Asymmetric synthesis of polyhydroxy α-amino acids with the sulfinimine-mediated asymmetric Strecker reaction: 2-amino 2-deoxy l-xylono-1,5-lactone (polyoxamic acid lactone)

Article abstract of DOI:10.1021/jo020302e

Polyhydroxylated sulfinimines derived from protected 1,2-O-isopropyliden-L-threoses undergo the sulfinimine-mediated Strecker syntheses to give α-amino nitriles in good yield and de. A double stereodifferentiation effect was not observed and the diastereoselectivity is controlled by the absolute configuration of the sulfinyl group. Hydrolysis of the amino nitriles afforded the lactone rather than polyoxamic acid.

Full text of DOI:10.1021/jo020302e

Asym m etr ic Syn th esis of P olyh yd r oxy r-Am in o Acid s w ith th e
Su lfin im in e-Med ia ted Asym m etr ic Str eck er Rea ction : 2-Am in o
2-Deoxy L-Xylon o-1,5-la cton e (P olyoxa m ic Acid La cton e)
Franklin A. Davis,*,† Kavirayani R. Prasad,† and Patrick J . Carroll‡
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122-2585, and
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
fdavis@astro.ocis.temple.edu
Received May 1, 2002
Polyhydroxylated sulfinimines derived from protected 1,2-O-isopropyliden-L-threoses undergo the
sulfinimine-mediated Strecker syntheses to give R-amino nitriles in good yield and de. A double
stereodifferentiation effect was not observed and the diastereoselectivity is controlled by the absolute
configuration of the sulfinyl group. Hydrolysis of the amino nitriles afforded the lactone rather
than polyoxamic acid.
SCHEME 1
As part of a program aimed at the asymmetric syn-
thesis of functionalized and polyfunctionalized R-amino
acids we have been examining the sulfinimine (N-sulfinyl
imine) mediated asymmetric Strecker synthesis. This
protocol entails the addition of ethylaluminumcyanoiso-
propoxide [EtAl(CN)O-i-Pr], generated in situ from di-
ethylaluminum cyanide and isopropyl alcohol, to func-
tionalized sulfinimines (Scheme 1).1 Hydrolysis of the
resultant R-amino nitriles, obtained diastereomerically
pure either by crystallization or chromatography, affords
directly the enantiopure R-amino acids. In this regard
highly efficient asymmetric synthesis of functionalized
R-amino acids, including â-alkyl (alloisoleucine),2 â-fluoro
(3-fluorophenylalanine, 3-fluoroleucine)3, and â-hydroxy
(phenylserine, â-hydroxyleucine)4 amino acids, have re-
sulted. Other examples include bis-R-amino acids (DAP
and actionidic acid)5,6 and oxo R-amino acids.7 In general
the de values of the R-amino nitriles were >90% with
the stereochemistry being controlled by the sulfinyl group
and consistent with intramolecular delivery of CN via a
six-membered transition state. A modest double-stereo-
differentiation effect was noted only for the protected
â-hydroxy sulfinimines.4
SCHEME 2
The only limitation of this protocol would appear to be
the ability to prepare the sulfinimine and the compat-
ibility of the functional groups with the hydrolysis
conditions. A rigorous test of this idea is the asymmetric
synthesis of polyoxamic acid (1), an amino acid having
three contiguous hydroxyl groups, two of which are
attached to stereogenic centers (Scheme 2). Numerous
lengthy synthesis of 1 or advanced precursors have been
reported starting from chiral pool sources such as car-
bohydrates, amino acids, and tartaric acid.8 Surprisingly,
the study by Merino and co-workers of the hydrocyana-
tion of chiral nitrones is the only reference to a Strecker-
like process for 1.9 However, the resultant R-(hydroxyami-
† Temple University.
‡ University of Pennsylvania.
(1) (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J .
Org. Chem. 1996, 61, 440. (b) Davis, F. A.; Fanelli, D. L. J . Org. Chem.
1998, 63, 909.
(2) Portonovo, P.; Liang, B.; J oullie, M. M. Tetrahedron: Asymmetry
1999, 10, 769.
(3) Davis, F. A.; Srirajan, V.; Titus, D. D. J . Org. Chem. 1999, 64,
6931.
(4) Davis, F. A.; Srirajan, V.; Fanelli, D. L., Portonovo, P. J . Org.
Chem. 2000, 65, 7663.
(5) Davis, F. A.; Srirajan, V. J . Org. Chem. 2000, 64, 3248.
(6) Boisnard, S.; Neuville, L.; Bois-Choussy, M.; Zhu, J . Org. Lett.
2000, 2, 2459.
(8) (a) For leading references to the asymmetric synthesis of
polyoxamic acid see: Bose, A. K.; Banik, B, K.; Mathur, C.; Wagle, D.
R.; Manhas, M. Tetrahedron 2000, 56, 5603. (b) For a review on the
application of tartrates in the synthesis of bioactive molecules see:
Ghosh, A. K.; Koltun, E. S.; Bilcer, G. Synthesis 2001, 1281.
(7) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 2, 759.
10.1021/jo020302e CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
7802
J . Org. Chem. 2002, 67, 7802-7806

Asymmetric Synthesis of Polyhydroxy R-Amino Acids
SCHEME 3
observed (Table 1: entry 6). Both diastereoisomers were
isolated by flash chromatography, affording the major
diastereoisomers (SS,2R,3S,4S)-(+)-6 in 66-71% yield
(Table 1).
