Asymmetric Synthesis of (2S,6S)- and meso-(2S,6R)-Diaminopimelic Acids from Enantiopure Bis(sulfinimines)

Full text of DOI:10.1021/jo000038u

3248
J . Org. Chem. 2000, 65, 3248-3251
synthesis of bis(R-amino acids) which is illustrated for
the asymmetric synthesis of DAP 1 and 2.
Asym m etr ic Syn th esis of (2S,6S)- a n d
m eso-(2S,6R)-Dia m in op im elic Acid s fr om
En a n tiop u r e Bis(su lfin im in es)
Franklin A. Davis* and Vaidyanathan Srirajan
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
To prepare (2S,6S)-1 DAP we need the bis(sulfinimine)
derived from the glutaraldehyde. However, all attempts
to condense (S)-(+)-p-toluenesulfinamide (3)9 with anhy-
drous glutaraldehyde10 using Ti(OEt)4 and/or 4 Å molec-
ular sieves failed. This result is probably due to the
instability of this dialdehyde under the reaction condi-
tions, because bis(sulfinimines) have been prepared from
dialdehydes such as terephthaldicarboxaldehyde.9 With
the failure of this approach, the more lengthy procedure,
which would be needed anyway for the preparation of
meso-DAP 2, was employed as outlined in Scheme 1.
Condensation of 5-(benzyloxy)pentanal (4)10 with (S)-
(+)-3 and 4.0 equiv of Ti(OEt)4 for 4 h at reflux afforded
a 95% isolated yield of sulfinimine (S)-(+)-5. The sulfin-
imine-mediated asymmetric Strecker synthesis involves
the addition of ethylaluminum cyanoisopropoxide [EtAl-
(O-i-Pr)CN], generated in situ by addition of i-PrOH to
diethylaluminum cyanide (Et2AlCN), to the sulfinimine.8
Thus treatment of (+)-5 at -78 °C in THF with 1.5/1.0
equiv of Et2AlCN/i-PrOH gave an 86% yield of R-amino
nitrile (+)-6 in >96% de. Re face addition of “CN” to the
sulfinimine C-N bond in (S)-5 is predicted to give (2S)-6
because the sulfinyl group controls the stereoselectivity.8
This was later confirmed in the synthesis of DAP 1 (vide
infra). We next needed to protect the amino group in 6
to avoid cyclization when the second aldehyde 11 was
generated. Rapoport has demonstrated the utility of
arylsulfonyl substituents as protecting groups for the
amino function in R-amino acids.11 Conversion of 6 to the
N-tosyl amino nitrile 7 was readily accomplished in 88%
yield, without epimerization, by oxidation with 57%
m-CPBA. Hydrolysis with methanolic-HCl gave the
amino acid methyl ester (S)-(+)-8 in 65% yield which was
further protected by treatment with NaH/SEM-Cl to give
9. Hydrogenation (H2/Pd) gave alcohol 10, and PCC
oxidation gave aldehyde 11 in 69% yield. The sulfinimine
(SS,2S)-(+)-12 was prepared as previously described and
treatment with “EtAl(O-i-Pr)CN” gave the R-amino nitrile
(SS,2S,6S)-(+)-13 in 69% yield and 86% de. Following
separation of the diastereoisomers by chromatography
and methanolic-HCl hydrolysis, the protected bis(R-
amino acid) (2S,6S)-(+)-14 was obtained in 84% yield.
Removal of the N-tosyl group was readily accomplished
by refluxing 14 with 48% HBr/PhOH to give the crude
product which was purified by ion-exchange chromatog-
Received J anuary 11, 2000
Interest in the development of efficient and versatile
routes to enantiopure bis(R-amino acids) stems mainly
from their ability to function as substrate-based inhibi-
tors, i.e., antibiotics.1 In this regard much of the recent
interest in this area, particularly by the groups of
Vederas,2 Williams,3 and others,4 have been directed at
the synthesis of (2S,6S)-diaminopimelic acid (DAP 1) and
meso-(2S,2R)-diaminopimelic acid (DAP 2), and their
analogues. The reason is that bacterial R-amino acid
biosynthesis is dependent upon (S,S)-DAP 1 which is
epimerized to meso-DAP 2 by L,L-DAP epimerase.1 Ste-
reoselective decarboxylation of 2 affords L-lysine which
is essential for the growth of bacteria and plants. In
addition, meso-2 is a cross-linking unit of the cell wall
peptidoglycan of most Gram-negative and some Gram-
positive bacteria and, therefore, responsible, in part, for
cell wall integrity.1,5 DAP-containing peptides also exhibit
diverse biological activities1a including cytotoxicity6 and
antitumor behavior.7 We report here a new strategy,
based on the sulfinimine (N-sulfinyl imine)-mediated
asymmetric Strecker synthesis,8 for the enantioselective
(1) For a review on DAP metabolism see: (a) Cox, R. J . Nat. Prod.
