Total synthesis of a stereoisomer of bistramide C and assignment of configuration of the natural product

Article abstract of DOI:10.1002/1521-3765(20020402)8:7<1670::AID-CHEM1670>3.0.CO;2-4

After the isolation of the bioactive polyether bistramide C from the marine ascidian Lissoclinum bistratum in 1988, NMR spectroscopic investigations over the next 12 years reduced the total number of possible stereoisomers of this compound from 1024 to 32. Based on the preparation of segments of the natural product as well as the total synthesis of a randomly selected stereoisomer of bistramide C, the stereochemical puzzle could be further simplified to eight possible stereoisomers. A convergent three-segment coupling strategy, the use of a common, D-glucose-derived intermediate for the preparation of pyran rings in two segments, a stereoselective photo-spiroketalization, and the use of azides to minimize protective group manipulations before segment couplings are highlights of the synthetic approach. The total synthesis also provided the key segments for a chiroptical analysis according to van't Hoff's principle of optical superposition, which was crucial for the assignment of a sole relative and absolute configuration of the natural product. Bistramide C represents therefore the first member of this class of structurally unusual marine polyethers whose configuration is known as a result of the combined use of synthetic and chiroptical tools.

Full text of DOI:10.1002/1521-3765(20020402)8:7<1670::AID-CHEM1670>3.0.CO;2-4

FULL PAPER
Total Synthesis of a Stereoisomer of Bistramide C
and Assignment of Configuration of the Natural Product
Peter Wipf,* Yoshikazu Uto, and Seiji Yoshimura[a]
Abstract: After the isolation of the
bioactive polyether bistramide C from
the marine ascidian Lissoclinum bistra-
tum in 1988, NMR spectroscopic inves-
tigations over the next 12 years reduced
the total number of possible stereoiso-
mers of this compound from 1024 to 32.
Based on the preparation of segments of
the natural product as well as the total
synthesis of a randomly selected stereo-
isomer of bistramide C, the stereochem-
ical puzzle could be further simplified to
eight possible stereoisomers. A conver-
gent three-segment coupling strategy,
the use of a common, d-glucose-derived
intermediate for the preparation of
pyran rings in two segments, a stereo-
selective photo-spiroketalization, and
the use of azides to minimize protective
group manipulations before segment
couplings are highlights of the synthetic
approach. The total synthesis also pro-
vided the key segments for a chiroptical
analysis according to van×t Hoff×s prin-
ciple of optical superposition, which was
crucial for the assignment of a sole
relative and absolute configuration of
the natural product. Bistramide C rep-
resents therefore the first member of
this class of structurally unusual marine
polyethers whose configuration is
known as a result of the combined use
of synthetic and chiroptical tools.
Keywords: absolute configuration ¥
bistramides ¥ glucose ¥ natural prod-
ucts ¥ total synthesis
However, in spite of an extensive use of two-dimensional
NMR techniques, the stereostructure of bistramides remained
elusive.[5a] The presence of ten stereogenic carbons in
bistramide C provides a group of 1024 possible diastereo-
and enantiomeric target structures. Recent synthetic and
NMR studies[5b] have established the relative stereochemistry
at carbons 6,9,11 and 22,23,27,31 and, thus, reduced the
isomeric possibilities to 32, still a challenge for stereochemical
analysis that can only be addressed efficiently by a synergistic
use of synthetic and chiroptical tools.
As part of our program for the total synthesis and biological
evaluation of rare marine natural products,[6] we became
interested in solving the stereochemical puzzle of bistramides.
We now report the synthesis of the (6S,9R,11R,15S,16R,22R,
23S,27S,31S,34R)-stereoisomer of bistramide C and selected
fragments suitable for a van×t Hoff analysis.[6b, 7] Figure 1
summarizes our convergent synthetic strategy. The absolute
Introduction
Bistramides are a new class of bioactive polyethers isolated
from the marine ascidian Lissoclinum bistratum. After the
isolation of bistramide A in 1988,[1] the Hawkins group in
Queensland identified bistratenes, which turned out to be
identical to bistramides.[2] More recently, several additional
members of this class of marine natural products have been
reported.[3] Bistramides demonstrate a broad range of attrac-
tive biological effects. Bistramide A has an IC50 of 0.03
0.32 mgmLÀ1 for P388/dox, B16, HT29, and NSCLC-N6 cell
lines. The latter cells are completely blocked in the G1 phase
in the presence of bistramide K, while bistramide A induces
growth arrest at G2/M in HL60 cells.[4] There is considerable
potential for the use of bistramides for the treatment of slowly
evolving tumors, such as non-small cell pulmonary carcino-
ma.[3] A complete structure assignment of these natural
products is necessary before initiation of SAR studies.
À
À
configuration at C(6) C(11) and C(22) C(31) of the target
molecule 1 was randomly selected, but the relative config-
[a] Prof. Dr. P. Wipf, Dr. Y. Uto, Dr. S. Yoshimura
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
¬
uration in these subunits was based on the work of Solladie
et al.[5b] Preparation of the syn- and anti-stereoisomers of an
N-acetamide methyl amide derivative of 3 in our lab and
NMR comparison to the natural product allowed an assign-
ment of the anti-stereochemistry at C(15) and C(16),[8] albeit
again with randomly selected absolute configuration. Finally,
no information was available for stereocenter C(34); the (R)-
configuration was randomly selected, thus providing only a
minor (1:16) chance that 1 was actually equivalent to the
Fax : (‡1)412-624-0787
E-mail: pwipf ‡ @pitt.edu
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author. Copies of
500 and 600 MHz 1H, 13C NMR, HMQC, HMBC, COSY, NOESY,
ROESY and DEPT spectra for 1, 1H NMR for semisynthetic
bistramide C, and a table comparing NMR data for 1, semisynthetic
and natural bistramide C.
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Chem. Eur. J. 2002, 8, No. 7

1670 1681
8
platinum catalyst. While one-carbon chain extension at
C(12) by cyanide displacement of the triflate derived from
the TBS ether was unsuccessful, use of the carboxylanion
equivalent 8[12] provided a high yield of the desired 9. The
trithioorthoester was converted to the methyl ester by Stork×s
protocol,[13] and the (E)-alkene terminus was introduced by
exposure of the aldehyde derived from the isopropylidene
acetal to a cold (À1008C) solution of in situ prepared
propenyl lithium. Silyl protection of the secondary alcohol
and saponification of the ester[14] led to acid 2.
Building block 5 was also used for the preparation of the
spiroketal moiety (Scheme 2). SN2' displacement[15] of the
allylic acetate was accompanied by partial cleavage of the
primary acetate; methanolysis and introduction of the piv-
aloate group led to diene 10 in 58% yield from 5.
O
O
2
H
15
N
O
N
11
H
OH
O
22
O
(6S,9R,11R,15S,16R,22R,23S,
27S,31S,34R)-Bistramide C (1)
O
31
O
34
TBSO
N3
+
+
N3
CO2Et
OTBS
CO2H
O
2
3
O
O
OAc
4
5
HO
OAc
O
Figure 1. Retrosynthetic analysis of a stereoisomer of bistramide C.
natural product. Pyran 2 as well as spiroketal segment 4 were
envisioned to derive from diacetate 5 which was obtained
from d-glucose. The core ester 3 was also prepared from a
chiral pool precursor and l-malic acid. For the formation of
both amide linkages in the segment condensation steps, azides
were used to mask the primary amine termini, thus to
minimize the need for protective group manipulations on
highly functionalized intermediates.
The preparation of segment 2 from readily available, d-
glucose-derived 5 is summarized in Scheme 1.[9] After dihy-
droxylation of the terminal alkene moiety in 5 with AD-mix-b
that took advantage of the greater chemoselectivity of the
Scheme 2. Preparation of the spiroketal segment.
Selective hydroboration oxidation of the terminal alkene,
silylation, and reductive removal of the pivaloate gave alcohol
11, which was converted to the triflate. Copper-catalyzed
substitution with allyl Grignard reagent, hydroboration oxi-
dation of the resulting terminal alkene, and perruthenate
oxidation[16] provided aldehyde 12. Reformatzky reaction with
the chromium enolate[17] generated from 13 proved to be the
method of choice for the introduction of the C(31) stereo-
center. After reductive removal of the oxazolidinone and
esterification of the primary alcohol, a readily separable about
3:1 mixture of diastereomers 14 was obtained. Oxidative
Scheme 1. Preparation of the pyran segment.
chiral reagent,[10] protection of the diol as the isopropylidene
acetal, hydrogenation of the remaining alkene over PtO2,
methanolysis of the acetates, and silylation of the primary
alcohol provided 6 in 66% overall yield over the five-step
sequence.
Conversion of the secondary hydroxy group in 6 to the
C(10)-b-methyl group was accomplished by oxidation, Wittig
olefination, and face-selective addition[11] of H2 over a
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P. Wipf et al.
FULL PAPER
spirocyclization in the presence of iodobenzene diacetate and
iodine was initiated by irradiation with a 250 W tungsten
lamp[18] and led, after reductive removal of pivaloate, to a
3.5:1 mixture of spiroketals 15 and 16 in 54% yield. Iodide-
containing side product 16 was readily converted to the
desired major product 15.[19] It is noteworthy that the
efficiency of this spiroketal formation was inferior with
C(25),C(26)-saturated analogues of 14. In preparation for
the stereoselective introduction of the C(35)-methyl group, 15
was oxidized to the aldehyde and condensed with the anion
derived from phosphonate 17.[20] Enoate 18 was hydrogenated,
converted to the sodium enolate and methylated[21] to give 19
in >95% diastereoselectivity after removal of the chiral
auxiliary and oxidation[22] to the aldehyde. The final challenge
in the preparation of segment 4 presented itself in the
installation of the C(36),C(37)-trisubstituted alkene. After
considerable experimentation, we found that a slow (8 d)
Wittig condensation with ylide 20 gave 66% of the (E)-double
bond. After conversion of the ester to the secondary alcohol,
deprotection of the silyl ether, mesylation, and substitution
with sodium azide completed the synthesis of spiroketal
segment 4 in 28 steps and an overall yield of 0.6% from 5.
The third segment for bistramide C, azide 3, was prepared
in six steps and 17% yield from l-malic acid.[9] Segment
coupling was then initiated by saponification of 3, temporary
protection of the carboxylate as the TIPS ester, reduction of
the azide, and PyBOP-mediated coupling[23] with acid 2
(Scheme 3). Use of the ethyl ester in place of the TIPS-group
to van×t Hoff×s principle of optical superposition. Previous
studies have established the validity of van×t Hoff analysis for
the assignment of configuration of natural products.[6b, 7]
Experimental molar rotations were measured for synthetic
derivatives 22 and 23;[26] the values for (‡)-normanicone 24
had been reported by Bestmann and co-workers (see Fig-
ure 2).[27] Since segment 23 contains the C(34) stereocenter in
8
TIPSO
O
O
2
H
15
N
O
N
11
22
H
OH
O
O
22 [M]D = +119
O
31
34
O
O
[M]D = +156
23 [M]D = +105
24 [M]D = +51
Configuration / van't Hoff sum of [M]D increments
(6S,9R,11R,15S,16R,22R,23S,27S,31S,34R) / [M]D = +224
(6S,9R,11R,15S,16R,22S,23R,27R,31R,34R) / [M]D = -88
(6S,9R,11R,15S,16R,22S,23R,27R,31R,34S) / [M]D = +14
(6S,9R,11R,15S,16R,22R,23S,27S,31S,34S) / [M]D = +326
(6R,9S,11S,15R,16S,22S,23R,27R,31R,34S) / [M]D = -224
(6R,9S,11S,15R,16S,22R,23S,27S,31S,34S) / [M]D = +88
(6R,9S,11S,15R,16S,22R,23S,27S,31S,34R) / [M]D = -14
(6R,9S,11S,15R,16S,22S,23R,27R,31R,34R) / [M]D = -326
8
O
O
2
H
15
N
O
N
11
H
OH
O
1. LiOH, EtOH
2. TIPS-Cl,
Bistramide C (25)
22
O
TBSO
O
Et3N; 73%
measured [M]D = +70
calculated [M]D = +88
3
OH
3. Pd/C, H2
O
N
O
31
H
4. 2, PyBOP,
iPr2NEt
O
21
TBSO
O
5. TBAF; 54%
34
1. nBu3SnH, AIBN
Figure 2. Increment systems for application of van×t Hoff×s principle of
optical superposition to bistramide C and proposed absolute configuration
of the natural product.
2. 21, PyBOP, iPr2NEt
4
1
3. PPTS, MeOH
4. Periodinane; 24%
Scheme 3. Completion of the total synthesis of a bistramide C stereo-
isomer.
the (R)-configuration, the van×t Hoff molar rotation incre-
ment of the (22R,23S,27S,31S)-spiroketal portion is calculated
as ‡105 À (À51) ˆ 156. Upon addition of the resulting molar
rotation value increments for the eight remaining stereo-
isomeric bistramides, a value of [M]D ˆ ‡224 can be predicted
for 1, which is an excellent match of the experimentally
measured value of [M]D ˆ ‡211. Since the natural product
was found to have [M]D ˆ ‡70,[3] its stereostructure can be
assigned accordingly as 25, which has a calculated [M]D ˆ ‡88
that closely matches the experimental value. This assignment
of stereochemistry is also in agreement with the NMR analysis
of 1, which indicated a potential stereochemical discrepancy
at C(34) with the natural product.
was accompanied by substantial hydrolysis of the C(13)-
amide during the saponification step. Avoiding extensive
purification of labile intermediates, the silyl ester was cleaved
with TBAF and carboxylic acid 21 was coupled to the primary
amine derived from spiroketal azide 4. Final protective group
removal under mild acidic conditions was followed by
oxidation of the allylic alcohols to give target molecule 1.[24]
The spectroscopic properties of 1 were in close agreement
with the data published for the natural product, with the
1
notable exception of the 13C NMR shift at C(34).[25] Since H
and 13C NMR shifts for the C(1) C(18) portion of 1
overlayed with the natural product, we concluded that the
relative configuration of this part of the molecule was correct.
This left the absolute configurations of the spiroketal moiety
as well as C(34) to be assigned, for example a total of eight
stereoisomeric target structures. Our total synthesis also
provided the key segments for a chiroptical analysis according
Conclusion
In conclusion, a convergent 3-segment coupling strategy led to
a stereoisomer of the structurally novel polyether bistrami-
de C. Highlights of our synthesis are the use of a common, d-
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Chem. Eur. J. 2002, 8, No. 7

Bistramide C
1670 1681
(m, 1H), 2.09 (s, 6H); 13C NMR: d ˆ 171.0, 170.6, 134.2, 133.1, 124.0, 117.8,
glucose-derived intermediate for the preparation of pyran
rings in segments 2 and 4, the steroselective spiroketalization
of 14, and the use of azides to minimize protective group
manipulations before segment couplings. The van×t Hoff
analysis of molar rotation angles of synthetic fragments
allows an unambiguous prediction of the relative and absolute
configuration of the natural product as 25 on the basis of the
optical rotation reported for the natural sample. This stereo-
chemical assignment is supported by NMR spectral and
chiroptical comparison with isomer 1 and illustrates the power
of a combined synthetic/molar rotation angle analysis.
71.6, 70.1, 65.3, 63.1, 38.1, 21.3, 21.0.
Acetyl (2R,3S,6R)-2-acetoxymethyl-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-
4-ylmethyl)-3,6-dihydro-2H-pyran-3-yl ester: AD-mix-b (9.36 g) was added
to an ice-cooled mixture of 5 (1.70 g, 6.69 mmol) in acetonitrile (30 mL)
and water (25 mL). The reaction mixture was stirred at 58C for 19 h,
quenched with sodium sulfite (12.1 g), stirred at room temperature for an
additional 1 h and extracted with ethyl acetate (3 Â ). The combined
organic layers were dried (Na2SO4) and concentrated. The residue was
passed through a small pad of silica gel to give crude diol (1.90 g) which was
used for the next step without any further purification.
To a solution of the crude diol prepared above (1.90 g) in 2,2-dimethoxy-
propane (15 mL) was added PPTS (77 mg, 306 mmol). The reaction mixture
was stirred at room temperature for 16 h, diluted with diethyl ether and
washed with water, saturated aqueous NaHCO3 and brine. The organic
layer was dried (Na2SO4) and concentrated. Chromatography on silica gel
(hexanes/ethyl acetate 8:1 then 2:1) gave a ꢀ2.6:1 mixture of C(4)-epimers
of acetic acid (2R,3S,6R)-2-acetoxymethyl-6-((4RS)-2,2-dimethyl-[1,3]di-
Experimental Section
General methods: NMR spectra were recorded at 300 MHz in CDCl3
unless otherwise noted. IR spectra were prepared by spreading a solution
oxolan-4-ylmethyl)-3,6-dihydro-2H-pyran-3-yl ester as
a colorless oil
(2.11 g, 96% over two steps). [a]D ˆ ‡53.2 (c ˆ 1.04, CH2Cl2, 228C); IR
of the sample in CHCl3 over
a NaCl disk, slow evaporation, and
(film): nÄ ˆ 1738 cmÀ1
;
1H NMR (major isomer): d ˆ 5.95 5.85 (m, 1H),
measurement of the resulting film. Anhydrous solvents were freshly
distilled from either sodium/benzophenone, P2O5, or CaH2. All reactions
were performed in oven dried glassware under nitrogen atmosphere.
