Total synthesis of (+)-myriocin and (-)-sphingofungin E from aldohexoses using overman rearrangement as the key reaction

c. Jpn.

Bull. Chem. Soc. Jpn., 75, 1927–1947 (2002) 1927

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Headline Articles

Total Synthesis of (+)-Myriocin and (−)-Sphingofungin E from

Aldohexoses Using Overman Rearrangement as the Key Reaction

02

27

47

SJA8

09-2673

098

T. Oishi et al.

Takeshi Oishi, Koji Ando, Kenjin Inomiya, Hideyuki Sato, Masatoshi Iida, and Noritaka Chida*

Department of Applied Chemistry, Faculty of Science and Technology, Keio University,

3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522

02

(Received April 18, 2002)

02

.2

Total synthesis starting from aldohexoses of naturally occurring α-substituted α-amino acids, (+)-myriocin (1) and

(−)-sphingofungin E (2), is described. Overman rearrangement of allylic trichloroacetimidate 6E derived from D-man-

nose effectively generated the tetrasubstituted carbon with nitrogen, and subsequent Wittig oleﬁnation afforded the high-

ly functionalized moiety 3 of myriocin stereoselectively. Sulfone-mediated coupling reaction of the allyl bromide 3 with

C

₁₂hydrophobic part 4 successfully constructed the carbon framework possessing E-oleﬁn 28. Removal of the sulfone

and protecting groups completed the chiral and stereoselective total synthesis of (+)-myriocin (1). A similar transforma-

tion starting from D-glucose also accomplished the total synthesis of (−)-sphingofungin E (2).

Recently, a large number of α-substituted α-amino acids (an

α-hydrogen atom of an α-amino acid is replaced with an alkyl

substituent) derivatives, such as myriocin,^1,2sphingofungins^3,4

and lactacystin,^5,6have been discovered in microorganisms or

marine creatures (Fig. 1). These natural products, reported to

possess intriguing biological activities, have attracted consid-

erable attention from many chemists and biologists.

(ATC 24400) in 1994, was found to be identical with myriocin.

This compound is reported to show the inhibitory activity

against T cell proliferation and to be a remarkable immunosup-

pressive agent^7awith potency equivalent to and 10- to 100-fold

higher than those of clinically used FK506 and cyclosporin A,

respectively. Sphingofungin E (2) and F, isolated from fer-

mentation of Paecilomyces variotii (ATCC 74097 = MF 5537)

by Merck in 1992^3bas antifungal agents, are reported to be in-

hibitors of the biosynthesis of sphingolipids, inducing apopto-

sis in both yeast and mammalian cells. These effects are due to

their potent inhibitory activities against serine palmitoyltrans-

ferase (SPT), an essential enzyme involved in the ﬁrst step of

sphingosine biosynthesis.^7bAlthough an immunosuppressive

activity of 2 has not been reported, it is anticipated that 2 has

such activity as potently as myriocin.^1cBecause of their potent

activities and new modes of action, myriocin and sphingofun-

gin E as well as their derivatives are expected to be promising

lead compounds for novel therapeutic agents on the basis of

modulation of sphingolipid biosynthesis.⁷

Myriocin^1a(also known as thermozymocidin^1b) (1) is an an-

tifungal agent isolated from culture broth of Myriococcum

albomyces^1aand Myceria sterilia^1bin 1972. Later, a novel po-

tent immunosuppresant ISP-I,^1cisolated from Isalia sinclairii

These interesting biological ﬁndings and architecturally

novel structures have stimulated a number of synthetic efforts,

and several total syntheses and synthetic approaches have been

reported.^2,4h–jStructural features of 1 and 2 are the unusual α-

substituted serine framework with E-oleﬁn and three or four

contiguous chiral centers including a tetrasubstituted carbon

with nitrogen. For a construction of the tetrasubstituted car-

bon, Payette and Just employed Strecker synthesis and they

synthesized an antipode of anhydromyriocin (γ-lactone deriva-

tive of myriocin) from L-arabinose.^2aScolastico’s group suc-

ceeded in the ﬁrst total synthesis of 1, in which they construct-

Fig. 1. Natural α-substituted α-amino acid derivatives.

1928 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

ed the tetrasubstituted carbon by hydrocyanation of an imine

derived from D-fructose, and employed the coupling reaction

with a dialkenylcupper reagent for the stereoselective forma-

tion of the E-oleﬁn.^2bYoshikawa’s group applied Darzens re-

action followed by treatment with NaN₃to a 1,3-dioxan-5-one

derived from 2-deoxy-D-glucose for generation of the tetrasub-

stituted carbon, and they utilized Wittig reaction followed by

hν-mediated isomerization with C₁₄phosphonium bromide to

extend the side chain.^2cFujita and Nagao reported the synthe-

sis of 1 in which Schöllkopf’s bislactim method for construc-

tion of the tetrasubstituted carbon and Schlosser-type Wittig

reaction to build the E-oleﬁn were used.^2dSynthesis of 1 by

Hatakeyama’s group employed the allenylmethylsilane chem-

istry and utilized intramolecular opening of a chiral epoxide by

an imidate, assembling the carbon framework with a tetrasub-

stituted carbon stereoselectively.^2ePd-Catalyzed hydroxyami-

nation of a vinyl epoxide^2fand Darzens condensation^2gwere

also employed for the stereoselective generation of the tetra-

substituted carbon in the formal synthesis of 1. Recently, total

synthesis of 2 has been reported from three laboratories. Trost

developed Pd-catalyzed asymmetric alkylation of an azlactone

to provide the key aldol-type intermediate bearing two stereo-

genic centers including the tetrasubstituted carbon, and suc-

ceeded in the stereoselective construction of E-oleﬁn by

Suzuki cross-coupling reaction, completing the asymmetric to-

tal synthesis of 2.^4hLin’s total synthesis of 2 from L-tartaric

acid employed Baylis–Hillman reaction and Hatakeyama’s

method for a preparation of an oxazoline derivative possessing

the tetrasubstituted carbon.⁴ⁱNakamura and Shiozaki reported

the total synthesis of 2 from D-glucose, in which Darzens reac-

tion and Suzuki coupling were involved as the key reactions.^4j

Synthesis and structure-activity relationship studies of

myriocin^4c,8and sphingofungins^4bhave also been carried out.

While several fascinating methods for construction of the

tetrasubstituted carbon with nitrogen and efﬁcient synthetic

approaches toward natural α-substituted α-amino acids have

been developed,⁹highly oxygenated structures of these natural

products led us to explore a novel synthetic methodology, in

which the rearrangement of allylic trichloroacetimidate

(Overman rearrangement)^10,11derived from aldohexoses is in-

volved as the key transformation (Fig. 2). This methodology is

supposed to be useful for the stereoselective synthesis of high-

ly functionalized amino acid derivatives based on the follow-

ing merits: (1) Overman rearrangement on furanose scaffolds

is expected to show moderate to high stereoselectivities, since

the chiral environment of sugars would control the facial selec-

tivities of the rearrangement; and (2) the residual functional-

ities in carbohydrate could be utilized for the transformation of

the rearranged product into highly functionalized acyclic or

heterocyclic amino acid structures.¹²Based on this concept,

we accomplished the total synthesis of lactacystin from D-glu-

cose.^6dIn this paper we report another total synthesis¹³of nat-

ural products in this class [myriocin (1) and sphingofungin E

(2)] from carbohydrates, which revealed the effectiveness of

our novel methodology.

Results and Discussion

1. Total Synthesis of (+)-Myriocin from D-Mannose.

Synthetic Plan. Myriocin (1) is a sphingosine-like com-

pound consisting of a functionalized head, an unusual α-sub-

stituted serine framework with three contiguous chiral centers

including a tetrasubstituted carbon with nitrogen, and a hydro-

phobic tail unit. Our retrosynthetic analysis, as mentioned

above, suggested that the Overman rearrangement on furanose

scaffolds, followed by further transformation utilizing the

functional groups in the carbohydrate residue, would provide

the highly functionalized intermediate for 1 in a stereoselective

manner and short reaction steps. This idea involves disconnec-

tion of the carbon framework of 1 into allyl bromide 3 and the

hydrophobic C₁₂counterpart, sulfone 4 (Fig. 3). The sulfone-

allyl bromide coupling reaction, which had been employed in

our previous total synthesis of sphingofungin D,^4ea congener

of sphingofungin E lacking a C-2 hydroxymethyl group, was

expected to construct the carbon backbone possessing E-oleﬁn

in 1 stereoselectively. On the basis of these considerations, the

functionalized part, allyl bromide 3 was planned to be pre-

pared from furanose derivative 5 with the tetrasubstituted car-

bon. The furanose 5 would derive from Overman rearrange-

Fig. 2. Our methodology for a synthesis of α-substituted α-

amino acids from aldohexofuranoses.

Fig. 3. Retrosynthetic analysis of myriocin (1).

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1929

ment of allylic trichloroacetimidate 6, which was envisioned as

arising from D-mannose. On the other hand, the sulfone 4, the

hydrophobic part of 1 was planned to be synthesized from cy-

clohexanone and C₆Grignard reagent.

gave 13, and subsequent Horner–Wadsworth–Emmons type

Wittig oleﬁnation¹⁸of 13 provided an inseparable mixture of

α,β-unsaturated ester 14 (E:Z = ca. 15:1 ratio, determined by

¹H NMR) in 90% yield from 12. When ketone 13 was subject-

ed to the typical Wittig reaction conditions with stabilized

ylide (Ph₃PwCHCO₂Et,¹⁹toluene, reﬂux), moderate Z-selectiv-

ity (E:Z = ca. 1:4 ratio, 78% yield) was observed.²⁰DIBAL-

H reduction of the ester 14, followed by separation by silica

gel column chromatography, gave 15E and 15Z in 93 and 6%

isolated yields, respectively; their structures including geome-

tries of the double bonds and anomeric conﬁgurations were

conﬁrmed by NOE experiments.

Overman Rearrangement. With the allylic alcohol 15E

in hand, we examined the crucial step, Overman rearrange-

ment. Thus, an o-xylene solution of allylic trichloroacetimi-

date 6E prepared from 15E by the action of Cl₃CCN and DBU

was heated at 140 °C in a sealed tube under argon in the pres-

ence of solid potassium carbonate²¹to afford the rearranged

products 16S and 16R in 90% yield, as an inseparable mixture

of diastereoisomers (16S:16R = ca. 7:1 ratio, determined by

¹H NMR). Under similar conditions, the isomeric allylic alco-

hol 15Z gave a 1:5 mixture of 16S and 16R in 70% yield

(Scheme 3). Overman rearrangements of allyl alcohols 15ꢀE

and 15ꢀZ, possessing 3ꢀ-O-methoxymethyl ether (C-3 position

of D-mannose) prepared from D-mannose by a procedure simi-

lar to that of 3ꢀ-O-benzyl ethers (15E and 15Z), were also car-

ried out. The E-allyl alcohol 15ꢀE afforded 16ꢀS and 16ꢀR

(4:1) in 65% yield, whereas its Z-isomer 15ꢀZ gave 16ꢀS and

16ꢀR (1:4) in 49% yield, respectively. These results suggest

that the geometry of the carbon–carbon double bond in allylic

trichloroacetimidates should be an important factor for the fa-

cial selectivity of the rearrangement, and that the ratio of the

rearrangement is slightly inﬂuenced by the substituents on hy-

droxy group at the C-3 position of furanoses.

Functionalization of a Furanose Derivative. The known

glycal 7, prepared from D-mannose in 3 step reactions^14,15[1)

conc. H₂SO₄–acetone; 2) (Me₂N)₃P–CCl₄then Li/NH₃–THF;

3) NaH–BnBr] in 70% overall yield, was converted into 8 by

an oxymercuration-reduction sequence (Scheme 1). The ace-

tonide group in 8 was removed by acid hydrolysis to give crys-

talline 3-O-benzyl-2-deoxy-β-D-glucose 9 in 91% yield from

7. The coupling constant observed in 9 (J_1,2= 9.8 Hz) re-

vealed its anomeric conﬁguration to be β. Treatment of 9 with

acidic methanol at 0 °C gave a mixture of methyl furanosides

10a and 10b, and pyranosides 11a and 11b [10a: (mixture of

10b, 11a, and 11b) = ca. 4:1, determined by ¹H NMR]. For-

tunately, the major isomer, α-furanoside 10a was obtained in

pure form by direct recrystallization in 69% isolated yield.

The mixture of undesired isomers could be again converted

into a mixture of 10a, 10b, 11a and 11b via 9 by acid hydroly-

sis followed by methyl glycoside formation. The primary hy-

droxy group in 10a was selectively protected by treatment with

dibutyltin oxide¹⁶followed by benzylation to afford 12 in 96%

yield (Scheme 2). Swern oxidation¹⁷of a hydroxy group in 12

It has been reported that Overman rearrangement proceeds

effectively in the presence of Pd(Ⅱ) or Hg(Ⅱ) catalysts at lower

reaction temperature.^6b,d,j–mHowever, attempted Pd(Ⅱ)-cata-

lyzed rearrangement of 6E and 6Z gave none of the rearranged

product, but only led to the decomposition of the imidates.

The failure of catalytic rearrangement of 6E and 6Z might be

due to the steric factor; the bulky furan moiety with oxygen

substituents would hinder the nucleophilic attack of imino-ni-

trogen to π-metal complex or/and the coordination of the cata-

lyst to oleﬁn. Furthermore, the Lewis acidity of Pd(Ⅱ)²²might

induce the decomposition of the trichloroacetiminoyl group.

Preparation of Allyl Bromide. The stereochemistry of

the newly generated tetrasubstituted carbon was conﬁrmed by

the following sequences. Ozonolysis of a mixture of the rear-

ranged products 16S and 16R (ca. 7:1, prepared from 15E),

followed by NaBH₄reduction, afforded a primary alcohol 17,

whose treatment with base (DBU) caused intramolecular cy-

clization to give oxazolidinone 18 as the major product in 63%

isolated yield after puriﬁcation with silica gel chromatography

(Scheme 4). Acid hydrolysis of 18 with 2 M HClaq–THF (1 M

= 1 mol dm⁻³) followed by acetylation gave bicyclic aminal

derivative 19. NOE experiments of acetate 19 showed that the

tetrasubstituted carbon in 19 possessed 6R conﬁguration, re-

vealing that the major stereoisomer of the rearrangement (16S)

should be 2S-isomer.

Scheme 1. Bn = –CH₂Ph. Reagents and conditions:

a) Hg-(OAc)₂, THF–H₂O, then KI, NaBH₄, 0 °C; b) 60%

AcOH aq, 91% from 7; c) AcCl, MeOH, 0 °C; 10a (69%).

Scheme 2. MPM = –CH₂C₆H₄(p-OMe). Reagents and con-

ditions: a) n-Bu₂SnO, toluene, reﬂux, then CsF, MPMCl,

DMF, 80 °C, 96%; b) Swern oxidation, 100%; c) (MeO)₂-

P(O)CH₂CO₂Me, LiBr, DBU, CH₃CN, −45 °C, 90%, E:Z

= 15:1; d) DIBAL-H, toluene, −78 °C.

1930 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

Scheme 4. Reagents and conditions: a) O₃, MeOH, −78 °C,

then NaBH₄, 0 °C; b) DBU, CH₂Cl₂, 63% for 2 steps; c) 2

M HCl aq–THF (1:1); d) Ac₂O, pyridine, 90% for 2 steps.

Scheme 5. Reagents and conditions: a) O₃, CH₂Cl₂, −78 °C,

then Me₂S, 0 °C, 81%; b) NaClO₂, NaH₂PO₄•2H₂O,

HOSO₂NH₂, t-BuOH–H₂O; c) Me₃SiCHN₂, MeOH, 98%

for 2 steps; d) 4 M HCl aq–THF (1:3), 76%.

Scheme 3. MOM = –CH₂OMe. Reagents and conditions:

a) Cl₃CCN, DBU, CH₂Cl₂, 0 °C; b) xylene, K₂CO₃, 140 °C,

in a sealed tube.

The stereochemical assignment has shown that the transfor-

mation of the vinyl function in 16S into carboxylic acid moiety

is required for the synthesis of 1. Although Lemieux–Johnson

oxidation²³of the mixture of 16S and 16R (ca. 7:1, prepared

from 15E) required long reaction time for completion and re-

sulted in a low yields of the desired products, ozonolysis of the

mixture (Me₂S workup), followed by chromatographic separa-

tion, successfully provided (S)-aldehyde 20 and its (R)-isomer

in 81 and 12% isolated yields, respectively (Scheme 5). Fur-

ther oxidation of 20 with NaClO₂and subsequent esteriﬁcation

(Me₃SiCHN₂)²⁴afforded methyl ester 22 in 98% yield. Acidic

hydrolysis of 22 provided lactol 5, possessing the correct stere-

ochemistries and proper functionalities for the introduction of

the side chain, in 76% yield.

Wittig reaction of the lactol 5 with stabilized ylide

(Ph₃PwCHCO₂Et, toluene, 25 °C) successfully afforded (E)-

α,β-unsaturated ester 23 exclusively in 89% yield (Scheme 6).

When compound 23 was treated with DIBAL-H (in THF,

−18 °C), only α,β-unsaturated ester function was reduced to

give allylic alcohol 24 in 82% yield. The observed coupling

constant in 24 (J_6,7= 15.4 Hz) clearly supported the (E)-geom-

etry of the double bond. Reaction with DIBAL-H in other sol-

vents (CH₂Cl₂or toluene) or higher reaction temperature re-

Scheme 6.

duced the methoxycarbonyl as well as N-trichloroacetamide

functions to give signiﬁcant amounts of more polar, undesired

products. In order to prepare allyl bromide suitable for the

coupling reaction, protection of the secondary hydroxy group

in 24 was investigated. Since attempted protection by ether

formation (Bn, MPM, MOM, TBS, TES and TMS) gave no

satisfactory results, we selected the cyclic carbamate as the

protecting group for both hydroxy and amino functions. Thus,

treatment of 24 with DBU smoothly induced cyclization to af-

ford oxazolidinone 25 in 86% yield. Although reaction of 25

with CBr₄and Ph₃P gave many unidentiﬁed products, it was

found that O-mesylation followed by treatment with LiBr²⁵

showed good results, and the desired 3 was obtained in 93%

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1931

ployed for the total synthesis of 1 would be applicable to the

synthesis of 2; thus Overman rearrangement of an imidate de-

rived from D-glucofuranose was expected to provide the proper

intermediate with correct stereochemistries for the synthesis of

2.

Overman Rearrangement of a Functionalized Furanose.

The known diol 32,²⁹prepared from D-glucose in 3-step reac-

tions [1) conc. H₂SO₄–acetone; 2) MOMCl–iPr₂NEt; 3) AcOH

aq], was heated with dibutyltin oxide in toluene under reﬂux,

and then treated with BnBr–CsF in DMF to give 33 in 88%

yield (Scheme 9). Swern oxidation gave ketone 34, which was

then reacted with stabilized ylide (Ph₃PwCHCO₂Et) to afford

an inseparable mixture of unsaturated ester 35 (E:Z = 1:4 ra-

tio) in 98% for 2 steps. DIBAL-H reduction of the ester func-

tion and subsequent chromatographic separation gave Z-allylic

alcohol 36Z (73%) and its E-isomer 36E (18%). The NOE ex-

periments of 36Z and 36E clearly assigned their structures.

Overman rearrangement of allylic trichloroacetimidates de-

rived from 36Z and 36E was found to show stereoselectivities

similar to those observed in the reactions of 15Z and 15E.

Treatment of 36Z with Cl₃CCN and DBU generated trichloro-

acetimidate, whose thermal rearrangement (140 °C in o-xylene

in the presence of K₂CO₃under Ar) afforded 37R and its (2S)-

isomer 37S in 64 and 14% isolated yields from 36Z, respec-

tively (Scheme 10). Similar treatment of 36E gave 37R and

37S in 12 and 45% isolated yields. Ozonolysis of 37R fol-

lowed by Me₂S treatment afforded the corresponding alde-

hyde. Reduction of the aldehyde by Zn(BH₄)₂³⁰provided alco-

hol 38 in 93% yield from 37R. It was required to use Zn(BH₄)₂

for the reduction of the aldehyde, because NaBH₄or

NaBH₃CN³¹reduction was found to be less satisfactory;

NaBH₄induced the partial formation of a carbamate, and

NaBH₃CN cleaved the methoxymethyl and/or acetonide

groups to give a complex mixture. The newly constructed ste-

reochemistry in the rearranged product 37R was conﬁrmed by

conversion of 37R into its bicyclic derivative 39. Thus, base

treatment followed by acid hydrolysis and acetylation afforded

bicyclic aminal 39 in 38% overall yield, whose single crystal

X-ray analysis³²clearly showed that the major isomer of the

rearrangement product 37R has (2R)-conﬁguration. Therefore,

it is now clear that the primary alcohol originating from D-glu-

cose should be transformed into a carboxylic acid moiety, and

the newly generated alcohol in 38 should correspond to the pri-

mary alcohol moiety of sphingofungin E.

Scheme 7. Reagents and conditions: a) n-C₆H₁₃MgBr, Et₂O;

b) I₂, o-xylene, reﬂux; c) O₃, MeOH, 0 °C then NaBH₄,

53% for 3 steps; d) CBr₄, Ph₃P, CH₂Cl₂, −15 °C; e) Jones

oxidation; f) PhSO₂Na•2H₂O, DMF; g) (TMSOCH₂)₂,

TMSOTf, CH₂Cl₂, 71% from 26.

yield from 25.

Coupling Reaction and Completion of the Total Synthe-

sis. A hydrophobic part of myriocin, the C₁₂side chain pos-

sessing a sulfone and a masked carbonyl group, was synthe-

sized from cyclohexanone (Scheme 7). The known diol 26,²⁶

prepared from cyclohexanone in 3-step reactions by essentially

the same procedure as that reported by Payette and Just,^2ewas

converted into primary bromide, whose oxidation gave bromo

ketone 27. Treatment of 27 with PhSO₂Na, followed by

ketalization²⁷gave 4 in 71% yield from 26.

Sulfone 4 was lithiated with n-BuLi in THF at −78 °C, and

then reacted with the allyl bromide 3 to give coupling product

28 as a mixture of diastereomers in 84% yield (Scheme 8). Sa-

poniﬁcation of 28 and subsequent Birch reduction (Li, liquid

NH₃) successfully removed sulfonyl, O-benzyl and O-(p-meth-

oxybenzyl) groups. Deprotections of the ketal group by acid

hydrolysis and of the carbamate function by alkaline hydroly-

sis, followed by conventional acetylation, provided the known

γ-lactone 30^2din 47% overall yield from 28. The spectral and

physical data for 30 were identical in all respects to those pro-

vided by Professor Hatakeyama. Saponiﬁcation^2dfollowed by

neutralization with IRC-76 resin (H⁺form) furnished (+)-my-

riocin 1 in 86% yield. The spectral (¹H and ¹³C NMR) data for

synthetic 1 were fully identical with those of natural myriocin,

and the physical properties of 1 showed good agreement

{168.4–170.1 °C, [α]_D²⁵+5.1 (c 0.175, MeOH); lit.^1c169–

171 °C, [α]_D+4.8 (c 0.286, MeOH)} with those reported for

the natural product. Therefore, total synthesis of myriocin has

been accomplished. However, the relatively low yields and

longer reaction sequences in conversion of 28 to 1 via 30

(6 steps in 40% overall yield) led us to search for more effec-

tive synthetic pathways. After several attempts, it was found

that use of Li–naphthalene²⁸gave excellent results. Thus,

treatment of 29 with Li–naphthalene in THF at −18 °C, fol-

lowed by acidic treatment, gave bicyclic γ-lactone 31 in 94%

yield from 28. Saponiﬁcation of 31 with 10% aqueous NaOH–

MeOH and subsequent neutralization with resin furnished 1 in

82% yield.

