A formal synthesis of 18-O-methyl mycalamide B

Article abstract of DOI:10.1055/s-1999-3633

A new approach to the C7-C 18 fragment 2 of the potent antitumour agent 18-O-methyl mycalamide B benefits from greater flexibility in side chain construction and a more efficient synthesis of the 1,3-dioxane ring.

Full text of DOI:10.1055/s-1999-3633

PAPER
2087
A Formal Synthesis of 18-O-Methyl Mycalamide B
Philip J. Kocienski,*a Piotr Raubo,a Christopher Smith,a F. Thomas Boyleb
a Department of Chemistry, Glasgow University, Glasgow G12 800, UK
Fax +44(141)3306867; E-mail: P.Kocienski@chem.gla.ac.uk
bZeneca Pharmaceuticals, Mereside, Macclesfield, Cheshire, SK10 4TG, UK
Received 14 June 1999
The first phase of our synthesis required appendage of hy-
droxymethyl and hydroxyl groups to the dihydropyranone
5 as outlined in Scheme 2. The sequence began with a
highly diastereoselective Cu(I)-mediated conjugate addi-
Abstract: A new approach to the C7–C18 fragment 2 of the potent
antitumour agent 18-O-methyl mycalamide B benefits from greater
flexibility in side chain construction and a more efficient synthesis
of the 1,3-dioxane ring.
tion
of
Tamao's
Grignard
reagent,
(i-
Key words: conjugate addition, Fleming–Tamao oxidation, asym-
metric dihydroxylation, 1,3-dioxane synthesis, stereoselective a-
hydroxylation of a ketone, addition reactions, Grignard reaction, re-
ductions, osmium, protecting groups
PrO)SiMe2CH2MgCl,5 to the dihydropyranone 5. The re-
action occurred in high yield to give the adduct 6 as a sin-
gle diastereoisomer (Note 1). The latent hydroxyl group
was unveiled by a Fleming–Tamao oxidation5-7 and the
nascent hydroxyl protected as its TBS ether 8 in 94%
18-O-Methyl mycalamide B (1, Scheme 1) is the most po-
tent derivative of the marine antitumour agent mycala-
mide B1 discovered during
a
structure-activity
SiMe2(OPri)
OH
relationship study by Munro and co-workers.2 With very
limited supplies of the natural product available for study,
we undertook a total synthesis which confirmed the high
potency of 1, but our synthesis was marred by two de-
fects.3 Firstly, construction of the dihydropyranone inter-
mediate 3 from (S)-(–)-malic acid (4) was long and
inefficient owing to low diastereoselectivity in the con-
struction of the C15 stereogenic centre. Secondly, con-
struction of the 1,3-dioxane in intermediate 2 from the
dihydropyranone 3 was capricious and difficult to scale
up. We now report an improved synthesis of C7–C18
fragment 2 from the readily available (R)-dihydropyra-
none 54 which circumvents both of the aforementioned
problems. An added bonus to the new route is the oppor-
tunity to vary the substitution in the side chain.
12
15
O
O
O
11
A
B
O
O
O
100%
87%
Cl
Cl
Cl
6
5
7
C
94%
O
OTBS
O
OTBS
O
OTBS
O
O
OTBS
Cl
OTBS
Cl
E
D
99%
100%
Cl
10
9
8
77%
F
OH OH
OH OH
O
O
O
O
O
O
H
O
O
O
H
OMe O
O
12
12
H
O
H
O
O
G
OMe
7
OMe
MeO
+
O
O
N
H
O
N
H
86%
OH
O
Cl
Cl
Cl
18
OMe
11a
mp 63.0–63.5 °C
11b
12
OMe
1
mp 60.0–60.5 °C
OMe
OMe
18-O-Methyl mycalamide B
2
Reagents and conditions: (7 steps, 53% overall yield)
O
O
CO2H
A
B
C
D
E
F
100% (i-PrO)SiMe2CH2MgCl/CuBr•SMe2/THF, –70 to –30 °C
87% H2O2/KF•2H2O/KHCO3/THF-MeOH-H2O, 0 °C, 6 h
94% TBSCl/Et3N/DMAP/CH2Cl2, r.t., 36 h
CO2H
O
15
O
15
OH
Cl
OMe
100% TBSOTf/Et3N/CH2Cl2, r.t., 1.5 h
99% oxone/KHCO3/18-crown-6/toluene-acetone-H2O, r.t., 1 h
77% (a) PPTS/MeOH-H2O, reflux, 18 h; (b) column chroma-
tographic separation
OMe
5
4
3
Scheme 1
G
86% 2-methoxypropene/PPTS/CH2Cl2, r.t., 4.25 h
Scheme 2
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

2088
P. J. Kocienski et al.
PAPER
yield. a-Hydroxylation of the ketone at C12 was accom-
plished by a three-step sequence beginning with the prep-
aration of the enol silane 9 (Note 2). Then epoxidation
with dimethyldioxirane generated in situ by phase-trans-
fer catalysis8,9 gave the sensitive oxirane 10 which was
immediately hydrolysed to give a mixture of the diastere-
oisomeric crystalline a-hydroxy ketones 11a and 11b
(dr = 1:15) which were separable by column chromatog-
raphy. The major product 11b was assigned the desired
(S)-stereochemistry based on the doublet (J = 7.9 Hz) for
the C12-H at d = 4.61. The corresponding signal in the mi-
nor isomer appeared as a dd (J = 8.5, 3.3 Hz) at d = 3.83.
To complete the sequence, the two hydroxyl groups were
protected as the isopropylidene acetal 12 in 86% yield.
O
O
O
O
O
O
O
OH
OH
13
13
A
O
O
O
+
1:7.5
88%
Cl
Cl
Cl
12
13a
mp 89.0–89.5 °C
13b (74%)
mp 96–97 °C
B
97%
OMe
Cl
O
O
O
O
O
O
OMe
OMe
D
C
O
O
O
99%
100%
SePh
The second phase of our synthesis entailed the elaboration
of the side chain at C15 (Scheme 3). But first the hindered
ketone 12 had to be reduced selectively to give the alcohol
13b. Efficiency and stereoselectivity depended strongly
on both the diol protecting group and the reducing agent.
The di-tert-butylsilylene group was introduced in highest
yield (99%) but it was the least reactive of the substrates
tried and it only gave a modest dr (13a:13b = 1:2–3) at
best in the reduction step. The benzylidene derivative
gave the best dr (13a:13b = 1:14) in the reduction step but
it was formed in meagre yield (30–40%) using benzalde-
hyde dimethylacetal and TsOH. The isopropylidene group
offered the best compromise because it was introduced in
good yield (86%) and reduction of the keto function was
sensitive to the reducing agent. Thus, reduction of 12 with
L-selectride in THF at –78 °C favoured the undesired di-
astereoisomer 13a (13a:13b = 10:1) and less hindered re-
ducing agents such as sodium borohydride in MeOH
likewise favoured 13a. However, sodium triacetoxyboro-
hydride in the presence of cerium trichloride in MeOH
favoured the desired isomer 13b.10 At room temperature,
the reduction gave 13a:13b = 1:2.5 but this improved to at
least 1:7.5 by conducting the reaction at 0 °C (Note 3). At
low temperature (–78 °C) the reaction was too slow to be
practical. Pure 13b obtained directly by crystallisation
from the mixture, was then O-methylated using phase-
transfer catalysis to give the methyl ether 14 in 97% yield.
16
mp 33.0–33.5 °C
15
14
mp 49-51 °C
E
99%
O
O
O
O
O
O
OMe
OMe
OMe
F
+
1:6.6
O
O
O
94%
OH
OH
OMe
OH
17a
mp 102–103 °C
OH
17b
mp 104.0–104.5 °C
OMe
18
Reagents and conditions: (7 steps, 55% overall yield)
A
B
C
D
74% NaB(OAc)3H/CeCl3•7H2O/MeOH-H2O, 0 °C, 4.25 h
97% (MeO)2SO2/Bu4NHSO4/NaOH/toluene-H2O, r.t., 14 h
100% (PhSe)2/NaBH4/EtOH, reflux, 40 min
99% (a) NaIO4/MeOH-H2O, r.t.; (b) Et3N/toluene, reflux,
10 min
E
83% (DHQ)2PYR/K2OsO4/K3Fe(CN)6/K2CO3/t-BuOH-
H2O, 0 °C, 3 h
F
94% NaH/MeI/THF, r.t., 7 h
Scheme 3
The third and final phase of the synthesis (Scheme 4) be-
gan with a series of protecting group manipulations to
produce the free primary alcohol 22 whose oxidation with
the Dess–Martin periodinane12 yielded the sensitive alde-
hyde 23. Conversion of the aldehyde 23 to its dibenzyl ac-
etal 24 was accompanied by partial deprotection of the
TES ether. Complete scission of the TES ether was
achieved with TBAF whereupon the nascent hydroxyl
group was used to initiate construction of the 1,3-dioxane
ring. Treatment of 24 with paraformaldehyde in the pres-
ence of HCl13 gave the diastereoisomeric 1,3-dioxane ac-
etals 25a,b (dr = 6.5:1) in 93% yield. Separation of the
acetals 25a,b by column chromatography was possibe but
useless since hydrogenolysis of the benzyl group gave the
same mixture of the hemiacetals 26 (dr = 3:1). To com-
plete the synthesis, the mixture of the hemiacetals 26 was
converted to the C7–C18 fragment 2 and thence to 18-O-
methyl mycalamide B as described previously.3
Initial attempts to convert the 3-chloropropyl side chain in
14 to its 2-propenyl analogue by dehydrohalogenation us-
ing DBU gave messy reactions as did similar experiments
on the corresponding iodoalkane. A longer but efficient
route via the selenide 15 gave the desired alkene 16 in
99% yield from 14. Poor stereoselectivity in the substrate-
controlled dihydroxylation of the terminal alkene with
OsO4 prompted a survey of several asymmetric variants.
