Diastereoselective Conjugate Addition to (+)-Camphorsulfonic Acid Derived Nitroalkenes: Synthesis of α-Hydroxy and α-Amino Acids

Article abstract of DOI:10.1021/jo980582r

Diastereoselective tandem conjugate addition of both oxygen- and nitrogen-centered nucleophiles to the novel (1S)-10-camphorsulfonic acid derived nitroalkenes 9, 10, and 11 and ozonolysis gave the α-hydroxy and α-amino thiol acid derivatives 12, 13, and 14. In all cases, the (R)-diastereomer was formed as the major component albeit with only modest levels of selectivity (33-71% de). The structures of the products and the stereochemistry of the Michael addition step were unequivocally established by X-ray crystallographic studies of nitroalkenes 9 and 10 and (2S)-12c and (2R)-13a and by alternative syntheses from (S)-alanine, (S)-valine, and ethyl (S)-lactate.

Full text of DOI:10.1021/jo980582r

5818
J . Org. Chem. 1998, 63, 5818-5823
Dia ster eoselective Con ju ga te Ad d ition to (+)-Ca m p h or su lfon ic
Acid Der ived Nitr oa lk en es: Syn th esis of r-Hyd r oxy a n d r-Am in o
Acid s
Anthony G. M. Barrett,*,† D. Christopher Braddock,† Paul W. N. Christian,†
Daniel Pilipauskas,‡ Andrew J . P. White,† and David J . Williams†
Department of Chemistry, Imperial College, South Kensington, London, SW7 2AY, UK and
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208
Received March 30, 1998
Diastereoselective tandem conjugate addition of both oxygen- and nitrogen-centered nucleophiles
to the novel (1S)-10-camphorsulfonic acid derived nitroalkenes 9, 10, and 11 and ozonolysis gave
the R-hydroxy and R-amino thiol acid derivatives 12, 13, and 14. In all cases, the (R)-diastereomer
was formed as the major component albeit with only modest levels of selectivity (33-71% de). The
structures of the products and the stereochemistry of the Michael addition step were unequivocally
established by X-ray crystallographic studies of nitroalkenes 9 and 10 and (2S)-12c and (2R)-13a
and by alternative syntheses from (S)-alanine, (S)-valine, and ethyl (S)-lactate.
Sch em e 1
In tr od u ction
1-(Phenylthio)-1-nitroalkenes 1 are useful intermedi-
ates for the elaboration of R-substituted phenylthioesters
3 by the Michael addition of oxygen-, nitrogen-, and
carbon-centered nucleophiles followed by in situ ozonoly-
sis of nitronate intermediates 2 (Scheme 1).1 1-(Benzyl-
oxy)-1-nitroalkenes show comparable reactivity. These
methods have been applied for the synthesis of nikko-
mycin B,2 bicyclic â-lactams,3 and 6-aminopenicillanic
acid.4 The availability of both enantiomers of camphor-
10-sulfonic acid as inexpensive bulk chemicals has been
exploited by Oppolzer in the development of a number
of practical chiral auxiliaries.5 These auxiliaries confer
good to excellent π-facial topological differentiation to
reaction of their enoyl as well as to their enolate deriva-
tives and have been exploited for such diverse transfor-
mations as Diels-Alder reactions,6 1,4-additions of or-
ganocopper reagents,7 electrophilic halogenation8 (and
hence R-amino acids by SN2 displacement with azide as
nucleophile9), and electrophilic amination reactions.10 We
now report the use of a novel (+)-camphor-10-sulfonic
acid derived auxiliary to effect diastereoselective conju-
gate additions to pendant nitroalkene moieties. In situ
ozonolysis of the intermediate nitronate anion gave rise
directly to protected R-hydroxy and R-amino acids in
moderate to good yield and diastereomeric excess.
Resu lts a n d Discu ssion
Thionation of the camphor derivative 46a with Lawes-
son’s reagent in toluene at reflux gave thione 5 (82%) and
this was directly reduced with sodium borohydride to
provide thiol 6 as a colorless crystalline single diastere-
omer in excellent yield (Scheme 2). In conversion of thiol
6 to nitromethyl sulfide 8, temperature control was found
to be critical. Addition of 1 equiv of sulfuryl choride to
thiol 6 at 0 °C or -20 °C or by slow warming from -78
°C resulted in the formation of significant quantities (20-
40%) of bornyl chloride. Slow addition of sulfuryl chloride
to thiol 6 at -40 °C, however, provided 7 of ca. 95% purity
1
as estimated from its H NMR spectrum, and this was
used without further purification. Disappointingly, the
action of sodium nitromethylate, freshly prepared from
sodium ethoxide and nitromethane, on sulfenyl chloride
7 produced 8 in only 15% yield. However, the use of
n-butyllithium to deprotonate nitromethane followed by
the addition of the resulting slurry to 7 in THF furnished
8 in a reproducible 50% overall yield from 6. Nitroalkane
8 was converted into the substituted nitroalkenes 9, 10,
and 11 all exclusively as Z-isomers by condensation with
the appropriate aldehydes in the presence of piperi-
dinium acetate.11
† Imperial College.
‡ Northwestern University.
(1) Barrett, A. G. M. Chem. Soc. Rev. 1991, 20, 95.
(2) Barrett, A. G. M., Lebold, S. A. J . Org. Chem. 1991, 56, 4875.
(3) Barrett, A. G. M.; Graboski, G. G.; Sabat, M.; Taylor, S. J . J .
Org. Chem. 1987, 52, 4693.
Three representative nucleophiles (potassium phthal-
imide, potassium toluene-4-sulfonamide, and sodium
methoxide) were examined to assay the levels of diaste-
reoselectivity imparted on conjugate additions to chiral
nitroalkenes 9-11 (Table 1). For the addition of potas-
sium phthalimide to 10, DMF was found to be the
preferred solvent, the nitroalkene being completely con-
sumed within 1 h at 0 °C. In situ ozonolysis at -78 °C
gave the thioester 13a (60%) with a 33% de (Table 1,
entry 1) in favor of the (2R) epimer (vide infra). The
(4) Barrett, A. G. M.; Sakdarat, S. J . Org. Chem. 1990, 55, 5110.
(5) Oppolzer, W. Tetrahedron 1987, 43, 1969.
(6) (a) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Tetrahedron Lett.
1984, 25, 5885. (b) Oppolzer, W.; Chapuis, C.; Kelly, M. J . Helv. Chim.
Acta 1983, 66, 2385.
(7) Oppolzer, W.; Dudfield, P.; Stevenson, T.; Godel, T. Helv. Chim.
Acta 1985, 68, 212.
(8) Oppolzer, W.; Dudfield, P. Tetrahedron Lett. 1985, 26, 5525.
(9) Oppolzer, W.; Pedrosa, R.; Moretti, R. Tetrahedron Lett. 1986,
27, 831.
(10) Oppolzer, W.; Moretti, R. Helv. Chim. Acta 1986, 69, 1923.
