A novel approach to the synthesis of amino-sugars. Routes to selectively protected 3-amino-3-deoxy-aldopentoses based on pyridinium salt photochemistry

Article abstract of DOI:10.1021/jo020038p

A new approach for the synthesis of selectively blocked 3-amino-3-deoxyaldopentoses is presented. The strategy is based on employment of a pyridinium salt photocyclization-aziridine ring-opening sequence to prepare stereochemically defined, enantiomerically enriched aminocyclopentendiol derivatives. Ring-opening reactions transform these substances into terminally differentiated aminopolyols, which serve as precursors to the target aminoaldopentoses. The utility of this strategy is demonstrated by its application to the syntheses of protected derivatives of D- and L-3-amino-3-deoxyxylose, L-3-amino-3-deoxyarabinose, and a late-stage intermediate in a potential route to N-acetylneuraminic acid.

Full text of DOI:10.1021/jo020038p

J . Org. Chem. 2002, 67, 3525-3528
3525
Sch em e 1
A Novel Ap p r oa ch to th e Syn th esis of
Am in o-Su ga r s. Rou tes To Selectively
P r otected 3-Am in o-3-d eoxy-a ld op en toses
Ba sed on P yr id in iu m Sa lt P h otoch em istr y
Haiyan Lu, Zhuoyi Su, Ling Song, and
Patrick S. Mariano*
Department of Chemistry, University of New Mexico,
Albuquerque, New Mexico 87131
Sch em e 2
mariano@unm.edu
Received J anuary 17, 2002
Abstr a ct: A new approach for the synthesis of selectively
blocked 3-amino-3-deoxyaldopentoses is presented. The strat-
egy is based on employment of a pyridinium salt photocy-
clization-aziridine ring-opening sequence to prepare stereo-
chemically defined, enantiomerically enriched amino-
cyclopentendiol derivatives. Ring-opening reactions trans-
form these substances into terminally differentiated amino-
polyols, which serve as precursors to the target amino-
aldopentoses. The utility of this strategy is demonstrated
by its application to the syntheses of protected derivatives
of D- and L-3-amino-3-deoxyxylose, L-3-amino-3-deoxyarabi-
nose, and a late-stage intermediate in a potential route to
N-acetylneuraminic acid.
Sch em e 3
Sch em e 4
Earlier, we described how pyridinium salt photocy-
clization-aziridine ring-opening sequences can be used
to prepare stereochemically defined, diversely function-
alized aminocyclopentenes.1 An example of this is found
in the conversion of pyridine to the aminodiol 1 (isolated
as the amido-diacetate 2) by irradiation in aqueous
perchloric acid (Scheme 1). In addition, employing enzy-
matic desymmetrization2 and Wipf alcohol inversion3
procedures allows 2 to be transformed into the cyclopen-
tenols 3 and 4 with modestly high levels of enantiomeric
purity.4 As we have pointed out in previous publications,4-6
these substances serve as key intermediates in routes for
the preparation of a variety of biomedically interesting
natural and nonnatural aminocyclopentitols (Scheme 2).
The strategies developed for these purposes take advan-
tage of the allylic alcohol functionality in 3 and 4 to
promote stereocontrolled dihydroxylation and Wittig
rearrangement reactions.
Another, synthetically relevant feature of the doubly
allylic enediol functionality present in aminocyclopen-
tenols 3 and 4 relates to ring-opening reactions. Accord-
ingly, oxidative cleavage of olefin moieties in these
substances can be used to construct stereochemically
defined, terminally differentiated five-carbon aminopo-
lyols. When viewed from this perspective (Scheme 3), the
ring-opening process would serve as a strategic element
linking pyridinium salt photochemistry to concise routes
for the synthesis of selectively protected 3-amino-3-
deoxyaldopentoses.7,8 Below, we summarize the results
of preliminary studies, which demonstrate the utility of
this strategy in the context of the preparation of N- and
O-protected derivatives of D- and L-3-amino-3-deoxyxylose
and L-3-amino-3-deoxyarabinose.
The route to the D-3-amino-3-deoxyxylose derivative 10
(Scheme 4) begins with the known4 conversion of ami-
docyclopentenol 3 to the TBS-analogue 5. Attempts to
carry out ozonolytic cleavage directly on the allylic alcohol
moiety in 5 were unsuccessful. In contrast, treatment of
the O-benzyl derivative 6 with ozone in a 2:1 CH2Cl2-
MeOH mixture, followed by addition of NaBH4, efficiently
produces the pentanediol 7. The stage is then set for
differentiation of the terminal alcohol groups by use of a
silyl ether cleavage-acetonide formation sequence. Swern
oxidation of the alcohol 9, obtained in this way, then
yields the selectively protected D-3-amino-3-deoxyxylose
10.
The enantiodivergent nature of this strategy for amino-
sugar synthesis is highlighted by conversion of amidocy-
clopentenol 3 to the protected L-3-amino-3-deoxyxylose
14. Accordingly, reversal of the alcohol protection steps
transforms 3 into the enantiomeric O-TBS-, O-Bn-blocked
amidocyclopentene 13 (Scheme 5). Application of the
(1) Ling, R.; Yoshida, M.; Mariano, P. S. J . Org. Chem. 1996, 61,
4439.
