxid e (tr a n s-6a ). The reaction was performed on
1.28 mmol of trans-20a . Yield 94% of a clear oil. 1H NMR δ
0.94 (t, 3), 1.40 (m, 7), 1.72 (m, 2), 3.98 (d, 1), 4.34 (q, 2), 4.53
(ddd, 1), 5.16 (dd, 1) ppm. 13C NMR δ 159.8, 111.5, 84.7, 77.4,
62.5, 32.5, 27.1, 22.7, 14.6, 14.2 ppm. [R]24D ) -158.63 (c 0.99,
CHCl3). Anal. Calcd for C10H17NO5: C, 51.94; H, 7.41; N, 6.06.
Found: C, 51.79; H, 7.38; N, 6.05.
CHCl3). Anal. Calcd for C27H37NO5Si: C, 67.05; H, 7.71; N,
2.90. Found: C, 66.88; H, 7.67; N, 2.95.
b. P r otection of 6b. The reaction was performed on 2.45
mmol. Overall yield 92%.
b.1. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r -
bon yl-5-p en tyl-2-isoxa zolin e 2-Oxid e (tr a n s-20b). Yield
34% of a clear oil. 1H NMR δ 0.80 (t, 3), 1.06 (m, 17), 1.16 (t,
3), 4.02 (dq, 1), 4.24 (dq, 1), 4.28 (ddd, 1), 5.05 (d, 1), 7.40 (m,
6), 7.70 (m, 4) ppm. 13C NMR δ 159.2, 136.3-128.2, 111.1,
85.1, 79.3, 62.1, 31.8, 31.6, 27.1, 24.6, 22.7, 19.8, 14.4, 14.3
ppm. [R]36D ) -34.45 (c 1.06, CHCl3). Anal. Calcd for C28H39
-
NO5Si: C, 67.57; H, 7.90; N, 2.81. Found: C, 67.71; H, 7.92;
N, 2.83.
b.2. (4S,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r -
bon yl-5-p en tyl-2-isoxa zolin e 2-Oxid e (cis-20b). Yield 25%
of a white solid. mp 99-101 °C. 1H NMR 0.86 (t, 3), 0.93 (t,
3), 1.08 (s, 9), 1.40 (m, 6), 1.90 (m, 1), 2.10 (m, 1), 3.32 (dq, 1)
3.87 (dq, 1), 4.40 (ddd, 1), 5.20 (d, 1), 7.45 (m, 6), 7.84 (m, 4)
ppm. 13C NMR δ 158.6, 136.4-128.1, 113.7, 83.6, 74.7, 61.5,
32.0, 27.2, 27.0, 25.6, 23.0, 20.2, 14.4, 14.0 ppm. [R]33D ) +2.24
(c 0.97, CHCl3). Anal. Calcd for C28H39NO5Si: C, 67.57; H,
7.90; N, 2.81. Found: C, 67.48; H, 7.92; N, 2.82.
c. P r otection of 6c. The reaction was performed on 10.9
mmol. Overall yield 97%.
c.1. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r -
bon yl-5-(4-p en t en yl)-2-isoxa zolin e 2-Oxid e (tr a n s-20c).
Yield 39% of a clear oil. 1H NMR δ 0.45-1.40 (m, 4), 1.06 (s,
9), 1.15 (t, 3), 1.85 (m, 2), 4.03 (dq, 1), 4.23 (dq, 1), 4.30 (ddd,
1), 4.90 (m, 2), 5.05 (d, 1), 5.60 (m, 1), 7.42 (m, 6), 7.70 (m, 4)
ppm. 13C NMR δ 158.8, 137.6, 135.9-127.7, 115.3, 110.6, 84.5,
b. (4S,5S)-5-Bu tyl-3-eth oxyca r bon yl-4-h yd r oxy-2-isox-
a zolin e 2-Oxid e (cis-6a ). 1H NMR δ 0.92 (t, 3), 1.30-1.50
(m, 7), 1.87 (m, 2), 3.21 (bs, 1), 4.36 (dq, 1), 4.37 (dq, 1), 4.56
(dt, 1), 5.25 (d, 1) ppm. 13C NMR δ 159.3, 112.5, 81.6, 72.8,
78.9, 61.6, 33.0, 30.8, 26.7, 23.7, 19.3, 14.0 ppm. [R]28
)
D
62.0, 27.5, 25.8, 22.5, 14.2, 13.9 ppm. [R]27 ) -15.66 (c 0.97,
D
-31.79 (c 1.01, CHCl3). Anal. Calcd for C27H35NO5Si: C,
67.33; H, 7.32; N, 2.91. Found: C, 67.23; H, 7.30; N, 2.92.