(11) Ashwell, M.; J ackson, R. F. W.; Kirk, J . M. Tetrahedron 1990,
21, 7429.
S0022-3263(98)00582-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/31/1998

Synthesis of R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 63, No. 17, 1998 5819
Sch em e 2
from hexanes, and this proved to be the 2R epimer.
Authentic samples of diastereomerically pure 2S-epimers
of N-tosyl derivatives 12b and 13b were available from
S-alanine and S-valine, respectively, by 1-(3-(dimethyl-
amino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI)
coupling13 of N-tosyl-protected amino acids14 with thiol
6. Similarly, coupling of thiol 6 with carboxylic acid 17
available from (S)-ethyl lactate 15 via silver oxide medi-
ated methylation and subsequent hydrolysis of the
resulting R-methoxy ester 16 (Scheme 3) furnished (2S)-
12c as a single diastereoisomer. In each case the
authentic 2S epimer proved to be identical to the minor
diastereomeric component from the tandem conjugate
addition-ozonolysis thereby confirming the preference
for re face attack. It is pertinent to compare our findings
with the results of related work by Oppolzer using similar
auxiliaries where the diastereoselectivities are generally
excellent. In Oppolzer’s studies there are two key
features that rationalize the observed π-facial discrimi-
nation.5,15 For substrates such as silyl ketene acetal 1816
the C7′-C1′-C10′-S′ torsion angle is close to 180°, and
as a result of sulfonamide conjugation the lone pair on
nitrogen bisects the O-S′-O angle. Additionally, there
is a syn-periplanar disposition of the C1-OSi and C2′-H
bonds which places a cyclohexyl ring firmly on top and
thus shielding the CR-re face of the olefinic double bond
(Figure 1). The X-ray crystal structures of 9 and 10 show
that these nitroalkenes also exhibit an anti-periplanar
disposition of the C10′-S′ and C1′-C7′ bonds with the
lone pair of nitrogen bisecting the O-S′-O angle. How-
ever, the C1-NO2 bond is rotated by 118° in 9 and 108°
in 10 with respect to the C2′-H bond about the C1...C2′
vector thus resulting in less than perfect shielding of the
CR-si face of the nitroalkene. It seems likely that this
stems from unfavorable stereoelectronic interactions
between the nitro group and the sulfonyl group, and it
is reasonable to speculate that this unfavorable solid-
state interaction translates to the solution phase also.
This may go part-way in explaining the unexpected
moderate levels of diastereoselectivity imparted by the
auxiliary in these systems. In any case, it is apparent
from the results obtained, that in the reactive conforma-
tion of the molecule, the CR-re face of the nitroalkene is
the less shielded, giving rise to a predominance of the
2R-epimer in the diastereoisomeric product mixtures.
diastereoselectivity could be improved to 43% de, (2R)
major, by performing the initial conjugate addition at -20
°C (entry 2). However, solubility factors prevented any
further temperature decreases. Accordingly, mixed sol-
vent systems were examined, and it was found that a
1:1 mixture of DMF and dichloromethane allowed the
conjugate addition to proceed smoothly at -40 °C with a
corresponding increase in de (71%) (entry 3).
The other nucleophiles examined were also found to
add with moderate to good levels of diastereoselectivity
to chiral nitroalkenes 9 and 10 (entries 5-8). For the
addition of potassium phthalimide to 9 (entry 4), a 1:1
mixture of epimers was isolated where a fast epimeriza-
tion is presumably responsible for this anomalous result.
Conjugated nitroalkene 11 was found to be resistant to
attack by both nitrogen-centered nucleophiles, potassium
phthalimide and potassium toluene-4-sulfonamide, as
well as sodium methoxide, consistent with the poor
reactivity previously encountered with 2-aryl-1-(phen-
ylthio)nitroalkenes.12 The presumably more reactive
potassium trimethylsilanolate was found to add, generat-
ing adduct 14a in 74% yield (entry 9) after ozonolysis.
In all the above cases the 2R-epimer resulting from
nucleophilic attack from the CR-re face of the nitroalkene
predominated, albeit with modest diastereoselectivity.
This was unequivocably demonstrated by a combination
of single-crystal X-ray analyses and by preparation of
thioesters of known absolute configuration and correla-
tion with the diastereomeric product mixtures. Thus,
single crystals of the major diastereomer of 13a were
available for X-ray analysis after two recrystallizations
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were carried out under
a dry argon or nitrogen atmosphere at ambient temperature
unless otherwise stated. Column chromatography was carried
out on E. Merck or BDH silica gel 60, 230-400 mesh ASTM
using flash chromatography techniques.17 Analytical thin-
layer chromatography (TLC) was performed on E. Merck
precoated silica gel 60F254 plates. Hexanes, CH2Cl2, EtOAc,
and Et2O as eluants were ACS reagent grade solvent or GPR
grade from BDH and undistilled. The following reaction
solvents were purified by distillation: MeOH (from Mg, I2),
DMF (from alumina), t-BuOH (from CaH2), CH2Cl2 (from
(13) Nieses, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(14) McChesney, E. W.; Swann, W. J . Am. Chem. Soc. 1937, 59,
1116.
(15) For an X-ray crystal structure of a sulfonamido-isobornyl
acrylate and a discussion of its π-facial selectivity in a Diels-Alder
cycloaddition, see ref 6a.
(16) Oppolzer, W.; Dudfield, P. Helv. Chim. Acta 1985, 68, 216.
(17) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(12) Christian, P. W. N. Ph.D. Thesis, Imperial College, 1997.

5820 J . Org. Chem., Vol. 63, No. 17, 1998
Ta ble 1. Con ju ga te Dia ster eoselective Ad d ition of Nu cleop h iles to Ch ir a l Nitr oa lk en es
Barrett et al.
de (%)d
entry
nitroalkene
nucleophilea
solvent
T (°C)a,b
product
yield (%)c
1
2
3
4
5
6
7
8
9
10
10
10
9
10
10
9
KPht
KPht
KPht
KPht
KNHTs
KNHTs
KNHTs
NaOMe
KOTMS
DMF
DMF
1:1 DMF:CH2Cl2
1:1 DMF:CH2Cl2
DMF
1:1 DMF:CH2Cl2
1:1 DMF:CH2Cl2
1:1 DMF:CH2Cl2
1:1 DMF:CH2Cl2
0
-20
-40
-45
0
0
0
-35
-20
13a
13a
13a
12a
13b
13b
12b
12c
14a
60
58
61
65
60
71
72
32
74e
33
43
71
0
52
50
33
51
40
9
11
a
b
Temperature at which conjugate addition performed. All ozonolyses were performed at -78 °C. With the exception of entry 1, all
given temperatures are the minimum at which the solution remained homogeneous. c Isolated yield after chromatography. Determined
by integration of the relevant diastereomeric resonances in the 1H NMR spectrum. e Isolated as the free alcohol by direct cleavage of the
TMS adduct with 10% methanolic citric acid.
d
to ride on their parent atoms. The absolute structures of all
four compounds were determined by internal reference to the
camphor moiety and independently by use of the Flack
parameter (see Table 2). Computations were carried out using
the SHELXTL PC program system.23
N,N-Diisop r op yl-(1R)-10-th ioca m p h or su lfon a m id e (5).