Rep. 1996, 13, 29. (b) Scapin, G.; Blanchard, J . S. Adv. Enzymol. Relt.
Areas Mol. Biol. 1998, 72, 279.
(2) (a) Sutherland, A.; Vederas, J . Chem. Soc. Chem. Commun. 1999,
1739. (b) Sutherland, A.; Caplan, J . F.; Vederas, J . C. J . Chem. Soc.
Chem. Commun. 1999, 555. (c) Gao, Y.; Lane- Bell, P.; Vederas, J . C.
J . Org. Chem. 1998, 63, 2133. (d) Cox, R. J .; Sherwin, W. A.; Lam, L.
K. P.; Vederas, J . C. J . Am. Chem. Soc. 1996, 118, 7449. (e) Song, Y.;
Niederer, D.; Lane-Bell, P. M,; Lam, L. K. P.; Crawley, S.; Palcic, M.
M.; Pickard, M. A.; Pruess, D. L.; Vederas, J . C. J . Org. Chem. 1994,
592, 5784. (f) Abbott, S. D.; Lane-Bell, P.; Sidhu, K. P. S.; Vederas, J .
C. J . Am. Chem. Soc. 1994, 116, 6513. (g) Gelb, M. H.; Lin, Y.; Pickard,
M. A.; Song, Y.; Vederas, J . C. J . Am. Chem. Soc. 1990, 112, 4932.
(3) (a) Williams, R. M.; Liu, J . J . Org. Chem. 1998, 63, 2130. (b)
Williams, R. M.; Fegley, G. L.; Gallegos, R.; Schaefer, F.; Pruess, D. L.
Tetrahedron, 1996, 52, 1149. (c) Williams, R. M.; Yuan, C. J . Org.
Chem. 1994, 57, 6190. (d) Williams, R. M.; Yuan, C. J . Org. Chem.
1992, 57, 6519. (e) Williams, R. M.; Im, M.-N.; Cao, J . J . Am. Chem.
Soc. 1991, 113, 6976.
(4) (a) Tanaka, K.; Swanishi, H. Tetrahedron: Asymmetry 1998, 9,
71. (b) Bull, S. D.; Chernega, A. N.; Davies, S. G.; Moss, W. O.; Parkin,
R. M. Tetrahedron 1998, 54, 10379. (c) Andrews, M. J . I.; Tabor, A. B.;
Tetrahedron Lett. 1997, 38, 3063. (d) Nadin, A.; Derrer, S.; McGeary,
R. P.; Goodman, J . M.; Raithby, P. R.; Holmes, A. B. J . Am. Chem.
Soc. 1995, 117, 9768. (e) Arakwa, Y.; Goto, T.; Kawase, K.; Yoshifuji,
S. Chem. Pharm. Bull. 1995, 43, 535. (f) Holcomb, R. C.; Schow, S.;
Ayral-Kaloustian, S.; Powell, D. Tetrahedron Lett. 1994, 35, 7005. (g)
J urgens, A. R. Tetrahedron Lett. 1992, 33, 4727. (g) Bold, G.; Allmend-
inger, T.; Herold, P.; Moesch, L.; Schar, H.-P.; Duthaler, R. O. Helv.
Chim. Acta 1992, 75, 865. (h) Gerhart, F.; Higgins, W.; Tardif, C.;
Ducep, J .-B. J . Med. Chem. 1990, 33, 2157.
(8) For examples of the sulfinimine-mediated asymmetric Strecker
synthesis, see: (a) Davis, F. A.; Srirajan, V.; Titus, D. D. J . Org. Chem.
1999, 64, 6931. (b) Portonovo, P.; Liang, B.; J oullie, M. M. Tetrahe-
dron: Asymmetry 1999, 10, 1451. (c) Davis, F. A.; Fanelli, D. L. J .
