Studies related to thromboxane A2: a formal synthesis of optically

Vilas N. Kale, and Derrick L. J. Clive. J. Org. Chem. , 1984, 49 (9), pp 1554–1563. DOI: 10.1021/jo00183a016. Publication Date: May 1984. ACS Legacy...
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J . Org. Chem. 1984,49, 1554-1563

1554

Studies Related to Thromboxane A2: A Formal Synthesis of Optically Active 9a,l la-Thiathromboxane A2 Methyl Ester from Levoglucosan Vilas N. Kal6 and Derrick L. J. Clive* Chemistry Department, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2 Received September 14, 1983

A synthesis of (*)-7-exo-(n-butyloxy)-2-oxa-6-thiabicyclo[3.1.1] heptane (4) from 2-(benzyloxy)-5,6-dihydropyran (Scheme I) and the conversion of levoglucosan 20 into 36 (Scheme IV) are described. Compound 36 is an intermediate in a published synthesis (Scheme 111) of the biologically active 9aJla-thiathromboxane A2 methyl ester (19). (5)

Introduction The metabolites of arachidonic acid constitute a large group of biologically important compounds, which are described in a very extensive literature.' This paper deals with the synthesis of analogues of one of these metabolites-thromboxane A,. Both this substance (1) and another eicosanoid, prostaglandin I2 (or prostacyclin) (2) are involved in mechanisms that control the behavior of blood platelets and blood vessels.lb Thromboxane A2 causes platelets to aggregate and to adhere to blood vessel walls. It also causes vasoconstriction. Prostacyclin 12,.on the other hand, exerts opposing effects; both aggregation of platelets and adherence to blood vessel walls are prevented and the substance induces vasodilation. Thromboxane A, is a very reactive substance under physiological conditions; it has a half-life of about 30 s at 37 O C in an aqueous medium of pH 7.2a More stable analogues could, in principle, be useful tools for biological studies; they would be easier to handle and they might differ from the natural material in ways that are quantitatively and/or qualitatively advantageous. The properties of analogues might also serve to corroborate the structure 1that was assigned to thromboxane A, on the basis of the structures of isolated breakdown products and mass spectral data., A number of thromboxane A, analogues, e.g., 3,3 had (1) See, for example: (a) Nelson, N. A.; Kelly, R. C.; Johnson, R. A. Chem. Eng. News 1982, August 16, 30. (b) "Prostaglandins and Thromboxanes", Newton, R. F.,Roberta, S. M., Eds.; Butterworth Scientific: London, 1982. (c) Dusting, G. J.; Moncada, S.; Vane, J. R. Prostaglandins 1977,13, 3. (d) Moncada, S.; Vane, J. R. "Advances in Prostaglandin and Thromboxane Research"; Samuelsson, B., Ramwell, P. W., Paoletti, R., Eds.; Raven Press: New York, 1980; Vol 6, p 43. (e) Samuelsson, B.; Folco, G.; Granstrom, E.; Kindahl, H.; Malmsten, C. "Advances in Prostaglandin and Thromboxane Research"; Coceani, F., Olley, P. M., E&.; Raven Press: New York, 1978; Vol4, p 1. (f) Ackroyd, J.; Scheinmann, F. Chem. SOC.Reu. 1982, 11, 321. (2) (a) Hamberg, M.; Svensson, J.; Samuelsson, B. P. Proc. Natl. Acad. Sci. U.S.A. 1975,72,2994. (b) Kelly, R. C. In "Organic Synthesis, Today and Tomorrow"; Trost, B. M., Hutchinson, C. R., Eds.;Pergammon Press Oxford, 1981; p 259. (c) Samuelsson, B.; Goldyne, M.; Granstrom, E.; Hamberg, M.; Hammarstrom, S.;Malmsten, C. Ann. Rev. Biochem. 1978, 47, 997. (3) For examples, see: (a) Nicolaou, K. C.; Magolda, R. L.; Smith, J. B.; Aharony, D.; Smith, E. F.;Lefer, A. M. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2566. (b) Ansell, M. F.; Caton, M. P. L.; Palfreyman, M. N.; Stuttle, K. A. J. Tetrahedron Lett. 1979, 4497. (c) Ohuchida, S.; Hamanaka, N.; Hayashi, M. Ibid. 1979, 3661. (d) Nicolaou, K. c.; Magolda, R. L.; Claremon, D. A. J. Am. Chem. SOC.1980,102, 1404. (e) Barraclough, P. Tetrahedron Lett. 1980,21,1897. (f) Ansell, M. F.;Caton, M. P.; Stuttle, K. A. J. Ibid. 1982,23, 1955. (9) Corey, E. J.; Ponder, J. W.; Ulrich, P. Ibid. 1980,21,137. (h) Maxey, K. M.; Bundy, G. L. Ibid. 1980, 21,445. (i) Ohuchida, S.; Hamanaka, N.; Hayashi, M. Ibid. 1981,22,1349. (j) Kosuge, S.; Hamanaka, N.; Hayashi, M. Ibid. 1981, 22, 1345. (k) Ohuchida, S.; Hamanaka, N.; Hayashi, M. J. Am. Chem. SOC.1981,103, 4597. (1) Ohuchida, S.; Hamanaka, N.; Hayashi, M. Tetrahedron Lett. 1981,22, 5301. (m) Kosuge, S.; Hamanaka, N.; Hayashi, M. Ibid. 1981, 22,1345. (n) Kosuge, S.; Hayashi, M.; Hamanaka, N. Ibid. 1982,23,4027. (0)Schaaf, T. K.; Bussolotti, D. L.; Parry, M. J.; Corey, E. J. J . Am. Chem. SOC.1981, 103,6502.