Best results were obtained using the hydroquinine 2,5-
diphenyl-4,6-pyrimidinediyl
diether
[(DHQ)2PYR]
ligand of Sharpless11 whereupon the crystalline diols
17a,b were obtained in a combined yield of 99% in the ra-
tio 17a:17b = 1:6.6. Even higher diastereoselectivity
(11:1) in favour of the undesired isomer 17a was obtained
using hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl di-
ether [(DHQD)2PYR] (Note 4). Phase 2 was completed by
O-methylation of the diol 17b to give 18 in 94% yield.
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Formal Synthesis of 18-O-Methyl Mycalamide B
2089
OPv OTES
O
O
O
OR OH
O
Notes
OMe
OMe
OMe
A
C
1. The efficient Cu(I)-catalysed 1,4-addition of (i-
PrO)SiMe2CH2MgCl to dihydropyranone was surprising
because Tamao and Ishida14 had established that the reac-
tion was of limited synthetic value.
O
100%
99%
OMe
OMe
OMe
OMe
21
mp 41–42 °C
98%
OMe
18
OMe
19 R = H
B
2. Attempts to convert the hydroxyketone 7 to the enol si-
lane 9 in a single step was thwarted by competing forma-
tion of the bicyclic TBS ether i.
100%
20 R = Pv
D
O
OTES
OMe
OH OTES
O
BnO
BnO
OH
OTBS
OH
OMe
OMe
O
F
E
OTBS
O
O
OTBS
Cl
O
G
TBSOTf, NEt3
CH2Cl2, rt
90%
100%
+
O
O
O
OMe
OMe
OMe
2:3
OMe
OMe
OMe
Cl
Cl
24
23
22
i
7
9
93%
3. The favourable stereochemistry in the reduction of the
ketone 12 is consistent with equatorial attack on conform-
er 12a involving intramolecular delivery of hydride from
a coordinated borohydride. The 1H NMR data for 12 sug-
gests 12a is the principal conformer since the C11 proton
appears as a broadened quartet at d 3.77 with J = 3.2 Hz.
By contrast, the corresponding signal from conformer 12b
would have a large trans-diaxial coupling.
O
O
O
O
H
O
O
H
H
H
O
H
O
OMe
OMe
OMe
BnO
BnO
HO
H
H
O
+
87%
6.5:1
OMe
OMe
OMe
OMe
25b
OMe
25a
OMe
26 (d.r. = 3:1)
I
AcO
2
O
O
68%
–
B
AcO
O
H
O
O
O
Reagents and conditions: (11 steps, 48% overall yield)
H
A
B
C
D
E
F
~100%
~100%
99%
98%
~100%
90%
PTSA/MeOH, r.t., 45 min
PvCl/pyr-CH2Cl2
O
Cl
O
δ 3.77
12a
12b
apparent q,
J 3.2 Hz
TESCl/imidazole/DMF, r.t., 2 h
DIBALH/CH2Cl2, –78 °C, 30 min
Dess–Martin periodinane/CH2Cl2, r.t., 40 min
(a) HC(OBn)3/CSA/CH2Cl2, r.t., 5 h; (b) TBAF/
THF, r. t., 11 h
Cl
4. Other ligands surveyed were: hydroquinine 1,4-ph-
thalazinediyl diether [(DHQ)2PHAL],15 17a:17b = 1:2;
G
H
I
93%
87%
68%
(HCHO)n/HCl (gas)/CH2Cl2, 0 °C, 30 min
H2/Pd-C/EtOAc, r.t., 17 h
2 steps (see Ref. 3)
hydroquinidine
1,4-phthalazinediyl
diether
[(DHQD)2PHAL],15 2.5:1; hydroquinine 9-phenanthryl
ether,15 1:2; hydroquinine 4-methyl-2-quinolyl ether,11
Scheme 4
1:2;
hydroquinidine
2,5-pyyridazinediyl
diether
[(DHQD)2PYDZ], 16,17 2.1:1.
For general experimental details, see Reference 3. The NMR as-
signments in the following experimental section are based on the
mycalamide numbering given below.
In conclusion, the modifications reported herein offers a
more practical and flexible route to 18-O-methyl mycala-
mide B and its relatives than the related route we reported
in 1996. Key features to the new route are: (1) the ready
availability of the dihydropyranone 5 on a large scale
from cheap, easily available materials; (2) the potential
for side chain variation offered by the chloroalkane inter-
mediate 14 and its alkene derivative 16; (3) the efficiency
of the 1,3-dioxane ring construction step 24Æ 25. All is
not well though: the synthesis is still in need of abbrevia-
tion.
1
O
O
12
OMe O
H
O
7
OMe
6
N
H
11
H
O
15
OH
18
OH
OMe
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

2090
P. J. Kocienski et al.
PAPER
(2S,6R)-6-(3-Chloropropyl)-2-[(isopropyloxydimethylsilyl)me-
thyl]-5,5-dimethyltetrahydro-2H-pyran-4-one (6)
Hz, C12-HAHB), 2.20–1.50 (5 H, m), 1.28 (3 H, s, C14-CH3), 1.02
(3 H, s, C14-CH3).
To a suspension of Mg turnings (5.60 g, 0.23 mol) in THF (80 mL),
was added 1,2-dibromoethane (250 mL) followed by chloromethyl-
isopropoxydimethylsilane (Aldrich, 2.0 mL, 11.1 mmol). The mix-
ture was heated gently until a strong exotherm indicated the reaction
had begun whereupon the remaining portion of chloromethylisopro-
poxydimethylsilane (18.6 mL, 103.2 mmol) was added carefully
maintaining a temperature range of 50–60 °C over a period of 20
min. After the addition was complete the mixture was left to cool to
r.t. and stirred for 24 h. To a mixture of CuBr•SMe2 (694 mg, 3.37
mmol) and SMe2 (10.4 mL) at –78 °C was added the Grignard re-
agent over 30 min whilst maintaining a temperature below –60 °C.
The mixture was diluted with THF (20 mL) and stirred at –70 °C for
10 min after which time the enone 5 (9.0 g, 44 mmol) was added.
After a further 1 h the mixture was left to warm to –30 °C and
quenched by the addition of sat. aq NH4Cl (200 mL), 10% aq NH3
(10 mL) and hexanes (200 mL). After stirring for 15 min the organic
layer was removed and the aqueous layer extracted with hexanes
(100 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to give the crude silane 6 (14.8 g, ~100%)
which was used immediately in the next step. A sample was purified
by column chromatography (silica gel, hexanes/Et2O, 10–20% and
Et3N 1%); [a]D22 +8.7 (c = 2.2, CHCl3).
13C NMR (67.5 MHz, CDCl3): d = 211.8 (0), 81.8 (1), 71.5 (1), 65.1
(2), 49.7 (0), 44.8 (2), 39.2 (2), 28.8 (2), 25.3 (2), 24.7 (3), 19.5 (3).
LRMS (CI, NH3): m/z (%) = 235 [(M + H)+, 30], 252 [(M + NH4)+,
45], 217 (10), 128 (100).
Anal. Calcd for C11H19ClO3: C, 56.29; H, 8.10. Found: C, 56.02; H,
7.98.
(2S,6R)-2-[(tert-Butyldimethylsilyloxy)methyl]-6-(3-chloropro-
pyl)-5,5-dimethyltetrahydro-2H-pyran-4-one (8)
To a solution of the alcohol 7 (12.15 g, 51.7 mmol), Et3N (93.0
mmol, 13.0 mL) and DMAP (230 mg) in CH2Cl2 (120 mL) was add-
ed t-BuMe2SiCl (9.35 g, 62.04 mmol) and the mixture left stirring
at room temperature for 36 h whereupon sat. aq NaHCO3 (200 mL),
H2O (300 mL) and hexanes (200 mL) were added successively. The
organic layer was removed and the aqueous layer was extracted
with hexanes (100 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residue was filtered
through a pad of silica eluting with hexanes/EtOAc (5:1) to give the
TBS ether 8 (17.0 g, 48.8 mmol, 94%) as a pale yellow oil:
[a]D22+0.1 (c = 2.4, CHCl3).
IR (neat): n = 1714s, 838s cm-1.
IR (neat): n = 1712s cm-1.
1H NMR (270 MHz, CDCl3): d = 3.99 (1 H, m, C11-H), 3.82 (1 H,
dd, J = 11.2, 3.3 Hz, C15-H), 3.72 (1 H, 4 lines of ABX system,
J = 10.8, 3.5 Hz, C10-HAHB), 3.69 (1 H, 4 lines of ABX system,
J = 10.8, 5.0 Hz, C10-HAHB), 3.59 (2 H, t, J = 6.6 Hz, C18-H2), 2.65
(1 H, dd, J = 14.7, 8.7 Hz, C12-HAHB), 2.38 (1 H, dd, J = 14.7, 5.0
Hz, C12-HAHB), 2.10–1.40 (4 H, m), 1.23 (3 H, s, C14-CH3), 1.03
(3 H, s, C14-CH3), 0.90 (9 H, s, t-C4H9Si), 0.08 and 0.07 [3 H each,
s, (CH3)2Si].
13C NMR (67.5 MHz, CDCl3): d = 212.3 (0), 81.0 (1), 72.0 (1), 66.0
(2), 49.3 (0), 44.7 (2), 39.2 (2), 28.9 (2), 25.9 (3, 3C), 25.4 (2), 23.6
(3), 19.2 (3), 18.3 (0), –5.4 (3), –5.5 (3).