c.2. (4S,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r -
bon yl-5-(4-pen ten yl)-2-isoxazolin e 2-Oxide (cis-20c). Yield
15% of a white solid. mp 94-96 °C. 1H NMR δ 0.86 (t, 3),
1.05 (s, 9), 1.50-1.90 (m, 4), 2.20 (m, 2), 3.26 (dq, 1), 3.82 (dq,
1), 4.39 (ddd, 1), 5.00 (m, 2), 5.17 (d, 1), 5.78 (m, 1), 7.42 (m,
8), 7.70 (m, 2) ppm. 13C NMR δ 158.6, 138.2, 136.4-128.1,
115.8, 113.6, 83.4, 74.8, 61.5, 33.9, 27.2, 26.5, 25.1, 20.2, 14.0
CHCl3). Anal. Calcd for C10H17NO5: C, 51.94; H, 7.41; N, 6.06.
Found: C, 51.85; H, 7.44; N, 6.09.
c. (4R,5S)-3-E t h oxyca r b on yl-4-h yd r oxy-5-p en t yl-2-
isoxa zolin e 2-Oxid e (tr a n s-6b). The reaction was performed
on 0.83 mmol of trans-20b. Yield 60% of a clear oil. 1H NMR
δ 0.88 (t, 3), 1.36 (t, 3), 1.50-1.26 (m, 6), 1.70 (m, 2), 3.45 (bs,
1), 4.32 (dq, 1), 4.36 (dq, 1), 4.53 (ddd, 1), 5.15 (d, 1) ppm. 13C
NMR δ 159.4, 111.0, 84.2, 77.0, 62.1, 32.3, 31.3, 24.3, 22.4,
14.1, 13.9 ppm. [R]35D ) -122.21 (c 1.22, CHCl3). Anal. Calcd
for C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 54.01;
H, 7.78; N, 5.73.
ppm. [R]31 ) +1.20 (c 1.10, CHCl3). Anal. Calcd for C27H35
-
D
NO5Si: C, 67.33; H, 7.32; N, 2.91. Found: C, 67.22; H, 7.33;
N, 2.92.
d . P r otection of 6d . The reaction was performed on 2.50
mmol. Overall yield 98%.
d .1. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-5-cycloh exy-
lm eth yl-3-eth oxyca r bon yl-2-isoxa zolin e 2-Oxid e (tr a n s-
20d ). Yield 48% of a clear oil. 1H NMR δ 0.50-1.70 (m, 25),
4.01 (dq, 1), 4.21 (dq, 1), 4.43 (ddd, 1), 5.04 (d, 1), 7.40 (m, 6),
d . (4S,5S)-3-E t h oxyca r b on yl-4-h yd r oxy-5-p en t yl-2-
isoxa zolin e 2-Oxid e (cis-6b). The reaction was performed
on 0.60 mmol of cis-20b. Yield 61% of a clear oil. 1H NMR
0.90 (m, 3), 1.34 (t, 3), 1.50-1.26 (m, 6), 1.88 (dt, 2), 3.45 (bs,
1), 4.32 (dq, 1), 4.36 (dq, 1), 4.57 (dt, 1), 5.26 (d, 1) ppm. 13C
NMR δ 159.3, 112.7, 81.8, 72.8, 62.1, 31.6, 26.0, 25.1, 22.4,

8244 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
14.2, 13.9 ppm. [R]33D ) -17.47 (c 0.83, CHCl3). Anal. Calcd
for C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.95;
H, 7.82; N, 5.73.
b. (4S,5S)-5-Bu tyl-4-(t-bu tyld ip h en ylsilyloxy)-3-eth ox-
yca r bon yl-2-isoxa zolin e (cis-21a ). The reaction was per-
formed on 1.83 mmol of cis-20a . Yield 97% of a clear oil. 1H
NMR δ 0.90 (t, 3), 1.02 (s, 9), 1.09 (t, 3), 1.35 (m, 4), 1.95 (m,
2), 3.70 (dq, 1), 3.89 (dq, 1), 4.06 (ddd, 1), 4.95 (d, 1), 7.40 (m,
8), 7.85 (m, 2) ppm. 13C NMR δ 160.6, 155.1, 136.1-127.9,
89.5, 74.7, 62.1, 28.6, 27.3, 26.4, 23.1, 20.1, 14.4, 14.3 ppm.
e. (4R,5S)-3-Eth oxycar bon yl-4-h ydr oxy-5-(4-pen ten yl)-
2-isoxa zolin e 2-oxid e (tr a n s-6c). The reaction was per-
formed on 1.25 mmol of trans-20c. Yield 75% of a clear oil.
