Non-iterative asymmetric synthesis of C15 polyketide spiroketals

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Non-iterative Asymmetric Synthesis of C₁₅Polyketide Spiroketals

by Kai Meilert^a)¹), George R.Pettit ^b), and Pierre Vogel*^a)

a

¡

¬

¬ ¬

) Laboratoire de glycochimie et de synthese asymetrique Ecole Polytechnique Federale de Lausanne, BCH,

CH-1015 Lausanne-Dorigny (tel.: 0216939371; fax: 0216939375; e-mail: pierre.vogel@epfl.ch)

^b) Cancer Research Institute, Arizona State University Tempe, Arizona 85287-2404, USA

The 2,2'-methylenebis[furan] (1) was converted to 1-{(4R,6S))-6-[(2R)-2,4-dihydroxybutyl]-2,2-dimethyl-

1,3-dioxan-4-yl}-3-[(2R,4R)-tetrahydro-4,6-dihydroxy-2H-pyran-2-yl)propan-2-one (()-18) and its (4S)-epi-

mer (À)-19 with high stereo- and enantioselectivity (Schemes 1 3). Under acidic methanolysis, ()-18 yielded a

single spiroketal, (3R)-4-{(1R,3S,4'R,5R,6'S,7R)-3',4',5',6'-tetrahydro-4'-hydroxy-7-methoxyspiro[2,6-dioxabicy-

clo[3.3.1]nonane-3,2'-[2H]pyran]-6'-yl}butane-1,3-diol ((À)-20), in which both O-atoms at the spiro center

reside in equatorial positions, this being due to the tricyclic nature of (À)-20 (methyl pyranoside formation).

Compound (À)-19 was converted similarly into the (4'S)-epimeric tricyclic spiroketal (À)-21 that also adopts a

similar (3S)-configuration and conformation. Spiroketals (À)-20, (À)-21 and analog (À)-23, i.e.,

(1R,3S,4'R,5R,6'R)-3',4',5',6'-tetrahydro-6'-[(2S)-2-hydroxybut-3-enyl]-7-methoxyspiro[2,6-dioxabicyclo[3.3.1]-

nonane-3,2'-[2H]pyran]-4'-ol, derived from (À)-20, were assayed for their cytotoxicity toward murine P388

lymphocytic leukemia and six human cancer cell lines. Only racemic (Æ)-21 showed evidence of cancer-cell-

growth inhibition (P388, ED₅₀: 6.9 mg/ml).

Introduction. A great variety of natural products of biological interest contain

spiroketal subunits [1]. The 1,7-dioxaspiro[5.5]undecane and 1,6-dioxaspiro[4.5]decane

ring systems are known in nature as simple derivatives [2a] (see also [2b], or, more

frequently, the spiroketal is more highly oxidized, as exemplified by the milbemycin-

avermectins [3], the polyether ionophores, and the phyllanthocin and related

metabolites [4]. While the literature abounds in methods for the synthesis of such

spiroketals and their thermodynamic aspects have been extensively studied [5],

particular interest has been focused during the last decade on the two AB and CD

spiroketal units found in the spongistatin class of compounds (see, e.g., spongistatin 1)

[6]. They appear to be the crucial pharmacophores for the unprecedented anticancer

activity of these marine macrolides [7]²).

We have published an approach to the EF rings of spongistatins embodying the

trienic side chain [8]. In the present paper, we disclose a non-iterative approach to

direct precursors of the AB and CD spiroketal moieties of spongistatins, based on our

new methodology towards long-chain polyols [9]. Additionally, the newly synthesized

spiroketals were evaluated against a mouse-leukemia cell line (P388) and six types of

human-cancer cell lines [10].

We have shown that the chemistry developed by Lautens and co-workers (see, e.g.,

[11]), Hoffmann and co-workers (see, e.g., [12]), and later Kaku and co-workers [13],

1

)

Actual address: Department of Organic and Medicinal Chemistry, University of Auckland, 23 Symonds

Street, Auckland, New Zealand.

For the biological activity of the bis-tetrahydropyran, see [7h].

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who converted 8-oxabicyclo[3.2.1]oct-6-en-3-one into C₇1,3-polyols and analogues

[14], can be extended to the synthesis of a large number of stereoisomeric pentadecane-

1,3,5,7,9,11,13,15-octols [9]. We have used also 8-oxabicyclo[3.2.1]oct-6-en-3-one

derivatives in the stereoselective synthesis of C-disaccharides [15] and analogues of

sialyl Lewis^xacid [16].

Results and Discussion. As already reported, meso-3 can be derived readily from

2,2'-methylenebis[furan] (1) via 2 (Scheme 1). The desymmetrization of meso-3 was

realized applying the Sharpless asymmetric dihydroxylation [17]. With AD-mix(a)

(five times more concentrated than in the initially published Sharpless procedure [9]),

we obtained ()-6 and ()-7 in 79% yield (Scheme 2). ¹⁹F-NMR spectroscopy (¹³C-¹⁹F

satellites) of Mosher×s esters 6M and 7M derived from (aS)-a-methoxy-a-(trifluor-

omethyl)benzeneacetyl chloride [18] showed ()-6 to have 98.4% ee and ()-7 4% ee.

Changing the substitution pattern of the carbocycles such as in 4 and 5 did not increase

the diastereoselectivity (4 :1) of the dihydroxylation. On the contrary, 4 gave a 3 :1

mixture of diastereoisomeric diols (77% yield), and 5 a 1:1 mixture (22% yield) of

diastereoisomeric diols. The absolute configuration of ()-6 was assumed to be

opposite to that of the diol obtained with AD-mix(b) (5Â), as the optical rotation was

Scheme 1

Helvetica Chimica Acta Vol. 87 (2004)

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Scheme 2

of similar magnitude but of opposite sign. The relative configuration of the two

diastereoisomers ()-6 and ()-7 was determined by the 2D ¹H-NMR NOESY

experiments of acetonide (À)-9, which was obtained in two steps by deacetylation of

()-6 to tetrol (À)-8, followed by acetonide formation under standard conditions

1

(Scheme 2). The H-NMR spectrum of (À)-9 implied a dipolar coupling of HÀC(4')

with HÀC(2'), which indicated clearly that, in the major diastereoisomer ()-6, the

CC bond has been dihydroxylated from the face cis with respect to the (4-

methoxybenzoyl)oxy group, in agreement with expectation [19].

Deacetylation of ()-6 with Mg(OMe)₂in MeOH ( ! (À)-8), followed by

treatment with NaIO₄gave a mixture of anomeric hemiacetals ()-10 (Scheme 3).

As already shown with the opposite series of enantiomers [9], hemiacetal ()-10 was

reduced to anti-diol ()-11 (70%) under Evans×s conditions [20]. To increase the

versatility of our methodology, the 1,3-syn diastereoisomer (À)-13 was prepared by

application of the NarasakaÀPrasadÀShapiro method [21]. Acetonides ()-12 and

()-14 derived from ()-11 and (À)-13, respectively, showed ¹³C-NMR signals

expected for these products [22].

Reduction of ()-12 with DIBAL-H (diisobutylaluminium hydride) gave tetrol

()-15. Dihydroxylation with OsO₄(cat.) and N-methylmorpholine N-oxide (NMO),

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Helvetica Chimica Acta Vol. 87 (2004)

Scheme 3

followed by treatment with lead tetraacetate furnished ()-18 (1,3-trans). In a similar

way, ()-14 was converted to ()-17 and then to ()-19 (1,3-cis). The crucial steps of

spiroketalization of ()-18 and (À)-19 were performed in pure MeOH/CH₂Cl₂under

acidic catalysis (TsOH). By ¹H-NMR, the reactions were complete after a few minutes

at room temperature, and no change in products was observed after prolonged standing

1

at 208 or heating to 608. The H-NMR spectra of the crude reaction mixtures showed

that they contained a mixture of anomeric methyl acetals, their proportions varying

slightly with the concentration of acid catalyst and the temperature of reaction. Flash

chromatography allowed us to isolate pure (À)-20 (68%) from the reaction of ()-18

(1,3-trans) and (À)-21 (65%) from the reaction of (À)-19 (1,3-cis). To the best of our

knowledge, such tricyclic systems have never been reported before. The side chain of

(À)-20 was modified in the following way. Treatment of (À)-20 with an excess of 2-

NO₂ÀC₆H₄ÀSeCN and Bu₃P led to selective selenation of the primary-alcohol

Helvetica Chimica Acta Vol. 87 (2004)

1497

function with formation of 22, which underwent oxidative elimination with m-CPBA

(3-chloroperbenzoic acid) [24] giving allylic alcohol (À)-23 (Scheme 4).

Scheme 4

The structure of (À)-20 was assigned as follows (see Fig.). The protons of cycle C

and B were assigned through a 2D-NMR COSY-45 experiment. Due to its anomeric

position, the proton HÀC(7) is strongly deshielded (d(H) 4.65, d(C) 104.8) and can,

thus, be easily identified. Starting from HÀC(7), the other proton signals were assigned

and their identities further confirmed by selective irradiation techniques. The

remaining protons were assigned in a similar way. From the coupled ¹³C-NMR spectra,

the C(1'') center was identified unambiguously as the unique t in the CHOH region

(68 > d(C) > 53) at d(C) 61.0( t, ¹J 139). A 2D-NMR HMQC experiment allowed us

to find the corresponding protons CH₂(1'') at d(H) 3.73 (t, ³J 7.5, 2 H). Again, the 2D-

NMR COSY-45 experiment allowed the assignments of the other protons of the side

chain (CH₂(2''), HÀC(3''), CH₂(4'')) and those from cycle A (HÀC(6'), CH₂(5'),

HÀC(4'), CH₂(3')). Selective irradiations were helpful to confirm these assignments.

The absolute configuration (3S) of (À)-20 could thus be determined by the 2D-NMR

NOESY correlations (Fig.).

Two absolute configurations around the spiro center ((3R) or (3S)) are possible for

the AB rings of (À)-20. For each absolute configuration, different conformations of the

three cycles are possible a priori. Correlations of one of the HÀC(9) protons with

CH₂(3') and HÀC(4') of cycle A are consistent with only the (3S) configuration. No

dipolar couplings of HÀC(8) or HÀC(7) with CH₂(3') and HÀC(4') (what would have

been consistent with the opposite configuration (3R)) were observed (Fig.). Addi-

tionally, the correlations between HÀC(5), HÀC(1), HÀC(3'), HÀC(4), and

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Figure. Representations of spiroketal 20 in its (3S)- (preferred) and (3R)-configuration

HÀC(6') are possible only for the (3S)-configuration (Fig.). While the correlation

between HÀC(5) and HÀC(3') would have been possible in the (3R)-configuration,

the dipolar couplings between HÀC(4) and HÀC(6') and between HÀC(1) and

HÀC(3') are not possible, as the corresponding protons point to opposite regions of

space.