Analytical TLC was performed with Merck silica gel 60 F-254 glass plates,
and flash chromatography was used to separate and purify the crude
reaction mixtures.
5.80 5.70 (m, 1H), 5.15 5.05 (m, 1H), 4.45 4.35 (m, 1H), 4.30 4.20 (m,
2H), 4.18 4.05 (m, 2H), 3.94 3.84 (m, 1H), 3.56 (t, J ˆ 7.7 Hz, 1H), 2.08
(s, 3H), 2.07 (s, 3H), 1.88 1.78 (m, 2H), 1.39 (s, 3H), 1.34 (s, 3H); 13C NMR
(major isomer): d ˆ 170.9, 170.5, 133.2, 123.8, 108.7, 73.7, 70.0, 69.6, 69.6,
‡
65.1, 63.0, 37.3, 27.1, 25.9, 21.2, 20.9; MS (EI): m/z (%): 328 (0.2) [M] , 313
‡
(43) [M À CH3] , 133 (44), 111 (67), 101 (100); HRMS: m/z: calcd for
‡
(2R,3S,6R)-Acetyl 3-acetoxy-6-allyl-3,6-dihydro-2H-pyran-2-ylmethyl es-
ter (5): a-d-Glucose (1.03 kg, 5.72 mol) was slowly added to a mixture of
acetic anhydride (4 L) and perchloric acid (69 72%, 25 mL) over a period
of 2.5 h to keep the temperature below 408C. After 1.5 h, red phosphorus
(300 g) was added to the mixture and the reaction mixture was cooled on an
ice bath. To this violet suspension was slowly added bromine (0.6 L) while
the temperature was kept below 258C. After the addition was complete,
water (300 mL) was slowly added to the mixture while the temperature was
kept below 308C. After 13 h, the reaction mixture was filtered and washed
with acetic acid. The filtrate was separated into two portions for the next
reaction. A small portion of the filtrate was concentrated and purified by
preparative TLC (hexanes/ethyl acetate 3:2) to give an analytical sample of
C15H21O7: 313.1287 [M À CH3] ; found: 313.1288.
(2R,3S,6S)-2-tert-Butyldimethylsilanyloxymethyl-6-((4RS)-2,2-dimethyl-
[1,3]dioxolan-4-ylmethyl)-tetrahydropyran-3-ol (6): A mixture of acetyl
(2R,3S,6R)-2-acetoxymethyl-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-yl-
methyl)-3,6-dihydro-2H-pyran-3-yl ester (18.6 g, 56.5 mmol) and PtO2
(50 mg, 0.22 mmol) in methanol (100 mL) was stirred under a hydrogen
atmosphere for 5 h. The reaction mixture was filtered and the filtrate was
concentrated. Chromatography on silica gel (hexanes/acetone 20:1, 15:1
and 2:1) gave a ꢀ2.6:1 mixture of C(4)-epimers of acetyl (2R,3S,6S)-2-
acetoxymethyl-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-tetrahy-
dropyran-3-yl ester as a colorless oil (13.3 g, 71%). [a]D ˆ ‡37.4 (c ˆ 1.04,
CH2Cl2, 228C); IR (film): nÄ ˆ 1742 cmÀ1
;
1H NMR (major isomer): d ˆ
2,3,4,6-tetra-O-acteyl-a-d-glucopyranosyl bromide as
a colorless oil:
4.77 4.70 (m, 1H), 4.33 (dd, J ˆ 11.7, 7.1 Hz, 1H), 4.27 4.02 (m, 3H),
3.97 3.84 (m, 2H), 3.52 (t, J ˆ 7.8 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00
1.57 (m, 6H), 1.39 (s, 3H), 1.34 (s, 3H); 13C NMR (major isomer): d ˆ 170.8,
170.3, 108.4, 73.6, 72.0, 69.8, 68.8, 67.4, 62.1, 37.6, 27.0, 26.9, 25.8, 24.3, 21.2,
1H NMR: d ˆ 6.62 (d, J ˆ 4.0 Hz, 1H), 5.57 (t, J ˆ 9.8 Hz, 1H), 5.17 (t,
J ˆ 9.9 Hz, 1H), 4.84 (dd, J ˆ 10.0, 4.1 Hz, 1H), 4.38 4.25 (m, 2H), 4.13 (d,
J ˆ 10.4 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H).
To a solution of sodium acetate (1.2 kg, 15 mol) in water (3 L) and acetic
acid (2 L) were added at room temperature a solution of CuSO4 ¥ 5H2O
(110 g, 0.440 mol) in water (400 mL) and Zn dust (1.1 kg, 17 mol). When
the blue color disappeared, half of the filtrate prepared above was added
slowly to the aqueous solution over a period of 3 h to keep the temperature
below 508C. The reaction mixture was extracted with ethyl acetate and the
combined organic layers were washed with saturated aqueous NaHCO3,
dried (K2CO3), filtered, and concentrated. This reaction was repeated with
the rest of the filtrate to give crude tri-O-acetyl-d-glucal (1.36 kg), which
was used for the next step without further purification. A small amount of
the crude residue was purified by chromatography on silica gel (hexanes/
ethyl acetate 4:1 to 1:1) to give tri-O-acetyl-d-glucal as a colorless oil:
1H NMR: d ˆ 6.48 (dd, J ˆ 6.7, 1.2 Hz, 1H), 5.35 (t, J ˆ 4.6 Hz, 1H), 5.23
(dd, J ˆ 7.3, 5.8 Hz, 1H), 4.86 (dd, J ˆ 6.1, 3.2 Hz, 1H), 4.41 (dd, J ˆ 11.7,
5.5 Hz, 1H), 4.30 4.16 (m, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H).
‡
‡
20.8; MS (EI): m/z (%): 330 (0.3) [M] , 315 (100) [M À CH3] ; HRMS:
‡
m/z: calcd for C15H23O7: 315.1444 [M À CH3] , found: 315.1443.
To a solution of the saturated pyran prepared above (13.3 g, 40.3 mmol) in
methanol (180 mL) was added sodium methoxide (110 mg, 2.00 mmol).
The mixture was stirred at room temperature for 16 h and concentrated.
The residue was purified by chromatography on silica gel (diethyl ether,
then ethyl acetate) to give a ꢀ2.6:1 mixture of C(4)-epimers of (2R,3S,6S)-
6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxymethyltetrahy-
dropyran-3-ol as a colorless oil (9.75 g, 98%). [a]D ˆ ‡43.7 (c ˆ 1.13,
CH2Cl2, 228C); IR (film): nÄ ˆ 3580 cmÀ1
;
1H NMR (major isomer): d ˆ
4.30 4.20 (m, 1H), 4.10 4.02 (m, 1H), 4.01 3.90 (m, 1H), 3.88 3.76 (m,
1H), 3.70 3.49 (m, 4H), 2.92 2.84 (m, 2H), 2.05 1.90 (m, 1H), 1.90 1.77
(m, 1H), 1.76 1.50 (m, 4H), 1.39 (s, 3H), 1.34 (s, 3H); 13C NMR (major
isomer): d ˆ 108.8, 76.0, 73.2, 69.7, 68.2, 66.2, 61.7, 36.1, 27.5, 27.3, 27.1, 25.8;
‡
‡
MS (EI): m/z (%): 246 (0.1) [M] , 231 (100) [M À CH3] ; HRMS: m/z:
To a solution of BF3 ¥ Et2O (49.4 mL, 0.393 mol) in CH3CN (200 mL) was
added a solution of the crude tri-O-acetyl-d-glucal prepared above (107 g)
and allyltrimethylsilane (62.6 mL, 0.393 mol) in CH3CN (600 mL) at
À458C. After 1 h, the reaction mixture was quenched with saturated
aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate
(2 Â ). The combined organic layers were dried (Na2SO4) and concentrated.
Purification of the residue by column chromatography on silica gel
(hexanes/ethyl acetate 10:1, then 4:1) gave 5 as a pale yellow oil (37.0 g;
‡
calcd for C11H19O5: 231.1232 [M À CH3] , found: 231.1236.
To an ice-cooled mixture of the diol prepared above (9.66 g, 39.2 mmol),
triethylamine (6.56 mL, 47.2 mmol) and 4-dimethylaminopyridine (103 mg,
843 mmol) was added tert-butyldimethylsilyl chloride (6.50 g, 43.1 mmol).
The reaction mixture was stirred at room temperature for 17 h, diluted with
diethyl ether and washed with saturated aqueous NH4Cl, saturated aqueous
NaHCO3 and brine. The organic layer was dried (Na2SO4) and concen-
trated. The residue was purified by chromatography on silica gel (hexanes/
diethyl ether 2:1, 1:1 and 1:2) to give a ꢀ2.6:1 mixture of C(4)-epimers of 6
as a colorless oil (14.1 g, 99%). [a]D ˆ ‡13.8 (c ˆ 1.01, CH2Cl2, 228C); IR
32% over four steps). [a]D ˆ ‡62 (c ˆ 0.86, CHCl3, 228C), lit.[28] [a]D
ˆ
‡62.3 (c ˆ 1.03, CHCl3); IR (film): nÄ ˆ 3073, 1740 cmÀ1; 1H NMR: d ˆ 5.94
(ddd, J ˆ 10.4, 2.4, 1.6 Hz, 1H), 5.90 5.75 (m, 2H), 5.18 5.08 (m, 3H),
4.33 4.25 (m, 1H), 4.24 (dd, J ˆ 11.8, 6.5 Hz, 1H), 4.16 (dd, J ˆ 3.5,
11.9 Hz, 1H), 3.42 (dt, J ˆ 3.5, 6.5 Hz, 1H), 2.53 2.41 (m, 1H), 2.38 2.28
(film): nÄ ˆ 3465 cmÀ1
;
1H NMR (major isomer): d ˆ 4.21 4.05 (m, 2H),
4.03 3.94 (m, 1H), 3.82 (dd, J ˆ 9.9, 5.1 Hz, 1H), 3.72 3.58 (m, 2H), 3.53
Chem. Eur. J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1673 $ 20.00+.50/0
1673

P. Wipf et al.
FULL PAPER
(t, J ˆ 7.6 Hz, 1H), 3.52 3.41 (m, 1H), 2.08 (ddd, J ˆ 14.3, 10.2, 5.2 Hz,
1H), 1.97 1.73 (m, 2H), 1.70 1.51 (m, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 0.90
(s, 9H), 0.10 (s, 6H); 13C NMR (major isomer): d ˆ 108.6, 74.0, 73.5, 70.0,
69.9, 69.5, 66.0, 35.5, 27.4, 27.1, 26.7, 26.0, 25.9, 18.3, À5.4, À5.5; MS (EI):
were washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by chromatography on silica gel (hexanes/ethyl acetate 4:1, 2:1
and then 1:1) to give a ꢀ1.6:1 mixture of C(4)-epimers of (2S,3R,6S)-6-
((4RS)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-methyltetrahydropyran-
2-yl-methanol as a white wax (2.71 g, 100%). [a]D ˆ ‡61.3 (c ˆ 1.16,
‡
‡
m/z (%): 345 (8) [M À CH3] , 245 (32) [M À C6H15Si] , 127 (42), 101 (57),
‡
75 (100); HRMS: m/z: calcd for C17H33O5Si: 345.2097 [M À CH3] , found:
CH2Cl2, 228C); IR (film): nÄ ˆ 3479 cmÀ1
;
1H NMR (major isomer): d ˆ
345.2010.
4.44 4.32 (m, 1H), 4.12 3.91 (m, 2H), 3.90 3.70 (m, 2H), 3.50 (t, J ˆ
7.6 Hz, 1H), 3.48 3.35 (m, 1H), 2.76 (d, J ˆ 11.1 Hz, 1H), 2.04 1.88 (m,
1H), 1.70 1.51 (m, 4H), 1.45 1.20 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H), 0.80
(d, J ˆ 7.1 Hz, 3H); 13C NMR (major isomer): d ˆ 108.5, 76.4, 72.5, 69.6,
65.3, 57.1, 38.7, 31.5, 31.2, 27.4, 26.9, 25.5, 16.3; MS (EI): m/z (%): 229 (17)
tert-Butyl-[(2S,6S)-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-
methylenetetrahydropyran-2-ylmethoxy]dimethylsilane
(7):
SO3 ¥ py
(3.12 g, 19.6 mmol) was added portionwise to an ice-cooled solution of 6
(1.40 g, 3.88 mmol), triethylamine (4.9 mL, 35 mmol), and dimethylsulf-
oxide (5.6 mL, 78 mmol) in CH2Cl2 (5 mL). The reaction mixture was
stirred at room temperature for 1.5 h, diluted with diethyl ether and
quenched with ice. The organic layer was washed with brine, dried
(Na2SO4), and concentrated. The residue was purified by chromatography
on silica gel (hexanes/diethyl ether 8:1 then 2:1) to give a ꢀ2.6:1 mixture of
C(4)-epimers of (2R,6S)-2-(tert-butyldimethylsilanyloxymethyl)-6-((4RS)-
2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-dihydropyran-3-one as a pale yel-
low oil (1.26 g, 91%). Small amount of the product was re-purified by
chromatography for analysis: [a]D ˆ ‡73.5 (c ˆ 1.13, CH2Cl2, 228C); IR
‡
‡
[M À CH3] , 213 (7) [M À CH2OH] , 155 (43), 86 (100); HRMS: m/z: calcd
‡
for C12H21O4: 229.1440 [M À CH3] , found: 229.1446.
[(2R,3R,6S)-6-((4RS)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-methyltet-
rahydropyran-2-yl]-acetyl methyl ester: To an ice-cooled mixture of
(2S,3R,6S)-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-methyltetra-
hydropyran-2-yl-methanol (100 mg, 409 mmol) and pyridine (50 mL,
0.61 mmol) in CH2Cl2 (3 mL) was added trifluoromethanesulfonic anhy-
dride (76 mL, 0.45 mmol). The reaction mixture was stirred at 08C for
10 min, quenched with ice and extracted with diethyl ether. The organic
layer was washed with water, saturated aqueous NaHCO3 and brine, dried
(Na2SO4), and passed through a small pad of silica gel. Evaporation of the
eluent gave crude triflate which was immediately used for the next coupling
without any further purification.
(film): nÄ ˆ 1713 cmÀ1
;
1H NMR (major isomer): d ˆ 4.53 4.41 (m, 1H),
4.35 4.23 (m, 1H), 4.11 (dd, J ˆ 8.0, 6.0 Hz, 1H), 4.05 3.98 (m, 1H), 3.98
(dd, J ˆ 10.8, 4.1 Hz, 1H), 3.90 (dd, J ˆ 10.6, 2.5 Hz, 1H), 3.55 (t, J ˆ 7.8 Hz,
1H), 2.53 2.35 (m, 2H), 2.17 2.00 (m, 1H), 1.92 1.70 (m, 3H), 1.40 (s,
3H), 1.37 (s, 3H), 0.83 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (major
isomer): d ˆ 209.8, 108.4, 81.3, 73.6, 69.9, 69.8, 65.9, 39.7, 38.0, 30.3, 27.0,
A solution of trimethylthiomethane (87 mL, 0.65 mmol) in THF (2mL) was
treated at À788C with a 1.6m solution of n-buthyllithium in hexanes
(396 mL, 634 mmol) over 10 min. After stirring at À788C for 15 min, the
triflate prepared above in THF (5 mL) was added. The reaction mixture
was stirred at À788C for 1 h, warmed to À408C and quenched with
saturated aqueous NH4Cl. The aqueous phase was extracted with diethyl
ether. The organic layer was washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and concentrated. The residue was purified by
chromatography on silica gel (hexanes/ethyl acetate 16:1) to give a ꢀ1.6:1
‡
26.0, 25.9, 18.2, À5.6, À5.7; MS (EI): m/z (%): 358 (0.2) [M] , 343 (40)
‡
‡
[M À CH3] , 243 (73) [M À C6H15Si] , 185 (43), 117 (100); HRMS: m/z:
‡
calcd for C17H31O5Si: 343.1941 [M À CH3] , found: 343.1944.
