Total asymmetric synthesis of a new 9,12-anhydroerythronolide aglycone

Article abstract of DOI:10.1002/1522-2675(200202)85:2<417::AID-HLCA417>3.0.CO;2-1

Two novel, potentially antimicrobial erythronolide aglycon analogs ((-)-9 and (-)-30, respectively), which incorporate a large number of contiguous stereogenic centers, have been prepared by multistep synthesis from simple chirons. The chemistry presented demonstrates the power of the so-called 'naked sugars of the second generation' approach. As for the sporeamicins, our macrolides are 9,12-anhydroerythronolides, yet presenting a higher degree of complexity due to additional functional groups.

Full text of DOI:10.1002/1522-2675(200202)85:2<417::AID-HLCA417>3.0.CO;2-1

Helvetica Chimica Acta Vol. 85 (2002)
417
Total Asymmetric Synthesis of a New 9,12-Anhydroerythronolide
Aglycone
by Sandrine Gerber-Lemaire, Simon W. Ainge, Ce¬cile Glanzmann, and Pierre Vogel*
¬
¬ ¬
Institut de Chimie Moleculaire et Biologique, Ecole Polytechnique Federale de Lausanne, BCH,
CH-1015 Lausanne-Dorigny (Phone: ‡41216939371, Fax: ‡41216939375, e-mail: pierre.vogel@epfl.ch)
Two novel, potentially antimicrobial erythronolide aglycon analogs ((À)-9 and (À)-30, respectively), which
incorporate a large number of contiguous stereogenic centers, have been prepared by multistep synthesis from
simple chirons. The chemistry presented demonstrates the power of the so-called −naked sugars of the second
generation× approach. As for the sporeamicins, our macrolides are 9,12-anhydroerythronolides, yet presenting a
higher degree of complexity due to additional functional groups.
Introduction. Evolution forces us to find new antibiotics [1]. This stimulates the
search of new metabolites of microorganism and to apply chemistry to either mimic or
modify them. Sporeamycin A (1), produced by Saccharopolyspora sp. L53-18A was
isolated and characterized in 1992 by Morishita and co-workers [2]. It is active against
Gram-positive bacteria [3]. Structurally, 1 is an analog of an oxidized form of
erythromycins (e.g. erythromycin A: 2) containing a 9,12-anhydro moiety. Sporeamycin
B (3) [4] and C (4) [5] have also been isolated. In 1996, 6-deoxysporeamycin A (5) [6]
was derived from 6-deoxyerythromycin A. The antibacterial spectrum of 5 is similar to
that of erythromycin A, but it has a higher potency against susceptible streptococci.
Other anhydrous derivatives of erythromycin A (2) such as the neotilides (8,9-anhydro-
6,9-hemiacetals) have been described and were shown to stimulate gastrointestinal
motility [7].
In a preliminary communication [8], we showed that the partially protected seco-
acid of the 9,12-anhydroerythronolide aglycon 6 can be derived from the Diels-Alder
adduct (À)-7 of 2,4-dimethylfuran to 1-cyanovinyl (1'S)-camphanate (a −naked sugar of
the second generation× [9]) and (3R,4S,5R,6S)-7-benzyloxy-3,5-(isopropylidenedioxy)-
4,6-dimethylheptane-2-one ((‡)-8) [10]. We present now the details of these trans-
formations and the conversion of the seco-acid to the corresponding macrolide 9.
Results and Discussion. The known methyl ketone (‡)-8 [10] was derived from
Paterson×s chiron 10 [11]. Tin-aldol-reaction with an excess of methacrolein gave a
mixture of diastereoisomeric allylic alcohols from which the pure syn aldol (‡)-11
could be isolated in 87% yield. Treatment of (‡)-11 with Et2BOMe, followed by NaBH4
in THF/MeOH at À788 [12] furnished a diol that was transformed in situ into its
acetonide under standard conditions, the ozonolysis of which provided (‡)-8 in an
overall yield of 66% (Scheme 1).
The conversion of (À)-7 into the 7-oxanorbornanone derivative (À)-12 (78%, 3
steps) has already been described [13]. The transformation of (À)-12 into the 8-

418
Helvetica Chimica Acta Vol. 85 (2002)
NMeR2
NMe2
O
HO
O
HO
O
O
9
O
O
HO
X
6
HO
O
12
HO
O
O
O
O
O
1
O
O
OH
OR1
O
OH
OMe
2
1 R1 = Me, R2 = Me, X = OH
3 R1 = H, R2 = Me, X = OH
4 R1 = Me, R2 = H, X = OH
5 R1 = Me, R2 = Me, X = H
H
O
O
O
O
H
9
HO
HO
8
O
10
O
OH
HO
6
5
OH
11
14
HO
13
O
HO2C
3
6
OH
1
15
O
O
O
O
(-)-9
CN
O
OR
(-)-7
R = (1S)-camphanoyl
OBn
Scheme 1
1. Et2BOMe, NaBH4
THF/MeOH, –78°
2. Me2C(OMe)2
OH
O
1. Sn(OTf)2, NEt3
CH2Cl2, –78°
O
(+)-8
TsOH cat., CH2Cl2
3. O3, NaHCO3
CH2Cl2, –78°
CHO
2.
–78 to –50°
OBn
10
(87%)
OBn
(66%)
(+)-11
oxabicyclo[3.2.1]oct-3-en-2-one (À)-13 employs the cyclopropanation with ICH2Cl and
Et2Zn [14] of the corresponding enoxysilane, obtained by quenching the lithium
enolate with Me3SiCl [15] (Scheme 2). The intermediate cyclopropane derivative was
not isolated but directly submitted to oxidation with FeCl3 in pyridine [16]. This

Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
419
1. (i-Pr)2NLi, Me3SiCl
O
O
THF, –78°
O
O
3 steps
[13]
2. ICH2Cl, ZnEt2
(–)-7
O
O
Cl(CH2)2Cl, 0°
3. FeCl3, pyridine
DMF, 50°
(78%)
O
O
(–)-13
(–)-12
(64%)
O
O
1. CuBr.Me2S, MeLi
Et2O, –78°
O
O
O
Pd(OAc)2 (cat), O2
O
DMSO, 40°
2. Me3SiCl
(100%)
(quant.)
O
OSiMe3
15
14
O
Pd(PPh3)2(OAc)2
PPh3, ZnCl2
1. (Me3Si)2NLi, HMPA
ArNTf2, THF
O
O
O
4
6
O
5
O
3
Ph2SiH2, CHCl3, 70°
2. Pd(PPh3)4 (cat.)
1
2
LiCl, CH2=CHSnBu3
7
(50%)
THF, 60°
(–)-16
(+)-17
O
(78%)
H
O
1. O3, CH2Cl2
MeOH, –78°
2. Me2S
OH
H2NNH2, H2O2
Cu(OAc)2 (cat.)
O
O
O
O
MeOH, –15°
O
OH
3. NaBH4, –78 to 0°
(75%)
(80%)
(+)-18
1 : 3 19/20
H
H
(PhS)2, P(Oct)3
SPh
SPh
O
O
O
MeCN, 20°
+
O
O
O
OH
OH
(90%)
21
(major)
(–)-22
H
(t-Bu)Me2SiOTf
3
X
1
O
O
2,6-lutidine
2
4
5
(–)-22
O
CH2Cl2
(99%)
6
OTBS
7
8
9
(–)-23 X = SPh
(+)-24 and (–)-25 X = S(O)Ph
NaIO4, MeOH/H2O, 20°
(95%)

420
Helvetica Chimica Acta Vol. 85 (2002)
provided (À)-13 in an overall yield of 64%. Michael addition of methylcuprate,
followed by trapping the intermediate enolate with Me3SiCl [17], gave the enoxysilane
14 quantitatively. Oxidation of 14 with O2, catalyzed by (AcO)2Pd in DMSO [18], gave
the enone 15 in quantitative yield. The latter was not purified but directly submitted to
stereospecific exo-face hydrogenation with Ph2SiH2 in the presence of PPh3, ZnCl2, and
a catalytic amount of a palladium catalyst [19] affording the ketone (‡)-16 (50% based
on (‡)-13). The relative endo configuration of its Me group at C(4) was confirmed by
1H-NMR (3J(HÀC(4),HÀC(5)) ˆ 3.6 Hz [20]; see Exper. Part). (‡)-16 was converted
into its enol trifluoracetate on treatment with LDA in THF at À788 and 2-[N,N'-
bis(trifluoromethylsulfonyl)amino]-5-chloropyridine [21], followed by direct Stille
coupling [22] with tributyl(vinyl)stannane (LiCl, [Pd (PPh3)4], THF), providing the
diene (‡)-17 in 78% yield. Selective reduction of the vinyl moiety was achieved on
treating (‡)-17 with a large excess of hydrazine and H2O2 in the presence of (OAc)2Cu
as a catalyst [23], furnishing the alkene (‡)-18 in 75% yield. Ozonolysis followed by
reductive workup with Me2S and with NaBH4 provided a 1:3 mixture of the secondary
alcohols 19 and 20, respectively. Selective displacement of the primary alcohol moieties
in both 19 and 20 was achieved by treatment with PhSSPh and trioctylphosphine in
MeCN. This led to a 1:3 mixture of the compounds 21 and (À)-22, which were
separated by flash chromatography (FC). The major alcohol (À)-22 was silylated under
standard conditions to yield the silyl ether (À)-23 almost quantitatively. Oxidation of
(À)-23 with NaIO4 resulted in a 3 :2 mixture of the sulfoxides (‡)-24 and (À)-25 (95%
yield) which were separated by FC.
The major sulfoxide (‡)-24 was used in the condensation with the methyl ketone
(‡)-8 (Scheme 3). The conjugate base of (‡)-24, obtained by treatment with LDA and
N,N,N',N'-tetramethylethylenediamine (TMEDA) in THF at À788, reacted with (‡)-8
to give a mixture from which (‡)-26 was isolated in 40% yield together with 35% of the
recovered ketone (‡)-8. The relative configuration of the generated stereogenic center
(tertiary alcohol) will be discussed below (Figure 1). Desulfurization of (‡)-26 was
realized on treatment with W2 Raney Ni in ether/ethanol solution. Debenzylation by
hydrogenolysis was catalyzed by the same Ni catalyst to give a primary alcohol. The
latter was not isolated but directly submitted to Swern oxidation [24], then treated with
NaClO2/NaH2PO4, in t-BuOH and 2-methylbut-2-ene [25] generating the carboxylic
acid (‡)-27 in 50% yield. Desilylation of (‡)-27 with Bu4NF in THF gave 28 in 80%
yield which was submitted to the Yamaguchi macrocyclization [26] in benzene (high
dilution, slow addition of 28 through an automatic syringe). The crude macrolactone
obtained was finally deprotected by acidic hydrolysis with aqueous TFA, and pure (À)-
9 was isolated in 55% yield by FC on silica gel.
When the desilylation of (‡)-27 was performed with 40% aqueous HF in MeCN,
the monoacetonide 29 was obtained in 51% yield. This compound was not fully
characterized but submitted directly to the Yamaguchi macrolactonization giving (À)-
30 in 68% yield, a dehydrated analog of (À)-9 (Scheme 4).
All new compounds described have been fully characterized by their spectral data,
by elemental analysis, and by their mode of formation. The relative configuration at
C(6) of (À)-9 was established by both computer modelling and 2D-NOESY-1H-NMR
(Figs. 1 and 2). The singlet at 1.22 ppm showed cross-peaks with signals at 3.29 and
3.53 ppm (HÀC(9) and HÀC(11)) and was thus assigned to MeÀC(10). The singlet at