The conformation of the bicyclic moiety BC and cycle A of (À)-20 could be

established by H,H coupling constants between vicinal protons. For cycle A, the

coupling constants indicate an axial-axial relationship between HÀC(6'), 1 HÀC(5'),

HÀC(4'), and 1 HÀC(3') (³J(6', 5') 11.8 Hz and ³J(5', 4') ³J(4', 3') 11.3 Hz). Thus,

cycle A in (À)-20 adopts a chair conformation. For the bicyclic system BC, two

characteristic ³J(H,H) coupling constants indicate a boat conformation for both the B

and C rings. ³J(4,5) 11.3, ³J(1,8) 11.3 Hz are only consistent with dihedral angles f

(HÀC(1), HÀC(8)) f (HÀC(4), HÀC(5)) ꢀ 08, possible only for boat conforma-

tions [23]).

Substituted 1,7-dioxaspiro[5.5]undecanes can adopt different conformations; the

relative populations of the different conformers depend on steric factors, anomeric and

related effects, and intramolecular H-bonding. In the case of spiroketal (À)-20, both

endocyclic O-atoms are disposed in equatorial position (e) relative to the other cycle

(see Fig.) and, therefore, this structure is not stabilized by a conformational anomeric

effect. The conformation (3S)-20' that disposes both endocyclic O-atoms in an axial

positions (a) and which is stabilized by a double conformational anomeric effect would

imply chair-chair conformation for its AB bicyclic moiety. This conformation is

impeded by steric factors that override the stabilized anomeric effect, as both

substituents on cycle A are disposed in unfavorable axial positions, and, additionally,

the side chain of cycle A is subject to severe steric interaction with the BC moiety. The

Helvetica Chimica Acta Vol. 87 (2004)

1499

formation of cycle C (pyranoside) seems to control the configuration of the spiroketal.

The NMR data of (À)-21 confirmed that this spiroketal adopts also the (3S)-

configuration and a conformation similar to that of (À)-20.

The spiroketals (À)-20, (À)-21, (À)-23, and (Æ)-21 were tested against the murine

P388 lymphocytic leukemia cell line and six human cancer cell lines (pancreas (BXPX-

3), breast (MCF-7), CNS Gliobl (SF 268), lung (NCI-H460), colon (KM20L2), and

prostate (DU-145)). None of these displays any growth inhibition (GI₅₀) against the

human cancer cell lines. While the enantiomerically pure (À)-20, (À)-21, and (À)-23

were also inactive against the mouse leukemia cell line, the racemic mixture (Æ)-21³)

displayed an effective median dose (ED₅₀) of 6.90 mg/ml, indicating potential activity of

ED₅₀3.45 mg/ml for ()-21.

Conclusions. Our non-iterative approach to the synthesis of long-chain polyols has

now been adapted to the synthesis of precursors of the spiroketals of spongistatins. The

versatility of our approach was further extended by the asymmetric dihydroxylation of

meso-3 with AD-mix(a) (5Â) and the 1,3-syn diastereoselective reduction of hemi-

acetal ()-10 ( ! (À)-13). Unfortunately, and, as for simpler spiroketals [7a], the new

tricyclic systems prepared in this study do not present significant anticancer activities.

¬

We thank the Swiss NationalScience Foundation and the Office Federal de l×Enseignement et de la

Recherche (Bern, European COSTD28/004/02 action) for financial support. We thank also Mr. MartialRey and

¬

Francisco Sepulveda for technical help. One of us (G. R. P.) also wishes to thank for financial support Grant

RO1-CA90441-02-03 with the Division of Cancer Treatment and Diagnosis, NationalCancer Institute ,

Department of Health and Human Services the Arizona Disease ControlResearch Commission , Dr. Alec D.

Keith, the Robert B. Dalton Endowment Fund and for other assistance, Dr. Jean-Charles Chapuis.

Experimental Part

General. See [24]. Flash column chromatography (FC): Merck silica gel (230 400mesh, No. 9385). TLC:

silica gel (Merck aluminium foils). ¹H- and ¹³C-NMR Spectra: assignments confirmed by coupled ¹³C-NMR,

2D-COSY, HMQC, or HSQC, and when required, by 2D-NOESY; d in ppm, J in Hz.

Cancer Assays. See [25].

(1S,6S)-6-(Acetyloxy)-4-{{(1R,2S,4S,6S)-6-(acetyloxy)-1,2-dihydroxy-4-[(4-methoxybenzoyl)oxy]cyclohep-

tyl}methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate (()-6) and (1S,6S)-6-(Acetyloxy)-4-{{(1S,2R,4S,6S)-6-(ace-

tyloxy)-1,2-dihydroxy-4-[(4-methoxybenzoyl)oxy]cycloheptyl)methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate

(()-7). A soln. of meso-3 (14.5 g, 0.023 mol) and MeSO₂NH₂(2.19 g, 0.023 mol) in 290 ml of H₂O/^tBuOH

1:1 with 10% of MeCN was cooled to 08 and AD-mix(a) (5Â) (34.7 g, 1490mg per mmol) was added

portionwise under vigorous mechanical stirring. After 24 h stirring (TLC, CH₂Cl₂/MeOH 95 :5), the mixture

was diluted with AcOEt (200 ml) and quenched by addition of Na₂SO₃(2.89 g, 0.023 mmol). After 1 h stirring,

the aq. layer was extracted with AcOEt (3 Â 400 ml). After drying (MgSO₄) of the org. phase, FC (silica gel,

CH₂Cl₂/AcOEt 4 :1) afforded starting material meso-3 (493 mg) and ()-6/()-7 4 :1 (12.9 g, 79%) that was

further separated by column chromatography (silica gel): 8.62 g of pure ()-6, 1.39 g of ()-6/()-7, and 1.86 g of

pure ()-7).

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Data of ()-6: a 56; a 60; a 67; a 122; a 156 (c 0.20, CHCl₃). UV

(MeCN): 255 (21500), 207 (22300). IR (KBr): 3500, 2940, 2360, 1735, 1710, 1605, 1510, 1370, 1255, 1170, 1100,

1025, 770, 695, 615. ¹H-NMR (400 MHz, CDCl₃): 7.98 (m, 1 MeOC₆H₄CO); 6.91 (m, 1 MeOC₆H₄CO); 5.63

(t, ³J 6.5, HÀC(3)); 5.38 (dddd, ³J 10.5, 8.7, 6.0, 1.8, HÀC(4')); 5.27 (m, HÀC(1)); 5.19 (dddd, ³J 10.5, 9.0,

6.1, 2.6, HÀC(6')); 5.11 (m, HÀC(6)); 3.85, 3.82 (2s, 2 MeOC₆H₄CO); 3.72 (br. d, ³J 10.7, HÀC(2')); 2.65

(m, HÀC(2)); 2.64 (m, HÀC(7)); 2.57 (d, ²J 13.3, 1 H, CH₂ÀC(4)); 2.48 (dd, ²J 15.0, ³J 6.5, HÀC(2));

3

)

Prepared as (À)-21, but by using OsO₄/NMO in the oxidative step meso-3 ! (Æ)-6.

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2.30( m, 1 HÀC(3'), 1 HÀC(5), 1 HÀC(7')); 2.27 (d, ²J 13.3, 1 H, CH₂ÀC(4)); 2.20( m, HÀC(5)); 2.10

(m, HÀC(7')); 2.05, 2.01 (2s, 2 MeCO); 2.03 (m, 1 HÀC(5'), 1 HÀC(3')); 1.81 (dd, ²J 14.7, ³J 10.5,

1 HÀC(5')). ¹³C-NMR (100.6 MHz, CDCl₃): 170.6, 170.2 (2s, MeCO); 165.5 (s, 2 C, MeOC₆H₄CO); 163.4,

163.3 (2s, 2 C, MeOC₆H₄CO); 136.9 (s, C(4)); 131.6 (d, ¹J 163, 4 C, MeOC₆H₄CO); 127.3 (d, ¹J 162, C(3));

122.6, 122.5 (2s, 2 C, MeOC₆H₄CO); 113.6 (d, ¹J 161, 4 C, MeOC₆H₄CO); 74.3 (s, C(1')); 73.0( d, ¹J 141,

C(2')); 68.7 (d, ¹J 154, C(1)); 68.2 (d, ¹J 137, C(6)); 68.1 (d, ¹J 149, C(6')); 66.9 (d, ¹J 147, C(4')); 55.4

(q, ¹J 145, 2 C, MeOC₆H₄CO); 50.8 (t, ¹J 127, CH₂ÀC(4)); 41.5, 40.9, 39.0, 38.6, 37.7 (5t, C(5), C(5'), C(7),

C(7'), C(3')); 32.3 (t, ¹J 127, C(2)); 21.3 (q, ¹J 130, 2 C, MeCO). CI-MS (NH₃): 673 (41, [M NH₄] ), 655 (8,

[M H] ), 595 (8), 503 (18), 443 (11), 337 (13), 135 (100), 106 (2), 78 (26). Anal. calc. for C₃₅H₄₂O₁₂(654.71): C

64.21, H 6.47, O 29.32; found: C 62.45, H 6.47 (corresponding to C₃₅H₄₂O₁₂¥ H₂O: C 62.49, H 6.59).

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Data of ()-7: a 1; a 1; a 4; a 13; a 15 (c 0.11, CH₂Cl₂). UV

(MeCN): 254 (34800), 208 (34500). IR (KBr): 3500, 2940, 1730, 1705, 1605, 1515, 1370, 1255, 1170, 1100, 1025,

845, 770, 610. ¹H-NMR (400 MHz, CDCl₃): 7.99 (m, 1 MeOC₆H₄CO); 6.92 (m, 1 MeOC₆H₄CO); 5.64 (t, ³J 6.2,

HÀC(3)); 5.47 (m, HÀC(4')); 5.31 (m, HÀC(1)); 5.10(br. t, ³J 9.4, HÀC(6)); 4.98 (br. t, ³J 9.4, HÀC(6'));

3.87, 3.86 (2s, 2 MeOC₆H₄CO); 3.85 (m, HÀC(2')); 2.74 2.56 (m, 2 HÀC(5), 1 HÀC(2)); 2.61 (d, ²J 13.5,

1 H, CH₂ÀC(4)); 2.48 (m, 1HÀC(2)); 2.46 (d, ²J 13.5, 1 H, CH₂ÀC(4)); 2.38 2.34 (m, 1 HÀC(7'),

1 HÀC(7), 1 HÀC(3')); 2.23 1.97 (m, 1 HÀC(7), 1 HÀC(3'), 2 HÀC(5')); 2.04, 1.79 (2s, 2 MeCO); 1.91

(dd, ²J 13.9, J 10.4, HÀC(7')). ¹³C-NMR (100.6 MHz, CDCl₃): 171.1, 170.0 (2s, 2 C, MeCO); 165.2 (s, 2 C,