To an ice-cooled suspension of methyltriphenylphosphonium bromide
(1.88 g, 5.27 mmol) in THF (10 mL) was added a 1.6m solution of n-
butyllithium in hexanes (3.1 mL, 4.9 mmol). After stirring at 08C for
10 min, a solution of the ketone prepared above (1.26 g, 3.51 mmol) in THF
(20 mL) was added. The reaction mixture was stirred at 08C for 1 h and at
room temperature for an additional hour, quenched with saturated aqueous
NH4Cl and extracted with diethyl ether. The organic layer was washed with
brine, dried (Na2SO4), and concentrated. The residue was purified by
chromatography on silica gel (hexanes/diethyl ether 16:1 then 8:1) to give a
ꢀ2.6:1 mixture of C(4)-epimers of 7 as a colorless oil (980 mg, 78%).
mixture of C(4)-epimers of 9 as a pale yellow oil (125 mg, 80%). [a]D
ˆ
‡27.3 (c ˆ 1.06, CH2Cl2, 228C); IR (film): nÄ ˆ 2918 cmÀ1; 1H NMR (major
isomer): d ˆ 4.40 4.17 (m, 2H), 4.04 (dd, J ˆ 7.7, 6.0 Hz, 1H), 3.84 3.73
(m, 1H), 3.43 (t, J ˆ 7.9 Hz, 1H), 2.35 2.15 (m, 2H), 2.09 (s, 9H), 2.00
1.50 (m, 5H), 1.35 (s, 3H), 1.29 (s, 3H), 1.30 1.10 (m, 2H), 0.89 (d, J ˆ
7.0 Hz, 3H); 13C NMR (major isomer): d ˆ 108.5, 89.8, 73.2, 73.1, 70.1, 67.5,
39.1, 35.4, 34.3, 30.5, 27.1, 27.1, 25.9, 16.4, 13.4; MS (EI): m/z (%): 365 (0.6)
[a]D ˆ ‡58.2 (c ˆ 1.10, CH2Cl2, 228C); IR (film): n ˆ 3073, 1651 cmÀ1
;
1H NMR (major isomer): d ˆ 4.84 4.78 (m, 2H), 4.30 4.03 (m, 2H), 4.09
(dd, J ˆ 8.1, 5.9 Hz, 1H), 3.93 3.80 (m, 2H), 3.68 (dd, J ˆ 10.5, 5.6 Hz, 1H),
3.50 (t, J ˆ 8.0 Hz, 1H), 2.47 2.22 (m, 2H), 1.80 1.70 (m, 2H), 1.70 1.52
(m, 1H), 1.37 (s, 3H), 1.34 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR
(major isomer): d ˆ 143.5, 110.9, 108.2, 79.3, 74.2, 70.3, 68.0, 63.6, 40.5, 33.6,
[M À CH3] , 333 (17) [M À SCH3] , 213 (25), 155 (100); HRMS: m/z: calcd
‡
‡
‡
for C16H29O3S2: 333.1558 [M À SCH3] , found: 333.1552.
A solution of the orthothioester 9 prepared above (626 mg, 1.64 mmol) in
methanol/water (10:1, 22 mL) was cooled at À40 to À358C and PhI(O-
COCF3)2 (1.77 g, 4.12 mmol) was added over 1.5 h. The reaction mixture
was stirred at À358C for 1 h, quenched with saturated aqueous NaHCO3
and extracted with ethyl acetate. The organic layer was washed with brine,
dried (Na2SO4) and concentrated. The residue was purified by chromatog-
raphy on silica gel (hexanes/diethyl ether 8:1, 4:1 and 2:1) to give a ꢀ1.6:1
mixture of C(4)-epimers of [(2R,3R,6S)-6-((4RS)-2,2-dimethyl-[1,3]dioxo-
‡
29.4, 27.0, 26.0, 25.9, 18.4, À5.3, À5.4; MS (EI): m/z (%): 356 (0.1) [M] ,
‡
‡
‡
341 (26) [M À CH3] , 299 (26) [M À C4H9] , 241 (94) [M À C6H15Si] , 101
‡
(100); HRMS: m/z: calcd for C18H33O4Si: 341.2148 [M À CH3] , found:
341.2149.
(2S,3R,6S)-6-((4RS)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-methyltet-
rahydropyran-2-yl-methanol: A mixture of 7 (5.51 g, 15.5 mmol) and PtO2
(28 mg, 0.12mmol) in ethyl acetate (120 mL) was stirred under a hydrogen
atmosphere for 36 h. The mixture was filtered and the filtrate was
concentrated. The residue was purified twice by chromatography on silica
gel (hexanes/diethyl ether 15:1, 10:1 and 1:1) to give a ꢀ1.7:1 mixture of
C(4)-epimers of tert-butyl-[(2S,3R,6S)-6-((4RS)-2,2-dimethyl-[1,3]dioxo-
lan-4-ylmethyl)-3-methyltetrahydropyran-2-ylmethoxy]-dimethylsilane as
a colorless oil (3.84 g, 69%). [a]D ˆ ‡32.7 (c ˆ 1.08, CH2Cl2, 228C); IR
lan-4-ylmethyl)-3-methyltetrahydropyran-2-yl]-acetyl methyl ester as
a
colorless oil (291 mg, 62%). [a]D ˆ ‡65.6 (c ˆ 1.13, CH2Cl2, 228C); IR
(film): nÄ ˆ 1739 cmÀ1
;
1H NMR (major isomer): d ˆ 4.31 4.19 (m, 1H),
4.10 4.01 (m, 1H), 3.97 (dd, J ˆ 8.1, 5.9 Hz, 1H), 3.76 3.65 (m, 1H), 3.68
(s, 3H), 3.44 (t, J ˆ 7.9 Hz, 1H), 2.74 (dd, J ˆ 14.2, 11.2 Hz, 1H), 2.30 (dd,
J ˆ 14.2, 4.2 Hz, 1H), 2.00 1.85 (m, 1H), 1.75 1.40 (m, 4H), 1.36 (s, 3H),
1.32 (s, 3H), 1.32 1.20 (m, 2H), 0.80 (d, J ˆ 6.8 Hz, 3H); 13C NMR (major
isomer): d ˆ 172.5, 108.1, 74.2, 74.1, 70.3, 67.0, 51.8, 40.1, 32.8, 32.5, 31.5, 27.0,
(film): nÄ ˆ 2930 cmÀ1
;
1H NMR (major isomer): d ˆ 4.30 4.18 (m, 1H),
26.7, 26.0, 17.0; MS (EI): m/z (%): 286 (1) [M] , 271 (10) [M À CH3] , 231
‡
‡
‡
4.10 (dd, J ˆ 9.7, 8.0 Hz, 1H), 3.88 3.62 (m, 4H), 3.52 (t, J ˆ 7.9 Hz, 1H),
1.95 1.82 (m, 1H), 1.80 1.57 (m, 4H), 1.55 1.23 (m, 2H), 1.39 (s, 3H),
1.35 (s, 3H), 0.90 (s, 9H), 0.90 (d, J ˆ 7.0 Hz, 3H), 0.06 (s, 6H); 13C NMR
(major isomer): d ˆ 108.2, 76.4, 74.3, 70.3, 68.4, 61.9, 39.2, 31.7, 30.4, 27.6,
(10), 105 (49); HRMS: m/z: calcd for C14H23O5: 271.1545 [M À CH3] ,
found: 271.1543.
[(2R,3R,6S)-3-Methyl-6-(2-oxoethyl)-tetrahydropyran-2-yl]-acetyl methyl
ester: A solution of [(2R,3R,6S)-6-((4RS)-2,2-dimethyl-[1,3]dioxolan-4-
ylmethyl)-3-methyltetrahydropyran-2-yl]-acetyl methyl ester (240 mg,
838 mmol) and PPTS (20 mg, 80 mmol) in methanol (8 mL) was stirred at
room temperature for 20 h. The reaction mixture was concentrated,
redissolved in methanol (8 mL) and stirred at room temperature for an
additional 20 h. This procedure was repeated twice. The solution was
concentrated and purified by chromatography on silica gel (diethyl ether,
and then ethyl acetate) to give a ꢀ1.7:1 mixture of C(4)-epimers of
[(2R,3R,6S)-6-((2RS)-2,3-dihydroxypropyl)-3-methyltetrahydropyran-2-yl]-
‡
27.1, 26.0, 26.0, 18.4, 16.0, À5.3; MS (EI): m/z (%): 358 (0.1) [M] , 343 (20)
‡
‡
[M À CH3] , 243 (85) [M À C6H15Si] , 101 (100); HRMS: m/z: calcd for
‡
C18H35O4Si: 343.2305 [M À CH3] , found: 343.2313.
To an ice-cooled solution of the saturated pyran prepared above (3.98 g,
11.1 mmol) in THF (15 mL) was added a 1m solution of tetrabutylammo-
nium fluoride in THF (16.7 mL, 16.7 mmol). The reaction mixture was
stirred at room temperature for 3 h, quenched with saturated aqueous
NH4Cl and extracted with ethyl acetate (2 Â ). The combined organic layers
1674
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1674 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 7

Bistramide C
1670 1681
acetyl methyl ester as a colorless oil (195 mg, 95%). [a]D ˆ ‡50.6 (c ˆ 1.03,
J ˆ 15.7, 10.3 Hz, 1H), 2.38 (dd, J ˆ 15.7, 3.9 Hz, 1H), 2.03 1.77 (m, 2H),
1.75 1.60 (m, 2H), 1.67 (dd, J ˆ 6.5, 0.9 Hz, 3H), 1.54 1.43 (m, 1H), 1.35
1.23 (m, 2H), 0.87 (s, 9H), 0.85 (d, J ˆ 7.0 Hz, 3H), 0.03 (s, 3H), 0.01 (s,
3H); 13C NMR (major isomer): d ˆ 177.0, 134.3, 126.2, 73.1, 70.9, 67.4, 43.7,
33.0, 32.7, 29.9, 26.6, 26.0, 18.3, 17.8, 16.4, À4.0, À4.7; MS (EI): m/z (%): 341
CH2Cl2, 228C); IR (film): nÄ ˆ 3477, 1726 cmÀ1
;
1H NMR (major isomer):
d ˆ 4.28 4.19 (m, 1H), 3.95 3.78 (m, 2H), 3.73 (s, 3H), 3.57 3.51 (m,
1H), 3.48 3.43 (m, 1H), 2.89 2.77 (m, 1H), 2.35 (dd, J ˆ 13.0, 3.7 Hz,
1H), 2.29 2.23 (m, 1H), 2.07 1.92 (m, 1H), 1.70 1.52 (m, 3H), 1.50 1.40
(m, 2H), 1.40 1.29 (m, 2H), 0.83 (d, J ˆ 6.9 Hz, 3H); 13C NMR (major
isomer): d ˆ 173.7, 74.6, 68.2, 66.6, 65.5, 52.2, 39.2, 33.0, 32.2, 31.6, 26.8, 17.2;
‡
‡
(0.04) [M À CH3] , 299 (1) [M À C4H9] , 231 (3), 185 (3), 157 (3); HRMS:
‡
m/z: calcd for C15H27O4Si: 299.1679 [M À C4H9] , found: 299.1665.
‡
‡
MS (EI): m/z (%): 247 (2) [M‡H] , 228 (2) [M À H2O] , 215 (52) [M À
[(2S,5S,6R)-6-Allyl-5-methyl-5,6-dihydro-2H-pyran-2-ylmethyl ester]-2,2-
dimethylpropionic acid (10): A solution of CuBr¥ SMe2 (1.43 g, 6.97 mmol)
in Et2O (20 mL) at À308C under a N2 atmosphere was treated with MeLi
(1.4m in Et2O, 10.0 mL) and warmed to 08C. The cuprate solution was
added very slowly, over a period of 1.5 h, to a solution of 5 (1.61 g,
6.34 mmol) in Et2O (90 mL) at À15 to À58C. The reaction mixture was
quenched with saturated aqueous NH4Cl. The organic layer was washed
with 0.5m NaOH and brine, dried (Na2SO4), and concentrated in vacuo to
give crude product (1.32 g). [a]D ˆ À25 (c ˆ 0.33, CHCl3, 228C); IR (film):
‡
‡
CH2OH] , 171 (100); HRMS: m/z: calcd for C12H23O5: 247.1545 [M‡H] ,
found: 247.1546.
To an ice-cooled solution of the diol prepared above (194 mg, 787 mmol) in
diethyl ether/water (2:1, 24 mL) was added KIO4 (272 mg, 1.18 mmol). The
reaction mixture was stirred at 08C for 2 h, diluted with diethyl ether and
water, and extracted with diethyl ether. The organic layer was combined,
washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by chromatography on silica gel (hexanes/diethyl ether 2:1 then
1:1) to give [(2R,3R,6S)-3-methyl-6-(2-oxoethyl)-tetrahydropyran-2-yl]-
acetyl methyl ester as a colorless oil (145 mg, 86%). [a]D ˆ ‡52.8 (c ˆ
nÄ ˆ 3075, 3027, 1742 cmÀ1
;
1H NMR: d ˆ 5.97 5.81 (m, 1H), 5.77 (dt, J ˆ
10.3, 2.4 Hz, 1H), 5.61 (dt, J ˆ 10.2, 2.4 Hz, 1H), 5.16 5.00 (m, 2H), 4.42
4.33 (m, 1H), 4.27 (dd, J ˆ 11.5, 8.1 Hz, 1H), 3.99 (dd, J ˆ 3.4, 11.5 Hz, 1H),
3.42 (dt, J ˆ 4.0, 7.4 Hz, 1H), 2.46 2.34 (m, 1H), 2.33 2.20 (m, 1H), 2.16
2.02 (m, 1H), 2.09 (s, 3H), 0.99 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ 171.2,
135.3, 133.7, 123.9, 116.7, 74.7, 70.5, 64.8, 37.3, 33.3, 21.2, 18.1; MS (EI): m/z
1.18, CH2Cl2, 228C); IR (film): nÄ ˆ 2731, 1734 cmÀ1
;
1H NMR: d ˆ 9.69
(brdd, J ˆ 2.3, 1.9 Hz, 1H), 4.35 4.13 (m, 2H), 3.60 (s, 3H), 2.69 (dd, J ˆ
14.0, 11.2 Hz, 1H), 2.53 (ddd, J ˆ 15.9, 8.5, 3.0 Hz, 1H), 2.44 2.35 (m, 1H),
2.35 (dd, J ˆ 13.9, 4.0 Hz, 1H), 2.05 1.91 (m, 1H), 1.77 1.61 (m, 2H),
1.48 1.26 (m, 2H), 0.84 (d, J ˆ 7.0 Hz, 3 H) ; 13C NMR: d ˆ 201.6, 172.2,
74.3, 65.2, 51.7, 49.0, 32.5, 32.4, 30.5, 26.3, 16.7; MS (EI): m/z (%): 213 (4)
‡
‡
(%): 210 (0.2) [M] , 209 (1) [M À H] , 169 (24), 137 (63), 109 (100);
‡
HRMS: m/z: calcd for C12H17O3: 209.1178 [M À H] , found: 209.1174.
‡
‡
‡
[M À H] , 199 (2) [M À CH3] , 185 (5) [M À CHO] , 171 (5); HRMS: m/z:
A solution of the crude residue prepared above (1.32 g) in MeOH (20 mL)
was treated with NaOMe (23 mg, 0.43 mmol) at room temperature, stirred
for 12 h, concentrated, and dried in vacuo. A mixture of the crude residue
(1.03 g) in pyridine (5 mL) was treated with pivaloyl chloride (0.93 mL,
7.6 mmol) at room temperature, stirred for 2 h, diluted with ethyl acetate,
washed with 1n HCl (2 Â ), saturated aqueous NaHCO3, and brine, dried
(Na2SO4), and concentrated. Purification of the residue by chromatography
on silica gel (hexanes/ethyl acetate 1:0, then 20:1) gave 10 as a pale yellow
oil (929 mg, 58% over three steps). [a]D ˆ À33 (c ˆ 0.83, CHCl3, 228C); IR
(film): nÄ ˆ 3075, 3027, 1729 cmÀ1; 1H NMR: d ˆ 5.96 5.80 (m, 1H), 5.75 (dt,
J ˆ 10.2, 2.2 Hz, 1H), 5.61 (dt, J ˆ 10.3, 2.4 Hz, 1H), 5.13 5.00 (m, 2H),
4.41 4.33 (m, 1H), 4.31 (dd, J ˆ 7.5, 11.2 Hz, 1H), 3.94 (dd, J ˆ 11.2, 3.2 Hz,
1H), 3.42 (dt, J ˆ 3.7, 7.8 Hz, 1H), 2.44 2.33 (m, 1H), 2.30 2.18 (m, 1H),
2.15 2.02 (m, 1H), 1.21 (s, 9H), 0.98 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ
178.6, 135.5, 133.6, 124.1, 116.6, 74.8, 70.7, 64.7, 39.0, 37.4, 33.5, 27.4, 17.9; MS
‡
calcd for C10H15O4: 199.0970 [M À CH3] , found: 199.0961.
{(2R,3R,6S)-6-[(2RS)-(3E)-2-(tert-Butyldimethylsilanyloxy)-pent-3-enyl]-
3-methyltetrahydropyran-2-yl}-acetic acid (2): A 1.7m solution of tert-
butyllithium in hexanes (198 mL, 337 mmol) was added over 20 min to a cold
solution (À788C) of trans-2-propenylbromide (14 mL, 0.16 mmol) in
diethyl ether (2 mL). The reaction mixture was stirred at À788C for
20 min, warmed to 08C, and transferred by cannula into a pre-cooled
(À1008C) solution of [(2R,3R,6S)-3-methyl-6-(2-oxoethyl)-tetrahydropyr-
an-2-yl]-acetyl methyl ester (20 mg, 93 mmol) in diethyl ether (2 mL). The
mixture was stirred at À1008C for 10 min and quenched with saturated
aqueous NH4Cl. The aqueous layer was extracted with diethyl ether. The
organic phase was washed with brine, dried (Na2SO4), and passed through a
short pad of silica gel. The crude allyl alcohol was used for the next
silylation without any further purification.
‡
(EI): m/z (%): 211 (30) [M À C3H5] , 137 (76), 81 (73), 57 (100); HRMS:
To an ice-cooled solution of the allyl alcohol prepared above and imidazole
(39 mg, 0.57 mmol) in dichloromethane (0.5 mL) was added tert-butyldi-
methylsilyl chloride (62 mg, 0.41 mmol). The reaction mixture was stirred
at room temperature for 16 h and quenched with saturated aqueous NH4Cl.