Helvetica Chimica Acta Vol. 85 (2002)
421
Scheme 3
HO
H
1. (i-Pr)2NLi, TMEDA
O
O
THF,–78°
O
O
(+)-24
S
O
O
OBn
2. + (+)-8, –78°
Ph
OTBS
(+)-26 (40%), recovery of (+)-24 (35%)
HO
H
1. Raney Ni, Et2O, EtOH
2. Raney Ni, H2, EtOH
3. DMSO, (COCl)2, NEt3
6
O
O
COOH
1
O
O
O
4. NaClO2, NaH2PO4
t-BuOH
2-methylbut-2-ene
13
OX
(50%)
(+)-27 X = TBS
28 X = H
Bu4NF, THF
–30° to 20°
(80%)
1. 2,4,6-trichlorobenzoyl chloride
(i-Pr)2NEt, PhH, 20°
(–)-9
2. DMAP, PhH, 80°
3. CF3COOH, H2O, 20°
(55%)
Scheme 4
HO
H
O
O
COOH
see
HF, MeCN
(51%)
(+)-27
O
OH OH
scheme 3
(68%)
OH
29
H
9
HO
8
O
OH
HO
6
11
HO
13
3
O
1
O
(–)-30

422
Helvetica Chimica Acta Vol. 85 (2002)
1.09 ppm showed cross-peaks with signals at 3.29 and 4.98 ppm (HÀC(9) and
HÀC(13)), and was thus assigned to MeÀC(12). The remaining singlet at 1.16 ppm
must be that of MeÀC(6). Computer modelling with the calculation program Spartan
gave two minimal conformations with enthalpy difference of 3.5 kcal/mol (Figs. 1 and
2). In the more stable one (conformation 1), the 2D-NOESY-1H-NMR spectrum is
expected to present cross-peaks between the signals of MeÀC(6) (1.16 ppm) and of
MeÀC(8) (doublet at 1.04 ppm) on the one hand, and between the signals of HÀC(2)
(2.54 2.50ppm) and that of H ÀC(5) (doublet at 3.16 ppm) on the other hand. These
two significant cross-peaks were indeed observed in the 2D-NOESY-1H-NMR
spectrum of (À)-9. For the less stable conformation (conformation 2), a cross-peak
between the signals of MeÀC(6) (1.16 ppm) and that of HÀC(9) (doublet at 3.29 ppm)
should be present in the 2D-NOESY-1H-NMR spectrum of (À)-9. This cross-peak was
indeed observed. As this conformation should exist in a very low proportion, it gives a
1
minor contribution to the coupling constants observed in the H-NMR spectrum of
(À)-9. These observations together with the calculated structure of (À)-9 unequivocally
establish the absolute configuration at C(6).
Fig. 1. Calculated structure of ( À )-9
H
H
H
H
H
OH
Me
8
H
HO
HO
H
H
H
6
6
Me
9
H
H
H
8
H
H
H
HO
5
9
5
HO
Me
H
H
O
H
H
HO
O
H
H
H
2
HO
12
Me
12
HO
O
O
3
1
OH
3
Me
Me
1
HO
O
H
13
13
O
H
Me
H
H
Me
Me
conformation 1
conformation 2
Fig. 2. NOE Effects observed in ( À )-9. 3J(HÀC(2,3))ˆ 10.7 Hz; 3J(HÀC(3,4) ˆ 0Hz; 3J(HÀC(8,9))ˆ 11.1 Hz.

Helvetica Chimica Acta Vol. 85 (2002)
423
Conclusions. Two new erythronolide aglycon analogs have been prepared starting
from −naked sugars of the second generation×. As for the sporeamicins, they are 9,12-
anhydroerythronolides. However, they are more complex since they contain a 3,4-
dihydroxy-2,4-dimethyltetrahydrofuran moiety. The chemistry presented demonstrates
that −naked sugars of the second generation× are suitable chirons for the construction of
complex polypropionates containing a large number of contiguous stereogenic centers,
including tertiary alcohols.1)
We are grateful to the Swiss National Science Foundation, the Fonds Herbette (Lausanne), and the Office
¬
¬
Federal de l×Education et de la Science (Bern, COST D13/010/00) for generous financial support. We thank Mr.
K. Meilert for his help with modelling. We also thank Mr. M. Rey and F. Sepulveda for technical assistance.
Experimental Part
1
General. See [28]. Signal assignments were confirmed by 2D COSY and NOESY H-NMR experiments.
Flash chromatography (FC) was performed on silica gel (SiO2).
(2S,4R,5R)-1-(Benzyloxy)-5-hydroxy-2,4,6-trimethylhept-6-en-3-one ((‡)-11). To a cooled (À 788) soln. of
Sn(OTf)2 (5 g, 11.97 mmol, 1.3 equiv.) and anh. Et3N (2.1 ml, 14.74 mmol, 1.6 equiv.) in anh. CH2Cl2 (120ml)
was added 10 (1.9 g, 9.21 mmol) diluted in CH2Cl2. The mixture was stirred at À788 for 2 h. Freshly distilled
methacrolein (2.3 ml, 27.63 mmol) was added dropwise. After stirring for 2 h at À788, the temp. was raised to
À508 for an additional hour. The mixture was poured into aq. pH 7 buffer (200 ml) and extracted with CH2Cl2
(3 Â 200 ml). The combined org. layers were dried (MgSO4) and concentrated in vacuo. The residue was
20
20
purified by FC (petroleum ether/AcOEt 7 :1) to yield 2.2 g (87%) of (‡)-11. Colorless oil. [a] ˆ 30.8, [a]
ˆ
589
577
20
20
20
30.5, [a] ˆ 35.9, [a] ˆ 54.3, [a] ˆ 59.9 (c ˆ 0.7, CHCl3). UV (MeCN): 205 (8240), 196 (8750). IR (film):
546
435
405
1
3475, 2975, 2935, 2876, 1700, 1455, 1375, 1100, 990, 905, 740, 700, 605. H-NMR (400 MHz, CDCl3): 7.37 7.29
(m, 5 arom. H); 5.10( s, HÀC(7)); 4.95 (br. s, HÀC(7)); 4.52 (d, 3J(HÀC(4,5)) ˆ 2.5, HÀC(5)); 4.50, 4.46
(2d, 2J ˆ 12.0, PhCH2); 3.63 (dd, 2J ˆ 8.7, J(HÀC(1,2)) ˆ 8.8, HÀC(1)); 3.49 (dd, 2J ˆ 8.7, J(HÀC(1,2)) ˆ 5.0,
3
3
HÀC(1)); 3.22 3.17 (m, HÀC(2), HOÀC(5)); 2.88 (qd, 3J(HÀC(4),MeÀC(4)) ˆ 6.9, 3J(HÀC(4,5)) ˆ 2.5,
HÀC(4));
1.64
(br. s,
MeÀC(6));
1.06
(d, 3J(HÀC(4),MeÀC(4)) ˆ 6.9,
MeÀC(4));
1.03
(d, 3J(HÀC(2),MeÀC(2)) ˆ 7.2, MeÀC(2)). 13C-NMR (100.6 MHz, CDCl3): 218.1 (s, C(3)); 143.3 (s, C(6));
137.5 (s, 1 arom. C); 128.4, 127.8, 127.7 (3d, 1J(C,H) ˆ 160, 161, 154, 5 arom. C); 111.4 (t, 1J(C,H) ˆ 157, C(7));
73.5, 73.1 (2t, 1J(C,H) ˆ 142, 143 C(1), PhCH2); 72.5 (d, 1J(C,H) ˆ 141, C(5)); 48.4 (d, 1J(C,H) ˆ 126, C(4)); 44.6
(d, 1J(C,H) ˆ 130, C(2)); 19.6 (q, 1J(C,H) ˆ 132, MeÀC(6)); 13.6 (q, 1J(C,H) ˆ 129, MeÀC(4)); 8.2
(q, 1J(C,H) ˆ 129, MeÀC(2)). CI-MS (NH3): 294 (9, [M ‡ NH4] ), 277 (2, [M ‡ H] ), 259 (6), 207 (37), 91
‡
‡
‡
(100, [PhCH2] ). Anal. calc. for C17H24O3 (276.37): C 73.88, H 8.75; found: C 73.94, H 8.82.
(3R,4S,5R,6S)-7-(Benzyloxy)-3,5-(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((‡)-8). To a soln. of
(‡)-11 (2.2 g, 7.96 mmol) in anh. THF/MeOH 4 :1 (45 ml), cooled to À788, Et2BOMe (1m in THF, 10.4 ml,
10.35 mmol, 1.3 equiv.) was added, and the mixture was stirred for 15 min. NaBH4 (423 mg, 11.14 mmol,
1.4 equiv.) was then added, and the mixture was stirred at À788 for 1.5 h. AcOH (1 ml) was added dropwise and
the soln. was poured into sat. aq. NaHCO3 (150ml). The aq. layer was extracted with AcOEt (4 Â 150ml). The
combined org. layers were washed with brine (150ml), dried (MgSO 4) and concentrated in vacuo to afford a
pale yellow oil, which was directly dissolved in CH2Cl2 (37.5 ml) and 4-(dimethylamino)pyridine (DMAP;
37.5 ml), containing TsOH (150mg). The mixture was stirred at 20 8 overnight and concentrated in vacuo.
Filtration over a pad of SiO2 (petroleum ether/AcOEt 7:1) and evaporation afforded a yellow oil (2.4 g, 95%
crude). The crude alkene (2.4 g, 7.55 mmol) was dissolved in anh. CH2Cl2 (300 ml) containing NaHCO3 (1.2 g),
and the mixture was cooled to À788. The soln. was ozonolyzed for 15 min and Me2S (15 ml) was added. The
mixture was stirred at 08 for 1 h and then poured into H2O (300 ml). The aq. layer was extracted with CH2Cl2
(2 Â 200 ml). The combined org. extracts were washed with brine (150 ml), dried (MgSO4), and evaporated in
vacuo. The residue was purified by FC (petroleum ether/Et2O 4 :1) to yield 1.68 g of (‡)-8 (66%, three steps).
20
20
20
20
20
White solid. M.p. 40-418. [a] ˆ 30, [a] ˆ 30, [a] ˆ 35, [a] ˆ 63, [a] ˆ 79 (c ˆ 1.0, CHCl3). UV
589
577
546
435
405
(MeCN): 206 (8460). IR (KBr): 3065, 3030, 2990, 2940, 2880, 1720, 1455, 1385, 1350, 1200, 1160, 985, 915, 870,
1
)
For other syntheses of erythronolides and derivatives, see [27].