(7) For recent examples of synthetic routes to 3-amino-3-deoxyal-
dopentoses, see: Al-Tel, T. H.; Al-Qawasmeh, R. A.; Schroder, C.;
Voelter, W. Tetrahedron 1995, 51, 3141. Voelter, W.; Khan, K. M.;
Shekhani, M. S. Pure Appl. Chem. 1996, 68, 1347. Sewald, N.; Hiller,
K. D.; Koerner, M.; Findeisen, M. J . Org. Chem. 1998, 63, 7263.
(8) For recent examples of synthetic routes to 3-amino-2,3-dideoxy-
aldopentoses, see: Hauser, F. M.; Ellenberger, S. R.; Rhee, R. P. J .
Org. Chem. 1987, 52, 5041. Krenitsky, T. A.; Freeman, G. A.; Shaver,
S. R.; Beacham, L. M.; Hurlbert, S.; Cohn, N. K.; Elwell, L. P.; Selway,
J . W. T. J . Med. Chem. 1983, 26, 891.
(2) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 1575.
(3) Deardorf, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth. 1995,
73, 25.
(4) Ling, R.; Mariano, P. S. J . Org. Chem. 1998, 63, 6072.
(5) Cho, J . C.; Ling, R.; Kim, A.; Mariano, P. S. J . Org. Chem. 2000,
65, 1574.
(6) Lu, H.; Mariano, P. S.; Lam, Y.-F. Tetrahedron Lett. 2001, 42,
4755.
10.1021/jo020038p CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

3526 J . Org. Chem., Vol. 67, No. 10, 2002
Notes
Sch em e 5
Sch em e 8
Sch em e 6
these substances by using TFA/MeOH affords the diols
26a and 26b. An oxymercuration-demercuration pro-
cess11 is then employed to convert 26b to the dihydro-
pyran target 23. Interestingly, the minor diol 26a does
not undergo Hg(II)-induced cyclization to form 23 under
these conditions. These results contrast with those
obtained earlier by Sinay11 in his studies of oxymercu-
ration-demercuration reactions on related but more
structurally complex substrates.
The chemistry summarized above further highlights
the synthetic value of photochemical processes that
transform pyridinium salts into functionalized aminocy-
clopentenes. These processes can be used to prepare gram
quantities of enantiomerically enriched substrates, which
are ideal starting materials in routes for synthesis of
cyclic and acyclic aminopolyol targets.
Sch em e 7
Exp er im en ta l Section
methodology shown in Scheme 4 can be used to convert
13 to the blocked L-aminoxylose derivative 14.
Gen er a l. 1H NMR and 13C NMR spectra were recorded on
CDCl3 solution unless specified otherwise, and chemical shifts
are reported in parts per million relative to CHCl3 (δ 7.24 ppm
for 1H and δ 77.0 ppm for 13C), which was used as a chemical
shift internal standard for samples in CDCl3. 13C NMR resonance
assignments were aided by the use of the DEPT-135 technique
to determine numbers of attached hydrogens. Optical rotations
[R] were measured at 25 °C at 589 nm (sodium D line). Mass
spectra were recorded by using electron impact ionization or fast
atom bombardment. Infrared absorption bands are recorded in
units of cm-1. All compounds were isolated as oils unless
otherwise specified, and their purities were determined to be
>90% by NMR analysis.
The ability to perform amide-directed stereochemical
inversion at one or both of the allylic hydroxyl centers
in the photochemically derived amidocyclopentenes
(Scheme 1) opens the way for application of this chem-
istry to the preparation of other diastereomeric 3-amino-
3-deoxyaldopentoses. An example of this is found in the
route targeted at the protected L-3-amino-3-deoxyarabi-
nose 21, starting with amidocyclopentenol 4 (Scheme 6).
In a manner similar to that outlined in Scheme 4, 4 is
converted to the O-TBS, O-Bn derivative 17. Ozonolysis
followed by reduction provides the diol 18. Sequential
desilylation and acetonide formation then sets the stage
for preparation of the L-arabinose analogue 21 by Swern
oxidation of the pentanol 20.
The methods presented above for amino-aldopentose
synthesis can be incorporated into sequences targeted at
higher homologues in the amino-sugar family. An ex-
ample of this is found in the strategy for synthesis of the
amino-glycero-nonulosonic acid, N-acetylneuraminic acid
(22) shown in Scheme 7. A late intermediate in this
proposed route is alcohol 23, a substance that could be
transformed to the target by using sequential alcohol
oxidation, Sharpless-Masamune9 polyol chain introduc-
tion, and enol ether to hemiacetal interconversion.10 In
addition, the approach to 23 takes advantage of the
aldehyde moiety in the blocked L-amino-arabinose 21 as
an ideal site for chain elongation.