The aqueous layer was extracted with diethyl ether. The organic phase was
washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by chromatography on silica gel (hexanes/diethyl ether 16:1 then
8:1) to give a >10:1 mixture of C(4)-epimers of {6-(2R,3R,6S)-[(2RS)-(3E)-
2-(tert-butyldimethylsilanyloxy)-pent-3-enyl]-3-methyltetrahydropyran-2-
yl}-acetyl methyl ester as a colorless oil (19.2 mg; 56% over two steps).
‡
m/z: calcd for C12H19O3: 211.1334 [M À C3H5] , found: 211.1337.
[(2S,5S,6R)-6-(3-Hydroxypropyl)-5-methyl-5,6-dihydro-2H-pyran-2-yl-
methyl ester]-2,2-dimethylpropionic acid: 9-BBN (0.5m in THF, 80 mL)
was added at room temperature to a solution of 10 (5.07 g, 20.1 mmol) in
THF (80 mL). After 17 h, 0.5m NaOH (80 mL) and 30% H2O2 (80 mL)
were added slowly to the reaction mixture at 08C. After stirring for an
additional 3 h at room temperature, the mixture was diluted with ethyl
acetate. The organic layer was washed with brine and the aqueous layer was
extracted with CHCl3 (2 Â ). The combined organic layers were dried
(Na2SO4), concentrated, and purified by chromatography on silica gel
(hexanes/ethyl acetate 4:1, 2:1, and 1:1) to give alcohol as a colorless oil
(4.60 g, 85%). [a]D ˆ À23 (c ˆ 0.91, CHCl3, 228C); IR (film): nÄ ˆ 3433,
3027, 1725, 1645 cmÀ1; 1H NMR: d ˆ 5.73 (dt, J ˆ 10.3, 2.2 Hz, 1H), 5.58 (dt,
J ˆ 10.3, 2.5 Hz, 1H), 4.41 4.33 (m, 1H), 4.29 (dd, J ˆ 7.8, 11.2 Hz, 1H),
3.94 (dd, J ˆ 2.8, 11.2 Hz, 1H), 3.63 (t, J ˆ 6.0 Hz, 2H), 3.31 (dt, J ˆ 2.2,
8.5 Hz, 1H), 2.43 2.30 (brs, 1H), 2.13 2.00 (m, 1H), 1.82 1.58 (m, 3H),
1.57 1.45 (m, 1H), 1.19 (s, 9H), 0.95 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ
178.6, 134.0, 123.7, 74.9, 71.1, 64.5, 62.8, 38.9, 34.1, 29.6, 29.0, 27.3, 17.8; MS
[a]D ˆ ‡55.5 (c ˆ 0.96, CH2Cl2, 228C); IR (film): nÄ ˆ 2932, 1745 cmÀ1
;
1H NMR (major isomer): d ˆ 5.60 5.38 (m, 1H), 5.43 5.34 (m, 1H), 4.33
4.24 (m, 1H), 4.18 4.08 (m, 1H), 3.69 (s, 3H), 3.68 3.52 (m, 1H), 2.65 (dd,
J ˆ 14.7, 9.8 Hz, 1H), 2.33 (dd, J ˆ 14.7, 4.6 Hz, 1H), 1.98 1.87 (m, 1H),
1.85 1.75 (m, 1H), 1.73 1.60 (m, 2H), 1.68 (brd, J ˆ 6.0 Hz, 3H), 1.48
1.37 (m, 1H), 1.35 1.20 (m, 2H), 0.87 (s, 9H), 0.82 (d, J ˆ 7.0 Hz, 3H), 0.04
(s, 3H), 0.01 (s, 3H); 13C NMR: d ˆ 172.7, 134.5, 125.7, 73.5, 70.8, 67.0, 51.8,
44.0, 33.3, 32.8, 30.2, 26.8, 26.0, 25.8, 18.3, 17.8, 16.5, À4.0, À4.7; MS (EI):
‡
‡
m/z (%): 355 (0.04) [M À CH3] , 313 (2) [M À C4H9] , 243 (18), 185 (8), 171
‡
‡
(8); HRMS: m/z: calcd for C16H29O4Si: 313.1835 [M À C4H9] , found:
(EI): m/z (%): 271 (60) [M‡H] , 211 (78), 182 (100), 155 (88), 57 (89);
‡
313.1827.
HRMS: m/z: calcd for C15H27O4: 271.1909 [M‡H] , found: 271.1917.
To a solution of the silyl ether prepared above (18.8 mg, 50.7 mmol) in THF
(1 mL) was added a 40 wt% solution of tetrabutylammonium hydroxide in
water (72 mL, 0.11 mmol). The reaction mixture was stirred at room
temperature for 4 h and poured into a stirred mixture of ethyl acetate and
0.01n hydrochloric acid. The organic layer was washed with brine, dried
(Na2SO4), and concentrated. The residue was purified by chromatography
on silica gel (hexanes/diethyl ether 16:1, 8:1, 4:1 and then 1:1) to give a
>10:1 mixture of C(4)-epimers of 2 as a colorless oil (15.2 mg, 84%).
[a]D ˆ ‡47.4 (c ˆ 1.03, CH2Cl2, 228C); IR (film): n ˆ 3500 2800 (br),
1713 cmÀ1; 1H NMR (major isomer): d ˆ 5.60 5.50 (m, 1H), 5.43 5.31 (m,
1H), 4.33 4.22 (m, 1H), 4.20 4.09 (m, 1H), 3.71 3.60 (m, 1H), 2.67 (dd,
{(2S,5S,6R)-5-Methyl-6-[3-(triisopropylsilanyloxy)-propyl]-5,6-dihydro-
2H-pyran-2-ylmethyl ester}-2,2-dimethylpropionic acid: TIPSCl (2.1 mL,
10 mmol) was added at room temperature to a solution of the alcohol
prepared above (1.35 g, 5.00 mmol), imidazole (0.68 g, 10 mmol), and
DMAP (61 mg, 0.50 mmol) in CH2Cl2 (13 mL). After 15 h, the mixture was
diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and
brine, dried (Na2SO4), concentrated, and purified by chromatography on
silica gel (hexanes/ethyl acetate 80:1, 40:1, and 20:1) to give TIPS ether as a
colorless oil (2.10 g, 100%). [a]D ˆ À9.0 (c ˆ 0.90, CHCl3, 228C); IR (film):
nÄ ˆ 3030, 1731 cmÀ1; 1H NMR: d ˆ 5.75 (dt, J ˆ 10.3, 2.3 Hz, 1H), 5.60 (dt,
J ˆ 10.2, 2.5 Hz, 1H), 4.40 4.31 (m, 1H), 4.27 (dd, J ˆ 7.7, 11.4 Hz, 1H),
Chem. Eur. J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1675 $ 20.00+.50/0
1675

P. Wipf et al.
FULL PAPER
3.96 (dd, J ˆ 11.4, 3.3 Hz, 1H), 3.74 3.63 (m, 2H), 3.30 (t, J ˆ 8.2 Hz, 1H),
2.10 1.96 (m, 1H), 1.87 1.66 (m, 2H), 1.66 1.37 (m, 2H), 1.21 (s, 9H),
1.12 1.00 (m, 21H), 0.97 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ 178.6, 133.9,
124.1, 74.9, 70.6, 64.7, 63.4, 38.9, 34.3, 29.3, 29.2, 27.4, 18.2, 18.0, 12.2; MS
(EI): m/z (%): 426 (0.03) [M] , 311 (22), 215 (88), 201 (66), 159 (62), 57
(100); HRMS: m/z: calcd for C24H46O4Si: 426.3165, found: 426.3163.
4-{(2R,5S,6R)-5-Methyl-6-[3-(triisopropylsilanyloxy)-propyl]-5,6-dihydro-
2H-pyran-2-yl}-butyraldehyde (12): A mixture of the alcohol prepared
above (5.18 g, 13.5 mmol), NMO (2.38 g, 20.3 mmol), and 4 ä powdered
molecular sieves (6.75 g) was treated with TPAP (0.24 g, 0.68 mmol) at
room temperature, stirred for 30 min, filtered through a short pad of silica
gel, and concentrated. Purification of the residue by chromatography on
silica gel (hexanes/ethyl acetate 20:1) gave 12 as a pale yellow oil (4.32 g,
84%). [a]D ˆ ‡6.6 (c ˆ 0.97, CHCl3, 228C); IR (film): nÄ ˆ 3025, 2709,
‡
(2S,5S,6R)-{5-Methyl-6-[3-(triisopropylsilanyloxy)-propyl]-5,6-dihydro-
2H-pyran-2-yl}-methanol (11): A solution of the TIPS ether prepared
1726 cmÀ1
;
1H NMR: d ˆ 9.77 (s, 1H), 5.62 (s, 2H), 4.13 4.03 (m, 1H),
above (2.10 g, 5.00 mmol) in THF (30 mL) was added slowly to
a
3.78 3.62 (m, 2H), 3.28 3.18 (m, 1H), 2.47 (t, J ˆ 7.2 Hz, 2H), 2.07 1.93
(m, 1H), 1.88 1.40 (m, 8H), 1.15 1.00 (m, 21H), 0.96 (d, J ˆ 7.1 Hz, 3H);
13C NMR: d ˆ 202.8, 131.1, 128.5, 74.6, 71.3, 63.4, 43.9, 34.4, 33.5, 29.6, 29.3,
suspension of LiAlH4 (380 mg, 10.0 mmol) in THF (15 mL) at room
temperature. The reaction mixture was stirred for 11.5 h, treated with 0.5m
NaOH for 3 h, filtered, dried (Na2SO4), and concentrated. Purification of
the residue by chromatography on silica gel (hexanes/ethyl acetate 4:1)
gave 11 as a colorless oil (1.59 g, 93%). [a]D ˆ ‡14 (c ˆ 0.95, CHCl3, 228C);
IR (film): nÄ ˆ 3413, 3022 cmÀ1; 1H NMR: d ˆ 5.73 (dt, J ˆ 10.3, 2.5 Hz, 1H),
5.57 (dt, J ˆ 10.3, 2.4 Hz, 1H), 4.26 4.18 (m, 1H), 3.77 3.67 (m, 2H),
3.67 3.58 (m, 1H), 3.57 3.47 (m, 1H), 3.37 3.28 (m, 1H), 2.13 (dd, J ˆ
9.1, 3.2 Hz, 1H), 2.10 2.00 (m, 1H), 1.85 1.65 (m, 2H), 1.65 1.48 (m,
2H), 1.12 1.00 (m, 21H), 0.98 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ 133.2,
124.2, 74.8, 72.7, 63.9, 63.3, 34.2, 29.4, 29.1, 18.4, 18.2, 12.2; MS (EI): m/z
‡
18.9, 18.4, 18.2, 12.2; MS (EI): m/z (%): 382 (0.1) [M] , 339 (16) [M À
‡
C3H7] , 201 (72), 159 (100); HRMS: m/z: calcd for C19H35O3Si: 339.2355
‡
[M À C3H7] , found: 339.2365.
(4R)-3-(Bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone (13): n-BuLi
(1.6m in hexane, 26 mL) and bromoacetyl chloride (3.6 mL, 44 mmol)
were added successively at À788C to a solution of (R)-4-(benzyl)-2-
oxazolidinone (7.11 g, 40.1 mmol) in THF (12 mL). The reaction mixture
was slowly warmed to room temperature over a period of 2 h, quenched
with saturated aqueous NH4Cl, and extracted with ethyl acetate. The
organic layer was washed with saturated aqueous NaHCO3 and brine, dried
(Na2SO4), concentrated, and purified by chromatography on silica gel
‡
‡
‡
(%): 342 (0.03) [M] , 311 (93) [M À CH3O] , 299 (100) [M À C3H7] , 159
‡
(61), 81 (96); HRMS: m/z: calcd for C18H35O2Si: 311.2406 [M À CH3O] ,
found: 311.2412.
(hexanes/ethyl acetate 4:1) to give 13 as a colorless oil (7.93 g, 66%). [a]D
ˆ
À73 (c ˆ 0.28, CHCl3, 228C), lit.:[29] [a]D ˆ À79.3 (c ˆ 1.01, CH2Cl2, 218C);
(2R,5S,6R)-[3-(6-But-3-enyl-3-methyl-3,6-dihydro-2H-pyran-2-yl)-pro-
poxy]triisopropylsilane: Trifluoromethanesulfonic anhydride (0.36 mL,
2.2 mmol) was added at À458C to a solution of 11 (687 mg, 2.01 mmol)
and pyridine (0.19 mL, 2.4 mmol) in CH2Cl2 (15 mL). After 30 min, the
reaction mixture was warmed to 08C, kept at the temperature for 10 min,
diluted with Et2O, washed with ice-cold 1n HCl, water, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), filtered through a short plug of silica
gel, concentrated, and dried in vacuo. The pale organic residue (915 mg,
96%) was used for the next step without further purification.
IR (film): nÄ ˆ 1779, 1711 cmÀ1
;
1H NMR: d ˆ 7.40 7.10 (m, 5H), 4.76 (s,
2H), 4.77 4.65 (m, 1H), 4.35 4.22 (m, 2H), 3.36 (dd, J ˆ 13.4, 3.3 Hz,
1H), 2.82 (dd, J ˆ 13.4, 9.6 Hz, 1H); 13C NMR: d ˆ 166.4, 153.4, 134.9,
‡
129.7, 129.5, 127.8, 67.3, 55.7, 43.9, 37.9; MS (EI): m/z (%): 299 (14) [M‡2] ,
‡
297 (13) [M] , 253 (21), 160 (33), 133 (100); HRMS: m/z: calcd for
C12H12NO3Br: 297.0001, found: 297.0006.
(4R)-Benzyl-3-((3S)-hydroxy-6-{(2R,5S,6R)-5-methyl-6-[3-(triisopropylsi-
lanyloxy)-propyl]-5,6-dihydro-2H-pyran-2-yl}-hexanoyl)-oxazolidin-2-one:
CrCl2 (3.48g, 28.3 mmol) and LiI (0.16 g, 1.1 mmol) were freshly flame-
dried in vacuo. After cooling to room temperature, THF (50 mL) was
added to the mixture. To the resulting suspension was added a solution of
12 (4.15 g, 10.9 mmol) and 13 (3.42 g, 11.5 mmol) in THF (50 mL) at room
temperature. The reaction mixture was stirred for 3.5 h, quenched with
brine, stirred for an additional 30 min, and extracted with ethyl acetate (4 Â
). The combined organic layers were dried (Na2SO4), concentrated, and
purified by chromatography on silica gel (hexanes/ethyl acetate 4:1, then
2:1) to give the desired aldol product as a pale yellow oil (3.38 g, 52%) and
the undesired aldol product as a pale yellow oil (1.06 g, 16%). Major
isomer: [a]D ˆ À11 (c ˆ 0.83, CHCl3, 228C); IR (film): nÄ ˆ 3478, 3024, 1784,
1686 cmÀ1; 1H NMR: d ˆ 7.48 7.16 (m, 5H), 5.70 5.55 (m, 2H), 4.70 (ddd,
J ˆ 12.8, 7.0, 3.4 Hz, 1H), 4.28 4.15 (m, 2H), 4.15 4.05 (m, 2H), 3.80 3.63
(m, 2H), 3.35 3.20 (m, 2H), 3.12 3.05 (m, 2H), 3.02 2.95 (m, 1H), 2.81
(dd, J ˆ 13.4, 9.7 Hz, 1H), 2.05 1.95 (m, 1H), 1.85 1.40 (m, 10H), 1.15
1.00 (m, 21H), 0.97 (d, J ˆ 7.0 Hz, 3H); 13C NMR: d ˆ 173.1, 153.6, 135.2,
130.8, 129.6, 129.2, 128.9, 127.6, 74.5, 71.5, 68.1, 66.5, 63.4, 55.2, 43.0, 38.0,
36.7, 34.4, 34.1, 29.5, 29.3, 22.1, 18.4, 18.3, 12.2; MS (EI): m/z (%): 601 (0.05)
To a suspension of CuBr2 ¥ SMe2 (80 mg, 0.39 mmol) in Et2O (10 mL) was
added allylmagnesium bromide (1.0m in Et2O, 2.9 mL) at À788C. After
15 min, a solution of the triflate prepared above (915 mg) in Et2O (10 mL)
was added via cannula to the brown solution at À788C. The reaction
mixture was slowly warmed to room temperature over a period of 2 h,
stirred for 12 h, quenched with saturated aqueous NH4Cl, washed with 0.5m
NaOH, and brine, dried (Na2SO4), and concentrated. Purification of the
residue by chromatography on silica gel (hexanes/ethyl acetate 40:1) gave
(2R,5S,6R)-[3-(6-but-3-enyl-3-methyl-3,6-dihydro-2H-pyran-2-yl)-propoxy]-
triisopropylsilane as a pale yellow oil (471 mg, 64%). [a]D ˆ ‡2.7 (c ˆ 0.86,
CHCl3, 228C); IR (film): nÄ ˆ 3078, 3023 cmÀ1; 1H NMR: d ˆ 5.91 5.75 (m,
1H), 5.65 (dt, J ˆ 10.3, 2.1 Hz, 1H), 5.60 (dt, J ˆ 10.2, 1.9 Hz, 1H), 5.04
(ddd, J ˆ 17.2, 3.5, 1.6 Hz, 1H), 5.00 4.92 (m, 1H), 4.15 4.08 (m, 1H),
3.80 3.65 (m, 2H), 3.28 3.20 (m, 1H), 2.30 2.08 (m, 2H), 2.08 1.93 (m,
1H), 1.90 1.40 (m, 6H), 1.15 1.00 (m, 21H), 0.96 (d, J ˆ 7.1 Hz, 3H);
13C NMR: d ˆ 138.6, 131.0, 128.9, 114.9, 74.3, 71.2, 63.4, 34.6, 33.4, 30.5, 29.6,
‡
29.4, 18.3, 18.2, 12.2; MS (EI): m/z (%): 323 (5) [M À C3H7] , 311 (4), 201
(54), 159 (74), 91(91), 81 (64), 69 (100); HRMS: m/z: calcd for C19H35O2Si:
‡
‡
[M] , 583 (0.6) [M À H2O] , 540 (2), 496 (24), 363 (53), 201 (49), 159 (100),
131 (69), 91 (60); HRMS: m/z: calcd for C34H53NO5Si: 583.3693 [M À
‡
323.2406 [M À C3H7] , found: 323.2414.