To examine the possibility of a match-mismatched
situation (double stereodifferentiation) and to determine
the effect of the tartrate moiety on diastereoselectivity,
sulfinimine (RS,2S,3S)-(+)-7 was prepared starting with
sulfinamide (R)-(+)-4 and aldehyde (+)-3 (Scheme 4). The
only difference between sulfinimines (+)-5 and (+)-7 is
the configuration of the sulfinyl group (Schemes 3 and
4). If CN addition is controlled by the tartrate moiety
then addition, under standard conditions, will furnish
amino nitrile (RS,2R,3S,4S)-(+)-8 as the major product.
Conversely, if the sulfinyl group controls the asymmetric
induction, amino nitrile (RS,2S,3S,4S)-(+)-8 will be the
major product. Indeed, the latter was observed, confirm-
ing that the sulfinyl group determines the stereoselec-
tivity for CN addition to sulfinimines. Noteworthy is the
fact that the ratio of the major and minor amino nitrile
products was 91:9, which is identical with that observed
for hydrocyanation of (+)-5c (Table 1, compare entries 3
and 7). Thus there was an absence of any double
stereodifferentiation effect. The absolute stereochemistry
of the major product (RS,2S,3S,4S)-(+)-8 was established
by X-ray crystallography.
With the N-sulfinyl amino nitriles in hand, all that was
necessary to obtain polyoxamic acid was hydrolysis. This
is usually easily accomplished by refluxing the amino
nitrile in 2-6 N HCl, which results in concomitant
removal of the N-sulfinyl auxiliary and hydrolysis of the
nitrile, to furnish the R-amino acids. Application of this
protocol to the N-sulfinyl amino nitrile (SS,2R,3S,4S)-(+)-
6a , 2 N HCl-reflux, resulted in decomposition. However,
smooth deprotection of the sulfinyl group and isopro-
pylidene ketal moiety followed by hydrolysis of the nitrile
was achieved with moist ethereal HCl, affording, after
16 h, hydrochloride (-)-9 in 95% yield (Scheme 5).
Unfortunately, all attempts to reductively remove the
benzyl group failed.
We thought that deprotection of the silyl ether would
prove easier and would give (-)-1 in one pot. However,
refluxing (SS,2R,3S,4S)-(+)-6b in 2 N HCl resulted in
decomposition and similar results were found with Et2O/
HCl/H2O. Sequential deprotection, where the TBDPS
group is first removed followed by the sulfinyl auxiliary,
proved to be successful. Thus treatment of (+)-6b with
tetrabutylammonium fluoride (TBAF) afforded alcohol
(+)-10 in 77% yield (Scheme 6). On exposure to Et2O/
HCl the alcohol underwent instantaneous sulfinyl depro-
tection to the amino cyanide hydrochloride 11. Hydrolysis
of (-)-11 with moist ethereal HCl (Et2O/HCl/H2O) gave
a hydrochloride that on treatment with propylene oxide
furnished lactone (2S,3S,4S)-(-)-12 in 36% yield for the
two steps. All attempts to isolated polyoxamic acid (1)
by using milder hydrolysis conditions failed. The struc-
ture of lactone 12 was established by comparison of its
spectral properties with literature values.16 Precedent
exists for formation of the enantiomer of 15 under related
hydrolysis conditions.16 Surprisingly, attempts to remove
the TBDMS group in amino nitrile 6b with HCl led to
decomposition.
no) nitriles were not transformed into the amino acids,
perhaps because of the sensitivity of the substrate under
the hydrolysis conditions. (+)-(2S,3S,4S)-2-Amino-3,4,5-
trihydroxypentanoic acid (polyoxamic acid 1) is a key
constituent of polyoxins such as 2, novel nucleosides that
are toxic to phytopathogenic fungi while being nontoxic
to bacteria, plants, or animals.10
Our synthesis begins with the preparation of the
requisite sulfinimines 5 by the Ti(OEt)4 assisted conden-
sation of commercially available (S)-(-)-p-toluenesulfi-
namide (4) with the known protected 1,2-O-isopropylidine-
L-threoses 3a -c (Scheme 3).11,12 These aldehydes are
readily prepared, on a large scale, from commercially
available (+)-2,3-O-isopropylidene-L-threitol or (+)-diethyl-
L-tartrate.13-15 The modest yields of (SS,2S,3S)-(+)-5 may
reflect partial hydrolysis of the ketal by the Lewis acid
Ti(OEt)4 (Table 1).
Hydrocyanation of 5a -c with 2.0 equiv of Et2AlCN and
1.5 equiv of i-PrOH gave the corresponding R-amino
nitriles in 70-78% isolated yield. The diastereoselec-
tivity varied from a low of 66% for the O-benzyl pro-
tected sulfinimine 5a to a high of 82% for the tert-
butyldiphenylsilyl derivative 5c (Table 1: entries 1 and
3). Fewer equivalents of Et2AlCN/i-PrOH resulted in
incomplete reaction (Table 1, entry 4), and in the ab-
sence of added i-PrOH the de decreased to 36% (Table 1,
entry 5). Surprisingly running the reaction at 40 °C did
not diminish the diastereoselectivity as is normally
(9) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. J . Org. Chem.
