Sugar Analogs Having Phosphorus in the Hemiacetal Ring

ADVANCES I N CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL.

42

SUGAR ANALOGS HAVING PHOSPHORUS IN THE HEMIACETAL RING BYHIROSHI YAMAMOTOAND SABURO INOKAWA Department of Chemistry, Faculty of Science, Okayama Uniuersity, Okayama 700,Japan

I. Introduction

.....................................................

11. Monosaccharides Having a Phosphinediyl or Phosphonyl Group in the

PyranoseRing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 5-Deoxy-5-phosphino- and -5-phosphinyl-~-xylopyranoses. ............. 2. 5-Deoxy-5-phosphinyl-~-ribopyranose. ............................. 3. 5-Deoxy-5-phosphino- and -5-phosphinyl-~-idopyranoses. .............. 4. 5-Deoxy-5-phosphinyl-~-glucopyranoses. ........................... 5. Structural Analysis of 5-Deoxy-5-phosphino- and -5-phosphinylaldopyranoses by X-Ray Crystallography, and by 400-MHz, Proton Nuclear Magnetic Resonance Spectroscopy and High-resolution Mass Spectrometry ................................................ III. Monosaccharides Having a Phosphonyl Group in the Furanose Ring . . . . . . . . 1. 2,3,4-Trideoxy-4-phosphinylpentofuranoses ......................... 2. 4,5-Dideoxy-4-phosphinylpentofuranoses........................... 3. 4-Deoxy-4-phosphinylaldopentofuranoses . .......................... 4. Structural Analysis of 4-Deoxy-4-phosphinylpentofuranoses by X-Ray Crystallography, and by 400-MHz, Proton Nuclear Magnetic Resonance Spectroscopy and High-resolution Mass Spectrometry . . . . . . . . . . . . . . . IV. Biological Activities of Monosaccharides Having Phosphorus in the Hemiacetal Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Conclusion ...................................................... VI. Table of Some Properties of Sugar Analogs Having Phosphorus in the Hemiacetal Ring ................................................

135 138 138 145 145

155

161 176 176 179 181 183 188 189

190

I. INTRODUCTION There exist many naturally occurring sugars in which a hydroxyl group of a monosaccharide is replaced by an amino or a thiol group. These compounds, commonly called amino or thio sugars, play a wide variety of important biological roles. Representative examples of these classes are 2-acetamido-2-deoxy-c~-~-glucose (1) and 7-(5-S-methyl-5-thio-P-~-ribosy1)adenine (vitamin L, ,2). The former is the product ofhydrolysis of 135

136

HIROSHI YAMAMOTO AND SABURO INOKAWA

chitin, and occurs in various mammalian polysaccharides and in certain proteins,' whereas the latter is known to be a factor necessary for lactation.2 No analogous sugars having phosphorus attached to a ring-carbon atom appear to occur in Nature, although numerous sugar phosphates, and some compounds containing a C-P bond, are known (see Section IV).

1

2

Monosaccharides are well known to exist preponderantly in cyclic, hemiacetal forms in solution, and it is generally supposed that, as illustrated in Scheme 1 for aldoses, the equilibrium between the various species depends upon: (I) the reactivities of the -XH, -YH, and -ZH groups towards the carbonyl group (the general order of nucleophilicity is -SH > -PH, > -NH2 > -OH > -NHCOR), and (2) the stability of the hemiacetal rings formed (pyranoid form > furanoid form >> septanoid form). However, the stability of the ring is greatly affected by steric and electronic factors arising both from the nature of the substituents and the configurations of the ring-carbon atoms to which they are attached. Accordingly, if such substituents as amino, thiol, or phosphino are introduced, in the appropriate position, onto a ring-carbon atom of a monosaccharide, corresponding ring closure is expected to take place, to afford sugar analogs having nitrogen, sulfur, or phosphorus in the hemiacetal ring. Indeed, extensive studies on the preparation of such sugar analogs having nitrogen or sulfur in the ring have been carried out by using this method. These analogs are interesting not only from the viewpoint of their physicochemical properties but also from that of their biological activities. For example, 5-amino-5-deoxy-~-ghcose(3, the antibiotic nojirimycin3a4)exhibits antibacterial activity. Also, 5-thio-~glucose (4) has been shown to be a potent, competitive inhibitor of (1) See, for example, M. J. R. Salton, Annu. Reu. Biochem., 35 (1966) 485-520. (2) W. Nakahara, F. Inukai, and S. Ugami, Sci, Pap. Inst. Phys. Chem. Res. (Jpn.), 40 (1943) 433-437; Chem. Abstr., 41 (1947) 6317. (3) S. Inouye,T. Tsuruoka, andT. Niida,J. Antibiot., Ser.A, 19 (1966) 288-292; Chem. Abstr., 66 (1967) 85,989. (4) S . Inouye, T. Tsuruoka, T. Ito, and T. Niida, Tetrahedron, 24 (1968) 2125-2144.

SUGAR ANALOGS HAVING RING PHOSPHORUS

137

CH,ZH

Furanoid form

CH,ZH

Pyranoid form

Acyclic form

It

HX Septanoid form Scheme 1

3 x=NH 4

x=s

cellular ~-glucose-transport,~~~ and it is also selectively toxic to hypoxic, radio-resistant, tumor Although the chemistry of these sugar analogs having nitrogen or sulfur in the hemiacetal ring has been well d o ~ u m e n t e d , ’ ~there - ’ ~ are no reviews available on the chemistry and biochemistry of sugar analogs (5) R. L. Whistler and W. C. Lake, Biochem.J.,130 (1970) 919-925. (6) M. Chen and R.L.Whistler, Arch. Biochem. Biophys., 169 (1975) 392-396, and references cited therein. (7) J. H. Kim, S . H. Kim, andE. W. Hahn, Science, 200 (1978) 206-207. (8) C. W. Song, D. P. Guertin, and S. H.Levitt, 1nt.J.Radiat. Oncol.,Biol. Phys., 5 (1979) 965-970; Chem. Abstr., 92 (1980) 16,911. (9) R. Sridhar, E. C. Stroude, and W. R. Inch, In Vitro, 15 (1979) 685-690; Chem. Abstr., 92 (1980) 34,110. (10) H. Paulsen and K. Todt, Ado. Carbohydr. Chem., 23 (1968) 115-232. (11) H. Paulsen, Angew. Chem., Int. Ed. EngE., 5 (1966) 495-516. (12) D. Horton and D. H. Hutson, Ado. Carbohydr. Chetn., 18 (1963) 123-199. (13) S.Inokawa, Kagaku (Kyoto), 24 (1969) 901-913; Chem. Abstr., 72 (1970) 90,757.

138

HIROSHI YAMAMOTO AND SABURO INOKAWA

having phosphorus in the ring. Therefore, the purpose of the present article is to draw attention to this relatively less-explored field of the chemistry of such “P sugars.” The article is divided into Sections, based on the ring size; first, the most thoroughly investigated substances, those having a pyranoid ring, will be discussed (SectionII), and then those with a furanoidring (Section 111);no P-septanoid-ring compound has yet been reported. Finally, some biological aspects will be briefly mentioned (Section IV). The literature has been surveyed up to August, 1983.

11. MONOSACCHARIDES HAVING A PHOSPHINEDIYL OR PHOSPHONYL GROUP IN THE PYRANOSE RING 1. 5-Deoxy -S-phosphino- and -5-phosphinyl-~-xylopyranoses

In order to synthesize monosaccharides having phosphorus in the hemiacetal ring, it is obvious that two fundamental problems have to be solved: (1) how to introduce a suitable phosphine group, having the desired orientation, into an appropriate position on the carbon skeleton of the precursor, and (2) how to accomplish efficient ring-closure in order to yield the desired monosaccharide possessing a ring-phosphorus atom. As direct replacement of the ring-oxygen atom with phosphorus is not feasible for monosaccharides, such a ring-transformation as that illustrated in Scheme 1 is applicable, utilizing an equilibrium shift. Indeed, this method has been employed in most cases for the preparation of monosaccharides having either a nitrogen or a sulfur atom in the hemiacetal ring. For example, 54hio-~-xylopyranose(7), which has been the most thoroughly studied of the monosaccharides having a sulfur-containing hemiacetal ring, was readily by nucleophilic displacement of the p-tolylsulfonyloxy group of the D-xylofuranose derivativela (5) by an RS- ion, followed by reductive conversion into the 5-thio-a-~-xylofuranosederivative (6). Acid hydrolysis resulted in spontaneous ring-expansion to yield 7. Because of the absence of a chiral center at C-5, such pentopyranoses as 7 were judged to be the most amenable to preparation and study. In (14)T. J. Adley and L. N. Owen, Proc. Chem.Soc., (1961)418. (15)J. C.P.Schwarz and K. C. Yule, Proc. Chem.SOC., (1961)417. (16)D.L.Ingles andR. L. Whistler,]. Org. Chm.,27 (1962)3896-3898. (17)R.L. Whistler, M. S.Feather, and D. L. Ingles, J. Am.Chem.SOC., 84 (1962)122. (18)P.A. Levene and A. L. Raymond,]. Elol. Chem.,102 (1933)317-330. (19)R. L.Whistler and C.-C. Wang, J. Org. Chem.,33 (1968)4455-4458. (20)S.Inokawa, H. Yoshida, C . 4 . Wang, and R.L. Whistler, Bull. Chem.Soc. Jpn., 41 (1968)1472-1474. (21) R.L. Whistler, C.-C. Wang, and S.Inokawa,J . Org. Chm.,33 (1968)2495-2497.

~?-Ho~OH

SUGAR ANALOGS HAVING RING PHOSPHORUS TsOCH,

(2) (1) NaBnSNa NH,

Q?

HSCH,

*

139

H,Ot

HO

0-CMe,

0-CMe,

5

7

6

Bn = PhCH,

fact, a similar scheme was employed by Whistler and coworker^^^-^^ in the first synthesis of the phosphorus analogs. To introduce phosphorus into the sugar molecule, application of the Michaelis- Arbuzov reactionZ2was effective in most cases. For this purpose, the hydroxyl group at C-3 of compound 5 was protected with a methyl group to avoid low yields and complication of the reaction (see later). The p-tolylsulfonyloxy group was then replaced by a more reactive leaving-group, leading to an intermediate, such as the 5-bromo d e r i v a t i ~ e l(8), ~ . ~or~better, the 5-iodo compound239 (because of its ease of preparation and also higher reactivity towards the nucleophile in the subsequent step, compared with 8). The reaction of both 5-halogeno compounds (8 and 9) with triethyl phosphite proceeded satisfactorily at 150",to afford the phosphonate 10 (100%yield The same treatment of the p-toluenesulfonate 5 with triethyl phosphite gavele product 10 in lower yield.

5

(1) MeI-Ag,O (2) Bu,N+Bror NaI 0-bMe, 8 X=Br 9 X=I

0-CMe, 10

0-CMe, 1 1 Y =PH, 12 Y = PH,(=O) 13 Y = PH(=O)OH

(22) See G. M. Kosolapoff, Org. React., 6 (1951) 273-338. (23) H. Yarnarnoto, T. Hanaya, S.Inokawa, K. Seo, M.-A. Arrnour, andT. T. Nakashirna, Carbohydr. Res., 114 (1983) 83-93.

140

HIROSHI YAMAMOTO AND SABURO INOKAWA

Reduction of 10 with lithium aluminum hydride (LAH) in ether furnished19 an intermediate, presumably the phosphine derivative l l , which was treated with acid to effect ring enlargement, giving the 5phosphino-D-xylopyranosederivative 14. This compound was immediately converted by air oxidationlQinto the stable crystalline compounds, 5-deoxy-3-O-methyl-5-C-(phosphinyl)-~-xylopyranose (15) and the 5-C-(hydroxyphosphinyl) derivative 16 in overall yields of 15 and 3.5%, respectively, from 10. Compound 16 was obtained in 90%yield from 15 by oxidation with bromine.lQNo mutarotation was o b ~ e r v e d for ' ~ compounds 15 and 16 in water during 48 h. The extremely air-sensitive phosphine 11 was later foundz3 to be also available by reduction of 10 with sodium dihydrobis(2-methoxyethoxy)aluminate (SDMA) in benzene for 1 h at 5" under a nitrogen atmosphere, a procedure that usually converts phosphinates and phosphonates into phosphine oxides (see later). The phosphine 11 was then oxidized with one equivalent of hydrogen peroxide in 2-propanol at 20", to give the 5-phosphinyl derivative 12, together with a small proportion of the further-oxidized product 13. The ring enlargement of the furanose to a pyranoid compound proceeded more efficiently when 12 was heated with oxygen-free, ethanolic 0.5 M hydrochloric acid under nitrogen for 4 h at 100". Compound 15, thus obtained, was then oxidized with an excess of hydrogen peroxide, to afford 16 (65% overall yield from 10). The a-~-pyranoid-~C, structure 18 was p r o p o ~ e d for ' ~ the crystalline product 15 (separated from the reaction mixture in low yield) on the evidence of the splitting patterns of the H-1 signal in the 'H-nuclear magnetic resonance (n.m.r.) spectrum (60 MHz, in deuterium oxide). The exact structure for the oxidized product 16 was not given, although the presence of a phosphinic acid group was supportedlgby infrared (i.r.) absorption at 2260 cm-' and the approximate pK, value (1.61). An unambiguous, structural assignment was made23by converting the anomeric mixture 16 into the tri-O-acetyl-5-C-(methoxyphosphinyl) derivatives 17 by treatment with diazomethane and then with acetic anhydride - pyridine; after chromatographic separation, structures 19 22 [all in the 4 C 1 ( ~conformation] ) were established for each product by analysis of the 400-MHz, 'H-n.m.r. and high-resolution mass spectra (see Section 11,5).The overall yields ofthese products from 10 were: 19 (6.5), 20 (2.7), 21 (4.9),and 22 (3.3%). Besides the four diastereoisomers 19-22, a small proportion of a byproduct was isolated (2.7% overall yield from lo), to which structure 23, namely, 5-C-[(R)-(l-acetoxyethenyl)phosphinyl]-l,2,4-tri-0-acetyl-5deoxy-3-0-methy~-j3-~-xylopyranose-~C, , was assigned24 from the (24) H. Yarnamoto, T. Hanaya, S. Inokawa, and M.-A. Armour, Carbohydr. Res., 124 (1983) 195-200.