Org. Chem. 1998, 63, 1981. (d) Davis, F. A.; Portonovo, P. S.; Reddy,
R. E.; Chiu, Y.-H. J . Org. Chem. 1996, 61, 440.
(5) (a) Patte, J .-C. In Amino Acids: Biosynthesis and Genetic
Regulation; Hermann, K. M., Somerville, R. L., Eds.; Adison-Wesley:
Reading, MA, 1983; p 213. (b) Girodeau, J .-M.; Agouridas, C.; Masson,
M.; Pineau, R.; Le Gofic, F. J . Med. Chem. 1986, 29, 1023.
(9) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J . Org. Chem. 1999, 64, 1043.
(6) Luker, K. E.; Collier, J . L.; Kolodziej, E. W.; Marshall, G. R.;
Goldman, W. E. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2365.
(7) Izumi, S. Nakahara, K.; Gotoh, T.; Hashimoto, S.; Kino, T.;
Okahara, M.; Aoki, H.; Imanaka, H. J . Antbiot. 1983, 36, 566.
(10) Borjesson, L.; Csoregh, I.; Welch, C. J . J . Org. Chem. 1995, 60,
2989.
(11) (a) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(b) Haskell, B. E.; Bowlus, S. B. J . Org. Chem. 1976, 41, 159.
10.1021/jo000038u CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/20/2000

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3249
Sch em e 1
Sch em e 2
versatile chiral building blocks for amine, aziridine, 2H-
azirine, and â-amino acid synthesis.13,1412-14 Studies
aimed at demonstrating this potential in the synthesis
of improved DAP substrate-based inhibitors is currently
underway and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analytical
and preparative thin-layer chromatography was performed on
precoated silica gel plates (250 and 1000 µm) purchased from
Analtech Inc. TLC plates were visualized with UV in an iodine
chamber or with phosphomolybdic acid unless noted otherwise.
THF was freshly distilled under nitrogen from a purple solution
of sodium and benzophenone.
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification. (S)-
(+) and (R)-(-)-p-toluenesulfinamides (3) were prepared as
previously described,9 and 5-(benzyloxy)penanal (4) was pur-
chased from Aldrich.
(S)-(+)-N-(5-Ben zyloxyva ler ylid en e)-p -t olu en esu lfin a -
m id e (5). In an oven-dried single-necked 250 mL round-bottom
flask equipped with a magnetic stir bar and reflux condenser
was placed a solution of 4 (4.6 g, 24 mmol) in CH2Cl2 (80 mL).
Titanium(IV) ethoxide (20 mL, 96 mmol) was added to the
solution followed by the (S)-(+)-p-toluenesulfinamide 3 (3.72 g,
24 mmol). The reaction mixture was refluxed for 4 h and cooled
to 0 °C, H2O (80 mL) was added, and the solution was filtered
through Celite. The phases were separated, and the organic
phase was washed with brine (40 mL), dried (MgSO4), and
concentrated. Flash chromatography (EtOAc:hexane, 10:90)
afforded 7.4 g (95%) of (+)-5 as an oil: [R]23D 168.0 (c 1.5, CHCl3);
raphy affording (2S,6S)-(+)-1 in 77% yield. Since earlier
studies had demonstrated that these sequences of steps
(i.e., protection/deportation) does not lead to racemization
(Scheme 1) DAP (+)-1 is obtained in high enantiomeric
purity (>97%). This was confirmed by comparison of its
optical rotation with literature values.3d
meso-DAP 2 was prepared in a related fashion by
condensing sulfinamide (R)-(-)-3 with aldehyde (S)-(-)-
11 to give (RS,2S)-(-)-15 (Scheme 2). Cyanide addition
and hydrolysis gave (2S,6R)-2 meso-DAP 2 in 58% yield.