LRMS (CI, NH3): m/z (%) = 366 [(M + NH4)+, 15], 349 [(M + H)+,
50], 291 (35), 185 (100), 117 (80).
1H NMR (270 MHz, CDCl3): d = 4.19 (1 H, dddd, J = 13.7 7.9, 6.2,
5.0 Hz, C11-H), 3.99 (1 H, septet, J = 6.2 Hz, CHMe2), 3.67 (1 H,
dd, J = 10.6, 3.9 Hz, C15-H), 3.58 (2 H, t, J = 6.2 Hz, C18-H2), 2.55
(1 H, 4 lines of ABX system, J = 14.3, 4.4 Hz, C12-HAHB), 2.48 (1
H, 4 lines of ABX system, J = 14.3, 8.3 Hz, C12-HAHB), 2.10–1.50
(4 H, m), 1.23 (3 H, s, C14-CH3), 1.14 [6 H, d, J = 6.2 Hz,
CH(CH3)2], 1.03 (3 H, s, C14-CH3), 1.02 (2 H, m, C10-H2), 0.16 [6
H, s, Si(CH3)2].
13C NMR (75 MHz, CDCl3): d = 212.7 (0), 80.2 (1), 69.4 (1), 65.2
(1), 49.6 (0), 45.9 (2), 45.0 (2), 29.2 (2), 25.9 (3, 2C), 25.7 (2), 25.3
(2), 24.0 (3), 19.5 (3), –0.2 (3), –0.4 (3).
LRMS (CI, NH3): m/z (%) = 335 [(M + H)+, 15], 275 (60), 229
(100), 170 (50).
HRMS (CI mode): m/z Found: (M + H)+, 349.1966. C17H34ClO3Si
requires 349.1966.
Anal. Calcd for C16H31ClO3Si: C, 57.19; H, 9.16. Found: C, 57.40;
H, 9.27.
(2S,6R)-4-(tert-Butyldimethylsilyloxy)-2-[(tert-butyldimethylsi-
lyloxy)methyl]-6-(3-chloropropyl)-5,5-dimethyl-5,6-dihydro-
2H-pyran (9)
(2S,6R)-6-(3-Chloropropyl)-2-hydroxymethyl-5,5-dimethyltet-
rahydro-2H-pyran-4-one (7)
Oxidation of a isopropoxydimethylsilyl group to a hydroxyl was ac-
complished by the method of Tamao et al.18 The crude silane 6 (14.7
g, 43.3 mmol) prepared as described above was dissolved in an ice
cold mixture of KF•2H2O (6.28 g, 66.7 mmol), KHCO3 (8.2 g, 82.0
mmol), THF (80 mL) and MeOH (80 mL). Aq H2O2 (30% wt solu-
tion, 45.0 mL) was added in several portions. The mixture was
stirred for 6 h at 0 °C and treated carefully with sat. aq Na2S2O3 so-
lution (200 mL) over 15 min whereupon the solution turned bright
yellow (strong exotherm!). H2O (200 mL) was added and the mix-
ture extracted with CH2Cl2 (4 × 100 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, hexanes/
EtOAc, 20–50%) to give the alcohol 7 (9.1 g, 87% yield over 2
steps) as a clear colourless oil; [a]D22 –8.7 (c = 1.2, CHCl3).
To a solution of the ketone 8 (16.8 g, 48.2 mmol) and Et3N (11.0
mL, 78.9 mmol) in CH2Cl2 (100 mL) was added dropwise t-
BuMe2SiOTf (13.3 mL, 57. 9 mmol) over 5 min. The yellow solu-
tion turned orange with a slight exotherm which was controlled by
cooling with a water bath. After 1.5 h, the reaction was quenched by
adding the mixture to a mixture of sat. aq NaHCO3 (200 mL) and
hexanes (200 mL). The organic layer was removed, dried (MgSO4)
and concentrated in vacuo to give the enol silane 9 as a pale yellow
oil (22.4 g, ~100%) which was used immediately in the next step. A
sample (200 mg) was purified by column chromatography (silica
gel, hexanes/Et2O, 2%); [a]D22 –24.8 (c = 2.0, CHCl3).
IR (neat): n = 1664s, 1471s, 1256s, 1126, 838s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.62 (1 H, d, J = 3.3 Hz, C12-H),
4.22 (1 H, ddd, J = 6.8, 5.2, 3.3 Hz, C11-H), 3.73–3.53 (3 H, m),
3.52–3.42 (2 H, m), 2.2–2.0 (1 H, m), 1.9–1.4 (3 H, m), 0.99 (3 H,
s, C14-CH3), 0.97 (3 H, s, C14-CH3), 0.95 (9 H, s, t-C4H9Si), 0.90
(9 H, s, t-C4H9Si), 0.172 and 0.170 [3 H each, s, (CH3)Si], 0.06 [6
H, s, (CH3)2Si].
IR (neat): n = 3436s, 1701s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.00 (1 H, m, C11-H), 3.78 (1 H,
dd, J = 11.6, 3.7 Hz, C15-H), 3.71 (1 H, 4 lines of ABX system,
J = 11.8, 3.6 Hz, C10-HAHB), 3.62 (1 H, 4 lines of ABX system,
J = 11.8, 6.0 Hz, C10-HAHB), 3.57 (2 H, t, J = 6.6 Hz, C18-H2), 2.72
(1 H, dd, J = 14.7, 10.0 Hz, C12-HAHB), 2.28 (1 H, dd, J = 14.7, 4.2
13C NMR (67.5 MHz, CDCl3): d = 156.7 (0), 99.0 (1), 77.6 (1), 72.9
(1), 65.2 (2), 45.4 (2), 38.9 (0), 30.2 (2), 26.5 (2), 26.1 (3, 3C), 25.9
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Formal Synthesis of 18-O-Methyl Mycalamide B
2091
(3, 3C), 22.3 (3), 19.6 (3), 18.4 (0, 2C), –4.2 (3), –4.7 (3), –5.2 (3,
2C).
LRMS (CI, NH3): m/z (%) = 463 [(M + H)+, 35], 347 (45), 317
(100), 157 (70).
HRMS (CI mode): m/z Found: (M + H)+, 463.2827. C23H48ClO3Si2
requires 463.2831.
1H NMR (360 MHz, CDCl3): d = 4.49 (1 H, dd, J = 9.6, 2.4 Hz,
C15-H), 3.94 (1 H, dd, J = 11.4, 3.2 Hz, C10-HAHB), 3.85 (1 H, dd,
J = 12.4, 3.3 Hz, C10-HAHB), 3.83 (1 H, dd, J = 12.4, 3.3 Hz, C11-
H), 3.69 (1 H, d, J = 3.2 Hz, C12-OH), 3.55 (2 H, apparent t, J = 6.2
Hz, C18-H2), 3.46 (1 H, ddd, J = 10.3, 9.5, 3.2 Hz, C11-H), 2.44 (1
H, br s, CH2OH), 1.95–1.40 (4 H, m), 1.41 (3 H, s, C14-CH3), 1.05
(3 H, s, C14-CH3).
13C NMR (90 MHz, CDCl3): d = 212.7 (0), 83.6 (1), 76.8 (1), 70.0
(2R,3S,4S,6R)-4-(tert-Butyldimethylsilyloxy)-2-[(tert-butyldi-
methylsilyloxy)methyl]-6-(3-chloropropyl)-3,4-epoxy-5,5-dime-
thyltetrahydro-2H-pyran (10)
(1), 63.2 (2), 49.7 (0), 44.6 (2), 28.1 (2), 26.0 (3), 24.5 (2), 19.5 (3).
LRMS (CI, NH3): m/z (%) = 268 [(M + NH4)+, 100].
To a mechanically stirred solution of the enol silane 9 (22.2 g, 48
mmol), KHCO3 (121.0 g, 120.0 mmol), 18-crown-6 (1.11 g, 4.21
mmol), toluene (600 mL), acetone (120 mL) and H2O (1.20 L) was
added oxone (200 g, 300 mmol) in portions over a period of 0.5 h.
Beware gas evolution! After the addition was complete the mixture
was stirred for 30 min and the organic layer was removed. The
aqueous layer was extracted with hexanes (2 × 100 mL), the com-
bined organic extracts were dried (MgSO4) and concentrated in vac-
uo to give the oxirane 10 (22.7 g, 99%) as a pale yellow oil which
was used immediately in the next step. A sample (200 mg) was pu-
rified by column chromatography (silica gel, hexanes/Et2O, 1%);
[a]D22 –8.6 (c = 1.0, CHCl3).
Anal. Calcd for C11H19ClO4: C, 52.69; H, 7.58. Found: C, 52.61; H,
7.56.
(2R,3S,6R)-6-(3-Chloropropyl)-3-hydroxy-2-hydroxymethyl-
5,5-dimethyltetrahydro-2H-pyran-4-one (11b)
Mp 60–60.5 °C (hexanes/Et2O); [a]D22 +90.0 (c = 1.5, CHCl3).
IR (neat): n = 3417s, 1714s, 1463s, 1376m cm-1.
1H NMR (270 MHz, CDCl3): d = 4.61 (1 H, d, J = 7.9 Hz, C12-H),
4.43 (1 H, ddd, J = 8.1, 5.2, 3.8 Hz, C11-H), 3.91 (1 H, dd, J = 12.6,
5.2 Hz, C10-HAHB), 3.80 (1 H, dd, J = 12.6, 3.5 Hz, C10-HAHB),
3.86–3.77 (2 H, m), 3.50–3.65 (2 H, complex AA’BB’, C18-H2),
2.20–1.75 (3 H, m), 1.70–1.50 (2 H, m), 1.18 (3 H, s, C14-CH3),
1.07 (3 H, s, C14-CH3).