‡
H2O] , found: 583.3680. Minor isomer: [a]D ˆ À34 (c ˆ 0.95, CHCl3,
4-{(2R,5S,6R)-5-Methyl-6-[3-(triisopropylsilanyloxy)-propyl]-5,6-dihydro-
2H-pyran-2-yl}-butan-1-ol: 9-BBN (0.5m in THF, 4.0 mL) was added at
room temperature to a solution of (2R,5S,6R)-[3-(6-but-3-enyl-3-methyl-
3,6-dihydro-2H-pyran-2-yl)-propoxy]triisopropylsilane (362 mg, 0.989 mmol)
in THF (21 mL). The reaction mixture was stirred for 23.5 h, treated with
0.5m NaOH (4 mL) and 30% H2O2 (4 mL), stirred for an additional 5.5 h,
and extracted with ethyl acetate. The combined organic layers were washed
with water and brine, dried (Na2SO4), concentrated, and purified by
chromatography on silica gel (hexanes/ethyl acetate 8:1, then 4:1) to give
alcohol as a colorless oil (290 mg, 77%). [a]D ˆ ‡7.1 (c ˆ 0.91, CHCl3,
228C); IR (film): nÄ ˆ 3478, 3062, 3023, 1785, 1690 cmÀ1; 1H NMR: d ˆ 7.50
7.10 (m, 5H), 5.70 5.54 (m, 2H), 4.75 4.63 (m, 1H), 4.30 4.05 (m, 4H),
3.80 3.63 (m, 2H), 3.35 3.20 (m, 2H), 3.18 (dd, J ˆ 17.5, 2.4 Hz, 1H), 2.99
(dd, J ˆ 17.5, 9.3 Hz, 1H), 2.89 (d, J ˆ 4.1 Hz, 1H), 2.78 (dd, J ˆ 13.3, 9.7 Hz,
1H), 2.07 1.95 (m, 1H), 1.88 1.70 (m, 3H), 1.70 1.40 (m, 7H), 1.20 1.00
(m, 21H), 0.97 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ 173.0, 153.6, 135.3, 130.8,
129.6, 129.2, 128.9, 127.7, 75.9, 71.6, 67.9, 66.6, 63.4, 55.3, 43.0, 38.2, 36.6, 34.4,
‡
34.1, 29.5, 29.3, 22.2, 18.5, 18.3, 12.2; MS (EI): m/z (%): 601 (0.3) [M] , 583
‡
‡
(0.4) [M À H2O] , 558 (1) [M À C3H7] , 470 (24), 201 (62), 159 (100), 131
(66), 91 (55), 71 (45); HRMS: m/z: calcd for C31H48NO6Si: 558.3251 [M À
228C); IR (film): nÄ ˆ 3381, 3019 cmÀ1
;
1H NMR: d ˆ 5.64 (dt, J ˆ 10.2,
‡
C3H7] , found: 558.3247.
1.9 Hz, 1H), 5.58 (dt, J ˆ 10.3, 1.8 Hz, 1H), 4.12 4.02 (m, 1H), 3.77 3.67
(m, 2H), 3.77 3.57 (m, 2H), 3.24 (dt, J ˆ 2.5, 8.2 Hz, 1H), 2.05 1.90 (m,
1H), 1.87 1.35 (m, 11H), 1.15 0.98 (m, 21H), 0.98 (d, J ˆ 6.3 Hz, 3H);
13C NMR: d ˆ 130.8, 128.9, 74.5, 71.6, 63.5, 63.1, 34.5, 33.9, 32.9, 29.6, 29.3,
2,2-Dimethylpropionic acid (3S)-hydroxy-6-{(2R,5S,6R)-5-methyl-6-[3-
(triisopropylsilanyloxy)-propyl]-5,6-dihydro-2H-pyran-2-yl}-hexyl
ester
(14): To a solution of the major aldol product prepared above (151 mg,
0.251 mmol) and EtOH (45 mL) in Et2O (4 mL) was added LiBH4 (2.0m in
THF, 0.25 mL) slowly at À258C. After 10 min, the reaction mixture was
quenched with 0.5m NaOH (2 mL) at À208C, stirred for an additional
‡
22.4, 18.4, 18.3, 12.2; MS (EI): m/z (%): 341 (3) [M À C3H7] , 311 (5), 201
(84), 159 (100), 71(100); HRMS: m/z: calcd for C19H37O3Si: 341.2512 [M À
‡
C3H7] , found: 341.2517.
1676
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1676 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 7

Bistramide C
1670 1681
30 min, poured into brine (4 mL), and extracted with ethyl acetate (3 Â ).
The combined organic layers were dried (Na2SO4), filtered, and concen-
trated to give crude diol (146 mg) which was used for the next reaction
without further purification. Analytical sample was prepared by purifying
small amount of the crude material on preparative TLC (hexanes/ethyl
acetate 1:2). [a]D ˆ ‡9.0 (c ˆ 0.50, CHCl3, 228C); IR (film): nÄ ˆ 3357,
3020 cmÀ1; 1H NMR: d ˆ 5.70 5.55 (m, 2H), 4.15 4.05 (m, 1H), 3.95 3.80
(m, 3H), 3.80 3.62 (m, 2H), 3.24 (dt, J ˆ 2.2, 8.0 Hz, 1H), 2.94 (brs, 2H),
2.10 1.95 (m, 2H), 1.85 1.35 (m, 11H), 1.20 1.00 (m, 21H), 0.96 (d, J ˆ
7.0 Hz, 3H); 13C NMR: d ˆ 130.8, 128.8, 74.6, 72.3, 71.5, 63.4, 62.0, 38.3, 37.8,
34.4, 34.0, 29.6, 29.2, 21.9, 18.4, 18.2, 12.2; MS (EI): m/z (%): 385 (3) [M À
0.714 mmol) in CH2Cl2 (35 mL) was added at room temperature to a
suspension of PCC (925 mg, 4.29 mmol) and sodium acetate (708 mg,
8.63 mmol) in CH2Cl2 (35 mL). After 1.5 h, the reaction mixture was
quenched by addition of Et2O and MgSO4, filtered, and concentrated.
Purification of the residue by chromatography on silica gel (hexanes/ethyl
acetate 10:1) gave (2S,6S,8R,9S)-{9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxa-spiro[5.5]undec-10-en-2-yl}-acetaldehyde as a colorless
oils (250 mg, 82%). [a]D ˆ ‡29 (c ˆ 0.14, CHCl3, 228C); IR (film): nÄ ˆ
3028, 2716, 1730 cmÀ1; 1H NMR: d ˆ 9.79 (t, J ˆ 2.2 Hz, 1H), 5.68 (dd, J ˆ
9.9, 1.7 Hz, 1H), 5.54 (dd, J ˆ 9.9, 2.6 Hz, 1H), 4.40 4.28 (m, 1H), 3.83
3.68 (m, 2H), 3.41 (dt, J ˆ 1.9, 9.6 Hz, 1H), 2.57 (ddd, J ˆ 16.4, 8.6, 2.7 Hz,
1H), 2.42 (ddd, J ˆ 16.3, 4.4, 1.8 Hz, 1H), 1.90 1.80 (m, 4H), 1.70 1.20 (m,
7H), 1.20 0.95 (m, 21H), 0.95 (d, J ˆ 7.2 Hz, 3H); 13C NMR: d ˆ 201.7,
135.1, 129.2, 94.4, 73.8, 65.9, 63.6, 49.9, 34.8, 34.6, 30.8, 29.9, 29.5, 18.9, 18.3,
‡
C3H7] , 367 (3), 201 (45), 159 (94), 71 (100); HRMS: m/z: calcd for
‡
C21H41O4Si: 385.2774 [M À C3H7] , found: 385.2794.
The crude diol (146 mg) prepared above was dissolved in pyridine (2 mL)
and pivaloyl chloride (37 mL, 0.30 mmol) was added to the solution at room
temperature. After 24 h, the mixture was diluted with ethyl acetate, washed
with 1n HCl (2 Â ), saturated aqueous NaHCO3, and brine, dried (Na2SO4),
concentrated, and purified by chromatography on silica gel (hexanes/ethyl
acetate 4:1) to yield 14 as a colorless oil (97 mg; 76% over two steps). [a] ˆ
‡
17.1, 12.2; MS (EI): m/z (%): 424 (1) [M] , 381 (32), 180 (100); HRMS: m/z:
calcd for C24H44O4Si: 424.3009, found: 424.3021.
(4R)-Benzyl-3-(4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-10-en-2-yl}-but-2-enoyl)-oxazolidin-2-
one (18): A solution of the aldehyde (105 mg, 0.248 mmol) and 17 (110 mg,
0.310 mmol) in THF (2 mL) was treated with LiCl (123 mg, 2.90 mmol) and
(iPr)2NEt (48 mL, 0.27 mmol) at room temperature, stirred for 3 d, diluted
with brine, and extracted with ethyl acetate (3 Â ). The combined organic
layers were dried (Na2SO4), concentrated, and purified by chromatography
on silica gel (hexanes/ethyl acetate 10:1, then 4:1) to give 18 as a colorless
oil (142 mg, 92%). [a]D ˆ À30 (c ˆ 0.20, CHCl3, 228C); IR (film): nÄ ˆ 3029,
‡6.5 (c ˆ 0.49, CHCl3, 228C); IR (film): nÄ ˆ 3442, 3023, 1729, 1709 cmÀ1
;
1H NMR: d ˆ 5.68 5.55 (m, 2H), 4.37 (ddd, J ˆ 11.3, 8.6, 4.9 Hz, 1H),
4.17 4.05 (m, 2H), 3.78 3.60 (m, 3H), 3.28 3.20 (m, 1H), 2.13 (d, J ˆ
4.5 Hz, 1H), 2.07 1.93 (m, 1H), 1.90 1.35 (m, 12H), 1.20 (s, 9H), 1.15
1.00 (m, 21H), 0.97 (d, J ˆ 7.1 Hz, 3H); 13C NMR: d ˆ 179.2, 130.8, 128.8,
74.6, 71.5, 68.8, 63.4, 61.9, 39.0, 37.5, 36.6, 34.4, 34.1, 29.6, 29.3, 27.4, 22.2,
‡
‡
1
18.5, 18.3, 12.2; MS (EI): m/z (%): 512 (0.01) [M] , 469 (21) [M À C3H7] ,
1779, 1683, 1631 cmÀ1; H NMR: d ˆ 7.40 7.15 (m, 7H), 5.69 (dd, J ˆ 9.9,
215 (45), 201 (84), 159 (92), 71 (100); HRMS: m/z: calcd for C26H49O5Si:
1.6 Hz, 1H), 5.59 (dd, J ˆ 9.9, 2.4 Hz, 1H), 4.73 (ddd, J ˆ 13.1, 7.0, 3.4 Hz,
1H), 4.30 4.10 (m, 2H), 4.00 3.88 (m, 1H), 3.85 3.65 (m, 2H), 3.45 (brt,
J ˆ 9.7 Hz, 1H), 3.34 (dd, J ˆ 13.3, 3.2 Hz, 1H), 2.78 (dd, J ˆ 13.3, 9.6 Hz,
1H), 2.60 2.35 (m, 2H), 2.12 2.00 (m, 1H), 2.00 1.80 (m, 3H), 1.70 1.35
(m, 6H), 1.35 1.20 (m, 1H), 1.20 1.00 (m, 21H), 0.97 (d, J ˆ 7.2 Hz, 3H);
13C NMR: d ˆ 165.0, 153.6, 148.3, 135.7, 134.9, 129.7, 129.6, 129.2, 127.5,
122.3, 94.5, 73.6, 69.1, 66.3, 63.6, 55.5, 39.7, 38.2, 34.9, 34.8, 30.6, 29.9, 29.5,
‡
469.3349 [M À C3H7] , found: 469.3353.
2-{(2S,6S,8R,9S)-9-Methyl-8-[3-(triisopropylsilanyloxy)-propyl]-1,7-dioxa-
spiro[5.5]undec-10-en-2-yl}-ethanol (15):
A solution of 14 (837 mg,
1.63 mmol) in CCl4 (40 mL) was added to a suspension of iodobenzene
diacetate (1.05 g, 3.26 mmol) and iodine (827 mg, 3.26 mmol) in CCl4
(80 mL). The reaction was initiated by light (250 W) and the reaction
mixture was kept under irradiation for 1 h, quenched with saturated
aqueous Na2S2O3 (150 mL) and stirred for 15 min. The aqueous layer was
extracted with ethyl acetate (2 Â ). The combined organic layers were dried
(Na2SO4), concentrated, and chromatographed through a short plug of
silica gel (hexanes/ethyl acetate 20:1, then 10:1) to give crude spiroketal
(731 mg).
‡
18.9, 18.3, 17.1, 12.3; MS (EI): m/z (%): 629 (1) [M] , 582 (100), 405 (41),
381 (86), 299 (40); HRMS: m/z: calcd for C33H48NO6Si: 582.3251 [M À
‡
C3H7] , found: 582.2228.
(4R)-Benzyl-3-(4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-10-en-2-yl}-butyryl)-oxazolidin-2-one: A
mixture of 18 (130 mg, 0.208 mmol) and Pt/C (5%, 45 mg) in MeOH
(5 mL) was treated with H2 for 2.5 h at room temperature, filtered through
To a suspension of LiAlH4 (124 mg, 3.26 mmol) in Et2O (10 mL) was added
a solution of the crude spiroketal prepared above (731 mg) in Et2O (5 mL)
at room temperature. After 1.5 h, the reaction mixture was quenched with
0.5m NaOH, stirred for an additional 15 min, filtered through a glass filter,
and concentrated. Purification of the residue by chromatography on silica
gel (hexanes/ethyl acetate 4:1) gave 15 as a colorless oil (295 mg; 42%,
over two steps) and 16 as a colorless oil (106 mg; 12%, over two steps). A
solution of 16 (93 mg, 0.17 mmol) and AIBN (9 mg, 0.05 mmol) in
tributyltin hydride (1 mL) was heated at 808C for 14 h. The mixture was
purified twice by chromatography on silica gel (hexanes/ethyl acetate 1:0,
then 4:1) to give 15 as a colorless oil (68 mg, 94%).
a
plug of Celite, and concentrated. Purification of the residue by
chromatography on silica gel (hexanes/ethyl acetate 4:1 then 1:1) gave
(4R)-benzyl-3-(4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-10-en-2-yl}-butyryl)-oxazolidin-2-one as
a colorless oil, which eventually crystallized to give a colorless solid
(80 mg, 63%). M.p. 54.1 55.18C; [a]D ˆ À0.5 (c ˆ 0.80, CHCl3, 228C); IR
(film): nÄ ˆ 1789, 1701 cmÀ1; 1H NMR: d ˆ 7.40 7.15 (m, 5H), 4.67 (ddd, J ˆ
13.1, 6.9, 3.4 Hz, 1H), 4.25 4.10 (m, 2H), 3.80 3.65 (m, 2H), 3.62 3.50
(m, 1H), 3.31 (dd, J ˆ 13.3, 3.2 Hz, 1H), 3.18 (dt, J ˆ 2.0, 9.7 Hz, 1H), 3.10
2.85 (m, 2H), 2.76 (dd, J ˆ 13.3, 9.7 Hz, 1H), 2.00 1.15 (m, 19H), 1.15
0.95 (m, 21H), 0.85 (d, J ˆ 6.5 Hz, 3H); 13C NMR: d ˆ 173.4, 153.6, 135.5,
129.6, 129.2, 127.5, 95.6, 74.8, 69.2, 66.3, 63.9, 55.4, 38.1, 36.3, 36.0, 35.9, 35.7,
35.3, 31.5, 29.6 (C2), 28.2, 20.9, 19.2, 18.3, 17.9, 12.2; MS (EI): m/z (%): 629
Compound 15: [a]D ˆ ‡37 (c ˆ 0.50, CHCl3, 228C); IR (film): nÄ ˆ 3445,
3033 cmÀ1
;
1H NMR: d ˆ 5.66 (dd, J ˆ 9.9, 1.7 Hz, 1H), 5.55 (dd, J ˆ 9.9,
2.5 Hz, 1H), 4.07 3.95 (m, 1H), 3.85 3.65 (m, 4H), 3.38 (dt, J ˆ 1.9,
9.7 Hz, 1H), 3.01 (dd, J ˆ 6.2, 4.7 Hz, 1H), 2.10 1.80 (m, 4H), 1.80 1.20
(m, 9H), 1.20 1.00 (m, 21H), 0.95 (d, J ˆ 7.2 Hz, 3H); 13C NMR: d ˆ 135.0,
129.5, 94.2, 74.0, 71.7, 63.7, 62.2, 38.2, 34.8 (2C), 31.1, 30.1, 29.5, 18.9, 18.3,
‡
(0.5) [M] , 611 (1), 586 (58), 343 (32), 227 (100); HRMS: m/z: calcd for
‡
C33H52NO6Si: 586.3564 [M À C3H7] , found: 586.3537.