Ketone 4 (1.00 g, 3.17 mmol) and 2,4-bis(4-methoxyphenyl)-
1,3-dithia-2,4-phosphetane 2,4-disulfide (Lawesson’s reagent)
(3.85 g, 9.52 mmol) were mixed in PhMe (80 mL) and heated
at reflux for 12 h. The mixture was allowed to cool to room
temperature, filtered through a plug of silica, and concentrated
in vacuo. Chromatography (1:3 EtOAc:hexane; Rf 0.27) fol-
lowed by recrystallization (hexane) gave thione 5 (0.86 g, 82%)
F igu r e 1.
23
as orange crystals, mp 92-93 °C; [R]D +194.0° (c 1.00,
CHCl3); IR (CHCl3) 1332, 1185 cm-1 1H NMR (300 MHz;
;
Sch em e 3
CDCl3) δ 3.92 (d, J ) 14.5 Hz, 1H), 3.83 (m, 2H), 2.92 (d, J )
14.5 Hz, 1H,), 2.84-2.69 (m, 2H), 2.49 (d, J ) 20.8 Hz, 1H),
2.17-2.09 (m, 2H), 1.63-1.40 (m, 2H), 1.36 (d, J ) 6.8 Hz,
6H), 1.35 (d, J ) 6.8 Hz, 6H), 1.26 (s, 3H), 0.86 (s, 3H); 13C
NMR (125 MHz; CDCl3) δ 266.0, 69.9, 55.0, 54.1, 49.8, 48.4,
45.1, 29.7, 27.1, 22.6, 22.1, 20.6, 19.8; m/z (CI+; NH3) 349 (M
+ NH4+•), 332 (M + H+•), 102. Anal. Calcd for C16H29NO2S2:
C, 57.98; H, 8.83; N, 4.23. Found: C, 57.97; H, 8.60; N, 4.19.
(1S)-10-(Diisop r op ylsu lfa m oyl)th ioisobor n eol (6). To
a stirred solution of thione 5 (0.95 g, 2.87 mmol) in 2-propanol
(19 mL) at 0 °C was added NaBH4 (0.46 g, 12.2 mmol). After
10 min, the mixture was allowed to warm to room tempera-
ture, stirred for 3 h, poured into crushed ice (75 g), extracted
with Et2O (3 × 30 mL), dried (MgSO4), and concentrated.
Chromatography (1:9 EtOAc:hexane; Rf 0.31) followed by
recrystallization (hexane) gave thiol 6 (0.87 g, 91%) as colorless
crystals, mp 97.5-98 °C; [R]25D-36.6° (c 1.00, CHCl3); IR
CaH2), Et2O (from Ph2CO-Na) and THF (from Ph2CO-K).
Commercial samples of n-butyllithium were titrated against
freshly recrystallized diphenylacetic acid.18 Powdered molec-
ular sieves were activated by drying at 120 °C for 24 h.
N,N-Diisopropyl-(1S)-10-camphorsulfonamide 46a was pre-
pared from (1S)-(+)-camphorsulfonic acid via (1S)-10-cam-
phorsulfonyl chloride.19 tert-Butyl 4-formylbenzoate was pre-
pared from the commercially available 4-formylbenzoic acid
employing N,N-dimethylformamide di-tert-butyl acetal20 in
refluxing PhMe. N-Phthalyl-L-valine and N-phthalyl-L-alanine
were prepared according to the method of Bose21 from L-valine
and L-alanine, respectively. Toluene-p-sulfonyl-L-valine and
toluene-p-sulfonyl-L-alanine were prepared according to the
method of McChesney14 from L-valine and L-alanine, respec-
tively. Silver(I) oxide was freshly prepared before use accord-
ing to the method of Schmitz.22
X-r a y Cr ysta llogr a p h y. Table 2 provides a summary of
the crystal data, data collection, and refinement parameters
for compounds 9, 10, (2S)-12c, (2R)-13a . The structures were
solved by direct methods and were refined by full matrix least-
squares based on F2. Due to a shortage of observed data, in
(2R)-13a only the nitrogen, oxygen, and sulfur atoms were
refined anisotropically. Also, in one of the two crystallographi-
cally independent molecules of this compound, disorder was
found in one of the isopropyl groupssthis was resolved into
three overlapping one-third occupancy orientations. All of the
non-hydrogen atoms in the other three structures were refined
anisotropically. In each structure the hydrogen atoms were
placed in calculated positions, assigned isotropic thermal
parameters, U(H) ) 1.2Ueq(C)[U(H) ) 1.5Ueq(C)], and allowed
1
(CHCl3) 2570, 1328 cm-1; H NMR (300 MHz; CDCl3) δ 3.79
(m, 2H), 3.71 (d, J ) 13.3 Hz, 1H), 3.45-3.40 (m, 1H), 2.71 (d,
J ) 13.4 Hz, 1H), 2.61 (d, J ) 7.4 Hz, 1H), 2.11-1.95 (m, 2H),
1.79-1.54 (m, 4H), 1.33 (d, J ) 6.8 Hz, 6H), 1.32 (d, J ) 6.8
Hz, 6H), 1.30-1.20 (m, 1H), 0.95 (s, 3H), 0.85 (s, 3H); 13C NMR
(75 MHz; CDCl3) δ 54.6, 49.9, 49.7, 48.3, 45.3, 44.2, 40.2, 33.4,
27.3, 23.0, 22.0, 21.0, 20.1; m/z (CI+, NH3) 351 (M + NH4+•),
334 (M + H+•). Anal. Calcd for C16H31NO2S2: C, 57.62; H,
9.37; N, 4.20. Found: C, 57.74; H, 9.21; N, 4.14.
[(1S)-10-(Diisop r op ylsu lfa m oyl)isob or n ylt h io]n it r o-
m eth a n e (8). To a solution of thiol 6 (1.53 g, 4.59 mmol)
in CH2Cl2 (50 mL) maintained at -40 °C was added sulfuryl
chloride (0.38 mL, 4.82 mmol). The solution was stirred
for 4 h and then allowed to warm to room temperature.
Concentration in vacuo gave the crude sulfenyl chloride
7 as a yellow oil (1.70 g). The 1H NMR spectrum showed
that 7 contained none of the starting material using the
methylene proton at 2.71 ppm as a probe: 1H NMR (300
MHz; CDCl3) δ 3.92-3.79 (m, 3H), 3.54 (d, J ) 13.8 Hz,
1H), 2.87 (d, J ) 13.8 Hz, 1H), 2.40-2.00 (m, 3H), 1.89-1.72
(m, 3H), 1.37 (d, J ) 6.8 Hz, 6H), 1.35 (d, J ) 6.8 Hz,
6H), 1.31-1.22 (m, 1H), 0.92 (s, 3H), 0.82 (s, 3H). To
a stirred solution of nitromethane (0.15 mL, 2.80 mmol)
(18) Kofron, W. G.; Backlawski, L. M. J . Org. Chem. 1976, 41, 1879.
