Synthesis of L, 2,3,4,6-Penta-0-acetyl-5-deoxy-5-C - ( (iZS) - Ethylphosphinyl) - A-Structural Analysis Proton Nuclear Magnetic
Synthesis of L, 2,3,4,6-Penta-0-acetyl-5-deoxy-5-C - ( (iZS) - Ethylphosphinyl) - A-Structural Analysis Proton Nuclear Magnetic
Synthesis of L, 2,3,4,6-Penta-0-acetyl-5-deoxy-5-C - ( (iZS) - Ethylphosphinyl) - A-Structural Analysis Proton Nuclear Magnetic
Synthesis of l,2,3,4,6-Penta-0-acetyl-5-deoxy-5-C-[(iZS)-ethylphosphinyl]-a-
and -ß-D-glucopyranoses and Their Structural Analysis by 400-MHz Proton
Nuclear Magnetic Resonance
Debenzylation of (5RS')-3,6-di-0-benzyI-5-deoxy-5-C-[ethylmethoxyphosphinyl]-l,2-0-isopropylidene-a-D-
ryZo-hexofuranose (13) over 10% Pd/C afforded the tricyclic compound 14, which, on treatment with chloro-
triphenylmethane in pyridine, provided a 1:1 mixture of (5fi)-5-deoxy-5-C-[(fi)-0-cycZo-ethylphosphinyl]-l,2-
0-isópropylidene-6-0-(triphenylmethyl)-a-D-xyZo-hexofuranose (15a) and its (5S)-5-C-[(S)-ethylphosphinyl]
diastereomer (15b). Treatment of 15a,b with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Downloaded via NICOLAUS COPERNICUS UNIV TORUN on June 17, 2023 at 08:22:16 (UTC).
action of mineral acid and acetic anhydride, yielded the title compounds (18a-d), the structures of which were
established on the basis of mass and 400-MHz NMR spectra. A possible reaction pathway for the exclusive
formation of these unsubstituted 5-deoxy-5-C-phosphmyl-D-glucopyranoses is discussed.
5-Amino-5-deoxy-D-glucose (1), a naturally occurring been shown to be a potent, competitive inhibitor of cellular
antibiotic (nojirimycin), is well-known to show various D-glucose transport3 and also selectively toxic to hypoxic
antibacterial activities.2 5-Deoxy-5-thio-o-glucose (2) has radioresistant tumor cells.4 5***Both compounds have already
been synthesized.2,3 Thus, sugar analogues, having a
phosphorus atom in the hemiacetal ring, are interesting
not only from the viewpoint of their physicochemical
properties but also from that of the potential utility of their
biological activities. As part of our effort to prepare such
hexopyranoses, along with pentofuranoses5,6 (e.g., 3), we
reported tetra-O-acetyl derivatives of 5,6-dideoxy-5-C-
X 3
[(&S)-phenylphosphinyl]-a,/?-L-idopyranoses (57,8 and 69
=
2 S
**""12)
Scheme I. Preparation of
5-Deoxy-5-C-(ethylphosphinyl)-D-glucopyranoses
9 X = 0 11 R1=Ph, r2=h 14 R -
H
10 X =
NNHTs 12 R1=Et, R2=NHNHTs 15 R = CPh
13 R1=Et, R2=H
AcO
R1
17 R =
H 18a R2=H, R2=0Ac 18c r2=h. R2=0Ac
18 R =
Ac 18b RI=0Ac, R2=H 18d R1=OAc , r2=h
Moreover, an inspection of the CPK models for 15 shows Chart I. Newman Projection Along the C(5)-P(5) Bond
the presence of considerable steric congestion between the and the </4 and J¡P Values
s
J.
Org.
Table I. NMR (400 MHz) Parameters for 5-Deoxy-5-C-(ethylphosphinyl)-D-xyZo-hexofuranoses and -D-glucopyranoses in CD Cl / Chem.,
chemical shift
Vol.
compd AcO-l/ H-l AcO-2,b H-2 AcO-3,b H-3 AcO-4,b H-4 H-5 AcO-6/ Ha-6 Hb-6 P-CH2-C P-C-CH3
48,
15a 1.31/ 1.48/ 4.55 (ddd, 4.73 (d) 2.36 (dd, 7.18-7.52d (m), 3.52 (ddd, 1.81 (dq, 1.19 (dt,
5.80 (d, 4.68 (dd, 43,p 22.9, =7&,P 6-5, 3.94 (dd, «7eb,P 15.0) 2«7H, P 15-0) 3=7h,p 19.2, No.