2

-

Eli 3 X

Y

S

S

0 CH,

CH, 0

R

ref

Na H

3k 3h 3g

H

been prepared when we began our synthesis and several were reported during the course of our work. We decided to make the thia compound 3 (X = S, Y = 0, R = Me or Na) in the expectation that the bicyclo[3.l.l]heptane portion would have similar hydrophobicity and chemical properties to the corresponding unit of the natural product but would react more slowly4 with water. In order to gain experience in the preparation of the hitherto unknown 2-oxa-6-thiabicyclo[3.l.l]heptanesystem we decided, first of all, to attempt to synthesize 4 (Scheme I) in the hope that it would be a fairly readily accessible member of the compound class with a high enough boiling point to allow manipulation on a small scale. After making5 compound 4, we began the synthesis of 3 (X = S, Y = 0, R = Me) from levoglucosan. During this work, the first synthesis of the same material was published? and so we took our experiments only to the stage where they provided an intermediate that was common to both routes. Synthesis of (f)-7-exo-(n-Butyloxy)-2-oxa-6-thiabicyclo[3.l.l]heptane (4). The approach to model compound 4 is summarized in Scheme I. Epoxidation (m-chloroperbenzoic acid) of the substituted dihydropyran 5 afforded7epoxides 6 and 7 in a ratio of about 3:l. The expected8 major product 6 (49%) had (4) Loewenthal, H. J. E. In "Protective Groups in Organic Chemistry"; Plenum: London, 1973;p 333. Jorritama, R.; Steinberg, H.; de Boer, Th. 1981,100,194. Modena, G.; Scorrano, G.; J. Red. Trau. Chim. PQYS-BUS Venturello, P. J. Chem. SOC.,Perkin Trans. 2 1979, 1. (5) Research Report to AFHMR. July, 1981. (6) Ohuchida, S.; Hamanaka, N.; Hashimoto, S. Tetrahedron Lett. 1982,23, 2883. (7) Mochalin, V. B.; Porshnev, Yu. N.; Samokhvalov, G. I. J. Gen. Chem. U.S.S.R. (Engl. Transl.) 1969,39, 645. ( 8 ) (a) Cahu, M. M.; Descotes, G. Bull. SOC.Chim. Fr. 1968,2975. (b) Sweet, F.; Brown, R. K. Can. J . Chem. 1968, 46, 707.

0022-3263/84/1949-1554$01.50/00 1984 American Chemical Society

J. Org. Chem., Vol. 49, No. 9, 1984 1555

Studies Related to Thromboxane A2

-

The acetyl groups were then removed (11 13,84%) by methanolysis and the resulting mercapto aldose 13 was subjected to the action of dry hydrogen chloride in ether at 0 "C for 2 days-standard condition^'^ for replacement of an anomeric hydroxyl by chlorine. The unstable product, presumed on the basis of precedent14J5to be the desired pyranosyl chloride 14, was employed directly for the final step of the synthesis. When the substance was refluxed with an excess of sodium hydride in a mixture of THF and benzene, it was converted into the desired 2oxa-6-thiabicyclo[3,l.l]heptanederivative (4) which was isolated in 44% yield (from 13) after flash chromatography. The material was contaminated by trace impurities as judged by TLC. The substance could be stored at 0 OC for several days and it could be distilled (Kugelrohr) under water pump vacuum with slight decomposition. Presumably, the ring closure takes place through the skew conformation 15. The structural assignment 4 rests in part on the mode of formation, on IR and MS measurements, and, in part, on the following spectroscopic study. 'H and 13CNMR Study of Compound 4. The small ring of compound 4 is a rigid unit and only the bridging fragment -0-C(3)-C(4)- is conformationally flexible. On this basis, three limiting conformations 16, 17, and 18 (34)

Scheme Ia

OBn 3

I

6

5 +

t-BUS

" Bo ( &c - - J

00"

t-BUS

OBU

OH

8

9

'OBU

10

1

AcS-OAC OBU

11

7

&+ 0

I OBU

I

OBu

15

H

16

OBU

4 a

All compounds are racemic.

spectral characteristics consistent with the structure shown: Jl,z5 1 Hz for 6 and 3 Hz for the minor ieomer.hg Epoxide 6 reacted cleanly (92% yield) with tert-butyl mercaptide to produce 8, and alkylation with iodobutane+odium hydride furnished 9 in 90% yield. In this sequence, the regiochemical course of the transformation 6 8 was expected on the basis of extensive precedenthlO and was also proved by appropriate 'H NMR decoupling experiments which showed that each of the substituents in 8 was in an equatorial conformation since the coupling constants, J1,2and J2,3,were large (7 and 10.25 Hz, respectively). Deprotection (61% yield) of the anomeric hydroxyl (9 10) was effected with 90% aqueous trifluoroacetic acid in dichloromethaneand the tert-butyl group was removedll by treatment with acetic anhydride and concentrated sulfuric acid. This reaction afforded (57%) the diacetate 1112(as a mixture of anomers) as well as the acyclic compound 12.13

-

-

(9) Buchanan, J. G.; Fletcher, R.; Parry, K.; Thomas, W. A. J. Chem. SOC. B 1969, 377. (10) Berti, G.; Catelani, G.; Ferretti, M.; Monti, L. Tetrahedron 1974, 30, 4013. Chmielewski, M.; Zamojski, A. Row. Chem. 1972, 46, 1767. (11) For other methods of deprotedion see: Pastuszak, J. J.; Chimiak, A. J. Org. Chem. 1981, 46, 1868. Greene, T. W. 'Protective Groups in Organic Synthesis"; Wiley: New York, 1981; p 203. (12) Direct acetolysis of 9 gave a complex mixture. For a review on acetolysis, see: Guthrie, R. D.; McCarthy, J. F. Adu. Carbohydr. Chem. 1967, 22, 11.