(19) Bartlett, P. D.; Knox, L. H. Org. Synth. 45, 14.
(20) Widmer, U. Synthesis 1983, 135.
(21) Bose, A. K.; Greer, F.; Price, C. C. J . Org. Chem. 1958, 23, 1335.
(22) Schmitz, E.; Ohme, R. Organic Syntheses; Wiley: New York,
1973; Coll. Vol. V, p 897.
(23) SHELXTL PC version 5.03, Siemens Analytical X-ray Instru-
ments, Inc., Madison, WI, 1994.

Synthesis of R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 63, No. 17, 1998 5821
Ta ble 2. Cr ysta l Da ta , Da ta Collection a n d Refin em en t P a r a m eter sa
data
9
10
(2S)-12c
(2R)-13a
formula
C
418.6
yellow platy
0.47 × 0.37 × 0.10
monoclinic
P21 (no. 4)
19H34N2O4S2
C21H38N2O4S2
446.7
clear prisms
0.63 × 0.38 × 0.38
orthorhombic
P212121 (no. 19)
C20H37NO4S2
419.6
clear platy needles
0.97 × 0.97 × 0.02
monoclinic
C29H42N2O5S2
562.8
clear prisms
0.20 × 0.17 × 0.13
orthorhombic
P212121 (no. 19)
formula weight
color, habit
crystal size/mm
crystal system
space group
cell dimensions
a/Å
P21 (no. 4)
9.769(1)
11.762(1)
10.925(1)
112.35(1)
1161.0(2)
2
11.651(2)
11.669(1)
18.226(1)
-
2478.0(4)
4
1.197
968
Cu-KR
2.17
11.077(5)
12.303(1)
17.518(2)
99.95(2)
2351(1)
4b
1.185
912
Cu-KR
2.24
11.310(5)
12.460(2)
43.398(7)
-
b/Å
c/Å
â/deg
V/Å3
6116(3)
Z
8b
Dc/g cm-3
F(000)
1.197
1.222
2416
Cu-KR
1.89
452
radiation used
Cu-KRc
2.28
µ/mm-1
θ range/deg
no. of unique reflections
measured
observed, |Fo|
4σ(|Fo|)
4.4-63.0
4.5-63.5
2.6-63.0
2.0-50.0
1979
1811
2312
2039
3994
3431
3435
2090
no. of variables
245
0.053
0.138
0.088, 0.215
-0.03(5)
0.29, -0.34
263
0.060
0.160
0.096, 0.886
0.08(5)
0.37, -0.27
488
0.072
0.192
0.153, 0.353
0.03(9)
0.44, -0.37
400
0.095
0.231
0.140, 14.716
-0.12(9)
0.39, -0.40
d
R1
e
wR2
weighting factors a, bf
Flack parameter
largest diff. peak, hole/eÅ-3
a
b
Details in common: graphite monochromated radiation, ω-scans, Siemens P4 diffractometer, 293 K, refinement based on F2. There
are two crystallographically independent molecules in the asymmetric unit. c Rotating anode source. R1 ) ∑|Fo| - |Fc|/∑|Fo|. e wR2
)
d
[∑w(Fo - Fc2)2/∑w(Fo2)2]1/2
.
f w-1 ) σ2(Fo2) + (aP)2 + bP.
2
in THF (10 mL) at -78 °C was added
a
solution of
3H), 0.89 (s, 3H); 13C NMR (75 MHz; CDCl3) δC 150.9, 141.1,
56.0, 54.2, 51.3, 49.5, 48.2, 45.4, 40.5, 33.8, 27.2, 23.1, 21.8,
20.7, 20.5, 16.2; m/z (CI+, NH3) 436 (M + NH4+•), 419 (M +
H+•); Anal. Calcd for C19H34N2O4S2: C, 54.52; H, 8.19; N, 6.69.
Found: C, 54.58; H, 7.98; N, 6.58.
n-butyllithium in hexane (1.91 mL, 1.6 M, 3.06 mmol). After
stirring for 1 h, the white suspension was added via cannula
into a stirred solution of crude 7 (0.93 g, 2.55 mmol) in
THF (10 mL) at -78 °C. After stirring for a further 1
h, the mixture was allowed to warm to room temperature.
Water (5 mL) was added and the mixture concentrated
in vacuo to remove all the solvents. The residue was
dissolved in CH2Cl2 (40 mL), washed with water (40 mL)
and brine (40 mL), dried (MgSO4), and concentrated in
(Z)-1-[(1′S)-10′-(Diisop r op ylsu lfa m oyl)isobor n ylth io]-
1-n itr o-3-m eth yl-1-bu ten e (10). A solution of nitroalkane
8 (0.48 g, 1.22 mmol), isobutyraldehyde (0.22 mL, 2.44 mmol),
and piperidinium acetate (18.0 mg, 0.12 mmol) in CH2Cl2 (40
mL) was heated at reflux with azeotropic removal of water
using a Soxhlet apparatus charged with 4 Å molecular sieves
for 5 h. The mixture was allowed to cool to room temperature,
washed with aqueous 1 M HCl (20 mL) and brine (20 mL),
dried (MgSO4), and concentrated in vacuo. Chromatography
on silica gel (1:10 ethyl acetate:hexane; Rf 0.29) gave nitroal-
vacuo to give
a
colorless oil. Chromatography (1:9
EtOAc:hexane; Rf 0.28) afforded 8 (0.49 g, 50%) as colorless
crystals, mp 104-105 °C; [R]25 -58.3° (c 1.00, CHCl3);
D
IR (CHCl3) 1555, 1326 cm-1
;
1H NMR (300 MHz; CDCl3)
δ 5.72 (d, J ) 13.8 Hz, 1H), 5.20 (d, J ) 13.8 Hz, 1H),
3.74 (m, 2H), 3.59 (d, J ) 13.5 Hz, 1H), 3.40 (dd, J
)
kene 10 (0.43 g, 79%) as green crystals, mp 149-150 °C; [R]25
D
1
9.3, 5.4 Hz, 1H), 2.76 (d, J ) 13.5 Hz, 1H), 2.27-2.10
(m, 3H), 1.81-1.64 (m, 3H), 1.34 (d, J ) 6.8 Hz, 6H),
1.33 (d, J ) 6.8 Hz, 6H), 1.31-1.25 (m, 1H), 0.88 (s, 3H),
0.87 (s, 3H); 13C NMR (75 MHz; CDCl3) δ 80.4, 56.2, 54.6,
51.5, 49.3, 48.3, 45.4, 41.8, 33.5, 27.3, 22.9, 22.0, 20.5, 20.0;
m/z (CI+, NH3) 410 (M + NH4+•), 393 (M + H+•). Anal.
Calcd for C17H32N2O4S2: C, 52.01; H, 8.22; N, 7.14. Found:
C, 52.31; H, 8.41; N, 7.08.