SUGAR ANALOGS HAVING RING PHOSPHORUS 11

H*02

141

12

i.e' :;q

JH~O+

Q m L ( + HO

0 II

HO

HO

H202

OH

OH

OH

1s

14

16 (1) CH2N2 (2) Ac20- C,H,N

0

0 I1

I

OH

18

0 It

A

c

Me0

o / W

R OMe ,

""""

AcO

""m~, 17

OMe P xi::0

Me0

R

19 R = OAC, R' = H 20 R = H , R' = OAc

OAc

AcO

R

21 R = H, R ' = OAc 22 R = OAC, R' = H

23

'H-n.m.r. and mass spectra (see Section 11,5); the corresponding 5-C-[(S)-phosphino] structure had been tentatively assignedz3 to this product. The chemical shifts and the splitting patterns of the ring-proton signals in the n.m.r. spectrum closely resembled those of 20, thus permitting the assignment of the (R)configuration to the phosphinyl group.

142

HIROSHI YAMAMOTO AND SABURO INOKAWA

This minor product 23 and its diastereoisomers were also isolated,e4in 23% yield, when 15 was treated with acetic anhydride -pyridine. Thus, these products were assumede4to have been formed by direct, "double" acetylation of the 5-C-phosphinyl group in 15, rather than by the previously proposede3pathway involving the disproportionation of 15. A similar acetylation reaction is known25for various primary and secondary phosphine oxides. Besides 23 and its diastereoisomers, a complex product resulting from phosphorus -phosphorus dimerization of 15 was isolated, in 25% yield, during the aforementioned acetylation; this appears to be analogous to the formation of tetraphenyldiphosphine monoxide [Ph2P-P( = O ) Ph,] from diphenylphosphine oxide in the presence of acetic anhydride and pyridine at room temperature.26 These results,23therefore, provided further proof for the formation of 5-deoxy-5-C-(phosphinyl)-and -(hydroxyphosphinyl)-D-xylopyranoses (15 and 16) from the 5-phosphinyl-~-xylofuranose precursor 10. Soon after the appearance of a brief report on compounds 15 and 16 by Whistler and Wang,le Inokawa and his coworkerse7 prepared 3- 0-benzyl- 5-deoxy-5-C-[(RS)-ethylphosphinyll-a$- D-xylopyranoses (29) in 27% yield from 3-0-benzyl-5-deoxy-5-iodo172-O-isopropylidene-a-D-xylofuranose28(24) by way of the ethylphosphine oxide 26, according to essentially the same procedures as those described earliere3 for preparation of 15 from 9. Structure 29 was supported by the 'H-n.m.r. spectrum (~O-MHZ, in Me,SO-d,) and i.r. spectrum. Similarly, the Michaelis - Arbuzov reaction of the 5-bromo-3-0methyl compound 8 with diethyl ethylphosphonite at 130- 150" resultedee in a quantitative yield of 5-deoxy-5-C-[(RS)-(ethoxy)ethylphosphinyl]-l,2-O-isopropylidene-3-O-methyl-a-~-xylofuranose, which, upon reduction with SDMA in oxolane for 1hat room temperature under a nitrogen atmosphere, gave an -100% yield of its 5-C-(ethylphosphinyl) derivative 27 (R' =Et). This ethylphosphine oxide 27 was apparently more stable than the phosphine oxide 12, and it clearly showed a characteristic lJH,p value30of 458 Hz at 6 6.92 in the 'H-n.m.r. spectrum (in CDCl,), and typical, i.r. absorptions due to a P-H group3' at 2320 cm-' and a P=O group3, at 1240 crn-'. The hydrolysis of 27 with 0.3 M sulfuric acid for 2 h at 100" gaveee (25) S.A. Buckler and M. Epstein, Tetrahedron, 18 (1962) 1221-1230. (26) S.Inokawa, Y. Tanaka, H. Yoshida, andT. Ogata, Chem. Lett., (1972) 469-470. (27) S. Inokawa, Y. Tsuchiya, K. Seo, H.Yoshida, andT. Ogata, Bull. Chem. Soc.]pn., 44 (1971) 2279. (28) R. C. Young, P. W. Kent, and R. A. Dwek, Tetrahedron, 26 (1970) 3984-3991. (29) K. Seo and S. Inokawa, Bull. Chem. Soc.]pn., 46 (1973) 3301-3302. (30) H. R. Hays.,J. Org. Chem., 33 (1968) 3690-3694. (31) R. A. Chittenden and L. C. Thomas, Spectrochim.Acta, 20 (1964) 489-502. (32) L. C. Thomas and R. A. Chittenden, Spectrochim.Ada, 20 (1964) 467-487.

SUGAR ANALOGS HAVING RING PHOSPHORUS

143

5-deoxy-5-C-(ethylphosphinyl)-3-O-methyl-~-xylopyranose (30) in a relatively good yield (70%). This product was characterized by derivatization to the triacetate, which was considered to be a mixture of the four diastereoisomers with respect to C-1 and the ring-phosphorus atom. A pure, crystalline compound (m.p. 227 - 229") separated from the mixture upon recrystallization from ethanol, and it became apparent,33 by comparison of its 'H-n.m.r. spectrum with those of the structurally similar compounds (see Section 11,5), that this product was the 5-C-[(R)ethylphosphinyll-B-~-xylopyranose 34. Likewise, the use of diethyl butylphosphonite in the Michaelis Arbuzov reaction of 8 gave2e 5-C-(butylphosphinyl)-~-xylopyranose 31 (50% yield) by way of intermediate 27 (R' = Bu). The product was also characterized as the tri-0-acetyl derivative: a single compound (m.p. 218.5 - 220") was r e c o ~ e r e dand , ~ ~structure 35, namely, 5-[(R)-butylphosphinyl]-P-~-xylopyranose, could be assigned33to this product from its n.m.r. spectrum.

0-CMe, 24 R = Bn 2 5 R = Ac or Bz Bz = PhCO

OH

0-CMe,

26 R = Bn, R' = Et 27 R = Me, R' = Et or Bu 28 R = H, A' = Et or Bu Bu = C,H,

29 30 31 32 33

R R R R R

= Bn, R' = Et = M e , R' = Et

= M e , R ' = Bu = H, R' = Et = H , R' = Bu

An analogous procedure was successfully applied34to 5-deoxy-5-iodo1,2-O-isopropylidene-a-~-xylopyranose (42),in which the hydroxyl group on C-3 had been protected with an acetyl or benzoyl group (to give 25), prior to the Michaelis-Arbuzov reaction with an alkylphosphonite. The intermediates 28 (R' = Et or Bu) were hydrolyzed with dilute sulfuric acid, to afford 5-deoxy-5-(ethylphosphinyl)-(32;95% yield) and -5-(butylphosphiny1)-D-xylopyranose(33;91% yield), respectively, as diastereoisomeric mixtures. Acetylation of 32 gave, again, a mixture of four diastereoisomers, from which two crystalline compounds were isolable. Although no exact configurations for C-1 and the ringphosphorus atom of these two products had been presented,34 they could be assigned33 the structures 1,2,3,4-tetra-O-acetyl-5-deoxy-5-C-[(R)ethylphosphinyll-P-~-xylopyranose (36)and its a anomer 37 on the basis (33) S. Inokawa and H. Yamamoto, unpublished results. (34) K. Seo and S . Inokawa, Bull. Chem.SOC.Jpn., 48 (1975) 1237-1239.

HIROSHI YAMAMOTO AND SABURO INOKAWA

144

0

0

34 R = Me, R' = Et 35 R = Me, R' = Bu 36 R = Ac, R' = Et

37 R = E t 38 R = Bu

of their 'H-n.m.r. spectra, melting points, and [a], values (see Table VIII in Section VI). For the per-0-acetyl derivatives of these p y r a n ~ i d - ~ c , sugar analogs, those compounds that have an equatorial acetoxyl group on C-1 normally show a higher melting point and a lower [a], value than those having an axial AcO-1 group. Likewise, 5-C-(butylphosphinyl)-5-deoxy-~-xylopyranose 33 was obtained34from 25 (R = Ac or Bz) by way of the phosphine oxide intermediate 28 (R' = Bu). An acetyl derivative having structure 38, namely, 1,2,3,4-tetra-O- acetyl- 5-C- [(R)-butylphosphinyll-5- deoxy- a -D-xylop y r a n o ~ ecrystallized ,~~ from the diastereomeric mixture of the per-0acetylated products from 33. 0 II

Bu-P-CH,

uT :rg*

f:

' QT

Bu-P-CH, Me0

0-CMe,

39

o*

+

LQ

,CHZ

SDMA-28

0-CMe,

0-CMe,

40

41

f

BuP(OEt),

0 - CMe, 42

In the course of these experiments, treatment of the 3-O-acetyl-5-C(butylethoxyphosphinyl) compound 39 with sodium methoxide in methanol was found34 to give, in 94% yield, a 5 : 1 mixture of the 5-C-(butylmethoxyphosphinyl)derivative 40 and crystalline 5-C-[(30,P-anhydro) butylphosphinyl] -5-deoxy - 1,2 - 0- isopropylidene - a - D xylo-furanose (41). The structure 41 was based on the n.m.r. spectrum, which showed neither a P-OMe nor an OH signal, and gave the H-3

SUGAR ANALOGS HAVING RING PHOSPHORUS

145

signal at much lower field (S 5.18)than that of 40 (6 4.00). On reduction with 1.2 equivalents of SDMA, both 40 and 41 gave the phosphine oxide 28 (R’ = Bu) in good yields. Compound 41 was obtained almost quantitatively by heating 42 in diethyl butylphosphonite, which provides, at least partly, the complicated reason for the lower yields from the Michaelis- Arbuzov reaction of 5-halogeno- 1,2-O-isopropy~idene-cr-~-xylofuranose where the hydroxyl group on C-3 was not protected (see earlier). 2. 5-Deoxy-5-phosphinyl-~-ribopyranose

Other than the 5-deoxy-5-phosphinyl-~-xylopyranoses described in the previous Subsection, there has been reported35 only one example of a different type of 5-deoxy-5-phosphinylpentopyranose. The Michaelis - Arbuzov reaction of methyl 5-deoxy-5-iodo-2,3-0isopropylidene-~-~-ribofuranoside~~ (43)with diethyl ethylphosphonite gave,35 in 80% yield, the 5-C-[(ethoxy)ethylphosphinyl]derivative which, on treatment with SDMA and then mineral acid, yielded (30%) 5-deoxy-5-C-[(RS)-ethylphosphinyl]-~-ribopyranose (44)as a mixture of diastereoisomers. These compounds showed no mutarotation in methanol during 24 h. Upon treatment with acetic anhydride- pyridine, the product, 44, was converted (90% yield) into a syrup, presumably consisting of four diastereoisomers of the peracetate 45,separation of which was not attempted. Treatment of 45 with sodium methoxide in methanol regenerated 44 quantitatively. 0

p J I; w m ” -

ICH,

II

(3) H 3 0 t \

/o

CMe,

43

Ac@ 0

HO

OH 44

AcO

OAc

45

3. 5-Deoxy-5-phosphino-and -5-phosphinyl-~-idopyranoses

If appropriate 5-deoxy-5-phosphino- or -5-phosphinyl-aldohexofuranoses are available as precursors, the analogous ring enlargement described in the previous Subsections would be expected to provide various 5-deoxy-5-phosphino- or -5-phosphinyl-aldohexopyranoses having (35)S. Inokawa, H.Kitagawa, K. Seo, H. Yoshida, and T. Ogata, Carbohydr. Res., 30 (1973)127-132. (36) P. A. Levene and E. T. Stiller,]. B i d . Chem.,106 (1934)421-429.

HIROSHI YAMAMOTO AND SABURO INOKAWA

146

a ring-phosphorus atom. For example, because of the chirality at C-5, 5-deoxy-5-C-[(RS)-phosphino(or phosphinyl)]-~-xyb-hexofuranoses46 and 47 would yield D-glucopyranoses (48) and L-idopyranoses (49), respectively, provided that no epimerization takes place at C-5. Much information concerning such a ring enlargement has been accumulated. For historical reasons, the preparation of L-idopyranose derivatives will be discussed first.

46 Y = PHR or P(=O)HR

47

HOCH,

H

o

a 48

HO O

I

o

S

HO O

H

49

Addition of dimethyl phosphonate to 3-0-acety1-5,6-dideoxy-l,2-0isopropy~idene-6-nitro-a-~-xy~o-hex-5-enofuranose (50) was known to provide3' an 89 : 11mixture of 6-nitro-5-phosphonylhexofuranoses having the D-gluco (51; 40%isolated yield) and the ~ - i d configuration o (53), whereas addition of methanol, ammonia, or phenylmethanethiol to 50 mainly a D-ghco compound. The assignment of the D-ghco configuration to compound 51 was based on the observation of anegative Cotton-effect in optical circular dichroism (c.d.) at 310 nm, which implies the (5A)D-gluco configuration. This effect is present for similar, model compounds, in accordance with the rule of Satoh and KiyoThese results were extended43 to the addition of methyl ethylphos(37)H.Paulsen and W. Grewe, Chern. Ber., 106 (1973)2114-2123. (38)H. Paulsen, Ann., 665 (1963)166-187. (39)H. H. Baer and W. Rank, Can. J . Chm., 43 (1965)3330-3339. (40)R. L.Whistler and R.E. Pyler, Carbohydr. Res., 12 (1970)201 -210. (41)C.Satoh, A. Kiyomoto, andT. Okuda, Carbohydr. Res., 5 (1967)140-148. (42)C.Satoh and A. Kiyomoto, Carbohydr. Res., 23 (1972)450-455. (43)H. Takayanagi, K. Seo, M. Yamashita, H. Yoshida, T. Ogata, and S. Inokawa, Carbohydr. Res., 63 (1978)105-113.

SUGAR ANALOGS HAVING RING PHOSPHORUS

147

phinate to 50, to give, in 95% yield, a 1: 1mixture of the D-gluco (52) and L-ido (54) compounds, from which crystalline 3-0-acetyl-5,6-dideoxy-5C-[(R or S)-ethylmethoxyphosphinyl]-l,2-O-isopropylidene-6-nitro-aD-glucofuranose (52) separated in 20% yield. The D-gluco configuration was assigned to 52 on the evidence of its 'H-n.m.r. spectrum, the chemical shifts and coupling constants of each proton of which closely resembled those of 51.