424
Helvetica Chimica Acta Vol. 85 (2002)
735, 700. 1H-NMR (400 MHz, CDCl3): 7.38 7.28 (m, 5 arom. H); 4.49 (s, PhCH2); 4.26 (d, 3J(HÀC(3,4)) ˆ 2.6,
HÀC(3)); 3.75 (dd, 3J(HÀC(5,6)) ˆ 9.6, 3J(HÀC(4,5)) ˆ 2.0, HÀC(5)); 3.39 3.31 (m, 2 HÀC(7)); 2.17
(s, 3 HÀC(1)); 2.16 2.14 (m, HÀC(4)); 2.05 2.01 (m, HÀC(6)); 1.49, 1.42 (2s, Me2C); 1.05 (d, 3J(HÀC(4),
MeÀC(4)) ˆ 6.6, MeÀC(4)); 0.81 (d, 3J(HÀC(6), MeÀC(6)) ˆ 6.8, MeÀC(6)). 13C-NMR (100.6 MHz, CDCl3):
209.9 (s, C(2)); 138.4 (s, 1 arom. C); 129.4, 127.6, 127.5 (3d, 1J(C,H) ˆ 160, 167, 162, 5 arom. C); 99.4 (s, Me2C);
79.4 (d, 1J(C,H) ˆ 137, C(3)); 75.2 (d, 1J(C,H) ˆ 138, C(5)); 73.2 (t, 1J(C,H) ˆ 141, PhCH2); 71.3 (t, 1J(C,H) ˆ
140, C(7)); 35.0 (d, 1J(C,H) ˆ 127, C(6)); 32.4 (d, 1J(C,H) ˆ 129, C(4)); 29.9, 19.3 (2q, 1J(C,H) ˆ 129, 123,
Me2C); 27.2 (q, 1J(C,H) ˆ 128, C(1)); 14.6 (q, 1J(C,H) ˆ 127, MeÀC(4)); 6.4 (q, 1J(C,H) ˆ 126, MeÀC(6)). CI-
‡
‡
MS (NH3): 321 (4, [M ‡ H] ), 277 (10), 263 (4), 245 (13), 155 (9), 127 (7), 91 (100, [PhCH2] ). Anal. calc. for
C19H28O4 (320.43): C 71.25, H 8.80; found: C 70.98, H 8.69.
(1S,5S,6S,7S)-6,7-(Isopropylidenedioxy)-1,6-dimethyl-8-oxabicyclo[3.2.1]oct-3-en-2-one ((À)-13). (À)-12
(8.3 g, 39.10mmol), dissolved in anh. THF (90ml), was added dropwise to a soln. of (i-Pr) 2NLi (1.1 equiv.,
prepared from 6.62 ml of (i-Pr)2NH and 31 ml of BuLi, 1.6m in hexane) in anh. THF (90ml), cooled to À788.
The mixture was stirred at À788 for 1 h. Then, Me3SiCl (8.4 ml, 66.5 mmol, 1.7 equiv.) was added dropwise. The
temp. was raised to 08. After 3 h, the soln. was concentrated in vacuo. The residue was taken up in pentane
(100 ml) and the Li salts were removed by filtration. This operation was repeated twice to give a pale yellow oil
(10.9 g, 97% crude). Then, ClCH2I (11.13 ml, 153.12 mmol, 4 equiv.) was added to a cooled (08) soln. of Et2Zn
(1.1m in toluene, 69 ml, 76.56 mmol, 2 equiv.) and Cl(CH2)2Cl (170ml). The crude silyl enol ether (10.9 g,
38.28 mmol), dissolved in Cl(CH2)2Cl (60ml), was added dropwise, and the mixture was stirred at 0 8 for 4 h.
The mixture was poured into sat. aq. NH4Cl soln. (150ml) and extracted with Et 2O (3 Â 150ml). The combined
org. layers were washed with brine (80ml), dried (MgSO 4), and concentrated in vacuo. The residue was taken
up in DMF (120ml) and transferred via cannula into a cooled (08) soln. of FeCl3 (18.3 g, 113.4 mmol, 3 equiv.) in
DMF (180ml). Pyridine (6.2 ml, 75.6 mmol, 2 equiv.) was added and the mixture was stirred at 50 8 for 4.5 h. The
soln. was poured into 1m aq. HCl soln. (300 ml) and extracted with pentane/ether 5 :1 (4 Â 250ml). The
combined org. extracts were washed with 1m aq. HCl soln. (150ml), brine (200ml), dried (MgSO 4), and
evaporated. The residue was purified by FC (petroleum ether/Et2O 5 :1 to 1:1) to yield 5.6 g of (À)-13 (64%,
20
20
20
20
20
3 steps). White solid. M.p. 83 848. [a] ˆ À285, [a] ˆ À305, [a] ˆ À380, [a] ˆ À1380, [a] ˆ À1565
589
577
546
435
405
(c ˆ 1.1, CH2Cl2). UV (MeCN): 232 (9070), 193 (7290). IR (KBr): 2985, 2860, 1695, 1370, 1240, 1205, 1180,
1100, 1075, 1045, 940. 1H-NMR (400 MHz, CDCl3): 7.26 (dd, 3J(HÀC(3,4)) ˆ 9.8, 3J(HÀC(4,5)) ˆ 5.1,
HÀC(4)); 6.06 (d, 3J(HÀC(3,4)) ˆ 9.8, HÀC(3)); 4.52 (d, 3J(HÀC(4,5)) ˆ 5.1, HÀC(5)); 4.14 (s, HÀC(7));
1.55, 1.52, 1.49, 1.46 (4s, MeÀC(1), MeÀC(6), Me2C). 13C-NMR (100.6 MHz, CDCl3): 197.6 (s, C(2)); 151.6
(d, 1J(C,H) ˆ 164, C(4)); 128.4 (d, 1J(C,H) ˆ 171, C(3)); 116.3 (s, Me2C); 93.7 (s, C(6)); 89.6 (s, C(1)); 88.9
(d, 1J(C,H) ˆ 157, C(7)); 79.4 (d, 1J(C,H) ˆ 167, C(5)); 27.7, 26.8, 23.0, 14.6 (4q, 1J(C,H) ˆ 130, 126, 126, 129,
‡
MeÀC(1), MeÀC(6), Me2C). CI-MS (NH3): 225 (11, [M ‡ H] ), 209 (2), 179 (3), 124 (7), 111 (100). Anal. calc.
for C12H16O4 (224.25): C 64.27, H 7.19; found: C 64.29, H 7.19.
(1S,4R,5S,6S,7S)-6,7-(Isopropylidenedioxy)-1,4,6-trimethyl-8-oxabicyclo[3.2.1]octan-2-one ((À)-16). A
complex of CuBr¥ DMS (7.2 g, 71.35 mmol, 1.6 equiv.) was suspended in anh. Et2O (100 ml) and cooled to
À788. MeLi (1.6m in Et2O, 83.6 ml, 133.77 mmol, 3 equiv.) was added dropwise, and the mixture was stirred at
À788 for 30min. The enone ( À)-13 (10g, 44.59 mmol), dissolved in anh. Et 2O (40ml), was added dropwise.
After 30min, Me 3SiCl (9.4 ml, 75.80mmol, 1.7 equiv.) was added and the mixture was warmed to 20 8 over 3.5 h.
The soln. was poured into sat. aq. NH4Cl soln. (600 ml) and extracted with Et2O (3 Â 500 ml). The combined
org. extracts were washed with H2O (200 ml), brine (200 ml), dried (MgSO4), and concentrated in vacuo to
afford 14 as a pale yellow oil (13.9 g, 100%, crude).
Data of the intermediate 14 ((1S,4S,5S,6S,7S)-6,7-(isopropylidenedioxy)-1,4,6-trimethyl-2-(trimethylsilyl-
oxy)-8-oxabicyclo[3.2.1]oct-2-ene): IR (film): 2985, 1655, 1450, 1375, 1225, 1160, 845, 755. 1H-NMR (400 MHz,
CDCl3): 4.57 (d, 3J(HÀC(3,4)) ˆ 4.9, HÀC(3)); 4.03 (s, HÀC(7)); 3.84 (s, HÀC(5)); 2.12 2.04 (m, HÀC(4));
1.51, 1.50, 1.42, 1.31 (4s, Me2C, MeÀC(1), MeÀC(6)); 1.12 (d, 3J(HÀC(4),MeÀC(4)) ˆ 6.9, MeÀC(4)); 0.21
(s, Me3Si). 13C-NMR (100.6 MHz, CDCl3): 153.6 (s, C(2)); 113.1 (s, Me2C); 104.1 (d, 1J(C,H) ˆ 157, C(3)); 93.3
(s, C(1)); 90.7 (d, 1J(C,H) ˆ 153, C(7)); 88.0( s, C(6)); 87.2 (d, 1J(C,H) ˆ 131, C(5)); 30.8 (d, 1J(C,H) ˆ 125,
C(4)); 27.6, 22.9, 20.4 (3q, 1J(C,H) ˆ 125, 126, 122, Me2C, MeÀC(1), MeÀC(6)); 14.5 (q, 1J(C,H) ˆ 127,
‡
MeÀC(4)); 0.2 (q, 1J(C,H) ˆ 116, Me3Si). CI-MS (NH3): 312 (100, M ), 297 (4), 211 (7), 197 (22), 183 (16), 170
(10), 149 (3), 96 (31), 85 (15). Anal. calc. for C13H28O4Si: C 61.50, H 9.03, Si 8.99; found: C 61.65, H 9.15, Si 8.91.
The crude silyl enol ether 14 (13.9 g, 44.48 mmol) was dissolved in DMSO (300 ml) and [Pd(OAc)2] (3.0g,
13.34 mmol, 0.3 equiv.) was added. The soln. was saturated with O2 and heated to 408 for 2 d, purging three
times per day with O2. The mixture was poured into cooled (08) H2O (450ml) and extracted with Et 2O (4 Â
400 ml). The combined org. extracts were washed with H2O (200 ml), dried (MgSO4), and concentrated in