(3R,4R,5S)-4-Aceta m id o-3-ter t-bu tyld im eth ylsilyloxy-5-
ben zyloxycyclop en ten e (6). After a mixture of the known silyl
ether 54 (0.7 g, 2.59 mmol) and sodium hydride (0.156 g, 3.9
mmol) in the dry THF (25 mL) was stirred at 25 °C for 1 h,
benzyl bromide (0.86 g, 5.18 mmol) and sodium iodide (0.76 g,
5.18 mmol) were introduced. The resulting mixture was stirred
at 25 °C for 48 h, diluted with water, and extracted with CH2-
Cl2. The CH2Cl2 extracts were concentrated in vacuo to afford
an oil, which was subjected to column chromatography (silica
gel, 2:1 hexane-acetone) to give the cyclopentene 6 (0.86 g, 94%)
as a solid. 1H NMR: δ 7.24-7.33 (m, 5H), 6.91 (d, J ) 7.5 Hz,
1H, NH), 5.83 (abq, J ) 5.5 Hz, 2H), 4.76 (d, J ) 5.0 Hz, 1H),
4.58 (abq, J ) 8.0 Hz, 2H), 4.50 (d, J ) 3.0 Hz, 1H), 3.92 (m,
1H), 1.91 (s, 3H), 0.89 (s, 9H), 0.61 (s, 6H). 13C NMR: δ 170.1
(CdO), 138.4, 135.7, 131.4, 128.3, 128.1, 127.5, 84.2, 78.2, 70.7,
66.7, 25.6, 23.2, -4.8, -5.0. HRMS (FAB) (m/z): calcd for
C20H32O3NSi, 362.2151; found, 362.2154.
(2R,3R,4S)-3-Aceta m id o-2-ter t-bu tyld im eth ylsilyloxy-4-
ben zyloxy-1,5-p en ta n ed iol (7). Ozone was passed through a
-78 °C solution of 6 (0.35 g, 0.97 mmol) in 15 mL of 2:1 CH2-
Cl2-MeOH for 3 h. Solid sodium borohydride (0.37 g, 9.7 mmol)
was then added, and the resulting solution was diluted with CH2-
Cl2 and filtered. The filtrate was diluted with water and
extracted with CH2Cl2. The CH2Cl2 extracts were concentrated
in vacuo to give a residue that was subjected to column
chromatography (silica gel, 2:1 hexane-acetone) to afford the
diol 7 (0.35 g, 90%) as a crystalline substance. 1H NMR: δ 7.20-
Thus, treatment of 21 with the anion of the phospho-
nate 24 provides the separable unsaturated esters 25 as
a 2:1 mixture of (E)- and (Z)-stereoisomers (25b and 25a ,
respectively) (Scheme 8). Acetonide removal in each of
(9) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless,
K. B.; Walker, F. J . Science 1983, 220, 949.
(10) J ulina, R.; Muller, I.; Vasella, A.; Wyler, R. Carbohydr. Res.
1987, 164, 415.
(11) Sinay, P.; Paquet, F. Tetrahedron Lett. 1984, 25, 3071.

Notes
J . Org. Chem., Vol. 67, No. 10, 2002 3527
7.32 (m, 5H), 6.34 (d, J ) 8.6 Hz, 1H, NH), 4.53 (abq, J ) 11.4
Hz, 2H), 4.20-4.27 (m, 1H), 4.15-4.19 (m, 1H), 3.88-3.93 (m,
1H), 3.64-3.71 (m, 2H), 3.37-3.51 (m, 2H), 1.94 (s, 3H), 0.83
(s, 9H), -0.02 (s, 6H). 13C NMR: δ 172.62, 137.28, 128.41, 127.96,
127.88, 80.37, 71.21, 63.32, 59.34, 48.67, 25.64, 25.38, 22.77,
18.01, -5.71.
7.32-7.22 (m, 5H), 5.86-5.90 (m, 1H), 5.74-5.82 (m, 2H), 4.80-
4.83 (m, 1H), 4.50-4.60 (abq, J ) 12.0 Hz, 3H), 3.66-3.74 (m,
1H), 1.93 (s, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13C
NMR: δ 170.1, 138.6, 135.9, 131.6, 128.3, 127.8, 127.6, 84.1, 77.8,
71.2, 67.7, 25.8, 23.6, 18.06, -4.7, -4.8. HRMS (FAB) (m/z):
calcd for C28H32O3NSi, 362.2151; found, 362.2153.
(2S,3R,4R)-Ben zyloxy-3-acetam ido-4,5-O-isopr opyliden e-
1-p en ta n ol (9). A solution of diol 7 (0.1 g, 0.25 mmol) and TBAF
(0.2 g, 0.35 mmol) in 10 mL of THF was stirred at 25 °C for 2 h.