1H NMR δ 1.35 (t, 3), 1.45-1.81 (m, 4), 2.11 (m, 2), 3.85 (bs,
1), 4.26 (q, 2), 4.52 (ddd, 1), 4.89 (m, 2), 5.14 (d, 1), 5.76 (m, 1)
ppm. 13C NMR δ 159.7, 138.0, 115.9, 111.4, 84.5, 77.4, 62.5,
[R]24 ) -57.89 (c 0.99, CHCl3). Anal. Calcd for C26H35NO4-
D
Si: C, 68.84; H, 7.78; N, 3.09. Found: C, 68.71; H, 7.78; N,
3.11.
33.5, 32.1, 24.3, 14.6 ppm. [R]27 ) -141.14 (c 1.06, CHCl3).
D
Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76.
Found: C, 54.42; H, 7.05; N, 5.77.
c. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r bo-
n yl-5-(4-p en ten yl)-2-isoxa zolin e (tr a n s-21c). The reaction
was performed on 3.24 mmol of trans-20c. Yield 91% of a clear
oil. 1H NMR δ 0.80-1.20 (m, 13), 1.30 (t, 3), 1.80 (m, 2), 4.23
(dq, 1), 4.27 (dq, 1), 4.40 (ddd, 1), 4.86 (m, 2), 4.92 (d, 1), 5.59
(m, 1), 7.40 (m, 6), 7.52 (m, 4) ppm. 13C NMR δ 160.8, 152.9,
138.3, 136.1-128.1, 115.5, 91.5, 80.8, 62.4, 36.3, 31.1, 27.2,
f. (4S,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-(4-p en ten yl)-
2-isoxa zolin e 2-Oxid e (cis-6c). The reaction was performed
on 0.33 mmol of cis-20c. Yield 62% of a clear oil. 1H NMR δ
1.35 (t, 3), 1.57 (m, 2), 1.91 (m, 2), 2.14 (m, 2), 3.25 (bs, 1),
4.34 (q, 1), 4.35 (q, 1), 4.59 (ddd, 1), 5.02 (m, 2), 5.27 (d, 1),
5.80 (m, 1) ppm. 13C NMR δ 159.3, 137.8, 115.3, 112.4, 81.3,
24.6, 19.8, 14.6 ppm. [R]24 ) -62.34 (c 0.99, CHCl3). Anal.
D
79.9, 62.0, 33.3, 25.6, 24.6, 14.2 ppm. [R]31 ) -18.70 (c 0.94,
Calcd for C27H35NO4Si: C, 69.64; H, 7.58; N, 3.01. Found: C,
69.75; H, 7.57; N, 3.02.
D
CHCl3). Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76.
Found: C, 54.29; H, 7.00; N, 5.72.
d . (4S,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r bo-
n yl-5-(4-p en ten yl)-2-isoxa zolin e (cis-21c). The reaction
was performed on 2.16 mmol of cis-20c. Quantitative yield of
a white solid. mp 48-50 °C. 1H NMR δ 1.03 (s, 9), 1.10 (t, 3),
1.55 (m, 2), 1.80-2.20 (m, 4), 3.72 (dq, 1), 3.89 (dq, 1), 4.06
(ddd, 1), 4.97 (d, 1), 5.04 (m, 2), 5.80 (m, 1), 7.45 (m, 2), 7.88
(m, 8) ppm. 13C NMR δ 160.6, 155.1, 138.3, 136.7-127.9,
g. (4R,5S)-5-Cycloh exylm et h yl-3-et h oxyca r b on yl-4-
h yd r oxy-2-isoxa zolin e 2-Oxid e (tr a n s-6d ). The reaction
was performed on 1.16 mmol of trans-20d . mp 73-75 °C. Yield
70% of a white solid. 1H NMR δ 0.80-1.80 (m, 16), 3.80 (bs,
1), 4.32 (q, 1), 4.65 (ddd, 1), 5.10 (d, 1) ppm. 13C NMR δ 159.8,
111.4, 82.9, 77.9, 62.5, 40.3, 34.2, 34.0, 32.9, 26.7, 26.5, 14.6
115.6, 88.2, 74.9, 62.1, 34.1, 27.3, 26.3, 20.1, 14.3 ppm. [R]26
ppm. [R]30 ) -134.47 (c 0.97, CHCl3). Anal. Calcd for
D
D
) -58.48 (c 1.01, CHCl3). Anal. Calcd for C27H35NO4Si: C,
69.64; H, 7.58; N, 3.01. Found: C, 69.55; H, 7.55; N, 2.99.