In summary, a general methodology is demonstrated
for the synthesis of bis(R-amino acids) using the sulfin-
imine-mediated asymmetric Strecker synthesis. The util-
ity of the N-tosyl group as an amino acid protecting group
is further demonstrated by these transformations as well
as the ease with which it is installed using sulfinimine
chemistry. Finally, polyfunctionalized R-amino acid sulfin-
imines such as (SS,2S)-(+)-12 and (RS,2S)-(-)-15 offer
significant potential for the asymmetric synthesis of
structural analogues of DAP because sulfinimines are
1
IR 1620 cm-1; H NMR (CDCl3) δ 1.6-1.8 (m, 5H), 2.4 (s, 3H),
2.45-2.40 (m, 1H), 3.45-3.50 (m, 2H), 4.5 (s, 2H), 7.3-7.4 (m,
7H), 7.6 (d, J ) 6.2 Hz, 2H), 8.25 (t, J ) 4.8 Hz, 1H); 13C NMR
(12) If some epimerization of one of the stereocenters had occurred,
diasteroisomers would have been produced. None was detected by 1H
(500 MHz) NMR.
(13) For leading references to sulfinimine (N-sulfinyl imine) chem-
istry, see: Davis, F. A.; Andemichael, Y. M. J . Org. Chem. 1999, 64,
8627.
(14) For reviews on the chemistry of sulfinimines, see: (a) Hua, D.
H.; Chen, Y.; Millward, G. S. Sulfur Rep. 1999, 21, 211. (b) Davis, F.
A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.

3250 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
(CDCl3) δ 22.0, 22.8, 29.8, 36.3, 70.4, 73.5, 125.2, 128.2, 128.3,
129.0, 130.5, 139.0, 142.0, 167.6. HRMS calcd for C19H23NO2S
(M + H) 330.1526. Found 330.1527 (M + H).
phy (EtOAc:hexane, 15:85) gave 1.32 g, (77%) of (-)-9 as an oil;
[R]23 -4.0 (c 0.3, CHCl3); IR 1744, 1597, 1454 cm-1; 1H NMR δ
D
(s, 9H), 0.8 (m, 2H), 1.30-1.95 (m, 7H), 2.40 (s, 3H), 3.42 (m,
2H), 3.49 (s, 3H), 3.6 (m, 1H), 4.38 (m, 1H), 4.5 (s, 2H), 4.9 (s,
2H), 7.2-7.4 (m, 7H), 7.75 (d, J ) 8 Hz, 2H); 13C NMR δ.1, 18.5,
22.5, 23.8, 30.0, 31.6, 52.5, 59.8, 67.0, 70.2, 73.2, 76.5, 128.2,
128.3, 128.9, 130.0, 138.5, 139.2, 144.0, 172.5. Anal. Calcd for
C27H41NO6SSi: C, 60.53; H, 7.71; N, 2.61. Found: C, 60.53; H,
7.51; N, 2.34.
(2S)-(+)-(2-N-p-Tolu en esu lfin a m id o)-6-(ben zyloxy)h ex-
a n on itr ile (6). In an oven-dried 250 mL two-necked round-
bottom flask fitted with a magnetic stir bar under argon balloon
was placed a solution of (+)-5 (3.29 g, 10 mmol) in THF (60 mL),
and the solution was cooled to -78 °C. In a separate two-necked
100 mL round-bottom flask fitted with a magnetic stir bar, under
an argon balloon was added a solution of diethylaluminum
cyanide (15 mL, 15 mmol) and i-PrOH (0.76 mL) in THF (30
mL). The reaction mixture was stirred at 0-10 °C for 10 min
and cannulated to the solution of (+)-5 at -78 °C. After the
reaction mixture was warmed to room temperature, the solution
was stirred for 12 h, cooled to -78 °C, and quenched with sat.
NH4Cl solution (40 mL). The reaction mixture was extracted
with EtOAc (3 × 30 mL), and the combined organic phases were
washed with brine (30 mL), dried (MgSO4), and concentrated.
Flash chromatography (EtOAc:hexane, 20:80) gave 3.0 g (86%)
of (+)-6 as an oil in >96% de; [R]23D 34.4 (c 0.9, CHCl3); IR 3464-
3032, 2243 cm-1; 1H NMR (CDCl3) δ 1.55-170 (m, 4H), 1.85 (q,
J ) 7.3 Hz, 2H), 2.43 (s, 3H), 3.5 (t, J ) 6.2 Hz, 2H), 4.12 (q, J
) 7.3 Hz, 1H), 4.5 (s, 2H), 4.8 (bs, 1H), 7.3-7.4 (m, 7H), 7.6 (d,
J ) 8 Hz, 2H); 13C NMR (CDCl3) δ 22.07, 23.06, 29.5, 35.5, 42.7,
70.4, 73.5, 119.8, 126.8, 128.3, 128.4, 129.1, 130.6, 139.1, 140.4,
142.7. HRMS calcd for C20H24N2O2S (M + H) 357.1642. Found
357.1636 (M + H).