Concentration in vacuo gave a residue that was eluted through
Florisil (1:1 hexane-acetone). The eluate was concentrated in
vacuo giving a residue, which was dissolved in acetone (6 mL)
containing 2,2-dimethoxy-propane (8 mL) and PTSA (0.02 g, 0.1
mmol). The resulting mixture was stirred at 25 °C for 1 h, diluted
with water, and extracted with CH2Cl2. The CH2Cl2 extracts
were dried and concentrated in vacuo to give a residue, which
was subjected to column chromatography (silica gel, 2:1 hexane-
acetone) to afford 9 (0.075 g, 94%). 1H NMR: δ 7.24-7.27 (m,
5H), 6.19 (d, J ) 8.9 Hz, 1H, NH), 4.50 (abq, J ) 11.6 Hz, 2H),
4.20-4.41 (m, 2H), 3.77-3.80 (m, 1H), 3.74-3.76 (m, 1H), 3.63
(s, 1H), 3.46-3.51 (m, 2H), 3.38-3.40 (m, 1H), 1.96 (s, 3H), 1.33
(s, 3H), 1.28 (s, 3H). 13C NMR: δ 171.5 (CO), 137.7, 1, 128.4,
128.1, 127.9, 109.4, 79.0, 75.0, 72.4, 66.8, 60.3, 49.9, 26.4, 25.3,
22.9. HRMS (FAB) (m/z): calcd for C17H26O5N (M + 1), 324.8111;
found, 324.1808.
(2S,3R,4R)-2-Ben zyloxy-3-acetam ido-4,5-O-isopr opylidin e-
p en ta n a l (10). To a solution of oxalyl chloride (42uL, 0.48 mmol)
in CH2Cl2 (5 mL) at -78 °C was added DMSO (90 µL, 1.28 mmol)
dropwise. The resulting solution was stirred at -78 °C for 1 h,
and then a solution of alcohol 9 (0.1 mg, 0.32 mmol) in CH2Cl2
(5 mL) was added dropwise. The mixture was stirred at -78 °C
for 1.5 h, followed by the dropwise addition of TEA (178uL, 1.28
mmol) and warming to 25 °C. After stirring at 25 °C for 2 h, the
mixture was diluted with water and extracted with CH2Cl2. The
CH2Cl2 extracts were washed, dried, and concentrated in vacuo
to yield aldehyde 10 (0.098 g, 97%). The crude aldehyde was
quickly eluted through a Florisil column (1:1 hexane-acetone),
and the eluate was concentrated in vacuo to give the pure but
unstable 10. 1H NMR: δ 9.61 (s, 1H), 7.29-7.33 (m, 5H), 5.91
(d, J ) 9.0 Hz, 1H, NH), 4.64 (abq, J ) 11.6 Hz, 2H), 4.47-4.49
(m, 1H), 4.42 (d, J ) 4.9 Hz, 1H), 3.92-3.95 (m, 1H), 3.86-3.87
(m, 1H), 3.63-3.66 (m, 1H), 1.99 (s, 3H), 1.38 (s, 3H), 1.31 (s,
3H).
(3S,4S,5R)-4-Aceta m id o-3-a cetoxy-5-ben zyloxycyclop en -
ten e (11). A solution of cyclopentenol 4 (35 mg, 0.18 mmol), Ag2O
(123 mg, 0.53 mmol), and PhCH2Br (46 mg, 0.26 mmol) in CH2-
Cl2 (1.5 mL) was stirred for 3 days at 25 °C, diluted with CH2-
Cl2, and filtered. The filtrate was concentrated to give a residue
that was subjected to column chromatography (silica gel, 2:1
hexane-acetone) to afford 11 (42 mg, 82%) as a crystalline
substance. Mp: 131-132 °C. 1H NMR: δ 7.24-7.34 (m, 5H),
6.00-6.05 (m, 1H), 5.86-5.90 (m, 1H), 5.68-5.72 (d, J ) 7.8
Hz, 1H, NH), 5.54-5.57 (m, 1H), 4.58-4.69 (abq, J ) 11.9 Hz,
2H), 4.47-4.49 (m, 1H), 4.09-4.17 (m, 1H), 2.05 (s, 3H), 1.95
(s, 3H). 13C NMR: δ 170.9, 170.1, 138.2, 134.9, 131.40, 128.4,
127.9, 127.7, 85.38, 80.7, 71.5. HRMS (FAB) (m/z): calcd for
C16H20O4N (M + 1), 290.1392; found, 290.1402.
(3S,4S,5R)-4-Acetam ido-5-ben zyloxycyclopen ten -3-ol (12).
A solution of 11 (60 mg, 0.21 mmol) and NaOMe (10 mg) in
MeOH (5 mL) was stirred for 12 h at 25 °C and concentrated in
vacuo to give a residue that was subjected to column chroma-
tography (silica gel, 1:1 hexane-acetone) to afford 12 (51 mg,
99%) as a crystalline solid. Mp: 106-107 °C. 1H NMR: δ 7.29-
7.37 (m, 5H), 5.88-5.93 (m, 2H), 5.80 (brs, 1H), 4.71 (s, 1H),
4.47-4.70 (abq, J ) 12.0 Hz, 2H), 4.44-4.47 (d, J ) 5.0, 1H),
4.32-4.36 (m, 1H), 3.81-3.90 (m, 1H), 1.93 (s, 3H). 13C NMR:
δ 172.6, 138.1, 134.8, 130.6, 128.7, 128.1, 128.0, 85.2, 79.8, 71.0,
68.0, 22.9. HRMS (FAB) (m/z): calcd for C14H18O3N (M + 1),
248.1287; found, 248.1290.