3

MeOC₆H₄CO); 163.4 (s, 2 C, MeOC₆H₄CO); 136.2 (s, C(4)); 131.7, 131.6 (2d, ¹J 163, 4 C, MeOC₆H₄CO); 127.8

(d, ¹J 159, C(3)); 122.5 (s, 2 C, MeOC₆H₄CO); 113.6, 113.5 (2d, ¹J 161, 4 C, MeOC₆H₄CO); 73.8 (s, C(1'));

71.1 (d, ¹J 141, C(2')); 68.8 (d, ¹J 149, C(1)); 68.2 (d, ¹J 149, C(6)); 67.6 (d, ¹J 149, C(4')); 66.4 (d, ¹J 149,

C(6')); 55.4 (q, ¹J 143, 2 C, MeOC₆H₄CO); 47.7 (t, ¹J 125, CH₂ÀC(4)); 43.1 (t, ¹J 133, C(7')); 41.5 (t, ¹J

130, C(7)); 41.1 (t, ¹J 130, C(5')); 39.6 (t, ¹J 125, C(5)); 35.6 (t, ¹J 124, C(3')); 31.8 (t, ¹J 127, C(2)); 21.3,

20.9 (2q, ¹J 129, 2 C, MeCO). CI-MS (NH₃): 673 (3, [M NH₄] ), 655 (1, [M H] ), 595 (4), 443 (4), 337 (7),

185 (7), 135 (81), 106 (100), 78 (25). Anal. calc. for C₃₅H₄₂O₁₂(654.71): C 64.21, H 6.47, O 29.32; found: C 62.44,

H 6.44 (corresponding to C₃₅H₄₂O₁₂¥ H₂O: C 62.49, H 6.59).

(1S,2R,4S,6S)-4-(Acetyloxy)-2-{{(4S,6S)-6-(acetyloxy)-4-[(4-methoxybenzoyl)oxy]cyclohept-1-en-1-yl}-

methyl}-2-hydroxy-6-[(4-methoxybenzoyl)oxy]cycloheptyl (aR)-a-Methoxy-a-(trifluoromethyl)benzeneacetate

(6M). To a soln. of ()-6 (24.6 mg, 0.036 mmol) in dry CH₂Cl₂(1 ml) was added dropwise Et₃N (10 ml,

0.072 mmol), N,N-dimethylpyridin-4-amine (one crystal), and ()-(S)MTPACl ((aS)-a-methoxy-a-(trifluoro-

methyl)benzeneacetyl chloride; 7 ml, 0.036 mmol). After 3 h (TLC, CH₂Cl₂/MeOH 95 :5), the reaction was

quenched with sat. NaHCO₃soln. (2 ml). The aq. phase was extracted with Et₂O (2 Â 2 ml) and the org. layers

were dried (MgSO₄). The ee was measured on the crude, which was further purified by FC (silica gel, Et₂O/light

petroleum ether 1:1): 6M (31 mg, 99%); 98.3% ee by ¹⁹F-NMR, 97.6% by ¹H-NMR (MeO s of the minor

25

diastereoisomer compared with the ¹³C satellite peaks of the MeO s of the major diastereoisomer). a 12;

589

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a 48; a 72; a 110; a 145 (c 0.07, CH₂Cl₂). UV (MeCN): 265 (18800), 252

(21300), 216 (15800). IR (KBr): 2955, 2845, 1780, 1715, 1605, 1580, 1520, 1450, 1420, 1370, 1315, 1260, 1170,

1100, 1025, 850, 770, 735, 700, 615. ¹H-NMR (400 MHz, CDCl₃): 7.98 (m, 1 MeOC₆H₄CO); 7.55 (m, 2 H,

PhC(CF₃)(MeO)CO); 7.38 (m, 3 H, PhC(CF₃)(MeO)CO); 6.91 (m, 1 MeOC₆H₄CO); 5.43 (t, ³J 6.3,

HÀC(6)); 5.34 (m, HÀC(1), HÀC(4')); 5.21 (dddd, ³J 2.3, 6.3, 8.6, 10.4, 1 HÀC(4)); 5.04 (m, HÀC(6'));

5.01 (dd, ³J 2.8, 10.4, HÀC(2')); 3.84, 3.87 (2s, 2 MeOC₆H₄CO); 3.57 (s, PhC(CF₃)(MeO)CO); 2.65 1.70

(m, 2 HÀC(3'), 2 HÀC(5'), 2 HÀC(7'), 2 HÀC(7), 2 HÀC(5), 2 HÀC(3), CH₂ÀC(2)); 2.05, 2.03 (2s, 2 Me-

CO). ¹³C-NMR (100.6 MHz, CDCl₃): 170.5, 170.3 (2s, 2 C, MeCO); 166.6, 166.3 (2s, 2 C, MeOC₆H₄CO); 165.4

(s, PhC(CF₃)(MeO)CO); 163.6, 163.4 (2s, 2 C, MeOC₆H₄CO); 135.1 (s, C(1')); 132.3 (d, ¹J 162, 4 C,

MeOC₆H₄CO); 130( d, ¹J 161, 2 C, PhC(CF₃)(MeO)CO); 128.4 (s, 1 C, PhC(CF₃)(MeO)CO); 128.1

(d, ¹J 162, 2 C, PhC(CF₃)(MeO)CO); 128.0( d, ¹J 162, C(2')); 127.6 (d, ¹J 162, 1 C, PhC(CF₃)(MeO)CO);

124.3 (s, PhC(CF₃)(MeO)CO); 122.6, 122.2 (2s, 2 C, MeOC₆H₄CO); 113.6 (d, ¹J 161, 4 C, MeOC₆H₄CO); 78.3

(d, ¹J 140, C(6')); 74.1 (s, C(2)); 68.8, 68.3 (d, ¹J 142, 140, C(6), C(4)); 68.0 (d, ¹J 151, C(1)); 66.1 (d, ¹J

149, C(4')); 55.1 (q, ¹J 138, 2 C, MeOC₆H₄CO); 48.9 (t, ¹J 129, CH₂ÀC(2)); 42.0, 40.8, 38.3, 38.0, 33.9, 31.4

(8t, C(3'), C(5'), C(7'), C(3), C(5), C(7)); 21.2 (q, ¹J 162, 2 C, MeCO). ¹⁹F-NMR (376.7 MHz, CDCl₃

CCl₃F): À 71.36 (s, 3 F, CF₃); À 71.54 (s, 3 F, CF₃) for the minor diastereoisomer. CI-MS (NH₃): 888 (100, [M

H₄] ), 654 (21), 570(12), 334 (31), 294 (16), 252 (89), 152 (29), 135 (53), 91 (23). Anal. calc. for C ₄₅H₄₉F₃O₁₄

(870.87): C 62.06, H 5.67, F 6.55, O 25.72; found: C 61.97, H 5.65.

(1R,2S,4R,6R)/(1S,2R,4S,6S)-4-(Acetyloxy)-2-{{(4S,6S)/(4R,6R)-6-(acetyloxy)-4-[(4-methoxybenzoyl)oxy]-

cyclohept-1-en-1-yl}methyl}-2-hydroxy-6-[(4-methoxybenzoyl)oxy]cycloheptyl (aR)-a-Methoxy-a-(trifluoro-

methyl)benzeneacetate (7M). As described for 6M, with ()-7 (20 mg, 0.029 mmol), CH₂Cl₂(1 ml), Et₃N

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(8 ml, 0.058 mmol), DMAP (one cristal), and ()-(S)-MTPACl (6 ml, 0.029 mmol): 7M (31 mg, 99%); 4% ee by

¹⁹F-NMR; the data were also photocopied, and the traces cut and weighted: 1% ee. ¹H-NMR (400 MHz,

CDCl₃): 8.07, 7.98 (2 m, 8 H, MeOC₆H₄CO₃) 7.54 (2m, 4 H, PhC(CF₃)(MeO)CO); 7.54 (2m, 6 H,

Ph(CF₃)(MeO)CO); 6.94, 6.90(2 m, 8 H, MeOC₆H₄CO); 5.62, 5.53 (2t, ³J 6.2, 6.2, 2 H, HÀC(2')); 5.41,

5.34 5.26, 5.13 4.89 (3m, 8 H, HÀC(4'), HÀC(6), HÀC(6'), HÀC(4)); 3.86, 3.85, 3.85, 3.84 (4s, 12 H,

MeOC₆H₄CO); 3.57, 3.52 (2s, 6 H, PhC(CF₃)(MeO)CO); 3.20 1.9 ( m, 28 H, 7 CH₂); 2.02, 2.01, 1.80, 1.78

(4s, 12 H, MeCO). ¹⁹F-NMR (376.7 MHz, CDCl₃ CCl₃F): À 71.49 (s, 3 F, CF₃); À71.43 (s, 3 F, CF₃) for the

minor diastereoisomer. CI-MS (NH₃): 888 (100, [M NH₄] ), 654 (14), 570(10), 334 (62), 294 (32), 252 (82),

170(87), 135 (46), 105 (18), 91 (26), 77 (10).

(1S,6S)-6-Hydroxy-4-{{(1R,2S,4S,6S)-1,2,6-trihydroxy-4-[(4-methoxybenzoyl)oxy]cycloheptyl}methyl}cy-

clohept-3-en-1-yl 4-Methoxybenzoate ((À)-8). To a soln. of ()-6 (4 g, 6.1 mmol) in anh. MeOH (200 ml) was

added dropwise 0.65m Mg(OMe)₂(76 ml, 49 mmol) in MeOH. The reaction was complete within 5 h (TLC,

CH₂Cl₂/MeOH 95 :5) and was quenched with oxalic acid (4.4 g, 49 mmol). The soln. was stirred for 10min and,

without stirring, cooled to 08 for 1 h. The soln. was filtered over a Celite pad and the filtrate evaporated: (À)-8

(3.34 g, 97%) as a white solid pure enough for the next step. For analysis, the product was purified by FC (silica

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gel, CH₂Cl₂/MeOH 92 :8). a À9; a À10; a À10; a À 16; a À19 (c 0.28, CH₂Cl₂).