(4R)-Benzyl-3-((2R)-4-{(2S,6S,8R,9S)-8-[3-(triisopropylsilanyloxy)-prop-
yl]-9-methyl-1,7-dioxaspiro[5.5]undec-2-yl}-2-methyl-butyryl)-oxazolidin-
2-one: NaHMDS (1.0m in THF, 0.13 mL) was added at À788C to a solution
of (4R)-benzyl-3-(4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-10-en-2-yl}-butyryl)-oxazolidin-2-one
(76 mg, 0.12 mmol) in THF (1 mL). After 30 min, the reaction mixture was
treated with MeI (37 mL, 0.60 mmol) at À788C, stirred for an additional
4 h, quenched with saturated aqueous NH4Cl, and extracted with ethyl
acetate (3 Â ). The combined organic layers were dried (Na2SO4),
concentrated, and purified by chromatography on silica gel (hexanes/ethyl
acetate 10:1) to give (4R)-benzyl-3-((2R)-4-{(2S,6S,8R,9S)-8-[3-(triisopro-
pylsilanyloxy)-propyl]-9-methyl-1,7-dioxaspiro[5.5]undec-2-yl}-2-methyl-
butyryl)-oxazolidin-2-one as a colorless oil (56 mg, 73%). [a]D ˆ À11 (c ˆ
0.50, CHCl3, 228C); IR (film): nÄ ˆ 1784, 1696 cmÀ1; 1H NMR: d ˆ 7.40 7.15
(m, 5H), 4.68 (ddd, J ˆ 13.0, 6.9, 3.2 Hz, 1H), 4.25 4.10 (m, 2H), 3.80 3.65
(m, 3H), 3.55 3.43 (m, 1H), 3.27 (dd, J ˆ 13.2, 3.2 Hz, 1H), 3.15 (t, J ˆ
‡
17.2, 12.3; MS (EI): m/z (%): 426 (3) [M] , 383 (47), 295 (59), 201 (62), 182
(99), 71 (100); HRMS: m/z: calcd for C24H46O4Si: 426.3165, found:
426.3174
Compound 16: [a]D ˆ ‡93 (c ˆ 0.55, CHCl3, 228C); IR (film): nÄ ˆ 3451,
3035 cmÀ1
;
1H NMR: d ˆ 5.78 (dd, J ˆ 9.9, 1.7 Hz, 1H), 5.45 (dd, J ˆ 9.9,
2.7 Hz, 1H), 4.20 4.05 (m, 1H), 4.07 (dd, J ˆ 12.9, 4.4 Hz, 1H), 3.85 3.65
(m, 4H), 3.43 (t, J ˆ 9.2 Hz, 1H), 2.65 2.45 (m, 2H), 2.30 2.10 (m, 2H),
2.00 1.80 (m, 2H), 1.80 1.45 (m, 6H), 1.20 0.90 (m, 21H), 0.97 (d, J ˆ
7.2 Hz, 3H); 13C NMR: d ˆ 137.2, 127.8, 94.9, 74.7, 70.7, 63.5, 61.8, 37.7, 34.8,
‡
33.5 (C2), 32.5, 29.6, 29.0, 18.3, 16.8, 12.2; MS (EI): m/z (%): 552 (0.9) [M] ,
509 (62), 381 (98), 71 (100); HRMS: m/z:calcd for C24H45O4SiI: 552.3132,
found: 552.2136.
(2S,6S,8R,9S)-{9-Methyl-8-[3-(triisopropylsilanyloxy)-propyl]-1,7-dioxa-
spiro[5.5]undec-10-en-2-yl}-acetaldehyde:
A solution of 15 (304 mg,
Chem. Eur. J. 2002, 8, No. 7 ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1677 $ 20.00+.50/0
1677

P. Wipf et al.
FULL PAPER
9.1 Hz, 1H), 2.77 (dd, J ˆ 13.3, 9.6 Hz, 1H), 1.95 1.15 (m, 19H), 1.25 (d,
J ˆ 6.9 Hz, 3H), 1.15 0.90 (m, 21H), 0.84 (d, J ˆ 6.5 Hz, 3H); 13C NMR:
d ˆ 177.3, 153.2, 135.6, 129.7, 129.2, 127.6, 95.7, 74.8, 69.4, 66.2, 63.9, 55.6,
38.3, 38.2, 36.4, 35.8, 35.3, 34.4, 31.5, 29.9, 29.7, 29.6, 28.3, 19.3, 18.3, 18.2,
17.9, 12.3; MS (EI): m/z (%): 643 (0.6) [M] , 600 (52), 423 (29), 357 (34),
178 (34), 95 (100); HRMS: m/z: calcd for C37H61NO6Si: 643.4268, found:
(28 mg, 95%). [a]D ˆ ‡32 (c ˆ 0.35, CHCl3, 228C); IR (film): nÄ ˆ
3410 cmÀ1
;
1H NMR: d ˆ 5.17 (dd, J ˆ 9.5, 1.2 Hz, 1H), 4.00 (d, J ˆ
5.2 Hz, 2H), 3.80 3.60 (m, 2H), 3.52 3.40 (m, 1H), 3.16 (dt, J ˆ 1.8,
9.8 Hz, 1H), 2.48 2.32 (m, 1H), 1.95 1.75 (m, 3H), 1.67 (d, J ˆ 1.2 Hz,
3H), 1.65 1.15 (m, 17H), 1.15 1.00 (m, 21H), 0.96 (d, J ˆ 6.7 Hz, 3H),
0.83 (d, J ˆ 6.5 Hz, 3H); 13C NMR: d ˆ 133.7, 133.0, 95.7, 74.6, 69.7, 69.3,
63.9, 36.4, 35.8, 35.4, 34.7, 34.2, 32.6, 31.7, 29.7 (2C), 28.3, 21.4, 19.3, 18.3
‡
643.4274.
‡
‡
(2C), 14.1, 12.3; MS (EI): m/z (%): 510 (11) [M] , 467 (100) [M À C3H7] ,
449 (97), 383 (98); HRMS: m/z: calcd for C27H51O4Si: 467.3557 [M À
(2R)-Methyl-4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-butan-1-ol: LiBH4 (2.0m in THF,
70 mL) was added slowly at À258C to a solution of (4R)-benzyl-3-((2R)-4-
{(2S,6S,8R,9S)-8-[3-(triisopropylsilanyloxy)-propyl]-9-methyl-1,7-dioxas-
‡
C3H7] , found: 467.3577.
(4R)-2,4-Dimethyl-6-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyl-
oxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-hex-2-enal: Dess Martin pe-
riodinane (15 wt% in CH2Cl2, 0.23 mL, 0.083 mmol) was added at room
piro[5.5]undec-2-yl}-2-methyl-butyryl)-oxazolidin-2-one
(45 mg,
0.070 mmol) and EtOH (10 mL) in Et2O (1 mL). The mixture was slowly
warmed to 08C over a period of 2 h and kept at 08C for 8 h. The reaction
mixture was quenched by 0.5m NaOH and brine, and extracted with ethyl
acetate (3 Â ). The combined organic layers were dried (Na2SO4),
concentrated, and purified by chromatography on silica gel (hexanes/ethyl
acetate 6:1) to give (2R)-methyl-4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopro-
pylsilanyloxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-butan-1-ol as a color-
less oil (29 mg, 89%). [a]D ˆ ‡41 (c ˆ 0.73, CHCl3, 228C); IR (film): nÄ ˆ
3405 cmÀ1; 1H NMR: d ˆ 3.80 3.60 (m, 2H), 3.58 3.35 (m, 3H), 3.16 (dt,
J ˆ 1.8, 9.8 Hz, 1H), 1.95 1.20 (m, 21H), 1.20 0.95 (m, 21H), 0.93 (d, J ˆ
6.7 Hz, 3H), 0.83 (d, J ˆ 6.5 Hz, 3H); 13C NMR: d ˆ 95.7, 74.7, 69.5, 68.2,
63.8, 36.3, 35.9, 35.8, 35.3, 33.6, 31.6, 29.7, 29.6, 29.4, 28.2, 19.3, 18.3 (2C),
temperature to
a solution of the alcohol prepared above (28 mg,
0.055 mmol) in CH2Cl2 (1 mL). After 35 min, the reaction mixture was
diluted with ethyl acetate, washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and concentrated. Purification of the residue by
chromatography on silica gel (hexanes/ethyl acetate 15:1) gave the
aldehyde as a colorless oil (26 mg, 93%). [a]D ˆ ‡36 (c ˆ 0.30, CHCl3,
1
228C); IR (film): nÄ ˆ 2699, 1692 cmÀ1; H NMR: d ˆ 9.41 (s, 1H), 6.25 (d,
J ˆ 10.0 Hz, 1H), 3.80 3.63 (m, 2H), 3.53 3.40 (m, 1H), 3.13 (t, J ˆ
9.7 Hz, 1H), 2.81 2.65 (m, 1H), 1.95 1.65 (m, 3H), 1.76 (d, J ˆ 1.1 Hz,
3H), 1.65 1.20 (m, 16H), 1.20 0.95 (m, 24H), 0.83 (d, J ˆ 6.4 Hz, 3H);
13C NMR: d ˆ 195.9, 160.6, 138.4, 95.7, 74.7, 69.5, 63.8, 36.3, 35.7, 35.3, 34.5,
34.0, 33.5, 31.6, 29.7, 29.6, 28.3, 20.2, 19.2, 18.3 (2C), 12.2, 9.7; MS (EI): m/z
‡
17.0, 12.2; MS (EI): m/z (%): 470 (2) [M] , 452 (3), 427 (75), 95 (100);
‡
‡
HRMS: m/z: calcd for C27H54O4Si: 470.3791, found: 470.3779.
(%): 508 (0.4) [M] , 465 (100) [M À C3H7] ; HRMS: m/z: calcd for
C30H56O4Si: 508.3948, found: 508.3943.
(2R)-Methyl-4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-
propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-butyraldehyde (19): Dess Martin
periodinane (15 wt% in CH2Cl2, 0.48 mL) was added at room temperature
to a solution of (2R)-methyl-4-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropyl-
(5R)-3,5-Dimethyl-7-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyl-
oxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-hept-3-en-2-ol:
MeMgBr
(3.0m in Et2O, 0.10 mL) was added at 08C to a solution of the aldehyde
prepared above (26 mg, 0.051 mmol) in Et2O (1 mL). After 45 min, the
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with ethyl acetate. The organic layer was washed with brine,
dried (Na2SO4), concentrated, and purified by chromatography on silica gel
(hexanes/ethyl acetate 4:1) to give (5R)-3,5-dimethyl-7-{(2S,6S,8R,9S)-9-
methyl-8-[3-(triisopropylsilanyloxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-
yl}-hept-3-en-2-ol as a colorless oil (26 mg, 98%). [a]D ˆ ‡36 (c ˆ 0.20,
silanyloxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-butan-1-ol
(54 mg,
0.11 mmol) in CH2Cl2 (1 mL). After 20 min, the reaction mixture was
diluted with ethyl acetate, washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and concentrated. Purification of the residue by
chromatography on silica gel (hexanes/ethyl acetate 20:1) gave 19 as a
colorless oil (41 mg, 80%). [a]D ˆ ‡30 (c ˆ 0.63, CHCl3, 228C); IR (film):
nÄ ˆ 2720, 1731, 1707 cmÀ1; 1H NMR: d ˆ 9.64 (d, J ˆ 1.9 Hz, 1H), 3.80 3.65
(m, 2H), 3.57 3.46 (m, 1H), 3.14 (dt, J ˆ 2.0, 9.7 Hz, 1H), 2.38 (dq, J ˆ 1.9,
6.9 Hz, 1H), 1.95 1.15 (m, 19H), 1.11 (d, J ˆ 7.0 Hz, 3H), 1.15 1.00 (m,
21H), 0.83 (d, J ˆ 6.5 Hz, 3H); 13C NMR: d ˆ 205.4, 95.7, 74.8, 69.1, 63.8,
46.6, 36.3, 35.7, 35.3, 33.9, 31.5, 29.7, 29.6, 28.2, 27.1, 19.2, 18.3 (2C), 13.7,
CHCl3, 228C); IR (film): nÄ ˆ 3419 cmÀ1
;
1H NMR: d ˆ 5.16 (dt, J ˆ 9.5,
1.1 Hz, 1H), 4.25 4.15 (m, 1H), 3.80 3.65 (m, 2H), 3.55 3.40 (m, 1H),
3.16 (dt, J ˆ 2.0, 9.6 Hz, 1H), 2.45 2.30 (m, 1H), 1.95 1.75 (m, 3H), 1.63
(d, J ˆ 1.2 Hz, 3H), 1.65 1.40 (m, 10H), 1.40 1.20 (m, 6H), 1.26 (d, J ˆ
6.4 Hz, 3H), 1.20 1.00 (m, 22H), 0.95, 0.93 (2d, J ˆ 6.4 Hz, 3H), 0.83 (d,
J ˆ 6.4 Hz, 3H); 13C NMR: d ˆ 137.5, 131.8, 131.6, 95.6, 74.6, 73.8, 73.6, 69.7,
63.8, 36.3, 35.8, 35.4, 34.7, 34.2, 32.3, 31.7, 29.7, 29.6, 28.3, 21.9, 21.4, 19.3, 18.3
‡
‡
12.2; MS (EI): m/z (%): 469 (0.3) [M‡H] , 468 (0.2) [M] , 441 (9), 425 (22),
95 (100); HRMS: m/z: calcd for C27H52O4Si: 468.3635, found: 468.3636.
(4R)-2,4-Dimethyl-6-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyl-
oxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-hex-2-enoic ethyl ester: A sus-
pension of the aldehyde 19 (41 mg, 0.088 mmol) and (carbethoxyethylide-
ne)triphenylphosphorane (20, 1.21 g, 3.34 mmol) in degassed toluene
(2 mL) was stirred at room temperature for 8.5 d, filtered through a short
plug of silica gel, and concentrated. Purification of the residue by
chromatography on silica gel (hexanes/ethyl acetate 15:1) and preparative
TLC (hexanes/ethyl acetate 15:1) gave recovered 19 as a colorless oil (6 mg,
15%) and (4R)-2,4-dimethyl-6-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropyl-
silanyloxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-hex-2-enoic ethyl ester
as a pale yellow oil (32 mg, 66%). [a]D ˆ ‡26 (c ˆ 0.43, CHCl3, 228C); IR
(film): nÄ ˆ 1708 cmÀ1; 1H NMR: d ˆ 6.60 6.45 (m, 1H), 4.19 (q, J ˆ 7.1 Hz,
2H), 3.80 3.65 (m, 2H), 3.55 3.40 (m, 1H), 3.14 (t, J ˆ 9.3 Hz, 1H), 2.58
2.42 (m, 1H), 1.84 (d, J ˆ 1.3 Hz, 3H), 1.95 1.75 (m, 3H), 1.70 1.45 (m,
9H), 1.45 1.20 (m, 7H), 1.30 (t, J ˆ 7.1 Hz, 3H), 1.20 1.05 (m, 21H), 1.02
(d, J ˆ 6.7 Hz, 3H), 0.83 (d, J ˆ 6.5 Hz, 3H); 13C NMR: d ˆ 168.7, 148.0,
126.9, 95.7, 74.7, 69.6, 63.8, 60.6, 36.4, 35.8, 35.4, 34.7, 33.8, 33.6, 31.7, 29.7,
29.6, 28.3, 20.4, 19.3, 18.3, 18.2, 14.5, 12.8, 12.4; MS (EI): m/z (%): 553 (0.2)
‡
(2C), 12.3, 12.0,11.8; MS (EI): m/z (%): 524 (0.1) [M] , 506 (19) [M À
‡
H2O] , 481 (14), 463 (100); HRMS: m/z: calcd for C31H58O3Si: 506.4155
‡
[M À H2O] , found: 506.4141.