Coupling Reaction and the Total Synthesis.

Acid hy-

drolysis of 38 removed methoxymethyl and acetonide protect-

ing groups to give furanose 40, which is then treated with the

stabilized ylide (Ph₃PwCHCO₂Et) to afford (E)-α,β-unsaturat-

ed ester 41 exclusively (Scheme 11). The resulting tetrol 41

was treated with (MeO)₂CMe₂–CSA to afford diacetonide 42

in 46% yield from 38. Treatment of 42 with DIBAL-H at

−78 °C, in contrast with the results of 23, reduced the ester

function as well as the N-trichloroacetamide moiety to afford

an amine, which was isolated as its N-Boc derivative 43 in

90% yield. The allylic alcohol was converted into bromide to

give the highly functionalized part 44 of sphingofungin E in

90% yield. Coupling reaction of the allyl bromide 44 with the

side chain 4, under conditions similar to those employed for

the coupling of 3 with 4, successfully afforded the carbon

2. Total Synthesis of (−)-Sphingofungin E from D-Glu-

cose. Synthetic Plan. Sphingofungin E (2) has four con-

secutive chiral centers including α-substituted α-amino acid

moiety. Recent successful total syntheses of 2^4h–jrevealed that

it is a (5R)-hydroxy derivative of myriocin. The structural re-

semblance of 2 and 1 suggested that the methodology em-

1932 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

Scheme 8.

Scheme 9. Reagents and conditions: a) n-Bu₂SnO, toluene,

reﬂux, then CsF, BnBr, DMF, 50 °C, 88%; b) Swern oxida-

tion; c) Ph₃PwCHCO₂Et, toluene, 100 °C, 98% for 2 steps,

E:Z = 1:4; d) DIBAL-H, toluene, −78 °C.

framework of sphingofungin E 45 in 85% yield as a mixture of

diastereomers.

Scheme 10. Reagents and conditions: a) Cl₃CCN, DBU,

CH₂Cl₂, 0 °C; b) xylene, 140 °C, in a sealed tube, K₂CO₃;

c) O₃, CH₂Cl₂, −78 °C then Me₂S, 0 °C; d) Zn(BH₄)₂,

Et₂O, 0 °C, 91%; e) DBU, CH₂Cl₂, 0 °C; f) TFA–H₂O

(1:1), 0 °C; g) Ac₂O, pyridine, 48% for 3 steps.

Treatment of 45 with Li and naphthalene in THF removed

both sulfonyl and O-benzyl groups to give primary alcohol 46

in 52% yield (Scheme 12). Swern oxidation followed by

NaClO₂treatment provided the protected amino acid 47. All

protecting groups in 47: two acetonides, an ethyleneketal and a

tert-butoxycarbonyl, were removed by acid hydrolysis (TFA–

THF–H₂O) to afford a mixture of sphingofungin E (2) and its

γ-lactone. Since the separation of them was found to be difﬁ-

cult at this stage, the mixture was treated with Ac₂O and pyri-

dine to give tetraacetylated γ-lactone 48 in 68% yield from 46.

Finally, (−)-2 was obtained in 88% yield by saponiﬁcation of

48, followed by neutralization with Amberlite IRC-76. The

physical properties of synthetic 2 {144.0–145.8 °C, [α]_D²⁵−5.6

(c 0.14, MeOH); lit.⁴ⁱ145–147 °C, [α]_D−5.43 (c 0.48,

MeOH)} as well as spectroscopic data (¹H and ¹³C NMR)

showed good accordance with those reported for the authentic

sample.⁴ⁱ

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1933

Scheme 11. Reagents and conditions: a) 12 M HCl aq–THF (1:2); b) Ph₃PwCHCO₂Et, CH₂Cl₂; c) Me₂C(OMe)₂, CSA, 46% from

38; d) DIBAL-H, toluene, −78 °C; e) Boc₂O, NaHCO₃, MeOH, 90% for 2 steps; f) MsCl, Et₃N, CH₂Cl₂then LiBr, THF, 90%;

g) 4, n-BuLi, THF, −78 °C, 85%.

nyl group, generated by the rearrangement. These results sug-

gested that our synthetic protocol is applicable to the stereose-

lective synthesis for either (R)- or (S)-α-substituted α-amino

acid structures. This work and previous success in total syn-

thesis of lactacystin^6dalso revealed that the methodology in-

volving Overman rearrangement on furanose scaffolds, fol-

lowed by further manipulation by use of the residual functional

groups in carbohydrates, is quite effective for the chiral synthe-

sis of natural products possessing complex α-substituted α-

amino acid structures.

Experimental

General. Melting points were determined on a Mitamura-

Riken micro hot stage and were not corrected. Optical rotations

were recorded using a sodium lamp (589 nm) with a JASCO DIP-

370 instrument with 1 dm tube. Infrared (IR) spectra were mea-

sured with a JASCO FT/IR-200 spectrometer and were reported in

wavenumbers (cm⁻¹). ¹H NMR spectra were recorded at 300

MHz on a JEOL Lambda 300 or on a Varian MVX-300 spectrom-

eter. Chemical shifts are reported as δ values in ppm relative to

tetramethylsilane (δ = 0) or chloroform (δ = 7.26). Coupling

constants (J) are reported in Hz. Abbreviations used are: b (broad

peak), s (singlet), d (doublet), t (triplet), q (quartet) and m (com-

plex multiplet). ¹³C NMR spectra were recorded at 75 MHz on a

JEOL Lambda 300 spectrometer. Chemical shifts are reported as

δ values in ppm relative to chloroform-d (δ = 77.00) or methanol-

d₄(δ = 49.00) as internal references. Mass spectra are measured

by a JEOL GC Mate spectrometer with EI (70 eV) or FAB mode.

Organic extracts were dried over solid anhydrous Na₂SO₄and

concentrated below 40 °C under reduced pressure. Column chro-

matography was carried out with silica gel (Merck Kieselgel 60

Scheme 12.

Conclusion

Total synthesis of myriocin (1) from D-mannose and sphin-

gofungin E (2) from D-glucose was accomplished. This work

established a novel synthetic pathway to myriocin, sphingo-

fungins, and their derivatives. In these studies, two intriguing

experimental facts were revealed: (1) Overman rearrangement

of allylic trichloroacetimidates derived from furanose deriva-

tives proceeded in high yields with moderate stereoselectivi-

ties, and the facial selection of the rearrangement was found to

depend mainly on the geometry of the carbon–carbon double

bonds in the allylic imidates; and (2) both stereoisomers of the

rearranged products could be converted into the amino acid

structure possessing the same conﬁguration by reductive or ox-

idative transformation of a formyl function derived from a vi-

F₂₅₄; 230–400 mesh) or alumina powder (WAKO alumina, activat-

ed; 300 mesh) for puriﬁcation. Preparative TLC (PLC) was per-

formed with Merck PLC plate (Kieselgel 60 F₂₅₄, 0.5 mm thick-

ness).

1,4-Anhydro-3-O-benzyl-5,6-O-isopropylidene-D-arabino-

hex-1-enitol (7).¹⁵

To a solution of diacetone-D-mannose¹⁴

(10.0 g, 38.4 mmol) in THF (160 mL) were added CCl₄(5.56 mL,

57.6 mmol) and (Me₂N)₃P (7.68 mL, 42.3 mmol) at −78 °C. The

reaction mixture was stirred at −78 °C for 1 h, then warmed up to

0 °C and stirred at 0 °C for 5 more min. The resulting yellow so-

lution of glycosyl chloride was added into a navy blue suspension

1934 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

of Li (5.33 g, 0.768 mol) in freshly distilled liquid ammonia

(200 mL, from Li) at −78 °C. After the reaction mixture had been

stirred at −78 °C for 30 min, solid NH₄Cl (61.6 g, 1.17 mol) was

added portionwise to it at −78 °C. The resulting suspension was

stirred at −40 °C until the blue color of the mixture disappeared.

Then the mixture was stirred at 0 °C for 1 h to evaporate the re-

maining ammonia. To the resulting gray suspension H₂O was

added carefully, and the products were extracted with CHCl₃and

then dried. Removal of the solvent gave a residue, which was

passed through a short column (100 g silica gel, 1:2 EtOAc–hex-

ane containing 1 vol% Et₃N as an eluent) to afford crude glycal

(6.77 g) as a pale yellow oil, which was used for the next reaction

without further puriﬁcation: R_f= 0.43 (1:1 EtOAc–toluene).

At 0 °C, a THF (100 mL) solution of the crude glycal (6.77 g)

was added dropwise to a suspension of NaH (2.91 g, 72.7 mmol,

washed with hexane) in THF (35 mL). Then the mixture was

stirred at 0 °C for 15 min. To this suspension were added BnBr

(9.51 mL, 80.0 mmol) and n-Bu₄NI (671 mg, 1.82 mmol) at 0 °C.

After the reaction mixture had been stirred at 25 °C for 2 h, H₂O at

0 °C was added to it until the mixture became homogenous. The

products were extracted with EtOAc and the organic layer was

washed successively with 20% aqueous Na₂S₂O₃solution and

brine, and then dried. Removal of the solvent gave a residue,

which was passed through a short column (100 g silica gel, 1:5

EtOAc–hexane containing 1 vol% Et₃N as an eluent) to afford gly-

cal benzyl ether 7 (9.74 g, 97%) as a pale yellow syrup: R_f= 0.67

(1:2 EtOAc–hexane); ¹H NMR (300 MHz, CDCl₃) δ 1.39 (s, 3H),

1.48 (s, 3H), 3.99 (dd, 1H, J = 6.6 and 8.4 Hz), 4.11 (dd, 1H, J =

6.6 and 8.4 Hz), 4.44 (dd, 1H, J = 5.1 and 7.0 Hz), 4.51 (d, 1H, J

= 11.8 Hz), 4.58 (d, 1H, J = 11.8 Hz), 4.59 (dd, 1H, J = 5.1 and

6.6 Hz), 4.66 (dd, 1H, J = 2.7 and 7.0 Hz), 5.29 (dd, 1H, J = 2.7

and 2.7 Hz), 6.62 (d, 1H, J = 2.7 Hz), 7.28–7.37 (m, 5H); ¹³C

NMR (75 MHz, CDCl₃) δ 25.4, 26.6, 66.1, 71.1, 73.2, 79.4, 84.3,

102.0, 108.8, 127.6, 127.7, 128.5, 138.6, 150.7. The spectral data

were identical with those reported.^14c

J = 2.3, 5.7 and 9.5 Hz), 3.39 (bdd, 1H, J = 9.5 and 9.5 Hz), 3.53

(ddd, 1H, J = 4.9, 9.5 and 11.6 Hz), 3.73 (dd, 1H, J = 5.7 and

11.7 Hz), 3.91 (dd, 1H, J = 2.3 and 11.7 Hz), 4.71 (s, 2H), 4.79

(dd, 1H, J = 2.0 and 9.8 Hz), 7.30–7.45 (m, 5H); ¹³C NMR (75

MHz, CD₃OD) δ 39.3, 63.0, 71.9, 72.7, 78.0, 80.3, 95.1, 128.6,

128.9, 129.3, 140.1; EI-MS m/z 254 (M⁺, 5.2%), 236 (3.3), 163

(10.6), 86 (100); EI-HRMS Calcd for C₁₃H₁₈O₅(M⁺): 254.1154,

Found: m/z 254.1142. Found: C, 61.20; H, 7.20%. Calcd for

C₁₃H₁₈O₅: C, 61.40; H, 7.14%.

α

3-O-Benzyl-2-deoxy- -D-arabino-hexofuranoside

Methyl

(10a). To a solution of AcCl (0.0617 mL) in MeOH (40 mL) was

added hexose 9 (2.00 g, 7.87 mmol) at 0 °C. After being stirred at

0 °C for 20 h, the reaction mixture was neutralized with Et₃N, and

concentrated to give a solid residue, which was recrystallized from

EtOAc–hexane (3:4, 21 mL) to afford methyl furanoside 10a

(1.46 g, 69%) as white crystals: R_f= 0.46 (6:1 EtOAc–hexane);

Mp 93.2–95.4 °C; [α]_D^24.0+31.9 (c 0.62, CHCl₃); IR (KBr) 1035,

1050, 2940, 3230 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.12 (ddd,

1H, J = 2.4, 6.1 and 13.7 Hz), 2.20 (ddd, 1H, J = 5.1, 5.1 and

13.7 Hz), 1.63–2.24 (m, 1H), 3.08 (bs, 1H), 3.31 (s, 3H), 3.64–

3.71 (m, 1H), 3.76–3.84 (m, 1H), 3.95–4.00 (m, 2H), 4.38 (d, 1H,

J = 11.6 Hz), 4.39 (m, 1H), 4.59 (d, 1H, J = 11.6 Hz), 5.11 (dd,

1H, J = 2.4 and 5.1 Hz), 7.27–7.37 (m, 5H); ¹³C NMR (75 MHz,

CDCl₃) δ 38.8, 55.1, 64.6, 70.5, 71.5, 78.8, 78.9, 104.1, 127.7,

128.1, 128.7, 137.2; EI-MS m/z 268 (M⁺, 6.2%), 236 (17.1), 177

(97.8), 99 (100); EI-HRMS Calcd for C₁₄H₂₀O₅(M⁺): 268.1311,

Found: m/z 268.1309. Found: C, 62.84; H, 7.59%. Calcd for

C₁₄H₂₀O₅: C, 62.67; H, 7.51%.

α

Methyl 3-O-Benzyl-6-O-(4-methoxybenzyl)-2-deoxy- -D-ar-

abino-hexofuranoside (12). To a solution of diol 10a (1.22 g,

4.55 mmol) in toluene (25 mL) was added dibutyltin oxide

(1.13 g, 4.55 mmol) and the mixture was stirred under reﬂux for

2 h. The resulting mixture was concentrated to give a residue,

which was dissolved in DMF (40 mL) at 40 °C. To this suspen-

sion were added CsF (0.83 g, 5.46 mmol) and p-methoxybenzyl

chloride (0.74 mL, 5.46 mmol) at 40 °C and the mixture was

stirred at 80 °C for 40 h. After cooling, to the reaction mixture

were added 20% aqueous KF solution (5 mL) and saturated aque-

ous NaHCO₃solution (5 mL). The resulting mixture was stirred

for 2 h at 25 °C, and then extracted with EtOAc. The organic layer

was washed successively with H₂O, 20% aqueous KF solution,

and brine, and then dried. Removal of the solvent gave a residue,

which was puriﬁed by column chromatography (50 g silica gel,

1:4 EtOAc–hexane as an eluent) to afford p-methoxybenzyl ether

12 (1.70 g, 96%) as a pale yellow syrup: R_f= 0.73 (3:1 EtOAc–

hexane); [α]_D^23.5+25.8 (c 0.85, CHCl₃); IR (neat) 1040, 1105,

1250, 1515, 1615, 2930, 3480 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 2.06 (ddd, 1H, J = 2.7, 6.1 and 14.1 Hz), 2.26 (ddd, 1H, J = 2.7,

5.6 and 14.1 Hz), 3.03 (d, 1H, J = 5.3 Hz), 3.33 (s, 3H), 3.60 (dd,

1H, J = 5.9 and 9.9 Hz), 3.71 (dd, 1H, J = 3.7 and 9.9 Hz), 3.80

(s, 3H), 3.99 (dd, 1H, J = 4.4 and 7.6 Hz), 4.16 (m, 1H), 4.32 (m,

1H), 4.41 (d, 1H, J = 11.7 Hz), 4.50 (s, 2H), 4.56 (d, 1H, J = 11.7

Hz), 5.14 (dd, 1H, J = 2.7 and 5.6 Hz), 6.87 (d, 2H, J = 8.3 Hz),

7.25–7.35 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 39.3, 55.2, 55.3,

69.1, 71.5, 71.7, 73.1, 78.9, 79.0, 104.2, 113.8, 127.7, 127.9,

128.5, 129.4, 130.3, 137.5, 159.2; EI-MS m/z 388 (M⁺, 2.1%),

356 (31.7), 121 (100); EI-HRMS Calcd for C₂₂H₂₈O₆(M⁺):

388.1886, Found: m/z 388.1884. Found: C, 67.99; H, 7.31%.

Calcd for C₂₂H₂₈O₆: C, 68.02; H, 7.27%.

β

3-O-Benzyl-2-deoxy- -D-arabino-hexopyranose (9).

To a

mixture of glycal 7 (5.85 g, 21.2 mmol) in THF–H₂O (1:1,

120 mL) was added Hg(OAc)₂(7.42 g, 23.3 mmol) at 25 °C. Af-

ter this mixture had been stirred at 25 °C for 30 min, the resulting

clear solution was cooled to 0 °C. To this solution was added an

aqueous solution of KI (17.5 g, 0.105 mol in 20 mL water) and the

resulting mixture was stirred at 0 °C for 15 min. To this reaction

mixture was added an aqueous solution of NaBH₄(801 mg, 21.2

mmol in 50 mL H₂O) dropwise over 1 h at 0 °C, and the resulting

suspension was stirred vigorously at 0 °C for 30 min. The insolu-

ble material was removed by ﬁltration through a pad of Celite; this

Celite was rinsed with EtOAc (100 mL × 3). The ﬁltrate was sep-

arated and the organic layer was washed successively with saturat-

ed aqueous KI solution, saturated aqueous Na₂S₂O₃solution and

brine, and then dried. Removal of the solvent afforded furanose 8

(6.33 g) as a pale yellow syrup, which was used for the next reac-

tion without further puriﬁcation: R_f= 0.19 (1:2 EtOAc–hexane).

A solution of crude 8 (6.33 g) in 60% aqueous AcOH solution

(130 mL) was stirred at 25 °C for 14 h. The resulting mixture was

concentrated to give a residue, which was recrystallized from

EtOH–petroleum ether (1:9, 200 mL) to afford hexose 9 (4.89 g,

91%) as white crystals. R_f= 0.1 (3:1 EtOAc–hexane); Mp

119.8–123.6 °C; [α]_D^23.5+25.4 (c 0.86, CH₃OH, after 3 h at

25 °C); IR (KBr) 1360, 1400, 1455, 1495, 2900, 2940, 3230 cm⁻¹

; ¹H NMR (300 MHz, CD₃OD) δ 1.46 (ddd, 1H, J = 9.8, 11.6 and

12.4 Hz), 2.33 (ddd, 1H, J = 2.0, 4.9 and 12.4 Hz), 3.29 (ddd, 1H,

α

3-O-Benzyl-6-O-(4-methoxybenzyl)-2-deoxy- -D-

Methyl

threo-hexofuranos-5-uloside (13). A mixture of (COCl)₂(2.0

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1935

M solution in CH₂Cl₂, 10.9 mL, 21.8 mmol) and DMSO (3.10

mL, 43.7 mmol) was stirred at −78 °C for 30 min. To the stirred

mixture was added a solution of alcohol 12 (1.70 g, 4.37 mmol) in

CH₂Cl₂(23 mL). After the reaction mixture had been stirred at

−78 °C for 2.5 h, Et₃N (9.13 mL, 65.5 mmol) was added , and the

resulting suspension was stirred at 0 °C for more 30 min. This

mixture was poured into saturated aqueous NH₄Cl solution, and

the products were extracted with EtOAc. The organic layer was

washed with brine, and then dried. Removal of the solvent gave a

residue, which was puriﬁed by column chromatography (32 g sili-

ca gel, 1:3 EtOAc–hexane as an eluent) to afford ketone 13 (1.68 g,

100%) as a colorless syrup: R_f= 0.48 (1:1 EtOAc–hexane);

[α]_D^26.5+14.0 (c 1.34, CHCl₃); IR (neat) 1035, 1060, 1115, 1250,

solution in toluene, 8.39 mL, 8.47 mmol) at −78 °C. After being

stirred at −78 °C for 15 min, the reaction mixture was quenched

by addition of MeOH, diluted with Et₂O, and washed with 1 M

aqueous HCl solution. The aqueous layer was re-extracted with

Et₂O. The combined organic layer was washed successively with

saturated aqueous NaHCO₃solution and brine, and then dried.

Removal of the solvent gave a residue, which was puriﬁed by col-

umn chromatography (50 g silica gel, 1:1 EtOAc–hexane as an

eluent) to afford ﬁrst the Z-isomer of allylic alcohol 15Z (83 mg,

6%) as a colorless syrup: R_f= 0.16 (1:1 EtOAc–hexane); [α]_D^25.0

+16.4 (c 0.82, CHCl₃); IR (neat) 1040, 1100, 1250, 1515, 1615,

2860, 2910, 3440 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.07 (ddd,

1H, J = 2.7, 6.1 and 14.1 Hz), 2.24 (ddd, 1H, J = 2.4, 5.6 and

14.1 Hz), 3.31 (s, 3H), 3.76 (s, 3H), 4.00 (bs, 2H), 4.06–4.17 (m,

2H), 4.28 (dd, 1H, J = 7.8 and 12.4 Hz), 4.33 (d, 1H, J = 11.9

Hz), 4.37 (d, 1H, J = 11.7 Hz), 4.41 (d, 1H, J = 11.7 Hz), 4.43 (d,

1H, J = 11.9 Hz), 4.72 (d, 1H, J = 4.3 Hz), 5.14 (dd, 1H, J = 2.7

and 5.6 Hz), 6.01 (bdd, 1H, J = 7.8 and 7.8 Hz), 6.82 (d, 2H, J =

8.8 Hz), 7.17–7.29 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 40.0,

55.25, 55.30, 58.4, 71.6, 71.7, 72.6, 79.5 (2C), 103.8, 113.7,

127.7, 127.8, 128.4, 129.2, 130.2, 130.4, 134.8, 137.7, 159.1;

FAB-MS m/z 415 (M + H, 3.4%), 397 (6.6), 121 (100); FAB-

HRMS Calcd for C₂₄H₃₁O₆(M + H)⁺: 415.2121, Found: m/z

415.2113.