18 ( = 4 )

17

require consideration."j The first of these, 16, is likely to be destabilized by severe nonbonded interactions between the pseudoaxial butyloxy group and the pseudoaxial hydrogen on C(3). The lH NMR spectrum (at 400 MHz) of 18 ( ~ 4 is) described in Table I. The assignments indicated were made by consideration of chemical shift, intensity, and decoupling measurements. The lH NMR assignments to the butyloxy group were made by comparison with the spectrum of dibutyl ether (and confirmed by decoupling measurements). Of the remaining signals, those at highest field (2.61 and 2.14 6) are due to protons [C(4)H, and (13) The coupling constants J1,2 = 4,J2,3= 2.5, J3t4a = 5, and J3,4b = 10 Hz for compound 12 suggest that it exists predominantly (in CDCl,) as the extended form (i).

i Cf. Moore, R. E.; Bartolini, B.; Barchi, J.; Bothner-By, A. A,; Dadok, J.; Ford, J. J . Am. Chem. SOC.1982, 104, 3776. (14)Micheel, F.; Kreutzer, U. Liebigs Ann. Chem. 1969, 722, 228. (15) Ferrier, R. J.; Collins, P. M. 'Monosaccharide Chemistry";Penguin: London, 1972; p 96. (16) Weigand, E.F.; Schneider, H. J. Org. Mugn. Reson. 1979,12,637 and reference cited therein.

1556

J. Org. Chem., Vol. 49, No. 9, 1984

Kale and Clive Scheme I1

Y

m

2 E ". ri ri

A-

\IS 19

ll

E 0

?

COOMe /

R-SO,

ri

€E LnN

"I"

mm

-

-COOMe

6H

&

20 levoglucosan

C(4)H,] on carbon not attached to a heteroatom while the signal at lowest field (5.54 6) is assigned to C(1)H. The above considerations, which are based on chemical shifts, led, tentatively, to the interpretation given and such an assignment was confirmed by the decoupling measurements. The signal produced by C(4)He, was identified by its large coupling to C(5)H. The flattened conformation 17 is excluded because J5,&and J5,& should be nearly equal for this conformation ?as judged from examination of Dreiding models), whereas the values are quite different (Jk,5= 1.5, J4eq,5 = 5.0 Hz)-as expected for conformation 18. The long range coupling, J1,5,has ample precedent.l' The signal due to C(4)H, is at lower field than that due to C(4)H,. This deshielding is due to the proximity of the C(7) oxygen atom. The axial proton attached to C(3) also resonates at lower field than the equatorial proton. Here, interaction with the sulfur atom is responsible. In the 13CNMR spectrum, the lowest field signal (89.51 6) is assigned to the anomeric carbon, C(1).18 This interpretation, and the others shown in Table I, were confirmed by single-frequencyproton decoupliig experiments. The lJC-H values for C(5) and C(7) are larger than those = 147.4 Hz and reported for 3-hydroxythietane [lJC-H 1Jcc3,-H = 150.7 Hz]." The anomeric carbon, C(l), showed two long-range couplings of about 5-7 Hz. These may be due to coupling with the proton attached to C(5) and with the equatorial proton attached to C(3), since C(l) has an approximately (17)(a) Swinton, P.F. J.Magn. Reson. 1974,13,304.Wiberg, K. B.; Barth, D. E. J. Am. Chem. SOC.1969,91,5124. (b) Wiberg, K. B.; Lampman, G. M.; Ciula, R. P.; Connor, D. S.; Schertler, P.; Lavanish, J. Tetrahedron 1965,21,2749. (c) Escale, R.; Khayat, A,; Girard, J. P.; Rossi, J. C.; Chapat, J. P. Org. Magn. Reson. 1981,17,217and references cited therein. (d) Ito, H.; Eby, R.; Kramer, S.; Schuerch, C. Carbohydr. Res. 1980,86, 193. (e) Jackman, L. M.; Sternhell, S. "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry", 4th ed.; Pergamon: Oxford, 1969;p 334. (18)Cf. Lundt, I.; Skelbaek-Pedersen, B. Acta Chem. Scand. Ser. B 1981,B35, 637. (19)Dittmer, D. C.; Patwardhan, B. H.; Bartholomew, J. T. Org. Magn. Reson. 1982,18, 82.

J. Org. Chem., Vol. 49, No. 9, 1984 1557

Studies Related to Thromboxane Az Scheme I11 QAc

,COOMe

- 19 Me0

21

antiperiplanar conformation with respect to each of these protons that are vicinal to it.20 Synthesis of 9a,lla-Thiathromboxane A2 Methyl Ester (19) [=3 (X = S, Y = 0,R = Me)]. As the model compound 4, having the representative 2-oxa-6-thiabicyclo[3.l.l]heptane skeleton appeared to be reasonably stable, we undertook the synthesis of 9a,lla-thiathromboxane A2 methyl ester (19) [=3 (X = S, Y = 0, R = Me)] in the natural, optically active, form. Our approach is summarized in Scheme 11and is based upon levoglucosan2’ (20) as the chiral starting material. The initial experiments involved use of a tosylate (see Scheme 11, R = p-toluenesulfonyl) but, part way through the project, a synthesis of 19, by the route summarized in Scheme I11 was reported.6P Therefore, we repeated our earlier experiments in the mesylate series so as to generate intermediate 21 (see Scheme 111). Levoglucosan (20), obtained by pyrolysis of starch,2’ was converted by literature procedures into 22,2323,23and 24.= Reduction of 24 with Superhydride= produced the alcohol 25 which was converted directly into its benzoate 26 (71% from 24). Generation of the formyl group (26 27) did not proceed cleanly with sodium metaperiodate and a catalytic amount of osmium tetroxide, but ozonolysis and reductive workup (dimethyl sulfide) was effective and gave the aldehyde in 88% yield. A t this stage the a-chain was introduced by reaction of aldehyde 27 with the Wittig reagent generated (in THF) from (4-carboxybutyl)triphenylphosphoniumbromide and potassium tert-butoxide. The product was debenzoylated with sodium methoxide and then esterified with diazomethane. Ester 28, produced in this way (64% from 27), was contaminated by a small amount (ca. 10%) of the corresponding E olefm as judged by the presence of several extra peaks in the olefinic region of the 13C NMR spec-

