Tetrahedron Letters,Vo1.27,No.50,pp 6071-6074,1986 0040-4039/86 $3.00 + .OO Printed in Great Britain Pergamon Journals Ltd.

THE OXIRANE RING OPENINGS OF THE DI ANHYDRO SUGAR WITH HIGH REGIOSELECTIVITY

AND ITS USE IN PREPARATION OF 7wo CHIRAL SEGMENTS OF 6-DEO/XYERYTHRONOLIDE B

Takesh i Wakamatsu,* Hideo Nakamura, Yujt Nishikimi, Kaoru Yoshida,

Tomoko Noda, and Masato Taniguchi

Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, Japan

Yoshio Ban

School of Pharmaceutical Science, Toho University, Miyama Z-2-1, Funabashi,

Chiba 274, Japan

Summary: The oxirane ring of the dianhydro sugar 2 obtained from levoglucosan

(1,6-anhydro-6-D-glucose) is opened regioselectively with organometall ic

carbon nucleophiles and its application to an asymmetric synthesis of the Cl-

C3 segment 9 together with the C9-Cl5 unit 18 of 6-deoxyerythronolide B 1 is

described.

Many monosaccharides and a large number of their derivatives are easily

available and versatile compounds. They prove to be now an important source

of chirality for the total synthesis of optically active natural products. 1

The structurally rigid and readily available levoglucosan 4 has been used

recently in the synthesis of biologically active natural products. 2

Most

recent report 3

that the 2,3-epoxide 2 was effectively opened trans-diaxially

only with the reagent of the lithium anion of thioanisole as carbon nucleo-

phi les prompted us to describe our own results, which provided a convenient

method for the preparation of dialkyl alcohol 3 from 2 by reaction with

organometallic reagents.

In connection with ongoing program directed toward utilization of levogluco-

san 4 for synthesis of naturally occurring macrolide antibiotics, its applica-

t ion to the synthesis of two chiral segments of 6-deoxyerythronolide B 1 is

described.

6071

d)

Levoglucosan 44 was converted, via the ditosylate, into the 3, -I-epoxy-

tosylate 5. 5

Compounds 2a and 2b were prepared in good yield by copper(I)

induced reaction Za,b

with methyl- or allylmagnesium chloride in TI!l-‘, f o I 1 owed

by treatment with sodium methoxide. A semi iar sequence for the preparat ion of

2c and 2d was applied to give rise to 62% yields respectrvely. Convrr s 1 on 0 f

the 2,3-epoxrde 2 into the dialkylated anhydro sugar 3 was achreved with a

preferential trans-diaxial opening of oxirane ring and 3 hide variety of

organometall ic reagents were attempted before suitable c 0 n d I t i 0 I, s fo1 the

transformation were found. The reactions as shown in Table I nerc carried

out

ew I

either by using copper(I) catalyzed additions of tirignard reagents or by

oying dimethylcopperlithium at 0°C in T-IF to afford 3 in acceptable yreld.

Table 1 Conversion of epoxide 2 to alcohol 3 a)

entry R1 R2 organometal I ic J- I e I d ( (10 1

reagent

a Me Me llie CuLi 2

31

b Me CH2 =CI-ICH2 CH2=CHCH2hIgBr .i,b)

ICU I

C CH2 =CHQ I2 ,\:ie MeMg I / Cu I 70

d Cf :2 =CHCH2 CH2 =CHCH2 Ct 12 =CHCt i2hlgC I 5 6

/cu I

e Et CH2 =CHCH2 CH2 =CHCH2hlgBr 55

/Cu 1 f CH2 =CMeCH2 Me MeMgBr /Cu I 33

z The reactions were performed at 0°C in THF unless trrdicatcd. The reaction was carried out at room temperature and the rcgioisomer (trans diequatrial opening) was Isolated in 13% yield.

In the remaining paragraph, we wil1 describe the synthesis of the optically

active segments c1 -%I

and C9-Cl5 of 6-deoxyerythronol ide B 1, tv h i c h is a

macrolrde antibiotic with ten asymmetric centers. 6

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Compounds 3a and 6a(R1=Me) can be used in the preparation of two units 9

and 18 of 1 as follows. Benzylation of 3a (PhCH2Br/NaH/cat.n-BuqNI, 94%)

followed by anhydro ring opening (CSA/MeOH) gave smoothly acetal 7, which in

turn was subjected to thioacetalization (HS(Ct12)3~~/ BF3.Et20) t0 furnish

thioacetal 3 in 65% yield. Oxidative cleavage of 8 with lead tetraacetate and

reduction wj th sodium borohydrjde led to the corresponding alcohol 9 in 6 3%

yield. Thioacetal 9 obtained in this way was also converted to lactone 10

via the fol lowing functional group manipulation i nvo I v i ng ( I ) AgPI:)3/:KS

(II) $ones oxidation (III) H2/Pd(OH)2-C. Lactone 10, which was obtained by

Gerson from part of (9S)-dihydroerythronolide A , had mp 8e°C, and [aID=-4.6”

(MeOH)[lit.7 mp 88-89”C, [a]D=-5.0”(MeOH)]. AX-I

d,e t&h

2. ‘0

a) BzlBr/NaH/n-Bt+Nl(cat) b) MeOHKSA c) HS(CH2)$H/BF3nEt20 d) Pb(OAct4/C& e) NaBH4/MeOH f) AgNO+NCS g) Jones oxld. ht H2/Pd(OH)2-C/MeOH