1

1515, 1615, 1730, 2840, 2910, 2935 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 2.09 (ddd, 1H, J = 2.7, 6.1 and 14.1 Hz), 2.29 (ddd, 1H,

J = 2.7, 5.4 and 14.1 Hz), 3.38 (s, 3H), 3.81 (s, 3H), 4.31 (d, 1H, J

= 17.0 Hz), 4.37 (d, 1H, J = 17.0 Hz), 4.38 (d, 1H, J = 11.8 Hz),

4.42 (d, 1H, J = 11.8 Hz), 4.49 (d, 1H, J = 11.8 Hz), 4.50 (d, 1H,

J = 11.8 Hz), 4.55–4.59 (m, 1H), 4.70 (d, 1H, J = 5.1 Hz), 5.29

(dd, 1H, J = 2.7 and 5.4 Hz), 6.59 (d, 2H, J = 8.5 Hz), 7.21–7.37

(m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 39.1, 55.2, 55.5, 71.6,

72.8, 74.1, 79.8, 84.1, 105.2, 113.7, 127.7, 127.8, 128.4, 129.4,

129.5, 137.3, 159.3, 204.9; EI-MS m/z 386 (M⁺, 0.2%), 295 (0.4),

121 (76.0), 91 (100); EI-HRMS Calcd for C₂₂H₂₆O₆(M⁺):

386.1729, Found: m/z 386.1732.

Further elution gave the E-isomer 15E (1.31 g, 93%) as a color-

less syrup: R_f= 0.14 (1:1 EtOAc–hexane); [α]_D^25.0+28.7 (c 1.48,

CHCl₃); IR (neat) 1050, 1100, 1175, 1250, 1455, 1515, 1615,

2860, 2910, 2930, 3445 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.11

(ddd, 1H, J = 2.4, 6.2 and 13.9 Hz), 2.22 (ddd, 1H, J = 3.6, 5.3

and 13.9 Hz), 3.36 (s, 3H), 3.80 (s, 3H), 4.01 (d, 1H, J = 11.9 Hz),

4.13 (d, 1H, J = 11.9 Hz), 4.17–4.21 (m, 3H), 4.33 (d, 1H, J =

11.9 Hz), 4.36 (d, 1H, J = 11.2 Hz), 4.447 (d, 1H, J = 11.2 Hz),

4.451 (d, 1H, J = 11.9 Hz), 4.59 (bd, 1H, J = 4.6 Hz), 5.17 (dd,

1H, J = 2.4 and 5.3 Hz), 6.75 (bt, 1H, J = 6.8 Hz), 6.86 (d, 2H, J

= 8.5 Hz), 7.20–7.33 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 39.7,

55.2 (2C), 58.8, 66.2, 71.4, 72.2, 79.3, 82.0, 103.9, 113.8, 127.5,

127.6, 128.3, 129.5, 129.9, 130.5, 136.1, 137.9, 159.2; FAB-MS

m/z 415 (M + H, 2.6%), 383 (3.3), 121 (100); FAB-HRMS Calcd

for C₂₄H₃₁O₆(M + H)⁺: 415.2121, Found: m/z 415.2123.

A Mixture of N-{(S)-2-[(2R,3R,5S)-3-Benzyloxy-5-methoxy-

oxolan-2-yl]-1-(4-methoxybenzyloxy)-3-buten-2-yl}trichloro-

acetamide (16S) and Its (R)-Isomer (16R). To a solution of al-

lylic alcohol 15E (1.56 g, 3.77 mmol) in CH₂Cl₂(20 mL) were

added trichloroacetonitrile (0.756 mL, 7.54 mol) and DBU

(0.0564 mL, 0.377 mmol) at 0 °C, and the mixture was stirred at

0 °C for 30 min. The reaction mixture was concentrated to give a

residue, which was passed through a short column (10 g silica gel,

1:3 EtOAc–hexane containing 1 vol% Et₃N as an eluent) to afford

a crude trichloroacetimidate 6E (2.14 g) as a yellow syrup. This

was used for the next reaction without further puriﬁcation: R_f=

0.67 (1:1 EtOAc–hexane).

An Inseparable Mixture of Methyl (E)-3-[(2R,3R,5S)-3-

Benzyloxy-5-methoxyoxolan-2-yl]-4-(4-methoxybenzyloxy)-

but-2-enoate and Its (Z)-Isomer (14). To a mixture of LiBr

(0.76 g, 8.73 mmol, dried at 140 °C under reduced pressure just

before use) in CH₃CN (10 mL) were added methyl dimethoxy-

phosphinoylacetate (1.41 mL, 8.73 mmol) and DBU (1.31 mL,

8.73 mmol) at 25 °C. The mixture was stirred at −45 °C for 15

min. To the resulting colorless solution was added a solution of

ketone 13 (1.68 g) in CH₃CN (10 mL) at −45 °C. After this mix-

ture had been stirred for 12 h at −45 °C, the resulting suspension

was diluted with EtOAc and washed successively with 1 M aque-

ous HCl solution, saturated aqueous NaHCO₃solution and brine,

and then dried. Removal of the solvent gave a residue, which was

puriﬁed by column chromatography (120 g silica gel, 1:6 EtOAc–

hexane as an eluent) to afford a mixture (E:Z = ca. 15:1) of un-

saturated ester 14 (1.74 g, 90%) as a colorless syrup: R_f= 0.52

(1:2 EtOAc–hexane); IR (neat) 1055, 1110, 1150, 1215, 1250,

1

1515, 1585, 1615, 1650, 1715, 2840, 2950 cm⁻¹; H NMR (300

MHz, CDCl₃, for the major isomer) δ 2.08 (ddd, 1H, J = 2.9, 6.1

and 14.1 Hz), 2.28 (ddd, 1H, J = 2.1, 5.6 and 14.1 Hz), 3.36 (s,

3H), 3.70 (s, 3H), 3.79 (s, 3H), 4.26 (d, 1H, J = 11.9 Hz), 4.28 (d,

1H, J = 11.2 Hz), 4.32–4.36 (m, 1H), 4.38 (d, 1H, J = 11.2 Hz),

4.41 (d, 1H, J = 11.9 Hz), 4.46 (bd, 1H, J = 14.9 Hz), 4.90 (bd,

1H, J = 3.4 Hz), 4.96 (bd, 1H, J = 14.9 Hz), 5.21 (dd, 1H, J =

2.9 and 5.6 Hz), 6.22 (m, 1H), 6.84 (d, 2H, J = 8.6 Hz), 7.15–7.32

(m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 40.1, 51.3, 55.4, 55.5,

68.4, 71.4, 72.9, 79.2, 79.9, 103.9, 113.9, 115.5, 127.8, 127.9,

128.5, 129.6, 130.3, 138.1, 154.8, 159.4, 166.9; EI-MS m/z 442

(M⁺, 0.1%), 410 (0.1), 351 (0.2), 274 (21.3), 91 (100); EI-HRMS

Calcd for C₂₅H₃₀O₇(M⁺): 442.1992, Found: m/z 442.1995.

Found: C, 67.69; H, 6.89%. Calcd for C₂₅H₃₀O₇: C, 67.86; H,

6.83%.

To a solution of the crude imidate 6E (2.14 g) in o-xylene (214

mL) was added solid K₂CO₃(581 mg). Then the mixture was hea-

ted at 140 °C for 60 h, in sealed tubes under Ar. The reaction mix-

ture was concentrated to give a residue, which was puriﬁed by col-

umn chromatography (80 g silica gel, 1:20 EtOAc–toluene as an

eluent) to afford a mixture (in a ratio of ca. 7:1) of rearranged

product 16S and 16R (1.91 g, 90% for 2 steps) as a light yellow

syrup.

(Z)-3-[(2R,3R,5S)-3-Benzyloxy-5-methoxyoxolan-2-yl]-4-(4-

methoxybenzyloxy)but-2-en-1-ol (15Z) and Its (E)-Isomer

(15E). To a solution of ester 14 (ca. 15:1 mixture, 1.50 g, 3.39

mmol) in toluene (30 mL) was added dropwise DIBAL-H (1.01 M

A small amount of the mixture was separated by PLC (1:9

EtOAc–hexane as an eluent) to provide each diastereomer in pure

1936 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

form and for use as analytical samples.

MHz, CDCl₃) δ 2.02 (ddd, 1H, J = 3.6, 4.6 and 14.6 Hz), 2.42

(dd, 1H, J = 5.7 and 14.6 Hz), 3.34 (s, 3H), 3.53 (dd, 1H, J = 3.4

and 10.0 Hz), 3.71 (d, 1H, J = 8.8 Hz), 3.80 (s, 3H), 3.89 (dd, 1H,

J = 10.0 and 11.7 Hz), 4.23–4.27 (m, 3H), 4.29 (d, 1H, J = 11.2

Hz), 4.44 (d, 1H, J = 11.4 Hz), 4.45 (bs, 1H), 4.48 (d, 1H, J =

11.2 Hz), 4.56 (d, 1H, J = 11.4 Hz), 5.20 (dd, 1H, J = 3.6 and 5.7

Hz), 6.87 (d, 2H, J = 8.5 Hz), 7.24 (d, 2H, J = 8.5 Hz), 7.29–7.36

(m, 5H), 7.87 (bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 39.2, 55.3,

55.5, 61.9, 63.6, 68.8, 71.2, 73.4, 77.6, 78.9, 92.9, 103.4, 113.8,

128.2, 128.45, 128.54, 129.3, 129.8, 136.7, 159.3, 161.5; EI-MS

m/z 563 (M + 2, 0.6%), 561 (M⁺, 0.9), 527 (4.2), 525 (5.4), 391

(100), 389 (93.8); EI-HRMS Calcd for C₂₅H₃₀³⁵Cl₃NO₇(M⁺):

561.1087, Found: m/z 561.1083.

16S: R_f= 0.44 (1:3 EtOAc–hexane); [α]_D^24.0+11.2 (c 1.16,

CHCl₃); IR (neat) 1045, 1105, 1250, 1515, 1720, 2835, 2930,

3330 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.96 (ddd, 1H, J = 3.6,

5.2 and 14.6 Hz), 2.39 (dd, 1H, J = 5.9 and 14.4 Hz), 3.35 (s, 3H),

3.78 (s, 3H), 3.85 (d, 1H, J = 8.8 Hz), 4.14 (bdd, 1H, J = 3.6 and

5.2 Hz), 4.22–4.52 (m, 6H), 5.23 (dd, 1H, J = 3.6 and 5.9 Hz),

5.26 (bd, 1H, J = 11.0 Hz), 5.35 (bd, 1H, J = 17.6 Hz), 6.05 (dd,

1H, J = 11.0 and 17.6 Hz), 6.94 (d, 2H, J = 8.8 Hz), 7.21–7.31

(m, 7H), 8.30 (bs, 1H) ; ¹³C NMR (75 MHz, CDCl₃) δ 39.2, 55.2,

55.4, 62.6, 70.6, 71.6, 73.2, 78.0, 79.9, 93.1, 103.7, 113.7, 115.9,

128.3, 128.5, 128.9, 129.1, 130.4, 134.4, 136.6, 159.1, 160.7; EI-

MS m/z 559 (M + 2, 0.2%), 557 (M⁺, 0.2), 528 (0.3), 526 (0.3),

468 (0.3), 466 (0.3), 388 (4.6), 387 (20.7), 386 (6.8), 385 (30.2),

121 (100); EI-HRMS Calcd for C₂₆H₃₀³⁵Cl₃NO₆(M⁺): 557.1138,

Found: m/z 557.1141. Found: C, 56.23; H, 5.28; N, 2.42%. Calcd

for C₂₆H₃₀Cl₃NO₆: C, 55.88; H, 5.41; N, 2.51%.

17R: R_f= 0.32 (1:2 EtOAc–hexane); [α]_D^19.0−23.4 (c 0.60,

CHCl₃); IR (neat) 1045, 1105, 1250, 1515, 1715, 2870, 2930,

2950, 3300, 3400 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.95 (ddd,

1H, J = 3.5, 5.4 and 14.6 Hz), 2.32 (dd, 1H, J = 5.9 and 14.6 Hz),

3.35 (s, 3H), 3.59 (d, 1H, J = 9.3 Hz), 3.92 (d, 1H, J = 9.3 Hz),

3.79 (s, 3H), 3.93 (d, 1H, J = 9.3 Hz), 4.08 (d, 1H, J = 10.7 Hz),

4.10 (d, 1H, J = 2.7 Hz), 4.22–4.25 (m, 1H), 4.27 (d, 1H, J = 9.3

Hz), 4.30 (d, 1H, J = 11.2 Hz), 4.36 (d, 1H, J = 10.7 Hz), 4.51 (d,

1H, J = 11.2 Hz), 5.19 (dd, 1H, J = 2.9 and 5.7 Hz), 6.89 (d, 2H,

J = 8.7 Hz), 7.13–7.33 (m, 7H), 8.55 (bs, 1H); ¹³C NMR (75

MHz, CDCl₃) δ 39.0, 55.3, 55.5, 63.3, 64.5, 68.6, 71.5, 73.4, 80.0,

80.2, 93.0, 103.7, 113.8, 128.4, 128.55, 128.64, 128.9, 129.7,

136.3, 159.4, 162.5; EI-MS m/z 563 (M + 2, 1.1%), 561 (M⁺,

1.4), 527 (6.4), 525 (8.8), 412 (2.2), 391 (100), 389 (100); EI-

HRMS Calcd for C₂₅H₃₀³⁵Cl₃NO₇(M⁺): 561.1087, Found: m/z

561.1088.

(S)-4-[(2R,3R,5S)-3-Benzyloxy-5-methoxyoxolan-2-yl]-4-(4-

methoxybenzyloxymethyl)-1,3-oxazolidin-2-one (18S) and Its

(R)-Isomer (18R). To a solution of the mixture (ca. 8:1) of

amides 17S and 17R (186 mg, 0.330 mmol) in CH₂Cl₂(4 mL) was

added DBU (0.010 mL, 0.0660 mmol) and the mixture was stirred

at 25 °C for 2 h. Removal of the solvent gave a residue, which

was puriﬁed by column chromatography (8 g silica gel, 1:2

EtOAc–hexane as an eluent) to afford S-isomer 18S (16.4 mg,

11%) as a pale yellow syrup: R_f= 0.39 (2:1 EtOAc–hexane);

[α]_D^26.0+37.4 (c 0.87, CHCl₃); IR (neat) 1050, 1110, 1180, 1250,

1360, 1515, 1615, 1745, 1770, 1780, 2910, 3000, 3320, 3440

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.04 (ddd, 1H, J = 2.9, 4.9

and 13.7 Hz), 2.27 (ddd, 1H, J = 1.6, 5.7 and 13.7 Hz), 3.34 (s,

3H), 3.41 (d, 1H, J = 9.0 Hz), 3.47 (d, 1H, J = 9.0 Hz), 3.79 (s,

3H), 4.04 (d, 1H, J = 11.0 Hz), 4.04–4.09 (m, 2H), 4.25 (d, 1H, J

= 11.6 Hz), 4.31 (d, 1H, J = 8.5 Hz), 4.390 (d, 1H, J = 11.0 Hz),

4.392 (d, 1H, J = 11.6 Hz), 4.44 (d, 1H, J = 8.5 Hz), 5.18 (dd,

1H, J = 2.9 and 5.7 Hz), 5.56 (s, 1H), 6.89 (d, 2H, J = 8.8 Hz),

7.16–7.39 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ 39.4, 55.2, 55.4,

60.6, 71.2, 72.0, 72.3, 73.1, 78.3, 78.9, 103.7, 113.9, 128.32,

128.34, 128.7, 129.2, 129.7, 136.4, 159.2, 159.5; EI-MS m/z 443

(M⁺, 6.1%), 411 (0.9), 352 (2.0), 322 (2.0), 261 (3.9), 260 (23.2),

236 (8.7), 235 (51.6), 234 (20.4), 121 (100); EI-HRMS Calcd for

C₂₄H₂₉NO₇(M⁺): 443.1944, Found: m/z 443.1944.

16R: R_f= 0.44 (1:3 EtOAc–hexane); [α]_D^22.0−2.9 (c 1.62,

CHCl₃); IR (neat) 1050, 1110, 1250, 1515, 1715, 2870, 2930,

3330, 3400 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.87 (ddd, 1H, J

= 3.4, 5.1 and 14.4 Hz), 2.28 (bdd, 1H, J = 5.8 and 14.4 Hz), 3.27

(s, 3H), 3.71 (s, 3H), 3.74 (d, 1H, J = 8.8 Hz), 3.96 (d, 1H, J =

11.0 Hz), 3.99 (d, 1H, J = 8.8 Hz), 4.04 (d, 1H, J = 3.4 Hz), 4.13

(bdd, 1H, J = 3.4 and 5.1 Hz), 4.19 (d, 1H, J = 11.4 Hz), 4.28 (d,

1H, J = 11.0 Hz), 4.36 (d, 1H, J = 11.4 Hz), 5.13 (dd, 1H, J =

3.4 and 5.8 Hz), 5.20 (d, 1H, J = 11.0 Hz), 5.27 (d, 1H, J = 17.6

Hz), 6.11 (dd, 1H, J = 11.0 and 17.6 Hz), 6.80 (d, 2H, J = 8.8

Hz), 7.05–7.24 (m, 7H), 8.15 (bs, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 39.1, 55.2, 55.5, 61.1, 70.1, 71.1, 73.2, 79.4, 80.5, 93.0,

103.2, 113.8, 115.2, 128.1, 128.4, 128.6, 129.7, 129.8, 136.4,

136.8, 159.3, 160.5; EI-MS m/z 559 (M + 2, 0.1%), 557 (M⁺,

0.1), 528 (0.1), 526 (0.1), 388 (0.4), 387 (1.6), 386 (0.7), 385

(2.4), 121 (100); EI-HRMS Calcd for C₂₆H₃₀³⁵Cl₃NO₆(M⁺):

557.1138, Found: m/z 557.1138. Found: C, 56.22; H, 5.27; N,

2.44%. Calcd for C₂₆H₃₀Cl₃NO₆: C, 55.88; H, 5.41; N, 2.51%.

Overman rearrangement of Z-allylic imidate 6Z derived from

allylic alcohol 15Z was carried out by the same procedure to af-

ford 16S and 16R in 1:5 ratio (70% yield).

A Mixture of N-{(S)-1-Hydroxy-3-(4-methoxybenzyloxy)-2-

[(2R,3R,5S)-3-benzyloxy-5-methoxyoxolan-2-yl]propan-2-

yl}trichloroacetamide (17S) and Its (R)-Isomer (17R). Ozone

was introduced into a solution of a mixture (ca. 7:1) of the rear-

ranged products 16S and 16R (289 mg, 0.516 mmol) in MeOH

(5.6 mL) at −78 °C for 9 min. After the complete consumption of

the starting material had been conﬁrmed (TLC analysis), excess

ozone was purged by a stream of argon gas. To this solution was

added portionwise NaBH₄(78.1 mg, 2.07 mmol) at −78 °C. The

resulting mixture was stirred at 0 °C for 15min, then quenched by

addition of 1 M aqueous HCl solution. The products were extract-

ed with EtOAc and the combined organic layer was washed suc-

cessively with saturated NaHCO₃solution and brine, and then

dried. Removal of the solvent gave a residue, which was puriﬁed

by column chromatography (15 g silica gel, 1:4 EtOAc–hexane as

an eluent) to afford a mixture (ca. 8:1) of amides 17S and 17R

(206 mg, 71%) as a colorless syrup.

Further elution gave R-isomer 18R (130 mg, 89%) as a pale

yellow syrup: R_f= 0.27 (2:1 EtOAc–hexane); [α]_D^25.5+24.4 (c

0.67, CHCl₃); IR (neat) 1045, 1110, 1250, 1515, 1745, 1755,

2865, 2920, 3290 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.05 (ddd,

1H, J = 2.8, 5.9 and 14.4 Hz), 2.27 (ddd, 1H, J = 2.0, 5.6 and

14.4 Hz), 3.34 (s, 3H), 3.44 (d, 1H, J = 9.0 Hz), 3.48 (d, 1H, J =

9.0 Hz), 3.80 (s, 3H), 3.86 (d, 1H, J = 9.4 Hz), 3.94–3.98 (m, 1H),

3.98 (d, 1H, J = 11.5 Hz), 4.21 (d, 1H, J = 4.4 Hz), 4.26 (d, 1H, J

A small amount of the mixture was separated by PLC (1:9

EtOAc–hexane as an eluent) to give each diastereomer in pure

form and for use as analytical samples.

17S: R_f= 0.36 (1:2 EtOAc–hexane); [α]_D^22.0+25.0 (c 0.71,

CHCl₃); IR (neat) 1040, 1110, 1175, 1250, 1455, 1505, 1520,

1615, 1715, 2840, 2935, 3005, 3380, 3460 cm⁻¹; H NMR (300

1

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1937

= 11.4 Hz), 4.37 (d, 1H, J = 11.5 Hz), 4.43 (d, 1H, J = 11.4 Hz),

4.56 (d, 1H, J = 9.4 Hz), 5.18 (dd, 1H, J = 2.8 and 5.6 Hz), 5.35

(s, 1H), 6.88 (d, 2H, J = 8.6 Hz), 7.13–7.37 (m, 7H); ¹³C NMR

(75 MHz, CDCl₃) δ 39.4, 55.3, 55.4, 61.6, 68.8, 70.9, 72.9, 73.2,

77.8, 79.8, 104.0, 113.9, 127.9, 128.1, 128.5, 129.3, 129.7, 136.9,

158.5, 159.5; EI-MS m/z 443 (M⁺, 4.7%), 411 (0.7), 352 (3.6),

322 (0.9), 293 (3.7), 292 (23.0), 261 (4.2), 260 (26.5), 236 (4.9),

235 (33.8), 121 (99.7), 91 (100); EI-HRMS Calcd for C₂₄H₂₉NO₇

(M⁺): 443.1944, Found: m/z 443.1944.

MHz, CDCl₃) δ 38.7, 55.3, 55.7, 69.8 (2C), 71.5, 73.4, 79.5, 79.9,

93.1, 104.4, 113.8, 128.2, 128.47, 128.50, 129.4, 129.6, 136.5,

159.3, 161.8, 195.8; EI-MS m/z 563 (M + 4, 0.3%), 561 (M + 2,

0.3), 559 (M⁺, 0.4), 527 (0.7), 525 (2.0), 523 (3.0), 442 (0.3), 440

(0.6), 438 (0.7), 389 (6.4), 387 (9.3), 338 (30.9), 337 (15.8), 336

(95.2), 335 (20.9), 334 (100); EI-HRMS Calcd for

C₂₅H₂₈³⁵Cl₃NO₇(M⁺): 559.0931, Found: m/z 559.0936.