Met h yl (2S)-(-)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(eth oxy)m eth yl)-6-h yd r oxyh exa n oa te (10). In an oven
dried two necked 100 mL round-bottom flask equipped with a
magnetic stir bar under a hydrogen balloon was placed a
suspension of (10%) Pd/C (0.12 g) in ethanol (40 mL). A solution
of (-)-9 (1.2 g, 2.4 mmol) in ethanol (20 mL) was added, and
the reaction mixture was stirred for 3 h at room temperature at
which time the solution was filtered and concentrated. The
residue was dissolved in EtOAc (60 mL), washed with brine (20
mL), dried (MgSO4) and concentrated. Flash chromatography
(EtOAc:hexane, 25:75) afforded 1.0 g (94%) of (-)-10 as an oil.;
[R]23D -9.0 (c 0.5, CHCl3); IR 3723-3029, 1744, 1597, 1450 cm-1
;
1H NMR δ (s, 9H), 0.8-0.9 (m, 2H), 1.30-1.65 (m, 6H), 1.8-1.9
(m, 2H), 2.4 (s, 3H), 3.45 (s, 3H), 3.6 (m, 2H), 4.4 (m, 1H), 4.95
(s, 2H), 7.25 (d, J ) 8.06 Hz, 2H), 7.7 (d, J ) 8.06 Hz, 2H); 13C
NMR δ.1, 19.2, 22.5, 23.0, 31.5, 32.5, 52.3, 59.1, 62.2, 66.4, 77.0,
127.8, 130.0, 138.2, 145.0, 172.6. HRMS calcd for C20H35NO6-
SSi (M + Na) 468.1834. Found 468.1852.
(2S)-(-)-(2-N-p-Tolu en esu lfon a m id o)-6-(ben zyloxy)h ex-
a n on itr ile (7). In a single-necked 100 mL round-bottom flask
fitted with a magnetic stir bar, under argon, was placed a
solution of (+)-(6) (2.85 g, 8 mmol) in CH2Cl2 (40 mL). m-
Chloroperbenzoic acid (57%) (2.75 g, 16 mmol) was added, and
the solution was stirred at room temperature for 4.5 h at which
time the reaction mixture was washed with sodium thiosulfate
solution (50 mL) and sat. sodium bicarbonate (30 mL), dried
(MgSO4), and concentrated. Filtration through a short column
of silica gel afforded 2.63 g (88%) of (-)-7; mp 77 °C; [R]23D -23.9
Met h yl (2S)-(-)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(eth oxy)m eth yl)-6-for m ylh exa n oa te (11). In an oven-
dried single-necked 100 mL round-bottom flask fitted with a
magnetic stir bar under argon balloon was placed a solution of
(-)-10 (0.8 g, 1.8 mmol) in CH2Cl2 (30 mL). Pyridinium chloro-
chromate (0.39 g, 1.8 mmol) was added, and the solution was
stirred for 1 h at room temperature. At this time the reaction
mixture was diluted with ether (30 mL), filtered through silica
gel, and concentrated. Flash chromatography (EtOAc:hexane,
10:90) gave 0.55 g (69%) of (-)-11 as an oil; [R]23 -7.7 (c 0.78,
D
(c 1.7, CHCl3); IR 3650-3030 (b), 2241, 1597, 1450 cm-1
;
1H
CHCl3); IR 1744, 1597 cm-1
;
1H NMR 0 (s, 9H); 0.86 (m, 3H),
NMR (CDCl3) δ 1.5-1.7 (m, 4H), 1.85 (q, J ) 7.3 Hz, 2H), 2.43
(s, 3H), 3.46 (t, J ) 5.9 Hz, 2H), 4.23 (m, 1H), 4.5 (s, 2H), 5.0 (d,
J ) 9.5 Hz, 1H); 7.3-7.4 (m, 7H), 7.7 (d, J ) 8 Hz, 2H); 13C
NMR (CDCl3) δ 21.0, 21.5, 28.0, 32.8, 43.8, 69.1, 72.4, 117.2,
126.7, 127.1, 127.2, 127.9, 129.5, 135.7, 137.8, 143.9. Anal. Calcd
for C20H24N2O3S: C, 64.49; H, 6.49; N, 7.52. Found: C, 64.15;
H, 6.41; N, 7.40.