-

(20)Schwarcz, J. A,; Perlin, A. s. Can. J. Chem. 1972, 50, 3667. Lemieux, R. U.;Nagabhushan, T. L.; Paul, B. Can. J. Chem. 1972,50, 773. (21)(a) Ward, R. B. Methods Carbohydr. Chem. 1963,2, 394. (b) Levoglucosan has become commercially available: Fluka AG, Switzerland. (c) For an alternative four-step synthesis of levoglucosan, see: Coleman, G. H. Methods Carbohydr. Chem. 1963,2,397. (22)Reference 6 does not indicate explicitly whether the compound is optically active. (23)Cernp, M.; Gut, V.; Paclk, J. Collect. Czech. Chem.Commun. 1961,26,2542. Carlson, L. J. J.O g . Chem. 1965,30,3953. Cernq, M.; StanBk, Jr., J.; Paclk, J. Collect. Czech. Chem. Commun. 1969,34,849. (24)Kelly, A. G.; Roberta, J. S. J. Chem. SOC.,Chem. Commun. 1980, 228.

trum. These impurities were removed at a later stage. Treatment of 28 with methanesulfonyl chloride and triethylamine in dichloromethane at room temperaturez5 afforded 29 in 85% yield. Methanolysis in the presence of an acidic resin and at room temperature slowly generated the methyl glycosides 30 as an 8515 mixture of a and @ anomers (90% yield). Collins oxidationz6then afforded (74%) the corresponding aldehydes 31. Wadsworth-Emmons olefination2’ served to produce (87%) the two a,@unsaturated ketones 32 (66% ) and 33 (4.7% ), which were separatedzs by flash chromatography and identified by their NMR characteristics. The anomeric proton of the a-isomer produced a signal at 4.87 6 (CDCl,) with Jl~ax,ll = 3 Hz, while the corresponding values for the @-anomer were 4.41 6 and 9.25 Hz. Both 32 and 33 showed, in their NMR spectra, large E olefinic couplings: J13,14 = 16 Yz for 32 and J13,14 = 15.5 Hz for 33. In principle, both anomers could be used for the remaining steps but the compounds were separated at this stage in order to avoid the formation of complicated diastereoisomeric mixtures and, in the event, only the a-isomer 32 was processed further. Reduction with sodium borohydride in methanol at -40 OC produced two isomeric alcohols, 34 and 35, in approximately equal amounts (76% yield). The compounds, which were separated chromatographically, were free (13C NMR) of the impurity detected in 29. The more polar material (34) is tentatively consideredmto be the (natural) 15-(S)-isomerby analogy with the chromatographic behavior of related compounds.29 Finally, benzoylation of 34 produced 36 which, together with the corresponding @-anomer,has been converted6into 9a,lla-thiathromboxane A2 methyl ester (19). The alcohol 35 was also benzoylated in order to obtain a reference compound for spectral comparison. The 15(S)-allylicbenzoate 36 shows in its CD spectrum (methanol) at ca. 230 nm a positive Cotton effect, while the 15(R)-isomer(37) is characterized by a negative eff“ect.% Spectroscopic Study of 34,35,36, and 37. The ‘H NMR spectra of the alcohols 34 and 35 are very similar. In both, the magnitude of J12,13 is 7.6 Hz and this value suggests, but by itself does not prove, that they exist extensively in a conformation in which C(12)H and C(13)H are near anti~eriplanarity.~’Such a conformation has been found in the crystalline state for TXB2.32 The effect of temperature on J12,13 and J14,15 in both alcohols 34 and 35 was studied in order to e ~ a l u a t e the ~ ~ 8conformational ~ preferences about C(12)-C(13) and C(14)-C(15). As the temperature is lowered the value of J12,13 should inc r e a ~ e because ~ ~ l ~ ~the population of the favored confor(25)Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970,35, 3195. (26)Arrick, R. E.; Baker, D. C.; Horton, D. Carbohydr. Res. 1973,26, 441. (27)Rosenthal, A.; Nguyen, L. B. J. Org. Chem. 1969, 34, 1029. Walker, B. J. In “Organophosphorus Reagents in Organic Synthesis”; Cadogan, J. I. G., Ed.; Academic Press: London, 1979;p 155. (28)A mixed fraction (16.7%) was also isolated. (29)Andersen, N. H. J.Lipid Res. 1969,10,316.Brash, A. R.; Jones, R. L. Prostaglandins 1974,5,441. Corey, E. J.; Shibasaki, M.; Knolle, J.; Sugahara, T. Tetrahedron Lett. 1977,785. Nelson, N. A.; Jackson, R. W. Ibid. 1976,3275. (30)Cf. Gonnella, N. C.; Nakanishi, K.; Martin, V. S.; Sharpless, K. B. J. Am. Chem. SOC.1982, 104, 3775 and references cited therein. Johnson, R. A.; Krueger, W. C.; Nidy, E. G.; Pschigoda, L. M.; Garry,M. J. J. Org. Chem. 1980,45,1528. See also: Chem. Abstr. 1955,49,836. (31)Karabatsos, G. J.; Fenoglio, D. J. “Topics in Stereochemistry”; Allinger, N. L., Eliel, E. L., Eds.; Wiley-Interscience: New York, 1980; Vol 5, p 167. Bothner-By, A. A.; Naar-Colin, C.; Giinther, H. J. Am. Chem. SOC.1962,84,2748. Becker, E.D. “High Resolution NMR”, 2nd ed.; Academic Press: New York, 1980;p 102. (32)Fortier, S.; Erman, M. G.; Langs, D. A.; DeTitta, G. T. Acta Crystallogr., Sect. B 1980,B36, 1099. (33)Kotowycz, G.;Lemieux, R. U. Chem. Rev. 1973,73,669. (34)De Mare, G. R.; Lapaille, S. Org. Magn. Reson. 1980,13, 75.