0

kH

II

QT

EtP(=O)H(OMe) HP(OMe), or 0-CMe, 50

CH,NO,

:: FaNOa

0,NCH

I:

R -8-CH "

'

O

q

T

0-CMe, 51 R = O M e 52 R = E t

HCPR(0Me) +

Q? 0-CMe, 53 R = OMe 54 R = E t

Reduction of 52 with hydrogen in the presence of Raney nickel was a ~ c o m p a n i e dby~ ~cyclization of the phosphinate group and transfer of the acetyl group, to give, in 60%yield, crystalline 6-acetamido-5-C-[(0,P- anhydro)ethylphosphinyl]-5,6- dideoxy-l,2 - 0-isopropyhdene-cDglucofuranose (55). However, hydrogenation of 52 in methanol in the presence of platinum oxide and hydrochloric acid afforded, in 80% yield, the stable hydrochloride 58, which was readily converted into 55 by means of an anion-exchange resin. Deamination of 58 with nitrous acid gave, in 59% yield, the 5-(ethylmethoxyphosphinyl)-~-glucofuranose derivative 59, which was spontaneously converted into the crystalline, 5-C-[(3-O,P-anhydro)ethylphosphinyl]compound 56. Upon treatment with an excess of SDMA, none of these precursors (52,55,56,58, and 59) gave the desired compound 57, but instead, almost complete decomposition. Thus, all attempts to convert the phosphinate group into a phosphine oxide group have remained unsuccessful; see Section 11,4, however, for a successful example of reduction (with SDMA) of compound 130, which is analogous to 55 and 56. Instead of employing the addition of phosphinates to 50, with subsequent reduction, the use of phenylphosphine for the addition reaction to 50 was found to give43.44a mixture of the crystalline ~ - i d compound o 60 (47% yield), the D-gluco isomer 61 (16% yield), and the 1: 2 adduct 62 (34% yield). Because of its negative Cotton-effect in c.d. at 229 nm, and taking into account the results3' using compound 51 (see earlier), the (44) H. Takayanagi,M. Yamashita,K. Seo, H. Yoshida, T. Ogata, and S. Inokawa, Carbohydr. Res., 38 (1974) c19-c21.

148

HIROSHI YAMAMOTO A N D SABURO INOKAWA

/

52

H, /Raney Ni or PtO,

\

H, /PtOz-HC1 0 CH,R

Et -P

0-&Me,

II

I -CH

Q7

SDMA

0-CMe,

55 R = NHAc 56 R = OAC

58 R = NH,*HC1 59 R = O H

/

qy

0 CH, II I Et-P-CH

ii

0-CMe, 57

major product 60 had been incorrectly assigned43the D-glucoconfiguration. However, the correct configuration (L-ido)of compound 60 was later determined from the precise structural assignments of the monosaccharides 66 - 68 that were derived from 60 as follows. Acid hydrolysis of 60 and of its oxidized derivative 64 afforded the 5-C-(phenylphosphino)-D-xylo-hexopyranose63 (81% yield) and the 5-C-phenylphos-

- qy CH,NO, I HC-PHPh

50

Ql

CH,NO, I PhHP-CH

PhPH2

+

0-CMe, 60

+

1:2 adduct

62

0-CMe, 61

phinyl derivative 65 (67%yield), respectively. After per-0-acetylation of these products, crystalline compounds 66 (26%yield from 60) and 67 (together with a small proportion of 68; 29% yield from 64) were isolated; these compounds were the first examples of hexopyranoses having a ring-phosphorus atom. X-Ray crystallographic analysis indicated45that (45) P.Luger, M. Yamashita, and S. Inokawa, Carbohydr. Res., 84 (1980) 25-33.

ek

SUGAR ANALOGS HAVING RING PHOSPHORUS

P-Ph

60

149 Ph

~

Ac,O- C5H5N

CH,NO,

AcO

HO

AcO

OH

\

OAc

66 X = lone pair 67 X = O

63 CH,NO,

I::

HC-PHPh

0-CMe, 64

0 II

0

'--.p h Ac,O- C,H5N * A

c

o CH,NO, n O

A

c

AcO 65

OH

68

compound 67 has the structure of 1,2,3,4-tetra-O-acetyI-5,6-dideoxy6-C-nitro-5-C-[(R)-phenylphosphinyl]-~-~-idopyranose, whereas the structures of compounds 66 and 68 were shown by 400-MHz, 'H-n.m.r.and the spectral analysis to be the 5-C-[(S)-phenylpho~phinoI-P-~~ d e r i ~ a t i v erespectively; ,~~ 5-C-[(S)-phenylphosphinyll-a-L-idopyranose see Section II,5 for a discussion. Treatment of the 1:2 adduct 62 with one equiv. of hydrogen peroxide in methanol gave mainly a pure, crystalline compound (m.p. 209210.5") whose structure was presumed to be bis(3-0-acetyl-5,6dideoxy - 1,2-0 - isopropylidene - 6-C-nitro - ~-~-idofuranose-5-yl)phenylphosphine oxide (69);therefore, the original 1 : 2 adduct 62 was assumed to be a mixture consisting mainly of the corresponding phosphine compound. The acid-catalyzed ring enlargement of 61, which could have given the D-gluco epimer of 63, was not attempted, because of the difficulty in separating pure compound 6 1. An alternative method of introducing a phosphinyl group at C-5 of (46) H. Yamamoto, C. Hosoyamada, H. Kawamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T. Nakashima, Carbohydr. Res., 102 (1982) 159-167.

jPPh

HIROSHI YAMAMOTO AND SABURO INOKAWA

150

a2L(?QT CH,NO, \ R

2

0-CMe, 69

5-deoxy-~-xy~o-hexofuranose has been developed as an extension of the reaction of l-(p-tolylsulfonyl)oxy-2-propanone(70) with dimethyl phosphonate (75) in the presence of one equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); this procedure readily gave4' methyl 1,2epoxy-1-methylethanephosphonate (71), which is an isomer of the antibiotic fosf~nornycin~~ (72). 0

I1 H.&--C--CH,OTs

0

It

HP(OMe),

/O\

DBU

0 / \ )PO~HZ

H3C\

H,C-C-CH,

P

H4c-c H '

I 0 =P(0Me b

72

71

70

Ts = SO,C,H,Me-p

Thus, treatment of 6-O-p-tolylsu~fonyl-a-~-xy~o-hexofuranos-5u 1 0 s e ~(73) ~ with 75 in methanol in the presence of one equivalent of DBU for 20 h at room temperature gave, in 70% yield, a 3 : 1mixture of (5RS)-5,6-anhydro-5-C-(dimethoxyphosphinyl)-~-xylofuranoses (77). The absolute structure of the major product was shown50by X-ray crysCH,OTs I

o=c

Q

0 HP, II,RfR"

-

0 II R'-P-C

l,O

DBU

AM

0-CMe,

73 R = B n 74 R = M e

F,

75 R' = R" = OMe 76 R' = Ph, R" = OEt

77 78 79 80

R R R R

QT

= Bn, = Bn. = Me, = Me,

0-CMe, R' = R" = OMe Rf = Ph, R" = OEt Rf = R" = OMe Rf = Ph, R" = OMe

S. Inokawa, Y. Kawata, K. Yamamoto, H. Kawamoto, H. Yamamoto, K. Takagi, and M. Yamashita, Carbohydr. Res., 88 (1981) 341-344. E.J. Glamkowski, G.Gal, R. Purick, A. J. Davidson, and M. Sletzinger,]. Org. Chem., 35 (1970) 3510-3512, and references cited therein. S. Inouye, Meijt Seika Kenkyu Nempo, (1970) 52-74; Chem. Abstr., 77 (1972) 48,736. S. Kashino, S. Inokawa, M. Hdsa, N. Yasuoka, and M. Kakudo, Acta Crystulbgr., Sect. B, 37 (1981) 1572-1575.

SUGAR ANALOGS HAVING RING PHOSPHORUS

151

tallography to be the (5R) epimer 82. The addition of 75 to 73 is presumed to take place in either the “Cram” or the “anti-Cram” f a s h i ~ n , ~ ’ to yield two diastereoisomers, 82 and 83, with respect to the configuration of C-5. The most likely orientations along the C-5-C-4 bond are illustrated in formula 8 1, which suggests that the anti-Cram type of addition is sterically the more favorable, leading to formation of 82 as the major product.

PhCH, \

82

M&O

OTs

81

83

Similarly, the (5R)-5-deoxy-5-C-[(RS)-(ethoxy)phenylphosphinyl] compound 78 was prepared4’ (69% yield) from 73 and ethyl phenylphosphinate (76). Also, condensation of the 3-O-methyl compound 74 with 75 and 76 (R” = OMe) respectively gave the (5RS)-5-C-[(RS)-phosphinyl] compounds 79 (75% yield) and 80 (46% yield). Hydrogenation of 78 in ethanol in the presence of Raney nickel (W-4) for 2 days at room temperature did not produce the anticipated 5-deoxy5-C-(phosphinyl)hexofuranose 84 but, instead, a i € ~ r d e d , in ~ ~90% *~~ yield, a 1 : 1 mixture of the (5R)-and (5S)-5,6-dideoxy-5-C-[(Rs)-(ethoxy)-phenylphosphinyl]-D-xylo-hexofuranoses($5), which was separated by thin-layer chromatography (t.1.c.). Similarly, (5RS)-5,6-dideoxy-l,2 - 0 - isopropylidene- 5 -C-[(RS)-(methoxy)phenylphosphinyI](51) D. J. Cram and F. A. A. Elhafez,J. Am. Chen. SOC.,71 (1952) 5851 -5859. (52) S. Inokawa, K.Yamamoto, Y. Kawata, H. Kawamoto, H.Yamamoto, K. Takagi, and M. Yamashita, Curbohydr. Res., 86 (1980) c l l - c l 2 . (53) S. Inokawa, K. Yamamoto, H. Kawamoto, H. Yamamoto, M. Yamashita, and P. Luger, Carbohydr. Rex, 106 (1982) 31-42.

HIROSHI YAMAMOTO AND SABURO INOKAWA

152

3-O-methyl-c~-~-xylo-hexofuranose was prepared in 85%yield from 80. Hydrogenation of each component of 85 in the presence of 10%Pd-C at room temperature gave the corresponding (5R)- and (5s)-hexofuranoses 86. Then, the (5R) and (5s)compounds (86) were individually reduced64 with SDMA, to afford a mixture of the (5s)-and (5B)-5,6dideoxy-5-C-(phenylphosphinyl)-~-xylo-hexofuranoses (88 and 89, respectively), along with a small proportion of byproducts (apparently formed by elimination of the phosphinate group). Acid hydrolysis of 88 and 89 was expected to give a mixture of 5,6-dideoxy-5-C-[(RS)-phenylphosphinyll-a,P-~-idopyranose 90 and the D-glum epimer 91. 0 CH,OH II I Ph-P-CH EtA

QT

-

:: 7%

Ph-P-CH

78-

0-CMe,

H,

EtA

%\h. 0-CMe,

85 R = B n 86 R = H 87 R = T H P

84

THP = tetrahydropyran-2-yl

0 II Ph-P-Ii

86 or 8 7 -

SDMA

0 II

Qy

H,C-&H

+

0-CMe,

$HS

=

ph-i-'(T 0-CMe,

p+

89

88

1H'. 0

OH

OH 90

OH 91

(54) H. Yamamoto, K. Yamamoto, S. Inokawa, andP. Luger, Carbohydr.Aes., 113 (1983) 31-43.

SUGAR ANALOGS HAVING N N G PHOSPHORUS

1 S3

Per-O-acetylation of this mixture with acetic anhydride - pyridine gave53five crystalline compounds, to which the structures 1,2,3,4-tetraO-acetyl-5,6-dideoxy-5-C-((S)-phenylphosphiny~]-ac-~-idopyranose (92; 4.5% yield from 86), its p anomer 93 (4.5%), the 5-C-[(R)-phenylphosphinyll-ac epimer 94 (5.7%),the /3 anomer 95 (8.5%), and 2,3,4-tri-Oacetyl- 1,5-anhydro-5,6 - dideoxy- 5 -C- [(S)-phenylphosphinyl]- ~ - i d i t o l (96; 3.9%)were assigned by X-ray crystallographic a n a l y s i ~(for ~ ~ 92, .~~ 93, and 96) and 400-MHz, ‘H-n.m.r. s p e c t r o ~ c o p y(for ~ ~ 92-96); see Section 11.5.

R = H, R’ = OAC 93 R = OAc, R’ = H 92

94 R = H, R’ = OAc 9 5 R = OAc, R’ = H

96

Although a precise configuration [(5R)or (5S)]could not b e assigned to the two starting-materials 86, both compounds were found to give almost the same proportions of the L-idopyranoses 92 -95, plus the byproduct 96; it is noteworthy that no “P sugar” of the D - ~ ~ U C type O was formed from 86. As expected, use of the 1 : 1 mixture 86 as the starting material also resulted in the formation of 92-96 in the same ratios. When the 3-O-(tetrahydropyran-2-y1)derivative 87 was reduced with a smaller proportion (2 equivalents) of SDMA, the yields of the L-idopyranoses 92- 95 were significantly increased (54% total yield from 87); moreover, this procedure totally suppressed both the formation of the over-reduced product 96 and the elimination reaction of the phosphinate group. The following mechanism was proposed54 for the preponderance of the L-idopyranoses 92 - 96. A thermodynamically controlled, more favorable production of the (5s) epimer 88 takes place after an equilibration caused by the strongly basic SDMA during the reduction. This occurs because there apparently exists less steric congestion between the bulky phenylphosphinyl and the 3-hydroxyl (or protected hydroxyl) group in 88 compared with the ( 5 8 ) epimer 89, as illustrated in Scheme 2. This (5s) epimer 88, in turn, readily affords 92-95 on per-O-acetylation, despite the presence of a slightly less favorable, steric requirement for the intermediate 97 compared with the counterpart 98. On the other hand, the formation of a small proportion of 96 from 86 was explained in terms of the further reduction of 88, by an excess of (55) H. Yamamoto, K. Yamamoto, H. Kawamoto, S . Inokawa, M.-A. Armour, and T. T. Nakashima,]. Org. Chem., 47 (1982) 191-193.