" ,
_
15b 1.33/ 1.48/ 4.29 (ddd, 4.80 (dd, 1.95 (dt, 7.18-7.52“ (m), 3.45 (ddd, 2.02 (dq, 1.26 (dt,
6.05 (d, 4.73 (dd, 43,P 21.0, «74,s 7.2) =7a,P 11-0, 3.61 (dt, =7eb,P 18.0) 2«7H P 15.0) 3«7H,p 17-9,
1983
JK2 3.2) 42,, 0.5) 43,4 3.0) «75,6a 7.0) «7ea,6b 10.0, 3«7H,h 7.6)
«7ea,P 7.0)
8e 1.88/ 1.87/ 4.70/ 1.86/ 2.65 (dddddd, 4.198 (d), 4.218 (d), 7.27h (m) 7.75' (m, ortho),
5.57 (ddd, 5.83 (ddd, 7.32b (m), 5.70 (ddd, «7s,6a 7.0, 3.89 (ddd, 3.79 (ddd, 7.47' (m, meta),
4,,2 H.2, 42,3 9-5, 3.88 (dd, «74,5 11-5, «7s,6b 6 0, «7ea,P 10.0, Jeb,p 14.5) 7.56' (m, para)
p 2.8, 42,p 3.0) 42,22 9.8) 44,p 2.8) «7s,P 4.0) «7ea,6b 9.8)
j,;5 o.3)
18a 2.16/ 2.07/ 2.01/ 2.06/ 2.37 (ddddd, 1.99/ 4.45 (ddd, 2.04 (dq, 1.19 (dt,
5.38 (ddd, 5.72 (ddd, 5.22 (t, 5.58 (ddd, «75,6a 7.4, 4.49 (td, «7eb,P 15.0) 2«7h,P 15) 3«7h,p 19.3,
4l2 11.0, 4 2,2 10.0, J2,, 10.0) H.5,
42,,s «7s,6b 5.0, «76a,p 11.5, 3«7h,h 7.6)
=7i,p 3.6, 4· ,p 3.0) ^4, 2.7) =75,p 3.5) «76a,6b 115)
«7,,5 0.2)
18b 2.21/ 2.09/ 2.03/ 2.07/ 2.50 (dddd, 1.98/ 4.41 (ddd, 1-72 (dq, 1.21 (dt,
5.84 (dd, 5.55 (ddd, 5.45 (dd, 5.58 (ddd, «7s,6a 8.3, 4.45 (ddd, «7eb,P 18.5) 2«7H,p 15) 3< p 18.3,
J1 P H.7, 4lt, 12.5, 42,a H.8) J4,s 14.5, «7s,6b 6-3, "7ea,P 16.2, 3«7h,h 7.5)
J,,’2 3.2) 42 p 0.3) <^4 p 3.0) «7s,p 4.5) «76a,6b 14.5)
18c 2.14/ 2.07/ 2.05/ 2.00/ 5.23·' 2.58' 2.00/ 4.29 (ddd, 2.1' 1.40 (dt,
5.70 (dd, 5.25 (t, 5.65 (t, 4.75 (ddd, «76b, P 9) 3«7h,p 18,
Ji,p 11, «72,3 11) «73,4 11) «7ea,P 23, 3«7h,h 7.5)
4t,2 10.5) «7ea,6b 12)
18d 2.09/ 2.07/ 2.06/ 2.08/ 2.53 (dddd, 2.04/ 4.29 (ddd, 1.84 (dq, 1.37 (dt,
5.53 (dd, 5.19 (ddd, 5.23 (dd, 4.87 (ddd, 4$,p 18.0, 4.68 (ddd, =7eb,P 3.7) 2«7h,p 15.2) 3«7h,p 17.6,
41P 11.0, 42,, 9.2, 42,2, 10.0) «74,s 12.0, •75,6a 3.8, «7ea,P 23.1, 3«7H,H 7.6)
JU1 2.0) 42,p 0.5) J4 P 4.0) «7s,6b 2.0) «7ea,6b 11-8)
0
Abbreviations: d, doublet; t, triplet; q, quartet. Coupling constants (J, Hz) were confirmed by double resonance. Chemical shifts (S values) are in parts per million from
6 d
Me4Si. Acetoxyl (assignments may have to be interchanged).
c
Methyl group of 1,2-O-isopropylidene. (C6Hs)3C-0(6).
e
Reference 11. ' C6H5CH20(3). 8 C6H5CH20(6);
J 11.8 Hz. h C6HsCH20(3,6). ' P-C6H5. 1 The splitting patterns of the signals closely resemble those of 18d, although exact coupling constants remain undetermined.