1558 J. Org. Chem., Vol. 49, No. 9, 1984

Kale and Clive Scheme IV

HO

20

TtCl

pyridine

R

OTs

OTs

22

Mea-

P

HO

PhCOO

I Q7

0

OTs

23

24

26

25

>

wooMe wcooM 27

28

-

MeS02

29

Me SO,

MeS02 1

o

w

M

I -BuOK /PhMe

17

"

Me0

Me0

30

e

/I

IMeO~2~-CH2CO(CH214Me

l2

'14

l5

16

19

18

20

OMe

31

32, oi -anomer 33, p-anomer

COOMe

Meb

mation (probably that with C(12)H and C(13)H antiperiplanar) increases. Measurement of the 'H NMR spectrum of 34 in CD2C12at 298 and 203 OK showed the expected trend: J12,13 rose from 7.6 to 8.6 f 0.02 Hz. Similar results were obtained with t h e alcohol 35. T h e magnitude of J14,15 for 34 is 6.0 Hz and for 35 i t is 7.0 Hz. Both values increase only slightly on lowering the temperature and so no conclusions could be drawn regarding the preferred conformation about C( 14)-C( 15). Partly for this reason, the spectra of t h e benzoates 36 and 37 were examined. Although t h e spectra of t h e alcohols are similar, those of t h e derived benzoates are readily distinguished. In the spectrum of 36 the signals due t o C(13)H and C(14)H are well separated while those produced by C(5)H and C(6)H are superimposed. For 36 the coupling constant J12,13 is 7.4 Hz. In t h e case of 37 the signals produced by C(13)H and C(14)H are superimposed while now those of C(5)H and C(6)H are separated. T h e value of Jlz,ls is a little smaller (6.25 Hz). T h e signals due to C(2)H2, C(3)H2,and C(4)H2of 37 are more shielded t h a n the corresponding signals of 36. In the latter, the C(2)H2signals appear as a triplet but in 37 they appear as two closely spaced triplets. These effects are understandable in terms of anisotropic shielding produced by the benzoate group. T h e lH NMR spectrum of 37 was measured at 298,263, and 233 O K . As the temperature was lowered the C(2)-C(4) protons became progressively more shielded and t h e separation of t h e C(2)H2 multiplets increased.

Experimental Section Except where stated to the contrary, the following particulars apply. For reactions carried out under nitrogen, oven-dried glassware (130 OC, 1 2 h) was used. The apparatus was allowed to cool in a desiccator or assembled hot, capped with rubber septa, and swept with nitrogen. Reactions were performed under a slight static pressure of nitrogen which was purified by passage through

a column (3.5 X 40 cm) of R-311 catalyst35and then through a similar column of Drierite. All solvents were distilled before use for chromatography. Solvents were dried, where specified, by distillation under a static nitrogen atmosphere from suitable desiccants, and transferred via oven-dried syringes. Dry ether and THF were distilled from sodium (benzophenone,indicator); dichloromethane, benzene, toluene, pyridine, triethylamine, and dimethylformamidewere distilled from calcium hydride [the last solvent under reduced pressure]. Methanol was distilled from magnesium methoxide. During product isolation, solutions were dried over magnesium sulfate and evaporated under water pump vacuum at room temperature. Where compounds were isolated simply by evaporation of their solutions,the residues were kept under oil pump vacuum and checked for constancy of weight. Isolated products were submitted directly for combusion analysis without need for additional purification, unless otherwise stated. Commercial thin-layer chromatography(TLC) plates were used: silica gel was Camag type DF-B or Merck 60F-254; alumina was Camag type DSF-B or Merck 60F-254. UV active spots were detected at 254 nm; spots detected by spraying with sulfuric acid (50% in methanol) were charred on a hot plate. Silica gel foy column chromatographywas Merck type 60,70-230 mesh ASTM; silica gel for flash chromatography36was Merck type 60,230-400 mesh ASTM. Infrared spectra were recorded on a Perkin-Elmer 297 infrared spectrometer or on a Nicolet 7199 FT-IR spectrometer. Liquids and oils were usually run as thin films on sodium chloride plates; solids were run as solutions in the specified solvent, using 0.5 mm sodium chloride cells, or as nujol mulls. Proton NMR spectra were recorded on Varian HA-100 (at 100 MHz), Bruker WH-200 (at 200 MHz), or Brucker WH-400 (at 400 MHz) spectrometers, in the specified deuterated solvent with tetramethylsilane as an internal standard. 13C NMR spectra were recorded on a Brucker HFX-90 (at 22.6 MHz), Brucker WH-200 (at 50.3 MHz), or Brucker WH-400 (at 100.4 MHz) spectrometers with tetra(35) Supplied by Chemical Dynamics Corporation, South Plainfield, NJ. (36) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