e. (4R,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r bo-
n yl-5-[(3S)-3-m eth ylp en tyl]-2-isoxa zolin e (tr a n s-21e). The
reaction was performed on 2.25 mmol of trans-20e. Yield 92%
of a clear oil. 1H NMR δ 0.64 (d, 3), 0.76 (t, 3), 0.82-1.20 (m,
15), 1.30 (t, 3), 4.20 (dq, 1), 4.31 (dq, 1), 4.37 (ddd, 1), 4.94(d,
1), 7.40 (m, 6), 7.70 (m, 4) ppm. 13C NMR δ 160.4, 152.5,
136.0-127.8, 91.8, 80.3, 61.9, 34.0, 31.5, 29.1, 28.9, 26.7, 19.3,
C
13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.40; H,
7.82; N, 5.18.
h . (4S,5S)-5-Cycloh exylm et h yl-3-et h oxyca r b on yl-4-
h yd r oxy-2-isoxa zolin e 2-Oxid e (cis-6d ). The reaction was
performed on 0.35 mmol of cis-20d . Yield 64% of a white solid.
mp 85-87 °C. 1H NMR δ 0.80-1.90 (m, 16), 3.30 (bs, 1), 4.32
(q, 1), 4.32 (q, 1), 4.70 (ddd, 1), 5.24 (d, 1) ppm. 13C NMR δ
159.8, 113.1, 80.3, 73.6, 62.5, 34.7, 34.1, 33.8, 33.3, 26.7, 26.6,
26.5, 14.6 ppm. [R]23D ) -20.94 (c 0.98, CHCl3). Anal. Calcd
for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.62;
H, 7.85; N, 5.16.
18.9, 14.1, 11.3 ppm. [R]25 ) -73.49 (c 1.06, CHCl3). Anal.
D
Calcd for C28H39NO4Si: C, 69.82; H, 8.16; N, 2.91. Found: C,
69.71; H, 8.15; N, 2.93.
i. (4R,5S)-3-Eth oxyca r bon yl-5-[(3S)-3-m eth ylp en tyl]-
4-h yd r oxy-2-isoxa zolin e 2-Oxid e (tr a n s-6e). The reaction
was performed on 1.41 mmol of trans-20e. Yield 92% of a clear
oil. 1H NMR δ 0.80 (m, 6), 1.04-1.60 (m, 8), 1.70 (m, 2), 3.70
(bs, 1), 4.36 (q, 1), 4.50 (dt, 1), 5.18 (d, 1) ppm. 13C NMR δ
159.8, 111.4, 85.0, 77.4, 62.6, 34.5, 31.6, 30.5, 29.6, 19.4, 14.6,
f. (4S,5S)-4-(t-Bu tyld ip h en ylsilyloxy)-3-eth oxyca r bo-
n yl-5-[(3S)-3-m eth ylp en tyl]-2-isoxa zolin e (cis-21e). The
reaction was performed on 1.99 mmol of cis-20e. Yield 98%
of a clear oil. 1H NMR δ 0.83 (m, 6), 0.90-1.60, (m, 17), 1.90
(m, 2), 3.72 (dq, 1), 3.90 (dq, 1), 4.02 (ddd, 1), 4.97 (d, 1), 7.30-
7.90 (m, 10) ppm. 13C NMR δ 160.7, 155.1, 136.7-127.9, 89.9,
74.8, 62.1, 34.8, 33.4, 29.6, 27.3, 24.6, 20.1, 19.5, 14.3, 11.7
11.7 ppm. [R]21 ) -140.55 (c 1.00, CHCl3). Anal. Calcd for
D
C
12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C, 55.70; H,
ppm. [R]25D ) -58.72 (c 1.07, CHCl3). Anal. Calcd for C28H39
-
8.16; N, 5.44.
NO4Si: C, 69.82; H, 8.16; N, 2.91. Found: C, 69.88; H, 8.18;
N, 2.90.
j. (4S,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-[(3S)-3-m e-
th ylp en tyl]-2-isoxa zolin e 2-Oxid e (cis-6e). Clear oil. 1H
NMR δ 0.85 (m, 6), 1.10-1.55 (m, 8), 1.85 (m, 2), 3.40 (m, 1),
4.35 (dq, 2), 4.55 (ddd, 1), 5.26 (d, 1) ppm. 13C NMR δ 159.8,
113.1, 82.5, 73.1, 62.4, 34.8, 32.4, 29.7, 24.1, 19.4, 14.6, 11.7
Dep r otection of Silyl Eth er s 21. The reactions were
performed as described above for silyl ethers 20.
a . (4R,5S)-5-Bu tyl-3-eth oxyca r bon yl-4-h yd r oxy-2-isox-
a zolin e (tr a n s-9a ). The reaction was performed on 1.96
mmol of cis-21a . Yield 62% of a clear oil. 1H NMR δ 0.92 (t,
3), 1.50-1.78 (m, 9), 3.92 (bs, 1), 4.36 (q, 2), 4.57 (ddd, 1), 5.03
(d, 1) ppm. 13C NMR δ 160.9, 152.4, 90.9, 78.8, 62.2, 31.8, 26.9,
ppm. [R]26 -9.94 (c 1.00, CHCl3). Anal. Calcd for C12H21
-
D
NO5: C, 55.58; H, 8.16; N, 5.40. Found: C, 55.61; H, 8.17; N,
5.42.