(3S,4R,5S)-5-Acetoxy-4-a ceta m id o-3-ter t-bu tyld im eth ys-
ilyloxy-1-cyclop en ten e (15). To a solution of cyclopentenol 4
(0.7 g, 3.52 mmol) in dry CH2Cl2 (20 mL) was added imidazole
(0.67 g, 9.87 mm0l) and tert-butyldimethylsilyl chloride (0.74 g,
4.92 mmol). The mixture was stirred at 25 °C for 12 h, diluted
with water and extracted with CHCl3. The CHCl3 extracts were
dried and concentrated in vacuo to give a residue, which was
subjected to column chromatography (silica gel, 1:1 hexane-
acetone) to provide silyl ether 15 (1.1 g, 100%) as a crystalline
substance. Mp: 84-85 °C. [R] ) +93.5 (c 2.2, CHCl3). 1H NMR:
δ 6.10 (d, J ) 12.5 Hz, 1H), 5.93 (m, 1H), 5.89 (dd, J ) 6.0, 1.5
Hz, 1H), 5.62 (dd, J ) 5.2, 1.5 Hz, 1H), 4.69 (ddd, J ) 6.0,1.7,
1.7 Hz, 1H), 4.33 (ddd, J ) 12.5, 6.0, 5.2 Hz, 1H), 2.01 (s, 3H),
1.93 (s, 3H), 0.84 (S, 9H), 0.03 (S, 3H). 13C NMR: δ 170.9, 169.8,
135.8, 133.7, 81.7, 73.7, 56.4, 25.6, 23.2, 21.0, 18.0, -4.6, -5.1.
HRMS (m/z): calcd for C15H27O4NSi, 313.1709; found, 313.1705.
(1S,4S,5R)-5-Aceta m id o-4-ter t-bu tyld im eth ylsilyloxy-2-
cyclop en ten -1-ol (16). A solution of the silyl ether 15 (0.513
g, 1.6 mmol) and NaOMe (0.018 g, 0.329 mmol) in MeOH (25
mL) at 25 °C was stirred for 12 h and concentrated in vacuo to
give a residue, which was subjected to column chromatography
(silica gel, 1:1 hexane-acetone) to give alcohol 16 (0.438 g, 100%)
as a crystalline substance. Mp: 98-100 °C. [R] ) +29.5 (c 1.3,
CHCl3). 1H NMR: δ 6.04 (brs, 1H), 6.00 (dd, J ) 6.0, 1.5 Hz,
1H), 5.83 (ddd, J ) 6.0, 2.0, 2.0 Hz, 1H), 4.76 (ddd, J ) 6.6, 2.0,
2.0 Hz, 1H), 4.68 (m,1H), 3.81 (m, 1H), 3.78 (brs, 1H), 2.01 (s,
3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C NMR: δ 171.9,
137.5, 132.4, 82.3, 74.6, 61.2, 25.7, 22.9, 18.1, -4.1, -5.0. HRMS
(m/z): calcd for C13H25O3NSi, 271.1604; found, 271.1615.
(3S,4R,5S)-4-Aceta m id o-3-ter t-bu tyld im eth ylsilyloxy-5-
ben zyloxy-cyclop en ten e (17). After a mixture of the silyl ether
16 (0.47 g, 1.73 mmol) and sodium hydride (0.104 g, 2.6 mmol)
in THF (25 mL) was stirred at 25 °C for 1 h, benzyl bromide
(0.59 g, 3.56 mmol), sodium iodide (0.51 g, 3.46 mmol), and
tetrabutylammonium acetate (0.156 g, 0.51 mmol) were sequen-
tially introduced. The resulting mixture was stirred at 25 °C
for 48 h, diluted with water, and extracted with CH2Cl2. The
CH2Cl2 extracts were concentrated in vacuo to afford a residue,
which was subjected to column chromatography (silica gel, 2:1
1
hexane-acetone) to give 17 (0.587 g, 95%) as a solid. H NMR:
δ 7.25-7.36 (m, 5H), 6.10 (d, J ) 6.7 Hz, 1H, NH), 5.95 (d, J )
6.1 Hz, 1H), 4.81, 4.63 (abq, J ) 11.9 Hz, 2H), 4.45 (brs, 1H),
4.34 (m, 1H), 1.98 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H). 13C NMR:
δ 169.5 (CO), 138.5, 136.0, 134.0, 128.2, 127.8, 127.4, 87.4, 74.6,
71.6, 55.9, 25.7, 23.4, 18.0, -5.0. HRMS (m/z): calcd for C20H32
NO3Si (M + 1), 362.3152; found, 362.3162.
-
(2S,3R,4S)-3-Aceta m id o-2-ter t-bu tyld im eth ylsilyloxy-4-
ben zyloxy-1,5-p en ta n ed iol (18). Ozone was passed through
a -78 °C solution of the cyclopentene 17 (0.236 g, 0.654 mmol)
in 15 mL of 2:1 CH2Cl2-MeOH. Solid sodium borohydride (0.248
g, 6.54 mmol) was then added, and the resulting solution was
diluted with CH2Cl2 and filtered. The filtrate was diluted with
water and extracted with CH2Cl2. The CH2Cl2 extracts were
concentrated in vacuo to give a residue that was subjected to
column chromatography (silica gel, 2:1 hexane-acetone) to afford
1
diol 18 (0.23 g, 87%) as a solid. H NMR: δ 7.25-7.38 (m, 5H),
6.12 (d, J ) 6.7 Hz, 1H, NH), 4.62, 4.54 (abq, J ) 11.4 Hz, 2H),
4.20 (m, 1H), 4.02 (m, 1H), 3.56-3.74 (m, 4H), 3.32 (dd, J )
11.7, 9.2 Hz, 1H), 1.98 (s, 3H), 0.86 (s, 9H), 0.05 (s, 6H). 13C
NMR: δ 171.8 (CO), 137.8, 128.5, 128.1, 128.1, 77.5, 72,8, 71.5,
64.4, 59.9, 50.2, 25.8, 23.0, 18.2, -5.5. HRMS (m/z): calcd for
C20H36NO5Si (M + 1), 398.2363; found, 398.2386.