36.2° (c 0.62, CHCl3); IR (CHCl3) 1529, 1325 cm-1; H NMR
(300 MHz; CDCl3) δ 7.32 (d, J ) 10.5 Hz, 1H), 3.88-3.78 (m,
2H), 3.47 (d, J ) 13.9 Hz, 1H), 3.45-3.41 (m, 1H), 3.12-3.06
(m, 1H), 2.82 (d, J ) 13.9 Hz, 1H), 2.23-2.15 (m, 2H), 1.93-
1.64 (m, 4H), 1.36 (d, J ) 6.8 Hz, 6H), 1.35 (d, J ) 6.8 Hz,
6H), 1.24-1.18 (m, 1H), 1.15 (d, J ) 6.5 Hz, 3H), 1.12 (d, J )
6.5 Hz, 3H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz;
CDCl3) δ 151.7, 148.0, 56.2, 54.4, 51.4, 49.5, 48.2, 45.5, 40.2,
34.0, 30.1, 27.2, 23.1, 21.7, 20.7, 20.5; m/z (CI+, NH3) 464 (M
+ NH4+•), 447 (M + H+•). Anal. Calcd for C21H38N2O4S2: C,
56.47; H, 8.58; N, 6.27. Found: C, 56.23; H, 8.36; N, 6.21.
(Z)-2-[4′′-(ter t-Bu t yloxyca r b on yl)p h en yl]-1-[(1′S)-10′-
(diisopr opylsu lfam oyl) isobor n ylth io]-1-n itr oeth en e (11).
A solution of nitroalkane 8 (50.0 mg, 0.13 mmol), tert-butyl
4-formylbenzoate (52.1 mg, 0.25 mmol), and piperidinium
acetate (1.8 mg, 0.02 mmol) in CH2Cl2 (15 mL) was heated at
reflux with azeotropic removal of water using a Soxhlet
apparatus charged with 4 Å molecular sieves for 12 h. The
mixture was allowed to cool to room temperature, washed with
aqueous 1 M HCl (5 mL) and brine (5 mL), dried (MgSO4),
and concentrated in vacuo. Chromatography (1:10 EtOAc:
hexane; Rf 0.26) gave nitroalkene 11 (52.4 mg, 71%) as yellow
(Z)-1-[(1′S)-10′-(Diisop r op ylsu lfa m oyl)isobor n ylth io]-
1-n itr op r op en e (9). Nitroalkane 8 (0.41 g, 1.01 mmol),
piperidinium acetate (14.7 mg, 0.10 mmol), and crushed 4 Å
molecular sieves (0.5 g) in CH2Cl2 (10 mL) were cooled to 0
°C. Acetaldehyde (0.33 mL, 5.80 mmol) was added dropwise
with stirring. After 30 min the mixture was allowed to warm
to room temperature and was filtered through a plug of Celite,
eluting with CH2Cl2 (20 mL). The filtrate was washed with
aqueous 1 M HCl (10 mL) and brine (10 mL), dried (MgSO4),
and concentrated in vacuo. Chromatography (1:10 EtOAc:
hexane; Rf 0.27) afforded nitroalkene 9 (0.28 g, 62%) as pale
green crystals, mp 110-111 °C; [R]25 -28.4° (c 0.58, CHCl3);
D
IR (CHCl3) 1528, 1331 cm-1; 1H NMR (300 MHz; CDCl3) δ 7.62
(q, J ) 7.3 Hz, 1H), 3.82 (m, 2H), 3.50 (d, J ) 13.8 Hz, 1H),
3.46-3.38 (m, 1H), 2.78 (d, J ) 13.8 Hz, 1H), 2.15 (d, J 7.3
Hz, 3H), 2.01-1.90 (m, 2H), 1.82-1.61 (m, 4H), 1.34 (d, J )
6.7 Hz, 6H), 1.33 (d, J ) 6.8 Hz, 6H), 1.24 (m, 1H) 1.06 (s,
crystals, mp 131-132 °C; [R]25 -39.8° (c 0.62, CHCl3); IR
D
(CHCl3) 1713, 1532, 1329 cm-1; 1H NMR (300 MHz; CDCl3) δ
8.22 (s, 1H,), 8.06 (d, J ) 8.3 Hz, 2H), 7.93 (d, J ) 8.3 Hz,

5822 J . Org. Chem., Vol. 63, No. 17, 1998
Barrett et al.
2H), 3.54-3.41 (m, 4H), 2.68 (d, J ) 13.7 Hz, 1H), 2.27-2.02
(m, 2H), 1.94-1.51 (m, 4H), 1.63 (s, 9H), 1.22 (d, J ) 7.5 Hz,
6H), 1.19 (d, J ) 7.5 Hz, 6H), 1.20 (m, 1H) 0.99 (s, 3H), 0.87
(s, 3H); m/z (CI+, NH3) 598 (M + NH4+•), 581 (M + H+•). Anal.
Calcd for C29H44N2O6S2: C, 59.97; H, 7.64; N, 4.82. Found: C,
60.12; H, 7.38; N, 4.76.
IR (CHCl3) 3266, 1687, 1331 cm-1; 1H NMR (300 MHz; CDCl3)
δ 7.72 (m, 2H), 7.29 (m, 2H), 5.26 (d, J ) 9.1 Hz, 0.67H), 5.12
(d, J ) 8.0 Hz, 0.33H), 4.20-4.08 (m, 1H), 3.91-3.87 (m, 1H),
3.78-3.69 (m, 2H), 3.11 (m, 1H), 2.69 (m, 1H), 2.42 (s, 3H),
2.25-2.02 (m, 2H), 1.99-1.69 (m, 4H), 1.33-1.29 (m, 16H) 0.90
(s, 1H), 0.89 (s, 2H), 0.87 (s, 2H), 0.84 (s, 1H); m/z (CI+, NH3)
576 (M + NH4+); HRMS (CI) Calcd for C26H46N3O5S3: 576.2600.
Found: 576.2603 (M + NH4+). The minor 2S epimer prepared
as a colorless oil from the EDCI mediated coupling of thiol 6
with toluene-p-sulfonyl-L-alanine followed by chromatography
(2:7 EtOAc:hexane; Rf 0.25) (33 mg, 28%) displayed the
following spectral characteristics: [R]25D -22.0° (c 0.83, CHCl3);
1H NMR (300 MHz; CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.31 (d,
J ) 8.2 Hz, 2H), 5.12 (d, J ) 8.1 Hz, 1H), 4.19-4.11 (m, 1H),
3.97-3.92 (m, 1H), 3.78-3.67 (m, 2H), 3.13 (d, J ) 13.8 Hz,
1H), 2.75 (d, J ) 13.7 Hz, 1H), 2.42 (s, 3H), 2.20-2.01 (m,
2H), 1.82-1.64 (m, 4H), 1.35-1.29 (m, 16H), 0.90 (s, 3H), 0.84
(s, 3H); 13C NMR (75 MHz; CDCl3) δ 197.3, 177.7, 158.8, 129.8,
127.1, 58.5, 54.9, 50.6, 49.7, 48.2, 48.1, 48.0, 45.5, 40.8, 33.9,
27.3, 22.8, 22.1, 21.6, 20.5, 20.2; m/z (CI+, NH3) 576 (M +
NH4+•), 559 (M + H+•); HRMS (CI) Calcd for C26H43N2O5S3:
559.2334. Found: 559.2335 (M + H+•).
Gen er a l P r oced u r e for th e Ta n d em Con ju ga te Ad d i-
tion -Ozon olysis of Nu cleop h iles to Nitr oa lk en es 9-11.