Deoxygen a tion of 2-Isoxa zolin es 2-Oxid es 20. A solu-
tion of the N-oxide 20 in trimethyl phosphite (0.25 M) was
heated to reflux until disappearance of the starting material
was observed by TLC. The reaction mixture was allowed to
cool to room temperature and taken up in diethyl ether. The
mixture was washed 4 times with 5% HCl, and the combined
aqueous layers were back extracted with a small portion of
diethyl ether. The crude product needed no further purifica-
tion.
22.3, 14.0, 13.8 ppm. [R]25 ) -216.57 (c 1.02, CHCl3). Anal.
D
Calcd for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C,
55.87; H, 7.99; N, 6.50.
b. (4S,5S)-5-Bu tyl-3-eth oxyca r bon yl-4-h yd r oxy-2-isox-
a zolin e (cis-9a ). The reaction was performed on 1.83 mmol
of cis-21a . Yield 84% of a waxy solid. 1H NMR δ 0.90 (t, 3),
1.20-1.65 (m, 7), 1.90 (m, 2), 3.20 (bs, 1), 4.40 (m, 3), 5.15 (d,
1) ppm. 13C NMR δ 161.2, 153.5, 87.7, 73.5, 62.3, 28.3, 25.6,
22.7, 14.1, 13.9 ppm. [R]23 ) -114.54 (c 1.01, CHCl3). Anal.
D
a . (4R,5S)-5-Bu tyl-4-(t-bu tyld ip h en ylsilyloxy)-3-eth ox-
yca r bon yl-2-isoxa zolin e (tr a n s-21a ). The reaction was
performed on 0.21 mmol of trans-20a . Yield 94% of a clear
oil. 1H NMR δ 0.70 (t, 3), 0.80 (m, 15), 1.30 (t, 3), 4.22 (dq, 1),
4.26 (dq, 1), 4.40 (ddd, 1), 4.95(d, 1), 7.40 (m, 6), 7.70 (m, 4)
ppm. 13C NMR δ 160.9, 152.9, 136.1-128.2, 91.8, 80.7, 62.4,
Calcd for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C,
55.72; H, 7.99; N, 6.52.
c. (4R,5S)-3-Eth oxycar bon yl-4-h ydr oxy-5-(4-pen ten yl)-
2-isoxa zolin e (tr a n s-9c). the reaction was performed on 1.39
mmol of trans-21c. Yield 87% of a clear oil. 1H NMR δ 1.40
(t, 3), 1.60 (m, 4), 2.12 (m, 2), 3.70 (bs, 1), 4.38 (q, 2), 4.60 (m,
1), 5.02 (m, 3), 5.80 (m, 1) ppm. 13C NMR δ 161.4, 152.6, 138.3,
31.4, 27.4, 27.3, 22.8, 19.8, 14.5, 14.2 ppm. [R]24 ) -64.05 (c
D
0.99, CHCl3). Anal. Calcd for C26H35NO4Si: C, 68.84; H, 7.78;
N, 3.09. Found: C, 68.97; H, 7.81; N, 3.11.
115.7, 91.1, 79.3, 62.8, 33.7, 32.0, 24.6, 14.5 ppm. [R]24
)
D

D-Mannitol as Chiral Source for EPC Synthesis
J . Org. Chem., Vol. 63, No. 23, 1998 8245
-198.29 (c 0.98, CHCl3). Anal. Calcd for C11H17NO4: C, 58.14;
95.4, 85.9, 78.6, 74.0, 62.3, 35.3, 31.8-26.3, 25.6, 22.5, 14.1,
H, 7.54; N, 6.16. Found: C, 58.22; H, 7.56; N, 6.13.
14.0, 0.2, -3.1 ppm. [R]34 ) +34.51 (c 1.02, CHCl3). Anal.
D
Calcd for C15H27NO5Si: C, 54.68; H, 8.26; N, 4.25. Found: C,
54.78; H, 8.27; N, 4.25.
(4S,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-(4-p en ten yl)-2-
isoxa zolin e (cis-9c). The reaction was performed on 2.04
mmol of cis-21c. Yield 80% of a white solid. mp 32-35 °C.