Further elution gave S-isomer 20S (486 mg, 81%) as a colorless

syrup: R_f= 0.48 (1:3 EtOAc–hexane, 2 times); [α]_D^23.5+16.6 (c

1.26, CHCl₃); IR (neat) 1045, 1110, 1250, 1505, 1515, 1615,

1715, 1735, 2840, 2930, 3360 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 2.13 (ddd, 1H, J = 2.9, 5.9 and 14.4 Hz), 2.37 (ddd, 1H, J = 1.9,

5.6 and 14.4 Hz), 3.36 (s, 3H), 3.85 (s, 3H), 4.13 (d, 1H, J = 9.6

Hz), 4.29 (ddd, 1H, J = 1.9, 4.1 and 5.9 Hz), 4.34 (d, 1H, J = 12.2

Hz), 4.38 (d, 1H, J = 9.6 Hz), 4.45 (d, 1H, J = 11.7 Hz), 4.52 (d,

1H, J = 12.2 Hz), 4.53 (d, 1H, J = 11.7 Hz), 4.73 (d, 1H, J = 4.1

Hz), 5.20 (dd, 1H, J = 2.9 and 5.6 Hz), 6.91 (d, 2H, J = 8.8 Hz),

7.22–7.42 (m, 7H), 8.07 (bs, 1H), 9.82 (s, 1H); ¹³C NMR (75MHz,

CDCl₃) δ 39.2, 55.3, 55.4, 66.3, 68.7, 71.5, 73.3, 78.5, 78.9, 92.7,

103.6, 113.9, 128.3, 128.67, 128.71, 129.4, 129.6, 136.7, 159.4,

161.1, 197.3; EI-MS m/z 563 (M + 4, 0.02%), 561 (M + 2, 0.03),

559 (M⁺, 0.03), 532 (0.07), 530 (0.1), 528 (0.1), 525 (0.2), 523

(0.3), 389 (0.8), 387 (1.2), 339 (0.9), 338 (5.9), 337 (3.1), 336

(18.1), 335 (4.0), 334 (19.1), 121 (100); EI-HRMS Calcd for

C₂₅H₂₈³⁵Cl₃NO₇(M⁺): 559.0931, Found: m/z 559.0925.

(2R,4R,5R,6R)-4-Benzyloxy-2,5-diacetoxy-6-(4-methoxy-

benzyloxymethyl)-1-aza-8-oxabicyclo[4.3.0]nonan-9-one (19).

To a solution of oxazolidinone 18R (23.2 mg, 0.0523 mmol) in

THF (1.0 mL) was added 2 M aqueous HCl solution (1.0 mL).

The resulting mixture was stirred at 25 °C for 12 h, and then

poured into saturated aqueous NaHCO₃solution. The products

were extracted with CHCl₃, and then dried. Removal of the sol-

vent gave a residue, which was dissolved in pyridine (0.5 mL) and

Ac₂O (0.5 mL). After being stirred at 25 °C for 12 h, the resulting

solution was diluted with EtOAc, and washed successively with 1

M aqueous HCl solution, saturated aqueous NaHCO₃solution and

brine, and then dried. Removal of the solvent gave a residue,

which was puriﬁed by column chromatography (1.5 g silica gel,

1:2 EtOAc–hexane as an eluent) to afford diacetate 19 (30.5 mg,

97%) as a pale yellow syrup: R_f= 0.46 (2:1 EtOAc–hexane);

[α]_D^22.5−21.0 (c 0.26, CHCl₃); IR (neat) 1020, 1080, 1180, 1220,

1370, 1415, 1515, 1615, 1730, 1770, 1790, 2875, 2940, 3020

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.87 (ddd, 1H, J = 4.1, 11.3

and 14.2 Hz), 1.97 (s, 3H), 2.00 (s, 3H), 2.41 (ddd, 1H, J = 2.0,

4.8 and 14.2 Hz), 3.58 (d, 1H, J = 10.0 Hz), 3.68 (d, 1H, J = 10.0

Hz), 3.80 (s, 3H), 3.89 (ddd, 1H, J = 4.8, 9.8 and 11.3 Hz), 4.25

(d, 1H, J = 8.8 Hz), 4.35 (d, 1H, J = 8.8 Hz), 4.44 (d, 1H, J =

11.6 Hz), 4.54 (d, 1H, J = 11.6 Hz), 4.55 (d, 1H, J = 11.7 Hz),

4.65 (d, 1H, J = 11.7 Hz), 4.97 (d, 1H, J = 9.8 Hz), 6.85 (dd, 1H,

J = 2.0 and 4.1 Hz), 6.88 (d, 2H, J = 8.7 Hz), 7.20 (d, 2H, J = 8.7

Hz), 7.24–7.38 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 20.7, 21.0,

34.4, 55.3, 62.2, 70.0, 71.5, 71.6, 72.4, 73.4, 74.4, 76.7, 113.9,

127.3, 127.9, 128.5, 128.9, 129.3, 137.7, 155.0, 159.4, 168.6,

170.2; EI-MS m/z 514 (M + H, 9.7%), 454 (30.3), 304 (4.9), 303

(100); EI-HRMS Calcd for C₂₇H₃₂NO₉(M + H)⁺: 514.2077,

Found: m/z 514.2075.

Methyl (S)-2-[(2R,3R,5S)-3-Benzyloxy-5-methoxyoxolan-2-

yl]-3-(4-methoxybenzyloxy)-2-(trichloroacetamido)pro-

panoate (22). To a solution of aldehyde 20S (390 mg, 0.696

mmol) in a mixed solvent of t-BuOH–H₂O (1:1, 8 mL) were add-

ed successively NaH₂PO₄•2H₂O (217 mg, 1.39 mmol),

HOSO₂NH₂(203 mg, 2.09 mmol) and NaClO₂(189 mg, 2.09

mmol) at 0 °C. After stirring at 25 °C for 15 min, 20 wt% aqueous

Na₂S₂O₃solution was added to the reaction mixture until the yel-

low color of the mixture disappeared. The products were extract-

ed with CHCl₃, and then dried. Removal of the solvent afforded

crude carboxylic acid 21 (401 mg, 100%) as a colorless oil, which

was used for the next reaction without further puriﬁcation: R_f=

0.35 (1:9 MeOH–CHCl₃).

To a stirring solution of this crude carboxylic acid 21 in MeOH

(8 mL) was added TMSCHN₂(2.0 M in hexane, 1.75 mL, 3.48

mmol) at 25 °C and the mixture was stirred at 25 °C for 1 h. Re-

moval of the solvent gave a residue, which was puriﬁed by column

chromatography (25 g silica gel, 1:19 EtOAc–toluene as an elu-

ent) to afford ester 22 (405 mg, 98% for 2 steps) as a pale yellow

syrup: R_f= 0.69 (1:3 EtOAc–toluene); [α]_D^25.0+50.6 (c 1.26,

CHCl₃); IR (neat) 1050, 1105, 1250, 1515, 1615, 1730, 1740,

2840, 2950, 3390 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.08 (ddd,

1H, J = 4.9, 4.9 and 13.7 Hz), 2.16 (ddd, 1H, J = 2.2, 6.6 and

13.7 Hz), 3.30 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 4.03 (d, 1H, J =

9.4 Hz), 4.31 (d, 1H, J = 11.0 Hz), 4.41–4.44 (m, 1H), 4.44 (d,

1H, J = 11.0 Hz), 4.45 (d, 1H, J = 11.9 Hz), 4.56 (d, 1H, J =

11.9 Hz), 4.66 (d, 1H, J = 6.1 Hz), 4.73 (d, 1H, J = 9.4 Hz), 5.15

(dd, 1H, J = 2.2 and 4.9 Hz), 6.84 (d, 2H, J = 8.5 Hz), 7.18–7.36

(m, 7H), 7.85 (bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 39.2, 52.6,

55.1, 55.2, 66.9, 69.4, 72.5, 72.9, 79.1, 79.3, 93.5, 103.9, 113.6,

128.2, 128.4, 128.5, 129.1, 130.1, 136.6, 159.1, 160.1, 170.2; EI-

MS m/z 593 (M + 4, 0.2%), 591 (M + 2, 0.4), 589 (M⁺, 0.4), 562

(0.5), 560 (1.3), 558 (1.3), 555 (1.1), 553 (1.6), 422 (3.8), 421

(16.7), 420 (13.6), 419 (67.8), 418 (20.3), 417 (100); EI-HRMS

Calcd for C₂₆H₃₀³⁵Cl₃NO₈(M⁺): 589.1036, Found: m/z 589.1037.

An Equilibrium Mixture of Methyl (S)-2-[(2R,3R,5R&S)-3-

N-{(S)-1-[(2R,3R,5S)-3-Benzyloxy-5-methoxyoxolan-2-yl]-

1-formyl-2-(4-methoxybenzyloxy)ethyl}trichloroacetamide

(20). Ozone was introduced into a solution of the mixture of re-

arranged products 16S and 16R (ca. 7:1, 600 mg, 1.07 mmol) in

MeOH (12 mL) at −78 °C for 15 min. After the complete con-

sumption of the starting material had been conﬁrmed (TLC analy-

sis), excess ozone was removed by a stream of argon gas. To the

reaction mixture was added Me₂S (0.79 mL, 10.7 mmol) at

−78 °C, and the resulting mixture was stirred at 0 °C for 2 h. Re-

moval of the solvent gave a residue, which was puriﬁed by column

chromatography (50 g silica gel, 1:39 EtOAc–toluene as an elu-

ent) to afford R-isomer 20R (72.8 mg, 12%) as a pale yellow syr-

up: R_f= 0.51 (1:3 EtOAc–hexane, 2 times); [α]_D^24.5+32.3 (c 0.37,

CHCl₃); IR (neat) 1045, 1105, 1250, 1505, 1515, 1615, 1715,

1

1730, 2870, 2930, 2950, 3360, 3450 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 1.89 (ddd, 1H, J = 4.0, 4.9 and 14.4 Hz), 2.30 (dd, 1H, J

= 5.6 and 14.4 Hz), 3.33 (s, 3H), 3.79 (s, 3H), 4.08 (d, 1H, J =

10.2 Hz), 4.17–4.21 (m, 3H), 4.38 (d, 1H, J = 11.2 Hz), 4.40 (d,

1H, J = 11.4 Hz), 4.46 (d, 1H, J = 11.4 Hz), 4.53 (d, 1H, J = 3.2

Hz), 5.19 (dd, 1H, J = 4.0 and 5.6 Hz), 6.86 (d, 2H, J = 8.5 Hz),

7.13–7.33 (m, 7H), 8.60 (bs, 1H), 9.63 (s, 1H); ¹³C NMR (75

1938 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

Benzyloxy-5-hydroxyoxolan-2-yl]-3-(4-methoxybenzyloxy)-2-

(trichloroacetamido)propanoate (5). A solution of methyl gly-

coside 22 (405 mg, 0.685 mL) in a mixed solvent (2 mL of 4 M

aqueous HCl solution and 6 mL of THF) was stirred at 25 °C for

10 h. The resulting solution was cooled to 0 °C and neutralized

carefully with 25% aqueous NaHCO₃solution. The products

were extracted with CHCl₃. Removal of the solvent gave a resi-

due, which was puriﬁed by column chromatography (16 g silica

gel, 2:5 EtOAc–hexane as an eluent) to give ﬁrst the starting ma-

terial 22 (44.2 mg, 11%). Further elution (2:3 EtOAc–hexane as

an eluent) gave lactol 5 (298 mg, 76%) as a mixture of anomers

(α:β ~ 1:1): R_f= 0.37 (1:1 EtOAc–hexane); [α]_D^25.0+6.6 (c 0.89,

CH₃OH, after 12 h at 25 °C); IR (neat) 1050, 1100, 1170, 1245,

1300, 1360, 1455, 1505, 1520, 1540, 1615, 1715, 1730, 2870,

umn chromatography (20 g silica gel, 1:2 EtOAc–hexane as an

eluent) to afford allylic alcohol 24 (228 mg, 82%) as a colorless

syrup: R_f= 0.31 (1:1 EtOAc–hexane); [α]_D^24.0+3.5 (c 1.31,

CHCl₃); IR (neat) 1070, 1090, 1250, 1300, 1505, 1515, 1715,

1730, 2870, 2950, 3390, 3470 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 1.69 (bs, 1H), 2.48 (bdd, 2H, J = 7.3 and 7.3 Hz), 3.47–3.54 (m,

1H), 3.52 (s, 3H), 3.67 (d, 1H, J = 9.0 Hz), 3.80 (s, 3H), 4.00–

4.05 (m, 2H), 4.04 (d, 1H, J = 10.5 Hz), 4.19 (dd, 1H, J = 1.2 and

9.0 Hz), 4.32 (d, 1H, J = 10.5 Hz), 4.37 (d, 1H, J = 11.0 Hz),

4.41 (d, H, J = 11.4 Hz), 4.49 (d, H, J = 11.4 Hz), 4.59 (d, 1H, J

= 11.0 Hz), 5.56 (bdt, 1H, J = 15.4 and 7.3 Hz), 5.73 (bdt, 1H, J

= 15.4 and 5.5 Hz), 6.86 (d, 2H, J = 8.5 Hz), 7.19 (d, 2H, J = 8.5

Hz), 7.24–7.35 (m, 5H), 8.06 (bs, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 33.0, 52.8, 55.3, 63.2, 66.2, 68.1, 71.5, 73.1, 73.5, 76.7,

92.3, 113.9, 126.8, 127.9 (2C), 128.3, 129.3, 129.4, 133.0, 137.4,

159.4, 161.7, 169.4; FAB-MS m/z 608 (M + 5, 44.2%), 607 (M +

4, 30.0), 606 (M + 3, 82.3), 605 (M + 2, 33.0), 604 (M + H,

81.0), 301 (100); FAB-HRMS Calcd for C₂₇H₃₃³⁵Cl₃NO₈(M +

H)⁺: 604.1271, Found: m/z 604.1274.

Methyl (4S,5R)-5-[(E,R)-1-Benzyloxy-5-hydroxypent-3-en-

1-yl]-4-(4-methoxybenzyloxymethyl)-2-oxooxazolidine-4-car-

boxylate (25). To a solution of amide 24 (182 mg, 0.301 mmol)

in CH₂Cl₂(3.6 mL) was added dropwise DBU (0.0045 mL,

0.0301 mmol) at 0 °C and the mixture was stirred at 25 °C for

20 h. Removal of the solvent gave a residue, which was puriﬁed

by column chromatography (8 g silica gel, 3:2 EtOAc–hexane as

an eluent) to afford oxazolidinone 25 (126 mg, 86%) as a colorless

syrup: R_f= 0.30 (3:1 EtOAc–hexane); [α]_D^22.5−85.8 (c 0.63,

CHCl₃); IR (neat) 1030, 1100, 1250, 1515, 1730, 1770, 2870,

2930, 2950, 3010, 3350 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.55

(bs, 1H), 2.47–2.64 (m, 2H), 3.34 (s, 3H), 3.52 (d, 1H, J = 8.7

Hz), 3.72 (d, 1H, J = 8.7 Hz), 3.76–3.83 (m, 1H), 3.80 (s, 3H),

4.10 (bd, 2H, J = 5.2 Hz), 4.21 (d, 1H, J = 11.9 Hz), 4.33 (d, 1H,

J = 1.4 Hz), 4.46 (s, 2H), 4.64 (d, 1H, J = 11.9 Hz), 5.62 (ddd,

1H, J = 6.4, 7.9 and 15.4 Hz), 5.73 (bs, 1H), 5.79 (dt, 1H, J =

15.4 and 5.2 Hz), 6.87 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.8

Hz), 7.20–7.32 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 31.7, 52.4,

55.3, 63.2, 65.5, 70.1, 73.3, 75.1, 76.0, 80.6, 113.9, 125.9, 126.3,

127.3, 128.2, 128.9, 129.3, 133.5, 137.7, 157.0, 159.5, 170.0;

FAB-MS m/z 486 (M + H, 52.2%), 469 (29.5), 468 (100); FAB-

HRMS Calcd for C₂₆H₃₂NO₈(M + H)⁺: 486.2128, Found: m/z

486.2128.

Methyl (4S,5R)-5-[(E,R)-1-Benzyloxy-5-bromopent-3-en-1-

yl]-4-(4-methoxybenzyloxymethyl)-2-oxooxazolidine-4-car-

boxylate (3). To a solution of allylic alcohol 25 (133 mg, 0.273

mmol) in CH₂Cl₂(3 mL) was added Et₃N (0.0762 mL, 0.547

mmol). After being stirred at 25 °C for 10 min, to this solution

was added MsCl (0.0423 mL, 0.547 mmol). The resulting mixture

was stirred at 25 °C for 30 min, and then diluted with EtOAc and

washed successively with 1 M aqueous HCl solution, saturated

aqueous NaHCO₃solution and brine, and then dried. Removal of

the solvent gave a crude mesylate: R_f= 0.48 (3:1 EtOAc–hex-

ane).

To a solution of the mesylate in THF (1.5 mL) was added LiBr

(119 mg, 1.37 mmol) and the mixture was stirred at 25 °C for 1 h.

The resulting mixture was diluted with CHCl₃and washed with

H₂O, and then dried. Removal of the solvent gave a residue,

which was puriﬁed by column chromatography (5 g silica gel, 2:5

EtOAc–hexane as an eluent) to afford allyl bromide 3 (135 mg,

93%) as a colorless syrup: R_f= 0.71 (3:1 EtOAc–hexane); [α]_D^24.0

−72.1 (c 0.96, CHCl₃); IR (neat) 1030, 1105, 1250, 1515, 1730,

1

2950, 3010, 3390, 3450 cm⁻¹; H NMR (300 MHz, CDCl₃, after

12 h) δ 2.02-2.30 (m, 2H), 3.04 (bs, 0.5H), 3.47 (d, 0.5H, J = 9.0

Hz), 3.62 (s, 1.5H), 3.68 (s, 1.5H), 3.80 (s, 3H), 3.99 (d, 0.5H, J =

8.8 Hz), 4.05 (d, 0.5H, J = 8.8 Hz), 4.30–4.52 (m, 2H), 4.40–4.49

(m, 3H), 4.59 (d, 0.5H, J = 8.8 Hz), 4.62 (d, 0.5H, J = 4.8 Hz),

4.68 (d, 0.5H, J = 8.8 Hz), 4.79 (d, 0.5H, J = 5.1 Hz), 5.51 (dd,

0.5H, J = 4.9 and 9.0 Hz), 5.69 (m, 0.5H), 6.82 (d, 2H, J = 8.5

Hz), 7.27–7.38 (m, 7H), 7.80 (bs, 0.5H), 7.91 (bs, 0.5H); EI-MS

m/z 577 (M + 2, 1.7%), 575 (M⁺, 5.0), 415 (23.0), 413 (29.4),

405 (33.8), 404 (12.4), 403 (54.1), 277 (100); EI-HRMS Calcd for

C₂₅H₂₈³⁵Cl₃NO₈(M⁺): 575.0880, Found: m/z 575.0880.

1-Ethyl 8-Methyl (E,5R,6R,7S)-5-Benzyloxy-6-hydroxy-7-

(4-methoxybenzyloxymethyl)-7-(trichloroacetamido)oct-2-

enedioate (23). To a solution of lactol 5 (298 mg, 0.517 mmol)

in toluene (6 mL) was added Ph₃PwCHCO₂Et (216 mg, 0.620

mmol) and the mixture was stirred at 25 °C for 20 h. Removal of

the solvent gave a residue, which was puriﬁed by column chroma-

tography (15 g silica gel, 1:7 EtOAc–hexane as an eluent) to af-

ford 23 (299 mg, 89%) as a pale yellow syrup: R_f= 0.54 (1:2

EtOAc–hexane); [α]_D^21.5+7.9 (c 0.95, CHCl₃); IR (neat) 1040,

1070, 1175, 1250, 1505, 1515, 1715, 1720, 1740, 2840, 2900,

1

2955, 3360, 3400 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 1.28 (t,

3H, J = 7.1 Hz), 2.50–2.72 (m, 2H), 3.52-3.58 (m, 1H), 3.54 (s,

3H), 3.80 (s, 3H), 3.83 (d, 1H, J = 8.5 Hz), 4.03 (d, 1H, J = 10.5

Hz), 4.12 (dd, 1H, J = 1.4, and 8.5 Hz), 4.18 (q, 2H, J = 7.1 Hz),

4.30 (d, 1H, J = 10.5 Hz), 4.38 (d, 1H, J = 11.2 Hz), 4.42 (d, 1H,

J = 11.7 Hz), 4.48 (d, 1H, J = 11.7 Hz), 4.55 (d, 1H, J = 11.2

Hz), 5.90 (bd, 1H, J = 15.6 Hz), 6.80–6.91 (m, 3H), 6.86 (d, 2H, J

= 8.5 Hz), 7.19 (d, 2H, J = 8.5 Hz), 7.25–7.35 (m, 5H), 8.06 (bs,

1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.2, 33.3, 52.9, 55.2, 60.4,

66.3, 68.3, 72.0, 73.4, 73.8, 92.2, 113.9, 124.5, 128.0, 128.0,

128.4, 129.2, 129.39, 129.44, 137.0, 143.3, 159.4, 161.7, 166.0,

169.2; EI-MS m/z 649 (M + 4, 0.3%), 647 (M + 2, 0.9), 645 (M⁺,

0.8), 612 (1.8), 611 (4.6), 610 (1.6), 609 (6.2), 528 (1.1), 527

(0.8), 526 (1.8), 525 (1.0), 524 (2.0), 478 (4.5), 477 (14.0), 476

(17.0), 475 (5.4), 474 (26.8), 473 (100); EI-HRMS Calcd for

C₂₉H₃₄³⁵Cl₃NO₉(M⁺): 645.1298, Found: m/z 645.1294.

Methyl

(E,2S,3R,4R)-4-Benzyloxy-3,8-dihydroxy-2-(4-

methoxybenzyloxymethyl)-2-(trichloroacetamido)oct-6-enoate

(24). To a solution of diester 23 (299 mg, 0.462 mmol) in THF

(12 mL) was added dropwise DIBAL-H (1.01 M solution in tolu-

ene, 0.915 mL, 0.924 mmol) at −18 °C. The resulting mixture

was stirred at −18 °C for 15 min, and then quenched by addition

of 1 M aqueous HCl solution. The products were extracted with

Et₂O, and the combined organic layer was washed successively

with saturated aqueous NaHCO₃solution and brine, then dried.

Removal of the solvent gave a residue, which was puriﬁed by col-

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1939

1770, 2865, 2950, 3010, 3340 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 2.48–2.66 (m, 2H), 3.35 (s, 3H), 3.53 (d, 1H, J = 8.8 Hz), 3.73

(d, 1H, J = 8.8 Hz), 3.79–3.85 (m, 1H), 3.81 (s, 3H), 3.93 (d, 2H,

J = 7.3 Hz), 4.23 (d, 1H, J = 11.7 Hz), 4.31 (d, 1H, J = 1.4 Hz),

4.47 (s, 2H), 4.64 (d, 1H, J = 11.7 Hz), 5.71 (dt, 1H, J = 15.0 and

7.4 Hz), 5.74 (bs, 1H), 5.86 (dt, 1H, J = 15.0 and 7.3 Hz), 6.88 (d,

2930, 3345 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, 3H, J =

6.9 Hz), 1.25–1.53 (m, 16H), 1.88 (m, 2H), 3.42 (t, 2H, J =

6.9 Hz), 3.52–3.68 (bs, 1H); ¹³C NMR (75 MHz) δ 14.1, 22.6,

24.8, 25.6, 28.2, 29.3, 31.8, 32.7, 33.8, 37.2, 37.6, 71.8; EI-MS

m/z 265 (M − H + 2, 0.3%), 263 (M − H, 0.3%), 249 (0.5), 248

(3.1), 247 (0.5), 246 (3.2), 183 (0.2), 182 (3.0), 181 (45.3), 180

(4.7), 179 (47.1), 164 (1.8), 163 (12.5), 162 (1.9), 161 (12.8), 115

(100); EI-HRMS Calcd for C₁₂H₂₄⁷⁹BrO (M − H): 263.1010,

Found: m/z 263.1016. Found: C, 54.40; H, 9.22%. Calcd for

C₁₂H₂₅BrO:C, 54.34; H, 9.50%.