UV (MeCN): 254 (14500), 202 (11800). IR (KBr): 3510, 3335, 2940, 2845, 1705, 1695, 1605, 1510, 1460, 1420,

1320, 1285, 1255, 1170, 1120, 1105, 1020, 985, 845, 770, 695, 665, 605. ¹H-NMR (400 MHz, CD₃OD): 7.95

(m, 1 MeOC₆H₄CO); 6.98 (m, 1 MeOC₆H₄CO); 5.63 (t, ³J 6.7, 1 HÀC(3)); 5.25 5.19 (m, HÀC(1),

HÀC(4')); 4.25 (dddd, ³J 9.5, 5.0, 4.9, 2.7, HÀC(6)); 4.12 (m, HÀC(6')); 3.86, 3.84 (s, 2 MeOC₆H₄CO); 3.53

(dd, ³J 10.9, 2.5, HÀC(2')); 2.69 (dd, ²J 14.8, ³J 9.5, 1 HÀC(5)); 2.66 (d, ²J 12.7, 1 H, CH₂ÀC(4)); 2.61

2.51 (m, 1 HÀC(5), 2 HÀC(2)); 2.34 (ddd, ²J 13.3, ³J 10.9, 10.9, 1 HÀC(3')); 2.21 (d, ²J 12.8, 1 H,

CH₂ÀC(4)); 2.26 2.14 (m, 2 HÀC(7), 1 HÀC(7'), 1 HÀC(5')); 2.03 (dd, ³J 8.2, 6.2, 1 HÀC(7')); 1.98

(m, 1 HÀC(3')); 1.61 (dd, ²J 14.5, ³J 10.5, 1 HÀC(5')). ¹³C-NMR (100.6 MHz, CD₃OD): 165.5 (s, 2 C,

MeOC₆H₄CO); 165.1 (s, 2 C, MeOC₆H₄CO); 139.6 (s, C(4)); 132.5 (d, ¹J 170, 4 C, MeOC₆H₄CO); 127.6

(d, ¹J 158, C(3)); 124.1 (s, 2 C, MeOC₆H₄CO); 114.8 (d, ¹J 162, 4 C, MeOC₆H₄CO); 76.0( s, C(1')); 74.0

(d, ¹J 138, C(2')); 70.5, 70.4 (2d, ¹J 159, C(1), C(4')); 67.1 (d, ¹J 139, C(6')); 64.4 (d, ¹J 143, C(6)); 56.0

(q, ¹J 144, 2 C, MeOC₆H₄CO); 50.8 (t, ¹J 128, CH₂ÀC(4)); 45.8 (t, ¹J 127, C(7)); 45.0( t, C(5')); 43.4 (t, ¹J

115, C(7')); 41.6 (t, C(5)); 38.5 (t, ¹J 127, C(3')); 34.4 (t, ¹J 127, C(2)). CI-MS (NH₃): 588 (7, [M NH₄] ),

419 (3), 277 (25), 152 (44), 135 (100), 107 (36). Anal. calc. for C₃₁H₃₈O₁₀(570.64): C 65.25, H 6.71, O 28.04;

found: C 65.19, H 6.79.

(3aS,5S,7S,8aR)-Hexahydro-7-hydroxy-8a-{{(4S,6S)-6-hydroxy-4-[(4-methoxy)benzoyl)oxy]cyclohept-1-

en-1- yl}methyl}-2,2-dimethyl-4H-cyclohepta[d]-1,3-dioxol-5-yl 4-Methoxybenzoate ((À)-9). To a soln. of (À)-8

(20 mg, 0.037 mmol) was added pyridinium p-toluenesulfonate (PPTS; 1 mg, 3.7 ¥ 10^À3mmol) and a soln. of

20% 2,2-dimethoxypropane/acetone (1 ml). The reaction was complete after 4 h at 608 (TLC, CH₂Cl₂/MeOH

95 :5). Evaporation and purification by FC (silica gel, CH₂Cl₂/MeOH 95 :5) afforded (À)-9 (18 mg, 80%).

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White foam. a À18; a À30; a À34; a À56; a À65 (c 0.11, CH₂Cl₂). IR (KBr):

3435, 2935, 1705, 1605, 1515, 1460, 1380, 1280, 1255, 1170, 1105, 1030, 850, 770, 730, 695, 610. UV (MeCN): 252

(40700), 207 (34200). ¹H-NMR (400 MHz, CDCl₃; numbering of (À)-8): 8.04 (d, ³J 9.1, 2 H, MeOC₆H₄CO);

7.91 (d, ³J 8.6, 2 H, MeOC₆H₄CO); 6.91 (d, ³J 9.1, 2 H, MeOC₆H₄CO); 6.89 (d, ³J 8.6, 2 H, MeOC₆H₄CO);

5.75 (dd, ³J 5.4, 8.1, 1 HÀC(3)); 5.37 (br. m, HÀC(4')); 5.22 (tt, ³J 2.7, 9.7, HÀC(1)); 4.34 (br. d, ³J 8.6,

HÀC(6)); 4.23 (br. s, HÀC(6')); 4.16 (d, ³J 6.4, HÀC(2')); 3.86 (2s, 2 MeOC₆H₄CH); 2.72 (t, ³J 6.4,

2 HÀC(3')); 2.68 (m, 1 HÀC(5)); 2.53 (m, 2 HÀC(2)); 2.56 2.32 (m, 1 HÀC(7), 1 HÀC(7'), 1 HÀC(5'),

CH₂ÀC(4)); 2.00 1.80 (m, 1 HÀC(7), 1 HÀC(5'), 1 HÀC(5), 1 HÀC(7')); 1.55, 1.44 (2s, Me₂CO₂). ¹³C-NMR

(100.6 MHz, CDCl₃; numbering of (À)-8): 165.6, 165.4 (s, 2 C, MeOC₆H₄CO); 163.2 (2s, 2 C, MeOC₆H₄CO);

136.9 (s, C(4)); 131.8, 131.5 (2d, ¹J 163, 4 C, MeOC₆H₄CO); 127.3 (d, ¹J 156, C(3)); 123.1, 123.0(2 s, 2 C,

MeOC₆H₄CO); 113.5, 113.4 (2d, ¹J 163, 4 C, MeOC₆H₄CO); 107.5 (s, Me₂CO₂); 83.6 (s, C(1')); 82.5 (d, ¹J

144, C(2')); 68.3 (d, ¹J 151, C(1)); 68.1 (d, ¹J 151, C(4')); 66.6 (d, ¹J 145, C(6')); 63.5 (d, ¹J 145, C(6)); 55.4

(q, ¹J 145, 2 C, MeOC₆H₄CO); 53.7 (t, ¹J 128, CH₂ÀC(4)); 46.8 (t, ¹J 127, C(5)); 44.2, 44.0( t, ¹J 127, 2 C,

C(7), C(5')); 39.8 (t, ¹J 125, C(2)); 34.3 (t, ¹J 130, C(3')); 31.8 (t, ¹J 125, C(7')); 27.8, 26.2 (2q, ¹J 125,

Me₂CO₂). CI-MS (NH₃): 629 (4, [M NH₄] ), 335 (13), 227 (6), 183 (23), 135 (100). Anal. calc. for C₃₄H₄₂O₁₀

(610.70): C 66.87, H 6.93, O 26.20; found: C 67.06, H 7.10.

(2R and 2S,4S,6S) Tetrahydro-2-hydroxy-6-{3-{(4S,6S)-6-hydroxy-4-[(4-methoxybenzoyl)oxy]cyclohept-1-

en-1-yl}-2-oxopropyl}-2H-pyran-4-yl4-Methoxybenzoate (()-10). To a soln. of (À)-8 (1.77 g, 3.1 mmol) in

dioxane (40ml) was added a soln. of NaIO ₄(9 ml, 5.58 mmol) in H₂O (660mg per 5 ml). After stirring

overnight (TLC, CH₂Cl₂/MeOH 95 :5), the soln. was diluted with sat. NaCl soln. (20ml) and extracted with

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Helvetica Chimica Acta Vol. 87 (2004)

AcOEt (3 Â 75 ml). The org. phase was dried (Na₂SO₄) and evaporated: 1.74 g (99%) of crude ()-10.

Purification by FC (silica gel, CH₂Cl₂/MeOH 98 :2) afforded pure anomer mixture ()-10 (1.55 g, 88%). White

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solid. a 35; a 37; a 40; a 66; a 79 (c 0.13, CH₂Cl₂). UV (MeCN): 264

(11100), 246 (12700), 214 (10400). IR (KBr): 3425, 2935, 1715, 1605, 1510, 1420, 1260, 1170, 1105, 1030, 850, 770,

1

700, 615. H-NMR (400 MHz, CDCl₃)⁴): 7.99 (m, 1 MeOC₆H₄CO); 6.92 (m, 1 MeOC₆H₄CO); 5.71 (t, ³J 6.6,

HÀC(2'')); 5.50( m, 2 H, HÀC(4)(a/b), HÀC(2)(a)); 5.25 (m, 1 H, HÀC(4'')); 5.16 (tt, ³J 11.5, 4.6, 1 H,

HÀC(4)(a/b)); 4.89 (br. d, ³J 9.3, 1 H, HÀC(2)(b)); 4.65 (m, 1 H, HÀC(6)(a/b)); 4.16 (m, 1 H, HÀC(6''));

4.06 (m, 1 H, HÀC(6)(a/b)); 3.87, 3.85 (s, 6 H, MeOC₆H₄CO); 3.37 (d, ²J 16.2, 1 H, HÀC(1')); 3.32 (d, ²J

16.2, 1 H, HÀC(1')); 2.94 (dd, ²J 15.5, ³J 9.1, 1 H, HÀC(3')); 2.81 (dd, ²J 15.5, ³J 9.5, 1 H, HÀC(3'));

2.60 2.44 ( m, 4 H, HÀC(3''), HÀC(7'')); 2.43 2.36 (m, 2 H, HÀC(3)(a/b)); 2.34 2.07 (m, 6 H, HÀC(5''),

HÀC(5)(a/b), HÀC(3)(a/b)); 1.74 (ddd, ²J 11.8, ³J 3.4, 3.4, HÀC(5)(a/b)); 1.61 1.43 (m, HÀC(5)(a/b),

HÀC(3)(a/b). ¹³C-NMR (100.6 MHz, CDCl₃)⁴): 208.5 (s, C(2')); 165.6, 165.5 (s, 2 C, MeOC₆H₄CO); 163.3

(s, 2 C, MeOC₆H₄CO); 133.7 (s, C(1'')); 131.6 (d, ¹J 163, 4 C, MeOC₆H₄CO); 127.0( d, ¹J 156, C(2'')); 123.0,

122.7 (2s, 2 C, MeOC₆H₄CO); 113.6 (d, ¹J 162, 4 C, MeOC₆H₄CO); 94.2, 92.3 (2d, ¹J(b) 189, ¹J(a) 167,

C(2)); 68.7 (d, C(4)); 68.5 (d, C(4'')); 68.4 (d, C(6)(b)); 66.7 (d, C(4)); 65.7 (d, C(6'')); 64.3 (d, C(6)(a)); 55.4

(q, ¹J 145, 2 C, MeOC₆H₄CO); 55.0, 54.6 (t, C(1')); 47.9, 47.4 (2t, ¹J 128, C(3')); 44.6 (t, ¹J 127, C(5'')); 39.6

(t, ¹J 125, C(7'')); 38.1, 37.2 (C(3)); 36.2, 35.6 (C(5)); 33.3 (t, ¹J 128, C(3'')). CI-MS (NH₃): 586 (4, [M

NH₄] ]), 568 (4, [M H] ), 399 (20), 301 (10), 251 (10), 229 (9), 170 (57), 135 (100).