1H NMR δ 1.38 (t, 3), 1.64 (m, 2), 1.90 (m, 2), 2.15 (m, 2), 3.30
(bs, 1), 4.35 (m, 1), 4.60 (q, 2), 5.02 (m, 2), 5.15 (d, 1), 5.83 (m,
1) ppm. 13C NMR δ 161.2, 153.5, 138.1, 115.0, 87.5, 73.5, 62.3,
d . Tr icycliza tion of 6c. The reaction was performed on
1.57 mmol of the mixture of trans- and cis-6c. The corre-
sponding two products, 6-exo-1c and 6-endo-1c, were separated
by column chromatography eluting with ethyl acetate/petro-
leum ether, 3:7. Overall yield 89%.
33.6, 25.4, 14.1 ppm. [R]21 ) -106.08 (c 0.99, CHCl3). Anal.
D
d .1. 6-exo-(4-P en ten yl)-HF TS (6-exo-1c). Clear oil. 1H
NMR δ 0.32 (s, 3), 0.40 (s, 3), 1.32 (t, 3), 1.30-1.80 (m, 4),
2.10 (m, 2), 2.45 (dd, 1), 4.07 (ddd, 1), 4.27 (q, 1), 4.28 (q, 1),
4.31 (dd, 1), 4.41 (dd, 1), 4.79 (d, 1), 4.98 (m, 2), 5.79 (m, 1)
ppm. 13C NMR δ 170.8, 138.7, 115.3, 93.6, 90.1, 86.9, 72.8,
Calcd for C11H17NO4: C, 58.14; H, 7.54; N, 6.16. Found: C,
58.08; H, 7.51; N, 6.15.
(4R,5S)-3-E t h oxyca r b on yl-5-[(3S)-3-m et h ylp en t yl]-4-
h yd r oxy-2-isoxa zolin e (tr a n s-9e). The reaction was per-
formed on 2.06 mmol of trans-21e. Yield 78% of a clear oil.
1H NMR δ 0.82 (d, 3), 0.83 (t, 3), 1.05-1.65 (m, 10), 3.40 (bs,
1), 4.35 (q, 1), 4.52 (ddd, 1), 5.01 (d, 1) ppm. 13C NMR δ 161.5,
152.9, 91.6, 79.1, 62.7, 34.6, 31.9, 30.2, 29.4, 19.5, 14.5, 11.7
62.8, 36.9, 33.8, 31.4, 25.2, 22.5, 14.5, 0.4, -2.0 ppm. [R]34
)
D
-16.30 (c 0.99, CHCl3). Anal. Calcd for C15H25NO5Si: C,
55.02; H, 7.70; N, 4.28. Found: C, 55.16; H, 7.72; N, 4.29.
ppm. [R]21 ) -194.98 (c 0.99, CHCl3). Anal. Calcd for
d .2. 6-en d o-(4-P en ten yl)-HF TS (6-en d o-1c). Clear oil.
1H NMR δ 0.32 (s, 3), 0.38 (s, 3), 1.32 (t, 3), 1.40-1.72 (m, 4),
2.09 (m, 2), 2.44 (dd, 1), 3.87 (dt, 1), 4.27 (dq, 2), 4.37 (dd, 1),
4.47 (dd, 1), 4.75 (d, 1), 4.97 (m, 2), 5.79 (m, 1) ppm. 13C NMR
δ 170.7, 138.7, 115.1, 95.8, 86.2, 76.8, 74.5, 62.6, 35.7, 34.0,
26.2, 25.4, 14.4, 0.1, -2.8 ppm. [R]28D ) +32.58 (c 0.98, CHCl3).
Anal. Calcd for C15H25NO5Si: C, 55.02; H, 7.70; N, 4.28.
Found: C, 55.09; H, 7.71; N, 4.29.
D
C
12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.12; H,
8.66; N, 5.75.
(4S,5S)-3-Eth oxyca r bon yl-4-h yd r oxy-5-[(3S)-3-m eth yl-
p en tyl]-2-isoxa zolin e (cis-9e). The reaction was performed
on 1.93 mmol of cis-21e. Yield 92% of a white solid. mp 33-
35 °C. 1H NMR δ 0.90 (t, 3), 0.91 (d, 3), 1.00-1.70 (m, 8), 1.85
(m, 2), 3.28 (bs, 1), 4.32 (ddd, 1), 4.37 (q, 1), 5.15 (d, 1) ppm.