Studies Related to Thromboxane Az

J. Org. Chem., Vol. 49, No. 9, 1984 1559

Cl6HZ4O3S:C, 64.83; H, 8.16; S, 10.82. Found: C, 65.04; H, 8.23; S, 10.84. Benzyl 2 - 0 -n -Butyl-3-(tert-butylthio)-3,4-dideoxy-a-~~threo-pentopyranoside(9). Sodium hydride (50% w/w as an oil dispersion, 2.0 g, 40 mmol) was added to a solution (50 mL) of compound 8 (8.28 g, 27.8 mmol) in dry DMF. The mixture was stirred for 30 min and then 1-iodobutane (7.71 g, 4.7 mL, 40 mmol) was added over 0.5 h. After 5 h more sodium hydride dispersion (1.5 g, 30 mmol) and a further portion of 1-iodobutane Benzyl 2,3-Anhydro-4-deoxy-fi-~~-erythro -pentowere added. Stirring at room temperature (4.85 g, 3 mL, 26 "01) pyranoside (6) and Benzyl 2,3-Anhydro-.l-deoxy-a-~~-was continued overnight. The mixture was diluted with water (100 mL) and extracted with ether (3 X 100 mL). The combined erythm-pentopyranoside(7). A solution of m-chloroperbenzoic organic extract was washed with water (2 X 50 mL) and with brine acid (16 g, 85%,78 "01) in dichloromethane (100 mL) was added (1 X 50 mL). The extract was dried and evaporated. Flash dropwise to a solution (130 mL) of 2-benzyloxy-5,6-dihydro-apyran (5)" (27.51 g, 144 mmol) in the same solvent. A further chromatography of the residue over silica gel (5 X 18 cm) with portion of m-chloroperbenzoic acid (10.4 g, 85%, 51 mmol) in 1:19 ethyl acetate-hexane gave pure 9 (9.0 g, 90%) as a colorless dichloromethane (100 mL) was added after 6 h. The mixture was oil: FT-IR (film) 1115,1085cm-l; NMR (CDC13,400 MHz) 6 0.89 (t,J = 7.25 Hz, 3 H, -CH,CH3), 1.34 (s, 9 H, -C(CH3),), 1.35 (m, stirred for an additional 4 h and filtered. The solids were washed with hexane (500 mL) and the combined organic phase was washed 2 H, -CH&H3), 1.54 (m, 2 H, -CH2CH2CH3),1.74 (m, 1H, H-4,), with 10% w/v aqueous sodium thiosulfate (200 mL), saturated 2.07 (m, 1H, H - 4 4 , 2.68 (m, J = 4 5 8 , 13.5 Hz, 1H, H-3), 2.97 (9, J = 5.25,8 Hz, lH, H-2), 3.43 (m, 1 H, H-5,), 3.65 (dt, 1 H) aqueous sodium bicarbonate (2 X 200 mL), water (2 X 150 mL), and brine (150 mL). The organic extract was dried and evapoand 3.75 (dt, 1 H, C(2)-0-CH2-), 3.94 (dt, 1 H, H-5,,), 4.43 (d, rated. Flash chromatography of the residue over silica gel (5 X J = 5.25 Hz, 1 H, H-l), 4.60 and 4.87 (AB q, J = 1 2 Hz, 2 H, -CH2Ph),7.3 (m, 5 H, aromatic protons); 13CNMR (CDC13,100.6 20 cm) with 1:9 ethyl acetate-hexane gave the epoxide 6" (14.8 g, 49%) as a homogeneous (TLC, silica gel, 1:9 ethyl acetateMHz) ppm 13.92 (q, -CH,CH3), 19.31 (t, -CH2CH3), 31.53 (9, hexane) oil: FT-IR (mull) 1447, 1010, 695 cm-'; NMR (CDC13, -C(CH3)3), 32.32 (t,C(P)-O-CH,CH,-), 34.87 (4, C-4), 42.47 (d, C-3), 43.50 (s, -C(CH3),), 62.23 (q, C-5), 70.33 (t) and 72.78 (t) 400 MHz) 6 1.81 (m, J = 2.5, 4.5, 5, 15 Hz, 1 H, H-4,,), 2.08 (m, 1 H, H-4,), 3.05 (br d, J = 4 Hz, 1 H, H-2), 3.34 (m, J = 1, 4, (-CH2Ph and C(2)-0433,-), 80.72 (d, C-2), 103.22 (d, C-1),127.52, 5 Hz, 1 H, H-3), 3.42 (m, J = 1, 2.5, 7, 12 Hz, 1 H, H-5,,), 3.77 127.79, 128.30 and 138.04 (aromatic carbons);exact mass, 352.2072; (m, J = 0.75,5, 11, 12 Hz, 1 H, H-5,), 4.56 and 4.81 (AB q, J = calcd for C20H3203S, 352.2072. Anal. Calcd for Cz0H3,O3S:C, 11.5 Hz, 2 H, -CH2Ph), 5.03 (br s, Wl12 = 2 Hz, 1 H, H-l), 7.3 68.14; H, 9.15; S, 9.10. Found: C, 67.97; H, 9.12; S, 9.35. (m, 5 H, aromatic protons); 13C NMR (CDC13,22.6 MHz) ppm 2-0 - n -Butyl-3-(tert -butylthio)-3,4-dideoxy-a,fi-~~-threo23.41 (C-4), 49.86, 54.47, 69.93 (-CHZPh), 94.56 (C-11, 127.86, pentopyranose (10). Trifluoroacetic acid (80% in water, 20 mL) 128.05,128.49and 137.41 (aromatic carbons);exact masa, 206.0938; was added to a solution of compound 9 (9.50 g, 26 mmol) in calcd for C12H1403,206.0943. Anal. Calcd for C12H1403: C, 69.89; dichloromethane (25 mL). The mixture was stirred at room H, 6.84. Found: C, 69.63; H, 6.91. temperature for 40 h, cooled in an ice bath, and diluted slowly On further elution, epoxide 7 (4.63 g, 15%) was obtained: with triethylamine (32 mL). The mixture was stirred at room FT-IR (film) 1045,1020 cm-'; NMR (CDC13,400 MHz) 6 1.95 (m, temperature for 3 h and washed with water. The organic layer 2 H, HH-4), 3.25 (9, J = 3 , 4 Hz, 1H, H-2), 3.33 (br t, 1H, H-3), was dried and evaporated. Flash chromatography of the residue 3.43 (m, 1 H, H-5,,), 3.85 (m, 1 H, H-5,), 4.60 and 4.80 (AB q, over silica gel (5 X 20 cm) with 0.7k9.25 ethyl acetate-hexane J = 12 Hz, 2 H, -CH,Ph), 5.00 (d, J = 3 Hz, 1 H, H-l), 7.3 (m, gave compound 10 (4.32 g, 61%) as a pure, pale yellow oil: FT-IR 5 H, aromatic protons); 13CNMR (CDCl,, 22.6 MHz) ppm 24.76 (film) 3400,1115 cm-'; NMR (CDC13,400 