1996, 61, 9028.
(10) For reviews see: (a) Isono, K.; Suzuki, S. Heterocycles 1979,
13, 333. (b) Isono, K. J . Antibiot. 1988, 41, 1711.
(11) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Faneli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A.
Org. Synth. 1999, 77, 50.
(12) For reviews on the chemistry of sulfinimines see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In Advances in Sulfur Chemistry; Rayner, C.
M., Ed.; J AI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis,
F. A.; Zhou, P.; Chen. B.-C. Chem. Soc. Rev. 1998, 27, 13.
(13) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron
1990, 46, 265.
(14) Uchida, K.; Kato, K.; Akita, H. Synthesis 1999, 1678.
(15) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1987, 52,
3337.
(16) Depezay, J .-C.; Dureault, A. Carbohydr. Res. 1983, 112, 51.
J . Org. Chem, Vol. 67, No. 22, 2002 7803

Davis et al.
TABLE 1. Hyd r ocya n a tion of Su lfin im in es 5 to r-Am in o Nitr iles 6 a t -78 °C to Room Tem p er a tu r e.
R-amino nitrile 6dr
% yield major (minor)a
entry
sulfinimine 5 (% yield)a
conditionsb
dr (% de)c
1
2
3
4
(+)-5a , PG ) Bn (48)
83:17 (66)
89:11 (78)
91:9 (82)
67 (11)
66 (4)
71 (6)
(+)-5b, PG ) TBDMS (53)
(+)-5c, PG ) TBDPS (59)
1.5Et2AlCN/
1.0 equiv of i-PrOH
2 equiv of Et2AlCN
40 °C
90:10 (80)
68:32 (36)
91:9 (82)
91:9 (82)
44 (5)d
5
6
7
66 (6)
65 (5)
(+)-7
a
b
Isolated yield of pure material. 2.0 equiv of Et2AlCN and 1.5 equiv of i-PrOH used unless otherwise noted. c Determined by NMR
d
on the crude reaction mixture. 5c recovered in 18% yield.
SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
Applying the same sequential deprotection-hydrolysis
technology to (RS,2S,3S,4S)-(+)-8, as outlined in Scheme
7, for 6 furnished lactone (2R,3S,4S)-(-)-(15).
1
In summary, we have shown that functionalized sul-
finimines derived from the chiral pool source tartaric
acid undergo the sulfinimine-mediated Strecker synthe-
sis to afford the corresponding R-amino nitriles in
good yield and de. The absolute stereochemistry of the
amino nitrile product was found to be consistent with
that found in other applications of the sulfinimine-
mediated asymmetric Strecker synthesis. Careful hy-
drolysis of the amino nitriles afforded polyoxamic acid
lactones 12 and 15.
phosphomolybdic acid, unless noted otherwise. H NMR and
13C NMR spectra were recorded at 500 and 125 MHz, respec-
tively.
THF and Et2O were freshly distilled under argon from a
purple solution of sodium and benzophenone. Unless stated
otherwise, all the reagents were purchased from commercial
sources and used without additional purification. (2S,3S)-(+)-
(1-Benzyloxy-2,3-isopropylidenedioxy)butyraldehyde (3a ),13
(2S,3S)-(-)-1-tert-butyldimethylsilyloxy-2,3-isopropylidene-
dioxybutyraldehyde (3b),14 and (2S,3S)-(-)-1-tert-butyldiphen-
ylsilyloxy-2,3-isopropylidenedioxybutyraldehyde (3c)15 were
prepared from 2,3-O-isopropylidene-L-threitol as previously
described. (S)-(+)- and (R)-(-)-p-toluenesulfinamide (4) were
prepared according to a literature procedure.11
Exp er im en ta l Section
Gen er a l P r oced u r es. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). TLC
plates were visualized with UV, in an iodine chamber, or with
Typ ica l P r oced u r e for th e Syn th esis of Su lfin im in es:
(SS,2S,3S)-(+)-N-(4-Ben zyloxy-2,3-isop r op ylid en ed ioxy)-
bu tr ylid in e-p-tolu en esu lfin a m id e (5a ). In a two-neck, 100-
7804 J . Org. Chem., Vol. 67, No. 22, 2002

Asymmetric Synthesis of Polyhydroxy R-Amino Acids
mL, round-bottom flask equipped with a magnetic stirring bar,
a rubber septum, and an argon-filled balloon was placed
aldehyde (+)-3a (0.25 g, 1.0 mmol) and sulfinamide (S)-(+) 4
(0.16 g, 1.1 mmol) in CH2Cl2 (25 mL). To this solution was
added titanium tetraethoxide (1 mL, 5 mmol) and the reaction
mixture was stirred at room temperature for 3 h. At this time
the solution was cooled to 0 °C, quenched with ice-cold H2O (5
mL), and filtered through a pad of Celite, and the pad was
washed with EtOAc (3 × 15 mL). The combined organic phases
were washed with brine (30 mL), dried (MgSO4), and concen-
trated. Flash chromatography (hexane/EtOAc 90:10) gave 0.19
mixture was stirred at -78 °C for 6 h, warmed to room
temperature, stirred for 16 h, cooled to -78 °C, and cautiously
quenched with saturated NH4Cl (5 mL). The turbid solution
was diluted with EtOAc (25 mL) and filtered through a pad of
Celite, and the pad was washed with EtOAc (2 × 20 mL). The
combined organic phases were washed with brine (15 mL),
dried (MgSO4), and concentrated. Flash chromatography (hex-
ane/EtOAc, 75:25) gave 0.28 g (67%) of a thick viscous mass;
[R]20 +25.5 (c 0.5 CHCl3); IR (neat) 3234, 2922, 2361 cm-1
;
D
1H NMR (CDCl3) δ 7.33 (d, J ) 8.2 Hz, 2H), 7.22-7.05 (m,
7H), 5.94 (d, J ) 6.3 Hz, 1H), 4.43 (s, 2H), 4.10 (dd, J ) 3.8,
8.68 Hz, 1H), 4.04 (dt, J ) 3.9, 8.9 Hz, 1H), 3.83 (dd, J ) 3.8,
7.8 Hz, 1H), 3.69 (dd, J ) 3.9, 9.0 Hz, 1H), 3.37 (t, J ) 9.1 Hz,
1H), 2.21 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3)
δ 142.66, 139.45, 136.78, 130.45, 129.23, 128.92, 128.71,
126.69, 117.40, 110.86, 81.44, 76.38, 74.72, 70.50, 43.02, 27.38,
27.03, 21.81; HRMS calcd for C22H27N2O4S (M + H) 415.1691,
found 415.1691.