IR (neat): n = 1664s, 1471s, 1256s, 1126s, 838s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.10 (1 H, dt, J = 7.0, 3.3 Hz, C11-
H), 3.69 (1 H, dd, J = 9.7, 7.5 Hz, C10-HAHB), 3.61 (1 H, dd,
J = 9.7, 6.8 Hz, C10-HAHB), 3.54 (2 H, m, C18-H2), 3.41 (1 H, d,
J = 3.3 Hz, C12-H), 3.24 (1 H, dd, J = 10.4, 1.0 Hz, C15-H), 2.1–
1.9 (1 H, m), 1.8–1.5 (2 H, m), 1.4–1.2 (1 H, m) 1.04 (3 H, s, C14-
CH3), 0.96 (3 H, s, C14-CH3), 0.91 and 0.90 (9 H each, s, t-C4H9Si),
0.14, 0.09, 0.08 and 0.07 [3 H each, s, (CH3)2Si].
13C NMR (90 MHz, CDCl3): d = 213.3 (0), 79.0 (1), 78.1 (1), 70.7
(1), 62.4 (2), 49.0 (0), 45.1 (2), 30.0 (2), 27.0 (2), 20.3 (3), 19.4 (3).
LRMS (CI, NH3): m/z (%) = 268 [(M + NH4)+, 65], 251 [(M + H)+,
50], 233 [(M + H – H2O)+, 25], 144 (100).
Anal. Calcd for C11H19ClO4: C, 52.69; H, 7.58. Found: C, 52.66; H,
7.45.
13C NMR (67.5 MHz, CDCl3): d = 86.1 (0), 75.6 (1), 71.0 (1), 60.7
(1), 60.2 (2), 45.3 (2), 39.1 (0), 30.3 (2), 26.9 (2), 26.0 (3, 3C), 25.9
(3, 3C), 18.6 (3), 18.4 (0), 18.0 (0), 16.9 (3), –3.2 (3), –3.4 (3), –5.3
(3), –5.2 (3).
(1S,6R,8R)-8-(3-Chloropropyl)-3,3,9,9-tetramethyl-2,4,7-
trioxabicyclo[4.4.0]decan-10-one (12)
A solution of diol the 11a (4.2 g, 16.6 mmol), 2-methoxypropene
(3.2 mL, 33.0 mmol) and PPTS (420 mg, 1.7 mmol) in CH2Cl2 (65
mL) was stirred at r.t. for 4.25 h. The mixture was poured onto sat.
aq NaHCO3 (300 mL) and extracted with CH2Cl2 (3 × 70 mL). The
combined organic extracts were dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, 120 g, hexanes/Et2O, 20–50%) to give the acetonide 12 (4.2 g,
86%) as a colourless oil; [a]D22 –1.5 (c = 1.4, CHCl3).
LRMS (CI, NH3): m/z (%) = 479 [(M + H)+, 65], 443 [(M + H–
HCl)+, 20], 347 [(M + H – TBSOH)+, 100].
HRMS (CI mode): m/z Found: (M
+
NH4)+, 496.3058.
C23H51ClO4NSi2 requires 496.3045; m/z found: (M + H)+, 479.2748.
C23H48ClO4Si2 requires 479.2780.
IR (neat): n = 1726s, 1090s cm-1.
Hydrolysis of the Oxirane 10
A mixture of the crude oxirane 10 (1.19 g, 2.48 mmol), pyridinium
p-toluenesulfonate (PPTS, 62 mg, 0.248 mmol), MeOH (5 mL) and
H2O (0.25 mL) was heated at reflux for 18 h. The mixture was
poured onto sat. aq NaHCO3 and extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried (Na2SO4) and con-
centrated. The residue was purified by column chromatography (sil-
ica gel, 20 g, hexanes/EtOAc, 20–70%) to give a mixture of the
diols 11a and 11b (537 mg, 86%) as a colourless oil. 1H NMR spec-
troscopic analysis (C6D6) of the mixture revealed doublets at
d = 4.29 (major) and 4.34 (minor) attributed to the methine proton
adjacent to the carbonyl corresponding to a 15:1 mixture of diaste-
reoisomers. The diastereoisomers were separated by recrystallisa-
tion to give the pure desired diastereoisomer 11a (335 mg, 54%) as
clear colourless crystals. The mother liquor was purified by column
chromatography (silica gel, 15 g, hexanes/EtOAc 20–70%) to give
more of the desired diastereoisomer 11a (137 mg, 23%) as a white
solid and the pure undesired diastereoisomer 11b (30 mg, 5%) as a
white solid.
1H NMR (360 MHz, CDCl3): d = 4.25 (1 H, dd, J = 11.5, 2.5 Hz,
C15-H), 4.21 (1 H, d, J = 3.2 Hz, C12-H), 4.09 (1 H, dd, J = 13.0,
3.6 Hz, C10-HAHB), 3.90 (1 H, dd, J = 13.0, 2.8 Hz, C10-HAHB),
3.77 (1 H, apparent q, J = 3.2 Hz, C11-H), 3.62 (2 H, apparent t,
J = 6.1 Hz, C18-H2), 2.05–1.78 (2 H, m), 1.70–1.60 (1 H, m), 1.55–
1.45 (1 H, m) 1.45 [3 H, s, C(CH3)2], 1.43 [3 H, s, C(CH3)2], 1.33 (3
H, s, C14-CH3), 1.03 (3 H, s, C14-CH3).
13C NMR (90 MHz, CDCl3): d = 208.3 (0), 99.1 (0), 80.4 (1), 72.8
(1), 65.7 (1), 62.8 (2), 49.2 (0), 44.8 (2), 29.1 (2), 28.6 (3), 25.5 (2),
24.5 (3), 19.8 (3), 19.5 (3).
LRMS (CI, NH3): m/z (%) = 291 [(M + H)+, 100], 275 (15), 203
(25), 132 (30), 101 (20), 73 (30).
Anal. Calcd for C14H23ClO4: C, 57.83; H, 7.91. Found: C, 57.79; H,
7.84.
(1R,6R,8S,10S)-8-(3-Chloropropyl)-3,3,9,9-tetramethyl-2,4,7-
trioxabicyclo[4.4.0]decan-10-ol (13)
(2R,3S,6R)-6-(3-Chloropropyl)-3-hydroxy-2-hydroxymethyl-
5,5-dimethyltetrahydro-2H-pyran-4-one (11a)
Solid CeCl3•7H2O (1.25 g, 3.35 mmol) was added to a stirred solu-
tion of the ketone 12 (718 mg, 2.47 mmol) in MeOH (45 mL) at
0 °C. The solution was stirred for 20 min and NaB(OAc)3H (2.0 g,
9.43 mmol) was added. The mixture was stirred at 0–5°C for 3.5 h,
then sat. aq NaHCO3 (100 mL) was carefully added and the MeOH
Mp 63–63.5 °C (hexanes:Et2O); [a]D22 +9.7 (c = 1.8, CHCl3).
IR (neat): n = 3443s, 1714s, 1048s cm-1.
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

2092
P. J. Kocienski et al.
PAPER
was removed on the rotary evaporator. The resulting mixture was
extracted with CH2Cl2 (3 × 50 mL), dried (Na2SO4) and concentrat-
ed. The residue was purified by chromatography on silica gel (40 g,
hexanes/Et2O, 20–70%) to give the diastereoisomeric alcohols
13a,b (643 mg, 88%) as a white solid. 1H NMR spectroscopic anal-
ysis of the mixture (C6D6) revealed singlets at d = 0.78 (major) and
0.88 (minor) corresponding to a dr = 1:7.5. Crystallisation from
hexanes/Et2O gave the diastereoisomerically pure alcohol 13a (535
mg, 74%) as colourless needles; mp 96–97 °C (hexanes/Et2O);
[a]D22 +30.4 (c = 1.2, CHCl3). On a larger scale (14.3 mmol of ke-
tone 12) the ratio of 13a:13b was better (1:11) but the yield was
lower (72% of the mixture).
IR (neat): n = 1454s, 1381s, 1276s, 1094s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.08 (1 H, dd, J = 12.7, 2.5 Hz,
C10-HAHB), 3.90 (1 H, apparent t, J = 2.3 Hz, C12-H), 3.86 (1 H,
dd, J = 12.7, 1.7 Hz, C10-HAHB), 3.59 (2 H, t, J = 6.6 Hz, C18-H2),
3.55–3.45 (2 H, m, C11-H and C15-H), 3.39 (3 H, s, OCH3), 2.84 (1
H, d, J = 2.7 Hz, C13-H), 2.20–2.05 (1 H, m), 1.95–1.45 (3 H, m),
1.47 and 1.45 [3 H each, s, C(CH3)2], 1.25 and 0.93 (3 H each, s,
C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 98.6 (0), 85.8 (1), 80.5 (1), 67.3
(1), 63.6 (2), 60.7 (1), 59.3 (3), 45.6 (2), 36.9 (0), 30.5 (2), 29.6 (3),
28.3 (3), 25.1 (2), 22.3 (3), 19.6 (3).
LRMS (CI, NH3): m/z (%) = 307 [(M + H)+, 100].
IR (neat): n = 3437 (br), 1462s, 1377s cm-1.