=
Yamamoto
et
al.
Synthesis of 5-Deoxy-5-C-phosphinyl-D-glucoses J. Org. Chem., Vol. 48, No. 4, 1983 439
Scheme II. Possible Pathway for the Formation of 5-Deoxy-5-C-phosphinyl-d -glucopyranoses 18a-d from Precursors 15a,b
(as were observed in the cases of 6c,d and 18d). A similar amount of the corresponding L-iodopyranoses could have
dependence of =/1 and «/li2 upon the 0=P—C(l)—H and actually been produced.
H—C(l)—C(2)—H dihedral angles can be applied to the Although more precise mechanistic study with regard
assignment of the C-l configurations of hexopyranoses to this intricate ring transposition, as well as the im-
18a-d in a similar manner as those of 611 and 8.15 provement of the yield, remains to be done, the present
As were observed in the formation of 18a-d, the phos- work clearly demonstrates a novel way for preparation of
phinyl sugars of only gluco type were isolated when the the unsubstituted 5-deoxy-5-C-phosphinyl-D-gluco-
1:1 mixture of the precursors 15a and 15b was reduced pyranoses from D-xyio-hexofuranoses and further estab-
with SDMA, followed by the action of mineral acid to lishes the effective use of NMR for determining the
effect the ring transpostion of the xy/o-hexofuranoses 16 configuration and conformation of sugars containing
to the phosphinylglucopyranoses 17. No peracetyl deriv- phosphorus in the ring.
atives of 5-deoxy-5-C-[(.fiS)-ethylphosphinyl]-L-ido-
pyranose (20) appeared to be present among the reaction Experimental Section
products. Such a predominant formation of the gluco-type Melting points were measured with a Yanagimoto MP-S3 in-
P sugars is in striking contrast to the result of the previous, strument and are uncorrected. NMR spectra were recorded
similar ring transformation of 4 to the L-idopyranoses 6 with a Hitachi Perkin-Elmer R-20A (60 MHz) or a Bruker WH-400
solely.11,12 cryospectrometer (400 MHz, for 15a,b and 18a-d) at 27 °C.
A possible explanation for these results is that the Chemical shifts are reported as values in parts per million relative
ring-closure of the open-chain phosphinyl intermediate 19a to tetramethylsilane ( 0.0) as an internal standard. Spin de-
is much faster than that of the counterpart 19b, because coupling was performed for each proton signal to confirm the
both precursors 16a and 16b are expected to be almost coupling constants. Mass spectra were measured with an AEI
MS 50 ultrahigh-resolution instrument (for the accurate mass
equally derived from 15a and 15b by reduction with measurement) and an AEI MS 12 apparatus (for chemical ion-
SDMA as illustrated in Scheme II. The combined yields ization with NH3) and are given in terms of m/z (relative intensity)
of the four diastereomers 18a-d were approximately 30%,
compared with the base peak and possible assignments. Optical
and a large amount of polar substances remained uneluted rotation was determined with a Nihonbunko DIP-4 polarimeter.
by the initial chromatographic purification. Thus, instead Microanalyses were performed in Sankyo Research Laboratories,
of the sluggish intramolecular cyclization to give L-ido- Sankyo Co. Ltd. Column chromatography was performed with
pyranoses 20, most of the epimer 19b presumably yielded Wako C-200 silica gel. TLC was carried out on silica gel 60F
intermolecularly condensed, polar products to a consid- precoated plates (0.25 mm, Merck).
erable extent. (5JZS)-3,6-Di-0-benzyl-5-deoxy-l,2-0-isopropylidene-5-
In contrast, the exclusive formation of the L-ido- C-(ethyImethoxyphosphinyl)-5-C-[(p-tolyIsuIfonyI)-
hydrazinol-a-D-xyfo-hexofuranose (12). Methyl ethyl-
pyranoses 5 and 6 from the precursors 4 may be ration-
phosphinate19 (7.0 g, 64.8 mmol) was added to a solution of 3,6-
alized in terms of the thermodynamically controlled pro-
di-0-benzyl-l,2-0-isopropylidene-a-D-xylo-hexofuranos-5-ulose
duction of a 5S epimer of 4 (corresponding to formula 16b) (E,Z)-5-(p-tolylsulfonyl)hydrazone15 (10; 6.16 g, 10.9 mmol) in dry
after an equilibration by the strongly basic SDMA during benzene (2 mL). The mixture was stirred under argon at 20 °C
the reduction, since there exists apparently less steric for 35 h and then diluted with CH2C12 (40 mL) and saturated
congestion between the bulky P-phenyl and the 3-hydroxyl aqueous NaHC03 (50 mL). After separation, the organic layer
group in 4. This 5S epimer in turn readily affords 5 and was washed with water, dried (Na2S04), and evaporated in vacuo.