g (48%) of (+)-5a as a viscous oil; [R]20 +176.2 (c 0.6, CHCl3);
D
IR (neat) 2987, 2867, 1627, 1454 cm-1; 1H NMR (CDCl3) δ 8.18
(d, J ) 4.3 Hz, 1H), 7.43 (d, J ) 8.2 Hz, 2H), 7.26-7.17 (m,
7H), 4.52 (dd, J ) 4.3, 7.7 Hz, 1H), 4.42 (s, 2H), 4.06 (m, 1 H),
3.47 (m, 2H), 2.3 (s, 3H), 1.39 (s, 3H), 1.32 (s, 3H); 13C NMR
(CDCl3) δ 164.75, 142.36, 141.49, 138.12, 130.29, 128.80,
128.13, 124.96, 111.69, 79.17, 78.35, 73.93, 69.76, 27.30, 26.92,
21.85; HRMS calcd for C12H25NO4SNa (M + Na) 410.1402,
found 410.1421.
(SS,2R,3S,4S)-(+)-N-(p-Tolu en esu lfin yl)-2-a m in o-5-ter t-
b u t yld im e t h ylsilyloxy-3,4-isop r op ylid e n e d ioxyp e n -
ta n e Nitr ile (6b). Chromatography (hexane/EtOAc, 70:30)
afforded 0.29 g (66%) of the major diastereomer as a white
solid: mp 66-68 °C; [R]20D +43.5 (c 0.5, CHCl3); IR (KBr) 2922,
2354, 1428 cm-1; 1H NMR (CDCl3) δ 7.42 (d, J ) 8.3 Hz, 2H),
7.18 (d, J ) 8.0 Hz, 2H), 6.23 (d, J ) 8.4 Hz, 1H), 4.17 (dd, J
) 3.8, 8.5 Hz, 1H), 3.95-3.88 (m, 2H), 3.86-3.76 (m, 1H), 3.49
(dd, J ) 9.1, 9.8 Hz, 1H), 2.25 (s, 3 H), 1.23 (s, 3H), 1.17 (s, 3
H), 0.79 (s, 9H), 0.00 (d, J ) 3.2 Hz, 6H); 13C NMR (CDCl3) δ
142.74, 139.44, 130.49, 126.77, 117.40, 110.73, 81.62, 78.33,
64.18, 42.67, 27.39, 27.04, 21.81, 18.83, -5.07; HRMS calcd
for C21H34N2O4SiSNa (M + Na) 461.1925, found 461.1906.
(SS,2S,3S)-(+)-N-(4-ter t-Bu tr yld im eth ylsilyloxy-2,3-iso-
pr opyliden edioxy)bu tr ylidin e-p-tolu en esu lfin am ide (5b).
Chromatography (hexane/EtOAc 90:10) gave 0.21 g (51%) of
a viscous oil; [R]20D +164.1 (c 1.5, CHCl3); IR (neat) 2932, 2865,
1
1612 cm-1; H NMR (CDCl3) δ 8.26 (d, J ) 4.2 Hz, 1H), 7.54
(d, J ) 7.9 Hz, 2H), 7.29 (d, J ) 8.0 Hz, 2H), 4.80 (dd, J ) 4.2,
7.5 Hz, 1H), 3.99 (m, 1H), 3.72 (dd, J ) 4.2, 11.3 Hz, 1H), 3.66
(dd, J ) 4.2, 11.3 Hz, 1H), 2.4 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3
H), 0.85 (s, 3H), 0.00 (d, J ) 3.1 Hz, 6H); 13C NMR δ 165.03,
142.25, 141.54, 130.25, 124.90, 111.40, 79.86, 78.69, 62.82,
32.96, 30.72, 26.26, 21.81, 18.72, -5.00; HRMS calcd for C20H34
NO4SiS (M + H) 412.1978, found 412.1990.