(2S,3R,4S)-2-Ben zyloxy-3-a cet a m id o-4,5-O-isop r op yli-
d en e-1-p en ta n ol (20). A solution of diol 18 (0.058 g, 0.147
mmol) and TBAF (0.2 g, 0.35 mmol) in THF (10 mL) was stirred
at 25 °C for 2 h. Concentration in vacuo gave a residue, which
was eluted through Florisil with 1:1 hexane-acetone as the
eluant. The eluate was concentrated in vacuo giving a residue,
which was dissolved in acetone (4 mL) containing 2,2-dimethoxy-
propane (6 mL) and PTSA (0.012 g, 0.06 mmol). The mixture
was stirred at 25 °C for 1 h, diluted with water, and extracted
(3S,4S,5R)-4-Aceta m id o-3-ter t-bu tyld im eth ylsilyloxy-5-
ben zyloxycyclop en ten e (13). A solution of 12 (23 mg, 0.09
mmol), imidazole (18 mg, 0.25 mmol), and TBSCl (20 mg, 0.13
mmol) in CH2Cl2 (5 mL) was stirred for 12 h at 25 °C, diluted
with water, and extracted with CH2Cl2. The extracts were
concentrated in vacuo, and the residue was subjected to column
chromatography (silica gel, 2:1 hexane-acetone) affording 13
1
(33 mg, 99%) as a crystalline solid. Mp: 71-72 °C. H NMR: δ

3528 J . Org. Chem., Vol. 67, No. 10, 2002
Notes
with CH2Cl2. The CH2Cl2 extracts were dried and concentrated
in vacuo giving a residue, which was subjected to column
chromatography (silica gel, 2:1 hexane-acetone) to afford the
acetonide 20 (0.043 g, 92%). 1H NMR: δ 7.29-7.34 (m, 5H),
4.13-4.18 (m, 2H), 4.02 (m, 1H), 3.93 (m, 1H), 3.81 (m, 1H), 3.65
(m, 1H), 3.65 (m, 1H), 3.34 (m, 1H), 3.11 (m, 1H), 1.99 (s, 3H),
1.34 (s, 3H), 1.41 (s, 3H). 13C NMR: δ 171.5 (CO), 137.9, 128.4,
128.1, 128.0, 109.7, 77.4, 74.2, 73.5, 60.5, 67.6, 52.2, 26.8, 25.4,
23.0. HRMS m/z: calcd for C17H25O5N, 323.1733; found, 323.1712.
(2S,3R,4S)-2-Ben zyloxy-3-acetam ido-4,5-O-isopr opylidin e-
p en ta n a l (21). To a solution of oxalyl chloride (21 uL, 0.24
mmol) in CH2Cl2 (5 mL) at -78 °C was added DMSO (45 uL,
0.64 mmol) dropwise. The resulting solution was stirred at -78
°C for 1 h, and then a solution of alcohol 20 (52 mg, 0.16 mmol)
in CH2Cl2 (5 mL) was added dropwise. The reaction mixture was
stirred at -78 °C for 1.5 h; triethylamine (89uL, 0.64 mmol) was
added, and the mixture was stirred at 25 °C for 2 h, diluted with
water, and extracted with CH2Cl2. The CH2Cl2 extracts were
dried and concentrated in vacuo to yield the aldehyde 21 (0.051
g, 100%). The crude aldehyde was quickly eluted through a
Florisil column (1:1 hexane-acetone), and the eluate was
concentrated in vacuo to give the pure but unstable aldehyde
21. 1H NMR: δ 9.49 (d, J ) 4.3 Hz, 1H, CHO), 7.24-7.31 (m,
5H), 6.00 (d, J ) 9.6 Hz, 1H, NH), 4.72, 4.46 (abq, J ) 11.2 Hz,
2H), 4.43 (m, 2H), 4.28 (d, J ) 4.3 Hz, 1H), 4.09 (m, 1H), 3.95
(dd, J ) 6.1, 8.5 Hz, 1H, 3.83 (s, 1H), 1.85 (s, 3H), 1.29, 1.31 (s,
6H).