(5R)-7-[(2S,6S,8R,9S)-8-(3-Hydroxy-propyl)-9-methyl-1,7-dioxaspiro[5.5]-
undec-2-yl]-3,5-dimethyl-hept-3-en-2-ol: A solution of the alcohol pre-
pared above (26 mg, 0.050 mmol) in THF (1 mL) was treated with TBAF
(1m in THF, 0.15 mL) at room temperature, stirred for 20.5 h, diluted with
ethyl acetate, washed with 10% citric acid (2 Â ) and brine, dried (Na2SO4),
and concentrated. Purification of the residue by chromatography on silica
gel (hexanes/ethyl acetate 2:1, then 1:1) gave diol as a colorless oil (17 mg,
92%), which eventually crystallized as a colorless solid. M.p. 76.3 77.08C;
[a]D ˆ ‡50 (c ˆ 0.14, CHCl3, 238C); IR (film): nÄ ˆ 3372 cmÀ1
;
1H NMR:
d ˆ 5.17 (dt, J ˆ 9.1, 1.3 Hz, 1H), 4.28 4.13 (m, 1H), 3.80 3.60 (m, 2H),
3.53 3.40 (m, 1H), 3.23 (brt, J ˆ 9.2 Hz, 1H), 2.50 2.20 (m, 1H), 1.95
1.70 (m, 3H), 1.70 1.30 (m, 16H), 1.63 (d, J ˆ 1.2 Hz, 3H), 1.30 1.05 (m,
5H), 0.95, 0.93 (2d, J ˆ 6.3 Hz, 3H), 0.84 (d, J ˆ 6.4 Hz, 3H); 13C NMR:
d ˆ 137.6, 131.7, 131.6, 96.0, 74.8, 73.7, 73.6, 69.9, 63.5, 36.5, 35.6, 34.7, 34.6,
34.2, 32.3, 31.5, 29.9, 28.9, 28.2, 22.0, 21.3, 19.3, 18.2 (2C), 12.0, 11.9; MS
‡
‡
‡
[M‡H] , 552 (0.2) [M] , 510 (100) [M À C3H7] ; HRMS: m/z: calcd for
‡
‡
C32H60O5Si: 552.4210, found: 552.4202.
(EI): m/z (%): 368 (0.1) [M] , 350 (2) [M À H2O] , 258 (36), 241 (67), 212
(100); HRMS: m/z: calcd for C22H40O4: 368.2927, found: 368.2921.
(4R)-2,4-Dimethyl-6-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyl-
oxy)-propyl]-1,7-dioxaspiro[5.5]undec-2-yl}-hex-2-en-1-ol: LiAlH4 (1.0m
in THF, 0.15 mL) was added at room temperature to a solution of 4R)-
2,4-dimethyl-6-{(2S,6S,8R,9S)-9-methyl-8-[3-(triisopropylsilanyloxy)-prop-
(5R)-7-[(2S,6S,8S,9R)-8-(3-Azido-propyl)-9-methyl-1,7-dioxaspiro[5.5]un-
dec-2-yl]-3,5-dimethylhept-3-en-2-ol (4): Methanesulfonyl chloride
(1.9 mL, 0.025 mmol) was added at room temperature to a solution of the
diol prepared above (3.5 mg, 0.0082 mmol) and (iPr)2NEt (8.9 mL,
0.050 mmol) in CH2Cl2 (0.5 mL). After 10 min, the reaction mixture was
diluted with ethyl acetate, washed with saturated aqueous NaHCO3, 10%
citric acid, and brine, dried (Na2SO4), and concentrated.
yl]-1,7-dioxaspiro[5.5]undec-2-yl}-hex-2-enoic
ethyl
ester
(32 mg,
0.058 mmol) in THF (1 mL). After 1 h, the reaction mixture was quenched
with 0.5m NaOH, filtered, concentrated, and purified by chromatography
on silica gel (hexanes/ethyl acetate 4:1) to give the alcohol as a colorless oil
1678
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1678 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 7

Bistramide C
1670 1681
A mixture of this crude mesylate (5.0 mg) and sodium azide (1.6 mg,
0.025 mmol) in DMF (0.1 mL) was heated at 658C for 15 h, diluted with
ethyl acetate, washed with water (2 Â ) and brine, dried (Na2SO4) and
concentrated. Purification of the residue by chromatography on silica gel
(hexanes/ethyl acetate 8:1, then 4:1) gave 4 as a colorless oil (2.6 mg, 80%).
ethyl acetate, washed with water (2 Â ) and brine, dried (Na2SO4), and
concentrated. Purification of the residue by chromatography on silica gel
(hexanes/ethyl acetate 8:1) gave azide as a colorless oil (260 mg, 74%).
[a]D ˆ À2.5 (c ˆ 1.02, CH2Cl2, 228C); IR (film): nÄ ˆ 3467, 2103, 1719 cmÀ1
;
1H NMR: d ˆ 4.20 (q, J ˆ 7.1 Hz, 2H), 3.88 (dd, J ˆ 10.2, 6.2 Hz, 1H), 3.44
(dd, J ˆ 12.7, 3.9 Hz, 1H), 3.35 (dd, J ˆ 12.7, 6.0 Hz, 1H), 3.25 3.05 (brm,
1H), 2.67 (pentet, J ˆ 7.1 Hz, 1H), 1.27 (t, J ˆ 7.1 Hz, 3H), 1.21 (d, J ˆ
7.2 Hz, 3H); 13C NMR: d ˆ 175.4, 72.7, 61.1, 54.4, 42.7, 14.2 (2C); MS (EI):
[a]D ˆ ‡45 (c ˆ 0.35, CHCl3, 238C); IR (film): nÄ ˆ 2091 cmÀ1
;
1H NMR:
d ˆ 5.17 (d, J ˆ 9.5 Hz, 1H), 4.25 4.15 (m, 1H), 3.45 3.25 (m, 3H), 3.17 (t,
J ˆ 9.8 Hz, 1H), 2.45 2.30 (m, 1H), 2.05 1.70 (m, 3H), 1.63 (d, J ˆ 1.4 Hz,
3H), 1.65 1.45 (m, 8H), 1.45 1.25 (m, 7H), 1.25 1.05 (m, 2H), 1.26 (d,
J ˆ 6.4 Hz, 3H), 0.96, 0.94 (2d, J ˆ 6.4 Hz, 3H), 0.84 (d, J ˆ 6.5 Hz, 3H);
13C NMR: d ˆ 137.5, 131.7, 131.6, 95.7, 74.3, 73.7, 73.6, 69.9, 52.2, 36.3, 35.7,
35.2, 34.6, 34.3, 32.3, 31.6, 30.5, 28.1, 25.7, 22.0, 21.9, 21.4, 19.4, 18.2 (2C),
‡
m/z (%): 142 (13) [M À HN2O] , 131 (67), 85 (5), 74 (100); HRMS: m/z:
‡
calcd for C7H12NO2: 142.0868 [M À HN2O] , found: 142.0863.
(2R,3S)-4-Azido-3-(tert-butyldimethylsilanyloxy)-2-methylbutyric
ethyl
ester (3): TBSCl (161 mg, 1.07 mmol) was added at 08C to a solution of
the azide prepared above (100 mg, 0.534 mmol) and imidazole (87 mg,
1.28 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at room
temperature for 16 h, diluted with Et2O, washed with water and brine, dried
(Na2SO4), and concentrated. Purification of the residue by chromatography
on silica gel (hexanes/Et2O 16:1, 8:1, 4:1, and 1:1) gave recovered azide as a
‡
‡
12.0, 11.9; MS (EI): m/z (%): 393 (0.1) [M] , 375 (2) [M À H2O] , 368 (4),
332 (6), 110 (100); HRMS: m/z: calcd for C22H37N3O2: 375.2886 [M À
‡
H2O] , found: 375.2889.
(S)-Diethyl malate: A solution of l-malic acid (12.6 g, 94.0 mmol) in
absolute ethanol (80 mL) was treated with concentrated HCl (0.3 mL) at
room temperature, heated at reflux for 15 h, concentrated, and purified by
chromatography on silica gel (hexanes/ethyl acetate 2:1) to give (S)-diethyl
malate as a colorless oil (16.4 g, 92%). 1H NMR: d ˆ 4.48 (dd, J ˆ 10.4,
5.4 Hz, 1H), 4.35 4.20 (m, 2H), 4.18 (q, J ˆ 7.1 Hz, 2H), 3.21 (d, J ˆ
5.4 Hz, 1H), 2.86 (dd, J ˆ 16.7, 4.6 Hz, 1H), 2.78 (dd, J ˆ 16.4, 6.0 Hz,
1H), 1.30 (t, J ˆ 7.1 Hz, 3H), 1.27 (t, J ˆ 7.1 Hz, 3H).
colorless oil (5.5 mg, 6%) and 3 as a colorless oil (140 mg, 87%). [a]D
ˆ
À21.9 (c ˆ 1.06, CH2Cl2, 228C); IR (film): nÄ ˆ 2103, 1736 cmÀ1; H NMR:
d ˆ 4.14 (q, J ˆ 7.1 Hz, 2H), 4.10 4.00 (m, 1H), 3.41 (dd, J ˆ 12.8, 3.7 Hz,
1H), 3.23 (dd, J ˆ 12.8, 5.4 Hz, 1H), 2.75 (pentet, J ˆ 6.9 Hz, 1H), 1.27 (t,
J ˆ 7.1 Hz, 3H), 1.12 (d, J ˆ 7.2 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.08 (s,
3H); 13C NMR: d ˆ 174.1, 73.2, 60.6, 54.2, 44.2, 25.8, 18.0, 14.3, 12.6, À4.3,
1
‡
À5.1; MS (EI): m/z (%): 244 (39) [M À C4H9] , 115 (51); HRMS: m/z:
Diethyl (2S,3R)-3-methylmalate: n-BuLi (1.6m in hexane, 38 mL) was
added slowly at 08C to a solution of diisopropylamine (9.3 mL, 66 mmol) in
THF (30 mL). The reaction mixture was stirred at 08C for 20 min and
cooled to À788C. A solution of (S)-diethyl malate (5.00 g, 26.3 mmol) in
THF (5 mL) was added to this mixture slowly at À788C. The resulting
orange solution was stirred for 15 min at À788C, slowly warmed to À208C
over a period of 2 h, stirred at À208C for 15 min, and cooled to À788C.
Methyl iodide (2.5 mL, 40 mmol) was added slowly to the reaction mixture
at À788C. The solution was stirred for 30 min at À788C, slowly warmed to
room temperature over a period of 3 h, stirred for 1 h at room temperature,
quenched with 10% citric acid, and extracted with ethyl acetate (3 Â ). The
combined organic layers were washed with water and brine, dried
(Na2SO4), and concentrated. Purification of the residue by chromatography
on silica gel (hexanes/ethyl acetate 4:1) gave diethyl (2S,3R)-3-methylma-
late as a pale yellow oil (3.44 g, 64% as a mixture of two diastereomers, 6:1
by 1H NMR analysis). 1H NMR (major isomer, 500 MHz): d ˆ 4.35 4.20
(m, 3H), 4.20 4.09 (m, 2H), 3.16 (d, J ˆ 6.3 Hz, 1H), 3.02 (dq, J ˆ 3.5,
7.2 Hz, 1H), 1.31 (t, J ˆ 7.1 Hz, 3H), 1.30 (d, J ˆ 7.2 Hz, 3H), 1.25 (t, J ˆ
7.2 Hz, 3H); 1H NMR (minor isomer, 500 MHz): d ˆ 4.61 (dd, J ˆ 5.2,
3.7 Hz, 1H), 4.35 4.20 (m, 2H), 4.20 4.09 (m, 2H), 3.07 (d, J ˆ 5.3 Hz,
1H), 2.92 (dq, J ˆ 3.6, 7.2 Hz, 1H), 1.35 1.30 (m, 3H), 1.30 1.25 (m, 3H),
1.17 (d, J ˆ 7.2 Hz, 3H).
‡
calcd for C9H18N3O3Si: 244.1117 [M À C4H9] , found: 244.1114.
(2R,3S)-3-(tert-Butyldimethylsilanyloxy)-4-(2-{(2S,3R,6S)-6-[2-(tert-butyl-
dimethylsilanyloxy)-pent-3-enyl]-3-methyltetrahydropyran-2-yl}-acetyl-
amino)-2-methylbutyric acid (21): LiOH (1m in H2O, 0.46 mL) was added
at 08C to a solution of 3 (58 mg, 0.192 mmol) in EtOH (1 mL). The reaction
mixture was stirred at room temperature for 2 d, cooled in an ice bath,
acidified with 1n HCl (0.46 mL) and extracted with ethyl acetate. The
organic layer was washed with brine, dried (Na2SO4), and concentrated in
vacuo to give crude (2R,3S)-4-azido-3-tert-butyldimethylsilanyloxy)-2-
methylbutyric acid as a colorless oil (50.3 mg).
To an ice-cooled solution of this acid (65.5 mg, 240 mmol) in THF/DMF 1:1
(1 mL) was added triethylamine (53 mL, 0.38 mmol) and TIPSCl (67 mL,
0.31 mmol). The reaction mixture was stirred at 08C for 15 min, diluted
with diethyl ether and washed with water, saturated aqueous sodium
bicarbonate, and brine. The organic layer was dried (Na2SO4) and
concentrated. The residue was purified by chromatography on silica gel
(hexane, then hexane/diethyl ether 16:1) to give (2R,3S)-4-azido-3-tert-
butyldimethylsilanyloxy)-2-methylbutyric triisopropylsilanyl ester as
a
colorless oil (82 mg, 80%). [a]D ˆ À12.1 (c ˆ 1.12, CH2Cl2, 228C); IR
(film): nÄ ˆ 2102, 1720 cmÀ1
;
1H NMR: d ˆ 4.14 (ddd, J ˆ 7.0, 4.1, 4.1 Hz,
1H), 3.37 (dd, J ˆ 12.5, 4.2 Hz, 1H), 3.29 (dd, J ˆ 12.5, 7.0 Hz, 1H), 2.74 (dq,
J ˆ 4.1, 7.2 Hz, 1H), 1.37 1.20 (m, 3H), 1.17 (d, J ˆ 7.2 Hz, 3H), 1.08 (d, J ˆ
6.8 Hz, 18H), 0.91 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H); 13C NMR: d ˆ 173.3,
72.7, 54.3, 45.7, 25.9, 17.9, 12.0, 11.5, À4.6, À4.8; MS (EI): m/z (%): 414 (1)
(2R,3S)-3-Hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)-butyric ethyl es-
ter: BH3 ¥ SMe2 (3.6 mL, 38 mmol) was added at 08C to a solution of
diethyl (2S,3R)-3-methylmalate (7.35 g, 36.0 mmol) in THF (75 mL). The
reaction mixture was warmed to room temperature, stirred for 15 min, and
treated with NaBH4 (68 mg, 1.8 mmol) at 48C. The solution was stirred at
room temperature overnight, quenched with methanol, and concentrated
to evaporate volatile impurities. The crude diol (5.80 g) was used for the
next step without further purification.
‡
‡
‡
[M À CH3] , 386 (2) [M À C3H7] , 372 (34) [M À C3H7 À N2] , 157 (32), 121
‡
(87), 73 (100); HRMS: m/z: calcd for C17H36O3Si2: 386.2295 [M À C3H7] ,
found: 386.2291.
A suspension of the TIPS ester prepared above (4.5 mg, 11 mmol) and Pd/C
(10 wt%, 1.6 mg) in THF (0.5 mL) was treated with H2 at room
temperature for 4.5 h. The mixture was filtered through a short plug of
Celite and concentrated.
To a solution of the diol prepared above (5.80 g) in CH2Cl2 (80 mL) was
added dibutyltin oxide (446 mg, 1.79 mmol), TsCl (6.82 g, 35.8 mmol), and
triethylamine (5.0 mL, 36 mmol) at room temperature. The reaction
mixture was stirred overnight, washed with brine, dried (Na2SO4), and
concentrated. Purification of the residue by chromatography on silica gel
(hexanes/ethyl acetate 2:1) gave (2R,3S)-3-hydroxy-2-methyl-4-(toluene-4-
sulfonyloxy)-butyric ethyl ester as a colorless oil (5.24 g, 46%). [a]D ˆ À9.0
(c ˆ 0.62, CHCl3, 228C); IR (film): nÄ ˆ 3504, 1730, 1590, 1438, 1357,
The crude amine was quickly dissolved in CH2Cl2 (1 mL) and treated
successively at room temperature with 2 (2.5 mg, 7.0 mmol), PyBOP
(4.4 mg, 8.4 mmol), and Et3N (1.2 mL, 8.6 mmol). After 19 h, the mixture
was diluted with Et2O, washed with water, saturated aqueous NaHCO3,
and brine, dried (Na2SO4), and concentrated. Purification of the residue by
chromatography on silica gel (hexanes/Et2O, gradient elution from 16:1, to
8:1 and 4:1) gave (2R,3S)-3-(tert-butyldimethylsilanyloxy)-4-(2-
{(2S,3R,6S)-6-[2-(tert-butyldimethylsilanyloxy)-pent-3-enyl]-3-methyltetra-
hydropyran-2-yl}-acetylamino)-2-methylbutyric triisopropylsilanyl ester as
a colorless oil (2.8 mg, 54%). [a]D ˆ ‡12 (c ˆ 0.79, CH2Cl2, 228C); IR
(film): nÄ ˆ 2950, 1695 cmÀ1; 1H NMR: d ˆ 6.58 (brt, J ˆ 5.2 Hz, 1H), 5.60
5.47 (m, 1H), 5.38 (dd, J ˆ 15.6, 6.8 Hz, 1H), 4.20 4.00 (m, 3H), 3.82 3.68
(m, 1H), 3.64 3.52 (m, 1H), 3.28 3.16 (m, 1H), 2.72 2.60 (m, 1H), 2.49
(dd, J ˆ 15.5, 10.0 Hz, 1H), 2.18 (dd, J ˆ 15.5, 3.2 Hz, 1H), 1.92 1.60 (m,
4H), 1.66 (brd, J ˆ 6.1 Hz, 3H), 1.59 1.45 (m, 1H), 1.40 1.20 (m, 5H),
1165 cmÀ1
;
1H NMR: d ˆ 7.80 (brd, J ˆ 7.8 Hz, 2H), 7.36 (brd, J ˆ 7.7 Hz,
2H), 4.20 4.00 (m, 4H), 3.89 (dd, J ˆ 9.6, 4.8 Hz, 1H), 2.82 (s, 1H), 2.73
2.60 (m, 1H), 2.45 (s, 3H), 1.30 1.13 (m, 6H); 13C NMR: d ˆ 175.2, 145.3,
132.7, 130.1, 128.2, 71.5, 71.4, 61.3, 41.6, 21.9, 14.3; MS (EI): m/z (%): 316
‡
(0.4) [M] , 271 (2), 243 (3), 172 (4), 155 (40), 131 (100), 91 (67); HRMS:
m/z: calcd for C14H20SO6: 316.0981, found: 316.0994.