-
Minor isomer (SS,2S,3S,4S)-(+)-N-p-(tolu en esu lfin yl)-2-
a m in o-5-ter t-bu tyld im eth ylsilyloxy-3,4-isop r op ylid en e-
d ioxyp en ta n e n itr ile (6b): 0.02 g (4%), mp 128-130 °C;
(SS,2S,3S)-(+)-N-(4-ter t-Bu tr yld ip h en ylsilyloxy-2,3-iso-
p r op ylid en ed ioxy)bu tr yilylid in e-p-tolu en esu lfin a m id e
(5c). Chromatography (hexane/EtOAc 90:10) gave 0.31 g (59%)
of a viscous mass; [R]20D +103.1 (c 0.6, CHCl3); IR (neat) 2931,
2858, 1617 cm-1; 1H NMR (CDCl3) δ 8.21 (d, J ) 4.0 Hz, 1H),
7.5-7.56 (m, 4H), 7.41 (d, J ) 8.1 Hz, 2H), 7.34-7.24 (m, 6H),
7.15 (d, J ) 8.0 Hz, 2H), 4.80 (dd, J ) 4.0, 7.3 Hz, 1H), 3.96
(m, 1H), 3.72 (dd, J ) 4.1, 11.2 Hz, 1H), 3.58 (dd, J ) 11.2,
3.6 Hz, 1H), 2.29 (s, 3 H), 1.40 (s, 3H), 1.31 (s, 3H), 0.94 (s,
9H); 13C NMR (CDCl3) δ 165.20, 142.20, 141.59, 136.00, 133.45,
130.26, 128.13, 124.55, 111.39, 79.74, 78.47, 63.10, 27.14,
21.83, 19.65; HRMS calcd for C30H37NO4SiSNa (M + Na)
558.2110, found 558.2115.
[R]20 +141.18 (c 0.3, CHCl3); 1H NMR (CDCl3) δ 7.64 (d, J )
D
8.1 Hz, 2H), 7.36 (d, J ) 8.0 Hz, 2H), 5.07 (d, J ) 10.0 Hz,
1H), 4.50-4.22 (br m, 1H), 3.99 (br s, 1 H), 3.74-3.71 (m, 1H),
3.59-3.53 (m, 1H), 2.44 (s, 3 H), 1.48 (s, 3H), 1.41 (s, 3H), 0.85
(s, 9H), 0.00 (d, J ) 0.8 Hz, 6H); 13C NMR (CDCl3) δ 142.69,
140.34, 130.38, 126.29, 117.31, 111.33, 81.11, 77.76, 63.85,
47.14, 28.56, 27.55, 26.23, 21.80, 18.60, -5.27.
(SS,2R,3S,4S)-(+)-N-(p-Tolu en esu lfin yl)-2-a m in o-5-ter t-
b u t yld ip h e n ylsilylo xy-3,4-iso p r op y lid e n e d io x y p e n -
ta n e n itr ile (6c). Chromatography (hexane/EtOAc 75:25) gave
0.4 g (71%) of viscous mass; [R]20 +25.7 (c 0.7, CHCl3); IR
D
(neat) 3208, 2931, 2859, 1471 cm-1; 1H NMR (CDCl3) δ 7.62-
7.59 (m, 4H), 7.49 (d, J ) 8.2 Hz, 2H), 7.38-7.34 (m, 6H), 7.26
(d, J ) 8.0 Hz, 2H), 5.98 (d, J ) 8.4 Hz, 1H), 4.39 (dd, J ) 3.4,
7.8 Hz, 1H), 4.23 (dd, J ) 3.4, 8.4 Hz, 1H), 4.09 (dt, J ) 3.5,
7.9 Hz, 1H), 3.87 (dd, J ) 3.5, 10.5 Hz, 1H), 3.67 (dd, J ) 8.1,
10.5 Hz, 1H), 2.35 (s, 3H), 1.32 (s, 3H), 1.24 (s, 3H), 1.04 (s,
9H); 13C NMR (CDCl3) δ 142.75, 139.49, 135.99, 135.96, 132.42,
132.29, 130.67, 130.49, 128.52, 126.66, 117.51, 110.78, 80.75,
77.99, 64.72, 42.39, 27.53, 27.44, 27.11, 21.84, 19.61. Anal.
Calcd: C, 66.16; H, 6.81; N, 4.98. Found: C, 66.33; H, 7.16;
N, 4.93.
(SR,2S,3S)-(-)-N-(4-ter t-Bu tr yld ip h en ylsilyloxy-2,3-iso-
p r op ylid en ed ioxy)bu tr ylid in e-p-tolu en esu lfin a m id e (7).
Chromatography (hexane/EtOAc 90:10) afforded 0.27 g (51%)
of a viscous oil; [R]20 -150.5 (c 0.5, CHCl3); IR (neat) 2930,
D
1617 cm-1; 1H NMR (CDCl3) δ 8.17 (d, J ) 4.5 Hz, 1H), 7.61-
7.57 (m, 4 H), 7.46 (d, J ) 8.2 Hz, 2H), 7.35-7.29 (m, 6H),
7.21 (d, J ) 7.9 Hz, 2H), 4.67 (dd, J ) 4.4, 7.38 Hz, 1H), 4.11-
4.07 (m, 1H), 3.80-3.65 (m, 2H), 2.34 (s, 3H), 1.37 (s, 3 H),
1.31 (s, 3H), 0.97 (s, 3H); 13C NMR (CDCl3) δ 164.88, 142.38,
141.31, 136.04, 133.43, 130.26, 128.15, 124.84, 111.51, 79.71,
63.69, 27.32, 27.18, 21.85, 19.65; HRMS calcd for C30H38NO4-
SiS (M + H) 536.2291, found 536.2288.