13C NMR δ 161.6, 154.0, 88.6, 73.9, 62.7, 34.9, 33.3, 29.9, 23.9,
e. 6-exo-Cycloh exylm eth yl-HF TS (6-exo-1d ). The reac-
tion was performed on 0.74 mmol of trans-6d . Yield 76% of a
clear oil. 1H NMR δ 0.32 (s, 3), 0.40 (s, 3), 0.80-1.87 (m, 16),
2.45 (dd, 1), 4.20 (ddd, 1), 4.28 (q, 1), 4.29 (q, 1), 4.32 (dd, 1),
4.41 (dd, 1), 4.76 (d, 1) ppm. 13C NMR δ 170.8, 93.6, 90.5, 84.8,
72.9, 62.7, 39.5, 36.9, 34.5, 34.1, 33.1, 26.9, 26.6, 26.5, 14.5,
19.3, 14.5, 11.8 ppm. [R]21 ) -100.90 (c 1.00, CHCl3). Anal.
D
Calcd for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C,
59.29; H, 8.73; N, 5.79.
Tr icycliza tion of 2-Isoxa zolin es 2-Oxid e 6. A solution
of the starting 2-isoxazoline 2-oxide 6 in anhydrous dichlo-
romethane (0.3 M, 1 equiv) was placed in a flask under a
nitrogen atmosphere. Imidazole (2.5 equiv) and chlorodim-
ethylvinylsilane (1.2 equiv) were added to the stirred mixture.
After 24 h, the mixture was partitioned between water and
dichloromethane. The aqueous layer was extracted 4 times
with dichloromethane. The crude product needed no further
purification.
0.4, -2.0 ppm. [R]26 ) -18.26 (c 0.99, CHCl3). Anal. Calcd
D
for C17H29NO5Si: C, 57.43; H, 8.22; N, 3.94. Found: C, 57.58;
H, 8.25; N, 3.93.
f. 6-en d o-Cycloh exylm eth yl-HF TS (6-en d o-1d ). The
reaction was performed on 1.00 mmol of cis-6d . Yield 73% of
a clear oil. 1H NMR δ 0.32 (s, 3), 0.38 (s, 3), 0.80-1.85 (m,
16), 2.42 (dd, 1), 3.90 (ddd, 1), 4.19 (q, 2), 4.29 (dd, 1), 4.39
(dd, 1), 4.67 (d, 1) ppm. 13C NMR δ 170.8, 95.8, 86.8, 76.8,
74.5, 62.7, 35.8, 35.0, 34.2, 33.6, 26.9, 26.6, 26.5, 14.5, 0.2, -2.7
a . 6-exo-Bu tyl-HF TS (6-exo-1a ). The reaction was per-
1
formed on 1.12 mmol of trans-6a . Yield 93% of a clear oil. H
ppm. [R]24D ) +21.65 (c 1.01, CHCl3). Anal. Calcd for C17H29
-
NMR δ 0.32 (s, 3), 0.40 (s, 3), 0.90 (t, 3), 1.28-1.80 (m, 9),
2.46 (dd, 1), 4.07 (ddd, 1), 4.29 (q, 1), 4.30 (q, 1), 4.34 (dd, 1),
4.41 (dd, 1), 4.80 (d, 1) ppm. 13C NMR δ 170.8, 93.6, 90.2, 87.1,
72.8, 62.8, 36.9, 31.7, 28.1, 22.9, 14.5, 14.4, 0.4, -2.0 ppm.
NO5Si: C, 57.43; H, 8.22; N, 3.94. Found: C, 57.31; H, 8.20;
N, 3.92.
g. 6-exo-[(3S)-3-Meth ylp en tyl]-HF TS (6-exo-1e). The
reaction was performed on 3.86 mmol of trans-6e. Yield 81%
of a clear oil. 1H NMR δ 0.32 (s, 3), 0.38 (s, 3), 0.85 (m, 6),
1.05-1.75 (m, 10), 2.45 (dd, 1), 4.05 (dt, 1), 4.28 (q, 1), 4.29 (q,
1), 4.31 (dd, 1), 4.41 (dd, 1), 4.80 (d, 1) ppm. 13C NMR δ 170.9,
93.6, 90.2, 87.5, 72.8, 62.8, 35.8, 34.6, 32.6, 29.8, 29.7, 19.4,
14.5, 11.8, 0.4, -1.9 ppm. [R]25D ) -6.75 (c 1.07, CHCl3). Anal.