X

ti 0

e,

h

m

v,

9

f

0 X

X

N

SUGAR ANALOGS HAVING RING PHOSPHORUS

155

SDMA, to the phosphine 99,which subsequently led to 96,by way of intermediate 100, by transfer of the oxygen atom from C-1 to the phos-

phorus atom, as in the following, frequently observed, example.56 RR'C=O

+ PH3

H+

RR'CH-P(=O)H,

+

The 5-C-[(R)-phenylphosphinyl]epimer of 96was not isolated, but was presumed to be present in the large quantity of polar substances that remained uneluted in the t.1.c. separation. The 1 : 1 ratio (ofthe combined yields of the compounds) of the (S) to the (R) isomers ofthe ring-phosphorus atom (92,93,96to 94,95)from 86 and 87 suggested that hemiacetal formation from 97 (and 100)to 92-95 (and 96) proceeds at almost the same rate for both 5-C-[(R)-and ( S ) phenylphosphinyll-L-idopyranoses.

-

4. 5-~eoxy-5-ghosphiny~-~-g~ucopyranoses

When either of the two methods in the previous Subsection is employed in order to introduce a phosphino (or phosphinyl) group at C-5 of 5-deoxy-~-xy~o-hexofuranoses, only 5-deoxy-5-phosphino- (or -5-phosphiny1)- L-idopyranoses are produced; for instance, 50 60 (and 64) 63 (and 65), and 73 -+ 78 -, 85 88 90. Therefore, in order to prepare hexopyranoses of the D-gluco type having phosphorus in the hemiacetal ring, an alternative approach had to be devised. In the meanwhile, a new method for preparing various sec-alkanephosphonates (103)from ketones by way of the hydrazone 101 and then By ' using this the substituted tolylhydrazines 102, had been d e v e l ~ p e d . ~

- -

-

0

101

102

103

method, many sugar derivatives having a phosphorus-carbon bond have been ~ b t a i n e d . ~For ~ - "example, ~ condensation of the D-xylo-hexofuranos-5-dose I04 (prepared"' from 6-deoxy- 1,2-O-isopropyIidene-a-~(56) S. A. Buckler and M. Epstein, 1.Am. C h .SOC., 82 (1960) 2076-2077. (57) S. Inokawa, Y. Nakatsukasa, M. Horisaki, M. Yamashita, H. Yoshida, and T. Ogata, Synthesis, (1977) 179-180. (58) M. Yamashita, Y. Nakatsukasa, M. Yoshikane, H. Yoshida, T. Ogata, and S. Inokawa, Carbohydr. Res., 59 (1977) c 1 2 - c l 4 . (59) M. Yamashita, Y. Nakatsukasa, S.Inokawa, K. Hirotsu, and J. Clardy, Chem.Lett., (1978) 871-872. (60) M. Yamashita, Y. Nakatsukasa, H. Yoshida, T. Ogata, S. Inokawa, K. Hirotsu, and J. Clardy, Carbohydr. Res., 70 (1979) 247-261. (61) H. Ohle and R. Deplanque, Ber., 66 (1933) 12- 18.

HIROSHl YAMAMOTO AND SABURO INOKAWA

156

xylo-hex-5-enofuranose) with p-tolylsulfonylhydrazine in methanol at room temperature gave hydrazone 106 in 80% yield. Similarly, the 3-0methyl derivatives 105 (obtained in 60% yield from 104) afforded hydrazone 107 (70% yield).

TSNHNH,~~~=~!~

y s

y

QT

o=c

0-CMe,

0 R-PH(0Me) II

0-CMe,

I

0

I1

YRt

0-CMe,

106 R = H 107 R = M e

104 R = H 105 R = M e

by

H,C TsNHNW-C-

3

1 0 8 R = M e , R' = OMe 1 0 9 R = M e , R' = Ph 110 R = H , R ' = P h

Treatment of 107 with 75 in the presence of 0.15-0.45 mol. equivalent ofp-toluenesulfonic acid for 40 - 50 hat room temperature gave60the (5RS)-5-[(RS)-dimethoxyphosphinyl]-5-(p-tolylsulfonylhydrazino)hexofuranoses 108 (70%yield). Likewise, compound 107 and methyl phenylphosphinate gave an 100% yield of the 5-[(methoxy)phenylphosphinyl] compound 109, whereas hydrazone 106 afforded four products, namely, two isomers of the xylofuranoses 110 (15%)and two isomers of the 5-C-[(RS)-(U,P-anhydro)phenylphosphinyl]derivatives 111 (51 and 26%). Compound 111 was considered to be produced from 110 during isolation employing sodium hydrogencarbonate, because 110 readily afforded 111 by treatment with sodium methoxide.

-

0 CH, I! I Ph-P-C-NHNHTs

0-&Me, 111

Reduction of compounds 108 and 109 with an excess of sodium borohydride in oxolane respectively gave (SRS)-S-C-[(RS)-dimethoxyphosphinyl]-~-xyb-hexofuranoses112 (21% yield) and the 5-C-[(RS)-(methoxy)phenylphosphinyl] compound 113 (70% yield). The phosphinate 113 was reduced with an excess of SDMA in oxolane at O", to give the 5-C-[(RS)-phenylphosphinyl] derivative (41% yield after purification by t.l,c.), which, on acid hydrolysis, yielded (75%)a mixture of 5,6-di-

SUGAR ANALOGS HAVING RING PHOSPHORUS

157

deoxy-3-O-methyl-5-C-[(RS)-phenylphosphinyl]-~-gZ~c~and - ~ - i d o pyranoses (1 14).Treatment of 114 with acetic anhydride-pyridine gave the per-O-acetylated products, from which two crystalline compounds, 1 , 2 , 4- tri- 0 -acetyl- 5,6-dideoxy- 3 -0-methyl-5 - C-[(S)-phenylphosphinyl]-P-~-glucopyranose-~C~ (1 15; 16% yield,) and, probably, its a anomer 116 (low yield), were isolated after recrystallization from ethanol. The structure of 115 was established by X-ray c r y s t a l l ~ g r a p h y ~ ~ ~ ~ ~ and 400-MHz, 'H-n.m.r. ~ p e c t r o s c o p y(see ~ ~ Section 11,5). The other isomers, which were assumed to be present in the mother liquor, remained uninvestigated.

R 115 R = H , R' = OAc 116 R = OAC, R' = H

By following the same scheme, the first example of a complete glucose structure having a ring-phosphorus atom was prepared.46Treatment of (ob5,6-anhydro-3-0-benzyl- 1,2-O-isopropylidene-a-~-g~ucofuranose tained'j2 from the 6-O-p-tolylsulfonyl compound 117) with sodium phenylmethoxide for 4 days at room temperature gave 3,6-di-O-benzyl-~glucofuranose 118 (70% yield). Compound 118 was oxidized with pyridinium chlorochromate over molecular s i e v e P in dichloromethane for 4 h at room temperature, to afford ketone 119 (90%yield). By using the method described earlier, 119 was converted (100% yield) into a mixture of E- and Z-hydrazones 120 and 121 in the ratio of 7 : 3. Treatment of the hydrazones with methyl phenylphosphinate in the presence (62) A. S. Meyer andT. Reichstein, Helo. Chim. Acta, 29 (1946) 152-163. (63) J. Herscovici and K. Antonakis,]. Chem. Soc., Chem. Commun., (1980) 561-562.

HIROSHI YAMAMOTO AND SABURO INOKAWA

158

of trifluoromethanesulfonic acid yielded (50%) the adduct 122 as a mixture of four diastereoisomers (with respect to C-S and the P atom). The p-tolylsulfonylhydrazino group of 122 was removed by reduction with sodium borohydride in oxolane, to give the intermediate 123 (34% yield), again as a mixture of four diastereoisomers. Reduction of 123 with CH,OR I HO-CH

CH,OBn 118

Q7

I

x=c

+

Q7

C,H, NCr0,CL;

* 0-CMe,

0-CMe,

117 R = T s 118 R = Bn

119 X = O 120 X =NNHTs ( E ) 121 X = NNHTs (2)

I,

120

0 CH,OBn II I Ph-P-C-R

PhP(=O)H(OMe) -

-

heQ 0-CMe,

122 R=NHNHTs 123 R = H

SDMA in toluene for 20 min at 0" under an argon atmosphere gave the 5-C-(phenylphosphinyl) compound 124, which, on acid hydrolysis, afforded the 5-C-(phosphinyl)hexopyranose125. This was treated with acetic anhydride-pyridine, to give the peracetates (126), from which (S)-phenylcrystalline 1,2,4-tri-O-acetyl-3,6-di-O-benzyl-5-deoxy-5-C-[ phosphinyl]-P-~-glucopyranose-~C, (127) was isolated in 2% overall yield from 123; none ofthe other diastereoisomers of 127 were obtained. Structure 127 was established by 400-MHz, 'H-n.m.r. spectroscopy (see Section 11,s). Subsequently, the first example of an unsubstituted D-glucose structure having a ring-phosphorus atom was p r e p a ~ - e din~improved ~ . ~ ~ yield by a modification of the same scheme. Condensation of hydrazones 120 and 12 1 with methyl ethylphosphinate in the presence of trifluoromethanesulfonic acid in benzene for 35 h (64) H. Yamamoto, K. Yamamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T. Nakashima, Carbohydr. Res., 102 (1982) c l - c 3 . (65) H. Yamamoto, K. Yamamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T. Nakashima,J. Org. Chem.,48 (1983) 435-440.

SUGAR ANALOGS HAVING RING PHOSPHORUS

0-CMe,

159

OH 125 R = H

124

OAC 127

126

at 2@",followed by reduction with sodium borohydride in oxolane, gave the (.5RS)-5-[(ethoxy)ethylphosphinyl)]compound 128 (58% overall yield) as a diastereomeric mixture. Debenzylation of 128 was accomplished by repeated hydrogenolysis in ethanol in the presence of 10% Pd-C at 4Q0,to give the tricyclic compound 129. Treatment of this product with chlorotriphenylmethane in pyridine for 84 h at 35 - 40" gave the 6-0-(triphenylmethyl) derivative 130 as a 1: 1 mixture of only two diastereoisomers (17% overall yield from 128). The most likely 0 CH,OBn I1 I Et -PN-C-H

120 121)

H, / Pd - C

(1) EtPH(=O)(OMe)

7 Q-CMe, 128

0 CH,OR 11 I Et-P--C--H

0-CMe, 129 R = H 130 R=CPh,

structures, namely, (5R)-5-C-[(l?)-(3-O,P-anhydro)ethylphosphinylj-aD-xylo-hexofuranose (130a) and its (5S)-5-C-[(S)-ethylphosphinyl] diastereoisomer (130h), for these products were derived from 400-MHz, 'H-n.m.r.-spectral analysis and inspection of a CPK model. Reduction of 130 with SDMA gave the 5-(ethylphosphinyl) intermediate 131, which was then converted into the 5-(ethylphosphinyl)hexopyranose 132 by acid hydrolysis. Treatment of 132 with acetic

HIROSHI YAMAMOTO AND SABURO INOKAWA

160

anhydride - pyridine, and chromatographic separation of the crude mixture 133, gave crystalline penta-O-acetyl-5-deoxy-5-C-[(R)-ethylphosH,

0-CPh,

,O-CPh,

I

0 CH,OCPh,

II

I

-P-vC-vH

0-CMe,

O-bMe,

131

130b

130a

H,Ot

131

H

O

Ac,O

G

- C,H,N

A

c

Ir

AcO

HO

o

u OAc

OAc OAc

OH

133

132

phinyl]-P-~-glucopyranose(134) in 4% overall yield from 130, and the syrupy a anomer 135 (7%yield), as pure products. The rest of the fractions contained the other diastereoisomers, namely, the 5-[(S)ethy~phospiny~]-~-~-glucopyranose derivative 136 (2%yield) and the a anomer 137 (2%yield), along with tetra-O-acetyl-1,5-anhydro-5-deoxy5-C-[(R)-ethylphosphyinyl]-~-glucitol~~ (138; 1%); structures 134 - 138 were established by 400-MHz, n.m.r. spectroscopy (see Section 11,5). AcOCH, -

O

0

AcOCH,

W AcO R

,

AcO-~,

Et ;$$0 AcO

AcOCH, A

R

R

134 R = H, R’ = OAc 135 R = OAc, R‘ = H

136 R = H, R’ = OAc 137 R = OAc, R’ = H

c

Et

L.,:$O

OAcO

qH H

138

In contrast to the r e s ~ l t ,described ~ ~ . ~ ~ earlier, of the similar ring-enlargement of 86 (or 87) to solely the L-idopyranoses 90, only D-glucopyranoses 132a were isolated when the 1 : 1 mixture of the precursors 130a and 130b was subjected to the usual procedure; no per-0-acetyl derivatives of L-idopyranose 132b were present among the reaction products. As a possible explanation of these results, the following mechanism has

SUGAR ANALOGS HAVING RING PHOSPHORUS

161

been proposed.65 Ring closure of the acyclic phosphinyl intermediate 139a to 132a is likely to be much faster than that of the counterpart 139b (to 132b), because the two precursors, 131a and 131b, would be expected to be almost equally derived from 130a and 130b by reduction with SDMA, as illustrated in Scheme 3.The combined yield of the four diastereomers 134- 137 and the glucitoll38 was- 30%.Thus, instead of giving L-idopyranoses 132b by (the sluggish) intramolecular cyclization, most of the epimer 139b presumably yielded intermolecularly condensed, polar products. The formation of a small proportion of the glucitol 138 is explained in terms of further reduction of the phosphinyl group of 131a to the 5phosphino compound by an excess of SDMA, followed by intramolecular oxygen-transfer similar to that described in Scheme 2 for the formation of 96. The fact that ring enlargement of the 5-(ethylphosphinyl)-~-xylohexofuranose 131 gave only D-glucopyranoses 132a suggests that the relative bulkiness of the substituents on P-5and 0 - 6 greatly affects the direction of the ring closure of the key intermediates, resulting in the formation of the P sugars of either the D-gluco or L-ido type. Accordingly, a relatively large to prepare 5-deoxy-5-phosphinyl-~-glucopyranoses, substituent on 0 - 6 and a smaller one on P-5(and also on 0-3)seem to be required in order to produce a larger proportion of the desired intermediates; see formulas 88 and 131a, and illustrations ofthe steric congestion around 0-3 and P-5of these compounds in Schemes 2 and 3.