Tr im eth yl r-Meth oxyp h osp h on oa ceta te (24). A general
procedure reported by Regitz12 was used to prepare the diazo-
phosponate intermediate. To a solution of trimethyl phospho-
noacetate (10 g, 55 mmol) in THF (50 mL) was slowly added a
hexane solution of n-BuLi (41 mL, 70 mmol). The mixture was
stirred at 25 °C for 1.5 h, followed by addition of tosyl azide
(10.83 g, 55 mmol). The resulting mixture was stirred at 25 °C
for 4 h, diluted with water, and extracted with CH2Cl2. The CH2-
Cl2 extracts were dried and concentrated in vacuo to afford a
residue, which was subjected to column chromatography (silica
gel, 3:1 hexane-acetone) to yield the R-diazophosphonate (2.38
g, 21%). IR: 2960, 2127, 1713, 1438, 1288, 1025. 1H NMR: δ
3.84 (s, 3H, CO2CH3), 3.72 (s, 6H, 2OCH3).
835, 778, 735. MS m/z (rel intensity): 408 (M + 1, 11), 368 (16),
126 (24), 91 (100). HRMS m/z: calcd for C21H30NO7 (M + 1),
408.2022; found, 408.2001.
1
25b. H NMR: δ 7.24-7.35 (m, 5H), 5.86 (d, J ) 8.9 Hz, 1H,
NH), 5.20-4.99 (abq, J ) 9.0 Hz, 2H), 4.53-4.43 (abq, J ) 11.5
Hz, 2H), 4.13 (m, 2H), 3.80 (m, 2H), 3.76 (s, 3H), 3.56 (s, 3H),
1.99 (s, 3H), 1.41, 1.33 (s, 6H). 13C NMR: δ 171.7.0, 163.2, 148.0,
138.1, 128.4, 128.0, 127.8, 109.5, 75.5, 72.8, 71.2, 67.2, 55.9, 55.6,
52.3, 26.8, 25.6, 23.4. IR: 3340, 2987, 1731, 1651, 1371, 1233,
1158, 1067, 842. MS m/z (rel intensity): 408 (M + 1, 14), 300
(42), 242 (30), 91 (100). HRMS m/z: calcd for C21H30NO7,
408.2022; found, 408.2031.
Met h yl (4S,5R,6S)-4-Ben zyloxy-5-a cet a m id o-6,7-d ih y-
d r oxyh ep ten oa tes (26a a n d 26b). A solution of 25a (148 mg,
0.36 mmol) in 15 mL of 1:4 TFA-MeOH was stirred at 25 °C
for 3 h, washed with aqueous NaHCO3, and extracted with CH2-
Cl2. The CH2Cl2 extracts were concentrated in vacuo to yield a
residue that was subjected to column chromatography (silica gel,
1
1:1 hexane-acetone) to afford diol 26a (93 mg, 82%). H NMR:
δ 7.24-7.36 (m, 5H), 6.18 (d, J ) 8.7 Hz, 1H, NH), 6.12 (d, J )
9.1 Hz, 1H, vinyl H), 5.02 (dd, J ) 9.1, 1.0 Hz, 1H), 4.55, 4.42
(abq, J ) 11.2 Hz, 2H), 3.80, 3.69 (s, 6H), 3.56 (m, 4H), 2.04 (s,
3H). 13C NMR: δ 172.0, 163.2, 148.3, 137.4, 128.4, 128.1, 128.0,
123.3, 71.7, 70.4, 70.3, 62.2, 60.2, 55.0, 52.2, 23.1. IR: 3369, 2952,
1728, 1651, 1436, 1309, 1245, 1072, 784, 740, 700. MS m/z (rel
intensity): 368 (M + 1, 55), 260 (74), 91 (100). HRMS m/z: calcd
for C18H26NO7, 368.1709; found, 368.1735.
A solution of 25b (93 mg, 0.23 mmol) in 15 mL of 1:4 TFA-
MeOH was stirred at 25 °C for 3 h, washed with aqueous
NaHCO3, and extracted with CH2Cl2. The CH2Cl2 extracts were
concentrated in vacuo to yield a residue that was subjected to
column chromatography (silica gel, 1:1 hexane-acetone) to afford
1
diol 26b (60 mg, 83%). H NMR: δ 7.24-7.34 (m, 5H), 6.26 (d,
J ) 8.8 Hz, 1H, NH), 5.35 (d, J ) 8.6 Hz, 1H), 5.06 (d, J ) 8.6
Hz, 1H), 4.55, 4.46 (abq, J ) 11.3 Hz, 2H), 3.77, 3.59 (s, 3H),
3.52-3.61 (m, 4H), 2.02 (s, 3H). 13C NMR: δ 171.7, 163.2, 147.9,
137.6, 128.4, 128.1, 128.0, 110.3, 72.3, 71.6, 71.1, 62.7, 55.6, 55.6,
52.4, 23.0. IR: 3369, 2952, 1728, 1651, 1436, 1309, 1245, 1072,
784, 740, 700. MS m/z (rel intensity): 368 (M + 1, 55), 260 (74),
91 (100). HRMS m/z: calcd for C18H26NO7 (M + 1), 368.1709;
found, 368.1735.