Helvetica Chimica Acta Vol. 85 (2002)
425
vacuo. FC (petroleum ether/AcOEt 5 :1 to 3 :1) afforded a pale yellow oil (8 g, 75%), which was dissolved in
CHCl3 (240ml). ZnCl 2 (5.9 g, 43.65 mmol, 1.3 equiv.), Ph2SiH2 (16.9 ml, 91.67 mmol, 2.1 equiv.), PPh3 (1.15 g,
4.37 mmol, 0.1 equiv.) and [Pd(PPh3)2(OAc)2] (3.3 g, 4.37 mmol, 0.1 equiv.) were successively added. The
mixture was stirred at 708 for 4 h, then diluted with CH2Cl2 (400 ml), and washed with H2O (2 Â 100 ml). The
org. layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by FC (petroleum ether/Et2O
9 :1) to yield 5.36 g (50%, 3 steps) of (À)-16.
20
20
20
20
20
Data of (À)-16: Colorless oil. [a] ˆ À35, [a] ˆ À38, [a] ˆ À47, [a] ˆ À127, [a] ˆ À202 (c ˆ 1.9,
589
577
546
435
405
CHCl3). UV (MeCN): 195 (4520). IR (film): 2985, 2935, 1725, 1380, 1215, 1085, 820. 1H-NMR (400 MHz,
CDCl3): 4.09 (dd, 3J(HÀC(4,5) ˆ 3.6, 4J(HÀC(3,5)) ˆ 2.2, HÀC(5)); 4.08 (s, HÀC(7)); 2.6 (ddd, 2J ˆ 19.2,
3J(HÀC(3,4) ˆ 6.3, J(HÀC(3,5)) ˆ 2.2, HÀC(3)); 2.56 (m, HÀC(4)); 2.06 (dd, 2J ˆ 19.2, J(HÀC(3,4)) ˆ 7.6,
HÀC(3)); 1.66, 1.53, 1.48, 1.33 (4s, Me2C, MeÀC(1), MeÀC(6)); 1.13 (d, 3J(HÀC(4), MeÀC(4)) ˆ 7.2,
MeÀC(4)). 13C-NMR (100.6 MHz, CDCl3): 206.1 (s, C(2)); 113.6 (s, Me2C); 92.4 (s, C(6)); 89.9 (d, 1J(C,H) ˆ
136, C(7)); 89.7 (s, C(1)); 86.6 (d, 1J(C,H) ˆ 130, C(5)); 42.3 (t, 1J(C,H) ˆ 126, C(3)); 35.6 (d, 1J(C,H) ˆ 127,
C(4)); 29.4, 27.9, 23.0(3 q, 1J(C,H) ˆ 127, 123, 124, Me2C, MeÀC(1), MeÀC(6)); 13.8 (q, 1J(C,H) ˆ 129,
3
3
‡
MeÀC(4)). CI-MS (NH3): 240(3, M ), 225 (77), 207 (12), 189 (19), 164 (8), 135 (19), 111 (70), 97 (82), 85
(100). Anal. calc. for C13H20O4 (240.30): C 64.98, H 8.39; found: C 64.94, H 8.46.
(1R,4R,5S,6S,7S)-6,7-2-Ethenyl-(Isopropylidenedioxy)-1,4,6-trimethyl-8-oxabicyclo[3.2.1]oct-2-ene ((‡)-
17). The ketone (À)-16 (4 g, 16.64 mmol), dissolved in anh. THF (50ml), was added to a cooled ( À 788)
soln. of (Me3Si)2NH (6.94 ml, 33.29 mmol, 2 equiv.), BuLi (1.6m in hexane, 20.8 ml, 33.29 mmol, 2 equiv.) and
HMPA (5.8 ml, 33.29 mmol, 2 equiv.) in anh. THF (120ml). The mixture was stirred at À788 for 2 h. Then, 2-
[N,N'-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (13 g, 33.29 mmol, 2 equiv.) was added and the
temp. was raised to À308 over 2 h. The soln. was poured into H2O (250ml) and extracted with Et 2O (3 Â
200 ml). The combined org. extracts were dried (Na2SO4) and concentrated in vacuo. Filtration over a pad of
SiO2 (petroleum ether/AcOEt 6 :1) and evaporation afforded a colorless oil (6 g, 97%). In a flame-dried
Schlenk tube, LiCl (2.05 g, 48.33 mmol, 3 equiv.), [Pd(PPh3)4] (373 mg, 0.322 mmol, 0.02 equiv.) and the crude
triflate (6 g, 16.11 mmol) were dissolved in anh. THF (90ml). Tributyl(vinyl)stannane (5.17 ml, 17.72 mmol,
1.1 equiv.) was added and the mixture was stirred at 608 for 12 h. The soln. was diluted with pentane (250ml),
washed with H2O (40ml) and brine (40ml), dried (MgSO 4), and concentrated in vacuo. The residue was
20
purified by FC (petroleum ether/Et2O 7 :1) to give 3.25 g (78%, 2 steps) of (‡)-17. Colorless oil. [a] ˆ 19.7,
589
20
20
20
20
[a] ˆ 26.9, [a] ˆ 36.1, [a] ˆ 39.3, [a] ˆ 46.1 (c ˆ 0.4, CH2Cl2). UV (MeCN): 238 (5570), 196 (3740). IR
577
546
435
405
(film): 2985, 1620, 1455, 1375, 1340, 1255, 1180, 1160, 1115, 1095, 1075, 985, 955, 870, 840. 1H-NMR (400 MHz,
CDCl3): 6.07 (dd, 3J ˆ 17.3, 11.0, vinyl CH); 5.68 (d, 3J(HÀC(3,4) ˆ 7.6, HÀC(3)); 5.28 (d, 3J ˆ 17.3, CH2 vinyl),
5.02 (d, 3J ˆ 11.0, vinyl CH2); 4.04 (s, HÀC(7)); 3.91 (br. s, HÀC(5)); 2.12 (m, HÀC(4)); 1.52, 1.47, 1.42, 1.41 (4s,
Me2C, MeÀC(1), MeÀC(6)); 1.19 (d, 3J(HÀC(4), MeÀC(4)) ˆ 7.1, Me ÀC(4)). 13C-NMR (100.6 MHz, CDCl3):
139.8 (s, C(2)); 134.2 (d, 1J(C,H) ˆ 153, C(3)); 128.2 (d, 1J(C,H) ˆ 157, vinyl CH); 114.4 (t, 1J(C,H) ˆ 151, vinyl
CH2); 112.0( s, CMe2), 93.8 (s, C(6)); 92.3 (d, 1J(C,H) ˆ 157, C(7)); 93.8 (s, C(1)); 86.3 (d, 1J(C,H) ˆ 140, C(5));
34.7 (d, 1J(C,H) ˆ 127, C(4)); 28.6, 27.6, 25.1, 17.0(4 q, 1J(C,H) ˆ 126, 130, 128, 127, Me2C, MeÀC(1), MeÀC(6));
15.6 (q, 1J(C,H) ˆ 127, MeÀC(4)). Anal. calc. for C15H22O3 (250.34): C 71.97, H 8.86; found: C 71.88, H 8.75.
(1R,4R,5S,6S,7S)-2-Ethyl-6,7-(isopropylidenedioxy)-1,4,6-trimethyl-8-oxabicyclo[3.2.1]oct-2-ene ((‡)-18).
Soln. A: H2O2 (35% in H2O, 172 ml) in MeOH (500 ml). Procedure: Cu(OAc)2 (0.001m, 4.12 ml) was added to a
soln. of the diene (‡)-17 (3.2 g, 12.78 mmol) in MeOH (1.2 l). The mixture was cooled to À158 and every 8 min,
soln. A (67 ml) and hydrazine (80% in H2O, 3.3 ml) were added simultaneously. After 10additions, the mixture
was stirred at À158 for 1.5 h. H2O (250ml) was added, and the soln. was concentrated to a volume of 500ml.
The aq. layer was extracted with pentane/Et2O 2 :1 (3 Â 500 ml). The combined org. extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by FC (petroleum ether/Et2O, 6 :1) to yield 2.4 g
20
20
20
20
20
(75%) of (‡)-18. Colorless oil. [a] ˆ 84, [a] ˆ 87, [a] ˆ 99, [a] ˆ 174, [a] ˆ 213 (c ˆ 1.2, CHCl3). UV
589
577
546
435
405
(MeCN): 196 (6950). IR (film): 2980, 2935, 1650, 1460, 1375, 1245, 1110, 1060, 870. 1H-NMR (400 MHz, CDCl3):
5.28 (m, HÀC(3)); 3.98 (s, HÀC(7)); 3.90(br. s, HÀC(5)); 2.12 (m, HÀC(4)); 2.11 2.01, 1.99 1.81 (2m, CH2);
1.53, 1.50, 1.42, 1.35 (4s, Me2C, MeÀC(1), MeÀC(6)); 1.13 (d, 3J(HÀC(4),MeÀC(4)) ˆ 7.2, MeÀC(4)); 1.05
(t, 3J ˆ 7.3, MeCH2). 13C-NMR (100.6 MHz, CDCl3): 141.2 (s, C(2)); 123.9 (d, 1J(C,H) ˆ 156, C(3)); 112.0
(s, CMe2); 93.8 (s, C(1)); 92.4 (d, 1J(C,H) ˆ 156, C(7)); 87.1 (d, 1J(C,H) ˆ 151, C(5)); 84.2 (s, C(6)); 34.5
(d, 1J(C,H) ˆ 126, C(4)); 28.8, 27.8, 25.4 (3q, 1J(C,H) ˆ 123, 124, 122, Me2C, MeÀC(1), MeÀC(6)); 24.3
(t, 1J(C,H) ˆ 123, CH2); 16.2 (q, 1J(C,H) ˆ 123, MeÀC(4)); 11.8 (q, 1J(C,H) ˆ 122, MeCH2). CI-MS (NH3): 270
‡
‡
(93, [M ‡ NH4] ), 253 (100, [M ‡ H] ), 195 (24), 123 (17). Anal. calc. for C15H24O3 (252.35): C 71.39, H 9.59;
found: C 71.41, H 9.60.