(2R,3S)-4-Azido-3-hydroxy-2-methylbutyric ethyl ester: A mixture of the
tosylate (569 mg, 1.89 mmol) and NaN3 (248 mg, 3.81 mmol) in DMF
(6 mL) was heated at 708C for 4 h. The reaction mixture was diluted with
Chem. Eur. J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1679 $ 20.00+.50/0
1679

P. Wipf et al.
FULL PAPER
1.17 (d, J ˆ 7.1 Hz, 3H), 1.08 (d, J ˆ 7.4 Hz, 18H), 0.89 (s, 9H), 0.86 (s, 9H),
0.85 (d, J ˆ 7.0 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H);
13C NMR: d ˆ 173.9, 171.7, 134.5, 125.7, 72.7, 72.4, 70.8, 67.6, 44.9, 42.7, 42.7,
35.5, 32.9, 32.9, 28.3, 26.5, 26.0, 26.0, 18.3, 18.2, 18.0, 17.7, 13.3, 12.0, À3.9,
(m, 2H), 1.78 (brd, 3H), 1.75 1.60 (m, 5H), 1.60 1.50 (m, 5H), 1.50 1.40
(m, 2H), 1.40 1.25 (m, 8H), 1.27 (d, J ˆ 7.8 Hz, 3H), 1.18 1.10 (m, 1H),
1.05 (d, J ˆ 6.6 Hz, 3H), 0.86 (d, J ˆ 6.9 Hz, 3H), 0.82 (d, J ˆ 6.5 Hz, 3H);
13C NMR (151 MHz): d ˆ 200.6, 199.2, 175.4, 173.7, 149.6, 144.8, 136.6,
132.3, 95.7, 75.0, 74.5, 74.0, 69.6, 64.9, 45.4, 44.9, 43.5, 39.7, 36.3, 35.6, 35.1,
34.6, 34.2, 33.5 (2C), 32.5, 31.5, 31.0, 30.7, 29.9, 28.1, 26.7, 25.8, 20.4, 19.3,
18.6, 18.2, 17.4, 15.7, 11.6; HRMS: m/z: calcd for C40H66N2O8: 702.4819,
found: 702.4788.
‡
‡
À4.3, À4.7, À4.7; MS(EI): m/z (%): 741 (0.03) [M] , 698 (0.3) [M À C3H7] ,
‡
684 (1) [M À C4H9] , 293 (5), 186 (42), 121 (100); HRMS: m/z: calcd for
‡
C35H70NO6Si3: 684.4511 [M À C4H9] , found: 684.4515.
To a solution of the amide prepared above (2.8 mg, 3.8 mmol) in THF
(1 mL) was added TBAF (0.1m in THF, 41 mL) at 08C. After 10 min, the
mixture was diluted with EtOAc, washed with 0.01n HCl and brine, dried
(Na2SO4), and concentrated to give 21 as a colorless oil (2.7 mg, 100%).
Acknowledgement
[a]D ˆ À4.0 (c ˆ 0.86, CH2Cl2, 228C); IR (film): nÄ ˆ 2950, 1730 cmÀ1
;
1H NMR: d ˆ 6.84 (brt, J ˆ 5.2 Hz, 1H), 5.61 5.47 (m, 1H), 5.40 (dd, J ˆ
15.4, 6.7 Hz, 1H), 4.20 3.95 (m, 3H), 3.86 3.73 (m, 1H), 3.61 3.49 (m,
1H), 3.35 3.22 (m, 1H), 2.69 2.46 (m, 2H), 2.21 (dd, J ˆ 15.5, 1.8 Hz, 1H),
1.97 1.62 (m, 4H), 1.66 (brd, J ˆ 5.9 Hz, 3H), 1.62 1.47 (m, 1H), 1.37
1.20 (m, 2H), 1.18 (d, J ˆ 7.0 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.86 (d, J ˆ
7.0 Hz, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.02 (s, 3H) ; 13C NMR:
d ˆ 177.3, 172.6, 134.3, 126.0, 73.1, 72.7, 71.1, 67.3, 43.5, 42.9, 42.4, 34.3, 33.0,
30.4, 28.5, 26.4, 26.0, 25.9, 18.3, 18.1, 17.7, 16.0, 13.2, À3.9, À4.3, À4.6, À4.9;
This work was supported by awards from Merck Research Laboratories,
Novartis, and Lilly & Co. S.Y. thanks Fujisawa Co. for support of his
sabbatical at Pittsburgh. The authors thank Prof. Dianne Watters (Griffith
University) for providing a sample of bistratene A (bistramide A), and
Prof. J. F. Biard (University of Nantes) for samples of bistramides A and C.
[1] D. Gouiffes, S. Moreau, N. Helbecque, J. L. Bernier, J. P. Henichart, Y.
Barbin, D. Laurent, J. F. Verbist, Tetrahedron 1988, 44, 451.
[2] B. M. Degnan, C. J. Hawkins, M. F. Lavin, E. J. McCaffrey, D. L. Parry,
D. J. Watters, J. Med. Chem. 1989, 32, 1354.
‡
‡
MS(EI): m/z (%): 585 (0.1) [M] , 528 (7) [M À C4H9] , 396 (4), 185 (28),
‡
121 (100); HRMS: m/z: calcd for C26H50NO6Si2: 528.3177 [M À C4H9] ,
found: 528.3159.
(6S,9R,11R,15S,16R,22R,23S,27S,31S,34R)-Bistramide C (1): A solution
of 4 (8.0 mg, 0.020 mmol), tributyltin hydride (22 mL, 0.080 mmol), and
AIBN (1 mg, 6 mmol) in benzene (2 mL) was heated at reflux for 2 h. The
mixture was cooled to room temperature and concentrated.
[3] J.-F. Biard, C. Roussakis, J.-M. Kornprobst, D. Gouiffes-Barbin, J.-F.
Verbist, P. Cotelle, M. P. Foster, C. M. Ireland, J. Nat. Prod. 1994, 57,
1336.
[4] W. E. B. Johnson, D. J. Watters, R. K. Suniara, G. Brown, C. M. Bunce,
Biochem. Biophys. Res. Commun. 1999, 260, 80.
A mixture of this residue (34 mg), 21 (15 mg, 0.026 mmol), and PyBOP
(33 mg, 0.060 mmol) in DMF (0.5 mL) was treated with (iPr)2NEt (14 mL,
0.080 mmol) at room temperature, stirred for 27 h, diluted with ethyl
acetate, washed with 10% citric acid, saturated aqueous NaHCO3, and
brine, dried (Na2SO4), and concentrated. Purification of the crude residue
by chromatography on silica gel (CHCl3/MeOH 1:0, then 20:1) gave impure
coupling product (27 mg).
[5] a) M. P. Foster, C. L. Mayne, R. Dunkel, R. J. Pugmire, D. M. Grant,
J.-M. Kornprobst, J.-F. Verbist, J.-F. Biard, C. M. Ireland, J. Am. Chem.
¬
Soc. 1992, 114, 1110; b) G. Solladie, C. Baudet, J.-F. Biard, Tetrahedron
Lett. 2000, 41, 7747.
[6] See, for example: a) P. Wipf, Y. Uto, J. Org. Chem. 2000, 65, 1037; b) S.
Ribe, R. K. Kondru, B. N. Beratan, P. Wipf, J. Am. Chem. Soc. 2000,
122, 4608; c) P. Wipf, J.-L. Methot, Org. Lett. 2000, 2, 4213.
[7] a) R. K. Kondru, S. Lim, P. Wipf, D. N. Beratan, Chirality 1997, 9, 469;
b) R. K. Kondru, P. Wipf, D. N. Beratan, J. Phys. Chem. 1999, 103,
6603; c) R. K. Kondru, P. Wipf, D. N. Beratan, J. Am. Chem. Soc. 1998,
120, 2204; d) R. K. Kondru, P. Wipf, D. N. Beratan, Science 1998, 282,
2247; e) K. M. Specht, J. Nam, D. M. Ho, N. Berova, R. K. Kondru,
D. N. Beratan, P. Wipf, R. A. Pascal, D. Kahne, J. Am. Chem. Soc.
2001, 123, 8961.
This impure residue was mixed with PPTS (19 mg, 0.076 mmol) in
methanol (1 mL), stirred for 20 h at room temperature, and concentrated.
The crude residue was purified twice by chromatography on silica gel
(CHCl3/MeOH 1:0, then 20:1) to give impure triol (4.6 mg) and impure
TBS ether (14 mg) which was re-subjected to the same reaction conditions
to provide impure triol (11.6 mg). The total amount of impure triol was
16 mg.
To a solution of this triol (11.6 mg) in CH2Cl2 (1 mL) was added Dess
Martin periodinane (15 wt% in CH2Cl2, 0.14 mL, 0.050 mmol) at room
temperature. After 20 min, the reaction mixture was diluted with ethyl
acetate, washed with saturated aqueous NaHCO3 and brine, dried
(Na2SO4), and concentrated. Purification of the residue by chromatography
on silica gel (CHCl3/MeOH 20:1) and preparative TLC (CHCl3/MeOH
10:1) gave bistramide C as a colorless oil (2.4 mg). The remainder of the
triol (4.6 mg) was subjected to the same reaction conditions to give 1 as a
colorless oil (0.9 mg). The total amount of 1 was 3.3 mg (24% over four
[8] In bistramide A, the chemical shifts and the 3J coupling constant of
CH(15) and CH(16) were found to be d ˆ 3.67, 2.34, and J ˆ 5.0 Hz,
respectively. The anti-4-acetylamino-3-hydroxy-2N-dimethylbutyra-
mide model system had corresponding values of d ˆ 3.69, 2.32, and
J ˆ 4.5 Hz, while the syn-diastereomer had values of d ˆ 3.86, 2.44,
and J ˆ 4.1 Hz. The 13C NMR shift of C(17) also confirmed this
assignment (d ˆ 15.6 for bistramide C vs. d ˆ 15.7 and 12.3 for anti-
and syn isomers, respectively).
[9] See Experimental Section for details.
steps): [a]D ˆ ‡34 (c ˆ 0.05, CHCl3, 238C); IR (film): nÄ ˆ 3353, 1641 cmÀ1
;
[10] a) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483; b) P. Wipf, Y. Kim, D. M. Goldstein, J. Am. Chem. Soc.
1995, 117, 11106.
[11] R. E. Ireland, J. P. Daub, J. Org. Chem. 1981, 46, 479. The stereo-
chemistry at the pyran ring C(9) was confirmed by 1D NOE
experiments.
[12] R. E. Damon, R. H. Schlessinger, Tetrahedron Lett. 1976, 1561.
[13] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 287.
[14] A. Abdel-Magid, J. H. Cohen, C. A. Maryanoff, R. D. Shah, F. J.
Villani, F. Zhang, Tetrahedron Lett. 1998, 39, 3391.
[15] H. L. Goering, V. D. Singleton, Jr., J. Am. Chem. Soc. 1976, 98, 7854.
[16] W. P. Griffith, S. V. Ley, Aldrichim. Acta 1990, 23, 13.
[17] a) L. Wessjohann, T. Gabriel, J. Org. Chem. 1997, 62, 3772; b) T.
Gabriel, L. Wessjohann, Tetrahedron Lett. 1997, 25, 4387.
[18] a) R. L. Dorta, A. Martin, J. A. Salazar, E. Suarez, J. Org. Chem. 1998,
63, 2251; b) S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G.
Selnick, R. Hungate, J. Am. Chem. Soc. 1989, 111, 2967.
[19] The stereochemistry of this spiroketal was confirmed by NOESY
analysis of a derivative of 15.
1H NMR (500 MHz): d ˆ 7.32 (brt, J ˆ 5.5 Hz, 1H), 6.96 (brt, J ˆ 5.5 Hz,
1H), 6.91 (dq, J ˆ 15.7, 6.9 Hz, 1H), 6.40 (brd, J ˆ 9.8 Hz, 1H), 6.13 (dq,
J ˆ 15.8, 1.5 Hz, 1H), 4.61 (brs, 1H), 4.20 (t, J ˆ 9.6 Hz, 1H), 4.07 (dd, J ˆ
11.2, 4.9 Hz, 1H), 3.76 3.70 (m, 1H), 3.54 3.46 (m, 1H), 3.46 3.40 (m,
1H), 3.35 3.25 (m, 2H), 3.24 (dt, J ˆ 13.8, 5.8 Hz, 1H), 3.14 (dt, J ˆ 2.0,
9.7 Hz, 1H), 2.91 (dd, J ˆ 17.0, 9.0 Hz, 1H), 2.76 (dd, J ˆ 15.2, 11.7 Hz, 1H),
2.67 2.53 (m, 1H), 2.53 (dd, J ˆ 17.0, 2.8 Hz, 1H), 2.42 2.36 (m, 1H), 2.32
(s, 3H), 2.14 (brd, J ˆ 15.2 Hz, 1H), 1.97 1.89 (m, 1H), 1.92 (dd, J ˆ 6.8,
1.4 Hz, 3H), 1.89 1.75 (m, 2H), 1.78 (brd, 3H), 1.75 1.50 (m, 10H), 1.50
1.40 (m, 2H), 1.40 1.25 (m, 8H), 1.27 (d, J ˆ 7.6 Hz, 3H), 1.18 1.10 (m,
1H), 1.05 (d, J ˆ 6.7 Hz, 3H), 0.86 (d, J ˆ 7.0 Hz, 3H), 0.82 (d, J ˆ 6.5 Hz,
3H); 1H NMR (600 MHz): d ˆ 7.33 (brs, 1H), 6.98 (brs, 1H), 6.91 (dq, J ˆ
15.6, 6.8 Hz, 1H), 6.40 (brd, J ˆ 9.8 Hz, 1H), 6.13 (brd, J ˆ 15.7 Hz, 1H),
4.60 (brs, 1H), 4.20 (t, J ˆ 9.6 Hz, 1H), 4.07 (dd, J ˆ 11.2, 4.9 Hz, 1H),
3.80 3.70 (m, 1H), 3.55 3.48 (m, 1H), 3.48 3.40 (m, 1H), 3.35 3.25 (m,
2H), 3.25 3.20 (m, 1H), 3.15 (dd, J ˆ 9.5, 8.6 Hz, 1H), 2.91 (dd, J ˆ 17.0,
9.0 Hz, 1H), 2.76 (dd, J ˆ 14.9, 11.6 Hz, 1H), 2.67 2.53 (m, 1H), 2.53 (dd,
J ˆ 17.0, 2.4 Hz, 1H), 2.42 2.37 (m, 1H), 2.33 (s, 3H), 2.14 (brd, J ˆ
14.5 Hz, 1H), 1.95 1.90 (m, 1H), 1.93 (brd, J ˆ 6.8 Hz, 3H), 1.89 1.80
[20] C. A. Broka, J. Ehrler, Tetrahedron Lett. 1991, 32, 5907.
1680
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1680 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 7

Bistramide C
1670 1681
[21] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104,
1737.
[22] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[23] E. Frerot, J. Coste, A. Pantaloni, M.-N. Dufour, P. Jouin, Tetrahedron
1991, 47, 259.
[24] This compound was extensively characterized by IR, MS, HRMS,
1H NMR, 13C NMR, DEPT, HMQC, HMBC, 2D NOESY and
ROESY.
[25] Oxidation of bistramide A with MnO2 provided semisynthetic bistra-
mide C for direct spectroscopic comparison (see Supporting Informa-
tion). A sample of natural bistramide C was generously provided by
Prof. Biard (University of Nantes).
[26] Segment 22 ([a]D ˆ ‡32 (c ˆ 0.21, CH2Cl2, 228C)) was obtained by
straightforward functional group manipulations of 21; segment 23
([a]D ˆ ‡20 (c ˆ 0.21, CHCl3, 228C)) was obtained by oxidation of an
intermediate in the conversion of 19 to 4.
[27] a) V. Martischonok, G. G. Melikyan, A. Mineif, O. Vostrowsky, H. J.
Bestmann, Synthesis 1991, 560; b) G. G. Melikyan, A. Mineif, O.
Vostrowsky, H. J. Bestmann, Synthesis 1991, 633.
[28] Y. Ichikawa, M. Isobe, T. Goto, Tetrahedron 1987, 43, 4749.
[29] M. Suzuki, T. Yamazaki, H. Ohta, K. Shima, K. Ohi, S. Nishiyama, T.
Sugai, Synlett 2000, 189.
Received: October 23, 2001 [F3721]
Chem. Eur. J. 2002, 8, No. 7
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0947-6539/02/0807-1681 $ 20.00+.50/0
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