1.6-1.9 (m, 5H), 2.4 (s, 3H), 3.45 (s, 3H), 3.57-3.59 (m, 2H);
4.3 (m, 1H), 4.9 (s, 2H), 7.27 (d, J ) 8 Hz, 2H), 7.7 (d, J ) 8 Hz,
2H); 9.7 (s, 1H); 13C NMR 0, 18.5, 19.3, 22.2, 30.6, 43.6, 52.7,
59.0, 66.5, 76.4, 128.2, 130.0, 138.0, 145.0, 172.0, 202.3.
Met h yl (2S)-(+)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(eth oxy)m eth yl)-6-en e-N-(S)-(p-tolu en esu lfin a m id o)-
h exa n oa te (12). The sulfinimine was prepared as described
earlier and flash chromatography (EtOAc:hexane, 10:90) gave
Meth yl (2S)-(+)-(N-p-Tolu en esu lfon am ido)-6-(ben zyloxy)-
h exon a te (8). In a single-necked 100 mL round-bottom flask
equipped with a magnetic stir bar, reflux condenser, and calcium
chloride drying tube was placed a solution of (-)-7 (2.1 g, 6 mmol)
in (4 M) methanolic-HCl (60 mL). The reaction mixture was
refluxed for 28 h. The progress of the reaction was monitored
by TLC by the disappearance of the starting material. The
solution was cooled to 0 °C and carefully neutralized by addition
of pyridine. Concentration gave a residue which was dissolved
in CH2Cl2 (80 mL), washed with water (2 × 20 mL) and brine
(30 mL), dried (MgSO4), and concentrated. Flash chromatogra-
phy (EtOAc:hexane, 20:80) gave 1.63 g (65%) of (+)-8; mp 38
0.465 g (80%) of (+)-12 as an oil; [R]23 66.3 (c 0.4, CHCl3); IR
D
1744, 1620, 1450 cm-1; 1H NMR δ (s, 9H), 0.8-0.9 (m, 2H), 1.6-
2.0 (m, 5H), 2.4 (2s, 6H), 2.41 (m, 1H), 3.45 (s, 3H), 3.6 (m, 2H),
4.4 (m, 1H), 4.9 (s, 2H), 7.27 (2d, J ) 8 Hz, 4H), 7.55 (d, J ) 8
Hz, 2H), 7.75 (d, J ) 8 Hz, 2H), 8.2 (t, J ) 4.5 Hz, 1H); 13C
NMR δ 18.5, 22.0, 22.2, 22.5, 30.6, 35.8, 52.7, 59.0, 66.4, 76.3,
125.3, 128.2, 130.0, 130.4, 138.0, 142.5, 142.6, 144.2, 166.9, 171.9.
HRMS calcd for C27H40N2O6S2Si (M + Na) 603.1985. Found
603.1994 (M + Na).
Met h yl (2S)-(+)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(et h oxy)m et h yl)-(6S)-(n it r ile-N-((S)-p -t olu en esu lfin -
im id o))h exa n oa te (13). The amino nitrile was prepared as
described earlier and flash chromatography (EtOAc:hexane, 20:
80) afforded 0.22 g (69%) of (+)-13 as an oil: [R]23D 24.39 (c 2.05,
°C; [R]23 14.9 (c 2, CHCl3); IR 3472-3080, 1741, 1599, 1452
D
cm-1; 1H NMR δ 1.4-1.7 (m, 6H), 2.4 (s, 3H), 3.42 (m, 2H), 3.47
(s, 3H), 3.9 (m, 1H), 4.5 (s, 2H), 5.1 (d, J ) 9.5 Hz, 1H), 7.25-
7.40 (m, 7H), 7.7 (d, J ) 8.4 Hz, 2H); 13C NMR δ 22.2, 22.4,
29.6, 33.8, 53.0, 56.3, 70.5, 73.6, 127.9, 128.2, 128.3, 129.0, 130.3,
137.5, 139.2, 144.3, 172.9. HRMS calcd for C21H27NO5S (M +
Na) 428.1519. Found (M + Na) 428.1507.