Minor diastereomer (SS,2S,3S,4S)-(+)-N-(p-tolu en esu l-
fin yl)-2-a m in o-5-ter t-b u t yld ip h en ylsilyloxy-3,4-isop r o-
Typ ica l P r oced u r e for th e Ad d ition of Et[Al(O-i-P r )-
CN] t o Su lfin im in es: (SS,2R,3S,4S)-(+)-N-(p-Tolu en e-
su lfin yl)-2-a m in o-3,4-isop r op ylid en ed ioxy-5-ben zyloxy-
p en ta n e Nitr ile (6). In a two-neck, 100-mL, round-bottom
flask fitted with a magnetic stirring bar and an argon-filled
balloon was placed (+)-5a (0.39 g, 1.0 mmol) in THF (15 mL)
and the reaction mixture was cooled to -78 °C. In a separate
100-mL, single-neck, round-bottom flask equipped with a
magnetic stirring bar under an argon-filled balloon was placed
a solution of diethyl aluminum cyanide (2 mmol, 2 mL of 1 M
solution in toluene) in THF (10 mL). The clear solution was
cooled to -78 °C and i-PrOH (0.11 mL, 1.5 mmol) was added.
The reaction mixture was stirred at -78 °C for 15 min and
warmed to room temperature, and after 5 min it was cannu-
lated to the sulfinimine solution at -78 °C. The reaction
p ylid en ed ioxyp en ta n e n itr ile (6c): 0.03 g (6%); [R]20
D
1
+96.8 (c 0.7, CHCl3); H NMR (CDCl3) δ 7.50-7.53 (m, 5H),
7.39-7.30 (m, 7H), 7.19 (d, J ) 6.8 Hz, 2H), 4.79 (d, J ) 10.4
Hz, 1H), 4.50-4.4 (m, 1H), 4.2 (dd, J ) 3.4, 10.4 Hz, 1H), 4.01
(dd, J ) 3.3, 7.9 Hz, 1H), 3.93 (dt, J ) 3.9, 7.4 Hz, 1H) 3.7 (dd,
J ) 4.0, 10.4 Hz, 1H), 3.55 (dd, J ) 7.0, 10.5 Hz, 1H), 2.27 (s,
3 H), 1.36 (s, 3H), 1.3 (s, 3H), 0.92 (s, 3H); 13C NMR (CDCl3)
δ 142.72, 140.35, 135.92, 132.95, 132.82, 130.49, 130.38,
128.38, 128.33, 126.18, 117.26, 111.31, 80.41, 78.06, 64.22,
47.15, 27.53, 27.25, 21.80, 19.48.
(SR,2S,3S,4S)-(-)-N-(p-Tolu en esu lfin yl)-2-a m in o-5-ter t-
bu tyld ip h en ylsilyloxy, 3,4-isop r op ylid en ed ioxyp en ta n e
Nitr ile (8). Chromatography afforded 0.36 g (65%) of a white
solid; mp 118-119 °C; [R]20 -30.14 (c 0.7, CHCl3); IR (KBr)
D
J . Org. Chem, Vol. 67, No. 22, 2002 7805

Davis et al.
3020, 2337, 1576 cm-1; 1H NMR (CDCl3) δ 7.58-7.51 (m, 5H),
7.40-7.31 (m, 7H), 7.23 (d, J ) 8.0 Hz, 2H), 5.21 (d, J ) 8.2
Hz, 1H), 4.28 (d, J ) 3.4, 8.2 Hz, 1H), 4.1 (dd, J ) 4.2, 7.8 Hz,
1H), 3.97 (dt, J ) 4.1, 7.9 Hz, 1H), 3.75 (dd, J ) 4.1, 10.1 Hz,
1H), 3.54 (dd, J ) 8.1, 10.1 Hz, 1H), 2.33 (s, 3H), 1.37 (s, 3H),
1.29 (s, 3H), 0.91 (s, 9H); 13C NMR (CDCl3) δ 142.71, 139.55,
136.00, 132.78, 132.58, 130.49, 128.36, 126.69, 117.04, 111.22,
81.42, 78.34, 64.63, 44.66, 27.45, 27.26, 21.83, 19.44; HRMS
calcd for C31H38N2O4SSiNa (M + Na) 585.2219, found 585.2239.