Turning next to elaboration of the segment 18 , the anhydro benzyl ether 11

was easily prepared from Ga(Rl=Me) in two steps ( (I) LiBEt3H/THF,80%2c (II)

C6H5CH2Br/NaH/cat. n-Bu4N1, 94% ) . Subsequent ring opening of 11 (MeOH/BF3*

Et20) gave an anomeric mixture of acetal 12 in quantitative yield. Transfor-

mation of 12 into 13 was performed by a conventional way in four steps ( (I)

PCC/MS4A8,80% (II) MeMgBr/THF,83% (III) PCC/MS4A (IV) Ph3P=CH2/THF,67% in two

steps). Hydrolysis of 13 with 10% H2S04 in THF and subsequent reduction with

LiAlH 4

gave diol 14 in 76% yield. Concomitant protection of the primary

hydroxy I group of 14 afforde_d 15 in 81% yield. Epoxidation’ of the allylic

alcohol 15 (VO(acac),/TBHP/C6H6) produced diastereomerically pure 16 in 7 9% I II

yield. When epoxide ;6

CF3.Et20, a 33% yield o

at C-10 position. 11

was allowed to react with NaBH3CN’” in the presence of

f diol 17 was obtained with the desired stereochemis try

a) t_1BEt3H/THF b) BzlBr/Nati/n-Bt+Nl(cat) c) MeOH/BF3sEt20 d) PCUMS4A e) MeMsBr/THF f) Ph3P+CH3Br-/n-BuLi/THF

by the follo~ving sequences shown

below. l‘he total synthesis directed t owa r d 6-deoxyerythronol tde E is

currently

1_3 i .‘,y* i _tBuf* i )

Y) 10%H2SOt,/THF h) LiAlH4/THF i)tBuCOC1/Pvr. j) VO(ac(~c)2/TBliP/C6ti6 k) NoBH3CN/BFjaEt20/THF 1) Me2C(OMe).$CSA in) LiAlHQ/Et20 1~1 TsCl/Pvi-. 0) LiBttjll/THF

References and Notes

1 . a) S. Hanesslan, &. Chem. R&, 12, 159 (1979); in organic Chemistry

Series, Vol. 3 ; Total Synthesis 0 f Natural Product s ; the Chi ron

Approach, Pergamon Press (1983). b) 0. Seebach, in Ziodern Synthet ic

Methods, R. Scheffold; Ed., Otto Sal le Ver lag, Furankfur t an :\lain

Germany, 91 (1980). c) B. Fraser-Reid and K. C. Anderson, Fortschr.

Chem. Org. Naturst., 39, I (1980); B. Fraser-Reid, .4cc . Chem. Res. , 4,

192 (1975). d) A. Vase] la, tn Modern Synthetic hiethods, K. Scheffold,

Ed., Otto Salle Verlag, Furankfurt am kiain, Germany, 173 (1980).

2. a) A. G. i<eily and J. S. Roberts, j. Chem. Sec. Chem. Comnun., 228

(19SG). b) N. K. Kochetkov, .A. F. Sviridov, and 21. S. trraolenko,

Tetrahedron 4315 (1981). c) M. P. Edwards, S. I’. I.ey, s. G.

Lister, and B. D. Palmer, J. Chem. Sot. Chem. Conmun., 630 (1983). d)

L. Xiagdzinski, B. Cwt,iber, and H. Fraser-Reid, ‘l’etrahedron_ Lett., 5823

(1983). e) S. Challenger and G. Procter, ‘ret rahedron Lett., 391 ( 1886).

3. P. J. Hodges and G. Procter, l‘etrahedron Lett., 4111 (1985). tZcctyI idr

anion as carbon nucleophile, see; ref. 2d.

4. R. B. Ward, Methods Carbohydr. Chemistry, 2, 396 (1963).

5. L. _I. Carlson, J. Org. Chem., 30, 3953 (1965).

6. Total synthesis of 6-deoxyerythronolide 13, see; S. kiasamune, %i. Tlirama,

S. Mar I , Sk. A. Al i , and D. S. Garvey, J. Am. Chern,_Soc., 103, 1568

(1981). Recent publications in this area, see; Y. Kobayash 1 , I{.

Uchiyama, tl. Kanbara, and F. Sato, J. Am. Chem. Sot., x, 5541 (1985)

and references cited therein.

7. K. Gerson, E. H. Flynn, M. V. Sigel , P. F. LVi ley, R. ~ionohan, aud U. C.

Quarck, J. Am. Chem. Sot., 78, 6396 (1956).

8. J. Herscovtci and K. Antonakis, J. Chem. Sot. Chem. Cornnun., 561 (1980).

9. K. B. Sharpless and T. R. Verhoeven, Aldrtchimica Acta, 12 -. 1 63 (1979).

10. r3. 0. tlutchins, I. Id. Taffer, and Iv. Burgoyne, J. Org . .I :d, Cilem ' 5214

(19SIJ

11. Efforts to improve this yield are currently under taken i II 0 u r

labolatory. Tetrahydrofuran derivative was isolated as by-product in

this reaction.

(Received in Japan 31 July 1986)