(1S,6S)-6-Hydroxy-4-{(2S,4R,6R)-2,4,8-trihydroxy-6-[(4-methoxybenzoyl)oxy]octyl}cyclohept-3-en-1-yl 4-

Methoxybenzoate (()-11). To a soln. of ()-10 (1.83 g, 3.2 mmol) in AcOH (40ml) was added Me ₄NBH(OAc)₃

(12.7 g, 48.2 mmol). After 24 h under stirring (TLC, CH₂Cl₂/MeOH 9 :1), the AcOH was completely

evaporated, and a mixture of H₂O and crushed ice (50ml) was added slowly to the residue. After 10min under

stirring, solid NaHCO₃(4 g) was added portionwise, and the soln. was stirred for another 20min. After

extraction of the aq. phase with AcOEt (5 Â 50ml), the org. layer was dried (Na ₂SO₄), and the product was

deposited on silica gel. Purification by FC (silica gel, CH₂Cl₂/MeOH 95 :5) afforded ()-11 (1.28 g, 70%). White

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solid. a 22; a 12; a 13; a 8; a 8 (c 0.14, CH₂Cl₂). UV (MeCN): 254

(45300), 201 (53000). IR (KBr): 3360, 2940, 1685, 1605, 1510, 1460, 1420, 1255, 1170, 1120, 1025, 845, 770, 695.

¹H-NMR (400 MHz, CD₃OD): 7.96 (m, 1 MeOC₆H₄CO); 6.90( m, 1 MeOC₆H₄CO); 5.65 (t, ³J 6.7, HÀC(3));

5.48 (dddd, ³J 8.6, 8.6, 5.2, 4.3, HÀC(6')); 5.17 (m, HÀC(1)); 4.68 (m, HÀC(6)); 4.09 (m, HÀC(2')); 3.98

(m, HÀC(4')); 3.85, 3.83 (s, 2 MeOC₆H₄CO); 3.76 3.62 (m, 2 HÀC(8')); 2.59 (dd, ²J 14.8, ³J 7.4,

1 HÀC(5)); 2.50, 2.46 (m, 1 HÀC(5), 2 HÀC(2)); 2.29 (ddd, ²J 13.6, ³J 6.2, 3.4, 1 HÀC(7)); 2.18

(dd, ²J 13.1, ³J 2.7, 1 HÀC(1')); 2.07 (d, ²J 13.1, 1 HÀC(1')); 2.11 2.03 (m, 1 HÀC(7'), 1 HÀC(7)); 1.94

(dddd, ²J 7.9, J 5.2, 5.2, 5.2, 1 HÀC(7')); 1.86 1.83 (m, 2 HÀC(5')); 1.64 1.61 (m, 2 HÀC(3')). ¹³C-NMR

3

(100.6 MHz, CD₃OD): 167.4, 165.6 (2s, 2 C, MeOC₆H₄CO); 163.6, 163.3 (2s, 2 C, MeOC₆H₄CO); 139.2 (s, C(4));

131.8, 131.5 (2d, ¹J 164, 165, 4 C, MeOC₆H₄CO); 124.2 (d, ¹J 155, C(3)); 122.9, 122.1 (2s, 2 C, MeOC₆H₄-

CO); 113.7, 113.5 (d, ¹J 161, 4 C, MeOC₆H₄CO); 69.5 (d, ¹J 145, C(2')); 69.4 (d, ¹J 145, C(6')); 68.6 (d, ¹J

151, C(1)); 66.2 (d, ¹J 149, C(6)); 65.2 (d, ¹J 140, C(4')); 58.6 (t, ¹J 140, C(8')); 55.4 (q, ¹J 145, 2 C,

MeOC₆H₄CO); 48.4 (t, ¹J 122, C(1')); 44.7 (t, ¹J 122, C(7)); 42.8 (t, ¹J 119, C(3')); 42.7 (t, ¹J 122, C(5'));

39.6 (t, ¹J 121, C(5)); 38.0( t, ¹J 120, C(7')); 33.5 (t, ¹J 122, C(2)). CI-MS (NH₃): 590(10, [ M NH₄] ), 573

(69, [M H] ), 421 (6), 297 (25), 233 (18), 135 (100), 92 (25). Anal. calc. for C₃₁H₄₀O₁₀(572.65): C 65.02, H 7.04,

O 27.94; found: C 64.99, H 7.00.

(1S,6S)-6-Hydroxy-4-{{(4S,6R)-6-{(2R)-4-hydroxy-2-[(4-methoxybenzoyl)oxy]butyl}-2,2-dimethyl-1,3-di-

oxan-4-yl}methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate (()-12). To a soln. of ()-11 (1.28 g, 2.23 mmol) in

50% 2,2-dimethoxypropane/acetone (40 ml), was added PPTS (56 mg, 0.22 mmol). After 24 h under stirring

(TLC, CH₂Cl₂/MeOH 95 :5), the soln. was evaporated, the crude product dissolved in CH₂Cl₂/MeOH 98 :2

(20ml), and PPTS added (56 mg, 0.22 mmol). The selective deprotection of the acetal at C(4 ''') was followed by

TLC to keep the acetonide intact. The reaction was quenched by addition of solid NaHCO₃(100 mg), and the

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a 30; a 37; a 71; a 92 (c 0.18, CH₂Cl₂). UV (MeCN): 252 (20200), 210 (13400).

IR (KBr): 3450, 2935, 1705, 1605, 1510, 1260, 1170, 1105, 1030, 850, 770, 695, 610. ¹H-NMR (400 MHz, CDCl₃):

8.01 7.94 (m, 1 MeOC₆H₄CO); 6.94 6.88 (m, 1 MeOC₆H₄CO); 5.63 (t, ³J 6.6, HÀC(3)); 5.46 (dddd, ³J 9.8,

9.8, 3.2, 3.2, HÀC(2''')); 5.16 (dddd, ³J 9.7, 9.7, 3.9, 3.8, HÀC(1)); 4.06 (m, HÀC(6)); 3.99 (m, HÀC(4'')); 3.91

(m, HÀC(6'')); 3.86, 3.84 (s, 2 MeOC₆H₄CO); 3.79 3.55 (m, 2 HÀC(4''')); 2.91 (br. s, OHÀC(4''')); 2.53 (br.

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Helvetica Chimica Acta Vol. 87 (2004)

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s, OHÀC(6)); 2.51 2.42 (m, 2 HÀC(2), 2 HÀC(5)); 2.26 2.09 (m, 2 HÀC(7), 2 HÀC(1')); 1.98 1.87

(m, 1 HÀC(3'''), 1 HÀC(1''')); 1.81 1.72 (m, 1 HÀC(3'''), 1 HÀC(1''')); 1.64 (ddd, ²J 21.7, ³J 12.8, 8.9,

1 HÀC(5'')); 1.63 (ddd, ²J 21.7, ³J 12.8, 9.0, 1 HÀC(5'')); 1.31, 1.14 (s, Me₂C(2'')). ¹³C-NMR (100.6 MHz,

CDCl₃): 167.0, 165.5 (2s, 2 C, MeOC₆H₄CO); 163.5, 163.2 (2s, 2 C, MeOC₆H₄CO); 137.5 (s, C(4)); 131.6, 131.5

(2d, ¹J 164, 4 C, MeOC₆H₄CO); 123.9 (d, ¹J 167, C(3)); 123.1, 122.2 (2s, 2C, MeOC₆H₄CO); 113.7, 113.5

(d, ¹J 161, 4 C, MeOC₆H₄CO); 100.8 (s, C(2'')); 68.7 (d, ¹J 151, C(1)); 68.3 (d, ¹J 149, C(2''')); 66.9 (d, ¹J

143, C(4'')); 65.9 (d, ¹J 143, C(6)); 63.0( d, ¹J 143, C(6'')); 58.2 (t, ¹J 140, C(4''')); 55.4 (q, ¹J 145, 2 C,

MeOC₆H₄CO); 45.9 (t, ¹J 120, C(1')); 44.8 (t, ¹J 120, C(7)); 40.9 (t, ¹J 131, C(1''')); 40.6 (t, ¹J 128, C(5));

38.4 (t, ¹J 126, C(5'')); 38.2 (t, ¹J 126, C(3''')); 33.1 (t, ¹J 128, C(2)); 24.4, 24.3 (2q, ¹J 128, 2 C, Me₂C(2'')).

CI-MS (NH₃): 613 (15, [M H] ), 555 (66), 401 (8), 279 (58), 135 (100). Anal. calc. for C₃₄H₄₄O₁₀(612.72): C

66.65, H 7.24, O 26.11; found: C 66.64, H 7.19.

(1S,6S)-6-Hydroxy-4-{(2R,4R,6R)-2,4,8-trihydroxy-6-[(4-methoxybenzoyl)oxy]octyl}cyclohept-3-en-1-yl

4-Methoxybenzoate ((À)-13). A soln. of ()-10 (200 mg, 0.35 mmol) in anh. THF/MeOH 4 :1 (2 ml) was cooled

to À 788 and a 1m Et₂BOMe in THF (1.75 ml, 1.75 mmol) was added dropwise. After 2 h, the soln. was allowed

to warm to À 208, and NaBH₄(40mg, 1.05 mmol) was added. Two further amounts of NaBH (40mg,

4

1.05 mmol) were added every 2 h until the reaction was almost complete (TLC, CH₂Cl₂/MeOH 9 :1). After

dilution with AcOEt (8 ml), the reaction was quenched with AcOH (200 ml) and H₂O (8 ml). The soln. was

neutralized by addition of NaHCO₃, the aq. layer extracted with AcOEt (4 Â 4 ml), the org. soln. dried

(Na₂SO₄), and the product deposited on silica gel. Purification by FC (silica gel, CH₂Cl₂/MeOH 95 :5) afforded

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(À)-13 (130mg, 65%). White solid. a À12; a À16; a À19; a À25; a À47 (c 0.03,

CHCl₃). UV (MeCN): 265 (13000), 248 (14900), 214 (12200). IR (KBr): 3405, 2935, 1705, 1605, 1510, 1420,

1260, 1170, 1105, 1030, 850, 770, 700, 610. ¹H-NMR (400 MHz, CDCl₃): 7.97 (m, 1 MeOC₆H₄CO); 6.91

(m, 1 MeOC₆H₄CO); 5.70( dd, ³J 7.7, 5.9, HÀC(3)); 5.48 (m, HÀC(6')); 5.12 (dddd, ³J 10.3, 10.3, 2.8, 2.8,

HÀC(1)); 4.20(br. s, HÀC(6)); 4.05 (m, HÀC(2')); 3.91 (m, HÀC(4')); 3.86, 3.85 (2s, 2 MeOC₆H₄CO); 3.70