Minor diastereomer (SR,2R,3S,4S)-(+)-N-(p-tolu en esu l-
fin yl)-2-a m in o-5-ter t-b u t yld ip h en ylsilyloxy-3,4-isop r o-
110.48, 78.67, 61.85, 45.46, 29.63, 26.95, 26.62, 21.36; HRMS
calcd for C15H20N2O4SNa (M + Na) 347.1042, found 347.1047
(2R,3S,4S)-(+)-2-Am in o-5-h yd r oxy-3,4-isop r op ylid en e-
d ioxyp en ta n e Nitr ile (11). In a 50-mL, single-necked, round-
bottom flask equipped with a magnetic stirring bar was placed
(+)-10 (0.10 g, 0.31 mmol) in ether (10 mL). Saturated ethereal
HCl (5 mL) was introduced to the reaction mixture with
vigorous stirring and resulted in the formation of a white
precipitate. After the reaction mixture was stirred for 15 min,
the precipitate was allowed to settle and most of the ether was
decanted. The residue was washed with dry ether (2 × 20 mL)
and dried under vacuum to give 0.055 g (81%) of the hydro-
p ylid en ed ioxyp en ta n e n itr ile (8): 0.03 g (5%) of a white
1
solid; mp 120-121 °C; [R]20 +7.58 (c 0.66, CHCl3); H NMR
chloride salt; mp 95-98 °C dec; [R]20 -10.73 (c 1.8, MeOH);
D
D
1
IR (KBr) 3417, 2918, 2338 cm-1; H NMR (CD3OD) δ 4.80 (d,
(CDCl3) δ 7.67-7.62 (m, 5H), 7.53 (d, J ) 8.2 Hz, 2H), 7.42-
7.38 (m, 5H), 7.28 (d, J ) 8.0 Hz, 2H), 6.38 (d, J ) 8.1 Hz,
1H), 4.42 (t, J ) 5.6 Hz, 1H), 4.34-4.30 (m, 2H), 4.28-4.21
(m, 2H), 3.90-3.82 (m, 1H), 2.36 (s, 3H), 1.32 (s, 3H), 1.18 (s,
3H), 1.06 (s, 9H); 13C NMR (CDCl3) δ 142.54, 139.27, 135.85,
135.79, 132.22, 130.59, 130.52, 130.29, 128.32, 126.58, 118.02,
109.91, 61.69, 42.25, 27.20, 26.93, 24.98, 21.67, 19.41.
J ) 7.0 Hz, 1H), 4.29 (t, J ) 7.5 Hz, 1H), 4.19-4.17 (m, 1H),
3.76 (t, J ) 4 Hz, 2H), 1.44 (d, J ) 3.0 Hz, 6H); 13C NMR (D2O)
δ 113.99, 112.71, 78.68, 74.85, 61.06, 44.62, 26.53, 26.41;
HRMS cacld for C8H17N2O3 (M + H) 187.1083, found 187.1075.
(2S,3S,4S)-(-)-2-Am in o-3,4-isop r op ylid en ed ioxy-5-h y-
d r oxyp en ta n e n itr ile (14). A similar procedure as above
afforded 0.052 g (78%) of the hydrochloride salt as a white
hydroscopic solid; mp 85-90 °C dec; [R]20D -2.11 (c 0.5, MeOH);
P r ep a r a tion of (2S,3S,4S)-(-)-5-Ben zyloxy-3,4-d ih y-
d r oxy-2-a m in o p en ta n oic Acid Hyd r och lor id e (9). In a
25-mL, single-necked, round-bottom flask equipped with a
magnetic stirring bar was placed 0.21 g (0.5 mmol) of (+)-6a .
Saturated ethereal HCl (20 mL) was added with vigorous
stirring, which resulted in the immediate formation of white
precipitate. A few drops of H2O was added and the reaction
mixture was stirred at room temperature for 12 h. At this time
the solution was diluted with ether (25 mL), and the precipi-
tated hydrochloride was filtered and dried under vacuum to
give 0.12 g (95%) of a white solid: mp 145-150 °C; [R]20D -57.5
1
IR (KBr) 3408, 2911, 2360 cm-1; H NMR (CD3OD) δ 4.60 (d,
J ) 4.4 Hz, 1H), 4.18 (dd, J ) 2.7, 8.1 Hz, 1H), 4.02-3.99 (m,
1H), 3.76-3.69 (m, 2H), 1.42 (s, 3H), 1.37 (s, 3H); 13C NMR
(CD3OD) δ 112.94, 111.65, 77.61, 73.79, 62.47, 45.97, 27.82,
27.57; HRMS calcd for C8H15N2O3 (M + H) 187.1083, found
187.1084.
(3S,4S,5S)-(-)-3-Am in o-4,5-dih ydr oxytetr ah ydr opyr an -
2-on e (12). In a 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar was placed 0.05 g (0.22
mmol) of hydrochloride (-)-11 in ethereal HCl (10 mL). A few
drops (4-5) of H2O was added and the solution was vigorously
stirred at room temperature for 12 h. At this time the reaction
mixture was concentrated and the white precipitate was dried
under high vacuum for 2 h. The residue was suspended in dry
ethanol (5 mL) and 0.15 g (2.5 mmol) of isopropylene oxide
was added under an argon atmosphere. After being stirred for
5 h at room temperature the solution was concentrated, dry
ether (25 mL) was added, and most of the solvent was
decanted. The solid residue was washed with ether (2 × 20
mL) and dried under high vacuum to give 0.013 g (36%) of a
brown hydroscopic solid; mp 65-72 °C; [R]20D -4.2 (c 1.0, H2O);
IR (KBr) 3400-3100, 1787 cm-1; 1H NMR (D2O) δ 4.17 (t, J )
3.3 Hz, 1H), 3.90-3.83 (m, 2H), 3.60 (dq, J ) 7.0, 11.7 Hz,
2H); 13C NMR (D2O) δ 73.49, 68.41, 62.79, 58.35; the lactone
has spectra properties identical with those reported for the
enantiomer;16,17 HRMS calcd for C5H10NO4 (M + H) 148.0610,
found 148.0610.