2H, J = 8.8 Hz), 7.18 (d, 2H, J = 8.8 Hz), 7.21–7.34 (m, 5H); ¹³

C

NMR (75 MHz, CDCl₃) δ 31.7, 32.3, 52.4, 55.3, 65.5, 70.2, 73.3,

75.0, 75.8, 80.6, 113.9, 126.3, 127.3, 128.2, 128.9, 129.3, 130.1,

130.6, 137.5, 156.9, 159.5, 170.0; FAB-MS m/z 550 (M + 3,

98.3), 548 (M + H, 100); FAB-HRMS Calcd for C₂₆H₃₁⁷⁹BrNO₇

(M + H)⁺: 548.1283, Found: m/z 548.1282.

To a suspension of bromo alcohol (1.19 g, 4.49 mmol) and

Celite (2.4 g) in acetone (24 mL) was added dropwise Jones’ re-

agent (2.67 M solution of CrO₃in aqueous sulfuric acid solution;

1.35 mL, 3.59 mmol) at 0 °C. After being stirred at 0 °C for 1 h,

the reaction mixture was quenched by addition of propan-2-ol un-

til the orange-yellow color of the mixture disappeared. The insol-

uble material was removed by ﬁltration through a pad of Celite;

this Celite was then rinsed with EtOAc (50 mL × 5). The ﬁltrate

was washed with saturated aqueous NaHCO₃solution, and then

dried. Removal of the solvent gave bromo ketone 27 (1.14 g,

97%) as a yellow oil: R_f= 0.69 (1:3 EtOAc–hexane); IR (neat)

1030, 1070, 1085, 1125, 1250, 1270, 1375, 1410, 1460, 1715,

2860, 2930 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, 3H, J =

6.9 Hz), 1.24–1.34 (m, 6H), 1.37–1.49 (m, 2H), 1.51–1.65 (m,

4H), 1.87 (m, 2H), 2.39 (t, 2H, J = 7.8 Hz), 2.42 (t, 2H, J = 7.8

Hz), 3.41 (t, 2H, J = 6.9 Hz); ¹³C NMR (75 MHz) δ 14.0, 22.5,

22.8, 23.8, 27.7, 28.9, 31.6, 32.5, 33.6, 42.4, 42.9, 211.0; EI-MS

m/z 264 (M + 2, 6.5%), 262 (M⁺, 6.8), 208 (0.8), 207 (4.9), 206

(0.8), 205 (5.0), 184 (3.6), 183 (26.9), 181 (0.4), 180 (1.4), 179

(19.2), 178 (1.5), 177 (19.7), 113 (100); EI-HRMS Calcd for

C₁₂H₂₃⁷⁹BrO (M⁺) : 262.0932, Found: m/z 262.0932. Found: C,

54.87; H, 8.50%. Calcd for C₁₂H₂₃BrO: C, 54.76; H, 8.81%.

6,6-Ethylenedioxy-1-phenylsulfonyldodecane (4). To a so-

lution of bromo ketone 27 (1.14 g, 4.33 mmol) in DMF (12 mL)

was added PhSO₂Na•2H₂O (1.44 g, 7.18 mmol) and the mixture

was stirred at 25 °C for 24 h. The resulting mixture was diluted

with EtOAc and washed successively with saturated NaHCO₃and

brine, and then dried. Removal of the solvent gave a residue,

which was puriﬁed by column chromatography (60 g silica gel,

1:5 EtOAc–hexane as an eluent) to afford keto sulfone (1.19 g,

85%) as white crystals: R_f= 0.30 (1:3 EtOAc–hexane); Mp 32.8–

33.9 °C; IR (KBr) 1090, 1150, 1275, 1285, 1320, 1445, 1470,

Dodecane-1,6-diol (26).²⁶To a mixture of Mg (turnings, 258

mg, 10.6 mmol) in Et₂O (20 mL) was added 1-bromohexane (1.49

mL, 10.6 mmol). This was stirred vigorously at 25 °C for 30 min.

To the resulting gray suspension was added cyclohexanone (1.0

mL, 9.65 mmol) dropwise at 25 °C. The resulting mixture was

stirred at 25 °C for 2 h, and then quenched by addition of 2 M

aqueous HCl solution at 0 °C. The products were extracted with

Et₂O and the organic layer was washed successively with 2 M

aqueous HCl solution, saturated aqueous NaHCO₃solution and

brine, and then dried. Removal of the solvent gave crude tert-al-

cohol, which was used for the next reaction without further puriﬁ-

cation: R_f= 0.50 (1:3 EtOAc–hexane).

To a solution of the tert-alcohol in o-xylene (10 mL) was added

I₂(24.5 mg, 0.0965 mmol) and this was stirred under reﬂux for 4

h. The resulting solution was quenched by addition of 20% aque-

ous Na₂S₂O₃solution until the red color of the reaction mixture

disappeared. The products were extracted with pentane, and the

organic layer was washed with 20% aqueous Na₂S₂O₃solution.

Pentane was evaporated off to afford a crude solution of 1-hexyl-

cyclohex-1-ene in o-xylene: R_f= 0.86 (1:9 EtOAc–hexane).

The solution of the crude alkene in o-xylene was diluted with

MeOH (10 mL), then ozone was introduced into the solution at

0 °C for 10 min. After the complete consumption of starting mate-

rial was conﬁrmed (TLC analysis), excess ozone was removed

with a stream of Ar. To the mixture was added portionwise

NaBH₄(1.83 g, 48.2 mmol) at 0 °C. The resulting mixture was

stirred at 0 °C for 30 min, then diluted with Et₂O and washed suc-

cessively with 1 M aqueous HCl solution, saturated aqueous

NaHCO₃solution and brine. The aqueous layer was re-extracted

with Et₂O and the combined organic layer was concentrated to

give a residue, which was puriﬁed by column chromatography

(30 g silica gel, 1:1 EtOAc–hexane as an eluent) to afford diol 26

(1.04 g, 53% for 3 steps) as white crystals: R_f= 0.33 (1:1

EtOAc–hexane); Mp 44.2–45.3 °C; IR (KBr) 1000, 1050, 1065,

1

1705, 2865, 2935, 3065 cm⁻¹; H NMR (300 MHz, CDCl₃); δ

0.88 (t, 3H, J = 6.9 Hz), 1.22–1.42 (m, 8H), 1.54 (m, 4H), 1.64–

1.78 (m, 2H), 2.35 (t, 2H, J = 7.5), 2.37 (t, 2H, J = 6.9 Hz), 3.08

(m, 2H), 7.54–7.93 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0,

22.45, 22.48, 22.9, 23.8, 27.8, 28.9, 31.6, 42.0, 42.9, 56.0, 128.0,

129.3, 133.6, 139.1, 210.7; EI-MS m/z 325 (M + 1, 0.4%), 324

(M⁺, 2.0), 268 (0.4), 267 (4.1), 255 (3.9), 254 (25.8), 240 (1.7),

239 (13.6), 211 (6.6), 197 (18.5), 113 (100); EI-HRMS Calcd for

C₁₈H₂₈O₃S (M⁺): 324.1759, Found: m/z 324.1759. Found: C,

66.58; H, 8.30; S, 9.94%. Calcd for C₁₈H₂₈O₃S: C, 66.63; H, 8.70;

S, 9.88%.

1

1135, 1155, 1465, 2850, 2930, 3300 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 0.87 (t, 3H, J = 7.1 Hz), 1.25–1.44 (m, 16H), 1.58 (m,

2H), 1.67 (bs, 1H), 1.69 (bs, 1H), 3.58 (bs, 1H), 3.64 (t, 2H, J =

6.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 25.4, 25.6, 25.7,

29.3, 31.8, 32.6, 37.3, 37.5, 62.8, 71.8; FAB-MS m/z 203 (M + H,

4.4%), 185 (34.5), 93 (100); FAB-HRMS Calcd for C₁₂H₂₇O₂(M

+ H)⁺: 203.2011, Found: m/z 203.2012.

1-Bromododecan-6-one (27).

To a solution of diol 26

To a solution of the keto sulfone (1.19 g, 3.68 mmol) in CH₂Cl₂

(24 mL) were added 1,2-bis(trimethylsilyloxy)ethane (2.69 mL,

11.0 mmol) and TMSOTf (0.0666 mL, 0.368 mmol) at 0 °C. After

stirring at 0 °C for 1 h, to the mixture was added Et₃N (0.1 mL) at

0 °C. The reaction mixture was diluted with CHCl₃and washed

with saturated aqueous NaHCO₃solution, and then dried. Remov-

al of the solvent gave a residue, which was puriﬁed by column

chromatography (60 g alumina, 1:9 EtOAc–hexane as an eluent)

(1.04 g, 5.14 mmol) in CH₂Cl₂were added Ph₃P (1.38 g, 5.25

mmol) and CBr₄(1.72 g, 5.19 mmol) at −15 °C. The resulting

mixture was stirred at 0 °C for 20 h. Removal of the solvent gave

a residue, which was puriﬁed by column chromatography (30 g

silica gel, 1:6 EtOAc–hexane as an eluent) to afford bromo alco-

hol (1.19 g, 88%) as a pale yellow oil: R_f= 0.78 (1:1 EtOAc–hex-

ane); IR (neat) 1020, 1065, 1080, 1245, 1265, 1440, 1460, 2875,

1940 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

to afford sulfone 4 (1.36 g, 100% for 2 steps) as a colorless syrup:

R_f= 0.30 (1:3 EtOAc–hexane); IR (neat) 1070, 1090, 1150, 1305,

1320, 1450, 1455, 2875, 2950 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 0.88 (t, 3H, J = 6.9 Hz), 1.23–1.43 (m, 12H), 1.51–1.58 (bt, 4H,

J = 7.8 Hz), 1.66–1.78 (m, 2H), 3.08 (m, 2H), 3.90 (m, 4H), 7.54–

7.94 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.57, 22.60,

23.2, 23.8, 28.5, 29.5, 31.8, 36.6, 37.1, 56.2, 64.9, 76.6, 111.5,

128.0, 129.2, 133.6, 139.2; EI-MS m/z 368 (M⁺, 0.1%), 325 (0.2),

285 (2.6), 284 (6.2), 283 (36.5), 157 (100); EI-HRMS Calcd for

C₂₀H₃₂O₄S (M⁺): 368.2021, Found: m/z 368.2010. Found: C,

64.83; H, 8.63; S, 8.43%. Calcd for C₂₀H₃₂O₄S: C, 65.18; H, 8.75;

S, 8.74%.

solvent of 2 M aqueous HCl solution and THF (1:1, 2 mL) was

stirred at 25 °C for 12 h. Removal of the solvent gave a residue,

which was dissolved in a mixed solvent of 10% aqueous NaOH

solution and MeOH (1:3, 2 mL). After stirring at 70 °C for 8 h,

the resulting mixture was concentrated and dissolved in pyridine

(0.5 mL). To this solution was added Ac₂O (0.5 mL) and the mix-

ture was stirred at 25 °C for 2 h. Removal of the solvent gave a

residue, which was puriﬁed by column chromatography (2 g silica

gel, 1:4 EtOAc–toluene as an eluent) to afford known 4-butano-

lide 30 (25.6 mg, 47%) as a colorless syrup: R_f= 0.45 (3:1

EtOAc–hexane) and 0.52 (1:3 MeOH–CHCl₃); [α]_D^20.0+53.6 (c

0.71, CHCl₃); IR (neat) 1030, 1190, 1230, 1375, 1685, 1695,

1

Methyl (4S,5R)-5-[(E,1R,6R&S)-1-Benzyloxy-11,11-ethyl-

enedioxy-6-phenylsulfonylheptadec-3-en-1-yl]-4-(4-methoxy-

benzyloxymethyl)-2-oxooxazolidine-4-carboxylate (28). To a

solution of sulfone 4 (93.5 mg, 0.254 mmol) in THF (2 mL) was

added dropwise n-BuLi (1.59 M hexane solution, 0.239 mL, 0.381

mmol) at −78 °C, and the resulting yellow solution was stirred at

−78 °C for 10 min. To this mixture was added a solution of allyl

bromide 3 (46.4 mg, 0.0846 mmol) in THF (2.5 mL) dropwise via

a cannula at −78 °C. The resulting solution was stirred at −78 °C

for 10 min, then poured into phosphate buffer (pH 8.1, 5 mL).

The products were extracted with CHCl₃, then dried. Removal of

the solvent gave a residue, which was puriﬁed by column chroma-

tography [5 g alumina powder (300 mesh), 1:2 to 3:1 EtOAc–

hexane (gradient) as eluents] to afford a diastereomeric mixture of

coupling product 28 (59.4 mg, 84%) as a colorless syrup: R_f=

0.35 (1:1 EtOAc–hexane); IR (neat) 1030, 1085, 1145, 1250,

1300, 1365, 1445, 1455, 1460, 1515, 1730, 1770, 2860, 2930,

2950, 3340 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, 3H, J =

6.6 Hz), 1.21–1.34 (m, 12H), 1.48–1.57 (m, 4H), 1.59–1.82 (m,

2H), 2.31–2.59 (m, 4H), 2.91–3.00 (m, 1H), 3.33 (s, 1.5H), 3.34

(s, 1.5H), 3.54 (d, 0.5H, J = 8.8 Hz), 3.57 (d, 0.5H, J = 8.8 Hz),

3.72–3.82 (m, 2H), 3.786 (s, 1.5H), 3.791 (s, 1.5H), 3.89 (bs, 2H),

3.90 (bs, 2H), 4.21 (d, 1H, J = 11.9 Hz), 4.43–4.49 (m, 3H), 4.62

(d, 0.5H, J = 11.9 Hz), 4.63 (d, 0.5H, J = 11.9 Hz), 5.38–5.59 (m,

2H), 5.67 (bs, 0.5H), 5.68 (bs, 0.5H), 6.83 (2d, 2H, J = 8.5 Hz),

7.14 (d, 1H, J = 8.5 Hz), 7.15 (d, 1H, J = 8.5 Hz), 7.23–7.33 (m,

5H), 7.53–7.86 (m, 5H); FAB-MS m/z 836 (M + H, 40.8), 794

(21.2), 793 (72.8), 792 (100); FAB-HRMS Calcd for C₄₆H₆₂NO₁₁S

(M + H)⁺: 836.4044, Found: m/z 836.4039.

(2S,3R,4R)-2-Acetamido-3-acetoxy-2-acetoxymethyl-4-[(E)-

10-oxohexadec-2-en-1-yl]-4-butanolide (30).^2dTo a solution of

coupling product 28 (89.7 mg, 0.107 mmol) in THF (2 mL) was

added 0.1% aqueous LiOH solution (2 mL) at 25 °C and the mix-

ture was stirred at 25 °C for 12 h. The resulting clear yellow solu-

tion was concentrated to give crude carboxylic acid lithium salt

29: R_f= 0.27 (1:9 MeOH–CHCl₃).

To a navy blue suspension of Li (74.3 mg, 10.7 mol) in freshly

distilled liquid ammonia (2 mL, from Li) was added a solution of

crude 29 in THF (2 mL) at −78 °C. After stirring at −78 °C for

30 min, to the resulting mixture was added dropwise MeOH at

−78 °C until the blue color of the mixture disappeared. The reac-

tion mixture was further stirred at 0 °C for 30 min to evaporate

any excess ammonia, and then the insoluble material was removed

by ﬁltration through a pad of Celite. The Celite was rinsed with

EtOAc and the ﬁltrate was washed with 2 M aqueous HCl solu-

tion. The aqueous layer was re-extracted with EtOAc, and the

combined organic layer was dried. Removal of the solvent gave a

crude oxazolidinecarboxylic acid: R_f= 0.24 (1:2 MeOH–CHCl₃).

A solution of the crude oxazolidinecarboxylic acid in a mixed

1715, 1745, 1755, 1790, 2860, 2930, 3340 cm⁻¹; H NMR (300

MHz, CD₃OD) δ 0.88 (t, 3H, J = 6.7 Hz), 1.20–1.39 (m, 12H),

1.50–1.61 (m, 4H), 1.96–2.07 (m, 2H), 2.03 (s, 3H), 2.05 (s, 3H),

2.10 (s, 3H), 2.36–2.46 (m, 2H), 2.38 (t, 4H, J = 7.4 Hz), 4.52 (s,

2H), 4.72 (dt, 1H, J = 4.4 and 8.7 Hz), 5.39 (dt, 1H, J = 15.2 and

7.0 Hz), 5.57 (dt, 1H, J = 15.2 and 6.7 Hz), 5.80 (d, 1H, J = 4.4

Hz), 6.01 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 20.4, 20.6,

22.5, 22.8, 23.77, 23.83, 28.8, 28.9, 29.0, 29.1, 31.6, 32.2, 32.5,

42.75, 42.83, 62.5, 62.6, 71.9, 81.6, 123.1, 135.1, 168.9, 169.4,

170.2, 172.4, 211.7; FAB-MS m/z 510 (M + H, 15.8), 93 (100);

FAB-HRMS Calcd for C₂₇H₄₄NO₈(M + H)⁺: 510.3067, Found:

m/z 510.3060. The spectral data were fully identical with those re-

ported.^1b

(1S,5R,6R)-1-Hydroxymethyl-6-[(E)-10-oxohexadec-2-en-1-

yl]-2-aza-4,7-dioxabicyclo[3.3.0]octane-3,8-dione (31). To a

solution of coupling product 28 (18.9 mg, 0.0226 mmol) in THF

(0.5 mL) was added 0.1% aqueous LiOH solution (0.5 mL) at

25 °C and the mixture was stirred at 25 °C for 12 h. The resulting

clear solution was concentrated to give crude carboxylic acid lithi-

um salt 29: R_f= 0.27 (1:9 MeOH–CHCl₃).

A mixture of Li (31.3 mg, 2.26 mmol) and naphthalene (580

mg, 2.26 mmol) in THF (6 mL) was sonicated with ultrasound at

15 °C for 30 min. The resulting moss-green suspension was

cooled to −18 °C. To this mixture was added a solution of the

crude carboxylic acid lithium salt 29 in THF (2 mL) at −18 °C.

After being stirred at −18 °C for 10 min, the reaction mixture was

quenched by addition of 2 M aqueous HCl solution. The products

were extracted with EtOAc, and then dried. The organic layers

were concentrated and passed through a short column (1 g silica

gel, 1:9 EtOAc–hexane) to remove naphthalene. Further elution

(1:1 MeOH–CHCl₃as an eluent) gave a mixture of hydroxy car-

boxylic acid and its γ-lactone. The mixture was dissolved in THF

(1.5 mL) and 2 M aqueous HCl solution (0.5 mL) at 25 °C. The

mixture was stirred at 25 °C for 30 min, then poured into an ice-

cooled saturated aqueous NaHCO₃solution. The products were

extracted with CHCl₃, and then dried. Removal of the solvent

gave a residue, which was puriﬁed with column chromatography

[1 g silica gel, 1:4 to 2:3 (gradient) EtOAc–toluene as eluents] to

afford bicyclic γ-lactone 31 (8.7 mg, 94%) as white crystals: R_f=

0.39 (3:1 EtOAc–hexane); Mp 43.4–44.8 °C; [α]_D^21.5+3.2 (c 0.21,

CHCl₃); IR (KBr) 1000, 1040, 1055, 1080, 1105, 1150, 1175,

1215, 1260, 1310, 1360, 1370, 1410, 1415, 1455, 1465, 1715,

1730, 1750, 1770, 1780, 1790, 2855, 2925, 2955, 3020, 3320

1

cm⁻¹; H NMR (300 MHz, CDCl₃) δ 0.88 (t, 3H, J = 6.6 Hz),

1.22–1.42 (m, 12H), 1.54 (m, 4H), 2.02 (dd, 2H, J = 6.6 and

6.6 Hz), 2.40 (t, 4H, J = 7.5 Hz), 2.60 (bdd, 2H, J = 7.2 and 7.2

Hz), 2.96–3.13 (bs, 1H), 3.93 (d, 1H, J = 11.1 Hz), 4.07 (d, 1H, J

= 11.1 Hz), 4.63 (dt, 1H, J = 4.8 and 7.2 Hz), 5.15 (d, 1H, J =

4.8 Hz), 5.40 (dt, 1H, J = 15.2 and 7.2 Hz), 5.67 (dt, 1H, J = 15.2

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1941

and 6.6 Hz), 5.97–6.16 (bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ

14.0, 22.5, 23.8, 28.52, 28.54, 28.8, 28.9, 31.6, 31.76, 31.78, 32.2,

42.7, 42.9, 62.1, 66.2, 79.9, 82.0, 122.1, 136.2, 156.4, 174.5,

212.9; EI-MS m/z 410 (M + 1, 4.4), 409 (M⁺, 18.0), 353 (2.6),

352 (10.0), 325 (2.6), 324 (14.0), 113 (77.3), 56 (100); EI-HRMS

Calcd for C₂₂H₃₅NO₆(M⁺): 409.2464, Found: m/z 409.2462.

(E,2S,3R,4R)-2-Amino-3,4-dihydroxy-2-hydroxymethyl-14-

oxoicos-6-enoic Acid [Myriocin (1)]. To a solution of γ-lactone

30 (14.9 mg, 0.0292 mmol) in MeOH (1 mL) was added 10%

aqueous NaOH solution (1 mL) and the resulting mixture was

stirred at 80 °C for 2 h. The mixture was cooled to 25 °C, then

neutralized with IRC-76 resin (H⁺type). The insoluble material

was removed by ﬁltration and the ﬁltrate was concentrated to give

a residue, which was puriﬁed by column chromatography [0.9 g

silica gel, 1:1:10 to 1:3:10 (gradient) H₂O–MeOH–CHCl₃(lower

phase) as eluents] to afford solid residue. Recrystallization

(MeOH–CHCl₃–hexane) gave myriocin 1 (10.1 mg, 86%) as

white crystals: R_f= 0.38 (1:3:10 H₂O–MeOH–CHCl₃, lower

phase); Mp 168.4–170.1 °C; [α]_D^24.0+5.1 (c 0.18, MeOH); IR

(KBr) 970, 1410, 1470, 1520, 1570, 1640, 1710, 2855, 2930, 3210,

(3.7), 309 (20.6), 91 (100); EI-HRMS Calcd for C₁₈H₂₆O₇(M⁺):

354.1678, Found: m/z 354.1684. Found: C, 60.91; H, 7.36%.