Calcd for C16H29NO5Si: C, 55.95; H, 8.51; N, 4.08. Found: C,
56.09; H, 8.49; N, 4.10.
h . 6-en do-[(3S)-3-Meth ylpen tyl]-HFTS (6-en do-1e). The
reaction was performed on 3.86 mmol of cis-6e. Yield 83% of
a clear oil. 1H NMR δ 0.32 (s, 3), 0.38 (s, 3), 0.70 (m, 6), 0.80-
1.40 (m, 8), 1.63 (m, 2), 2.29 (dd, 1), 3.68 (dt, 1), 4.12 (dq, 1),
4.13 (dq, 1), 4.24 (dd, 1), 4.36 (dd, 1), 4.62 (d, 1) ppm. 13C NMR
δ 170.8, 95.9, 86.3, 79.4, 74.5, 62.7, 35.7, 34.8, 32.9, 29.7, 24.3,
19.4, 14.5, 11.8, 0.2, -2.7 ppm. [R]22D ) +37.10 (c 1.00, CHCl3).
Anal. Calcd for C16H29NO5Si: C, 55.95; H, 8.51; N, 4.08.
Found: C, 55.86; H, 8.48; N, 4.07.
[R]27 ) -14.88 (c 1.11, CHCl3). Anal. Calcd for C14H25NO5-
D
Si: C, 53.31; H, 7.99; N, 4.44. Found: C, 53.44; H, 7.95; N,
4.45.
b. 6-en d o-Bu tyl-HF TS (6-en d o-1a ). The reaction was
performed on 1.30 mmol of cis-6a . Yield 93% of a clear oil. 1H
NMR δ 0.32 (s, 3), 0.39 (s, 3), 0.70 (t, 3), 1.30-1.46 (m, 7),
1.65 (m, 2), 2.44 (dd, 1), 3.87 (dt, 1), 4.28 (q, 1), 4.29 (q, 1),
4.38 (dd, 1), 4.49 (dd, 1), 4.78 (d, 1) ppm. 13C NMR δ 170.8,
95.8, 86.3, 79.0, 74.5, 62.7, 35.8, 28.4, 26.4, 23.2, 14.5, 14.3,
0.2, -2.7 ppm. [R]26 ) +33.31 (c 1.03, CHCl3). Anal. Calcd
D
for C14H25NO5Si: C, 53.31; H, 7.99; N, 4.44. Found: C, 53.18;
H, 7.95; N, 4.42.
c. Tr icycliza tion of 6b. The reaction was performed on
5.35 mmol of the mixture of trans- and cis-6b. The corre-
sponding two products, 6-exo-1b and 6-endo-1b, were sepa-
rated by column chromatography eluting with ethyl acetate/
petroleum ether, 3:7. Overall yield 85%.
c.1. 6-exo-P en tyl-HF TS (6-exo-1b). Clear oil. 1H NMR
CDCl3 δ 0.32 (s, 3), 0.40 (s, 3), 0.90 (t, 3), 1.20-1.80 (m, 11),
2.45 (dd, 1), 4.07 (ddd, 1), 4.27 (dq, 1), 4.28 (dq, 1), 4.38 (dd,
1), 4.47 (dd, 1), 4.75 (d, 1) ppm. 13C NMR δ 170.4, 93.2, 89.8,
86.6, 72.4, 62.3, 36.5, 31.5, 25.2, 22.5, 14.0; 13.9, 0.0, -2.4 ppm.
Ack n ow led gm en t. This work was supported in part
by research grants from the Ministero dell’Universita`
e della Ricerca Scientifica e Tecnologica (MURST), the
Consiglio Nazionale delle Ricerche (CNR), Italy, and the
Universita` di Bologna (Progetto d’Ateneo: Biomodula-
tori organici). Financial support from the MURST,
Rome, Italy and the University of Bologna, Italy (Na-
tional Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni”) is gratefully acknowl-
edged.
[R]34 ) -8.71 (c 1.05, CHCl3). Anal. Calcd for C15H27NO5Si:
D
C, 54.68; H, 8.26; N, 4.25. Found: C, 54.81; H, 8.28; N, 4.23.
c.2. 6-en d o-P en tyl-HF TS (6-en d o-1b). Clear oil. 1H
NMR δ 0.32 (s, 3), 0.38 (s, 3), 0.90 (t, 3), 1.25-1.50 (m, 9),
1.63 (m, 2), 2.44 (dd, 1), 3.86 (dt, 1), 4.26 (dq, 1), 4.27 (dq, 1),
4.38 (dd, 1), 4.47 (dd, 1), 4.75 (d, 1) ppm. 13C NMR δ 170.4,

8246 J . Org. Chem., Vol. 63, No. 23, 1998
Marotta et al.
Su p p or tin g In for m a tion Ava ila ble: Actual 1H NMR and
HPLC chromatograms of the Mosher’s esters 16 and details
about the assignment of their absolute configuration as well
as actual 13C NMR of compounds 6a -e, 9a ,c,e, and 1a -e (34
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 O980941I