MHz) 6 0.93 (two sets (C-4), 49.78 and 51.29,55.43,68.95 (-CH,Ph), 92.69 (C-1), 127.71, oft, J = 7.25 Hz, 3 H, -CH,CH3), 1.3-1.4 (m, 11 H, -C(CH3)3and 128.15,128.42 and 137.72 (aromatic carbons);exact maes, 206.0942; -CH&H3), 1.59 (m) and 1.72 (m) (3 H, -CH2CH,CH3 and H-4,), calcd for C12H1403, 206.0943. Anal. Calcd for C12H1403: C, 69.89; 2.15 (m, 1 H, H-4,,), 2.70 (m, 0.5 H, H-3, of the @-isomer),2.93 H, 6.84. Found: C, 69.73; H, 6.90. (9, J = 5.5, 8 Hz, 0.5 H, H-2 of the @-isomer),3.30 (br q, 0.5 H, Benzyl 3-( tert -Butylthio)-3,4-dideoxy-a-~~-threo-pento-H-3 of the a-isomer, 3.25 (9, J = 2.25, 6 Hz, 0.5 H, H-2 of the pyranoside (8). tert-Butyl mercaptan (1.46g, 1.83 mL, 16 mmol) a-isomer), 3.45-3.86 (three sets of m, 4 H, HH-5 and C(2)-0was added to a solution of sodium methoxide (0.88 g, 16 mmol) CH2-), 3.53 (d, J = 8 Hz, 0.5 H, a-OH), 3.84 (d, J = 6 Hz, 0.5 H, in absolute methanol (10 mL). The solution was stirred for 15 @-OH),4.70 (t, J = 5.50, 6 Hz, 0.5 H, H-1 of the @-isomer(it min and then epoxide 6 (3.05 g, 14 mmol) in methanol (10 mL) collapsed to a doublet with J = 5.5 Hz on D20 exchange)), 4.98 was added. The mixture was refluxed for 2 h, cooled, and diluted (q, J = 2.25,8 Hz, 0.5 H, H-1 of the a-isomer (it collapsed to a with water (10 mL). Most of the methanol was evaporated and doublet with J = 2.25 Hz on D20 exchange)); 13CNMR (CDCI,, the residue was extracted with ether (2 X 75 mL). The organic 22.6 MHz) ppm% 13.70 and 13.76 (-CH,CH3), 19.12 (-CH2CH3), phase was washed with water (50 mL) and brine (50 mL), dried, 31.15 and 31.28 (-C(CH3)3),31.87, 32.03 and 34.11 (C-4 and Cand evaporated to give compound 8 (4.07g, 92%) which was used (2)-0-CHz-CH2-), 38.33 and 41.65 (C-3),43.56 and 43.69, (C(Cfor the next stage without further purification. An analytical H3)3,60.72 and 61.69 (C-5),70.67 and 72.49 (C(2)+CH2-), 79.60 sample was prepared by crystallization from hexane. The purified and 80.91 (C-2), 91.44 ((3-1of the a-isomer), 97.74 (C-1 of the material: FT-IR (nujol) 3420,1455,1077 cm-'; NMR (CDC13,200 @-isomer);exact mass, 262.1600; calcd for Cl3HZ6o3S, 262.1603. MHz) 6 1.34 (s, 9 H, -C(CH3)3), 1.70-2.09 (m, 2 H, HH-4), 2.66 Anal. Calcd for C13H2603S:C, 59.50; H, 9.99; S,12.22. Found: (m, J = 5,10.25, 12 Hz, 1H, H-3), 2.76 (d, J = 1.75 Hz, 1H, -OH), C, 59.53; H, 10.00; S, 12.09. 3.22 (m, J = 1.75, 7, 10.25 Hz, 1 H, H-2), 3.49 (m, J = 3, 11.25, 1 - 0-Acetyl-3-S-acetyl-2-O-n -butyl-3,4-dideoxy-a,fi-~~11.75 Hz, 1 H, H-5,), 3.97 (m, J = 2, 4.5, 11.75 Hz, 1 H, H-5,,), threo-pentopyranose (11) and ( & ) - t h e 0-1,1,5-Triacetoxy4.37 (d, J = 7 Hz, 1 H, H-l), 4.66 and 4.91 (AB q, J = 11.5 Hz, 3-(acetylthio)-2-(butyloxy)pentane(12). Concentrated sulfuric 2 H, -CH,Ph), 7.3 (m, 5 H, aromatic protons); 13CNMr (CDCl,, acid (0.75 mL) was added over 10 min to a stirred, ice cold solution 22.6 MHz) ppm% 31.64 (-C(CH3)3),35.66 (C-4),43.79 (-C(CH3)3), of 10 (4.1 g, 15.6 mmol) in acetic anhydride (35 mL). Stirring 45.36 (C-3),64.20 (C-5),70.44 and 72.72 (C-2 and -CH,Ph), 103.39 at 0 "C was continued for a further 30 min and then anhydrous (C-l),127.76, 128.03, 128.42 and 137.52 (aromatic carbons); exact sodium acetate (2.00 g) was added. The mixture was allowed to mass, 296.1451; calcd for Cl6HZ4o3S,296.1446. Anal. Calcd for attain room temperature and was then evaporated. Ethanol (50 mL) was added and the solution was again evaporated. This evaporation procedure was repeated with ethanol (2 X 50 mL) (37) Vogel, A. I. "Practical Organic Chemistry", 3rd ed.; Longmans, and then with toluene (1X 50 mL). The residue was partitioned Green & Co.: London, 1956; p 190. between ether and saturated aqueous sodium bicarbonate. The (38) These assignments are tentative; they were not confirmed by organic extract was washed with brine, dried, and evaporated. measuring a 13C Spin Echo Spectrum with gated proton decoupling: Flash chromatography of the residue over silica (5 X 16 cm) with Brown, D. W.; Nakashima, T. T.; Rabenstein, D. L. J.Mugn. Reson. 1981, 1:9 ethyl acetate-hexane gave 11 (2.60 g, 57%) as a homogeneous 45, 302. methylsilane or deuterated chloroform as an internal standard. Electron-impact mass spectra were determined on an Associated Electrical Industries (AEI)MS-9 double-focusinghigh-resolution mass spectrometer and chemical-ionization mass spectra were recorded on an AEI MS-12 using ammonia as reagent gas. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter at 589 nm in a 1-dm cell. Melting points were determined on a Kofler block melting point apparatus. Cuprous chloride was freshly prepared by the literature method.37