1
CHCl3); IR 3420-3055, 2243, 1746, 1597, 1444 cm-1; H NMR
δ (s, 9H), 0.9 (m, 2H), 1.5-2.0 (m, 6H), 2.46 (2s, 6H), 3.5 (s, 3H),
3.6 (m, 2H), 4.05 (d, J ) 7 Hz, 1H), 4.38 (t, J ) 7.3 Hz, 1H), 4.9
(m, 3H), 7.3 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.1 Hz, 2H); 13C
NMR δ, 18.6, 22.1, 22.2, 30.1, 34.8, 41.8, 52.8, 58.7, 66.7, 76.3,
119.4, 126.8, 128.3, 130.2, 130.7, 137.9, 140.3, 142.9, 144.4, 171.7.
HRMS calcd for C28H41N3O6S2Si (M + Na) 630.2095. found
630.2103 (M + Na).
Met h yl (2S)-(-)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(eth oxy)m eth yl)-6-(ben zyloxy)h exon a te (9). In an oven-
dried two-necked 250 mL round-bottom flask equipped with a
magnetic stir bar under an argon balloon was placed a solution
of NaH (0.22 g, 4.8 mmol), prewashed with n-hexane (3 × 15
mL), in dry DMF (25 mL) and cooled to 0 °C. A solution of (+)-8
(1.29 g, 3.2 mmol) in dry DMF (20 mL) was slowly added. The
solution was stirred at 0 °C for 5 min and trimethylsilyl(ethoxy)-
methyl chloride (0.56 mL, 3.2 mmol) (Aldrich) was added and
the solution stirred for 5 min. At this time the reaction mixture
was quenched with brine (60 mL) and extracted with EtOAc (3
× 30 mL), and the organic phases combined, washed with brine
(20 mL), dried (MgSO4), and concentrated. Flash chromatogra-
Meth yl (2S,6S)-(+)-2-N-(p-Tolu en esu lfon am ido)-6-am in o-
bish exa n oa te (14). In a single-necked 100 mL round-bottom
flask fitted with a magnetic stir bar and a condenser was placed
a solution of (+)-13 (0.14 g, 0.22 mmol) in (4 M) methanolic-
HCl (15 mL), and the solution was refluxed for 12 h. The reaction
mixture was cooled to 0 °C, carefully neutralized with pyridine
(pH indicator paper), and concentrated and the residue dissolved
in EtOAC (15 mL). The organic phase was washed with brine
(10 mL), dried (MgSO4), and concentrated to give 0.068 g (84%)

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3251
of (+)-14 as an oil: [R]23D 15 (c 0.4, CHCl3); IR 3469-3069, 1736,
20:80) gave 0.170 g (62%) of (-)-16 as an oil; [R]23 -21.33 (c
D
1597, 1439 cm-1; H NMR δ 1.2-2.0 (m, 6H), 2.4 (s, 3H), 3.44
0.45, CHCl3); IR 3395-3079, 2245, 1740 cm-1
;
1H NMR δ (s,
1
(s, 3H), 3.45 (m, 1H), 3.7 (s, 3H), 3.95 (m, 1H), 5.2-5.4 (bs, 1H),
7.3 (d, J ) 8 Hz, 2H), 7.7 (d, J ) 8 Hz, 2H); 13C NMR δ 22.2,
22.5, 33.0, 34.5, 52.5, 53.0, 54.5, 56.0, 127.5, 130.0, 137.4, 144.7,
172.6, 177. HRMS calcd for C16H24N2O6S (M + Na) 395.1264.
Found 395.1252 (M + Na).
9H), 1.0-1.8 (m, 8H), 2.25 (2s, 6H), 3.3-3.4 (m, 5H), 3.95 (m,
1H), 4.2 (m, 1H), 4.8 (s, 2H), 5.25 (m, 1H), 7.2 (2d, J ) 7.9 Hz,
4H), 7.45 (d, J ) 8 Hz, 2H), 7.6 (d, J ) 8 Hz, 2H); 13C NMR δ
18.4, 21.5, 21.9, 30.2, 34.7, 41.9, 52.6, 58.7, 66.4, 76.2, 119.2,
126.6, 128.1, 129.9, 130.5, 137.8, 140.1, 142.7, 144.2, 171.6.
HRMS calcd for C28H41N3O6S2Si (M + Na) 630.2095. Found
630.2104 (M + Na).