(c 0.2 MeOH); IR (KBr) 3410, 1690, 1458 cm-1 1H NMR
;
(CD3OD) 7.36-7.25 (m, 5H), 4.77-4.71 (m, 2H), 4.57 (q, J )
11.7, 22 Hz, 2H), 4.37 (d, J ) 9.7 Hz, 1H), 3.94 (d, J ) 11.3
Hz, 1H), 3.79 (dd, J ) 2.3, 11.2 Hz, 1H); 13C NMR (CD3OD)
169.84, 137.62, 127.95, 127.33, 127.26, 79.42, 73.14, 70.01,
66.40, 54.27; HRMS calcd for C12H18NO5 (M + 1) 256.1185,
found 256.1178.
(SS,2R,3S,4S)-(+)-N-(p-Tolu en esu lfin yl)-2-a m in o-5-h y-
d r oxy-3,4-isop r op ylid en ed ioxyp en ta n e Nitr ile (10). In a
25-mL, single-necked, round-bottom flask equipped with a
magnetic stirring bar and argon-filled balloon was placed (+)-
6c (0.28 g, 0.5 mmol) in THF (10 mL). The solution was cooled
to 0 °C, tetrabutylammonium fluoride (0.75 mmol, 0.75 mL of
a 1 M solution in THF) was added, and the reaction mixture
was stirred for 2 h until the reaction was complete as indicated
by TLC. The reaction mixture was diluted with ether (30 mL)
and washed with 1 N HCl (20 mL). The organic phase was
separated, washed with water (20 mL) and brine (30 mL),
dried (MgSO4), and concentrated. Chromatography (hexane/
(3R,4S,5S)-(-)-3-Am in o-4,5-dih ydr oxytetr ah ydr opyr an -
ethyl acetate, 75:25) gave 0.12 g (77%) of a viscous oil; [R]20
D
2-on e (15). A similar procedure gave 0.014 g (38%) of a viscous
+6.61 (c 1.9, CHCl3); IR (neat) 3420, 2918, 2360 cm-1; 1H NMR
(CDCl3) δ 7.53 (d, J ) 8.2 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H),
5.99 (d, J ) 8.5 Hz, 1H), 4.27 (dd, J ) 3.1, 8.6 Hz, 1H), 4.1 (dt,
J ) 3.9, 8.2 Hz, 1H), 3.99 (dd, J ) 3.2, 8.0 Hz, 1H), 3.94 (br
dd, J ) 3.8, 10.8 Hz, 1H), 3.60 (br t, J ) 9.2 Hz, 1H), 3.11 (br
s, 1H), 2.37 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H); 13C NMR δ
143.07, 138.84, 130.67, 130.41, 126.69, 126.12, 117.34, 110.73,
80.29, 77.75, 62.69, 42.94, 27.36, 27.16, 21.84; HRMS calcd
for C15H20N2O4SNa (M + Na) 347.1042, found 347.1052.
(SR,2S,3S,4S)-(-)-N-(p-Tolu en esu lfin yl)-2-a m in o-5-h y-
d r oxy-3,4-isop r op ylid en ed ioxyp en ta n e Nitr ile (13). Pu-
rification by chromatography (hexane/ethyl acetate, 75:25)
gave 0.11 g (71%) of a viscous oil; [R]20D -17.77 (c 1.4, CHCl3);
IR (neat) 3420, 2935, 2334 cm-1; 1H NMR (CDCl3) δ 7.53 (d, J
) 8.3 Hz, 2H), 7.30 (d, J ) 8.1 Hz, 2H), 5.36 (d, J ) 8.1 Hz,
1H), 4.16 (dd, J ) 4.4, 8.1 Hz, 1H), 4.09 (dd, J ) 4.4, 7.8 Hz,
1H), 3.98-3.93 (m, 1H), 3.76 (dd, J ) 4.1, 11.3 Hz, 1H), 3.64
(dd, J ) 6.4, 11.24 Hz, 1H), 2.37 (s, 3H), 1.39 (s, 3H), 1.36 (s,
3H). 13C NMR (CDCl3) δ 142.58, 139.60, 129.92, 127.65, 117.01,
1
mass: [R]20 -2.3 (c 0.6, H2O); H NMR (D2O) δ 4.17 (t, J )
D
3.3 Hz, 1H), 3.90-3.83 (m, 2H), 3.60 (dq, J ) 7.0, 11.7 Hz,
2H); 13C NMR (D2O) δ 72.07, 67.44, 62.75, 59.13; spectral
properties were nearly identical with those of (3S,4S,5S)-
(-)-12.
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health General
Medical Sciences (NIGMS 57870).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 5a , 5b, 5c, 6a , 6b, 6c, 8, 9, 10, 11, 12, and 13 and
an ORTEP view of (SS,2S,3S,4S)-(+)-8. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020302E
(17) Hoppe, I.; Schoellkopf, U. Liebig. Ann. Chem. 1982, 8, 1548.
7806 J . Org. Chem., Vol. 67, No. 22, 2002