(m, 2 HÀC(8')); 2.45 (m, 2 HÀC(5), 2 HÀC(2), 1 HÀC(7)); 2.10( d, ³J 6.7, 2 HÀC(1')); 1.98 1.93

(m, 2 HÀC(7'), 1 HÀC(7)); 1.81 (dd, ³J 6.4, 6.4, 2 HÀC(5')); 1.57 (m, 2 HÀC(3')). ¹³C-NMR (100.6 MHz,

CDCl₃): 167.1, 165.5 (2s, 2 C, MeOC₆H₄CO); 163.5, 163.2 (2s, 2 C, MeOC₆H₄CO); 137.4 (s, C(4)); 131.8, 131.5

(2d, ¹J 163, 4 C, MeOC₆H₄CO); 124.9 (d, ¹J 154, C(3)); 122.9, 122.2 (2s, 2 C, MeOC₆H₄CO); 113.6, 113.4

(2d, ¹J 166, 4 C, MeOC₆H₄CO); 69.2 (d, ¹J 147, C(6')); 68.5 (2d, ¹J 141, C(4'), C(2')); 68.2 (d, ¹J 152,

C(1)); 65.9 (d, ¹J 143, C(6)); 58.5 (t, ¹J 143, C(8')); 55.4, 55.3 (2q, ¹J 144, 2 C, MeOC₆H₄CO); 48.4 (t, ¹J

128, C(1')); 44.9 (t, ¹J 133, C(7)); 43.1 (t, ¹J 126, C(5')); 42.5 (t, ¹J 126, C(3')); 38.0( t, ¹J 127, C(7')); 36.5

(t, ¹J 123, C(5)); 34.1 (t, ¹J 126, C(2)). CI-MS (NH₃): 590(23, [ M NH₄] ), 573 (100, [M H] ), 421 (6),

297 (17), 233 (7), 135 (74), 92 (19). Anal. calc. for C₃₁H₄₀O₁₀(572.65): C 65.02, H 7.04, O 27.94; found: C 64.99,

H 6.87.

(1S,6S)-6-Hydroxy-4-{{(4R,6R)-6-{(2R)-4-hydroxy-2-[(4-methoxybenzoyl)oxy]butyl}-2,2-dimethyl-1,3-di-

oxan-4-yl}methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate (()-14). To a soln. of (À)-13 (1.00 g, 1.74 mmol) in

50% 2,2-dimethoxypropane/acetone (10 ml) was added PPTS (44 mg, 0.17 mmol) at 08. After stirring overnight

(TLC, CH₂Cl₂/MeOH 95 :5), the soln. was evaporated and the residue dissolved in CH₂Cl₂/MeOH 97:3 (10ml)

in the presence of additional PPTS (22 mg, 0.08 mmol). The selective deprotection of the acetal at C(4'') was

followed by TLC (CH₂Cl₂/MeOH 95 :5) to avoid complete deprotection. After 10min, the reaction was

quenched with NaHCO₃(80mg), and the product was deposited on silica gel. Purification by FC (silica gel,

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CH₂Cl₂/MeOH 95 :5) afforded ()-14 (1.06 g, 78%). White foam. a 9; a 5; a 3; a

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3; a 2 (c 0.20, CH₂Cl₂). UV (MeCN): 251 (37400), 209 (28900). IR (KBr): 3460, 1705, 1605, 1510,

1460, 1420, 1380, 1260, 1170, 1105, 1030, 975, 850, 770, 695, 615. ¹H-NMR (400 MHz, CDCl₃): 7.97

(m, 1 MeOC₆H₄CO); 6.92 (m, 1 MeOC₆H₄CO); 5.64 (dd, ³J 6.6, 6.6, HÀC(3)); 5.48 (m, HÀC(2''')); 5.16

(dddd, ³J 8.8, 8.8, 3.4, 3.4, 1 HÀC(1)); 4.06 (m, HÀC(6)); 3.99 (m, HÀC(4''), HÀC(6'')); 3.86, 3.84

(2s, 2 MeOC₆H₄CO); 3.69 3.57 (m, 2 HÀC(4''')); 2.45 (m, 2 HÀC(5), 2 HÀC(2)); 2.29 (ddd, ²J 13.3, ³J

6.2, 3.4, HÀC(7)); 2.21 (dd, ²J 13.9, ³J 7.3, 1 HÀC(1')); 2.15 (dd, ²J 13.9, ³J 4.8, 1 HÀC(1')); 2.05

(ddd, ²J 13.3, ³J 8.8, 2.8, 1 HÀC(7)); 1.95 (dddd, ²J 14.4, ³J 9.3, 5.6, 3.6, 1 HÀC(3''')); 1.88 1.74

(m, 1 HÀC(5''), 1 HÀC(3'''), 2 HÀC(1''')); 1.45 (ddd, ²J 12.9, ³J 2.5, 2.5, 1 HÀC(5'')); 1.36, 1.27

(2s, Me₂C(2'')). ¹³C-NMR (100.6 MHz, CDCl₃): 166.9, 165.4 (2s, 2 C, MeOC₆H₄CO); 163.6, 163.2 (2s, 2 C,

MeOC₆H₄CO); 136.4 (s, C(4)); 131.7, 131.5 (2d, ¹J 164, 4 C, MeOC₆H₄CO); 125.3 (d, ¹J 161, C(3)); 123.1,

122.2 (2s, 2 C, MeOC₆H₄CO); 113.7, 113.5 (2d, ¹J 161, 4 C, MeOC₆H₄CO); 99.1 (s, C(2'')); 68.4 (d, ¹J 125,

C(1)); 68.3 (d, ¹J 133, C(2''')); 67.1 (d, ¹J 131, C(4'')); 65.8 (d, ¹J 135, C(6)); 65.5 (d, ¹J 141, C(6'')); 58.3

(t, ¹J 140, C(4''')); 55.4 (q, ¹J 145, 2 C, MeOC₆H₄CO); 46.8 (t, ¹J 121, C(1')); 44.8 (t, ¹J 120, C(7)); 41.6

(t, ¹J 127, C(1''')); 38.8 (t, ¹J 126, C(5)); 38.2 (t, ¹J 125, C(3''')); 36.8 (t, ¹J 128, C(5'')); 33.6 (t, ¹J 126,

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Helvetica Chimica Acta Vol. 87 (2004)

C(2)); 29.9, 19.3 (2q, ¹J 126, 123, 2 C, Me₂C(2'')). CI-MS (NH₃): 613 (5, [M H] ), 555 (30), 279 (70), 233

(7), 135 (100). Anal. calc. for C₃₄H₄₄O₁₀(612.72): C 66.65, H 7.24, O 26.11; found: C 66.62, H 7.34.

(1S,3S)-5-{{(4S,6S)-6-[(2R)-2,4-Dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}methyl}cyclohept-5-ene-1,3-

diol (()-15). A soln. of CH₂Cl₂(30ml) containing ( )-12 (1.11 g, 1.81 mmol) was cooled to À 788, and 1m

DIBAL-H in CH₂Cl₂(5.1 ml, 5.10mmol) was added dropwise over 10min ( the hydride supplied by Sigma-

Aldrich gave better results than the one from Fluka). The same quantity of reagent was added two more times,

after 1 h intervals, while the temp. rose to À 308. After 7 h overall reaction time, the mixture was cooled to

À 788, and the reaction was quenched with MeOH (50ml). The soln. was stirred for 1 h 20and then evaporated.

The product was left over silica gel. FC (silica gel, CH₂Cl₂/MeOH 9 :1) afforded ()-15 (548 mg, 88%). White

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solid. a 32; a 32; a 38; a 63; a 80( c 0.05, MeOH). UV (MeCN): 255

(1200), 212 (2200). IR (KBr): 3380, 2935, 1690, 1605, 1510, 1445, 1380, 1260, 1225, 1165, 1095, 1035, 940, 905,

810, 735, 700. ¹H-NMR (400 MHz, CD₃OD): 5.54 (t, ³J 6.9, HÀC(6)); 4.10( dtd, ³J 2.5, 7.4, 10.4, HÀC(4''));

4.06 3.83 (m, HÀC(1), HÀC(3), HÀC(6''), HÀC(2''')); 3.78 (t, ³J 6.4, 2 HÀC(4''')); 2.40( m, 2 HÀC(4));

2.32 (m, 2 HÀC(7)); 2.25 (dd, ³J 7.4, ²J 13.8, 1 HÀC(1')); 2.17 (dd, ³J 5.9, ²J 13.8, 1 HÀC(1')); 2.02

(m, 2 HÀC(2)); 1.72 1.47 (m, 2 HÀC(5''), 2 HÀC(1'''), 2 HÀC(3''')); 1.37, 1.35 (2s, Me₂C(2∫)). ¹³C-NMR

(100.6 MHz, CD₃OD): 139.0( s, C(2'')); 125.9 (d, ¹J 155, C(6)); 102.5 (s, C(5)); 67.7, 67.5, 67.3, 67.1 (4d, ¹J 144,

143, 144, 144, 4 C, C(3), C(1), C(6''), C(2''')); 65.7 (d, ¹J 146, C(4'')); 60.9 (t, ¹J 140, C(4''')); 50.8 (t, C(2));

48.5 (t, ¹J 125, C(1')); 45.6 (t, ¹J 123, C(5'')); 42.4, 42.3 (2t, ¹J 124, 124, C(4), C(3''')); 40.4 (t, ¹J 127,

C(1''')); 37.3 (t, ¹J 122, C(7)); 26.1, 26.0(2 q, ¹J 126, 2 C, Me₂C(2'')). CI-MS (NH₃): 362 (32, [M NH₄] ), 345

(100, [M H] ), 287 (79), 267 (27), 203 (11), 121 (34), 83 (17). Anal. calc. for C₁₈H₃₂O₆(344.45): C 62.77, H

9.36, O 27.87; found: C 62.65, H 9.27.

(1S,3S)-5-{{(4R,6S)-6-[(2R)-2,4-Dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}methyl}cyclohept-5-ene-

1,3-diol (()-17). As described for ()-15, with ()-14 (500 mg, 0.81 mmol), CH₂Cl₂(15 ml), and 1m DIBAL-H

in CH₂Cl₂(2.2 ml, 2.2 mmol). After quenching with MeOH (25 ml), the soln. was stirred for 1 h at 208 in the

presence of silica gel and then evaporated. FC (silica gel, CH₂Cl₂/MeOH 9 :1) gave ()-17 (231 mg, 83%).

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White foam. a 3; a 5; a 5; a 15; a 30( c 0.04, MeOH). UV (MeCN):

201 (9200). IR (KBr): 3385, 2990, 2940, 1650, 1430, 1385, 1265, 1200, 1165, 1090, 1040, 980, 930, 870, 735.