(2S,6S)-(+)-Dia m in op im ilic Acid (1). In an one-necked 50
mL round-bottom flask equipped with a magnetic stir bar and
a reflux condenser was placed a solution of (+)-14 (0.048 g, 0.13
mmol) in 48% HBr in acetic acid (12 mL) and phenol (20 mg).
The reaction mixture was refluxed for 10 h, cooled to 0 °C, and
washed with ether (10 mL). The aqueous phase was loaded on
to Dowex-50 ion-exchange resin, and eluted with H2O (70 mL)
followed by 10% NH4OH (150 mL) solution to give 0.019 g (77%)
of 1; mp 309-312 °C; [R]23 42.7 (c 1.1, 1 N HCl); (lit.3d [R]23
Meth yl (2S,6R)-(+)-2-N-(p-Tolu en esu lfon am ido)-6-am in o-
bish exa n oa te (17). Flash chromatography (EtOAc:n-hexane 30:
70) gave 0.055 g (82%) of (+)-17 as an oil; [R]23 2.0 (c 0.5,
D
CHCl3); IR 3434-3044, 1740, 1597, 1439 cm-1; 1H NMR δ 1.3-
1.8 (m, 6H), 2.38 (s, 3H), 3.4 (m, 4H), 3.65 (s, 3H), 3.85 (m, 1H),
7.25 (d, J ) 8.1 Hz, 2H), 7.65 (d, J ) 8.1 Hz, 2H); 13C NMR δ
21.8, 22.1, 33.4, 34.5, 52.7, 53.0, 54.6, 56.2, 127.8, 130.2, 137.5,
144.2, 172.7, 176.7. HRMS calcd for C16H24N2O6S (M + Na)
395.1264. Found 395.1253 (M + Na).
D
D
44.5 (c 0.95, 1 N HCl); 1H NMR: δ 1.2-1.45 (m, 2H), 1.5-1.9
(m, 4H), 3.45-3.75 (m, 2H).
Met h yl (2S)-(-)-N-(p -Tolu en esu lfon a m id o-t r im et h yl-
silyl(eth oxy)m eth yl)-6-en e-N-(R)-(p-tolu en esu lfin a m id o)-
h exa n oa te (15). Prepared from (S)-(-)-11 and (R)-(-)-3 and
purified by flash chromatography (EtOAc:hexane, 10:90) to give
m eso-(2S,6R)-Dia m in op im ilic Acid (2). Yield 0.011 g (58%);
mp: >312 °C (dec). 1H NMR δ 1.2-1.4 (m, 2H), 1.5-1.8 (m, 4H),
3.4-3.7 (m, 2H). Spectral properties were identical to literature
values.3d
0.315 g (73%) of (-)-15 as an oil; [R]23 -93.18 (c 1.1, CHCl3);
D
IR 1744, 1620, 1450 cm-1; 1H NMR δ (s, 9H), 0.8 (m, 2H), 1.5-
1.9 (m, 5H), 2.35 (2s, 6H), 2.4 (m, 1H), 3.39 (m, 1H), 3.4 (s, 3H),
3.5 (m, 1H), 4.35 (m, 1H), 4.85 (s, 2H), 7.25 (2d, J ) 8.8 Hz,
4H), 7.5 (d, J ) 8.1 Hz, 2H), 7.7 (d, J ) 8.1 Hz, 2H); 8.15 (t, J
) 4 Hz, 1H); 13C NMR δ, 18.5, 22.0, 22.1, 22.4, 30.6, 35.8, 52.6,
59.0, 66.4, 76.3, 125.2, 128.2, 130.0, 130.4, 138.1, 142.2, 142.5,
144.2, 166.8, 171.8. HRMS calcd for C27H40N2O6S2Si (M + Na)
603.1985. Found (M + Na) 603.1995.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM57870).
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and IR
spectra for compounds (+)-5, (+)-6, (-)-7, (+)-8, (-)-9, (-)-10,
(-)-11, (+)-12, (+)-13, (+)-14, (-)-15, (-)-16, and (+)-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Met h yl (2S)-(-)-N-(p -t olu en esu lfon a m id o-t r im et h yl-
silyl(et h oxy)m et h yl)-(6R)-(n it r ile-N-((S)-p -t olu en esu lfin -
im id o))h exa n oa te (16). Flash chromatography (EtOAc:hexane,
J O000038U