426
Helvetica Chimica Acta Vol. 85 (2002)
(1S)-1-((3aR,4S,6R,6aS)-3a,4,6,6a-Tetrahydro-6-{(1S)-1-[1-methyl-2-(phenylthio)]ethyl}-2,2,4,6a-tetra-
methyl-2H-furo[3,4-d][1,3]dioxol-4-yl)propan-1-ol ((À)-22). A stream of O3 was passed through a cooled
(À 788) soln. of (‡)-17 (1.57 g, 6.23 mmol) in anh. CH2Cl2/MeOH 4 :1 (250ml) for 10min. The soln. was purged
with O2 for 2 min, and Me2S (90 ml, 12.46 mmol, 2 equiv.) was added. After stirring for 5 min at À788, NaBH4
(473 mg, 12.46 mmol, 2 equiv.) was added, and the mixture was stirred for 1 h at 08. The soln. was poured into 1m
aq. HCl soln. (250ml) and extracted with CH 2Cl2 (2 Â 200 ml). The combined org. extracts were dried (MgSO4)
and concentrated in vacuo. The residue was purified by CC (petroleum ether/AcOEt 2 :1 to 1:2) to afford a
white solid (1.44 g, 80%) as an inseparable mixture of the diols 19 and 20, respectively. To a soln. of the crude
diols (1.44 g, 4.99 mmol) in MeCN (90ml) were added PhSSPh (3.27 g, 14.97 mmol, 3 equiv.) and Oct 3P (8.9 ml,
19.96 mmol, 4 equiv.), and the soln. was stirred at 208 for 3 h. The mixture was diluted with Et2O (300 ml) and
washed with 2m aq. NaOH soln. (2 Â 200 ml). The aq. layers were re-extracted with Et2O (150ml each). The
combined org. extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo. The residue
was purified by FC (AcOEt/petroleum ether 1:5): 428 mg of 21 (22%) and 1.29 g of (À)-22 (68%). Colorless
oils.
20
20
20
20
20
Data of the Major Isomer (À)-22: [a] ˆ À18, [a] ˆ À18, [a] ˆ À20, [a] ˆ À28, [a] ˆ À36 (c ˆ
589
577
546
435
405
1.0, CHCl3). UV (MeCN): 201 (8570). IR (film): 3495, 2985, 2935, 1585, 1480, 1455, 1380, 1255, 1210, 1115, 1060,
740. H-NMR (400 MHz, CDCl3): 7.35, 7.27, 7.15 (3m, 5 arom. H); 4.31 (s, HÀC(5)); 3.50( d, 3J(HÀC(8,7)) ˆ
1
10.3, HÀC(7)); 3.41 3.35 (m, 1 HÀC(9), HÀC(3)); 2.66 (dd, 2J ˆ 12.6, J(HÀC(9,8)) ˆ 8.9, 1 HÀC(9)); 2.32
3
(br. s, HOÀC(3)); 1.86 (ddq, 2J ˆ 13.1, 3J(HÀC(3,2)) ˆ 10.3, 3J(HÀC(2,1)) ˆ 6.5, HÀC(2)); 1.65 (dm, 2J ˆ 13.1,
HÀC(2)); 1.53, 1.38, 1.35, 1.15 (4s, Me2C, MeÀC(6), MeÀC(4)); 1.45 1.33 (m, HÀC(8)); 1.10
(d, 3J(HÀC(8),MeÀC(8)) ˆ 7.1, Me ÀC(8)); 1.05 (t, 3J(HÀC(2,1)) ˆ 6.5, 3 HÀC(1)). 13C-NMR (100.6 MHz,
CDCl3): 137.4 (s, 1 arom. C); 128.7, 128.4, 125.4 (3d, 1J(C,H) ˆ 161, 162, 162, 5 arom. C); 114.4 (s); 88.4 (s, C(6));
88.2 (d, 1J(C,H) ˆ 155, C(5)); 84.8 (d, 1J(C,H) ˆ 144, C(7)); 84.7 (s, C(4)); 77.6 (d, 1J(C,H) ˆ 132, C(3)); 38.2
(t, 1J(C,H) ˆ 142, C(9)); 33.3 (d, 1J(C,H) ˆ 129, C(8)); 27.9, 26.7 (2q, 1J(C,H) ˆ 127, 126, 2 Me); 24.1
(t, 1J(C,H) ˆ 126, C(2)); 19.3, 16.3 (2q, 1J(C,H) ˆ 127, 128, 2 Me); 14.9 (q, 1J(C,H) ˆ 130, MeÀC(8)); 11.0
(q, 1J(C,H) ˆ 122, C(1)). CI-MS (NH3): 398 (32, [M ‡ NH4] ), 381 (100, [M ‡ H] ), 321 (11), 263 (32), 123
‡
‡
(22). Anal. calc. for C21H32O4S (380.55): C 66.28, H 8.48, S 8.43; found: C 66.36, H 8.43, S 8.40.
(3aR,4S,6R,6aS)-4-{(1S)-1-[1-(tert-Butyl)dimethylsilyloxy]propyl}-3a,4,6,6a-tetrahydro-6-{(1S)-1-[1-meth-
yl-2-(phenylthio)]ethyl}-2,2,4,6a-tetramethyl-2H-furo[3,4-d][1,3]dioxole ((À)-23). To a cooled (08) soln. of (À)-
22 (920mg, 2.42 mmol) in anh. CH 2Cl2 (44 ml), 2,6-lutidine (843 ml, 7.26 mmol, 3 equiv.) and (t-Bu)Me2SiO-
SO2CF3 (945 ml, 1.7 equiv.) were added. After stirring at 08 for 1 h, the soln. was poured into a 2m aq. NaOH
soln. (80ml) and extracted with CHCl 3 (3 Â 80ml). The combined org. extracts were washed with 1 m aq. HCl
soln. (80ml), brine (50ml), dried (MgSO 4), and concentrated in vacuo. The residue was purified by FC
20
20
20
(petroleum ether/AcOEt 10:1) to give 1.18 g (99%) of ( À)-23. Colorless oil. [a] ˆ À20, [a] ˆ À22, [a]
ˆ
589
577
546
20
20
À25, [a] ˆ À43, [a] ˆ À51 (c ˆ 1.9, CHCl3). UV (MeCN): 254 (10760), 196 (16910). IR (film): 2930, 1585,
435
405
1460, 1380, 1255, 825, 765, 740, 670. 1H-NMR (400 MHz, CDCl3): 7.37, 7.27, 7.15 (3m, 5 arom. H); 4.23
(s, HÀC(5)); 3.46 (d, 3J(HÀC(2,3)) ˆ 10.2, HÀC(3)); 3.41 (dd, 2J ˆ 13.3, 3J(HÀC(1,2)) ˆ 2.7, HÀC(1)); 3.38
(dd, 3J(HÀC(7,8)) ˆ 6.9, 3.6, HÀC(7)); 2.64 (dd, 2J ˆ 13.3, 3J(HÀC(1,2)) ˆ 9.1, HÀC(1)); 1.85 1.75
(m, HÀC(2), 1 HÀC(8)); 1.54 (s, Me); 1.47 (m, 1 HÀC(8)); 1.35, 1.25, 1.17 (3s, 3 Me); 1.0
(d, 3J(HÀC(2),MeÀC(2)) ˆ 6.5, MeÀC(2)); 1.01 (t, 3J(HÀC(8,9)) ˆ 7.5, HÀC(9)); 0.89 (s, (t-Bu)); 0.12, 0.10
(2s, Me2Si). 13C-NMR (100.6 MHz, CDCl3): 137.6 (s, 1 arom. C); 128.7, 128.3, 125.2 (3d, 1J(C,H) ˆ 160, 154, 161,
5 arom. C); 113.7 (s); 90.0 (d, 1J(C,H) ˆ 155, C(5)); 87.9 (s, C(4)); 84.6 (d, 1J(C,H) ˆ 141, C(3)); 84.1 (s, C(6));
78.4 (d, 1J(C,H) ˆ 140, C(7)); 38.2 (t, 1J(C,H) ˆ 141, C(1)); 33.0( d, 1J(C,H) ˆ 130, C(2)); 28.1 (t, 1J(C,H) ˆ 126,
C(8)); 26.0( q, 1J(C,H) ˆ 119, (t-Bu)); 19.5 (s, C); 18.3, 15.0(2 q, 1J(C,H) ˆ 126, 128, 4 Me)); 14.6 (q, 1J(C,H) ˆ
127, MeÀC(2)); 11.2 (q, 1J(C,H) ˆ 129, C(9)); À3.8, À4.1 (2q, 1J(C,H) ˆ 118, 118, Me2Si). CI-MS (NH3): 495
7
‡
(32, [M ‡ H] ), 403 (100), 345 (17), 271 (15), 229 (22). Anal. calc. for C27H46O4SSi (494.81): C 65.54, H 9.37,
S 6.48; found: C 65.50, H 9.29, S 6.47.
(3aR,4S,6R,6aS)-4-{(1S)-1-[1-(tert-Butyl)dimethylsilyloxy]propyl}-3a,4,6,8a-tetrahydro-2,2,4,6a-tetrameth-
yl-6-{(1S)-1-methyl-2-(phenylsulfinyl)]ethyl}-2H-furo[3,4-d]dioxole ((‡)-24 and (À)-25). To a soln. of (À)-23
(565 mg, 1.14 mmol) in MeOH/H2O 28 :1.6 (n/n), NaIO4 (1.37 mmol, 1.2 equiv.) was added, and the mixture was
stirred at 208 for 12 h. The soln. was poured into H2O (60ml) and extracted with CHCl 3 (4 Â 60ml). The
combined org. extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by FC
(petroleum ether/ether 2 :1) to yield 325 mg (55%) of (‡)-24 and 126 mg (40%) of (À)-25. Colorless oils.
20
20
20
20
20
Data of (‡)-24: [a] ˆ 30.7, [a] ˆ 48.4, [a] ˆ 65.8, [a] ˆ 125.8, [a] ˆ 156.4 (c ˆ 0.8, CH2Cl2). UV
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546
435
405
(MeCN): 215 (15430). IR (film): 2935, 2865, 1735, 1465, 1375, 1255, 1215, 1160, 1025, 940, 900, 860, 835, 775, 750.
1H-NMR (400 MHz, CDCl3): 7.67 7.65, 7.56 7.49 (2m, 5 arom. H); 4.22 (s, C(3a)); 3.44 (d, 3J ˆ 10.0, HÀC(6));