Calcd for C₁₈H₂₆O₇: C, 61.00; H, 7.39%.

α

6-O-Benzyl-1,2-O-isopropylidene-3-O-methoxymethyl- -D-

xylo-hexofuranos-5-ulose (34). A mixture of (COCl)₂(2.0 M

solution in CH₂Cl₂, 16.3 mL, 32.7 mmol) and DMSO (4.63 mL,

65.3 mmol) was stirred at −78 °C for 30 min. To this mixture was

added a solution of alcohol 33 (5.78 g, 16.3 mmol) in CH₂Cl₂(90

mL) at −78 °C. After being stirred at −45 °C for 1 h, the reaction

mixture was quenched by addition of Et₃N (13.7 mL, 98.0 mmol).

The resulting suspension was further stirred at 0 °C for 30 min,

and then poured into saturated aqueous NH₄Cl solution. The

products were extracted with EtOAc and the organic layer was

washed with brine, and then dried. Removal of the solvent gave a

residue, which was passed through a short column (100 g silica

gel, 1:9 EtOAc-toluene as an eluent) to afford ketone 34 (5.75 g,

100%) as colorless syrup: R_f= 0.32 (1:5 EtOAc–toluene); [α]_D^25.5

= −81.7 (c 1.05, CHCl₃); IR (neat) 1020, 1040, 1090, 1110,

1

1155, 1220, 1380, 1385, 1740, 2900, 2940, 2990 cm⁻¹; H NMR

(300 MHz, CDCl₃); δ 1.32 (s, 3H), 1.47 (s, 3H), 3.30 (s, 3H), 4.34

(d, 1H, J = 18.9 Hz), 4.47 (d, 1H, J = 18.9 Hz), 4.50 (d, 1H, J =

3.6 Hz), 4.55 (d, 1H, J = 6.9 Hz), 4.61 (d, 1H, J = 6.9 Hz), 4.58

(d, 1H, J = 3.3 Hz), 4.60 (s, 2H), 4.78 (d, 1H, J = 3.6 Hz), 6.00

(d, 1H, J = 3.3 Hz), 7.26–7.38 (m, 5H); ¹³C NMR (75 MHz,

CDCl₃) δ 26.3, 26.9, 55.9, 73.2, 74.2, 81.3, 82.3, 84.6, 96.0,

105.7, 112.5, 127.9, 128.0, 128.4, 137.2, 204.4; FAB-MS m/z 353

(M + H, 100%); FAB-HRMS Calcd for C₁₈H₂₄O₇(M + H)⁺:

353.1600, Found: m/z 353.1600. Found: C, 61.13; H, 7.07%.

Calcd for C₁₈H₂₄O₇: C, 61.35; H, 6.78%.

1

3340 cm⁻¹; H NMR (300 MHz, CD₃OD) δ 0.89 (t, 3H, J = 6.6

Hz), 1.21–1.39 (m, 12H), 1.52 (m, 4H, J = 7.0 Hz), 1.99 (dd, 2H,

J = 6.5 and 6.5 Hz), 2.26 (dd, 2H, J = 6.8 and 6.8 Hz), 2.43 (t,

4H, J = 7.3 Hz), 3.75 (s, 1H), 3.81 (t, 1H, J = 6.8 Hz), 3.84 (d,

1H, J = 11.0 Hz), 3.98 (d, 1H, J = 11.0 Hz), 5.37 (dt, 1H, J =

14.7 and 6.8 Hz), 5.52 (dt, 1H, J = 14.7 and 6.5 Hz); ¹³C NMR

(75 MHz, CD₃OD) δ 14.4, 23.6, 24.9, 30.0, 30.1, 30.2, 30.4, 32.8,

33.7, 33.8, 38.7, 43.4, 43.5, 65.1, 70.3, 71.3, 73.6, 126.8, 134.7,

173.5, 214.3; FAB-MS m/z 402 (M + H, 70.2%), 57 (100); FAB-

HRMS Calcd for C₂₁H₄₀NO₆(M + H)⁺: 402.2856, Found: m/z

402.2859. The spectral data were identical with those of the natu-

ral product.

An Inseparable Mixture of Ethyl (Z)-4-Benzyloxy-3-

{(1R,5R,7R,8S)-8-methoxymethoxy-3,3-dimethyl-2,4,6-triox-

abicyclo[3.3.0]octan-7-yl}but-2-enoate and Its (E)-Isomer (35).

To a solution of ketone 34 (5.75 g, 16.3 mmol) in toluene (85 mL)

was added Ph₃PwCHCO₂Et (8.53 g, 24.5 mmol) at 25 °C, and the

mixture was stirred at 100 °C for 17 h. Removal of the solvent

gave a residue, which was puriﬁed by column chromatography

(200 g silica gel, 1:7 EtOAc–hexane as an eluent) to afford a geo-

metrical mixture (E:Z = ca. 1:4) of ester 35 (6.75 g, 98%) as a

colorless syrup: R_f= 0.48 (1:5 EtOAc–toluene); IR (neat) 1040,

1085, 1105, 1155, 1220, 1240, 1375, 1380, 1655, 1715, 2940,

Under similar conditions, γ-lactone 31 was also converted into

1 in 82% yield.

α

6-O-Benzyl-1,2-O-isopropylidene-3-O-methoxymethyl- -D-

gluco-hexofuranose (33). To a solution of diol 32²⁹(4.89 g,

18.5 mmol) in toluene (100 mL) was added dibutyltin oxide

(4.86 g, 19.5 mmol) and the mixture was stirred under reﬂux for

3 h. The resulting suspension was concentrated to give a residue,

which was dissolved in DMF (90 mL) at 40 °C. To this solution

were added CsF (3.56 g, 23.4 mmol) and BnBr (3.47 mL, 23.4

mmol) at 40 °C and the mixture was stirred at 80 °C for 13 h. Af-

ter cooling, to the reaction mixture were added 20% aqueous KF

solution (5 mL) and saturated aqueous NaHCO₃solution (5 mL),

and the mixture was stirred at 25 °C for 1h. The products were ex-

tracted with EtOAc, and the organic layer was washed successive-

ly with water, 20% aqueous KF solution, and brine, and then

dried. Removal of the solvent gave a residue, which was puriﬁed

by column chromatography (140 g silica gel, 1:4 EtOAc–toluene

as an eluent) to afford benzyl ether 33 (5.78 g, 88%) as a colorless

syrup: R_f= 0.57 (1:1 EtOAc–toluene); [α]_D^26.0−20.2 (c 1.00,

CHCl₃); IR (neat) 1020, 1085, 1155, 1165, 1220, 1375, 1455,

1

2990 cm⁻¹; H NMR (300 MHz, CDCl₃, for the major isomer) δ

1.29 (t, 3H, J = 7.6 Hz), 1.32 (s, 3H), 1.52 (s, 3H), 3.26 (s, 3H),

4.19 (m, 2H), 4.33–4.36 (m, 2H), 4.50 (d, 1H, J = 6.6 Hz), 4.54

(d, 1H, J = 3.6 Hz), 4.571 (d, 1H, J = 6.6 Hz), 4.574 (s, 2H), 4.61

(d, 1H, J = 3.6 Hz), 5.86–5.89 (m, 1H), 5.91 (d, 1H, J = 3.6 Hz),

6.22 (dd, 1H, J = 1.8 and 3.6 Hz), 7.26–7.35 (m, 5H); EI-MS m/z

423 (M + 1, 1.7%), 422 (M⁺, 5.6), 408 (4.1), 407 (16.4), 391

(1.8), 378 (2.8), 377 (10.2), 362 (2.0), 361 (10.6), 360 (42.9), 333

(6.6), 332 (21.7), 331 (100); EI-HRMS Calcd for C₂₂H₃₀O₈(M⁺):

422.1941, Found: m/z 422.1937. Found: C, 62.37; H, 7.29%.

Calcd for C₂₂H₃₀O₈: C, 62.55; H, 7.16%.

(Z)-4-Benzyloxy-3-{(1R,5R,7R,8S)-8-methoxymethoxy-3,3-

dimethyl-2,4,6-trioxabicyclo[3.3.0]oct-7-yl}but-2-en-1-ol (36Z)

and Its (E)-Isomer (36E). To a solution of a mixture (ca. 4:1)

of ester 35 (20.0 g, 44.5 mmol) in toluene (300 mL) was added

dropwise DIBAL-H (1.5 M solution in toluene, 59.3 mL, 88.9

mmol) at −78 °C. After being stirred at −78 °C for 3 h, the reac-

tion mixture was quenched by addition of MeOH. The mixture

was diluted with Et₂O and washed with 1 M aqueous HCl solu-

tion. The aqueous layer was extracted with Et₂O. The combined

organic layer was washed successively with saturated aqueous

1

2940, 2990, 3480 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 1.31 (s,

3H), 1.48 (s, 3H), 2.87 (d, 1H), 3.41 (s, 3H), 3.62 (dd, 1H, J = 5.9

and 9.8 Hz), 3.77 (dd, 1H, J = 2.7 and 9.8 Hz), 4.02–4.10 (m,

1H), 4.16 (dd, 1H, J = 2.9 and 8.8 Hz), 4.25 (d, 1H, J = 2.9 Hz),

4.55 (d, 1H, J = 3.7 Hz), 4.57 (s, 1H), 4.59 (s, 1H), 4.70 (d, 1H, J

= 6.4 Hz), 4.75 (d, 1H, J = 6.4 Hz), 5.89 (d, 1H, J = 3.7 Hz),

7.26–7.35 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 26.3, 26.8, 55.9,

67.6, 71.9, 73.4, 79.6, 80.4, 83.3, 96.7, 105.1, 111.9, 127.70,

127.73, 128.4, 138.0; EI-MS m/z 354 (M⁺, 0.1%), 339 (0.6), 310

1942 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

NaHCO₃solution and brine, and then dried. Removal of the sol-

vent gave a residue, which was puriﬁed by column chromatogra-

phy (300 g silica gel, 1:5 EtOAc–toluene as an eluent) to afford Z-

allylic alcohol 36Z (13.1 g, 73%) ﬁrst as a colorless syrup: R_f=

0.35 (1:1 EtOAc–hexane); [α]_D^24.5−46.9 (c 1.02, CHCl₃); IR

(neat) 1030, 1085, 1150, 1165, 1215, 1375, 1385, 1455, 2890,

(2.6), 363 (27.3), 362 (100); EI-HRMS Calcd for C₂₂H₂₈³⁵Cl₃NO₇

(M⁺): 523.0931, Found: m/z 523.0931. Found: C, 50.54; H, 5.44;

N, 2.47%. Calcd for C₂₂H₂₈Cl₃NO₇: C, 50.35; H, 5.38; N, 2.67%.

Further elution gave R-isomer 37R (89.4 mg, 64%) as a pale

yellow syrup: R_f= 0.56 (1:10 EtOAc–toluene); [α]_D^29.0~0.0 (c

1.00, CHCl₃); IR (neat) 1030, 1090, 1160, 1215, 1520, 1720,

2895, 2940, 2990, 3360, 3405 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 1.32 (s, 3H), 1.49 (s, 3H), 3.26 (s, 3H), 3.97 (d, 1H, J = 9.6 Hz),

4.04 (d, 1H, J = 9.6 Hz), 4.25 (s, 2H), 4.36 (d, 1H, J = 6.8 Hz),

4.485 (d, 1H, J = 6.8 Hz), 4.490 (d, 1H, J = 9.6 Hz), 4.57 (d, 1H,

J = 9.6 Hz), 4.58 (d, 1H, J = 3.9 Hz), 5.31 (d, 1H, J = 17.6 Hz),

5.32 (d, 1H, J = 11.0 Hz), 5.90 (d, 1H, J = 3.9 Hz), 6.12 (dd, 1H,

J = 11.0 and 17.6 Hz), 7.27-7.38 (m, 5H), 8.27 (bs, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 26.4, 26.7, 56.5, 62.2, 70.4, 73.3, 77.4,

82.3, 82.4, 93.4, 96.9, 104.4, 112.2, 116.4, 127.37, 127.44, 128.2,

128.4, 133.7, 138.1, 160.4; EI-MS m/z 527 (M + 4, 2.7%), 526

(M + 3, 2.4), 525 (M + 2, 5.9), 524 (M + 1, 2.3), 523 (M⁺, 4.7),

513 (2.2), 512 (6.3), 511 (5.1), 510 (14.0), 509 (4.1), 508 (14.7),

407 (4.1), 406 (20.9), 405 (9.9), 404 (46.6), 403 (10.1), 402

(44.4), 364 (5.1), 363 (30.8), 362 (100); EI-HRMS Calcd for

C₂₂H₂₈³⁵Cl₃NO₇(M⁺): 523.0931, Found: m/z 523.0931. Found:

C, 50.57; H, 5.49; N, 2.58%. Calcd for C₂₂H₂₈Cl₃NO₇: C, 50.35;

H, 5.38; N, 2.67%.

1

2935, 2990, 3450 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 1.33 (s,

3H), 1.51 (s, 3H), 2.14 (bs, 1H), 3.30 (s, 3H), 4.05 (s, 2H), 4.18 (d,

1H, J = 2.9 Hz), 4.22 (dd, 1H, J = 7.1 and 12.7 Hz), 4.30 (dd, 1H,

J = 7.1 and 12.7 Hz), 4.48–4.63 (m, 5H), 4.98 (m, 1H), 5.94 (d,

1H, J = 3.7 Hz), 6.04 (bt, 1H, J = 7.1 Hz), 7.26–7.34 (m, 5H);

¹³C NMR (75 MHz, CDCl₃) δ 26.2, 26.8, 55.9, 58.4, 72.2, 72.3,

79.6, 81.7, 83.2, 96.1, 104.3, 111.8, 127.6 (2C), 128.4, 129.7,

133.5, 138.2; FAB-MS m/z 381 (M + H, 100); FAB-HRMS Calcd

for C₂₀H₂₉O₇(M + H)⁺: 381.1913, Found: m/z 381.1916. Found:

C, 62.84; H, 7.61%. Calcd for C₂₀H₂₈O₇: C, 63.14; H, 7.42%.

Further elution gave E-isomer 36E (3.23 g, 18%) as a yellow

syrup: R_f= 0.26 (1:1 EtOAc-hexane); [α]_D^24.5−44.7 (c 1.02,

CHCl₃); IR (neat) 1030, 1080, 1150, 1165, 1215, 1375, 1385,

1455, 2860, 2930, 2990, 3440 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 1.33 (s, 3H), 1.51 (s, 3H), 1.76 (bs, 1H), 3.29 (s, 3H), 4.07–4.27

(m, 3H), 4.21 (d, 2H, J = 6.6 Hz), 4.47–4.60 (m, 5H), 4.78 (m,

1H), 5.89 (d, 1H, J = 3.7 Hz), 6.11 (bt, 1H, J = 6.6 Hz), 7.27–

7.38 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 26.5, 27.0, 56.0, 59.0,

66.2, 72.8, 81.4, 81.6, 83.7, 96.3, 104.7, 112.0, 128.0 (2C), 128.7,

131.0, 134.1, 137.9; FAB-MS m/z 381 (M + H, 32.9), 241 (100);

FAB-HRMS Calcd for C₂₀H₂₉O₇(M + H)⁺: 381.1913, Found:

m/z 381.1917. Found: C, 62.84; H, 7.68%. Calcd for C₂₀H₂₈O₇:

C, 63.14; H, 7.42%.

N-[(R)-1-Benzyloxy-2-{(1R,5R,7R,8S)-3,3-dimethyl-8-meth-

oxymethoxy-2,4,6-trioxabicyclo[3.3.0]octan-7-yl}but-3-en-2-

yl]trichloroacetamide (37R) and Its (S)-Buten-2-yl Isomer

(37S). To a solution of allylic alcohol 36Z (102 mg, 0.268

mmol) in CH₂Cl₂(2 mL) were added trichloroacetonitrile (0.0537

mL, 0.535mol) and DBU (0.008 mL, 0.0535mmol) at 0 °C, and

the mixture was stirred at 0 °C for 30 min. Removal of the solvent

gave a residue, which was passed through a short column chroma-

tography (1 g silica gel, 1:4 EtOAc–hexane containing 1 vol%

Et₃N as an eluent) to afford trichloroacetimidate (139 mg) as a

yellow syrup, which was used for the next reaction without further

puriﬁcation: R_f= 0.48 (1:2 EtOAc–hexane).

Overman rearrangement of E-allylic imidate derived from allyl-

ic alcohol 36E was carried out by the same procedure, and gave

the rearranged products 37R and 37S in 12 and 45% yields, re-

spectively.

N-[(R)-1-Benzyloxy-2-{(1R,5R,7R,8S)-3,3-dimethyl-8-meth-

oxymethoxy-2,4,6-trioxabicyclo[3.3.0]octan-7-yl}-3-hydroxy-

prop-2-yl]trichloroacetamide (38). Ozone was introduced into

a solution of compound 37R (1.13 g, 2.15 mmol) in CH₂Cl₂(20

mL) at −78 °C for 20 min. After the complete consumption of the

starting material was conﬁrmed (TLC analysis), excess ozone was

removed with a stream of argon gas. To this mixture was added

Me₂S (2.20 mL, 29.5 mmol) at −78 °C, and the resulting mixture

was further stirred at 0 °C for 2.5 h. Removal of the solvent gave

a residue, which was puriﬁed by column chromatography (50 g

silica gel, 1:4 EtOAc–hexane as an eluent) to afford aldehyde: R_f

= 0.33 (1:3 EtOAc–hexane); IR (neat) 1025, 1090, 1160, 1215,

1

1375, 1385, 1505, 1715, 1730, 2890, 2940, 2990, 3355 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 1.31 (s, 3H), 1.50 (s, 3H), 3.32 (s, 3H),

4.15 (d, 1H, J = 3.3 Hz), 4.16 (d, 1H, J = 10.2 Hz), 4.31 (d, 1H, J

= 10.2 Hz), 4.46 (d, 1H, J = 12.3 Hz), 4.48 (d, 1H, J = 6.6 Hz),

4.51 (d, 1H, J = 6.6 Hz), 4.53 (d, 1H, J = 12.3 Hz), 4.54 (d, 1H, J

= 3.3 Hz), 4.98 (d, 1H, J = 3.6 Hz), 5.91 (d, 1H, J = 3.6 Hz),

7.18-7.38 (m, 5H), 8.29 (s, 1H), 9.63 (s, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 26.2, 26.8, 56.5, 66.2, 66.4, 73.6, 79.6, 80.9, 82.2, 92.1,

96.7, 104.9, 112.6, 127.6, 127.9, 128.4, 137.2, 161.4, 195.3; EI-

MS m/z 529 (M + 4, 1.2%), 528 (M + 3, 1.4), 527 (M + 2, 2.8),

526 (M + 1, 1.0), 525 (M⁺, 2.7), 514 (1.6), 512 (3.8), 510 (3.8),

499 (4.3), 498 (5.0), 497 (11.0), 496 (7.5), 495 (10.6), 438 (8.1),

437 (4.5), 436 (12.2), 435 (6.3), 434 (12.3), 408 (8.3), 407 (4.4),

406 (16.0), 405 (4.5), 404 (17.6), 308 (32.5), 307 (14.0), 306

(97.5), 305 (19.9), 304 (100); EI-HRMS Calcd for C₂₁H₂₈Cl₃NO₈

(M⁺): 525.0723, Found: m/z 525.0724.

To a solution of the crude imidate (139 mg, 0.265 mmol) in o-

xylene (14 mL) was added solid K₂CO₃(40 mg), and the mixture

was heated at 140 °C for 156 h in a sealed tube under Ar atmo-

sphere. Removal of the solvent gave a residue, which was puriﬁed

by PLC (1:49 EtOAc–toluene as an eluent) to afford 37S (19.4

mg, 14%) as a pale yellow syrup: R_f= 0.59 (1:10 EtOAc–tolu-

ene); [α]_D^29.0−8.9 (c 1.02, CHCl₃); IR (neat) 1030, 1090, 1160,

1

1215, 1520, 1725, 2890, 2940, 2990, 3350 cm⁻¹; H NMR (300

MHz, CDCl₃) δ 1.33 (s, 3H), 1.46 (s, 3H), 3.38 (s, 3H), 3.85 (d,

1H, J = 8.5 Hz), 4.46 (d, 1H, J = 8.5 Hz), 4.17 (d, 1H, J = 2.6

Hz), 4.59 (s, 2H), 4.64 (d, 1H, J = 3.3 Hz), 4.64 (d, 1H, J = 7.1

Hz), 4.71 (d, 1H, J = 7.1 Hz), 4.72 (d, 1H, J = 2.6 Hz), 5.35 (d,

1H, J = 11.0 Hz), 5.42 (d, 1H, J = 17.9 Hz), 5.97 (d, 1H, J = 3.3

Hz), 6.11 (dd, 1H, J = 11.0 and 17.9 Hz), 7.26–7.34 (m, 5H), 8.27

(bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 26.3, 26.7, 56.3, 61.5,

70.1, 73.9, 80.8, 82.6, 82.8, 93.3, 97.2, 103.8, 112.0, 115.8, 128.0,

128.1, 128.4, 135.6, 137.4, 160.4; EI-MS m/z 527 (M + 4, 2.0%),

526 (M + 3, 1.8), 525 (M + 2, 2.8), 524 (M + 1, 1.8), 523 (M⁺,

2.8), 512 (4.0), 511 (2.7), 510 (10.6), 509 (2.4), 508 (10.2), 407

(4.1), 406 (17.8), 405 (8.4), 404 (40.5), 403 (8.9), 402 (42.7), 364

At 0 °C, to a solution of the aldehyde in Et₂O (30 mL) was add-

ed dropwise Zn(BH₄)₂¹⁹(0.184 M solution in Et₂O, 11.7 mL, 2.15

mmol). After being stirred at 25 °C for 1 h, the reaction mixture

was quenched by addition of H₂O, then diluted with EtOAc, and

washed successively with 1 M aqueous HCl solution and brine,

and then dried. Removal of the solvent gave a residue, which was

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1943

puriﬁed by column chromatography (50 g silica gel, 1:2 EtOAc–

toluene as an eluent) to afford alcohol 38 (1.05 g, 93%) as a color-

less syrup: R_f= 0.30 (1:2 EtOAc–hexane); [α]_D^28.5−7.7 (c 1.00,

CHCl₃); IR (neat) 1025, 1065, 1085, 1100, 1160, 1215, 1260,

1375, 1385, 1455, 1530, 1715, 2890, 2940, 2990, 3330, 3350

C₂₃H₃₀NO₁₁(M + H)⁺: 496.1819, Found: m/z 496.1814. Found:

C, 55.71; H, 5.72; N, 2.80%. Calcd for C₂₃H₂₉NO₁₁: C, 55.75; H,

5.90; N, 2.83%.