1H NMR (270 MHz, C6D6): d = 3.77 (1 H, dd, J = 12.4, 3.3 Hz,
C10-HAHB), 3.67 (1 H, dd, J = 12.4, 3.7 Hz, C10-HAHB), 3.60 (1 H,
dd, J = 3.7, 3.1 Hz, C12-H), 3.44 (1 H, apparent q, J = 3.5 Hz, C11-
H), 3.35 (1 H, d, J = 3.9 Hz, OH), 3.34 (1 H, dd, J = 3.8, 2.9 Hz,
C13-H), 3.25 (3 H, t, J = 6.8 Hz, C18-H2, C15-H), 2.10–1.90 (1 H,
m), 1.85–1.80 (1 H, m), 1.60–1.40 (1 H, m), 1.45 [3 H, s, C(CH3)2],
1.40–1.25 (1 H, m), 1.24 and 1.23 [3 H each, s, C(CH3)2 and C14-
CH3], 0.80 (3 H, s, C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 98.5 (0), 80.3 (1), 75.0 (1), 70.5
(1), 62.9 (2), 60.3 (1), 45.2 (2), 36.4 (0), 29.8 (2), 28.9 (3), 27.1 (3),
24.6 (2), 21.2 (3), 19.8 (3).
LRMS (CI, NH3): m/z (%) = 293 [(M + H)+, 100], 277 (20), 217
(20).
Anal. Calcd for C15H27ClO4: C, 58.73; H, 8.81. Found: C, 57.80; H,
8.74.
(1R,6R,8R,10S)-10-Methoxy-3,3,9,9-tetramethyl-8-(3-phenylse-
lenylpropyl)-2,4,7-trioxabicyclo[4.4.0]decane (15)
NaBH4 (208 mg) was added portionwise to a stirred suspension of
Ph2Se2 (773 mg, 2.47 mmol) in anhyd EtOH (11.5 mL). Addition of
NaBH4 was continued until the solution of NaPhSe formed became
colourless. A solution of the chloride 14 (990 mg, 3.23 mmol) in an-
hyd EtOH (3 × 2.5 mL) was transferred via cannula to the solution
of NaPHSe. The resulting mixture was stirred at reflux for 40 min.
After cooling to r.t. the mixture was diluted with Et2O (160 mL) and
extracted with 2 M aq solution of NaOH (2 × 35 mL) and brine. The
organic layer was dried (MgSO4) and concentrated. The residue was
purified by column chromatography (silica gel, 10 g, hexanes/Et2O,
0–30%) to give the selenide 15 (1.40 g, ~100%) as a colourless oil;
[a]D22+17.9 (c = 1.4, CHCl3).
Anal. Calcd for C14H25ClO4: C, 57.43; H, 8.55. Found: C, 57.42; H,
8.55.
Column chromatography (silica gel, hexanes/Et2O, 50–70%) of the
mother liquor gave a pure sample of the minor isomer 13b.
IR (neat): n = 1579s cm-1.
1H NMR (270 MHz, CDCl3): d = 7.52–7.45 (2 H, m), 7.29–7.21 (3
H, m), 4.01 (1 H, dd, J = 12.7, 2.5 Hz, C10-HAHB), 3.87 (1 H, t,
J = 2.3 Hz, C12-H), 3.76 (1 H, dd, J = 12.7, 1.7 Hz, C10-HAHB),
3.46 (1 H, dd, J = 12.2, 2.9 Hz, C15-H), 3.42 (1 H, apparent q,
J = 2.3 Hz, C11-H), 3.38 (3 H, s, OCH3), 3.01 (1 H, ddd, J = 11.8,
7.9, 6.0 Hz, C18-HAHB), 2.88 (1 H, ddd, J = 12.0, 7.9, 7.1 Hz, C18-
HAHB), 2.81 (1 H, d, J = 2.7 Hz, C13-H), 2.11 (1 H, dddd, J = 14.1,
12.2, 9.1, 4.6 Hz, C16-H), 1.90–1.60 (3 H, m), 1.46 and 1.44 [3 H
each, s, C(CH3)2], 1.22 and 0.89 (3 H each, s, C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 132.7 (1, 2C), 130.5 (0), 129 (1,
2C), 126.7 (1), 98.3 (0), 84.9 (1), 80.6 (1), 66.5 (1), 63.4 (2), 59.4
(3), 59.3 (1), 36.3 (0), 29.4 (3), 27.9 (3), 27.8 (2), 27.0 (2), 26.9 (2),
22.4 (3), 18.8 (3).
(1R,6R,8S,10R)-8-(3-Chloropropyl)-3,3,9,9-tetramethyl-2,4,7-
trioxabicyclo[4.4.0]decan-10-ol (13b)
Mp 89–90°C (hexanes/Et2O); [a]D22 +47.0 (c = 1.0, CHCl3).
IR (neat): n = 3516m, 1461s, 1377s cm-1.
1H NMR (270 MHz, C6D6): d = 3.66 (1 H, dd, J = 12.7, 1.9 Hz,
C10-HAHB), 3.59 (1 H, dd, J = 4.2, 2.1 Hz, C12-H), 3.53 (1 H, dd,
J = 12.6, 2.9 Hz, C10-HAHB), 3.39 (1 H, dd, J = 11.5, 3.1 Hz, C15-
H), 3.37–3.30 (1 H, m, C13-H), 3.28–3.10 (2 H, m, C18-H2), 2.72
(1 H, apparent q, J = 2.1 Hz, C11-H), 2.31 (1 H, d, J = 10.6 Hz,
OH), 1.65–1.15 (4 H, m), 1.37 and 1.27 [3 H each, s, C(CH3)2], 1.13
and 0.88 (3 H each, s, C14-CH3).
13C NMR (90 MHz, CHCl3): d = 98.9 (0), 81.8 (1), 71.6 (1), 67.5
(1), 63.2 (2), 62.7 (1), 45.1 (2), 37.7 (0), 29.4 (3), 29.1 (2), 24.6 (3),
22.6 (3), 22.6 (2), 18.7 (3).
LRMS (CI, NH3): m/z (%) = 446 [(M + NH4)+, 17], 429 [(M + H)+,
9].
LRMS (CI, NH3): m/z (%) = 310 [(M + NH4)+, 60], 293 [(M + H)+,
55].
Anal. Calcd for C21H32O4Se: C, 59.02; H, 7.49. Found: C, 59.27; H,
7.61.
Anal. Calcd for C14H25ClO4: C, 57.43; H, 8.55. Found: C, 57.36; H,
8.47.
(1R,6R,8R,10S)-10-Methoxy-3,3,9,9-tetramethyl-8-(prop-2-
enyl)-2,4,7-trioxabicyclo[4.4.0]decane (16)
NaIO4 (1.01 g, 4.70 mmol) was added in several portions to a stirred
mixture of the selenide 15 (1.31 mg, 3.23 mmol), H2O (18 mL) and
MeOH (45 mL) at r.t. The mixture was stirred for 15 min and then
diluted with H2O (55 mL) and extracted with CH2Cl2 (3 × 40 mL).
The combined organic extracts were dried (MgSO4) and concentrat-
ed. The residue was treated with toluene (4.5 mL) and Et3N (4.5
mL) and heated at reflux for 10 min. The yellow mixture was cooled
to r.t., poured onto sat. aq NaHCO3 .and extracted with CH2Cl2
(3 × 40 mL). The combined organic extracts were dried (MgSO4)
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, 30 g, hexanes/Et2O, 0–20%) to give the alkene 16
(780 mg, 99%) as a colourless oil which solidified on storage in the
(1R,6R,8R,10S)-8-(3-Chloropropyl)-10-methoxy-3,3,9,9-
tetramethyl-2,4,7-trioxabicyclo[4.4.0]decane (14)
Dimethyl sulfate (4.0 g, 3.0 mL, 32.0 mmol) was added to a vigor-
ously stirred mixture of the alcohol 13a (2.42 g, 8.27 mmol),
Bu4NHSO4 (573 mg, 1.70 mmol), toluene (32 mL) and 50% aq
NaOH (21 mL). The mixture was stirred vigorously for 14 h where-
upon MeOH (9 mL) was added and after 15 min the mixture was
treated with H2O (220 mL). The mixture was extracted with CH2Cl2
(3 × 80 mL) and the combined organic extracts were dried (MgSO4)
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 80 g, hexanes/Et2O, 10–25%) to give
the methyl ether 14 (2.47 g, 97%) as a colourless oil which solidi-
fied; mp 49–50 °C (MeOH/H2O); [a]D22 –1.9 (c = 1.2, CHCl3).
22
refrigerator; mp 33–33.5 °C (MeOH/H2O); [a]D –11.2 (c = 1.1,
CHCl3).
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Formal Synthesis of 18-O-Methyl Mycalamide B
IR (CCl4): n = 3441 (br) cm-1.
2093
IR (neat): n = 1651m 1463m, 1390s cm-1.
1H NMR (270 MHz, CDCl3): d = 5.82 (1 H, dddd, J = 17.6, 10.2,
7.5, 6.0 Hz, C17-H), 5.03 (1 H, dq, J = 16.9, 1.7 Hz, C18-Htrans),
4.98 (1 H, dm, J = 10.2 Hz, C18-Hcis), 4.05 (1 H, dd, J = 12.7, 2.7
Hz, C10-HAHB), 3.90 (1 H, t, J = 2.5 Hz, C12-H), 3.82 (1 H, dd,
J = 12.7, 2.1 Hz, C10-HAHB), 3.59 (1 H, dd, J = 12.0, 3.7 Hz, C15-
H), 3.53 (1 H, apparent q, J = 2.3 Hz, C11-H), 3.40 (3 H, s, OCH3),
2.84 (1 H, d, J = 2.7 Hz, C13-H), 2.79 (1 H, dddt, J = 15.0, 11.4,
7.3, 1.1 Hz, C16-HAHB), 2.17 (1 H, dddt, J = 15.5, 5.4, 3.5, 1.5 Hz,
C16-HAHB), 1.47 and 1.44 [3 H each, s, C(CH3)2], 1.25 and 0.93 (3
H each, s, C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 136.7 (1), 115.2 (2), 98.1 (0),
84.8 (1), 80.7 (1), 66.3 (1), 63.2 (2), 59.3 (3), 59.1 (1), 36.2 (0), 32.2
(2), 29.2 (3), 27.6 (3), 22.4 (3), 18.7 (3).