To a stirred solution of nitroalkene 9, 10, or 11 (30.0 mg) in
DMF or 1:1 CH2Cl2:DMF (0.5 mL) at temperature T (Table 1)
was added the representative nucleophile. Potassium phthal-
imide (18.5 mg, 0.10 mmol) and potassium trimethylsilanolate
(13 mg, 0.10 mmol) were added as solids all in one portion.
Potassium toluene-4-sulfonamide was generated from toluene-
4-sulfonamide (13.5 mg, 0.07 mmol) in 1:1 CH2Cl2:DMF (0.4
mL) and a solution of potassium tert-butoxide in THF (86 µL,
1.0 M, 0.09 mmol) at 0 °C. NaOMe was added as a solution
in MeOH (25 µL, 5M, 0.12 mmol) with DMF as cosolvent (0.2
mL). The homogeneous solution was stirred at temperature
T for 6 h or until TLC demonstrated complete consumption of
nitroalkene, diluted with CH2Cl2 (2.5 mL) and cooled to -78
°C. In the cases where NaOMe was the nucleophile the
mixture was instead diluted with MeOH (2.5 mL) and similarly
cooled to -78 °C. Ozone was bubbled through the mixture
until the characteristic faint blue color persisted (ca. 5 min).
After quenching with water (2 mL), the mixture was separated
and the aqueous phase extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were washed with water (4 ×
10 mL), dried (MgSO4), and concentrated in vacuo. Purifica-
tion was effected by flash column chromatography (EtOAc:
hexane). When potassium trimethylsilanolate had been used
as the nucleophile the residue after evaporation was instead
taken up in 10% citric acid in MeOH (1 mL) and stirred for 1
h before being poured into water (5 mL), extracted with EtOAc
(3 × 10 mL), dried (MgSO4), and evaporated under reduced
pressure followed by flash column chromatography (EtOAc:
hexane).
S-[(1′S,2′R)-10′-(Diisopr opylsu lfam oyl)isobor n yl] (2R,S)-
Meth oxyp r op a n eth ioa te (12c). Tandem conjugate addi-
tion-ozonolysis of NaOMe to nitroalkene 9 and purification
by chromatography (1:10 EtOAc:hexane, Rf 0.20) afforded
thioester 12c (12.7 mg, 32%) as a 3.1:1 mixture of the 2R and
2S epimers as a colorless oil: IR (CHCl3) 1688, 1332 cm-1; 1H
NMR (300 MHz; CDCl3) δ 5.01 (m, 1H), 4.04 (dd, J ) 9.2, 4.9
Hz, 0.33H) 3.88-3.61 (m, 4H), 3.43 (s, 1H), 3.41 (s, 3H), 3.30-
3.20 (m, 1.33H), 2.81-2.62 (m, 1.33H), 2.10-1.95 (m, 2.67H),
1.93-1.80 (m, 5.33H), 1.39 (d, J ) 6.5 Hz, 3H), 1.36-1.18 (m,
18.33H), 1.00 (s, 3H), 0.95 (s, 1H), 0.92 (s, 1H), 0.90 (s, 3H);
m/z (CI+, NH3) 437 (M + NH4+•), 420 (M + H+•); HRMS (CI)
Calcd for C20H38NO4S2:420.2242. Found 420.2235 (M + H+•).
The minor 2S epimer prepared as colorless crystals from the
EDCI-mediated coupling of thiol 6 with (S)-carboxylic acid 17
followed by chromatography (1:10 EtOAc:hexane; Rf 0.20) (56.3
mg, 64%) displayed the following spectral characteristics: mp
Gen er a l P r oced u r e for th e 1-(3-Dim eth yla m in o)p r o-
p yl)-3-eth ylca r bod iim id e Hyd r och lor id e Med ia ted Cou -
p lin g of Th iol 6 w ith En a n tiom er ica lly P u r e r-Su bsti-
t u t ed Ca r b oxylic Acid Der iva t ives. 1-(3-(Dimethyl-
amino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI) (49
mg, 0.26 mmol) was added to a stirred solution of carboxylic
acid (0.21 mmol), DMAP (1.8 mg, 0.02 mmol), and thiol 6 (71
mg, 0.21 mmol) in DMF (0.3 mL) (for 12a , 12b, 13a , and 13b)
or CH2Cl2 (0.3 mL) (for 12c) at 0 °C. The mixture was allowed
to warm and stirred at room temperature for 5 h. The solution
was diluted with CH2Cl2 (10 mL), washed with water (5 × 15
mL) and brine (10 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed (EtOAc:hexane).
S-[(1′S,2′R)-10′-(Diisopr opylsu lfam oyl)isobor n yl] (2R,S)-
P h th a lim id op r op a n eth ioa te (12a ). Tandem conjugate ad-
dition-ozonolysis of potassium phthalimide to nitroalkene 9
and purification by chromatography on silica gel (1:6 EtOAc:
hexane; Rf 0.27) afforded thioester 12a (25.0 mg, 65%) as a
1:1 mixture of the 2R and 2S epimers as a colorless oil: IR
92.5-93 °C (from hexane); [R]25 -26.2° (c 0.51, CHCl3); 1H
D
NMR (300 MHz; CDCl3) δ 4.04 (dd, J ) 9.2, 4.9 Hz, 1H), 3.87
(q, J ) 6.7 Hz, 1H), 3.78-3.68 (m, 2H), 3.43 (s, 3H), 3.22 (d, J
) 13.7 Hz, 1H), 2.69 (d, J ) 13.7 Hz, 1H), 2.15-2.07 (m, 2H),
1.88-1.70 (m, 4H), 1.37 (d, J ) 6.7 Hz, 3H), 1.37-1.28 (m,
1H), 1.30 (d, J ) 6.8 Hz, 12H) 0.94 (s, 3H), 0.91 (s, 3H); 13C
NMR (75 MHz; CDCl3) δ 200.8, 83.5, 58.3, 54.7, 50.5, 49.5,
48.1, 46.6, 45.7, 41.1, 34.0, 27.3, 22.9, 21.9, 20.6, 20.3, 19.0;
m/z (CI+, NH3) 437 (M + NH4+•), 420 (M + H+•); HRMS (CI)
Calcd for C20H38NO4S2: 420.2242. Found: 420.2236 (M + H+).
Anal. Calcd for C20H37NO4S2: C, 57.24; H, 8.89; N, 3.34.