¹H-NMR (400 MHz, CD₃OD): 5.50( t, ³J 6.5, HÀC(6)); 4.15 (ddt, ³J 2.9, 5.5, 11.3, HÀC(4'')); 4.06 (dtd, ³J

2.3, 6.4, 13.5, HÀC(6'')); 3.96 3.86 (m, HÀC(1), HÀC(3), HÀC(2''')); 3.67 (t, ³J 6.4, 2 HÀC(4''')); 2.34

(dd, ³J 6.1, 14.5, 2 HÀC(2)); 2.28 (t, ³J 6.5, 2 HÀC(7)); 2.20( dd, ³J 6.4, ²J 13.5, 1 HÀC(1')); 2.10

(dd, ³J 6.1, ²J 13.5, 1 HÀC(1')); 1.97 (t, ³J 5.6, 2 HÀC(4)); 1.62 (m, 2 HÀC(3''')); 1.51 (m, 2 HÀC(1'''));

1.46, 1.32 (2s, Me₂C(2'')); 1.12 (m, 2 HÀC(5'')). ¹³C-NMR (100.6 MHz, CD₃OD): 137.2 (s, C(5)); 125.6 (d, ¹J

155, C(6)); 100.0 (s, C(2'')); 67.7 (d, ¹J 138, C(6'')); 67.3 (d, ¹J 142, C(4'')); 66.7, 66.5, 66.0(3 d, ¹J 141, 144,

140, C(3), C(1), C(2''')); 60.1 (t, ¹J 144, C(4''')); 49.8 (t, C(1')); 49.2 (t, C(4)); 45.4 (t, ¹J 125, C(1''')); 41.5

(t, ¹J 123, C(3''')); 41.2 (t, ¹J 125, C(2)); 38.5 (t, ¹J 126, C(5'')); 36.6 (t, ¹J 126, C(7)); 30.5, 20.2 (2q, ¹J

126, 2 C, Me₂C(2'')). CI-MS (NH₃): 362 (47, [M NH₄] ), 345 (100, [M H] ), 305 (23), 287 (72), 267 (19), 121

(26), 83 (22). Anal. calc. for C₁₈H₃₂O₆(344.45): C 62.77, H 9.36, O 27.87; found: C 62.64, H 9.16.

1-{(4R,6S)-6-[(2R)-2,4-Dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}-3-[(2R,4R)-tetrahydro-4,6-dihy-

droxy-2H-pyran-2-yl]propan-2-one (()-18). To a soln. of ()-15 (548 mg, 1.59 mmol) in acetone/H₂O 8 :1

(30ml) containing NMO (644 mg, 4.77 mmol) at 20 8 was added 0.1m OsO₄in CCl₄(6.36 ml, 0.64 mmol). After

24 h stirring, the soln. was quenched with Na₂SO₃(600 mg, 4.77 mmol) and MeOH (5 ml). After 2 h stirring, the

soln. was dried (Na₂SO₄) and evaporated. The residue, a 1 :1 diastereoisomer mixture, was used without further

purification for the next step.

To a soln. of the dihydroxylated product (601 mg, 1.59 mmol) in MeOH (30 ml) was added Pb(OAc)₄

(3.52 g, 7.95 mmol) at 208. The reaction was complete after 10min and quenched with NaHCO ₃(133 mg,

1.59 mmol) and Na₂SO₃(200 mg, 1.59 mmol). After evaporation, the product was left over silica gel. FC (silica

gel, CH₂Cl₂/MeOH 9 :1) provided ()-18 (374 mg, 62%; over 2 steps) as a ca. 1:1 mixture of anomers. Whitish-

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yellow foam. a 64 (c 0.02, MeOH). UV (MeCN): 200 (4390). IR (KBr): 3410, 2935, 1705, 1650, 1555,

1385, 1255, 1220, 1165, 1120, 1050, 985, 810, 765, 695. ¹H-NMR (400 MHz, CD₃OD): 5.26 (d, ³J 2.7, 0.5 H,

H_eqÀC(6)); 4.64 (dd, ³J 2.2, 9.7, 0.5 H, H_axÀC(6)); 4.28 (tt, ³J 5.9, 9.7, HÀC(4'')); 4.11 4.02 (m, HÀC(2'''));

4.04 (m, HÀC(4)); 3.91 3.82 (m, HÀC(6''), HÀC(2)); 3.68 (t, ³J 6.5, 2 HÀC(4''')); 2.80 2.65

(m, 2 HÀC(1')); 2.65 2.53 (m, 2 HÀC(3')); 2.10, 1.88 (m, 2 HÀC(3)); 1.96 (m, 2 HÀC(5)); 1.70 1.54

(m, 2 HÀC(3'''), 2 HÀC(5'')); 1.54 1.36 (m, 2 HÀC(1''')); 1.32 (s, Me₂C(2'')). ¹³C-NMR (100.6 MHz,

CD₃OD)⁴): 206.6 (s, C(2')); 102.6 (s, C(2'')); 96.2, 94.2 (2d, ¹J 157, 166, C(6)(a/b)); 70.1, 68.0 (2d, ¹J 144,

143, C(2)(a/b)); 67.2 (d, ¹J 143, C(6'')); 66.0, 64.6 (2d, ¹J 138, 139, C(4'')(a/b)); 65.5 (d, ¹J 145, C(2''')); 65.3

(d, ¹J 147, C(4'')); 60.9 (t, ¹J 140, C(4''')); 50.8 (t, ¹J 129, C(1')); 50.2 (t, ¹J 127, C(3')); 45.5 (t, ¹J 124,

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C(1''')); 43.9, 42.8 (2t, ¹J 126, 125, C(3)(a/b)); 42.4 (t, ¹J 125, C(3''')); 41.8, 41.2 (2t, ¹J 125, 123, C(5)(a/b));

40.3 (t, ¹J 129, C(5'')); 25.9 (q, ¹J 127, Me₂C(2'')). CI-MS (NH₃): 394 (1, [M NH₄] ), 377 (1, [M H] ), 322

(6), 283 (10), 168 (5), 149 (4), 127 (11), 105 (12), 81 (100). Anal. calc. for C₁₈H₃₂O₈(376.45): C 57.43, H 8.57, O

34.00; found: C 57.39, H 8.37.

1-{(4S,6S)-6-[(2R)-2,4-Dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}-3-[(2 R,4R)-tetrahydro-4,6-dihy-

droxy-2H-pyran-2-yl]propan-2-one ((À)-19). To a soln. of ()-17 (60mg, 0.17 mmol) in Me ₂CO/H₂O 8 :1 (3 ml)

was added NMO (70 mg, 0.5 mmol) and 0.1m OsO₄in CCl₄(700 ml, 0.064 mmol). The reaction was complete

after one night (TLC, CH₂Cl₂/MeOH 9 :1). The mixture was diluted with MeOH (3 ml) and quenched by

addition of Na₂S₂O₅(58 mg, 0.35 mmol). After 2 h stirring, the soln. was dried (Na₂SO₄), filtered over a Celite

pad, and evaporated.

To a soln. of the dihydroxylated product (65 mg, 0.17 mmol) in dry MeOH (3 ml) was added portionwise

Pb(OAc)₄(377 mg, 0.85 mmol). After 30 min (TLC, CH₂Cl₂/MeOH 9 :1), the mixture was treated with

NaHCO₃(20mg), and the product was deposited on silica gel. FC (silica gel, CH ₂Cl₂/MeOH 9 :1) gave (À)-19

20

(45 mg, 71%; over 2 steps) as a ca. 1:1 anomer mixture. Yellowish foam. a À30; a À25; a À20;

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a À15; a À10( c 0.02, MeOH). IR (KBr): 3385, 2940, 1710, 1575, 1385, 1265, 1200, 1165, 1095, 980,

935, 875. ¹H-NMR (400 MHz, CD₃OD): 5.26 (d, ³J 3.5, 0.5 H, H_eqÀC(6)); 4.66 (dd, ³J 1.7, 9.4, 0.5 H,

H_axÀC(6)); 4.42 (m, HÀC(6'')); 4.18 (ddt, ³J 2.3, 5.3, 8.2, HÀC(4'')); 4.07 (dddd, ³J 4.7, 9.4, 11.2, 11.8, 0.5,

HÀC(4)); 3.92 (dtd, ³J 3.5, 8.2, 12.3, HÀC(2''')); 3.82 (m, HÀC(2)); 3.75 (dtd, ³J 4.3, 10.8, 11.6, 0.5,

HÀC(4)); 3.66 (t, ³J 6.5, 2 HÀC(4''')); 2.79 2.58 (m, 2 HÀC(1')); 2.56 2.48 (m, 2 HÀC(3')); 2.07 (ddd, ³J

2.2, 4.3, ²J 11.9, 1 HÀC(5)); 1.95 (m, 1 HÀC(3)); 1.87 (ddd, ³J 2.2, 4.3, ²J 11.9, 1 HÀC(5)); 1.61

(m, 2 HÀC(3''')); 1.52 (m, 2 HÀC(1''')); 1.46, 1.28 (2s, Me₂C(2'')); 1.52, 1.16 (2m, 2 HÀC(5'')); 1.08

(m, 1 HÀC(3)). ¹³C-NMR (100.6 MHz, CD₃OD): 206.2 (s, C(2')); 100.0 (s, C(2'')); 95.3, 93.3 (2d, ¹J 167,

161, C(6)); 69.2 (d, ¹J 140, C(2)); 67.2, 63.8 (2d, ¹J 138, 140, C(4)); 67.1 (d, ¹J 138, C(4'')); 66.9, 65.2 (d, ¹J

144, 142, C(6'')); 66.0( d, ¹J 133, C(2''')); 60.1 (t, ¹J 137, C(4''')); 50.7 (t, ¹J 126, C(1')); 50.5 (t, ¹J 126,

C(3')); 45.4 (t, ¹J 124, C(1''')); 43.0, 41.9 (2t, ¹J 129, 124, C(5)); 41.4 (t, ¹J 123, C(3''')); 40.9, 40.5 (2t, ¹J

127, 130, C(3)); 38.2 (t, ¹J 128, C(5'')); 30.5, 20.0 (2q, ¹J 126, Me₂C(2'')). CI-MS (NH₃): 394 (8, [M NH₄] ),

376 (13, M ), 359 (62), 341 (47), 319 (53), 301 (68), 283 (100), 265 (43), 185 (21), 134 (47). Anal. calc. for

C₁₈H₃₂O₈(376.45): C 57.43, H 8.57, O 34.00; found: C 57.26, H 8.57.