LRMS (CI, NH3): m/z = 271 [(M + H)+, 30], 229 (80), 171 (70), 101
(55), 85 (80), 71 (100).
1H NMR (270 MHz, CDCl3): d = 4.09 (1 H, dd, J = 12.7, 2.2 Hz,
C10-HAHB), 3.93–3.81 (4 H, m), 3.64–3.48 (2 H, m), 3.39 (3 H, s,
OCH3), 2.85 (1 H, d, J = 2.8 Hz, C13-H), 2.86 (1 H, d, J = 2.7 Hz,
C13-H) 2.76 (1 H, d, J = 4.3 Hz, OH), 2.29 (1 H, dd, J = 8.1, 4.1
Hz, OH), 2.13 (2 H, ddd, J = 17.9, 12.2, 2.9 Hz, C16-HAHB), 1.50
and 1.46 [3 H each, s, C(CH3)2], 1.27 and 0.92 (3 H each, s, C14-
CH3).
13C NMR (67.5 MHz, CDCl3): d = 98.5 (0), 84.5 (1), 77.7 (1), 68.9
(1), 67.7 (2), 66.4 (1), 63.3 (2), 59.5 (1, 2, 2C), 36.0 (0), 30.3 (2),
29.3 (3), 27.8 (3), 22.5 (3), 18.6 (3).
LRMS (CI, NH3): m/z (%) = 305 [(M + H)+, 5], 289 (20), 273 (10),
231 (15), 87 (100).
Anal. Calcd for C15H28O6: C, 59.21; H, 9.21. Found: C, 59.23; H,
9.29.
Anal. Calcd for C15H26O4: C, 66.66; H, 9.62. Found: C, 66.64; H,
9.61.
(1R,6R,8R,10S)-10-Methoxy-8-[(S)-2,3-dimethoxypropyl]-
3,3,9,9-tetramethyl-2,4,7-trioxabicyclo[4.4.0]decane (18)
NaH (500 mg, 60% in oil, 12.5 mmol) was added to a stirred solu-
tion of the diol 17b (1.65 g, 4.96 mmol) and MeI (1.0 mL, 16.7
mmol) in THF (18 mL) at 0 °C. After 5 min the cooling bath was
removed and the mixture was stirred at r.t. for 7 h and then poured
onto brine and extracted with CH2Cl2 (3 × 40 mL). The combined
organic extracts were dried (Na2SO4) and concentrated. The residue
was purified by column chromatography (silica gel, 20 g, hexanes/
EtOAc, 10–50%) to give the methyl ether 18 (1.55 g, 94%) as a co-
lourless oil; [a]D23 +7.6 (c = 1.1, CHCl3).
Dihydroxylation of Alkene 16
The asymmetric dihydroxylation was performed according to the
procedure of Sharpless et al.19 The alkene 16 (918 mg, 3.4 mmol)
and (DHQ)2PYR (34 mg, 0.039 mmol) were stirred in warm t-
BuOH (21 mL) until the ligand dissolved (ca 30 min). After cooling
to r.t., H2O (21 mL), K3Fe(CN)6 (3.4 g, 10.32 mmol) and K2CO3
(1.43 g, 10.36 mmol) were added and the mixture was cooled to
0°C. Potassium osmate dihydrate (12.5 mg, 0.034 mmol) was then
added. The mixture was stirred for 3 h at 0 °C, treated with sat. aq
Na2SO3 (42 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were washed with brine, dried (Na2SO4)
and concentrated to give a 1:6.6 mixture of the diols 17a,b accord-
ing to integration of the singlets at d = 0.86 (major) and 0.92 (mi-
nor) revealed in the 1H NMR spectrum (C6D6) of the mixture. The
diastereoisomers were separated by column chromatography (silica
gel, 20 g, CH2Cl2/MeOH, 0–4%) to afford the pure major diol 17b
(860 mg, 83%) and a mixture of diols 17a,b (165 mg, 16%).
IR (neat): n = 2878s, 2821s, 1455s, 1380s, 1094s, 850s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.09 (1 H, dd, J = 12.6, 2.5 Hz,
C10-HAHB), 3.93 (1 H, t, J = 2.1 Hz, C12-H), 3.85 (1 H, dd,
J = 12.7, 1.7 Hz, C10-HAHB), 3.63 (1 H, apparent q, J = 1.9 Hz,
C11-H), 3.57 (1 H, dd, J = 12.3, 3.0 Hz, C15-H), 3.51 (1 H, 4 lines
of ABX system, J = 10.2, 3.5 Hz, C18-HAHB), 3.46 (1 H, 4 lines of
ABX system, J = 10.2, 5.0 Hz, C12-HAHB), 3.42–3.32 (1 H, m,
C17-H), 3.37 (6 H, s, OCH3), 3.36 (3 H, s, OCH3), 2.83 (1 H, d,
J = 2.5 Hz, C13-H), 2.35 (1 H, ddd, J = 14.8, 12.4, 4.6 Hz, C16-
HAHB), 1.57 (1 H, ddd, J = 14.9, 7.9, 3.1 Hz, C16-HAHB), 1.47 and
1.44 [3 H each, s, C(CH3)2], 1.23 and 0.91 (3 H each, s, C14-CH3).
(1R,6R,8R,10S)-8-[(2S)-2,3-Dihydroxypropyl]-10-methoxy-
3,3,9,9-tetramethyl-2,4,7-trioxabicyclo[4.4.0]decane (17b)
Recrystallised from hexanes/Et2O to form thick colourless needles;
mp 102–103 °C (Et2O/hexanes); [a]D17 –19.1 (c = 1.0, CHCl3).
13C NMR (67.5 MHz, CDCl3): d = 98.3 (0), 84.8 (1), 78.7 (1), 78.6
(1), 73.2 (2), 66.5 (1), 63.5 (2), 59.7 (1), 59.4 (3), 59.2 (3), 57.2 (3),
36.3 (0), 29.4 (3), 28.2 (2), 27.7 (3), 22.3 (3), 18.7 (3).
IR (CCl4): n = 3441 (br) cm-1.
1H NMR (270 MHz, CDCl3): d = 4.09 (1 H, dd, J = 12.9, 2.5 Hz,
C10-HAHB), 3.93 (1 H, t, J = 2.5 Hz, C12-H), 3.88 (1 H, m, C17-H),
3.86–3.73 (3 H, m), 3.64 [1 H, m (in presence of D2O appears as dd,
J = 11.2, 3.7 Hz), C18-HAHB], 3.50 [1 H, m (in presence of D2O ap-
pears as dd, J = 11.2, 6.0 Hz, C18-HAHB], 3.40 (3 H, s, OCH3), 2.86
(1 H, d, J = 2.9 Hz, C13-H), 2.20 (1 H, br, OH), 2.19 (1 H, ddd,
J = 15.1, 12.0, 8.9 Hz, C16-HAHB), 1.67 (1 H, br, OH), 1.56 (1 H,
ddd, J = 3.5, 2.1 Hz, C16-HAHB), 1.47 and 1.45 [3 H each, s,
C(CH3)2], 1.23 and 0.93 (3 H each, s, C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 98.4 (0), 84.5 (1), 81.1 (1), 72.5
(1), 66.5 (1), 66.0 (2), 63.2 (2), 60.3 (1), 59.3 (3), 36.5 (0), 30.0 (2),
29.2 (3), 27.4 (3), 21.9 (3), 18.8 (3).
LRMS: (CI, NH3): m/z (%) = 305 [(M + H)+, 50], 289 (25), 273 (15),
247 (55), 87 (100).
LRMS (CI, NH3): m/z (%) = 350 [(M + NH4)+, 55], 333 [(M + H)+,
100].
HRMS (CI mode): m/z Found: (M + H)+, 333.2270. C17H33O6 re-
quires 333.2277.
(2R,3R,4S,6R)-2-[(tert-Butylcarbonyloxy)methyl]-4-methoxy-6-
[(S)-2,3-dimethoxypropyl]-5,5-dimethyltetrahydro-2H-pyran-
3-ol (20)
A solution of the acetal 18 (1.38g, 4.15 mmol) and p-TsOH (16 mg,
0.083 mmol) in MeOH (14 mL) was stirred at r.t. for 45 min. Then
solid NaHCO3 (0.4 g) was added and the mixture was concentrated.
The residue was treated with CH2Cl2, filtered through a pad of
Celite and concentrated to give the crude diol 19 which was con-
verted to the pivalate ester 20 (1.58 g, ~100% for the two steps) us-
ing pivaloyl chloride and pyridine as described previously.3
Anal. Calcd for C15H28O6: C, 59.21; H, 9.21. Found: C, 59.31; H,
9.11.
(2R,3R,4S,6R)-2-[(tert-Butylcarbonyloxy)methyl]-4-methoxy-6-
[(S)-2,3-dimethoxypropyl]-5,5-dimethyl-3-(triethylsilyloxy)tet-
rahydro-2H-pyran (21)
A solution of the alcohol 20 (1.58 g, 4.21 mmol), imidazole (331
mg, 5.0 mmol) and Et3SiCl (0.81 mL, 4.72 mmol) in anhyd DMF (6
mL) was stirred at r.t. for 2 h. The mixture was poured onto H2O (60
A sample of the undesired diastereoisomer 17a was obtained by
further column chromatography.
(1R,6R,8R,10S)-8-[(2R)-2,3-Dihydroxypropyl]-10-methoxy-
3,3,9,9-tetramethyl-2,4,7-trioxabicyclo[4.4.0]decane (17a)
Mp 104–104.5 °C (Et2O/hexanes); [a]D17 +6.9 (c = 0.9, CHCl3).