5. Structural Analysis of 5-Deoxy-5-phosphino-and -5-phosphinylaldopyranoses by X-Ray Crystallography, and by 400-MHz, Proton Nuclear Magnetic Resonance Spectroscopy and High-resolution Mass Spectrometry a. X-Ray Crystallography. -For sugar analogs having phosphorus in the hemiacetal ring, precise, X-ray crystallographic analyses have been performed on the following compounds: L-idopyranoses 67 (for two independent molecules, Ref. 45), 92 (Ref. 53),and 93 (Ref. 53),L-iditol96 (Ref. 54),and L-lyxofuranose 163a (Ref. 66; for a discussion, see Section 111,3).The precise structures of all of these compounds had not been established until the crystallographic results were available, although their gross structural assignments had been made ~ o r r e c t l y ~(for ~ . ~96 ' and 163a) or i n ~ o r r e c t l (for y ~ ~67) by 'H-n.m.r. spectroscopy. Therefore, it was considered that such an X-ray analysis would be of value not only (66) P. Luger, H. Yamamoto, and S.Inokawa, Carbohydr. Res., 110 (1982) 187-194.

(67) H. Yamamoto, Y . Nakamura, H. Kawamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T. Nakashima, Carbohydr. Res., 102 (1982) 185-196.

134 -137 (30%yield from 130)

H,O+ l3Ob

0 II

0

HO%o

___t

HO 0-CMe, l3lb

no 139b

P-Et

no

HO 132b

(-0% yield) Scheme 3

OH

SUGAR ANALOGS HAVING RING PHOSPHORUS

163

FIG.1. - O R T E P Representations3 of a Molecule of 1,2,3.4-Tetra-O-acetyl-5,6-dideoxy-5-C-[(S)-~henylphosphii1yl]-~-~-idopyranose (93).

from the viewpoint ofX-ray crystallography but also from that of molecular biology. An ORTEP8 representation of the molecular structure of 93 is shown in Fig. 1, as a representative example of the 5-phosphinylaldopyranoses. Seven ofthese compounds are in the T 1 (conformation; ~) the methyl and nitromethyl groups on C-5 are linked axially (thus showing the ~ - i d o form), and the phenyl rings on P-5are linked axially (for 67), or equatorially (for 92, 93, and 96). The acetoxyl groups, all linked equatorially (except for AcO-l of 67 and 93), have the usual orientation: the carbonyl bond is almost syn-parallel to the corresponding C - H bond at the pyranoid ring. The geometry of the pyranoid rings of these compounds is that of a regular chair, as indicated by the Cremer puckering parameters (see Table 1) and the ring-torsion angles. The inclination of the (66) C. K. Johnson, ORTEPReport ORNL-3794 (2nd revision), Oak Ridge National Laboratory, Tennessee, U.S.A., 1970. (69) D. Cremer and J. A. Pople,]. Am. Chern. SOC., 97 (1975)1354-1358. (70)G.A. Jeffreyand J. H. Yates, Carbohydr. Res., 74 (1979)319-322.

164

HIROSHI YAMAMOTO AND SABURO INOKAWA 163

96 0-50

FIG.2. -"Newman" Projection Down the P-C(pheny1) Bond in the Equatorial (Left) and Axial (Right) Case, I l l ~ s t r a t i n gthe ~ ~Phenyl Ring. [The digits mark the phenyl rings for compounds 92 (92); 93 (93); 96 (96); 67, mols. 1 and 2 (67a and 67b), and 163a (163).]

phenyl ring for the analogous derivatives 92,93, and 96, for which the phenyl ring is always equatorial, is illustrated in Fig. 2 (Ref. 54). With respect to the P=O bond, the inclination angle is smallest for 96, medium for 92, and almost 90" for 93; thus, it is apparently affected by the steric situation at C-1. When the phenyl ring is linked axially, as in 67 and 163a, a similar change of inclination of the phenyl ring is observed: it is near 90" for 67, and almost 0" for 163a, although these two compounds have slightly different steric situations at the neighboring ring-atoms. The distribution of the bond lengths and the average bond-angles of the pyranoid ring are tabulated for comparison (see Tables I1 and 111, respectively). The lengths of the phosphorus-carbon bonds of these compounds are longer than those of the carbon-carbon bond of the usual hemiacetal ring by a factor of 1.2, which is consistent with the TABLE I Cremer-Pople Puckering Parameters for the 5-(Phenylphosphinyl)-~-idopyranoses and -L-iditol" Compound

Q(pm)

e(')

4(7

67 mol. 1 mol. 2 92 93 96

61 59 69 67 65.3

3.7 3.8 12.5 6.1 13.7

338.7 329.2 20.0 346.5 347.3

Refs. 45, 53, and 54.

165

SUGAR ANALOGS HAVING RING PHOSPHORUS

TABLE I1 Bond Lengths (pm) of the Pyranoid Ring in the 5-(Phenylphosphinyl)-~idopyranoses and -L-iditol (E.s.d. Values in Parentheses)" ~

~

~

_

_

_

_

_

_

Compound

C-1 -C-2

C-2-C-3

C-3-C-4

C-4-C-5

C-5-P-5

C-1-P-5

67 mol. 1 mol. 2 92 93 96

153.0(6) 150.7(6) 151.9(4) 153.6(5) 151(1)

152.4(6) 152.4(7) 153.4(4) 152.5(5) 152.7(7)

154.1(7) 153.6(7) 152.5(4) 153.0(5)

153.9(6) 153.6(6) 153.9(4) 152.9(5) 150(1)

182.5(4) 183.7(5) 181.5(3) 191.3(4) 181.6(5)

184.1(4) 185.0(5) 183.8(3) 183.2(4) 180.3(7)

~~

a

153.2(8)

Refs. 45, 53, and 5 4

reported ratio (- 1.2 : 1)for such phosphorus-containing, six-membered The P-C rings as that of 4,4-dimethyl-l-phenyIpho~phorinane.~~~~~ bonds are slightly longer for the 5-C-[(R)-P] configurations than for the 5-C-[(S)-P]forms. For exocyclic P=O and P - C bonds, all bond lengths are almost identical. The bond angles of C-2 - C-1 -P-5 and C-4 - C-5 P-5 are slightly larger for the (R) than for the (S) configuration. Although it was not as accurate as the analyses just described, an X-ray 115 established the D-glucopyraanalysis p e r f ~ r m e d ~on ~ Jcompound j~ n~se-~C structure. ,

b. 400-MHz, 'H-N.m.r. Spectroscopy. -The precise structures of these newly prepared sugar analogs having a ring-phosphorus atom could not be determined by the usual 'H-n.m.r. spectroscopy, because of insufficient resolution of the ring-proton signals, even at 100 MHz. However, with the aid of the results obtained by X-ray crystallographic analysis, 400-MHz, 'H-n.m.r. spectroscopy has allowed the establishment of the precise configurations, as well as the most probable conformations, of these sugar analogs. By this method, assignments of the signals are, in most cases, readily made by employing first-order analysis with the aid of a decoupling technique, the effectiveness of which is exemplified by the various spec~~ tra (see Fig. 3) of ~ - g l u c o p y r a n o s e134. The 'H-n.m.r. parameters for these P sugars are summarized in Table IV. In these detailed, spectral data, there are some interesting features with regard to the chemical shifts (6values) and coupling constants (J values) of the ring protons. The general trends of these values are summarized in Table V. (71) A. T. McPhail, J. J. Breen, J. H. Somers, J. C. H. Steele, Jr., andL. D. Quin, Chem. Commim., ( 1 97 1) 1 020 - 1 02 1. (72) A . T . McPhail, J. J. Breen,andL. D. Quin,].Am. Chem. Soc.,93(1971) 2524-2525.

TABLE 111 Bond Andes of the Pyranoid Ring in the 5-(Phenylphosphinyl)-~-idopyranoses and -L-iditol (E.s.d. Values in Parenthesesy

67 mol. 1 mol. 2 92 93 96 a

111.7(4) 113.9(3) 107.4(2) 107.4(2) 109.5(4)

Refs. 45, 53, and 54.

114.8(3) 114.2(4) 111.8(3) 114.4(2) 115.1(5)

113.3(3) 113.0(3) 113.7(2) 110.5(3) 113.9(5)

113.8(4) 116.5(3) 115.5(2) 115.2(3) 115.9(5)

111.4(2) 109.7(4) 108.0(2) 105.5(2) 106.2(3)

101.6(2) 10 1.6(2) 99.8(1) 103.1(2) 10 1.3(3)

I

JI.

, , , , . ,

I

1 , 1 , , , , , , , , , 1 , , , , , , , /

H -2

H-4

H-1

H-3

ti-60 H-6b

H -5

FIG.3. -400-MHz, 'H-N.m.r. Spectra of 1 , 2 , 3 , 4 , 6 - P e n t r a - 0 - a c e t y ~ - 5 - d e o x y - 5 - C - l ( o s e (134). [(a) Ring-proton signals without decoupling, and (b-e) those with decoupling, on irradiation at H-5 (b), at H,-6 (c), at H-4 (d),and at H-3 (e ).]

TABLE IV 400-MHz, 'H-N.m.r. Parameters for 5-Deoxy-5-C-phosphino-and -phosphinyl-aldopyranosesin CDCI, -~

~

~

~

Chemical shifts (6) Compound Enbylb 20 c.

23

m

m

36h 68 92 96' 115 127

134

H-le H-la

H-2

H-3

H-4

5.27 5.43 5.3 5.94 6.11 2.66 2.50 5.60 5.57

5.45

3.42

5.24

5.63

3.49

5.40

5.63

5.16

5.3

5.87

5.54

5.88

5.80

5.55

5.76

5.60

5.44

5.72

5.78

3.58

5.52

5.83

3.88

5.70

5.38

5.72

5.22

5.58

H-5e

H-5a

2.55 1.91 2.61 1.95 2.60 1.9 3.57 2.79 2.77 2.15 2.65 2.37

H-6a H-6b

4.58 4.34 1.10'

1.04" 1.06' 3.86 3.70 4.49 4.45

AcO-1,2,3,4,6" R-P 2.16, 2.10, 3.48", 2.08, 3.77d 2.11, 2.09, 3.51', 2.08, 6.19'. 6.08f, 2.26' 2.10, 1.98, 1.98, 195,2.0, 1.16' 2.04, 1.98, 2.02, 1.93, 7.92, 7.62, 7.71' 2.06, 2.01, 2.06, 1.95, 7.80, 7.54, 7.60' - 2.05, 2.07, 2.05, 7.72, 7.54, 7.60' 2.14, 2.05, 3.49, 1.90, 7.74, 7.54, 7.61' 1.88, 1.87, 4.70", 1.86, 4.19"' 7.27" 4.21" 7.32" 7.27" 7.75, 7.47, 7.56' 2.16, 2.07, 2.01, 2.06, 1.99 2.04, 1.19'

References 23 26 33 46 55 55 46 65

65

Entry 2" 19

5.60

5.41

3.62

5.24

5.4

5.3

5.4

5.4

5.3

5.4

-

37h 38h

93 135

5.67 5.60 6.09 5.84 -

5.75

5.68

5.78

5.55

5.45

5.57

5.22

3.36

4.98

5.24

5.49

5.10

5.25

5.65

5.23

4.87

5.22

5.20

5.04

3.54

4.96

4.90

5.75

5.3

4.91

5.65

5.04

2.43 2.13 2.56 2.0 2.56 2.0 3.05 2.50

Entry 39 21

-

94

5.44 5.95

136 138' Entry 4' 22 66h 95

-

5.70 2.73 2.1 5.64 6.25 6.15 -

2.52 1.92 3.11 2.58 2.53 2.48 2.22 4.2 3.20 -

-

-

1.36'

4.45 4.41 1.50

4.75 4.29 4.68 4.29 5.3 5.1 1.56k

2.22, 2.12, 3.51', 2.09, 3.73d 2.16, 2.00, 2.00, 1.95, 1.75, 1.20' 2.17, 2.02, 2.02, 1.96, 1.7, 0.88P 2.15, 2.09, 2.08, 1.98, 7.78, 7.54, 7.62' 2.21, 2.09, 2.03, 2.07, 1.98 1.71, 1.22'

23 33

33 55 65

2.14, 2.12,3.51",2.09, 3.94d 2.12, 2.03, 2.07, 2.02, 8.00, 7.62, 7.651 2.14, 2.07, 2.05, 2.00, 2.00 2.1, 1.40' - 2.07, 2.09, 2.08, 2.06 1.84, 1.83, 1.37'

23

2.22, 2.12, 3.50', 2.06, 3.88d 2.25, 2.00, 1.96, 198, 8.0, 7.6, 7.6-1 2.23, 2.02, 2.13, 2.01,7.94, 7.65, 7.65-1

23

55 65 33

33 55

(continued)

TABLE IV (continued) Coupling constants (Hz)'

Entry l b 20

23 36h CI

68

-4

0

92 96'

10.5

-

10.8

-

11

-

10.5 10.75 4.5 11.7 14.0"

115 127 134 Entry 2" 19

-

11.0

-

11.2

-

11.0 2.8

-

5.5 0 1.6 0

8.7 3.8 9.2 2.6 10 3 9.5 3.5 9.5 2.4 9.5 2.5

2.2 0 2.75 0 17.8 2.0 5.3 0 2.7 0.3 2.8 0.3 3.6 0.2

9.6 2.8 9.5 3.0 10.0 3.0

14.2 2.0

9.8 1.0

8.6 9.5 9.5

4.5 12.5 4.4 12.0

0.8 3.2 4

22.5 11.0 20.0 5.3

-

-

14.8

-

14.4 14 -

-

3.5 11.0 16.8

-

-

3.2

10.1

6.5 4.6

3.4

21.7

8.5 2.0 7.6

9.7

4.5

3.7

20.0

7.5

-

16.9

-

2.7

3.5

7.0

-

15.0

-

7.0 6.0 7.4 5.0

-

9.8 11.5

10.0 14.5 11.5 15.0

-

-

14.0

-

9.8

9.8 9.8 10.0

-

-

12.0 11.5

-

11.5 9.3

4.5 12.0

11.5

-

2.8

-

2.7

-

3.0

22.5 12

4.0

3.5

-

-

14.0 -

-

-

15'

-

-

-

19.3' 7.6' 11.0d -

37*

3

38h

3

93

3.1

135

3.2

Entry 3q

21 94 136 138'

-

10 2 10 2 11.5 2.1 11.7 0

-

3.6

-

-

10.8

-

10.8

-

10.5 4.5 10.0 14.0"

0

10.4 0 11 0 15.0 0

17.5' 7.0' 9.7 0.9 12.5 0.3 9.6 2.1 8.6 4.5 11

9.9 11.8

4.7

-

14.5 9.6 2.0 9.1 11

10.0 2

10.0

10.0 0 9.6 2.5 9.4 3.4

9.7

4.5 12.0 4.3

-

3.1

3.0

2.0 0

21.6

7.6

-

16.2

4.5

8.3 6.3

14.5

-

16.2 18.5

23.6 10.0 15.6

7.6

14.8

-

-

14.3

-

-

-

-

4

-

3.0

66

2.5

95

3.0

-

-

-

23 9 23.1 8.7

-

14.3

-

7.5

-

12

18.0

3.2 2.0

25.0 12.0

15.5

11.5

15'

15.2'

7.0p

-

18.3' 7.5' 10.5d

-

18' 7.5' 17.6' 7.6'

0

Entry 4'

22

-

-

12.0

-

-

15.0 2.0 8.5 1.2 8.6 1.7

9.6 9.1

4.8 12.0

2.1

4.6 -

6.1

-

-

13.7

-

10.5d

-

-

-

a Acetoxyl assignments are interchangeable. * Pyranoses having Ac0,-1 and P=O,. Me0-3. P-OMe. PC=C-H(2) (3]H,p 10.2, '1H.H 2.8 Hz). fP-C=C-H(E) 29.8, ' J H , ~ 2.8 Hz). KP-C(OAc)=C. Measured at 100-MHz.'P-CH,-CH3.jP-Ph(o,m,p). H,-6.' 1.5-Anhydro-~-iditol."O-CH2Ph(]11.8Hz)." 0-C-C,H,. Pyranoses having Ac0,-1 and P=O,. p P-CH,-C,H,. Pyranoses having Ac0,-1 and P=O,. ' 1,5-Anhydro-~glucitol. Pyranoses having Ac0,-1 and P=O,. ' J Values confirmed by double resonance.