(3R)-4-{(1R,3S,4'R,5R,6'S,7R)-3',4',5',6'-Tetrahydro-4'-hydroxy-7-methoxyspiro[2,6-dioxabicyclo[3.3.1]-

nonane-3,2'-[2H]pyran]-6'-yl}butane-1,3-diol ((À)-20). To a soln. of ()-18 (50mg, 0.13 mmol) in CH ₂Cl₂/

MeOH 1:1 (1 ml) at 208 was added TsOH (2.9 mg, 0.013 mmol). After 1 h (TLC, CH₂Cl₂/MeOH 9 :1), the

reaction was quenched with NaHCO₃(30mg), and the product was deposited on silica gel. FC (silica gel,

25

CH₂Cl₂/MeOH 9 :1) afforded (À)-20 (29 mg, 68%). White foam. a À53; a À47; a À29;

589

577

546

25

435

25

405

a À27; a À24 (c 0.13, MeOH). UV (MeCN): 195 (550). IR (KBr): 3555, 2925, 2850, 1450, 1390,

1370, 1250, 1180, 1120, 1030, 965, 880, 805, 735. ¹H-NMR (400 MHz, CD₃OD): 4.65 (dd, ³J 3.2, 7.0, HÀC(7));

4.06 (tt, ³J 4.8, 11.3, HÀC(4')); 4.03 (m, HÀC(3'')); 3.99 (tt, ³J 11.8, 3.2, HÀC(6')); 3.88 (ddt, ³J 2.7, 4.3,

11.3, HÀC(5)); 3.80( ddt, ³J 2.7, 5.9, 11.3, HÀC(1)); 3.73 (t, ³J 7.5, 2 HÀC(1'')); 3.35 (s, MeOÀC(7)); 2.00

(m, 1 HÀC(5'), 1 HÀC(4'')); 1.91 (m, 1 HÀC(3'), 1 HÀC(9)); 1.78, 1.71 (2m, 2 HÀC(8)); 1.74

(m, 2 HÀC(2'')); 1.64 (m, 1 HÀC(4)); 1.55 (m, 1 HÀC(4)); 1.30( t, ²J ³J 11.8, 1 HÀC(4'')); 1.29

(m, 1 HÀC(5')); 1.14 1.13 (m, 1 HÀC(9), 1 HÀC(3')). ¹³C-NMR (100.6 MHz, CD₃OD): 104.8 (d, ¹J 161,

C(7)); 101.1 (s, C(3)); 67.5 (d, ¹J 161, C(6')); 67.3 (d, ¹J 162, C(5)); 67.0( d, ¹J 142, C(1)); 65.9 (d, ¹J 144,

C(3'')); 65.7 (d, ¹J 142, C(4')); 61.0( t, ¹J 139, C(1'')); 53.9 (q, ¹J 142, MeOÀC(7)); 46.3 (t, ¹J 127, C(4''));

46.2 (t, ¹J 127, C(5')); 46.0( t, ¹J 127, C(4)); 42.9 (t, ¹J 128, C(3')); 42.6 (t, ¹J 130, C(2'')); 42.5 (t, ¹J 128,

C(9)); 40.5 (t, ¹J 126, C(8)). CI-MS (NH₃): 333 (7, [M H] ), 318 (25, [M H À Me] ), 301 (17, [M À

MeO] ), 283 (76, [M À H₂O À MeO] ), 265 (55), 75 (100). Anal. calc. for C₁₆H₂₈O₇(332.39): C 57.82, H 8.49, O

33.69; found: C 57.89, H 8.42.

(3R)-4-{(1R,3S,4'S,5R,6'R)-3',4',5',6'-Tetrahydro-4'-hydroxy-7-methoxyspiro[2,6-dioxabicyclo[3.3.1]no-

nane-3,2'-[2H]pyran]-6'-yl}butane-1,3-diol ((À)-21). As described for (À)-20, with (À)-19 (24 mg, 0.063 mmol),

CH₂Cl₂/MeOH 1 :1 (500 ml), and TsOH (14.5 mg, 0.063 mmol) (quenching with NaHCO₃(10mg)): ( À)-21

25

589

25

577

25

546

25

435

25

405

(13 mg, 65%). White solid. a À28; a À32; a À32; a À59; a À71 (c 0.17, MeOH).

UV (MeCN): 201 (750). IR (KBr): 3420, 2930, 2850, 1650, 1435, 1395, 1370, 1260, 1235, 1160, 1120, 1035, 965,

895, 840, 735. H-NMR (400 MHz, CDCl₃)⁵): 4.65 (dd, ³J 4.1, 5.9, HÀC(7)); 4.22 (br. t, ³J 10.5, HÀC(5));

1

4.08 (m, HÀC(6')); 4.05 (m, HÀC(3'')); 4.02 (m, HÀC(1)); 3.99 (br. t, ³J 11.4, HÀC(4')); 3.73 (t, ³J 6.2,

5

)

a refers to (7R) and b to (7S) configuration.

1506

Helvetica Chimica Acta Vol. 87 (2004)

2 HÀC(1'')); 3.36, 3.33 (2s, 3 H, MeOÀC(7)(a/b)); 1.99 1.83 (m, 1 HÀC(8), 1 HÀC(3'), 1 HÀC(5'),

1 HÀC(4'')); 1.75 1.45 (m, 2 HÀC(4), 1 HÀC(8), 2 HÀC(9), 2 HÀC(2''), 1 HÀC(3')); 1.25

(m, 1 HÀC(4'')); 1.20( q, ²J ³J 11.4, 1 HÀC(5')). ¹³C-NMR (100.6 MHz, CDCl₃)⁵): 104.2 (d, ¹J 161,

C(7)); 100.2 (s, C(3)); 67.1 (d, ¹J 143, C(4')); 66.1, 66.0(2 d, ¹J 148, 143, C(1), C(3'')); 64.5 (d, ¹J 146,

C(6')); 61.8 (d, ¹J 143, C(5)); 60.0 (t, ¹J 142, C(1'')); 54.1, 53.0(2 q, ¹J 143, MeOÀC(7)(a/b)); 45.0, 44.9

(2t, ¹J 125, 125, C(9), C(5')); 41.8, 41.6 (2t, ¹J 122, 130, C(8), C(3')); 41.0( t, ¹J 129, C(4'')); 39.4 (2t, ¹J

126, C(4), C(2'')). CI-MS (NH₃): 350(16, [ M NH₄] ), 333 (40, [M H] ), 318 (63, [M H À Me] ), 301 (56,

[M À MeO] ), 283 (100, [M À H À H₂O À MeO] ), 265 (48), 167 (9), 95 (18), 75 (71). Anal. calc. for C₁₆H₂₈O₇

(332.39): C 57.82, H 8.49, O 33.69; found: C 56.38, H 8.58 (corresponding to C₁₆H₂₈O₇¥ 1/2 H₂O: C 56.29, H 8.56).

(1R,3S,4'R,5R,6'R)-3',4',5',6'-Tetrahydro-6'-[(2S)-2-hydroxybutyl-3-enyl]-7-methoxyspiro[2,6-dioxabicy-

clo[3.3.1]nonane-3,2'-[2H]pyran]-4'-ol ((À)-23). Under Ar, (À)-20 (25 mg, 0.075 mmol) and 2-nitrophenyl

selenocyanate (170 mg, 0.75 mmol) were dissolved in dry THF (500 ml). At 208, tributylphosphine (185 ml,

0.75 mmol) was added dropwise. After 6 h (TLC, CH₂Cl₂/MeOH 9 :1), MeOH (1 ml) was added, and the

solvents were evaporated. FC (silica gel, CH₂Cl₂/MeOH 98 :2) afforded the selenated compound 22 (35 mg,

97%) as a deep yellow oil, contaminated with tributylphosphine. The phosphine could be removed by several

FCs or eliminated by oxidation in the next step.

A soln. of the crude selenated compound 22 (20 mg, 0.038 mmol) in dry THF (500 ml) was cooled to À 788,

and Et₃N (10 ml, 0.076 mmol) was added dropwise, followed by 3-chloroperbenzoic acid (27 mg, 0.152 mmol).

After 3 h, additional 3-chloroperbenzoic acid (27 mg, 0.152 mmol) was added. After 2 h (TLC, CH₂Cl₂/MeOH

95 :5), the mixture was diluted with MeOH (1 ml) and treated with Na₂SO₃(40mg) and NaHCO ₃(40mg) while

the soln. was allowed to warm up to r.t. The product was deposited on silica gel and purified by FC (silica gel,

25

589

25

577

25

546

CH₂Cl₂/MeOH 98 :2 ! 95 :5): (À)-23 (10mg, 86%). Slightly yellowish foam. a À12; a À17; a

25

435

25

405

À19; a À20; a À37 (c 0.10, MeCN). UV (MeCN): 249 (940). IR (KBr): 3420, 2925, 2865, 1705,

1650, 1605, 1515, 1430, 1380, 1260, 1170, 1100, 1030, 805, 735, 705. ¹H-NMR (400 MHz, CDCl₃)⁵): 5.90( ddd, ³J

5.4, 10.4, 16.2, HÀC(3'')); 5.30( m, 1 HÀC(4'')); 5.10( dd, ³J 10.4, ²J 1.7, 1 HÀC(4'')); 4.64 (m, HÀC(7));

4.36 (m, HÀC(2'')); 4.12 (tt, ³J 5.8, 10.8, HÀC(4')); 4.05 (m, HÀC(5)); 3.84 (m, HÀC(6')); 3.71 (m, HÀC(1));

3.33, 3.28 (2s, 3 H, MeOÀC(7)(a/b)); 2.09 (m, 1 HÀC(3'), 1 HÀC(4)); 1.97 (m, 1 HÀC(4)); 1.92

(m, 1 HÀC(9), 1 HÀC(5')); 1.82 1.68 (m, 2 HÀC(8), 1 HÀC(1'')); 1.61 (m, 1 HÀC(1'')); 1.46

(m, 1 HÀC(3'')); 1.40 1.19 ( m, 1 HÀC(5'), 1 HÀC(9)). ¹³C-NMR (100.6 MHz, CDCl₃)⁵): 140.7 (d, ¹J 152,

C(3'')); 114.0( t, ¹J 155, C(4'')); 100.9, 100.7 (2d, ¹J 168, 168, C(7)(a/b)); 99.1 (s, C(3)); 68.6 (d, ¹J 146,

C(2'')); 64.6, 64.5 (2d, ¹J 135, 141, C(6'), C(1)); 64.4, 64.1 (2d, ¹J 139, 138, C(5), C(4')); 53.0, 51.2 (2q, ¹J

148, 148, MeOÀC(7)(a/b)); 44.4, 44.0(2 t, ¹J 126, 128, C(3'), C(5')); 42.6 (t, ¹J 132, C(1'')); 40.8, 40.6 (2t, ¹J

128, 126, C(9), C(4)); 37.7 (t, ¹J 127, C(8)). CI-MS (NH₃): 316 (100, [M D] ), 300 (49, [M H À Me] ), 283

(28, [M À MeO] ), 235 (29), 81 (26), 75 (69). HR-MS-ESI (MeOH): 369.1896 (C₁₆H₂₆O₆ MeOH Na] ,

C

₁₇H₃₀NaO₇; calc. 369.1889.

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Received February 7, 2004

Article Doi

Non-iterative asymmetric synthesis of C15 polyketide spiroketals

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