6 despite the presence of a slightly less favorable steric The residue was chromatographed on a silica gel column with ethyl
acetate-benzene (1:1) as the eluant. The hexofuranose 12, which
requirement for the intermediate similar to 19b in Scheme was a mixture of four diastereomers with respect to C-5 and
II.
The formation of the glucopyranoses 7 and 8, both of phosphorus, was obtained as a colorless syrup: 6.41 g (88%);
NMR (CDC13) 0.72-2.20 (10 H, m, CMe2, P-CCH3, NH), 2.36
which were isolated only in a few percent yield, is pre-
sumably due to the facile crystallization of these com-
pounds from the crude reaction mixture.7,8,15 As the rest (19) Petrov, K. A.; Bliznyuk, N. K.; Studnev, Yu. N.; Kolomiets, A. F.
of the products were not examined in detail, an appreciable Zh. Obshch. Khim. 1961, 31, 179.
440 J. Org. Chem., Vol. 48, No. 4, 1983 Yamamoto et al.
(3 H, s, S-C6-CH3), 3.84-4.70 (12 H, m, H-2,3,4,6,6', OCH2Ph-3,6, To a solution of the above product 16 in ethanol (2 mL) was
POMe), 5.80-6.0 (1 H, m, H-l), 6.35-6.60 (1 H, m, NH), 7.09-7.58 added oxygen-free 0.5 M HC1 (20 mL), and the mixture was
(14 H, m, 0-C-C6H5-3,6, S-C6H4-C). Anal. Caled for refluxed under argon for 5 h. The mixture was cooled, the acid
C33H43N209SP: C, 58.74; H, 6.42; N, 4.15. Found: C, 58.66; H, neutralized by passing the mixture through a column of Amberlite
6.47; N, 3.96. IRA-45 anion-exchange resin (weakly basic), the eluant was fil-
(5 RS )-3,6-Di-0 -benzyl-5-deoxy-1,2- 0 -isopropylidene-5- tered, and the filtrate was evaporated in vacuo to give (SRS )-
C-(ethylmethoxyphosphinyl)-a-D-xy/o-hexofuranose (13). 5-deoxy-5-C-[(RS)-ethyIphosphinyl]-a,d-D-gluco- and/or -
Sodium borohydride (5.2 g, 13.7 mmol) was added to a solution L-idopyranoses (17) as a colorless syrup.
of 12 (4.2 g, 6.23 mmol) in dry THF (120 mL). The mixture was To a solution of 17 in dry pyridine (3.5 mL) was added acetic
stirred at 20 °C for 23 h and then brought to pH 4 with 1.7 M anhydride (2.2 mL) at 0 °C, and the mixture was stirred at 20
acetic acid at 0 °C. After solvent evaporation in vacuo, the residue °C for 22 h. A small amount of water was added, and most of
was diluted with CH2C12, washed with saturated aqueous NaHC03 the pyridine was evaporated in vacuo. The residue was diluted
and then with water, dried over anhydrous Na2S04, and evapo- with CH2C12 and successively washed with 0.3 M HC1, saturated
rated in vacuo. The residue was chromatographed on a silica gel aqueous NaHC03, and water. The organic layer was dried
column with ethyl acetate-benzene (1:1) as the eluant, thus giving (Na2S04) and evaporated in vacuo. The residue was chromato-
13 as a mixture of diastereomers: 2.02 g (66%, a colorless syrup); graphed on a silica gel column with MeOH-CH2Cl2 (1:99) as the
NMR 0.72-1.80 (9 H, m, CMe2, P-CCH3), 2.35 (1 H, m, H-5), eluant. The fraction having Rf 0.5-0.3 (in 1:19 MeOH-CH2Cl2)
3.40-3.75 (12 H, m, H-2,3,4,6,6', OCH2Ph-3,6, POMe), 5.85, 5.93 was collected and concentrated in vacuo, giving the peracetates
(1 H, 2 d, Jli2 = 4 Hz), 7.33, 7.36 (10 H, 2 s, 0-C-C6H5-3,6). 18 as a diastereomeric mixture: colorless oil; 85.6 mg (30% overall
(5R)-5-Deoxy-5-C-[(R)-0-cycfo-ethylphosphinyl]-l^-O- yield from 15a,b).