HIROSHI YAMAMOTO AND SABURO INOKAWA

172

TABLE V Characteristic Features in the 6 and J Values for the 54 Phosphinyl)aldopyranoses Pyranose-'C, with P(=O,)

Ring proton

He-1

11.2

11.P

K-1 H-2

Ii.sr

11.2 1L.P

H-4

6 6 6

He-5

14.5r

s 15e.P

Ho-5

14,5n

15o.P

2.8-3.2 10-14 2 10.5-11.2 2.4-3.6 5.4- 5.6" 5.6-5.82b 5.25- 5.46a 5.5-5.88b 4.5-6.5 20-22.5 11.5- 14.5 3.5-5.3

Pyranose-'C, with P(=O,)

2.5-3.0 8.5-9 1.2-2.0 10.5-10.8 10-11 5.0-5.2" 4.87-5.0b 4.98-5.2" 5.05-5.3b 4.5-4.8 15-16 12 10-18

For 5-(alkylphosphinyl)aldohexopyranoses.bFor 5-(pheny1phosphinyl)aldohexopyranoses.

The values of the geminal P-C-H coupling constants andJ,,,) d these phosphinyl compounds apparently depend upon the magnitude of their approximate O=P-C-H dihedral angles, as shown in Table V. Thus, the anti orientation of the O=P-C-H group exhibits a lower magnitude of coupling than the gauche orientation. A similar dependence of the geminal P-C-H coupling constant on the dihedral angle has been reported both for linear and cyclic phosphonyl compounds.73-75 Application of these principles to the structural analysis permitted establishment of the configurations of the ring-carbon atoms and the orientations of the protons thereon, and the stereochemistry of the phosphorus atom in these pento- and hexo-pyranoses. c. High-resolution Mass Spectrometry. -Because of the versatile applicability to structural assignments, an extensive, systematic investigation of the mass spectra of carbohydrate derivatives has been undertaken, and a wide variety of general degradation-pathways has been well (73) A. N. Pudovik, I. V. Konovalova, M. G. Zimin, T. A. Kvoinishnikowa, L. I. Vinogradov, and Yu. Yu. Samitov, Zh. Obshch. Khim., 47 (1977) 1696-1703. (74) Yu. Yu. Samitov, E. A. Suvalova, I. E. Boldeskul, Zh. M. Ivanova, and Yu. G. Gololobov, Zh. Obshch. Khim., 47 (1977) 1022- 1027. (75) For a review of 'H-n.m.r. spectroscopy of cyclic phosphorus compounds, see L. D . Quin, The Heterocyclic Chemistry ofphosphorus, Wiley, New York, 1981, pp. 31 9 359.

SUGAR ANALOGS HAVING RING PHOSPHORUS

173

e s t a b l i ~ h e d . ~Detailed "~~ analysis of the mass spectra of some of those sugar analogs having phosphorus in the hemiacetal ring has revealede1 certain characteristic features that are considered to be of use in structural assignments for these phosphorus sugars. As a representative example of these compounds, the analysis of the high-resolution, electron-impact (e.i.) mass spectrum of the D-glucopyranose derivative 134 is shown in Fig. 4. Although not of high intensity, the molecular-ion peaks of these phosphinyl sugar analogs are usually detectable as the protonated species [(M l)+;probably due to the resonance-stabilizedoxoniumform] in the e.i. mass spectra, whereas the molecular ions of the usual carbohydrate derivatives (having a ring-oxygen atom) are barely observable7eowing to their lability. A highly unusual feature in the mass spectra of the per-0-acetylated derivatives of these P sugars is that the most intense peaks (except for the peaks at m/z 43, due to CH,CO+ ions of much higher intensity) are normally those for the fragments still having the phosphorus-containing ring. This is also in striking contrast to the spectra76of per-0-acetylated monosaccharides having an oxygen-containing ring; in these, the intensities of the fragments retaining the hemiacetal ring are generally much lower than those of the ring-ruptured ions. The most probable fragment-ions of the first series (A, according to ~ ~134 ) are illusthe nomenclature used by Kochetkov and C h i ~ h o v of trated in Scheme 4; these ions are produced by loss of the substituent from C-1, with subsequent, stepwise elimination of other substituents. The species A31, formed from the molecular ion by successive loss of one acetic acid and two ketene groups, consists of the base peak, suggesting high stability of the phosphorus-containing ring-system. Further elimination of two molecules of acetic acid from this species leads to the species As2 and As3 having the 1,2-dihydr0-l-methylene-1~-phosphorine ring-system, which still possesses high intensity owing to the resonancestabilized forms (see Scheme 4).The presence of such a set of fragment ions of the A series is, in turn, strongly indicative of the 5-deoxy-5C-(phosphiny1)hexopyranose structure. The mass spectrum of the Q anomer (135) closely resembles that of the

+

(76) K. Biemann, D. C. DeJongh, and H. K. Schnoes, J . Am. Chem. SOC., 85 (1963) 1763-1771. (77) N. K. Kochetkov and 0.S. Chizhov, Ado. Carbohydr. Chem., 21 (1966) 39-93. (78) K. Heyns, H. F. Grutzmacher, H. Scharmann, and D. Mueller, Fortschr. Chem. Forsch.,5 (1966) 448-490. (79) O.S. ChizhovandN. K.Kochetkov,MethodsCarbohydr.Chem., 6(1972) 540-554. ( 8 0 ) J. Lonngren and S. Svensson, Ado. Carbohydr. Chem. Biochem., 29 (1974) 41 - 106. (81) H. Yamamoto and S. Inokawa, Phosphorus Sulfur, 16 (1983) 135-141.

h

0

n

I-.

0. N

sn

4

t

4

0

f

0

n

v1 0

N

0

N 0

Y) 0

v

U

h

3

L

I

d

4

rz

SUGAR ANALOGS HAVING RING PHOSPHORUS

+

t

- m,co

OAC

-

AcOCH,

OAC

+ OH Et

OAC (1.4%

- CH,CO

Et

OH

OH

m/s 391

m/z 451 [2.69; @ I)'] l+

-

+

OH

AcOCH,

AcO

AcO

OAc

P 75

OH

m/z 307

m/e 349

4)

(66.4%

4)

AcOCH,

HO

-CH CO 1 ACO

HO OH m / z 241

OH

m/z 205

(83.6%;

OH m/z 306

OH

m/z 289

4')

):A

(76.28;

- CH,CO -H

HO

m / z 187 (70.09; 4 2 )

HO

- CH,CO

HO

-H

Ac 0

m/z 229 4')

m/z 1% (66.7%; 4 ')

-

m/z 265 (19.8% &*)

(16.6%

OH

A0

t----c etc.

Scheme 4

+

anomer 134, but the corresponding peaks of the A series [(M 1)and A, - A3] are of higher intensities than those of 134; this is in accord with the fact that the A, peak in the mass spectrum of a-D-glucose pentaacetate is more intense than in that of its j3 a n ~ r n e r . ' ~ Simultaneous, or stepwise, rupture of two bonds (C-2- C-3 and C-4 C-5) of the pyranoid ring in species A,' (or in its precursors) gives rise to ring-opened fragments of another series, B, which accounts for the peaks at mass 165 (Be1), followed by degradation producing the peaks at m/z 145, 136, 121, 103, 93, and 77. These peaks, of relatively low intensities, imply the minor importance of these ring-opening fragmentations in the e.i. mass spectrum. Besides the ring rupture (series B), there exists another type of cleav-

176

HIROSHI YAMAMOTO AND SABURO INOKAWA

age that gives fragments of appreciable intensities, at m/z 111 and 95, which are produced by the pathway illustrated in Scheme 5. This type of removal of only the heteroatom from the ring (as a phosphinyl group) is another characteristic feature that is normally absent from the spectrum of the usual sugar derivati~es.'~-~O

W+1)

OH I

- CH,CO

- Et P(=0)H

7

0 Ac 0

OAc

OAc

- 2 AcOH - CH,CO

m/z 95 (33.0%) Scheme 5

m/z 111 (29.0%)

Similarly, the mass spectra of the tri-0-acetyl derivative (127) of 3,6di-O-benzyl-5-(phenylphosphinyl)-~-glucopyranose and of those (19 and 20) of 5-(methoxyphosphinyl)xylopyranosehave been analyzed*'; the main fragmentation is, again, the stepwise removal of the substituents from the ring-carbon atoms and C-6 (series A), leading to the formation of similar 1,2-dihydro-A5-phosphorine derivatives.

111. MONOSACCHARIDES HAVING A PHOSPHONYL GROUP IN THE FURANOSE RING 1. 2,3,4-Trideoxy-4-phosphinylpentofuranoses

Many examples of monosaccharides having nitrogen or sulfur in the furanose ring have been reported,1°-13and some of these compounds, for example, the 4-thio-~-ribofuranosyl derivative 140, possess a variety of

OH

HO 140

SUGAR ANALOGS HAVING RING PHOSPHORUS

177

novel biochemical properties.s2 On the other hand, relatively few examples of monosaccharides having phosphorus in the furanose ring have been reported. The main reason for this seems to be the difficulty in preparing their precursors, compared with those for pyranose compounds described in the previous Section. A first, very preliminary study of the preparation of compounds of this class has been r e p ~ r t e d ,utilizing ~ ~ . ~ ~an equilibrium shift that involves ring contraction of a pyranoid to a furanoid ring (see Scheme 1). For the preparation of the precursor, methyl 2,3-dideoxy-(lS)-~~pent-2-enopyranosid-4-uloses4 (141)was hydrogenated in the presence of Pd-C, to give an almost quantitative yield of the pentopyranosid-4ulose 142.Treatment of 142 with p-tolylsulfonylhydrazine, followed by condensation of the product with 75 and 76,respectively, in the presence of p-toluenesulfonic acid, afforded the methyl 4-(dimethoxyphosphinyl)-4-(p-tolylsulfonylhydrazino)pentopyranoside derivative 143 (42% overall yield from 142),and the 4-[(methoxy)phenylphosphinyl] compound 144 (57% yield from 142),respectively. Reduction of 143 and 144 with an excess of sodium borohydride respectively gave methyl 2,3,4-trideoxy-4-C-(dimethoxyphosphinyl)and -4-C-[(methoxy)phenylphosphinyl]-DL-glycero-pentopyranosides[ 145 (78% yield) and 146 (66% yield), respectively]. Treatment of compound 146 with SDMA, followed by acid hydrolysis, gave 2,3,4-trideoxy-4-C-(phenylphosphinyl)-DL-glycero-pentofuranose(147;36% overall yield from 146). As usual, the product 147 was characterized by derivatization to the per-0-acetyl compounds, 1,5-di-O-acetyl-4-C-(phenylphosphinyl)pentofuranoses 148.Although separation was not attempted, the acetates (S)-phen148 apparently consist of 1,5-di-O-acetyl-2,3,4-trideoxy-4-C-[ ylphosphinyl]-P-~-glycero-pentofuranose (148a),its cy anomer (148b), the 4-C-[(R)-phenylphosphinyll-/?-~-glycero-pentofuranose 1,5-diacetate (148c), and its a anomer (148d)(together with enantiomers of these compounds). The most plausible conformers, 148a-d, are speculative, but are presumed by analogy with those of the structurally similar compounds 160- 163 (see Section 111,2); however, assignment of the exact structures, as well as presentation of the yields of the individual components, are not yet possible (because of the low resolution of the 'H-n.m.r. spectra at 60 MHz). (82) A. K. M. Anisuzzarnan andR. L. Whistler, Carbohydr.Res., 55 (1977) 205-214, and references cited therein. (83) M . Yarnashita, M. Yoshikane, T. Ogata, and S. Inokawa, Tetrahedron, 35 (1979) 741 - 743. (84) 0.Achmatowicz, Jr.. P. Bukowski, B. Szechner, Z. Zwierzchowska, and A. Zamojski, Tetrahedron, 27 (1971) 1973-1996.