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

2094
P. J. Kocienski et al.
PAPER
mL) and extracted with hexanes (3 × 40 mL). The combined organ-
ic extracts were dried (Na2SO4) and concentrated. The residue was
purified by column chromatography (silica gel, 15 g, hexanes/
EtOAc, 0–10%) to give the silyl ether 21 (1.96 g, 99%) as colourless
crystals; mp 41–42 °C (MeOH/H2O); [a]D23 +70.9 (c = 1.2, CHCl3).
IR (neat): n = 1729s, 1604s cm-1.
1H NMR (270 MHz, CDCl3): d = 10.1 (1 H, s, C10-H), 4.31 (1 H,
d, J = 7.3 Hz, C11-H), 4.14 (1 H, dd, J = 9.7, 7.1 Hz, C12-H), 3.72–
3.56 (3 H, m, C17-H, C18-H2), 3.52 (3 H, s, OCH3), 3.51 (1 H, dd,
J = 9.6, 2.7 Hz, C15-H), 3.43 (3 H, s, OCH3), 3.40 (3 H, s, OCH3),
2.64 (1 H, d, J = 9.7 Hz, C13-H), 1.70–1.50 (2 H, m, C16-H2), 1.00
(9 H, t, J = 8.3 Hz, CH3CH2), 0.89 (3 H, s, C14-CH3), 0.85 (3 H, s,
C14-CH3), 0.696 (4 H, q, J = 7.9 Hz, CH3CH2), 0.692 (2 H, q,
J = 7.9 Hz, CH3 CH2).
13C NMR (67.5 MHz, CDCl3): d = 202.8 (1), 88.1 (1), 80.7 (1), 77.8
(1), 77.0 (1), 72.6 (2), 71.1 (1), 62.3 (3), 59.1 (3), 57.8 (3), 41.4 (0),
29.7 (2), 22.9 (3), 13.6 (3), 6.7 (3, 3C), 4.8 (2, 3C).
LRMS (CI): m/z (%) = 405 [(M + H)+, 100].
HRMS (CI mode): m/z Found: (M + H)+, 405.2668. C20H41O6Si re-
IR (CCl4): n = 1730s cm-1.
1H NMR (270 MHz, CDCl3): d = 4.52 (1 H, dd, J = 12.4, 9.5 Hz,
C10-HAHB), 4.27 (1 H, dd, J = 12.4, 2.3 Hz, C10-HAHB), 4.12 (1 H,
ddd, J = 9.5, 6.9, 4.3 Hz, C11-H), 3.93 (1 H, dd, J = 9.5, 6.8 Hz,
C12-H), 3.50 (3 H, s, OCH3), 3.50–3.30 (4 H, m), 3.361 (3 H, s,
OCH3), 3.359 (3 H, s, OCH3), 2.78 (1 H, d, J = 9.6 Hz, C13-H), 1.68
(2 H, m, C16-H2), 1.23 (9 H, s, t-C4H9), 0.973 (3 H, t, J = 8.1 Hz,
CH3CH2), 0.971 (6 H, t, J = 8.1 Hz, CH3CH2), 0.94 (3 H, s, C14-
CH3), 0.87 (3 H, s, C14-CH3), 0.633 (4 H, q, J = 7.9 Hz, CH3CH2),
0.629 (2 H, q, J = 7.9 Hz, CH3CH2).
13C NMR (67.5 MHz, CDCl3): d = 178.6 (0), 86.5 (1), 77.9 (1), 75.3
(1), 73.8 (1), 73.4 (2), 70.2 (1), 62.3 (3), 60.1 (2), 59.3 (3), 56.9 (3),
41.1 (0), 38.8 (0), 29.8 (2), 27.3 (3, 3C), 23.4 (3), 14.0 (3), 6.8 (3,
2C), 6.7 (3), 5.9 (2), 4.9 (2, 2C).
quires 405.2672.
(2S,3R,4S,6R)-2-Dibenzyloxymethyl-4-methoxy-6-[(S)-2,3-
dimethoxypropyl]-5,5-dimethyltetrahydro-2H-pyran-3-ol (24)
A solution of the aldehyde 23 (891 mg, 2.19 mmol), benzyl
orthoformate20 (2.22 g, 6.6 mmol) and camphorsulfonic acid (109
mg, 0.43 mmol) in CH2Cl2 (10 mL) was stirred at r.t. for 5 h. Solid
K2CO3 (138 mg) was added and the solvent removed in vacuo. The
residue was treated with THF (20 mL) and TBAF (3.15 g, 10 mmol)
and stirred at r.t. After 11 h, the mixture was concentrated. The res-
idue was taken into Et2O (150 mL), washed with H2O (2 × 50 mL)
and brine. The organic extracts were dried (Na2SO4) and concentrat-
ed. The residue was purified by column chromatography (silica gel,
30 g, hexanes/Et2O, 10–80%) to give the hydroxy acetal 24 (908
mg, 90%) as a yellow oil; [a]D20 +89.6 (c = 1.6, CHCl3).
LRMS (CI, NH3): m/z (%) = 508 [(M + NH4)+, 30], 491 [(M + H)+,
20].
Anal. Calcd for C25H50O7Si: C, 61.22; H, 10.20. Found: C, 61.08;
H, 10.10.
(2R,3R,4S,6R)-2-Hydroxymethyl-4-methoxy-6-[(S)-2,3-
dimethoxypropyl]-5,5-dimethyl-3-[(triethylsilyl)oxy]tetrahy-
dro-2H-pyran (22)
DIBALH (neat, 2 mL, 11.2 mmol) was added dropwise to a stirred
solution of the ester 21 (3.03 g, 6.17 mmol) in CH2Cl2 (25 mL) at –
78 °C. The mixture was stirred for 30 min before being treated with
sat. aq Na2SO4 (2 mL) and CH2Cl2 (50 mL). After stirring for a fur-
ther 1 h at r.t., the resulting milky suspension was filtered through a
pad of Celite and concentrated to give the alcohol 22 (2.47 g, 98%)
as a colourless oil: [a]D20 +57.8 (c = 1.0, CHCl3).
IR (neat): n = 3452 (br) cm-1.
1H NMR (360 MHz, CDCl3, 333K): d = 7.45–7.25 (10 H, m), 5.11
(1 H, d, J = 5.3 Hz, C10-H), 4.78 (1 H, d, J = 11.6 Hz), 4.77 (1 H,
d, J = 11.6 Hz), 4.72 (1 H, d, J = 11.6 Hz), 4.65 (1 H, d, J = 11.6
Hz), 4.16 (1 H, t, J = 5.5 Hz, C11-H), 4.0 (1 H, m, C12-H), 3.57 (1
H, dd, J = 10.5, 2.2 Hz, C15-H) 3.52–3.36 (3 H, m, C17-H, C18-
H2), 3.50 (3 H, s, OCH3), 3.31 (3 H, s, OCH3), 3.29 (3 H, s, OCH3),
2.99 (1 H, d, J = 8.1 Hz, C13-H), 2.80 (1 H, d, J = 4.6 Hz, OH), 1.76
(1 H, ddd, J = 14.5, 10.5, 3.1 Hz, C16–HAHB), 1.66 (1 H, ddd,
J = 14.3, 8.8, 2.2 Hz, C16–HAHB), 0.97 (3 H, s, C14-CH3), 0.90 (3
H, s, C14-CH3).
13C NMR (90 MHz, CDCl3, 333K): d = 138.2 (0), 137.5 (0), 128.8
(1), 128.6 (1), 128.3 (1, 2C), 128.2 (1, 2C), 127.9 (1, 4C), 101.4 (1),
87.3 (1), 78.3 (1), 77.5 (1), 73.6 (2), 72.6 (1), 70.4 (2), 69.8 (1), 68.3
(2), 61.7 (3), 59.3 (3), 57.0 (3), 40.1 (0), 30.1 (2), 24.8 (3), 16.0 (3).
IR (neat): n = 3476 (br) cm-1.
1H NMR (270 MHz, CDCl3): d = 4.02–3.88 (3 H, m), 3.69 (1 H, br,
C10-H), 3.62 (1 H, dd, J = 9.5, 4.6 Hz, C12-H), 3.58–3.32 (3 H, m,
C17-H and C18-H2), 3.51 (3 H, s, OCH3), 3.41 (3 H, s, OCH3), 3.38
(3 H, s, OCH3), 2.79 (1 H, d, J = 9.3 Hz, C13-H), 1.70–1.50 (1 H,
br, OH), 1.68 (2 H, t, J = 6.4 Hz, C16-H2), 0.972 (3 H, t, J = 8.3 Hz,
CH3CH2), 0.970 (6 H, t, J = 8.0 Hz, CH3CH2), 0.92 (3 H, s, C14-
CH3), 0.87 (3 H, s, C14-CH3), 0.626 (4 H, q, J = 7.9 Hz, CH3CH2),
0.623 (2 H, q, J = 8.0 Hz, CH3CH2).
13C NMR (67.5 MHz, CDCl3): d = 86.7 (1), 78.3 (1), 76.7 (1), 75.8
(2), 72.3 (1), 71.0 (1), 62.5 (3), 59.1 (3), 57.3 (3), 57.1 (2), 41.3 (0),
31.2 (2), 23.2 (3), 13.7 (3), 6.8 (3, 3C), 6.0 (2), 4.9 (2, 2C).
LRMS (CI, NH3): m/z (%) = 506 [(M + NH4)+, 2], 489 [(M + H)+,
0.4], 398 (0.8), 381 (0.8).
LRMS (CI, NH3): m/z (%) = 407 [(M + H)+, 80], 377 (50), 345 (30),
HRMS (CI mode): m/z Found: (M + H)+, 489.2859. C28H41O7 re-
213 (100).
quires 489.2852.