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J. Org. Chem., Vol. 49, No. 9, 1984

(TLC, silica gel, 1:9 ethyl acetate-hexane), pale yellow oil: FT-IR (film)1742,1692,1229,1118 cm-'; NMR (CDCl,, 400 MHz) 6 0.87 (two sets of t, J = 7.25 Hz, 3 H, -CHzCH3), 1.35 (m, 2 H, -CHzCH3), 1.51 (m, 2 H, -CHzCHzCH3),1.61-2.28 (series of m, 2 H, HH-4), 2.11 (s) and 2.14 (s) (3 H, -OCOCH,), 2.34 ( 8 ) and 2.35 (s) (3 H, -SCOCH3), 3.16 (q, J = 5,7 Hz, 0.31 H, H-2 of the @-isomer),3.36 (q, J = 3, 11 Hz, 0.66 H, H-2 of the a-isomer), 3.39-3.98 (series of m, 5 H, H-3, HH-5, and C(2)-O-CHz-), 5.69 (d, J = 5 Hz, 0.31 H, H-1 of the @-isomer),6.30 (d, J = 3 Hz, 0.66 H, €j-1of the a-isomer); NMR (CDCI,, 22.6 MHz) ppm%13.78 (-CHzCH3), 19.08, 19.17 and 21.03 (-CHzCH3 and -OCOCH,), 29.73, 30.64, 30.84, 31.81, 32.07 and 32.31 (-SCOCH,, -CHzCHzCH3, and C-4) 41.34 and 41.49 (C-3), 60.90 and 62.01 (C-5),70.81 and 71.85 (C(B)-O-CH,-), 76.4 and 76.72 (C-21, 89.98 (C-1of the a-isomer),94.43 (C-1 of the &isomer), 169.01 and 169.63 (-OCOCH3), 194.76 (-SCOCH,); exact mass, 290.1177; calcd for Cl3HzzOSS,290.1178. Anal. Calcd for C13HzzO5S: C, 53.77; H, 7.64; S, 11.04. Found: C, 53.82; H, 7.76; S, 11.16. On further elution, compound 12 (0.72 g, 11.74%) was obtained as a colorless thick oil, which solidified on standing. An analytical sample was obtained by keeping the material for one day under oil pump vacuum. The material was homogeneous by TLC (silica gel, 1:9 ethyl acetate-hexane). Compound 12: FT-IR (nujol) 1689, 1735, 1749, 1767 cm-'; NMR (CDCl,, 400 MHz) 6 0.90 (t,J = 7.25 Hz, 3 H, -CHzCH3), 1.34 (m, 2 H, -CHzCH3), 1.52 (m, 2 H, -CHzCHzCH3),1.92 (m, 1 H, H-4), 2.07 (s, 3 H, -OCOCH3), 2.08 (s, 3 H, -OCOCH,), 2.09 (s, 3 H, -OCOCH3), 2.14 (m, 1 H, H-4), 2.31 (s, 3 H, -SCOCH3), 3.57 (dt) and 3.67 (dt) (C(2)-O-CHz-), 3.63 (q, J = 2.5, 7 Hz, 1H, H-2), 3.91 (m, J = 2.5, 5 , 10 Hz, 1 H, H-3), 4.14 (m, 2 H, HH-5), 6.91 (d, J = 7 Hz, 1H, H-1); 13C NMR (CDCl,, 22.6 MHz) ppm 13.57 (q, -CHzCH3),18.90 (t,-CHzCH3), 20.43 and 20.58 (-OCOCH,), 30.21, 31.48 and 31.89 (-SCOCH,, -CHzCHzCH3,and C-4), 41.17 (d, C-3), 61.24 (t, C-5), 72.94 (t, C(2)-O-CHz-), 80.94 (d, C-2), 87.99 (d, C-1); mass (chemical ionization, NH,), 410 (M + 18). Anal. Calcd for Cl7HZ8O8S:C, 52.03; H, 7.19; S, 8.17. Found: C, 52.05; H, 7.30; S, 8.34. 2 - 0 -II -Butyl-3,4-dideoxy-3-mercapto-a,j3-~~threo -pentopyranose (13). A solution (6.5%, w/v, 1mL) of sodium methoxide in methanol was added to a solution of the diacetate 11 (2.00 g, 6.88 mmol) in dry methanol (25 mL). The mixture was stirred for 3.5 h, neutralized with IRA-120 (H') resin, filtered, and concentrated at room temperature. Flash chromatography of the residue over silica gel (4.5 X 16 cm) with 2:8 ethyl acetate-hexane gave the mercapto alcohol 13 (1.20 g, 84%) as a homogeneous (TLC, silica gel, 2:8 ethyl acetate-hexane) oil which solidified on standing for several days. Compound 13: FT-IR (nujol) 3400, 1460 cm-'; NMR (CDCl,, 400 MHz) 6 0.93 (br t, J = 7.25 Hz, 3 H, CHZCH,), 1.3-2.08 (series of m, 6 H), 1.97 (d, J = 4.5 Hz, -SH), 2.85-4.1 (series of m, 7 H), 4.52 (q, J = 5.5, 6.5 Hz, 0.31 H, H-1 of the @-isomer(it collapsed to a doublet, J = 6.5 Hz on DzO exchange)), 5.27 it, J = 3 Hz, 0.63 H, H-1 of the a-isomer (it collapsed to a dopblet, = 3 Hz on DzO exchange)); 13C NMR (CDCl,, 22.6 MHz) ppm 13.70 (q, -CHzCH3), 19.14 (t,-CHzCH3), 31.89,32.16, 33.39 and 34.05 (-CHzCHzCH3and C-4), 35.59 and 39.83 (d, C-3), 58.74 and 63.74 (t, C-5), 70.57 and 72.90 (t, C(2)-0-CHz-), 82.39 and 85.06 (d, C-2), 90.45 (d, C-1 of the aisomer), 98.64 (d, C-1 of the b-isomer); exact mass, 188.0870; calcd for CgH160zS(M - HzO), 188.0871; 173.1176; calcd for CgH& (M - SH), 173.1178. Anal. Calcd for C9H1803S:C, 52.40; H, 8.79; S, 15.54. Found: C, 52.53; H, 8.85; S, 15.53.