Helvetica Chimica Acta Vol. 85 (2002)
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3.38 (dd, 3J ˆ 6.7, 4.0, EtCH); 3.02 (d, 2J ˆ 13.2, 1 H, SCH2); 2.37 (dd, 2J ˆ 13.2, 3J ˆ 10.5, 1 H, SCH2); 2.34 2.26
(m, SCH2CH); 1.75 1.67, 1.48 1.44 (2m, MeCH2); 1.42, 1.38, 1.31, 1.15 (4s, 4 Me); 1.28 (d, 3J ˆ 6.3,
MeCHCH2S); 0.96 (t, 3J ˆ 7.5, MeCH2); 0.90 (s, (t-Bu)); 0.09 (s, Me2Si). 13C-NMR (100.6 MHz, CDCl3): 144.7
(s, 1 arom. C); 130.8, 129.2, 124.0 (3d, 1J(C,H) ˆ 164, 162, 161, 5 arom. C); 113.9 (s, C(2)); 89.9 (d, 1J(C,H) ˆ
151, C(3a)); 87.9 (s, C(6a)); 84.7 (d, 1J(C,H) ˆ 143, C(6)); 84.3 (s, C(4)); 78.2 (d, 1J(C,H) ˆ 150, EtCH); 61.4
(t, 1J(C,H) ˆ 143, SCH2); 29.0( d, 1J(C,H) ˆ 130, SCH2CH); 28.1, 26.6 (2q, 1J(C,H) ˆ 128, 128, 2 Me); 26.1
(q, 1J(C,H) ˆ 130, (t-Bu)); 25.7 (t, 1J(C,H) ˆ 129, CH2Me); 20.1, 17.3 (2q, 1J(C,H) ˆ 127, 129, 2 Me); 18.3
(s, 1 C); 15.2 (q, 1J(C,H) ˆ 130, MeCHCH2S); 11.0( q, 1J(C,H) ˆ 127, CH2Me); À3.9 (q, 1J(C,H) ˆ 116, Me2Si).
‡
‡
CI-MS (NH3): 511 (7, [M ‡ H] ), 453 (20, [M À (t-Bu)] ), 395 (6), 337 (24), 125 (30), 73 (100). Anal. calc. for
C27H46O5SSi (510.81): C 63.49, H 9.08; found: C 63.60, H 9.15.
20
20
20
20
20
Data of (À)-25: [a] ˆ À11.0, [a] ˆ À18.3, [a] ˆ À30.7, [a] ˆ À81.0, [a] ˆ À115.3 (c ˆ 0.3,
589
577
546
435
405
CH2Cl2). UV (MeCN): 195 (16960). IR (film): 2990, 2955, 2935, 2850, 1740, 1460, 1380, 1255, 1115, 835, 775, 750.
1H-NMR (400 MHz, CDCl3): 7.73 7.70, 7.58 7.53 (2m, 5 arom. H); 4.14 (s, C(3a)); 3.34 (d, 3J ˆ 10.1, HÀC(6));
3.32 (dd, 3J ˆ 5.2, 3.9, EtCH); 3.05 (dd, 2J ˆ 13.1, 3J ˆ 2.3, 1 H, SCH2); 2.72 (dd, 2J ˆ 13.1, 3J ˆ 10.4, 1 H, SCH2);
1.78 1.73 (m, SCH2CH); 1.70 1.63, 1.44 1.40(2 m, MeCH2); 1.29, 1.24, 1.19, 1.13 (4s, 4 Me); 1.18 (d, 3J ˆ 6.5,
MeCHCH2S); 0.92 (t, 3J ˆ 7.0, MeCH2); 0.89 (s, (t-Bu)); 0.08, 0.03 (2s, Me2Si). 13C-NMR (100.6 MHz, CDCl3):
144.2 (s, 1 arom. C); 131.2, 129.2, 124.5 (3d, 1J(C,H) ˆ 162, 163, 164, 5 arom. C); 114.0( s, C(2)); 89.6
(d, 1J(C,H) ˆ 152, C(3a)); 87.6 (s, C(6a)); 84.6 (d, 1J(C,H) ˆ 137, C(6)); 84.2 (s, C(4)); 78.2 (d, 1J(C,H) ˆ 160,
EtCH); 60.5 (t, 1J(C,H) ˆ 142, SCH2); 29.2 (d, 1J(C,H) ˆ 137, SCH2CH); 28.0, 26.6 (2q, 1J(C,H) ˆ 127, 129,
2 Me); 26.0( q, 1J(C,H) ˆ 122, (t-Bu)); 25.6 (t, 1J(C,H) ˆ 128, CH2Me); 19.4, 18.1 (2q, 1J(C,H) ˆ 125, 127, 2 Me);
18.3 (s, 1 C); 15.3 (q, 1J(C,H) ˆ 131, MeCHCH2S); 10.9 (q, 1J(C,H) ˆ 128, CH2Me); À4.1 (q, 1J(C,H) ˆ 114,
‡
‡
Me2Si). CI-MS (NH3): 511 (100, [M ‡ H] ), 453 (36, [M À (t-Bu)] ), 395 (11), 325 (42), 251 (13), 173 (55), 73
(70). Anal. calc. for C27H46O5SSi (510.81): C 63.49, H 9.08; found: C 63.95, H 9.28.
(1S,3S,4R,5S,6R,7S)(-8-(Benzyloxy)-1-((3aS,4R,6S,6aR)-6-{(1S)-1-[1-(tert-butyl)dimethylsilyloxy]pro-
pyl}-3a,4,6,6a-tetrahydro-2,2,3a,6-tetramethyl-2H-furo[3,4-d][1,3]dioxol-4-yl)-4,6-(isopropylidenoxy)-2-(phe-
nylsulfinyl)-1,3,5,7-tetramethyloctan-3-ol ((‡)-26). In a flame-dried Schlenk tube, BuLi (1.5m in hexane, 418 ml,
0.627 mmol, 1.6 equiv.) was added to a cooled (À608) soln. of i-Pr2NH (105 ml, 0.745 mmol, 1.9 equiv.) in anh.
THF (8 ml). After stirring for 15 min at À608, the mixture was cooled to À788, and a cooled (À 788) soln. of (‡)-
24 (200 mg, 0.392 mmol) in anh. THF (1 ml) was added dropwise. After 2 min, TMEDA (94 ml, 0.627 mmol,
1.6 equiv.) was added, followed by a cooled (À 788) soln. of (‡)-8 (163 mg, 0.510 mmol, 1.3 equiv.) in anh. THF
(1 ml). After stirring for 5 min at À788, the soln. was poured into sat. aq. NH4Cl soln. (20ml) and extracted with
AcOEt (3 Â 20ml). The combined org. extracts were dried (MgSO 4) and concentrated in vacuo. The residue
was purified by FC (petroleum ether/AcOEt 15 :1 to 3 :1) to give 130mg (40%) of ( ‡)-26 and 70mg (35%) of
20
20
20
20
20
recovered (‡)-24, resp. Colorless oil. [a] ˆ 5.6, [a] ˆ 4.7, [a] ˆ 4.9, [a] ˆ 10.2, [a] ˆ 11.4 (c ˆ 0.5,
589
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405
CH2Cl2). UV (MeCN): 273 (15030), 260 (12720), 217 (11413). IR (film): 3285, 2935, 2855, 1455, 1380, 1260,
1205, 1115, 1070, 1015, 945, 870, 835, 775, 740, 700. 1H-NMR (400 MHz, CDCl3): 7.92 7.90, 7.42 7.39, 7.36 7.30
(3m, 10arom. H); 7.00(br. s, HOÀC(3)); 4.52 (s, CH2Ph); 4.35 (s, EtCHCCH); 4.05 (d, 3J ˆ 10.1, S(CH)2CH);
3.60( d, 3J ˆ 2.2, HÀC(4)); 3.46 (dd, 3J ˆ 6.7, 3.9, EtCH); 3.33 (dd, 2J ˆ 10.0, 3J ˆ 3.8, HÀC(8)); 3.26 (dd, 2J ˆ
10.0, 3J ˆ 5.9, HÀC(8)); 2.86 (br. s, HÀC(2)); 2.83 (dd, 3J(HÀC(6,7)) ˆ 9.7, 3J(HÀC(5,6)) ˆ 1.4, HÀC(6));
2.57 2.53 (m, HÀC(1)); 1.80 1.70( m, HÀC(7), HÀC(5), 1 H, CH2Me); 1.67 (d, 3J(HÀC(1),MeÀC(1)) ˆ 6.8,
MeÀC(1)); 1.61, 1.42, 1.40, 1.27 (4s, 2 Me2C); 1.56 1.43 (m, 1 H, CH2Me); 1.21 (br. s, S(CH)3CMe, EtCHCMe);
0.99 (t, 3J ˆ 7.5, CH2Me); 0.97 (d, 3J(HÀC(5),MeÀC(5)) ˆ 6.7, MeÀC(5)); 0.93 (s, (t-Bu)); 0.88 (d, 3J(HÀC(7),
MeÀC(7)) ˆ 6.7, MeÀC(7)); 0.56 (s, MeÀC(3)); 0.12 (s, Me2Si). 13C-NMR (100.6 MHz, CDCl3): 143.5, 138.7
(2s, 2 arom. C); 130.4, 129.2, 128.4, 127.8, 127.6 (5d, 10arom. C); 114.7, 98.7 (2 s); 90.3 (d, 1J(C,H) ˆ 149,
EtCHCC); 89.0( s, C(3)); 85.3, 83.5 (2s, S(CH)3C, EtCHC); 84.0( d, 1J(C,H) ˆ 158, S(CH)2C); 78.3
(d, 1J(C,H) ˆ 139, EtCH); 78.0( d, 1J(C,H) ˆ 141, C(4)); 76.7 (d, 1J(C,H) ˆ 141, C(6)); 73.3 (t, 1J(C,H) ˆ 142,
CH2Ph); 71.3 (t, 1J(C,H) ˆ 143, C(8)); 64.4 (d, 1J(C,H) ˆ 144, C(2)); 34.4 (d, 1J(C,H) ˆ 123, C(7)); 33.3
(d, 1J(C,H) ˆ 128, C(1)); 30.7 (d, 1J(C,H) ˆ 126, C(5)); 29.8, 28.1, 26.8 (3q, 1J(C,H) ˆ 129, 3 Me); 26.1
(q, 1J(C,H) ˆ 119, (t-Bu)); 25.9, 20.9, 19.2 (3q, 1J(C,H) ˆ 127, 126, 128, 3 Me); 24.3 (t, 1J(C,H) ˆ 128, CH2Me);
18.4 (s, 1 C); 15.8 (q, 1J(C,H) ˆ 126, Me); 14.9, 14.8 (2q, 1J(C,H) ˆ 122, 122, MeÀC(7), MeÀC(1)); 10.8
(q, 1J(C,H) ˆ 120, CH2Me); 7.5 (q, 1J(C,H) ˆ 121, MeÀC(5)); À3.9, À4.1 (2q, 1J(C,H) ˆ 117, 116, Me2Si). CI-
‡
‡
MS (NH3): 832 (74, [M ‡ H] ), 774 (10, [M À (t-Bu)] ), 688 (77), 629 (28), 427 (100), 235 (47), 91 (50,
‡
[PhCH2] ). Anal. calc. for C46H74O9SSi: C 66.47, H 8.97; found: C 66.78, H 8.79.
(2S,3R,4S,5R,6S,8S)-8-((3aS,4R,6S,6aR)-6-{(1S)-1-[1-(tert-Butyl)dimethylsilyloxy]propyl}-3a,4,6,6a-tetra-
hydro-2,2,3a,6-tetramethyl-2H-furo[3,4-a][1,3]dioxol-4-yl)-6-hydroxy-3,5-(isopropylidenoxy)-2,4,6,8-tetra-
methyloctanoic acid ((‡)-27). To a soln. of (‡)-26 (100 mg, 0.12 mmol) in Et2O/EtOH 7:3 (v/v) W2 Raney Ni