HIROSHI YAMAMOTO AND SABURO INOKAWA

178

141

142 ( 1 ) TaNHMI,

0 MeO-P

0

II

NaBH,

H ' O

O

M

e

MeO--P

II

c -

143 R=OMe 1 4 4 R = Ph

1 4 5 R = OMe 1 4 6 R = Ph

0 (1)SDMA 146

(2)HCl

-

OR

H 147R=H 1 4 8 R = AC

wb CH,OAc

148m

CH,OAc

$0 148c

'4-0 AcO 148b

ppa CH,OAc

OAc

B

148d

SUGAR ANALOGS HAVING RING PHOSPHORUS

179

2. 4,5-Dideoxy-4-phosphinylpentofuranoses A further example of this class of compound was ~ r e p a r e dfrom ~ ~ .an~ ~ acyclic precursor. 2,3-O-Isopropylidene-~-ribose diethyl dithioacetale5 (149), which ~ f ' D-ribose, ~ was used as the starting material for may be ~ r e p a r e d ~from this synthesis. The hydroxyl groups of 149 were first acetylated with acetic anhydride-pyridine, to give 150 (89%),and diacetate 150 was treated with mercuric chloride-cadmium carbonate, to afford the dimethyl acetal 151 (92% yield). This compound was deacetylated with sodium methoxide, providing a quantitative yield of the dimethyl acetal 152.Compound 152 was then converted into the 5-p-toluenesulfonate 153 (96% yield), and 153 was efficiently oxidized (96% yield) to the pentos-4-ulose derivative 154 by means of dimethyl sulfoxide - oxalyl chloride - triethylamines8 in dichloromethane at - 70". In accordance H

EtSCSEt

H MeOCOMe

HCO,

HCO,

I

I

,CM%

HCO

I

HCOR

I

149 R = H 1 5 0 R = AC

H MeOCOMe

II HCO,

I

150

HgCl,-CdCO, MeOH

*

I

HCO'

CMez

II

HCOR I 151 R = R ' = A c 152 R = R' = H 1 5 3 R = H , R' = Ts

153

I

HCO'

CMez

II

c=o I

164

with the ~ c h e m e ~described ~ * ~ * in Section I1,3, compound 154 was treated with 1 equivalent of methyl phenylphosphinate in the presence of 1.2equivalents of DBU at room temperature, to give (4RS)-4,5-anhydro-4-C-[(RS)- (methoxy)phenylphosphinyl]-D-erythro-pentosedimethyl acetals 155a (19% yield) and 155b (43% yield); the structures of these epimers were derived from study of their 'H-n.m.r. spectra. The anti-Cram type of addition seems to afford the major product 155b, as had been observed in the formation of the a-D-xybhexofuranose 82 (see formula 81 for the addition reaction). Although hydrogenation of 155a and 155b in the presence of Raney nickel was conducted separately, both compounds gave, in 60% yield, an almost identical mixture of (4RS)-4,,5-dideoxy-2,3-O-isopropylidene-4(85) K . Blumberg, A. Fuccello, and T. van Es, Curbohydr. Res., 70 (1979) 217-232. (86) G . W. Kenner, H. J. Rodda, and A. R. Todd,J.Chem. Soc., (1949) 1613-1620. (87) M. A. Bukhari, A. B. Foster, J. Lehrnann, and J. M. Webber,J. Chem. SOC., (1963) 2291 - 2295. (88) A. J. Mancuso, S..-L.Huang, and D. Swern,]. Org. Chem.,43 (1978) 2460-2482.

HIROSHI YAMAMOTO AND SABURO INOKAWA

180

C-[(methoxy)phenylphosphinyl]-~-erythro-pentosedimethyl acetals (156a and 156b) in the ratio of 3 : 1 (with respect to the configuration of C-4).This result suggested the formation of acommon intermediate, such isopropylidene - 4 - C- [(RS)- (methoxy)as (4RS) - 4,s - dideoxy - 2,3- 0phenylphosphinyl]-~-erythro-pent-4-enose dimethyl acetal, by deoxygenation, prior to the reduction during hydrogenation. Reduction of the mixture of 156a and 156b with SDMA gave a diastereoisomeric mixture of phosphinyl compounds 157, which was immediately hydrolyzed by acid, to afford 4,5-dideoxy-4-C-[(RS)-phenylphosphinyl]-~-ribo-and -L-lyxo-furanose (158). The structure 158 was determined6' by 400-MHz, 'H-n.m.r. spectroscopy of the per-0-acetyl derivatives 159; these are 1,2,3-tri-O-acety1-4,5-dideoxy-4-C-[(RS)H MeOCOMe

H MeOCOMe

HCO,

HCO,

I

154

PhPH(=O)OMe

I

I

H,-Raney Ni

* HCO

I

,C--P(

=O)Ph(OMe)

0l,

CH, 1550 (4s) 155b (4R)

I CMe, I 40 H-C-P-Ph I R' HCO/

CH,

156a, b R = OMe 157 R=H

0

RO

I

OR

158 R = H

159 R = A c

phenylphosphinyll-~-ribo-and -L-lyxo-furanoses 160 - 163; see Scheme 6 for their probable conformations (and yields from 156). The exact configuration and conformation of the crystalline product 163a was determined66by X-ray crystallography (see later). As regards the yields of the eight diastereoisomers, the p anomers (160b and 16lb) preponderated on formation of the D-ribofuranoses, whereas, for the L-lyxofuranoses, more of the a anomers (162a and 163a) was produced; this behavior was explained in terms of the thermodynamic stability of precursor 158. The ratio of the combined yields of D-ribofuranoses (160a,b and 161a,b) to the L-lyxofuranoses (162a,b and 163a,b) was 9 : 10, whereas that of the (S) to ( R )isomers of the ring-phosphorus atom (160a,b and 162a,b to 163a,b) was 11 : 26.

SUGAR ANALOGS HAVING RING PHOSPHORUS

181

I

AcO 162a (ZE; 3.6%) M2b (0%)

163a ( E 3 ; 12.5%) 163b (E9;3.2%)

a R = H , R’ = OAc; b R = OAc, R’ = H (conformations in CDCI,; yields) Scheme 6

Possible factors influencing these results were that an almost equimolar (4R and 4s) equilibration had been caused by the strongly basic SDMA during the reduction of 156,but the hemiacetal formation from 157 to 158 proceeded more readily for the [ (R)-phenylphosphinyllpentofuranoses 158, because there is less steric congestion between the P-phenyl and the 2-and 3-hydroxyl groups in the precursors of 158.

3. 4-Deoxy-4-phosphinylaldopentofuranoses Following a scheme similar to that described in Section III,l, compounds having a complete D-ribofuranose structure and a ring-phosphorus atom were prepared.33g89 Methyl 2,3-O-isopropylidene-c~-~-lyxopyranoside (164),preparedso (89) H.Yamamoto, Y. Nakamura, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T. Nakashima, Carbohydr. Res., 118 (1983) c7-c9. (90) M. Bobek and R. L. Whistler, Methods Carbohydr. Chem., 6 (1972) 292-296.

HIROSHI YAMAMOTO AND SABURO INOKAWA

182

from D-galacturonic acid, was oxidized by the procedure of Mancuso and coworkerss8 to give methyl 2,3-O-isopropylidene-P-~-erythro-pentopyranosid-4-u!ose, which was then converted into the p-tolylsulfonylhydrazone. The addition of methyl ethylphosphinate to this hydrazone, followed by reduction with sodium borohydride in oxolane, afforded the phosphinate 165 (28% overall yield from 164).

0,

o,

0,

CMe,

164

so

o,

CMe,

165

166

Compound 165 was reduced with SDMA and the product was hydrolyzed with acid to effect ring contraction, affording 4-deoxy-4-C-[(R,S)ethylphosphinyl]-a,p-~-ribo-and -L-lyxo-furanoses (166), which were characterized by conversion into the peracetates. After separation by chromatography on silica gel, structures 167 - 170 were established for these peracetates by 400-MHz, 'H-n.m.r. spectroscopy and high-resolution mass spectrometry; the structures of these products, their probable conformations, and the yields from 165 are summarized in Scheme 7 . [(S)-P]-D-Tdbo

[(R)-P]-D-n'bO

H

H HA

AcO

Rf

167a ('E, 12%)

167b CE

= 'E,

CH,OAc

p

;

p

ACO (E214%)

12.7%)

168b ( E , == E , , 12.8%)

aR=H,R'=OAc

bR=OAc,R'=H

-

[ (S) PI - L- zyxo

[(R)-P]-L-lyxO

H

Et

R 169a ('E

-

,

AcO 5.3%)

170a (E,

Scheme 7

*

ES,2.8%)

SUGAR ANALOGS HAVING RING PHOSPHORUS

183

n

FIG.5. -ORTEPs8 Representations4of a Molecule of 1,2,3-Tri-O-acetyI-4,5-dideoxy-4C-[(R)-phenyIphosphinyl]-cu-~-lyxofuranose (163a).

It is noteworthy that, by employing this method, the D-ribofuranose derivatives (167 and 168)were preponderantly produced (41.5%)compared with the L-lyxofuranoses (169 and 170; 8.1%yield from 165). 4. Structural Analysis of 4-Deoxy-4-phosphinylpentofuranoses by X-Ray Crystallography, and by 400-MHz, Proton Nuclear Magnetic Resonance Spectroscopy and High-resolution Mass Spectrometry a. X-Ray Crystallography. -The precise structure of the crystalline compound 163a has been established66by X-ray crystallographic analysis, and the ORTEP69representation of the molecular structure is shown in Fig. 5. The fivemembered ring has the E, conformation, with a tendency ~.'~ towards the ,T2 form; the Cremer -Pople puckering p a r a r n e t e r ~ ~are q = 42.0 pm and 42= 102.98", and the asymmetry parameters after Duax and coworkersQ1are ACs = 8.4"for the E, conformation and AC2 = 12.9" for the ,T2 conformation. The acetoxyl group on C-2 and the methyl group on C-4 are linked quasi-equatorially, whereas the Ac0-3 (91) W. L. Duax, C. M. Weeks, and D. C. Rohrer, Top.S t e r e o c h . , 9 (1976)271-383.

184

HIROSHI YAMAMOTO AND SABURO INOKAWA

group is linked axially; thus, C-3 is the out-of-plane atom in the E3 conformation. The endocyclic lengths P-5-C-1 and P-5-C-4 are 186.1 and 182.6 pm, respectively. The bond angle of C-1 -P-5 -C-4 is 94.3", whereas the rest of the angles for the furanoid ring range between 105.4 and 108.5". The plane of the phenyl ring has an orientation parallel to the P-5 - 0-5 bond, and its inclination is shown in Fig. 2 (see Section 11,5). In this orientation, steric collisions with the adjacent acetoxyl group on C-1 are avoided. The acetoxyl group on C-1 differs considerably from the usual, syn-parallel arrangement of the C=O bond with the C-H bond of the corresponding ring-atom.

b. 400-MHz, 'H-N.m.r. Spectroscopy. -The parameters of the n.m.r. spectra for the 4,5-di- and 4-deoxy-4-C-[(R,S)-phenylphosphinyl]-~ribo- and -L-lyxo-furanoses (160- 163 and 167 - 170) are summarized in Table VI, and some important features of these spectral data for the structural analysis are as follows. When the methyl signal of 160- 163 appears at relatively low field (6 1.3- 1.4), the methyl group apparently lies close to the oxygen atom on the phosphorus, whereas a small S value (-0.95) indicates that the two groups are remote; this may be inferred by analogy with the n.m.r. data for similar, cyclic phosphorus c o r n p ~ u n d s . ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Relatively large values (7 - 12 Hz) suggest a trans relationship between H-3 and H-4 (thus indicating the D-ribofuranose form), whereas smallerJ,,, values (4.3 - 5.8 Hz) suggest the L-lyxofuranose structure. On the other hand, the large J4,, values (22-24 Hz) for the H-4 signal suggest a trans relationship of the methyl and P=O groups, whereas the small J4,p values (6 Hz) support a cis (or gauche) relationship; these features are generally observed (see Section 11,5).This result permits establishment of the configuration of P-4. Similarly, the large J1,, value (8- 1 2 Hz) of the H-1 signal indicates a cis (or gauche) relationship of the H-1 and P=O groups, whereas the small value (0.8-5 Hz) suggests a trans relationship, thus establishing the configuration of C-1. The significant difference in the magnitudes of and I,,, is indicative of an unsymmetrical conformation with respect to H-2 and H-3. It has been proposede7that, when these 4-C-(phosphinyl)pentofuranoses have a largeJ,,,value (23- 28 Hz) and a smallJ,,, value (0-5Hz), as in 163a,b, the compounds exist in the E, conformation, wherein the approximate dihedralanglesofp-C-4-C-3-HandP-C-1 -C-2-Hare 150and9Oo, respectively; the E, conformation of 163a was later confirmed by X-ray crystallographic analysis.ee On the other hand, reversed magnitudes of and],,,, as with 161a and 162a, support the E2 conformation for the compounds, whereas when these magnitudes are almost the same, as for 160b, this suggests an averaging between the E , and E3 (or ,E and ,E)

TABLE VI 400-MHz, 'H-N.m.r. Parameters for 4-Deoxy- and 4,5-Dideoxy-4-C-(phosphinyl)aldopentofuranosesin CDCI, Chemical shiftsa (6) Compounds

H-1

H-2

H-3

H-4

H-5

160a 160b 161a 161b 162a 163a 163b 167a 167b 168a 168b 169a 170a

5.49 5.15 5.24 5.29 5.33 5.51 5.26 5.45 4.97 4.97 5.43 4.98 5.92

5.72 5.92 5.62 5.75 5.38 5.40 5.78 5.66 5.75 5.36 5.50 4.80

5.46 5.00 5.33 5.71 5.70 5.59 5.39 5.54 5.00 5.20 5.68 5.8"

2.75 2.67 3.01 2.90 2.75 2.50 2.57 2.58 2.62 3.12 2.95 2.88 2.48

1.30d 1.3gd 0.96d 1.06d 0.95d 1.2Sd 1.36d 4.46 4.53 4.47 4.43 4.45" 4.29

H-5'

A~0-1,2,3,5~

-

cc

-

2.23, 2.14, 2.12, 2.16, 2.23, 2.14, 2.21, 2,21, 2.15, -

-

1.61, 2.22, 2.08, 2.22, 2.28, 2.14,2.17, 2.13, 2.12, 2.08 2.23, 2.13, 2.12, 2.10 2.22, 2.19.2.11, 2.09 2.19, 2.18,2.14,2.11 2.22, 2.17, 2.13.2.09 2.20, 2.16.2.13, 2.02