A general procedure reported by Reimlinger13 was used to
transform the diazophosphonate to 24. A solution of the diazo-
phosphonate (2.24 g, 10.67 mmol) and rhodium acetate dimer
(94 mg, 0.21 mmol) in methanol (50 mL) was stirred at reflux
for 6 h, diluted with water, and extracted with CH2Cl2. The CH2-
Cl2 extracts were washed with brine and concentrated in vacuo
to afford a residue that was subjected to column chromatography
(silica gel, 1:1 hexane-acetone) to yield the trimethyl R-meth-
oxyphosphonoacetate (24) (1.58 g, 70%). 1H NMR: δ 4.22 (d,
J ) 18.6 Hz, 1H), 3.83 (d, J ) 3.3 Hz, 3H), 3.80 (m, 6H), 3.48 (s,
3H). 13C NMR: δ 167.0 (CO2Me), 78.6, 76.1, 60.1, 59.9, 53.6,
52.3. IR: 3487, 2960, 2853, 1734, 1440, 1260, 1121, 1025.
Met h yl (4S,5R,6S)-4-Ben zyloxy-5-a cet a m id o-6,7-O-iso-
p r op ylid en e-h ep ten oa te (25a a n d 25b). A solution of the
phosphonate 24 (45.5 mg, 0.215 mmol) and sodium hydride (14
mg, 0.36 mmol) in dry THF (10 mL) was stirred at 25 °C for 2
h. To this solution at 0 °C was dropwise added freshly prepared
aldehyde 21 (46 mg, 0.14 mmol) in THF (5 mL). The mixture
was stirred at 0 °C for 1 h and then at 25 °C for 4 h before being
diluted with water. Extraction with CH2Cl2 gave CH2Cl2 extracts
that were concentrated in vacuo to afford a residue, which was
subjected to column chromatography (silica gel, 1:2 ethyl
acetate-hexane) to provide the 25a (18 mg, 30%) and 25b (34
mg, 59%).
Meth yl (2S,3R,4S)-2-Hyd r oxym eth yl-3-a ceta m id o-4-ben -
zyloxy-1,2-d ih yd r op yr a n osyl-6-ca r boxyla te (23). A solution
of diol 26b (0.134 g, 0.367 mmol) and Hg(O2CCF3)2 (0.313 g,
0.734 mmol) in THF (20 mL) was stirred at 0 °C for 2 h.
Saturated aqueous KCl (2 mL) was added. After stirring at 0-25
°C for 12 h, the mixture was diluted with water and extracted
with CH2Cl2. The CH2Cl2 extracts were dried and concentrated
in vacuo to yield a residue. To a solution of the residue in toluene
(15 mL) was added Ph3SnH (0.322 g, 0.917 mmol) and NaOAc
(10 mg). The resulting mixture was stirred at 25 °C for 12 h,
diluted with water, and extracted with CH2Cl2. The CH2Cl2
extracts were dried and concentrated in vacuo to yield an oil,
which was subjected to column chromatography (silica gel, 1:1
hexane-acetone) to furnish dihydropyran 23 (0.121 g, 99%) as
1
a crystalline material. Mp: 100-102 °C. H NMR: δ 7.23-7.32
(m, 5H), 6.1 (d, J ) 3.33 Hz, 1H), 5.64 (d, J ) 7.4 Hz, 1H, NH),
4.58 (abq, J ) 11.8 Hz, 2H), 4.26 (m, 1H), 4.09 (d, J ) 3.6 Hz,
2H), 3.78 (s, 3H), 3.77 (m, 2H), 3.36 (s, 1H, OH), 1.95 (s, 3H).
13C NMR: δ 171.0, 162.4, 144.4, 137.4, 128.5, 128.1, 127.9, 108.0,
78.7, 71.0, 70.3, 60.5, 52.5, 47.2, 23.1. HRMS m/z: calcd for
C17H21NO6 (M + 1), 336.1447; found, 336.1459.
Ack n ow led gm en t . This investigation was sup-
ported by grants from the National Institutes of Health
(GM-27251) and the Petroleum Research Fund of the
ACS (35546-AC1). The expert mass spectrometric analy-
ses performed by Noel Whittaker (National Institutes
of Health Mass Spectrometry Facility, Bethesda, MD)
are gratefully acknowledged.
1
25a . H NMR: δ 7.24-7.35 (m, 5H), 6.07 (d, J ) 9.0 Hz, 1H,
vinyl H), 5.86 (d, J ) 9.0 Hz, 1H, NH), 4.85 (dd, J ) 9.0, 1.1 Hz,
1H), 4.52, 4.40 (abq, J ) 11.2 Hz, 2H), 4.10 (m, 2H), 3.92 (m,
2H), 3.77 (s, 3H), 3.69 (s, 3H), 1.98 (s, 3H), 1.40 (s, 3H), 1.33 (s,
3H). 13C NMR: δ 170.0, 163.3, 147.9, 137.8, 128.3, 128.0, 127.8,
109.4, 103.8, 75.2, 71.5, 71.3, 67.2, 60.2, 55.0, 52.1, 26.8, 25.6,
23.3. IR: 3348, 2953, 2858, 1651, 1535, 1469, 1374, 1254, 1112,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all previously unreported compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Regitz, M.; Anschutz, W.; Liedhegener, A. Chem. Ber. 1968, 101,
3734.
(13) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J .; Teyssie,
P. Tetrahedron Lett. 1973, 24, 2233.
J O020038P