isopropylidene-6-0-(triphenylmethyl)-a-D-xy7o-hexo- The product was diluted with ethyl acetate (3 mL) and allowed
furanose (15a) and Its (5S)-5-C-[(S )-ethylphosphinyl] to stand at 5 °C overnight, thus depositing 18a (11 mg, 4% yield
Diastereomer 15b. To a solution of 13 (1.70 g, 3.47 mmol) in from 15) as colorless needles (from ethanol-ethyl acetate): mp
absolute ethanol (8 mL) was added 10% Pd/C (1.0 g). The 233 °C dec; R, 0.47 (MeOH-CHCl3,1:19); [a]28D +3.64= (c 0.66,
mixture was hydrogenated at 40 °C until the absorbtion of hy- CHC13); NMR (400 MHz, CDC13), see Table I; El MS, m/z
drogen ceased. After filtration of the catalyst, the filtrate was (relative intensity) 451 (2.7, + 1), 408 (1.1, M CH2CO), 349 -
evaporated to dryness. The residue, which was found (by TLC) (66, M AcO CH2CO), 307 (100; M AcO 2CH2CO), 306 (72),
- - - -
still to contain the starting material 13, was repeatedly hydro- 289 (33, M 2AcO Ac), 265 (20, M AcO 3CH2CO), 247 (93.6,
- - - -
genated until 13 disappeared, thus giving (51ZS)-5-deoxy-5- M 2AcO Ac CH2CO), 246 (20), 205 (73, M 2AcO Ac
- - - - - -
C -[(RS )-3-O -cyclo -ethylphosphinyl]-l,2-0 -iso- 2CH2CO), 204 (23), 203 (17, 2AcO 3Ac), 187 (70, M 3AcO - - -
propylidene-a-D-xylo-hexofuranose (14) as a colorless syrup 2Ac), 186 (67); exact mass caled for C18H28OnP [( + 1)+]
(0.99 g). This was directly used in the next step without puri- 451.1369, found 451.1362.
fication. The above filtrate was then separated by chromatography on
A mixture of the above crude product 14 (0.99 g) and tri- a silica gel column (Merck Lobar prepacked, Size A) with
phenylmethyl chloride (2.00 g, 7.17 mmol) in dry pyridine (12 mL) MeOH-CH2Cl2 (1:99) as the eluant into three fractions, A-C.
was heated at 35-40 °C for 84 h. After addition of a small amount Fraction A (R, 0.45) gave 18b as a colorless oil: 18.5 mg (7%
of water, the solvent was evaporated at 15 °C in vacuo (pump). from 15); NMR (400 MHz, CDC13), see Table I; El MS, m/z
The residue was diluted with CH2C12, washed with saturated (relative intensity) 451 (5.6, + 1), 408 (4.7, M CH20), 391 -
aqueous NaHCOa and then with water, dried (Na2S04), and (10, M AcO), 349 (77, M AcO CH2CO), 307 (99), 306 (100,
- - -
evaporated in vacuo. Chromatography of the residue on a silica M AcO Ac CH2CO), 289 (44, M 2AcO CH2CO), 247 (75,
- - - - -
gel column with ethyl acetate-benzene (1:1) as the eluant gave M 2AcO Ac CH2CO), 205 (42, M 2AcO Ac 2CH2CO),
- - - - - -
a mixture of 15a and 15b (1:1) as a colorless syrup: 0.53 g (17% 187 (41, M 3AcO 2Ac), 186 (51); exact mass caled for C^H^OuP
- -
yield from 13); NMR (400 MHz, CDC13), see Table I; Cl (NH3) [(M+l)+] 451.1369, found 451.1376.
MS, m/z (relative intensity) 521 (0.4, + 1), 520 (0.2, M), 519 Fraction B (Rf 0.40) gave a colorless oil (5 mg, 2% from 15)
(0.7, M 1), 279 (41, M CPh3 + 2), 243 (100, CPh3); El MS,
- -
which was mostly 18c but contained a small amount of 18d and
m/z (relative intensity) 505 (0.34, M CH3), 277 (12.5, M CPh3),
- -
some impurities; NMR (CDC13), see Table I.
244 (23, Ph3CH), 243 (100, Ph3C); exact mass caled for C^^OgP Fraction C (Rf 0.37) gave a colorless oil (5 mg, 2% from 15)
[(M CH3)+] 505.1780, found 505.1751, caled for CuH1806P [(M
-
which consisted mainly of 18d; NMR (400 MHz, CDC13), see
CPh3)+] 277.0841, found 277.0835. Table I.
-