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Helvetica Chimica Acta Vol. 85 (2002)
(500 mg) was added, and the mixture was vigorously stirred at 208 for 15 h. Filtration over a pad of SiO2
(AcOEt) and concentration in vacuo afforded a colorless oil (86 mg, 100%, crude), which was taken up in EtOH
(8 ml). W2 Raney Ni (400 mg) was added, and the mixture was vigorously stirred under H2 (1 bar) at 208 for
12 h. Filtration over a pad of SiO2 (AcOEt) and concentration in vacuo afforded the corresponding alcohol
(88%, crude, 2 steps), that was oxidized as follows: DMSO (37 ml, 0.526 mmol, 5 equiv.) was added to a cooled
(À 788) soln. of oxalyl chloride (22 ml, 0.252 mmol, 2.4 equiv.) in anh. CH2Cl2 (4 ml). After stirring for 15 min at
À788, a soln. of the above intermediate (65 mg, 0.105 mmol) in anh. CH2Cl2 (2 ml) was added dropwise. After
stirring for 30min at À788, Et3N (150 ml) was added, and the temp. was raised to À308. After 5 min, the soln. was
poured into H2O (15 ml) and extracted with AcOEt (4 Â 15 ml). The combined org. extracts were washed with
H2O (20ml), dried (MgSO 4), and concentrated in vacuo. The residue was taken up in t-BuOH (4 ml) and 2-
methylbut-2-ene (78 ml). A soln. of NaH2PO4 (182 mg, 1.172 mmol, 11.6 equiv.) and NaClO2 (137 mg,
1.515 mmol, 15 equiv.) in distilled H2O (4 ml) was added, and the mixture was stirred at 208 for 2 h. The soln.
was poured into brine (15 ml) and extracted with AcOEt (4 Â 15 ml). The combined org. extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by FC (CH2Cl2/MeOH 15 :1) to yield 38 mg
20
20
20
20
20
(50%, 4 steps) of (‡)-27. Colorless oil. [a] ˆ 10.8, [a] ˆ 12.5, [a] ˆ 22.9, [a] ˆ 40.1, [a] ˆ 62.7 (c ˆ 0.3,
589
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405
CH2Cl2). UV (MeCN): 262 (10050), 212 (4750). 1H-NMR (400 MHz, CDCl3): 4.20( s, (Me2C)OCH); 3.92
(dd, 3J(HÀC(2,3)) ˆ 8.9, 3J(HÀC(3,4)) ˆ 0.9, HÀC(3)); 3.59 (d, 3J(HÀC(4,5)) ˆ 1.9, HÀC(5)); 3.38 (d, 3J ˆ
10.2, OCHC(8)); 3.37 (dd, 3J ˆ 7.5, 3.0, EtCH); 2.73 2.69 (m, HÀC(2)); 1.89 1.86 (m, HÀC(4), HÀC(8));
1.80 1.61 ( m, 1 HÀC(7), 1 H, MeCH2); 1.49 1.29 (m, 1 HÀC(7), 1 H, MeCH2); 1.53, 1.48, 1.44, 1.41 (4s,
2 Me2C); 1.35, 1.23, 1.15 (3s, MeÀC(6), (Me2C)OCMe, EtCHCMe); 1.26 (d, 3J(HÀC(2),MeÀC(2)) ˆ 6.9,
MeÀC(2)); 1.04 (d, 3J(HÀC(4),MeÀC(4)) ˆ 6.9, MeÀC(4)); 0.98 (d, 3J(HÀC(8),MeÀC(8)) ˆ 6.6,
MeÀC(8)); 0.95 (t, 3J ˆ 6.9, MeCH2); 0.92 (s, (t-Bu)); 0.12, 0.11 (2s, Me2Si). 13C-NMR (100.6 MHz, CDCl3):
177.0( s, C(1)); 113.4, 99.7 (2s, 2 Me2C); 90.0 (d, (Me2C)OCH); 86.7 (d, OCHC(8)); 80.0 (d, C(5)); 78.4
(d, EtCH); 76.1 (d, C(3)); 87.6, 84.9, 72.7 (3s, C(6), (Me2C)OCMe, EtCHC); 46.0( t, C(7)); 41.2 (d, C(2)); 31.5,
27.6 (2d, C(4), C(8)); 29.8, 28.1, 26.5 (3q, 3 Me); 26.0( q, Me3C); 25.0( t, MeCH2); 23.2, 19.3, 18.6 (3q, 4 Me);
18.3 (q, MeÀC(8)); 17.5 (s, 1 C); 14.1 (q, MeÀC(2)); 11.1 (q, MeCH2); 7.0( q, MeÀC(4)); À3.6, À4.3 (2q,
‡
‡
Me2Si). CI-MS (NH3): 649 (100, [M ‡ NH4 ‡ 1] ), 632 (87, [M ‡ H ‡ 1] ), 574 (53), 429 (45), 73 (48). Anal.
calc. for C33H62O9Si (630.93): C 62.82, H 9.90; found: C 63.01, H 9.98.
(1R,2R,5R,6S,7S,8R,9R,11R,12R,13S,14S)-2-Ethyl-6,8,9,13,14-pentahydroxy-1,5,7,9,11,13-hexamethyl-3,15-
dioxabicyclo[10.2.1]pentadecan-4-one ((À)-9). To a cooled (À 308) soln. of (‡)-27 (15 mg, 24 mmol) in anh. THF
(1 ml), Bu4NF (1m in THF, 150ml) was added dropwise, and the mixture was allowed to react at 20 8 for 1 h. The
solvent was evaporated, and the residue was filtered over a pad of SiO2 (AcOEt). Concentration in vacuo
afforded a pale yellow oil (28, 10mg, 80%, crude), which was directly engaged in the macrolactonization. The
seco-acid 28 (10mg), was dissolved in a 0.4 m soln. of i-Pr2NEt (1.45 ml, 0.580 mmol, 30 equiv.) in benzene. A
0.4m soln. of 2,4,6-trichlorobenzoyl chloride (967 ml, 0.387 mmol, 20 equiv.) was added dropwise. After stirring
for 3 h at 208, the soln. was diluted with PhH (11 ml) and added through a syringe pump over 24 h to a refluxing
soln. of 4-(Me2N)-pyridine (118 mg, 0.967 mmol) in benzene (20 ml). The mixture was cooled to 208 and a sat.
aq. soln. of NaHCO3 (25 ml) was added to dissolve the white precipitate. The layers were separated and the aq.
layer was extracted with AcOEt (3 Â 25 ml). The combined org. extracts were washed with brine (20ml), dried
(MgSO4) and concentrated in vacuo. The residue was filtered over a pad of SiO2 (AcOEt/petroleum ether 1:2)
and concentrated in vacuo. The crude macrolactone (8 mg, 16.03 mmol) was stirred for 1 h at r.t. in 80% aq.
CF3COOH (1 ml). The solvent was evaporated and the residue was purified by FC (CH2Cl2/MeOH 15 :1) to
20
20
20
20
give 4.5 mg (55%, 2 steps) of (À)-9. Colorless oil. [a] ˆ À0.2, [a] ˆ À1.0, [a] ˆ À2.0, [a] ˆ À6.5,
589
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20
[a] ˆ À9.0( c ˆ 0.2, MeOH). UV (MeCN): 265 (10620), 258 (11450), 215 (3820). IR (film): 3475, 2970, 2940,
405
1750, 1465, 1370, 1215, 1185, 1140, 1030, 990, 920, 640, 615. 1H-NMR (400 MHz, CD3CN): 4.98 (dd, 3J ˆ 11.2, 2.4,
HÀC(2)); 3.69 (d, 3J(HÀC(5,6)) ˆ 10.7, HÀC(6)); 3.53 (s, HÀC(14)); 3.29 (d, 3J(HÀC(11,12)) ˆ 11.1,
HÀC(12)); 3.16 (d, 3J(HÀC(7,8)) ˆ 1.9, HÀC(8)); 2.54 2.50( m, HÀC(5)); 2.18 2.15 (m, HÀC(7)); 2.00
1.97 (m, HÀC(11)); 1.73 1.67 (dm, 2J ˆ 14.7, 1 H, MeCH2); 1.62 1.56 (m, 1 H, MeCH2, 2 HÀC(10)); 1.22
(s, MeÀC(13)); 1.16 (s, MeÀC(9)); 1.13 (d, 3J(HÀC(5),MeÀC(5)) ˆ 6.8, MeÀC(5)); 1.09 (s, MeÀC(1)); 1.04
(d, 3J(HÀC(11),MeÀC(11)) ˆ 6.2, MeÀC(11)); 1.01 (d, 3J(HÀC(4),MeÀC(7)) ˆ 6.9, MeÀC(7)); 0.85 (t, 3J ˆ
7.4, MeCH2). 1H-NMR (400 MHz, CD3OD): 5.02 (dd, 3J ˆ 11.0, 2.4, HÀC(2)); 3.75 (d, 3J(HÀC(2,3)) ˆ 10.8,
HÀC(6)); 3.59 (s, HÀC(14)); 3.33 (masked, HÀC(12)); 3.20( d, 3J(HÀC(7,8)) ˆ 1.0, HÀC(8)); 2.57 2.53
(m, HÀC(5)); 2.18 (qd, 3J(HÀC(7),MeÀC(7)) ˆ 6.8, 3J(HÀC(7,8)) ˆ 1.0, HÀC(7)); 2.07 1.99 (m, HÀC(11));
1.77 1.64 (m, MeCH2); 1.50 1.37 ( m, 2 HÀC(10)); 1.27 (s, MeÀC(13)); 1.22 (s, MeÀC(9)); 1.21
(d, 3J(HÀC(5),MeÀC(5)) ˆ 7.1, Me ÀC(5)); 1.17 (s, MeÀC(1)); 1.09 (d, 3J(HÀC(11),MeÀC(11)) ˆ 6.2,
MeÀC(11)); 1.08 (d, 3J(HÀC(7),MeÀC(7)) ˆ 6.8, MeÀC(7)); 0.91 (t, 3J ˆ 7.3, 2 MeCH2). 13C-NMR