-

4.37 4.30 4.34 4.34 4.30 4.20

P-CH-Me, P-CH'-Me, P-C-CH, 7.90, 7,58, 7.62" 7.75, 7,58, 7.62' 7.73, 7.57, 7.61' 7.90, 7.6, 7.6' 7.72, 7.56, 7.62' 7.75, 7.57, 7.61' 2.1' 1.92 2.28 2.01 2.08 2.05 2.00 1.94 2.04c 1.83 1.74 1.69

1.39 1.35 1.30 1.29 1.23 1.21 (continued)

TABLE VI (continued)

~

160a 160b 161a 161b 162a 163a 163b 167a 167b 168a

168b 169a 170a

5 5.7 4.6 3.0 10.5 9.4 3.2 4.5 6.0 4.8 3.6 10.0 8.6

11.5 1.4 0.8 8.0 0.6 12.1 5.8 12.5 2.5 2.6 7.8 0.5 10.2

0.5 0 0.6

0

0 0

0.5 0 0.5 0

c

c

3.8 3.0 3.5 3.0 3.2 2.8 3.0 3.6 3.0 3.8 1.0 3.0

11.7 26.6 16.2 27 0 5.0 26.5 10.5 24.6 15.1 3.5 15.2

7.0 12.3 10.5 4.8 4.3 5.8 11.2 6.0 12.0 10.0 4.0 1.8

13.5 0.5 6.0 27.5 22.8 1.0 13.5 1.0 5.5 25 31

7.0 7.5 7.2 7.4 7.5 7.3 7.2 8.5 7.3 4.8 5.2 9.5 11.5

6.0 24.0 22.5 22 6.0

5.8 7.5 7.0 6.8 6.0 5.2

6.5

8.7 6.5 22.0 21.2 20.5 12.0

11.2 12.0 12.0 11.8 12 11.5

14.8 14.2 16.5 16.5 16.5 15.1 14.6 12.0 9.2 14.8 14.8

17.0 12.2 17.0 16.0

15.0 15.0

9.0 11.5

15.0 15.0

15.0

10.5

15.0

c

c

18.5 17.0 17.0 17.0 17.0 16.5

7.8 7.5 7.5 7.5 7.5 7.5

Chemical shifts (6 values) are in parts per million from Me,% Acetoxyl assignments are interchangeable. Values are approximate, or uncertain. CH, . P-C6H5 (0, p , m).f] values confirmed by double resonance.

SUGAR ANALOGS HAVING RING PHOSPHORUS

187

conformations. It was presumeds7 that these shapes would allow minimization of the nonbonded interaction between the phenyl ring on the ring-phosphorus atom and the substituents on the adjacent atoms. When the energy barrier between these two forms (E, and E3) is relatively low, the rapidly interconverting conformations are expected to exist in solution. There have been reported some examples of similar angular dependence of P- C - C - H vicinal coupling-constants upon the dihedral angles in the case of phosphonate compoundsse and P(V)-heterocyclic systems.Q3,Q4 c. High-resolution Mass Spectrometry. -Analysis of the mass spectrum of tri-O-acetyl-4,5-dideoxy-4-f(R)-phenylphosphinyl~-~-~-lyxofuranose (163a) has been made,81 and the most important of the series of degradation pathways are shown in Scheme 8. Here again, the preponderant fragmentation is the A series, to give rise to ions A,-A, of the As-phosphorole structure, followed by removal of the phenylphosphine oxide from the furanoid ring; the molecular-ion peak of 163a was con-

m / z 368 (0%; M)

m/r 326 (2.5%; A,)

I

m / z 267 (100%; &)

- CH,CO

m / z 84 (69.1%)

m / z 207 (57.2%; A:)

m / z 225 (99.6%; A:)

+

H-P=O I Ph

m / z 125 (66.5%)

Scheme 8

(92) C. Benezra, Tetrahedron Left., (1969) 4471 -4474. (93) T. C. Chan and K. T. Nwe, Tetrahdron, 31, (1975) 2537-2542. Awerbouch and Y. Kashman, Tetrahedron, 3 1 (1975) 33-43. (94) 0.

188

HIROSHI YAMAMOTO AND SABURO INOKAWA

firmed by 23Na, field-desorption, mass spectrometry. Careful comparison of these fragmentation patterns of 163a with those of the pyranoid compounds (see Section II,5,c) would provide a convenient method for characterizing phosphorus-containing, furanoid structures of related compounds. The mass spectra of 167b, 168a, and 168b showedae fragmentation patterns similar to that of 163a.

IV. BIOLOGICAL ACTIVITIESOF MONOSACCHARIDES HAVING PHOSPHORUS IN THE HEMIACETAL RING Since the first isolation of 2-aminoethanephosphonic acid (17 1)from rumen ciliate protozoa,e5 related compounds (for example, phosphinolipides.e7172) in considerable number have been found in Nature, and 0

II H,NCH,CH,-P-OR I

OH

171 R = H 1 7 2 R = CH,CH(OCOR')-CH,OCOR"

the biochemistry of such substances containing a carbon - phosphorus ~ ~ * ~ ~these 2bond appears to be drawing increasing i n t e r e ~ t . Besides aminophosphonic acid derivatives and several antibiotics found in Nature [such as f o s f o n o r n y ~ i n(72) ~ ~ and phosphinothricinloO(173), a wide 0 H0,C -CH- C!H,CH,I

NH,

II P -CH, I

OH 173

(95) M. Horiguchi and M. Kandatsu, Nature, 184 (1959) 901-902; Bull. Agric. Chem. S o c . j p . , 24 (1960) 565-570. (96) G . Rouser, C. Kritchefsky, D. Heller, andE. Lieber,j. Am. Oil Chem. Soc., 40 (1963) 425-454. (97) E. Baer and N. Z. Stanacev,]. B i d . Chem., 239 (1964) 3209-3214. (98) M. Tamari, Kogakuno Ryoiki, 31 (1977) 955-965; Chem. Abstr., 88 (1978) 116,400. (99) T. Hori and M. Horiguchi, Bfochemkity of C - P Compounds, Gakkai Shuppan, Tokyo, 1978, pp. 1- 372. (100) E. Bayer, K. H. Gugel, K. Haegel, H. Hagenmaier, S. Jessipow, W. A. Koenig, and H. Zaehner, Helv. Chirn. Acta, 55 (1972) 224-239.

SUGAR ANALOGS HAVING RING PHOSPHORUS

189

variety of synthetic compounds containing a C-P bond are well known to possess useful biological activities, as exemplified by the antibacterial ~-'~~ nucleotide analogs'01J02 (174) and the insecticide d i p t e r e ~ ' ~ (175). 0

0

0

w

II II It HO-P- 0-P-0-P- CH,-OCH, I I I HO OH OH

HO

0 OH It

I

(MeO),P-CH --CCl, se

175

OH

174

In view of these facts, along with the unique activities of sugar analogs having a ring-nitrogen or -sulfur atom (see earlier), biological testing was conducted33 for a large majority of the phosphorus-containing compounds mentioned herein, and the results are summarized in Table VII. On the whole, it may be stated that, although some mild, biological activities were observed for certain compounds, no remarkable result has thus far been obtained. It therefore seems desirable to prepare a far greater variety of sugar analogs having a ring-phosphorus atom, and to explore their various activities. V. CONCLUSION Although to a far smaller extent than that of nitrogen and sulfur analogs, there has obviously been considerable development in the synthesis of carbohydrates having phosphorus in the ring, and valuable physical data in support of their structures have been accumulated. However, much more work is needed in order to clarify the reaction mechanisms discussed, and, consequently, to improve the yields of many of the steps needed for preparing both the precursors and the final products. It would also be desirable to increase the regio- and stereo-selectivities during the introduction of a phosphorus-containing group into carbohydrates, in order to prepare larger quantities of the desired monosaccha(101) T. C. Myers, K . Nakarnura, and A. B. Darnielzadeh, J . Orig. Chem., 30 (1965) 1517- 1520. (102) A. Holy, personal communication. (103)W. Lorenz, U.S. Pat. 2,701,115 (1955); Chem. Abstr., 49 (1955) 7180. (104) W. F. Barthel, P. A. Gang, andS. A. Hal1.J.Am. C h m . SOC., 76 (1954) 4186-4187. (105) W. Lorenz, A. Henglein, andG. SchraderJ. Am. C h m . SOC., 77 (1955) 2554-2556. (106) S . Inokawa, T. Gornyo, H. Yoshida, and T. Ogata, Synthesis, (1973) 364-365. (1 07) T. Gomyo, H. Yoshida, T. Ogata, H. Inokawa, and S. Inokawa, Nippon Kagaku Kaishi, (1974) 1093 - 1096.

190

HIROSHI YAMAMOTO AND SABURO INOKAWA

TABLE VII Biological Activities of Phosphorus Sugars

Compounds

A‘

19,20,21,22 30,34 43,44,45 51,52,53,62 67 71,75,76 92,93,94,95 134,135 160b 176,177,178h

>loo

Bb

44

C‘

_

-

_ -

5 9 - -

>loo

g

8

Ff

E” 8

8

0 0 0 0 0

4,l.O 0 2 0 0

0 0 0

0 0

8

8

8

g

8

8

0

2,2,1

3.1.1

8

-

DA

Anticarcinogenic activity: ED,, Values (pg/mL) obtained by tn oitro screening, using KB cells (derived from a human, epidermoid carcinoma of the mouth) in Eagle’s MEM- 10% calf-serum culture-medium. Values below 4 pg/mL are regarded as being effective; Cancer Chemotherapeutic Center, Tokyo. b.c Antibacterial and antiviral activity, respectively. The -sign indicates “not effective”; Sankyo Pharmaceutical Co., Ltd. d*e*fInsecticidal,fungicidal, and herbicidal activity, respectively. Testing was performed by using various kinds of plants or insects, and the effectiveness is shown in terms of six grades (5-0), grades 5 and 0 corresponding to 100 and 0%, respectively, of the activities of the reference drugs or chemicals; Asahikasei Co., Ltd., and Nissan Kagaku Kogyo Co., Ltd. 8 Under investigation. hRefs. 106 and 107. Me 0 I II C3H,- CH -P(OEt),

HO 0 I II Me- C-P-Ph I

t

Me Ph 176

177

178

rides having phosphorus in the ring. In the near future, the development of new, efficient procedures and reagents may be expected for the preparation of various other kinds of P sugars, such as nucleoside and nucleotide analogs, which are of considerable interest from the viewpoint of both their physicochemical properties and their biological activities.

VI. TABLE OF SOME PROPERTKES OF SUGAR ANALOGS HAVKNC PHOSPHORUS IN THE MEMIACETAL RING

The follGwing abbreviations are used in Table WII: C, chloroform; E, ethanol; W, water.

TABLE VIII

Properties of Sugar Analogs Having Phosphorus in the Hemiacetal Ring

[a],

M.p.

Compound

("C)

(degrees)

Rotation solvent

References

Tri-O-acetyl-l,5-anhydro-5-deoxy-5-C-[(S)phenylphosphinyll-~-iditol 158 Tetra-O-acetyl-5-deoxy-~-xy~opyranose 5-C-[ (R)-butylphosphinyl]-a156.5-158.5 5-C-[ (R)-ethylphosphiny1)-a176-178 5-C-[(R)-ethylphosphinyl]-/l232-234.5 Tetra-O-acetyl-5-deoxy-5-C(ethylphosphiny1)-D-ribopyranose syrup Tri-O-acety~-5-deoxy-3-Q-methyl-~-xylopyranose 5-C-[(S)-( 1-acetoxy)ethenylphosphinyl]-/3189-190 5-C-[ (R)-butylphosphinyl]-p218.5-220 5-C-[ (R)-ethylphosphinyl]-/3227-229 5-C-[ (R)-methoxyphosphinyl]-asyrup 5-C-[ (R)-methoxyphosphinyI]-/3194-195 5-C-[ (S)-rnethoxyphosphinyI]-asyrup 5-C-[ (S)-methoxyphosphiny1]-/3syrup Tetra-O-acetyl-5,6-dideoxy-~-idopyranose 6-C-nitro-5-C-[ (R)-phenylphosphinyl]-j?158-157 6-C-nitro-5-C-[(S)-phenylphosphinyl]-a305 (dec.) 6-C-nitro-5-C-[(S)-phenylphosphino]-/3150-152 5-C-[(R)-phenyIphosphinylj-cY138 5-C-[(R)-phenylphosphinyl]-/3168 5-C-[(S)-phenylphosphinylj-a215 5-C-[(S)-phenylphosphinyIj-P199 Tri-O-acetyl-4,5-dideoxy-4-C-[ (R)phenylphosphinyll-a-~-l yxofuranose 155-156 5-Deoxy-3-O-methy~-~-xy~opyranose 5-C-(hydroxyphosphinyl)-a-(or -p-) 192 J-C-(phosphinyl)-a208-210 D-Ghcopyranose tri-O-acetyl-3,6-di-O-benzyl-5-deoxy5-C-[ (S)-phenylphosphinylj-P210 penta-O-acetyl-5-deoxy-5-C-[(R)ethylphosphinylj-csyrup penta-O-acetyl-5-deoxy-5-C-[(R)ethylphosphinyll-p233 tri-O-acetyl-5,6-dideoxy-3-O-methyl5-C-[ (S)-phenylphosphinylj-a164-165 tri-O-acetyl-5,6-dideoxy-3-O-methyl5-C-[(S)-phenylphosphinylj-/?304- 306 o-Ribofuranose tetra-O-acetyl-4-deoxy-4-C-[ (R)ethylphosphinyl]-/3syrup tetra-O-acetyl-4-deoxy-4-C-[ (S)ethylphosphinyll-a145-146 tetra-O-acetyl-4-deoxy-4-C-[ (S)ethylphosphinyl]-,!?syrup tri-O-acetyl-4,5-dideoxy-4-C-[(S)phenylphosphinyl]-/lsyrup

53,54

+ 28 + 26

C

- 22

C C

34 34 34

- 24

C

36

- 10.0

C C

23 29 29 23 23 23 23

-8.1 0.0 27.0 - 17.4 +6.2 -0.14

+

- 8.7

- 3.2

-9.3 -31.8 - 10.3 -7.1 18.4

+

C C

C

C

C C C C

E E E E

33,43 33,43 43 53 53 53 53 67

- 25.8

+ 35.0

W W

19 19 34 65

+3.65

+ 37.3 + 23.2 -0.20

C

65

C

60

C

60

C

89 89

-0.38

C

33 67