Ethyl (E,4S,5R,6R,7S)-7-Benzyloxymethyl-4,5:6,8-bis(iso-

propylidenedioxy)-7-(trichloroacetamido)oct-2-enoate (42).

To a solution of alcohol 38 (955 mg, 1.81 mmol) in THF (20 mL)

was added dropwise 12 M aqueous HCl solution (10 mL) at 0 °C,

and the mixture was stirred at 25 °C for 3 h. The products were

extracted with CHCl₃, and then dried. Removal of the solvent

gave a residue, which was passed through a short column (20 g sil-

ica gel, 1:15 MeOH–CHCl₃as an eluent) to give crude lactol 40

as a pale yellow syrup: R_f= 0.23 (1:8 MeOH–CHCl₃).

To a solution of the lactol 40 in CH₂Cl₂(16 mL) were added

Ph₃PwCHCO₂Et (1.89 g, 5.42 mmol) and benzoic acid (22.2 mg,

0.181 mmol) at 25 °C, and the mixture was stirred at 25 °C for

2.5 h. Removal of the solvent gave a residue, which was passed

through a short column (20 g silica gel, 1:2 EtOAc–toluene as an

eluent) to afford crude tetrol 41 as a yellow syrup: R_f= 0.47 (2:1

EtOAc–toluene).

To a solution of the tetrol 41 in a mixed solvent of benzene

(5 mL) and 2,2-dimethoxypropane (15 mL) was added CSA until

the pH value of the solution became lower than 4.0. After being

stirred at 50 °C for 13 h, the reaction mixture was diluted with

EtOAc and washed successively with saturated aqueous NaHCO₃

solution and brine, and then dried. Removal of the solvent gave a

residue, which was puriﬁed by column chromatography (50 g sili-

ca gel, 1:10 EtOAc–hexane as an eluent) to afford ester 42 (641

mg, 46% for 3 steps) as a colorless syrup: R_f= 0.60 (1:5 EtOAc–

toluene); [α]_D^24.0+20.1 (c 0.82, CHCl₃); IR (neat) 1085, 1160,

1240, 1305, 1370, 1385, 1455, 1540, 1665, 1715, 1730, 2870,

2905, 2940, 2990, 3340 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.32

(t, 3H, J = 7.1 Hz), 1.38 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.46

(s, 3H), 3.67 (d, 1H, J = 9.7 Hz), 3.87 (d, 1H, J = 9.7 Hz), 3.96

(d, 1H, J = 12.2 Hz), 4.03 (d, 1H, J = 8.3 Hz), 4.09 (s, 1H), 4.25

(q, 2H, J = 7.1 Hz), 4.39 (d, 1H, J = 11.9 Hz), 4.53 (d, 1H, J =

12.2 Hz), 4.54 (d, 1H, J = 11.9 Hz), 4.69 (ddd, 1H, J = 1.0, 6.1

and 8.3 Hz), 6.10 (dd, 1H, J = 1.0 and 15.6 Hz), 6.87 (dd, 1H, J =

6.1 and 15.6 Hz), 7.20-7.38 (m, 5H), 8.50 (bs, 1H); ¹³C NMR (75

MHz, CDCl₃) δ 14.3, 19.4, 26.1, 27.1, 28.3, 57.8, 60.8, 61.5, 67.2,

68.0, 73.6, 75.6, 78.7, 93.2, 96.1, 99.6, 111.2, 123.5, 127.8, 128.0,

128.5, 137.2, 142.9, 161.4, 165.6; EI-MS m/z 582 (M − CH₃+ 2,

2.7%), 580 (M − CH₃+ 1, 6.5), 578 (M − CH₃, 6.5), 522 (4.9),

520 (4.8), 502 (2.9), 501 (5.1), 500 (3.9), 499 (6.3), 170 (100);

EI-HRMS Calcd for C₂₅H₃₁³⁵Cl₃NO₈(M − CH₃): 578.1114,

Found: m/z 578.1119. Found: C, 52.67; H, 5.55; N, 2.22%. Calcd

for C₂₆H₃₄Cl₃NO₈: C, 52.49; H, 5.76; N, 2.35%.

1

cm⁻¹; H NMR (300 MHz, CDCl₃) δ 1.32 (s, 3H), 1.49 (s, 3H),

3.28 (s, 3H), 3.90 (s, 2H), 3.92 (d, 1H, J = 12.5 Hz), 4.25 (d, 1H,

J = 12.5 Hz), 4.29 (m, 2H), 4.40–4.62 (m, 5H), 5.89 (d, 1H, J =

3.7 Hz), 7.26–7.35 (m, 5H), 8.66 (bs, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 26.2, 26.8, 56.4, 63.0, 65.2, 69.3, 73.9, 79.8, 82.4, 84.0,

93.1, 97.1, 103.9, 112.1, 128.06, 128.11, 128.5, 137.3, 162.2; EI-

MS m/z 529 (M + 2, 0.2%), 527 (M⁺, 0.2), 514 (0.2), 512 (0.2),

498 (0.5), 496 (0.5), 378 (2.5), 376 (2.4), 228 (4.9), 91 (100); EI-

HRMS Calcd for C₂₁H₂₈³⁵Cl₃NO₈(M⁺): 527.0880, Found: m/z

527.0882. Found: C, 47.83; H, 5.56; N, 2.45%. Calcd for

C₂₁H₂₈Cl₃NO₈: C, 47.70; H, 5.34; N, 2.65%.

(2S,3R,4S,5R,6S)-2,3,5-Triacetoxy-6-benzyloxymethyl-4-

methoxymethoxy-8-oxa-1-azabicyclo[4.3.0]nonan-9-one (39).

To a solution of alcohol 38 (161 mg, 0.304 mmol) in CH₂Cl₂(3.2

mL) was added DBU (0.0044 mL, 0.0304 mmol) and the mixture

was stirred at 25 °C for 29 h. Removal of the solvent gave a resi-

due, which was puriﬁed by column chromatography (4 g silica

gel, 1:1 EtOAc–hexane as an eluent) to afford oxazolidinone (123

mg, 98%) as a colorless syrup: R_f= 0.18 (1:1 EtOAc–hexane);

[α]_D^28.5−8.8 (c 1.12, CHCl₃); IR (neat) 1035, 1085, 1160, 1215,

1260, 1375, 1385, 1455, 1475, 1760, 2870, 2940, 2990, 3320 cm⁻¹

;

¹H NMR (300 MHz, CDCl₃) δ 1.32 (s, 3H), 1.49 (s, 3H), 3.29 (s,

3H), 3.47 (d, 1H, J = 9.0 Hz), 3.51 (d, 1H, J = 9.0 Hz), 4.04 (d,

1H, J = 3.2 Hz), 4.28 (d, 1H, J = 3.2 Hz), 4.29 (d, 1H, J = 8.5

Hz), 4.44 (d, 1H, J = 6.8 Hz), 4.47 (d, 1H, J = 11.9 Hz), 4.51 (d,

1H, J = 8.5 Hz), 4.58 (m, 1H), 4.59 (d, 1H, J = 6.8 Hz), 4.60 (d,

1H, J = 11.9 Hz), 5.69 (bs, 1H), 5.93 (d, 1H, J = 3.7 Hz), 7.28–

7.40 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 26.2, 26.8, 56.6, 60.3,

71.4, 72.6, 73.7, 78.7, 81.9, 82.9, 96.6, 104.4, 111.8, 128.0, 128.2,

128.6, 137.0, 159.2; EI-MS m/z 410 (M + 1, 5.7), 409 (M⁺, 15.5),

395 (8.0), 394 (39.7), 379 (3.2), 378 (14.8), 366 (3.7), 365 (12.1),

364 (58.2), 320 (2.2), 319 (12.3), 318 (55.8), 290 (9.5), 289

(50.9), 288 (100).

A solution of the oxazolidinone (123 mg, 0.300 mmol) in TFA

and H₂O (1:1, 3 mL) was stirred at 0 °C for 18 h. The reaction

mixture was neutralized with saturated aqueous NaHCO₃solution

and extracted with EtOAc, and then dried. Removal of the solvent

gave a residue, which was dissolved in a mixed solvent of pyridine

(0.5 mL) and Ac₂O (0.5 mL). After being stirred at 25 °C for 7 h,

the reaction mixture was concentrated to give a residue, which

was puriﬁed by column chromatography (1.5 g silica gel, 1:3

EtOAc–toluene as an eluent) to afford triacetate 39 (57.9 mg, 38%

from 38) as white crystals: R_f= 0.54 (1:1 EtOAc–toluene); Mp

154.7–157.2 °C; [α]_D^21.5+7.9 (c 0.94, CHCl₃); IR (KBr) 1040,

1110, 1225, 1370, 1410, 1745, 1755, 1770, 1780, 2895, 2930,

tert-Butyl

N-[(E,2S,3R,4R,5S)-2-Benzyloxymethyl-8-hy-

droxy-1,3:4,5-bis(isopropylidenedioxy)oct-6-ene-2-yl]carba-

mate (43). To a solution of DIBAL-H (1.01 M in toluene, 2.99

mL, 3.02 mmol) in toluene (3 mL) was added a solution of ester

42 (359 mg, 0.603 mmol) in toluene (12 mL) dropwise via a can-

nula at −78 °C. The mixture was stirred at −78 °C for 4 h, and

then quenched by slow addition of cooled acetone. To the result-

ing solution was added solid Na₂SO₄•10H₂O (large excess) at 0

°C. After stirring for 1 h at 25 °C, the insoluble materials were ﬁl-

tered off and the ﬁltrate was concentrated to give crude amine: R_f

= 0.54 (1:8 MeOH–CHCl₃).

1

2940, 3030 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 2.02 (s, 3H),

2.06 (s, 3H), 2.09 (s, 3H), 3.38 (s, 3H), 3.62 (d, 1H, J = 9.0 Hz),

3.97 (dd, 1H, J = 2.7 and 2.7 Hz), 4.06 (d, 1H, J = 9.0 Hz), 4.21

(d, 1H, J = 9.3 Hz), 4.30 (d, 1H, J = 9.3 Hz), 4.52 (d, 1H, J =

11.7 Hz), 4.56 (d, 1H, J = 11.7 Hz), 4.63 (d, 1H, J = 6.6 Hz),

4.70 (d, 1H, J = 6.6 Hz), 5.05 (dd, 1H, J = 2.7 Hz), 5.14 (d, 1H, J

= 2.7 Hz), 6.41 (bs, 1H), 7.23–7.43 (m, 5H); ¹³C NMR (75 MHz,

CDCl₃) δ 20.88, 20.93, 21.1, 56.2, 60.2, 66.9, 67.8, 68.9, 71.3,

71.7, 73.8, 75.3, 96.4, 127.9, 128.3, 128.7, 137.2, 155.9, 168.3,

169.2, 169.7; FAB-MS m/z 496 (M + H, 1.1%), 459 (1.2), 304

(4.9), 437 (6.5), 436 (37.3), 277 (100); FAB-HRMS Calcd for

To a solution of the crude amine in MeOH (6 mL) were added

NaHCO₃(63.4 mg, 0.754 mmol) and Boc₂O (0.523 mL, 2.37

mmol) at 25 °C. The reaction mixture was stirred at 25 °C for

12 h, and then diluted with EtOAc. The organic layer was washed

1944 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

successively with 1 M aqueous HCl solution, saturated aqueous

NaHCO₃solution and brine, and then dried. Removal of the sol-

vent gave a residue, which was puriﬁed by column chromatogra-

phy (5 g silica gel, 1:3 EtOAc–toluene as an eluent) to afford tert-

butyl carbamate 43 (223 mg, 90%) as a colorless syrup: R_f= 0.55

(1:8 MeOH–CHCl₃); [α]_D^24.0+1.9 (c 0.74, CHCl₃); IR (neat)

1075, 1160, 1250, 1370, 1385, 1455, 1505, 1515, 1520, 1685,

The products were extracted with EtOAc, and then dried. Remov-

al of the solvent gave a residue, which was puriﬁed by column

chromatography (4 g alumina, 1:9 EtOAc–hexane as an eluent) to

afford a diastereomeric mixture of coupling product 45 (91.3 mg,

85%) as a colorless syrup: R_f= 0.45 (1:3 EtOAc–toluene, 3

times); IR (neat) 1075, 1150, 1160, 1250, 1305, 1365, 1380, 1455,

1

1505, 1520, 1715, 2870, 2930, 3405 cm⁻¹; H NMR (300 MHz,

1

1715, 2870, 2940, 2995, 3405, 3460 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 0.87 (t, 3H, J = 6.6 Hz), 1.15–1.92 (m, 39H), 2.25–2.66

(m, 2H), 2.95 (m, 1H), 3.71–4.23 (m, 9H), 4.29–4.56 (m, 4H),

5.38–5.52 (m, 1H), 5.69–5.85 (m, 1H), 6.19 (s, 1H), 7.20–7.37

(m, 5H), 7.49–7.99 (m, 5H); FAB-MS m/z 858 (M + H, 19.3%),

680 (100); FAB-HRMS Calcd for C₄₇H₇₂NO₁₁S (M + H)⁺:

858.4826, Found: m/z 858.4819.

CDCl₃) δ 1.40 (bs, 21H), 1.62 (bs, 1H), 3.74 (d, 1H, J = 9.8 Hz),

3.85 (d, 1H, J = 9.8 Hz), 3.92 (d, 1H, J = 11.9 Hz), 3.96 (s, 1H),

3.99 (d, 1H, J = 8.5 Hz), 4.10 (bt, 2H, J = 4.9 Hz), 4.34 (d, 1H, J

= 11.9 Hz), 4.41–4.50 (m, 3H), 5.60 (dd, 1H, J = 8.0 and 15.6

Hz), 5.92 (dt, 1H, J = 15.6 and 4.9 Hz), 6.18 (bs, 1H), 7.22–7.38

(m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 20.2, 26.1, 27.4, 27.5,

28.4, 56.0, 62.6, 63.4, 67.2, 70.4, 73.4, 77.5, 78.8, 78.9, 96.1,

99.5, 110.2, 127.4, 127.7, 128.4, 134.9, 138.1, 155.3; FAB-MS

m/z 530 (M + Na, 9.1%), 508 (M + H, 100%); FAB-HRMS Cal-

cd for C₂₇H₄₂NO₈(M + H)⁺: 508.2910, Found: m/z 508.2912.

Found: C, 63.98; H, 8.10; N, 2.61%. Calcd for C₂₇H₄₁NO₈: C,

63.88; H, 8.14; N, 2.76%.

tert-Butyl N-[(E,2S,3R,4R,5S)-2-Benzyloxymethyl-8-bromo-

1,3:4,5-bis(isopropylidenedioxy)oct-6-ene-2-yl]carbamate

(44). To a solution of allylic alcohol 43 (71.4 mg, 0.141 mmol)

in CH₂Cl₂(2.2 mL) was added Et₃N (0.0492 mL, 0.353 mmol) at

0 °C. After stirring at 0 °C for 5 min, to this solution was added

MsCl (0.0273 mL, 0.353 mmol) at 0 °C. The resulting mixture

was stirred at 25 °C for 20 min and then diluted with EtOAc. The

organic layer was washed successively with 1 M aqueous HCl so-

lution, saturated NaHCO₃solution and brine, and then dried. Re-

moval of the solvent gave a crude mesylate: R_f= 0.34 (1:3

EtOAc–toluene).

tert-Butyl

N-[(E,2S,3R,4R,5S)-14,14-Ethylenedioxy-2-hy-

droxymethyl-1,3:4,5-bis(isopropylidenedioxy)icos-6-ene-2-

yl]carbamate (46). A mixture of Li (22.3 mg, 3.22 mmol) and

naphthalene (412 mg, 3.22 mmol) in THF (1 mL) was sonicated

with ultrasound at 15 °C for 30 min. The resulting moss-green

suspension was cooled to −18 °C. To this mixture was added a

solution of coupling product 45 (27.6 mg, 0.0322 mmol) in THF

(1 mL) at −18 °C via a cannula. The reaction mixture was stirred

at −18 °C for 10 min, and then quenched by addition of H₂O until

the green color of the mixture disappeared. The products were ex-

tracted with EtOAc, and then dried. Removal of the solvent gave a

residue, which was chromatographed on a short column (2.5 g sil-

ica gel, 1:19 EtOAc–hexane) to remove naphthalene. Further elu-

tion (1:6 EtOAc–hexane as an eluent) provided alcohol 46 (10.5

mg, 52%) as colorless syrup: R_f= 0.57 (1:2 EtOAc–hexane);

[α]_D^24.0+2.9 (c 0.45, CHCl₃); IR (neat) 1050, 1065, 1170, 1250,

1365, 1380, 1455, 1505, 1520, 1695, 1715, 2860, 2930, 2985,

3410, 3480 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, 3H, J =

6.7 Hz), 1.23-1.37 (m, 16H), 1.40 (s, 6H), 1.44 (s, 6H), 1.45 (s,

9H), 1.53–1.63 (m, 4H), 2.06 (dd, 2H, J = 6.8 and 6.8 Hz), 3.54–

3.61 (m, 1H), 3.58 (s, 1H), 3.71 (d, 1H, J = 8.3 Hz), 3.77 (d, 1H, J

= 12.5 Hz), 3.87–3.94 (m, 1H), 3.92 (s, 4H), 4.22 (d, 1H, J =

12.5 Hz), 4.37 (dd, 1H, J = 8.3 and 8.3 Hz), 4.43 (bdd, 1H, J =

3.4 and 9.0 Hz), 5.40 (dd, 1H, J = 8.3 and 15.3 Hz), 5.76 (dt, 1H,

J = 15.3 and 6.8 Hz), 6.07 (bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ

14.1, 17.5, 19.1, 22.6, 23.7, 23.8, 26.1, 27.4, 28.3, 28.4, 28.8,

29.0, 29.59, 29.64, 31.8, 32.2, 37.1, 37.2, 56.4, 63.5, 64.9, 65.9,

69.2, 77.2, 78.4, 78.9, 79.8, 99.2, 99.9, 109.8, 111.9, 126.3, 138.0,

157.1; FAB-MS m/z 628 (M + H, 100%); FAB-HRMS Calcd for

C₃₄H₆₂NO₉(M + H)⁺: 628.4424, Found: m/z 628.4402.

To a solution of the crude mesylate in THF (2.2 mL) was added

LiBr (120 mg, 1.41 mmol) at 25 °C. After being stirred at 25 °C

for 40 min, the mixture was diluted with EtOAc and washed with

H₂O. Removal of the solvent gave a residue, which was puriﬁed

by column chromatography (3.5 g silica gel, 1:7 EtOAc–hexane

as an eluent) to afford allyl bromide 44 (72.2 mg, 90%) as a color-

less syrup: R_f= 0.76 (1:3 EtOAc–toluene); [α]_D^22.5+5.8 (c 1.25,

CHCl₃); IR (neat) 1070, 1125, 1170, 1205, 1250, 1365, 1385,

1

1455, 1505, 1515, 1715, 2870, 2940, 2990, 3410 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 1.40–1.44 (bs, 21H), 3.74 (d, 1H, J = 9.8

Hz), 3.83 (d, 1H, J = 9.8 Hz), 3.86–3.90 (m, 3H), 3.94 (s, 1H),

3.98 (d, 1H, J = 8.5 Hz), 4.33 (d, 1H, J = 11.9 Hz), 4.42 (d, 1H, J

= 11.9 Hz), 4.45 (dd, 1H, J = 7.6, and 8.5 Hz), 4.51 (d, 1H, J =

11.9 Hz), 5.56 (dd, 1H, J = 7.6 and 15.1 Hz), 5.97 (dt, 1H, J =

15.1 and 7.3 Hz), 6.16 (bs, 1H), 7.24–7.39 (m, 5H); ¹³C NMR (75

MHz, CDCl₃) δ 20.2, 26.1, 27.3, 27.4, 28.4, 30.9, 56.1, 63.4, 67.3,

70.3, 73.4, 76.9, 78.8, 78.9, 99.5, 110.4, 127.5, 127.7, 128.4,

131.1, 131.3, 138.0, 155.3; FAB-MS m/z 572 (M + 3, 100%), 570

(M + H, 91.3); FAB-HRMS Calcd for C₂₇H₄₁⁸¹BrNO₇(M + H)⁺:

572.2046, Found: m/z 572.2059.

(2S,3R,4R)-2-Acetamido-3-acetoxy-2-acetoxymethyl-4-

[(E,S)-1-acetoxy-10-oxohexadec-2-en-1-yl)-4-butanolide (48).

A solution of (COCl)₂(2.0 M solution in CH₂Cl₂, 0.179 mL, 0.358

mmol) and DMSO (0.0509 mL, 0.717 mmol) was stirred at −78 °C

for 30 min. To this mixture was added a solution of alcohol 46

(10.5 mg, 0.0163 mmol) in CH₂Cl₂(1 mL) at −78 °C. After stir-

ring at a temperature under −45 °C for 2 h, to the reaction mixture

was added Et₃N (0.145 mL, 1.08 mmol) at 0 °C. The resulting

suspension was further stirred at 0 °C for 30 min, and then diluted

with EtOAc. The organic layer was washed with brine, and then

dried. Removal of the solvent gave a residue, which was passed

through a column chromatograph (1 g silica gel, 1:19 EtOAc–tol-

uene as an eluent) to afford crude aldehyde, which was used for

the next reaction without further puriﬁcation: R_f= 0.57 (1:3

EtOAc–hexane).

tert-Butyl

N-[(E,2S,3R,4R,5S,9R&S)-2-Benzyloxymethyl-

14,14-ethylenedioxy-1,3:4,5-bis(isopropylidenedioxy)-9-phen-

ylsulfonylicos-6-ene-2-yl]carbamate (45). To a solution of

sulfone 4 (93.6 mg, 0.254 mmol) in THF (1 mL) was added n-

BuLi (1.59 M hexane solution, 0.447 mL, 0.710 mmol) at −78 °C

and the resulting yellow solution was stirred at −78 °C for 10

min. To the mixture was added a solution of allyl bromide 43

(72.2 mg, 0.127 mmol) in THF (1 mL) dropwise via a cannula at

−78 °C. The resulting yellow solution was stirred at −78 °C for

15 min, and then poured into phosphate buffer (pH 8.1, 5 mL).

To a solution of the crude aldehyde in a mixed solvent of t-

BuOH and H₂O (1:1, 0.5 mL) were added successively

NaH₂PO₄•2H₂O (7.5 mg, 0.048 mmol), HOSO₂NH₂(7.0 mg,

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1945

ly identical with those of the authentic sample.^4j

0.072 mmol) and NaClO₂(6.5 mg, 0.072 mmol) at 25 °C. After

being stirred at 25 °C for 15 min, to the mixture was added 20

wt% aqueous Na₂S₂O₃solution until yellow color of the mixture

disappeared. The products were extracted with CHCl₃, and then

dried. Removal of the solvent afforded a crude carboxylic acid 47

as a colorless oil, which was used for the next reaction without

further puriﬁcation: R_f= 0.58 (1:6 MeOH–CHCl₃).