Helvetica Chimica Acta Vol. 85 (2002)
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(100.6 MHz, CD3OD): 175.2 (s, C(4)); 87.6 (d, C(14)); 84.7 (d, C(2)); 83.2, 75.8, 74.1 (3s, C(1), C(9), C(13));
80.7 (d, C(12)); 78.7 (d, C(6)); 78.1 (d, C(8)); 46.0( t, C(10)); 42.3 (d, C(5)); 38.1 (d, C(7)); 31.8 (d, C(11)); 30.6
(q, MeÀC(1)); 24.2 (q, MeÀC(9)); 23.7 (q, MeÀC(13)); 21.7 (t, MeCH2); 16.3 (q, MeÀC(11)); 15.4
‡
(q, MeÀC(5)); 11.2 (q, MeÀC(7)); 7.8 (q, MeCH2). CI-MS (NH3): 419 (58, [M ‡ H] ), 401 (61, [M À H2O ‡
‡
1] ), 383 (95), 360(16), 294 (29), 242 (23), 167 (24), 125 (66), 98 (29), 83 (100). Anal. calc. for C 21H38O8
(418.52): C 60.27, H 9.15; found: C 60.40, H 9.17.
(1R,2R,7S,8R,9R,11R,12R,13S,14S)-2-Ethyl-8,9,13,14-tetrahydroxy-1,5,9,7,11,13-hexamethyl-3,15-dioxabi-
cyclo[10.2.1]pentadec-5-ene-4-one ((À)-30). HF (40% in H2O, 60 ml) was added dropwise to a cooled (08) soln.
of (‡)-27 (18 mg, 28.53 mmol) in MeCN (1 ml). After 15 min, the mixture was allowed to react at 208 for 1.5 h.
Sat. aq. NaHCO3 soln. (6 ml) was added until pH 8 was reached. Then, the mixture was re-acidified with 1m aq.
HCl soln. (5 ml). The mixture was extracted with AcOEt (4 Â 12 ml), and the combined org. extracts were dried
(MgSO4) and concentrated in vacuo. FC (CH2Cl2/MeOH 10:1) afforded the intermediate 29 (white foam, 7 mg,
51%), which was directly engaged in the macrolactonization. The seco-acid 29 (7 mg, 15 mmol) was dissolved in
i-Pr2NH (0.4m soln. in PhH, 1.1 ml, 0.440 mmol, 30 equiv.) and a soln. of 2,4,6-trichlorobenzoyl chloride (0.4m in
PhH, 734 ml, 0.294 mmol, 20 equiv.) was added dropwise. The mixture was stirred at 208 for 3 h. The soln. was
diluted with benzene (8.5 ml) and added through a syringe pump over 23 h to a refluxing soln. of DMAP
(90mg) in benzene (15 ml). The mixture was cooled to 20 8, and sat. aq. NaHCO3 soln. (20ml) was added to
dissolve the white precipitate. The layers were separated, and the aq. layer was extracted with AcOEt (3 Â
20ml). The combined org. extracts were washed with brine (15 ml), dried (MgSO 4), and concentrated in vacuo.
The residue was filtered over a pad of SiO2 (AcOE/petroleum ether 1:3) and concentrated in vacuo to give a
pale yellow oil, which was immediately exposed to 80% aq. CF3CO2H (1 ml) for 1 h at r.t. The solvent was
evaporated, and the residue was purified by FC (MeCN/25% aq. NH3 7:1) to give 4 mg (68%, 2 steps) of (À)-30.
20
20
20
20
20
Colorless oil. [a] ˆ À2, [a] ˆ À15, [a] ˆ À34, [a] ˆ À79, [a] ˆ À103 (c ˆ 0.1, MeOH). UV
589
577
546
435
405
(MeCN): 273 (13330), 214 (3460). IR (film): 3055, 2985, 2870, 1690, 1585, 1555, 1425, 1405, 1290, 1200, 1115,
1025, 930, 815, 755, 695, 665. H-NMR (400 MHz, CD3OD): 685 (dd, 3J(HÀC(6,7)) ˆ 6.5, J(HÀC(6,8)) ˆ 1.3,
HÀC(6)); 4.32 (br. d, 3J(HÀC(7,8)) ˆ 3.0, HÀC(8)); 3.46 (s, HÀC(14)); 3.27 (dd, 3J ˆ 10.4, 1.7, HÀC(2)); 3.22
(d, 3J(HÀC(11,12)) ˆ 9.5, HÀC(12)); 2.68 2.66 (m, HÀC(7)); 2.08 1.96 (m, HÀC(11)); 1.91 (br. s,
MeÀC(5)); 1.65 1.60( m, HÀC(10), 1 H, MeCH2); 1.41 1.35 (m, HÀC(10), 1 H, MeCH2); 1.29 (s, MeÀC(9),
ÀC(13)); 1.14 (d, 3J(HÀC(7),MeÀC(7)) ˆ 7.0, Me ÀC(7)); 1.12 (d, 3J(HÀC(11),MeÀC(11)) ˆ 6.3,
MeÀC(11)); 1.11 (s, MeÀC(5)); 1.05 (t, 3J ˆ 7.3, MeCH2). 13C-NMR (100.6 MHz, CD3OD): 171.6 (s, C(4));
151.6 (d, C(6)); 129.5 (s, C(5)); 89.2 (d, C(14)); 88.4 (d, C(12)); 83.6 (d, C(2)); 82.6 (d, C(8)); 88.8, 80.0, 77.0 (3s,
C(1), C(9), C(13)); 49.6 (t, C(10)); 34.9 (d, C(7)); 33.2 (d, C(11)); 27.9, 26.0, 24.7 (3q, MeÀC(9), MeÀC(13),
MeÀC(1)); 21.3 (t, MeCH2); 19.3 (q, MeÀC(5)); 16.9 (q, MeÀC(7)); 15.8 (q, MeÀC(11)); 14.2 (q, MeCH2). CI-
1
4
‡
MS (NH3): 401 (100, [M ‡ H] , 294 (7), 223 (10), 123 (15). Anal. calc. for C21H36O7 (400.51): C 62.98, H 9.06;
found: C 62.96, H 9.08.
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Received June 29, 2001