Found: C, 57.21; H, 8.65; N, 3.30.
S-[(1′S,2′R)-10′-(Diisop r op ylsu lfa m oyl)isobor n yl] (2R)-
3-Meth yl-2-ph th alim idobu tan eth ioate (13a). Tandem con-
jugate addition-ozonolysis of potassium phthalimide to ni-
troalkene 10 and purification by chromatography (1:6 EtOAc:
hexane; Rf 0.27) afforded thioester 13a (23.1 mg, 61%) as a
5.8:1 mixture of the 2R and 2S epimers. The major 2R epimer
was isolated after two recrystallizations (from hexane) as
(CHCl3) 1778, 1720, 1695, 1331 cm-1 1H NMR (300 MHz;
;
CDCl3) δ 7.91-7.84 (m, 4H), 7.81-7.74 (m, 4H), 5.03-4.95 (m,
2H), 4.15-4.06 (m, 2H), 3.80-3.69 (m, 4H), 3.11 (br d, J )
13.7 Hz, 2H), 2.76 (d, J ) 13.8 Hz, 1H), 2.70 (d, J ) 13.7 Hz,
1H), 2.26-2.06 (m, 4H), 1.81-1.51 (m, 14H), 1.37-1.28 (m,
26H), 0.92 (s, 3H), 0.86 (s, 6H), 0.78 (s, 3H); m/z (CI+, NH3)
552 (M + NH4+•), 535 (M + H+•), HRMS (CI) Calcd for
C27H42N3O5S2: 552.2570 (M + NH4+•). Found: 552.2566.
Anal. Calcd for C27H38N2O5S2: C, 60.65; H, 7.16; N, 5.24.
Found: C, 60.79; H, 7.33; N, 5.26. The mixture of epimers
was identical to that obtained from the EDCI-mediated
coupling of thiol 6 with N-phthalyl-L-alanine where presum-
ably a fast epimerization occurred.
S-[(1′S,2′R)-10′-(Diisopr opylsu lfam oyl)isobor n yl] (2R,S)-
(p-Tolu en esu lfa m oyl)p r op a n eth ioa te (12b). Tandem con-
jugate addition-ozonolysis of potassium toluene-4-sulfonamide
to nitroalkene 9 and purification by chromatography (2:7
EtOAc:hexane; Rf 0.25) afforded thioester 12b (28.8 mg, 72%)
as a 2.0:1 mixture of the 2R and 2S epimers as a colorless oil:
colorless crystals: mp 115-116 °C; [R]25 -41.4° (c 0.82,
D
CHCl3); IR (CHCl3) 1722, 1331 cm-1
;
1H NMR (300 MHz;
CDCl3) δ 7.93-7.88 (m, 2H), 7.82-7.75 (m, 2H), 4.53 (d, J )
9.5 Hz, 1H), 4.13-4.07 (m, 1H), 3.80-3.70 (m, 2H), 3.14 (d, J
) 13.7 Hz, 1H), 2.95-2.86 (m, 1H), 2.69 (d, J ) 13.7 Hz, 1H),
2.17-2.09 (m, 2H), 1.87-1.71 (m, 4H), 1.35 (d, J ) 6.8 Hz,
6H), 1.33-1.22 (m, 1H), 1.31 (d, J ) 6.8 Hz, 6H), 1.17 (d, J )
6.5 Hz, 3H), 0.86 (s, 3H), 0.83 (d, J ) 6.8 Hz, 3H), 0.76 (s,
3H); 13C NMR (75 MHz; CDCl3) δ 192.9, 167.5, 134.3, 132.0,
123.7, 65.0, 54.6, 50.7, 49.4, 48.3, 48.2, 45.5, 40.9, 33.8, 27.7,
27.3, 22.9, 21.8, 21.1, 20.6, 20.2, 19.3; m/z (CI+, NH3) 580 (M
+ NH4+•); HRMS (CI+, NH3) Calcd for C29H46N3O5S2: 580.2879.
Found: 580.2876 (M
+
NH4+).
Anal.
Calcd for
C
29H42N2O5S2: C, 61.89 H, 7.52 N, 4.98. Found: C, 61.71; H,
7.75; N, 4.73. The minor 2S epimer prepared as a colorless
oil from the EDCI-mediated coupling of thiol 6 with N-
phthalyl-L-valine followed by chromatography (1:6 EtOAc:

Synthesis of R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 63, No. 17, 1998 5823
hexane; Rf 0.22) (32.8 mg, 28%) displayed the following spectral
characteristics: 1H NMR (300 MHz; CDCl3) δ 7.90-7.84 (m,
2H), 8.00-7.73 (m, 2H), 4.59 (d, J ) 9.7 Hz, 1H), 4.04 (dd, J
) 8.9, 4.9 Hz, 1H), 3.72-3.62 (m, 2H), 3.06 (d, J ) 13.8 Hz,
1H), 3.06-2.98 (m, 1H), 2.73 (d, J ) 13.8 Hz, 1H), 2.31-2.08
(m, 2H), 1.89-1.72 (m, 4H), 1.35-1.20 (m, 13H), 1.14 (d, J )
6.6 Hz, 3H), 0.90-0.87 (m, 9H); m/z (CI+, NH3) 580 (M +
NH4+), 563 (M + H+).
1.25 (m, 4.6H), 1.14-1.11 (m, 12H), 0.87 (m, 5.1H), 0.80 (s,
0.9H); m/z (CI+, NH3) 585 (M + NH4+•), 569 (M + H+•); HRMS
(CI+, NH3) Calcd for C29H49N2O6S2: 585.3032. Found: 585.3029
(M + NH4+).