Anal. Calcd for C20H42O6Si: C, 59.11; H, 10.34. Found: C, 59.06;
H, 10.17.
Formation of 1,3-Dioxanes 25a,b
HCl gas was passed through a stirred mixture of the hydroxy acetal
24 (908 mg, 1.97 mmol) and paraformaldehyde (635 mg, 21.2
mmol) in CH2Cl2 (80 mL) at 0 °C for 30 min. The white suspension
of paraformaldehyde disappeared to give a colourless solution.
Then a stream of N2 was passed through the reaction mixture for 1
h to form a white suspension. The mixture was poured onto sat. aq
NaHCO3 and the organic layer was separated. The aqueous phase
was extracted with CH2Cl2 (3 × 25 mL). The combined extracts
were dried (Na2SO4) and concentrated. The residue was purified by
column chromatography (silica gel, 13 g, hexanes/Et2O, 5–40%) to
give the acetals 25a,b (740 mg, 93%) as a 6.5:1 mixture of diastere-
oisomers according to integration of the C-10 methine doublets at
d = 5.15 (major) and 5.25 (minor) revealed in the 1H NMR spectrum
(CDCl3). The acetals were separated by column chromatography
(2S,3R,4S,6R)-2-Formyl-4-methoxy-6-[(S)-2,3-dimethoxypro-
pyl]-5,5-dimethyl-3-(triethylsilyloxy)tetrahydro-2H-pyran (23)
Dess–Martin periodinane12 was added in one portion to a solution
of the alcohol 22 (200 mg, 0.49 mmol) in CH2Cl2 (8 mL) at r.t. After
40 min the reaction was quenched by the addition of sat. aq
NaHCO3 (20 mL). After stirring for 10 min, the organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were dried (MgSO4) and concentrat-
ed to give the crude aldehyde 23 as a colourless oil (~100%). Due
to the instability of the aldehyde it was used immediately in the next
step. The analytical and spectral data were collected without further
purification; [a]D20 +29.2 (c = 1.7, CHCl3).
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Formal Synthesis of 18-O-Methyl Mycalamide B
2095
(silica gel, hexanes/Et2O, 5–30%) to give to give 25a; [a]D20 +32.3
(c = 0.7, CHCl3).
mg, 87%) according to integration of the C14-CH3 singlets at
d = 0.91 (major) and 0.94 (minor) revealed in the 1H NMR spectrum
(CDCl3) of the mixture. 1H and 13C NMR spectroscopic data were
identical to those previously reported.3
(1R,5S,6S,8R,10S)-6-benzyloxy-8-[(2S)-2,3-dimethoxypropyl]-
9,9-dimethyl-2,4,6-trioxabicyclo[4.4.0]decane (25a)
IR (neat): n = 2879s, 1455s, 1178s, 1101s, 1044s, 981s, 821s, 735s,
700s cm-1.
Acknowledgement
1H NMR (270 MHz, CDCl3): d = 7.40–7.27 (5 H, m), 5.15 (1 H, d,
J = 6.0 Hz, OCHAHBO), 4.86 (1 H, d, J = 6.0 Hz, OCHAHBO), 4.85
(1 H, s, C10-H), 4.81 (1 H, d, J = 12.0 Hz, PhCH2), 4.58 (1 H, d,
J = 11.8 Hz, PhCH2), 3.94 (1 H, t, J = 2.7 Hz, C12-H), 3.71 (1 H, t,
J = 1.7 Hz, C11-H), 3.57 (1 H, dd, J = 12.2, 3.1 Hz, C15-H), 3.56–
3.40 (2 H, m, C18-H2), 3.40–3.30 (1 H, m, C17-H), 3.38 (3 H, s,
OCH3), 3.33 (3 H, s, OCH3), 3.30 (3 H, s, OCH3), 2.89 (1 H, d,
J = 3.1 Hz, C13-H), 2.28 (1 H, ddd, J = 15.3, 12.4, 4.6 Hz, C16-
HAHB), 1.59 (1 H, ddd, J = 14.9, 7.7, 3.1 Hz, C16-HAHB), 1.22 (3 H,
s, C14-CH3), 0.91 (3H, s, C14-CH3).
13C NMR (67.5 MHz, CDCl3): d = 137.2 (0), 128.6 (1, 2C), 128.2
(1, 2C), 128.0 (1), 96.7 (1), 85.3 (2), 83.8 (1), 78.7 (1), 78.5 (1), 73.5
(2), 70.1 (1), 69.1 (2), 63.1 (1), 59.6 (3), 59.3 (3), 57.2 (3), 37.0 (0),
28.4 (2), 27.4 (3), 21.8 (3).
We thank Zeneca Pharmaceuticals and the EPSRC for financial
support.
References
(1) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M.
J. Org. Chem. 1990, 55, 223.
(2) Thompson, A. M.; Blunt, J. W.; Munro, M. H. G.; Perry, N.
B.; Pannell, L. K. J. Chem. Soc., Perkin Trans. 1 1992, 1335.
(3) Kocienski, P.; Raubo, P.; Davis, J. K.; Boyle, F. T.; Davies, D.
E.; Richter, A. J. Chem. Soc., Perkin Trans. 1 1996, 1797.
(4) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle,
F. T. Synlett 1998, 869.
(5) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Org. Synth. Coll.
Vol. VIII 1993, 315.
(6) Tamao, K. In Advances in Silicon Chemistry; Larson, G. L.,
Ed.; Jai Press Inc:55 Old Post Road/ No 2/Greenwich/CT
06836, 1996; Vol. 3; p 1.
LRMS (CI, NH3): m/z (%) = 411 [(M + H)+, 45], 307 (50), 345 (25),
277 (65), 126 (100).
Anal. Calcd for C22H34O7: C, 64.39; H, 8.29. Found: C, 64.16; H,
8.47.
(7) Fleming, I. Chemtracts: Organic Chemistry 1996, 9, 1.
(8) Adam, W.; Hadjiarapoglou, L.; Wang, X. Tetrahedron Lett.
1989, 30, 6497.
(9) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R.
H. J. Org. Chem. 1980, 45, 4758.
(10) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(11) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,
J.; Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.;
Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585.
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4157.
(13) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.
(14) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4249.
(15) Sharpless, B. K.; Amberg, W.; Bennani, G. A. C.; Martung, J.;
Heong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, X. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768.
(16) Corey, E. J.; Noe, M. C.; Sarshar, S. J. Am. Chem. Soc. 1993,
115, 3828.
(1R,5R,6S,8R,10S)-6-Benzyloxy-8-[(2S)-2,3-dimethoxypropyl]-
9,9-dimethyl-2,4,6-trioxabicyclo[4.4.0]decane (25b)
[a]D20 +11.4 (c = 0.8, CHCl3).
IR (neat): n = 2879s, 1455s, 1178s, 1101s, 1044s, 981s, 821s, 735s,
700s cm-1.
1H NMR (360 MHz, CDCl3, 333 K): d = 7.40–7.27 (5 H, m), 5.24 (1
H, d, J = 6.3 Hz, OCHAHBO), 5.00 (1 H, d, J = 3.6 Hz, C10-H), 4.89
(1 H, d, J = 11.8 Hz, PhCH2), 4.63 (1 H, d, J = 6.3 Hz, OCHAHBO),
4.60 (1 H, d, J = 11.8 Hz, PhCH2), 4.11 (1 H, dd, J = 6.1, 3.6 Hz,
C12-H), 4.03 (1 H, dd, J = 10.2, 2.5 Hz), 3.98 (1 H, dd, J = 18.8, 6.1
Hz), 3.50–3.20 (3 H, m), 3.50 (3 H, s, OCH3), 3.39 (1 H, d, J = 2.4
Hz, C13-H), 3.34 (3 H, s, OCH3), 3.20 (3 H, s, OCH3), 1.74–1.56 (2
H, m, C16-H2), 0.99 (3 H, s, C14-CH3), 0.87 (3 H, s, C14-CH3).
13C NMR (90 MHz, CDCl3, 333 K): d = 137.5 (0), 128.7 (1, 2C),
128.1 (1, 2C), 128.0 (1), 99.0 (1), 82.2 (2), 81.9 (1), 78.5 (1), 76.8
(1), 74.2 (2), 73.6 (1), 70.4 (2), 67.3 (1), 61.2 (3), 59.2 (3), 57.1 (3),
40.2 (0), 30.4 (2), 24.5 (3), 15.2 (3).
(17) Corey, E. J.; Noe, M. C.; Ting, A. Y. Tetrahedron Lett. 1996,
37, 1735.
(18) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M.
Organometallics 1983, 2, 1649.
LRMS (CI, NH3): m/z (%) = 411 [(M + H)+, 45], 307 (15), 294 (20),
277 (35), 126 (100), 91 (70).
(19) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu,
D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(20) Alexander, E. R.; Busch, H. M. J. Am. Chem. Soc. 1952, 74,
554.
Anal. Calcd for C22H34O7: C, 64.39; H, 8.29. Found: C, 64.22; H,
8.41.
(1R,5RS,6R,8R,10S)-10-Methoxy-8-[(2S)-2,3-dimethoxypro-
pyl]-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decan-5-ol (26)
A solution of the acetals 25a,b (400 mg, 0.97 mmol) in EtOAc (30
mL) was hydrogenated (1 atmosphere) with 5% Pd/C (760 mg) for
17 h. The mixture was filtered through a pad of Celite and concen-
trated. The residue was passed through a pad of silica gel (7 g, hex-
anes/EtOAc, 50%) to give a 3:1 mixture of the hemiacetals 26 (271
Article Identifier:
1437-210X,E;1999,0,12,2087,2095,ftx,en;H04299SS.pdf
Synthesis 1999, No. 12, 2087–2095 ISSN 0039-7881 © Thieme Stuttgart · New York