We thank Professor S. Hatakeyama (Nagasaki University,

Nagasaki, Japan) for providing us with spectral data of natural

and authentic sample of 1 and its lactone acetate 30, and valu-

able pieces of advice. We also thank Dr. T. Nakamura and Dr.

M. Shiozaki (Exploratory Chemistry Research Laboratories,

Sankyo Co. Ltd., Tokyo, Japan) for providing us with spectral

data of an authentic sample of 2.

To a solution of carboxylic acid 47 in THF (0.2 mL) was added

TFA (0.4 mL) at 25 °C, and the mixture was stirred at 25 °C for 1

h. To the resulting pale yellow solution was added H₂O (0.2 mL)

at 25 °C, and the mixture was further stirred at 50 °C for 2.5 h.

Removal of the solvent gave a residue, which was diluted with

MeOH. Then the pH of the solution was made basic by addition

of K₂CO₃. Insoluble materials were ﬁltered off, and then the ﬁl-

trate was concentrated to give a residue, which was dissolved with

a mixed solvent of pyridine (0.3 mL) and Ac₂O (0.3 mL) at 25 °C.

After being stirred at 25 °C for 2 h, the mixture was diluted with

EtOAc and washed with brine, and then dried. Removal of the

solvent gave a residue, which was puriﬁed with column chroma-

tography [0.5 g silica gel, 1:2 to 3:1 (gradient) EtOAc–hexane as

eluents] to afford acetoxy-4-butanolide 48 (6.3 mg, 68% for 4

steps) as a colorless syrup: R_f= 0.53 (9:1 EtOAc–hexane); [α]_D^23.2

+48.6 (c 0.27, CHCl₃); IR (neat) 1040, 1180, 1230, 1375, 1435,

References

1

For isolation and the structure determination of myriocin,

see: a) D. Klurpfel, J. Bagli, H. Baker, M.-P. Charest, A. Kudelski,

S. N. Sehgal, and C. Vézina, J. Antibiot., 25, 109 (1972); J. F.

Bagli, D. Kluepfel, and M. S. Jacques, J. Org. Chem., 38, 1253

(1973) (myriocin). b) F. Aragozzini, P. L. Manachini, R. Craveri,

B. Rindone, and C. Scolastico, Tetrahedron, 28, 5493 (1972); R.

Destro and A. Colombo, J. Chem. Soc., Perkin Trans. 2, 1979, 896

(thermozymocidin). c) T. Fujita, K. Inoue, S. Yamamoto, S.

Sasaki, R. Toyama, M. Yoneta, Y. Hoshino, and T. Okumoto, J.

Antibiot., 47, 208 (1994); T. Fujita, K. Inoue, S. Yamamoto, T.

Ikumoto, S. Sasaki, R. Toyama, M. Yoneta, K. Chiba, Y. Hoshino,

and T. Okumoto, J. Antibiot., 47, 216 (1994); S. Sasaki, R.

Hashimoto, M. Kiuchi, K. Inoue, T. Ikumoto, R. Hirose, K. Chiba,

Y. Hoshino, T. Okumoto, and T. Fujita, J. Antibiot., 47, 420 (1994)

(ISP-1).

1460, 1540, 1695, 1710, 1745, 1765, 1790, 2860, 2930, 3340 cm⁻¹

;

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, 3H, J = 6.7 Hz), 1.18–1.36

(m, 12H), 1.46–1.61 (m, 4H), 1.96–2.05 (m, 2H), 2.02 (s, 6H),

2.09 (s, 3H), 2.12 (s, 3H), 2.38 (t, 4H, J = 7.4 Hz), 4.49 (d, 1H, J

= 11.4 Hz), 4.56 (d, 1H, J = 11.4 Hz), 4.76 (dd, 1H, J = 4.9 and

7.8 Hz), 5.33 (bdd, 1H, J = 7.8 and 15.3 Hz), 5.53 (dd, 1H, J =

7.8 and 7.8 Hz), 5.80 (d, 1H, J = 4.9 Hz), 5.86 (dt, 1H, J = 15.3

and 7.2 Hz), 5.97 (bs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0,

20.5, 20.6, 21.1, 22.5, 22.7, 23.7, 23.8, 28.2, 28.9, 29.0, 31.6,

32.3, 42.7, 42.8, 62.4, 62.9, 70.4, 71.6, 77.2, 80.6, 122.0, 139.5,

168.1, 169.2, 169.6, 170.2, 171.7, 211.6; EI-MS m/z 567 (M⁺,

1.2%), 507 (11.0), 449 (4.7), 448 (18.7), 423 (4.3), 422 (16.2),

390 (1.2), 389 (6.9), 388 (26.7), 382 (1.1), 381 (7.1), 380 (35.7),

348 (4.0), 347 (22.2), 346 (88.5), 277 (100); EI-HRMS Calcd for

C₂₉H₄₅NO₁₀(M⁺): 567.3044, Found: m/z 567.3046.

2

For total synthesis of myriocin and synthetic approaches,

see: a) G. Just and D. R. Payette, Tetrahedron, 21, 3219 (1980);

Can. J. Chem., 59, 269 (1981). b) L. Banﬁ, M. G. Beretta, L.

Colombo, C. Gennari, and C. Scolastico, J. Chem. Soc., Chem.

Commun., 1982, 488; J. Chem. Soc., Perkin Trans. 1, 1983, 1613.

c) M. Yoshikawa, Y. Yokokawa, Y. Okuno, and N. Murakami,

Chem. Pharm. Bull., 42, 994 (1994); Tetrahedron, 51, 6209

(1995). d) S. Sano, Y. Kobayashi, T. Kondo, M. Takebayashi, S.

Maruyama, T. Fujita, and Y. Nagao, Tetrahedron Lett., 36, 2097

(1995). e) S. Hatakeyama, M. Yoshida, T. Esumi, Y. Iwabuchi, H.

Irie, T. Kawamoto, H. Yamada, and M. Nishizawa, Tetrahedron

Lett., 38, 7887 (1997). f) A. V. R. Rao, M. K. Gurjar, T. R. Devi,

and K. R. Kumar, Tetrahedron Lett., 34, 1653 (1993). g) S.

Deloisy, T. T. Thang, A. Olesker, and G. Lukacs, Terahedron Lett.,

35, 4783 (1994).

(E,2S,3R,4R,5S)-2-Amino-3,4,5-trihydroxy-2-hydroxymeth-

yl-14-oxo-icos-6-enoic Acid [Sphingofungin E (2)]. To a solu-

tion of acetoxy-4-butanolide 48 (3.0 mg, 0.053 mmol) in MeOH

(0.6 mL) was added 10% aqueous NaOH solution (0.6 mL) at 25 °C.

The mixture was stirred at 70 °C for 2 h, and then neutralized with

IRC-76 resin (H⁺type) at 25 °C. Insoluble materials were ﬁltered

off, and the ﬁltrate was concentrated to give a residue, which was

puriﬁed by column chromatography [0.5 g silica gel, 1:1:8 to

1:1:3 (gradient) H₂O–MeOH–CHCl₃(lower phase) as eluents] to

afford sphingofungin E (2) (2.0 mg, 88%) as white crystals: R_f=

0.23 (1:3 MeOH–CHCl₃); Mp 144.0–145.8 °C; [α]_D^25.0−5.6 (c

0.14, MeOH); IR (KBr) 1060, 1105, 1195, 1270, 1385, 1405,

3

For islolation of sphingofungins A-D, see: a) F.

VanMiddlesworth, R. A. Giacobbe, M. Lopez, G. Garrity, J. A.

Bland, K. Batizal, R. A. Frontling, K. E. Wilson, and R. L.

Monaghan, J. Antibiot., 45, 861 (1992); F. VanMiddlesworth, C.

Dufresne, F. E. Wincott, R. T. Mosley, and K. E. Wilson, Tetrahe-

dron Lett., 33, 297 (1992). For isolation of sphingofungins E and

F, see: b) W. S. Horn, J. L. Smith, G. F. Bills, S. L. Raghoobar, G.

L. Helms, M. B. Kurta, J. A. Marrinan, B. R. Frommer, R. A.

Thornton, and S. M. Mandala, J. Antibiot., 45, 1692 (1992).

1465, 1500, 1505, 1640, 1715, 2855, 2930, 3200, 3360 cm⁻¹; H

1

NMR (300 MHz, CD₃OD) δ 0.94 (t, 3H, J = 6.7 Hz), 1.21–1.45

(m, 12H), 1.48–1.60 (m, 4H), 1.98–2.10 (m, 2H), 2.43 (t, 4H, J =

7.4 Hz), 3.63 (d, 1H, J = 7.3 Hz), 3.84 (d, 1H, J = 11.0 Hz), 3.94

(bs, 1H), 3.97 (d, 1H, J = 11.0 Hz), 4.10 (dd, 1H, J = 7.6 and 7.6

Hz), 5.44 (dd, 1H, J = 7.6 and 15.4 Hz), 5.77 (dt, 1H, J = 15.4

and 6.3 Hz); ¹³C NMR (75 MHz, CD₃OD) δ 14.4, 23.6, 24.8, 24.9,

30.02, 30.03, 30.15, 30.18, 32.8, 33.4, 43.47, 43.51, 64.9, 70.0,

71.2, 75.6, 76.3, 130.2, 135.7, 173.2, 214.4; FAB-MS m/z 418 (M

+ H, 25.9%), 55 (100); FAB-HRMS Calcd for C₂₁H₄₀NO₇(M +

H)⁺: 418.2805, Found: m/z 418.2805. The spectral data were ful-

4

For total syntheses of sphingofungin B, see: a) S.

Kobayashi, T. Hayashi, S. Iwamoto, T. Furuta, and M.

Matsumura, Synlett, 1996, 672. b) S. Kobayashi, M. Matsumura,

T. Furuta, T. Hayashi, and S. Iwamoto, Synlett, 1997, 301. c) S.

Kobayashi, T. Furuta, T. Hayashi, M. Nishijima, and K. Hanada, J.

Am. Chem. Soc., 120, 908 (1998). d) S. Kobayashi and T. Furuta,

Tetrahedron, 54, 10275 (1998). For total syntheses of sphingofun-

gin D, see: e) N. Chida, H. Ikemoto, A. Noguchi, S. Amano, and

S. Ogawa, Nat. Prod. Lett., 6, 295 (1995). f) K. Mori and K.

Otaka, Tetrahedron Lett., 35, 9207 (1994). g) K. Otaka and K.

1946 Bull. Chem. Soc. Jpn., 75, No. 9 (2002)

HEADLINE ARTICLES

Mori, Eur. J. Org. Chem., 1999, 1795. For total syntheis of sphin-

gofungin E, see: h) C.-B. Lee and B. M. Trost, J. Am. Chem. Soc.,

123, 12191 (2001). i) B. Wang, X.-M. Yu, and G.-Q. Lin, Synlett,

2001, 904. j) T. Nakamura and M. Shiozaki, Tetrahedron Lett.,

42, 2701 (2001). For total synthesis of sphingofungin F, see: (k)

B. M. Trost and C. B. Lee, J. Am. Chem. Soc., 120, 6818 (1998).

l) D.-G. Liu, B. Wang, and G.-Q. Lin, J. Org. Chem., 65, 9114

(2000), and also see: (4b)–(4d).

62, 1449 (1997). k) L. E. Overman and G. G. Zipp, J. Org. Chem.,

62, 2288 (1997). l) T. K. Hollis and L. E. Overman, Tetrahedron

Lett., 38, 8837 (1997). m) Y. Donde and L. E. Overman, J. Am.

Chem. Soc., 121, 2933 (1999).

11 For some examples of utilization of Overman rearrange-

ment in organic syntheses, see: a) S. Takano, M. Akiyama and K.

Ogasawara, J. Chem. Soc., Chem. Commun., 1984, 770. b) A. K.

Saksena, R. G. Lovey, V. M. Girijavallabhan and A. K. Ganguly,

J. Org. Chem., 51, 5024 (1986). c) S. Danishefsky and J.Y. Lee, J.

Am. Chem. Soc., 111, 4829 (1989). d) N. Yamamoto and M.

Isobe, Chem. Lett., 1994, 2299; T. Nishikawa, M. Asai, N.

Ohyabu, N. Yamamoto, M. Isobe, Angew. Chem. Int. Ed., 38, 3081

(1999); T. Nishikawa, M. Asai, N. Ohyabu, N. Yamamoto, Y.

Fukuda, M. Isobe, Tetrahedron, 57, 3875 (2001). e) M. Haddad,

H. Imogaï and M. Larchevêque, J. Org. Chem., 63, 5680 (1998).

f) S. Demay, A. Kotschy and P. Knochel, Synthesis, 2001, 863. g)

C. Martin, M. Bortolussi and R. Bloch, Tetrahedron Lett., 40,

3735 (1999). h) H. Ovaa, J. D. C. Codée, B. Lastdrager, H. S.

Overkleeft, G. van der Marel and J. H. van Boom, Tetrahedron

Lett., 39, 7987 (1998). i) M. Mehmandoust, M. Petit and Y.

Larchevêque, Tetrahedron Lett., 33, 4313 (1992). j) J. Gonda, A.-

C. Helland, B. Ernst and D. Bellus, Synthesis, 1993, 729. k) K.

Estieu, J. Olliver and J. Salaun, Tetrahedron Lett., 36, 2975

(1995). l) H. Ovaa, J. D. C. Codée, B. Lastdrager, H.

S.Overkleeft, G. A. van der Marel and J. H. van Boom, Tetrahe-

dron Lett., 40, 5063 (1999).

5

For isolation of lactacystin, see: S. Omura, T. Fujimoto, K.

Otoguro, K. Matsuzaki, R. Moriguchi, H. Tanaka, and Y. Sasaki,

J. Antibiot., 44, 113 (1991); S. Omura, K. Matsuzaki, T. Fujimoto,

K. Kosuge, T. Furuya, S. Fujita, and A. Nakagawa, J. Antibiot., 44,

117 (1991).

6

For total synthesis of lactacystin and synthetic approaches,

see: a) E. J. Corey and G. A. Reichard, J. Am. Chem. Soc., 114,

10677 (1992); E. J. Corey, G. A. Reichard, and R. Kania, Tetrahe-

dron Lett., 34, 6977 (1993); E. J. Corey, W. Li, and T. Nagamitsu,

Angew. Chem., Int. Ed., 37, 1676 (1998). b) T. Sunazuka, T.

Nagamitsu, K. Matsuzaki, H. Tanaka, S. Omura, and A. B. Smith

ꢁ, J. Am. Chem. Soc., 115, 5302 (1993); T. Nagamitsu, T.

Sunazuka, S. Omura, P. A. Sprengler, and A. B. Smith ꢁ, J. Am.

Chem. Soc., 118, 3584 (1996). c) H. Uno, J. E. Baldwin, and A. T.

Russel, J. Am. Chem. Soc., 116, 2139 (1994). d) N. Chida, J.

Takeoka, N. Tsutsumi, and S. Ogawa, J. Chem. Soc., Chem. Com-

mun., 1995, 793; N. Chida, J. Takeoka, K. Ando, N. Tsutsumi, and

S. Ogawa, Tetrahedron, 53, 16287 (1997). e) S. H. Kang, H.-S.

Jun, and J.-H. Youn, Synlett, 1998, 1045; S. H. Kang and H.-S.

Jun, Chem. Commun., 1998, 1929. f) J. S. Panek and C. E. Masse,

Angew. Chem., Int. Ed., 38, 1093 (1999). g) S. Iwama, W. G. Gao,

T. Shinada, and Y. Ohfune, Synlett, 2000, 1631.

12 For a report of Overman rearrangement on the sugar skele-

ton, conversion of the rearranged products into α-amino acids, and

kinetic and theoretical study, see: T. Eguchi, T. Koudate, and K.

Kakinuma, Tetrahedron, 49, 4527 (1993).

7

a) Y. Miyake, Y. Kozutsumi, S. Nakamura, T. Fujita, and T.

13 For the preliminary communications, see: T. Oishi, K.

Ando, and N. Chida, Chem. Commun., 2001, 1932 (myriocin). b)

T. Oishi, K. Ando, K. Inomiya, H. Sato, M. Iida, and N. Chida,

Org. Lett., 4, 151 (2002) (sphingofungin E).

Kawasaki, Biochem. Biophys. Res. Commun., 211, 396 (1995). b)

M. M. Zweerink, A. M. Edison, G. B. Wells, W. Pinto, and R. L.

Lester, J. Biol. Chem., 267, 25032 (1992).

8

T. Fujita, M, Yoneta, R. Hirose, S. Sasaki, K. Inoue, M.

14 J. B. Lee and T. J. Nolan, Tetrahedron, 23, 2789 (1967).

15 a) R. E. Ireland, D. W. Norbeck, G. S. Mandel, and N. S.

Mandel, J. Am. Chem. Soc., 107, 3285 (1985). b) K. Dax, B. I.

Glänzer, G. Schulz, and H. Vyplel, Carbohydr. Res., 162, 13

(1987). c) A. Fürstner and H. Weidmann, J. Cabohydr. Chem., 7,

773 (1988).

Kiuchi, S. Hirase, K. Adachi, M. Arita, and K. Chiba, BioMed.

Chem. Lett., 5, 847 (1995); T. Fujita, R. Hirose, N. Hamamichi, Y.

Kitao, S. Sasaki, M. Yoneta, and K. Chiba, BioMed. Chem. Lett.,

5, 1857 (1995).

9

a) U. Schöllkopf, Pure. Appl. Chem., 1983, 1799. b) D.

Seebach, J. D. Aebi, M. Coquoz, and R. Naef, Helv. Chim. Acta,

70, 1194 (1987). c) Y. Ito, M. Sawamura, E. Shirakawa, K.

Hayashizaki, and T. Hayashi, Tetrahedron Lett., 29, 235 (1988).

d) Y. Ito, M. Sawamura, and T. Hayashi, Tetrahedron Lett., 29,

239 (1988). e) S.-H. Moon and Y. Ohfune, J. Am. Chem. Soc.,

116, 7405 (1994). f) S. Hatakeyama, H. Fukuyma, Y. Mukugi,

and H. Irie, Tetrahedron Lett., 37, 4047 (1996), and also see: (2b),

(2f), and (4j).

10 a) L. E. Overman, J. Am. Chem. Soc., 96, 597 (1974); J.

Am. Chem. Soc., 98, 2901 (1976); Acc. Chem. Res., 13, 218

(1980). b) T. Ikariya, Y. Ishikawa, K. Hirai, and S. Yoshikawa,

Chem. Lett., 1982, 1815. c) L. E. Overman, Angew. Chem., Int.

Ed. Engl., 23, 579 (1984). d) T. G. Schenck and B. Bosnich, J.

Am. Chem. Soc., 107, 2058 (1985). e) I. Savage and E. J. Thomas,

J. Chem. Soc., Chem. Commun., 1989, 717. f) P. Metz, C. Mues,

16 F. Guibe, Tetrahedron, 53, 13509 (1997).

17 a) K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978).

b) A. J. Mancuso, S.-L. Huang, and D. Swern, J. Org. Chem., 43,

2480 (1978). c) A. J. Mancuso, D. S. Brownfair, and D. Swern, J.

Org. Chem., 44, 4148 (1979). d) A. J. Mancuso and D. Swern,

Synthesis, 1981, 165.

18 a) L. Horner, H. Hoffmann, and H. G. Wippel, Chem. Ber.,

91, 61 (1958). b) L. Horner, H. Hoffmann, H. G. Wippel, and G.

Klahre, Chem. Ber., 92, 2499 (1959). c) W. S. Wadsworth, and W.

D. Emmons, J. Am. Chem. Soc., 83, 1733 (1961). d) L. Horner,

W. Klink, and H. Hoffmann, Chem. Ber., 96, 3133 (1963). e) J.

Boutagy and R. Thomas, Chem. Rev., 74, 87 (1974). f) W. S.

Wadsworth, Org. React., 25, 73 (1977). g) M. A. Blanchette, W.

Choy, and J. T. Davis, Tetrahedron Lett., 25, 2183 (1984). h) M.

W. Rathke and M. Nowak, J. Org. Chem., 50, 2624 (1985).

19 D. B. Denney and S. T. Ross, J. Am. Chem. Soc., 84, 998

(1962).

and A. Schoop, Tetrahedron, 48, 1071 (1992).

g) M.

Mehmandoust, M. Petit, and Y. Larcheveque, Tetrahedron Lett.,

33, 4313 (1992). h) J. Gonda, A.-C. Hell, B. Ernst, and D. Bellus,

Synthesis, 1993, 729. i) A. Chen, I. Savage, E. J. Thomas, and P.

D. Wilson, Tetrahedron Lett., 34, 6769 (1993). j) M. Calter, T. K.

Hollis, L. E. Overman, J. Ziller, and G. G. Zipp, J. Org. Chem.,

20 a) J. M. J. Tronchet and B. Gentile, Helv. Chim. Acta, 62,

2091 (1979). b) S. Valverde, M. M. Lomas, B. Herradon, and S.

G. Ochoa, Tetrahedron, 43, 1895 (1987). c) M. K. Gurjar, S. K.

Das, and U. K. Saha, Tetrahedron Lett., 35, 2241 (1994).

T. Oishi et al.

Bull. Chem. Soc. Jpn., 75, No. 9 (2002) 1947

21 T. Nishikawa, M. Asai, N. Ohyabu, and M. Isobe, J. Org.

Chem., 63, 188 (1998).

27 T. Tsunoda, M. Suzuki, and R. Noyori, Tetrahedron Lett.,

21, 1357 (1980).

22 B. H. Lipshutz, D. Pollart, J. Monforte, and H. Kotsuki,

Tetrahedron Lett., 26, 705 (1985).

28 H.-J. Liu, J. Yip, and K.-S. Shia, Tetrahedron Lett., 38,

2253 (1997).

23 R. Pappo, D. S. Allen, Jr., R. U. Lemieux, and W. S.

Johnson, J. Am. Chem. Soc., 78, 478 (1956).

24 T. Shioiri, T. Aoyama, and S. Mori, Org. Synth., 68, 1

(1987).

29 J. Mulzer, A. Angermann, W. Münch, G. Schlichthörl, and

A. Hentzschel, Liebigs. Ann. Chem., 1987, 7.

30 W. J. Gensler, F. Johnson, and A. D. B. Sloan, J. Am.

Chem. Soc., 82, 6074 (1960).

25 E. W. Collington and A. I. Meyers, J. Org. Chem., 36, 3044

(1971).

26 B. I. Akal, Fette. Seifen. Anstrichm, 74, 524 (1972).

31 For a review, see: C. F. Lane, Synthesis, 1975, 135.

32 Y. Kani, S. Ohba, T. Oishi, K. Ando, K. Inomiya, and N.

Chida, Acta Crystallogr., Sect. C., 56, e223 (2000).

Article Doi

Total synthesis of (+)-myriocin and (-)-sphingofungin E from aldohexoses using overman rearrangement as the key reaction

DOI: 10.1246/bcsj.75.1927

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Full text of DOI:10.1246/bcsj.75.1927

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