(S)-Eth yl 2-Meth oxyp r op a n oa te (16). To a solution of
(S)-(-)-ethyl lactate (15) (0.50 g, 4.23 mmol) in MeCN (2.7 mL)
was added MeI (2.17 mL, 33.8 mmol) followed by silver oxide
(1.08 g, 4.68 mmol). The mixture was heated at reflux for 5 h
with vigorous stirring. After being allowed to cool to room
temperature, the reaction mixture was filtered through Celite,
eluting with CH2Cl2 (20 mL). The resulting solution was
washed with water (2 × 15 mL) and brine (10 mL), dried
(MgSO4), and concentrated in vacuo. Short path distillation
of the crude product (pot temperature 50 °C, 20 mmHg)
S-[(1′S,2′R)-10′-(Diisopr opylsu lfam oyl)isobor n yl] (2R,S)-
3-Meth yl-2-(p-tolu en esu lfam oyl)bu tan eth ioate (13b). Tan-
dem conjugate addition-ozonolysis of potassium toluene-4-
sulfonamide to nitroalkene 10 and purification by chroma-
tography (2:7 EtOAc:hexane; Rf 0.27) afforded thioester 13b
(28.0 mg, 71%) as a 3.0:1 mixture of the 2R and 2S epimers
as a colorless oil: IR (CHCl3) 3275, 1681, 1331 cm-1; 1H NMR
(300 MHz; CDCl3) δ 7.70 (d, J ) 8.2 Hz, 2H), 7.29 (m, 2H),
5.29 (d, J ) 10.0 Hz, 0.75H), 4.96 (d, J ) 9.6 Hz, 0.25H), 4.04
(m, 0.25H), 3.85-3.79 (m, 1.75H), 3.74-3.67 (m, 2H), 3.01 (d,
J ) 13.7 Hz, 0.25H), 3.00 (d, J ) 13.7 Hz, 0.75H), 2.75 (d, J )
13.7 Hz, 0.25H) 2.66 (d, J ) 13.7 Hz, 0.75H), 2.41 (s, 0.75H),
2.40 (s, 2.25H), 2.12-1.99 (m, 2H), 1.85-1.47 (m, 5H), 1.28
(m, 13H), 1.04 (d, J ) 6.8 Hz, 2.25H), 0.99 (d, J ) 6.4 Hz,
0.75H) 0.90-0.80 (m, 9H); m/z (CI+, NH3) 604 (M + NH4+•),
587 (M + H+•); HRMS (CI+, NH3) Calcd for C28H50N3O5S3:
604.2910. Found: 604.2911 (M + NH4+•). The minor 2S
epimer prepared as a colorless oil from the EDCI-mediated
coupling of thiol 6 with toluene-p-sulfonyl-L-valine followed by
chromatography (2:9 EtOAc:hexane; Rf 0.27) (67.6 mg, 48%)
displayed the following spectral characteristics: [R]25D -37.3°
(c 0.99, CHCl3); 1H NMR (300 MHz; CDCl3) δ 7.71 (d, J ) 8.3
Hz, 2H), 7.29 (d, J ) 8.3 Hz, 2H), 5.08 (d, J ) 9.6 Hz, 1H),
4.02 (dd, J ) 9.6, 4.6 Hz, 1H), 3.87-3.81 (m, 1H), 3.75-3.65
(m, 2H), 3.02 (d, J ) 13.8 Hz, 1H), 2.73 (d, J ) 13.7 Hz, 1H),
2.41 (s, 3H), 2.21-1.98 (m, 3H), 1.80-1.72 (m, 3H), 1.61-1.49
(m, 1H), 1.31-1.21 (m, 1H), 1.30 (d, J ) 6.8 Hz, 12H), 0.91 (d,
J ) 6.8 Hz, 3H), 0.88 (s, 3H), 0.83 (d, J ) 6.8 Hz, 3H), 0.82 (s,
3H); 13C NMR (75 MHz; CDCl3) δ 197.3, 143.6, 137.5, 129.8,
127.1, 68.0, 54.9, 50.2, 49.7, 48.6, 48.2, 45.5, 41.1, 33.9, 32.1,
27.2, 22.9, 22.0, 21.6, 20.6, 20.3, 19.4, 16.6.
afforded the ester 16 (0.51 g, 92%) as a colorless oil: [R]25
D
-115.9° (c 1.05, CHCl3) (lit.24 -116.4°, neat); 1H NMR (300
MHz; CDCl3) δ 4.20 (q, J ) 7.1 Hz, 2H), 3.85 (q, J ) 6.8 Hz,
1H), 3.38 (s, 3H), 1.38 (d, J ) 6.8 Hz, 3H), 1.27 (t, J ) 7.1 Hz,
3H); 13C NMR (75 MHz; CDCl3) δ 173.1, 76.4, 60.8, 57.6, 18.4,
14.2; m/z (CI+, NH3) 150 (M + NH4+•), 133; HRMS (CI+, NH3)
Calcd for C6H16NO3: 150.1130. Found: 150.1128 (M + NH4+•).
(S)-2-Meth oxyp r op ion ic Acid (17). Cooled aqueous 0.20
M LiOH (7.6 mL, 1.51 mmol) was added dropwise over 10 min
to ester 16 (0.10 g, 0.76 mmol) in THF (7.6 mL) at 0 °C. After
being stirred at room temperature for 3 h, the solution was
concentrated in vacuo to one-half volume. The resulting
aqueous mixture was acidified with aqueous 5% HCl and
extracted with Et2O (3 × 10 mL). The organic layers were
combined, dried (MgSO4), and concentrated in vacuo to afford
the carboxylic acid 17 (76.4 mg, 97%) as a colorless oil: [R]25
D
-70.9° (c 1.00, CHCl3) (lit.25 -70.4°, neat); 1H NMR (300 MHz;
CDCl3) δ 10.5-9.2 (br s, 1H) 3.95 (q, J ) 6.9 Hz, 1H), 3.47 (s,
3H), 1.48 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz; CDCl3) δ
178.1, 76.0, 57.8, 18.0; m/z (CI+, NH3) 122 (M + NH4+•); HRMS
(CI+, NH3) Calcd for C4H12NO3: 122.0817. Found: 122.0819
(M + NH4+•).
Ack n ow led gm en t. We thank Parke Davis for pro-
viding a studentship (to P.W.N.C.), Glaxo Group Re-
search Ltd. for the most generous endowment (to
A.G.M.B), and the Wolfson Foundation for establishing
the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College.
S-[(1′S,2′R)-10′-(Diisopr opylsu lfam oyl)isobor n yl] (2R,S)-
2-[4-(ter t-Bu toxyca r bon yl)p h en yl]-2-h yd r oxyeth a n eth io-
a te (14a ). Tandem conjugate addition-ozonolysis of KOSiMe3
to nitroalkene 11 and purification by chromatography (1:6
EtOAc:hexane; Rf 0.15) afforded thioester 14a (21.7 mg, 74%)
as a 2.3:1 mixture of the 2R and 2S epimers as a colorless oil:
1
IR (CHCl3) 3452, 1711, 1686, 1331 cm-1; H NMR (500 MHz;
CDCl3) δ 7.97 (d, J ) 8.3 Hz, 2H), 7.48 (d, J ) 8.3 Hz, 1.4H),
7.46 (d, J ) 8.2 Hz, 0.6H) 5.23 (s, 0.7H), 5.21 (s, 0.3H), 4.13-
4.10 (m, 1H), 3.73-3.68 (m, 0.6H), 3.44-3.38 (m, 1.4H), 3.13
(d, J ) 13.7 Hz, 0.3H), 2.90 (d, J ) 13.6 Hz, 0.7H), 2.73 (d, J
) 13.7 Hz, 0.3 H), 2.63 (d, J ) 13.6 Hz, 0.7H), 2.17-2.04 (m,
2H), 1.85-1.73 (m, 4H), 1.58 (s, 6.3H), 1.57 (s, 2.7H), 1.33-
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of (S)-12b, (S)-13b, and (2R,S)-14a (1H NMR
only) and X-ray crystallographic data for 9, 10, (2S)-12c, and
(2R)-13a (36 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.
(24) El-Abadelah, M. M. Tetrahedron 1973, 29, 589.
(25) Kochetkov, N. N.; Likhosherstov, A. M.; Kulakov, V. N.
Tetrahedron 1969, 25, 2313.
J O980582R