Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: Total synthesis of (+)-wailupemycin B

Article abstract of DOI:10.1002/chem.200500640

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5)

Full text of DOI:10.1002/chem.200500640

FULL PAPER
DOI: 10.1002/chem.200500640
Diastereoselective Reactions at Enantiomerically Pure, Sterically Congested
Cyclohexanes as an Entry to Wailupemycins A and B:
Total Synthesis of (+)-Wailupemycin B
Stefan F. Kirsch and Thorsten Bach*[a]
Abstract: Wailupemycin A (1) and B
(2) are polyketide natural products
with a highly substituted cyclohexa-
none core. Three different routes for
the syntheses of these compounds were
pursued, which commenced from
either (R)-(ꢀ)-carvone (ent-5) or (S)-
(+)-carvone (5). In the first approach
it was attempted to construct the skele-
ton of wailupemycin A from triol 19
(nine steps from ent-5; 19% yield) by a
sequence of diastereoselective epoxida-
tion, nucleophilic ring opening at C-13
and carbonyl addition at C-5. The syn-
thetic plan failed at the stage of the
carbonyl addition to aldehyde 27,
which had been obtained in seven steps
(18% yield) from triol 19. The second
route included an epoxide ring opening
at C-13 and a carbonyl addition at C-7
as key steps. It could have led to either
wailupemycin A or B depending on the
diastereoselectivity of the addition
step. Starting from allylic alcohol 30
(six steps from ent-5; 59% yield) the
cyclohexanone 28 was obtained in five
steps (54% yield). Unfortunately, the
carbonyl addition failed also in this in-
stance. In the eventually successful
third attempt the skeleton of wailupe-
mycin B was built from cyclohexanone
43 (eight steps from 5; 53% yield) by
highly diastereoselective carbonyl addi-
tion reactions at C-7 and C-12. The
phenyl group at C-14 was introduced at
a late stage of the synthetic sequence.
Careful protecting group manipulation
finally allowed for the total synthesis of
(+)-wailupemycin B. The absolute and
relative configuration of the natural
product was unambiguously confirmed.
The total yield of wailupemycin B
amounted to 6% over 23 steps starting
from (S)-(+)-carvone (5).
Keywords:
antibiotics
·
asymmetric synthesis · ketones ·
polyketides · total synthesis
Introduction
terest arose from the structurally unique, highly substituted
cyclohexanone skeleton which is not precedented in
common antibiotics.[2] Although the indication for antibacte-
rial activity of either compound was limited, the possibility
to establish a new class of antibiotics and the challenge to
construct a sterically congested, enantiomerically pure six-
membered ring was sufficient motivation for us to embark
on a synthesis of the wailupemycins A and B. From a medic-
inal chemistry point of view, the possible decoration of the
core with aromatic substituents different from phenyl (C-15
to C-21) and 6-oxopyran-2-yl (C1 to C5) could be a promis-
ing handle to further increase a potential activity of the wai-
lupemycins.
According to the structure assignment by Davidson et al.
wailupemycin A and B differ in the relative configuration at
carbon atom C-7 and in the acetal part at C-14. Wailupemy-
cin B (2) is characterized by a tricylic structure resulting
from the formation of an intramolecular acetal between the
cis-hydroxy groups at C-7 and C-9 and the carbonyl group
at C-14. In wailupemycin A (1) an acetal formation is not
feasible and the compound presents itself as a highly substi-
Wailupemycin A (1) and wailupemycin B (2) are polyketide
natural products the structures of which were elucidated by
Davidson et al. in 1996 (Figure 1).[1] They were obtained to-
gether with other a-pyrone-containing metabolites from an
actinomycete designated BD-26T(20). The organism was
isolated from sediments collected at Wailupe beach park on
the south-east shore of Oahu, Hawaii. From 40 L of fermen-
tation broth 4 mg wailupemycin A and 7 mg wailupemycin
B were obtained. Due to the limited amount of material a
comprehensive antimicrobial assay was not possible. It was,
however, shown in preliminary experiments that compound
1 shows inhibitory activity against E. coli. Our synthetic in-
[a] Dr. S. F. Kirsch, Prof. Dr. T. Bach
Lehrstuhl für Organische Chemie I
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax:(+49)89-2891-3315
E-mail: thorsten.bach@ch.tum.de
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Scheme 1. Suggested[3] biosynthetic pathway to the biosynthetic wailupe-
mycin precursor 4.
Figure 1. Proposed[1] structures of the natural products wailupemycin A
and B isolated from the actinomycete BD-26T(20).
cloned and sequenced.[6] Intermediate 4 is presumed to be
also a key intermediate in the biosynthesis of the more
abundant polyketide enterocin (vulgamycin)[7] and its deoxy-
derivatives 5-deoxyenterocin and 3-epi-5-deoxyenterocin.
Despite the beauty of the natural pathway to wailupemy-
cins A and B it appeared unlikely to implement the cycliza-
tion of an open-chain precursor into a laboratory synthesis.
Our retrosynthetic analysis was therefore guided by the
functional group pattern found in the target and by a struc-
ture-based analysis of possible starting materials. The central
cyclohexane core of wailupemycins A and B is tetrasubsti-
tuted exhibiting a 1,2,3,5-relationship of substituents with
stereogenic centers at three positions. Following this analy-
sis, we were looking for a chiral pool starting material that
would exhibit at least one defined stereogenic center and
would allow for the direct functionalization of four positions
in the above-mentioned relationship. The monoterpene car-
vone which is available in both enantiomeric forms 5 and
ent-5 (Figure 2) fulfilled this requirement almost ideally. The
tuted cyclohexanone. Biosynthetically, the compounds are
ꢀ
formed by C C bond formation between carbon atoms C-7
and C-12, that is, by cyclohexane ring closure from an open-
chain precursor 4 (Scheme 1).[3] The linear octaketide 3,
which is derived from an uncommon benzoate starter[4] and
seven malonate-SCoA units, undergoes a rare Favorskii-type
oxidative rearrangement. The rearrangement accounts for
the polarity reversal which is required for the crucial C-7/C-
12 bond formation step in the biosynthesis of wailupemycin
A and B. It is catalyzed by an oxidase (“favorskiiase”)
which is encoded by the gene encM,[5] a member of the en-
terocin gene cluster. The 21.3 kb Enc gene cluster from the
marine bacterium Streptomyces maritimus has recently been
Abstract in German: Die Wailupemycine A (1) und B (2)
sind polyketide Naturstoffe mit einem hochsubstituierten Cy-
clohexanongerüst. Zur Synthese dieser Verbindungen wurden
drei verschiedene Routen eingeschlagen, die von natürlichem
(R)-(ꢀ)-Carvon (ent-5) oder (S)-(+)-Carvon (5) ausgingen.
Im ersten Anlaufwurde versucht, aus dem Triol 19 (neun
Stufen aus ent-5 in 19% Ausbeute) über eine diastereose-
lektve Epoxiderung, eine nucleophile Ringçffnung an C-13
und eine Carbonyladdition an C-5 das Gerüst von Wailupe-
mycin A aufzubauen. Die Reaktionssequenz scheiterte auf
der Stufe der Carbonyladdition an Aldehyd 27, der in sieben
Stufen (18% Ausbeute) aus dem Triol 19 erhalten worden
war. Die zweite Route sah eine Epoxid-Ringçffnung an C-13
und eine Carbonyladdition an C-7 vor. Sie konnte je nach Di-
astereoselektivität des Additionsschritts zu Wailupemycin A
oder B führen. Ausgehend von Allylalkohol 30 (sechs Stufen
aus ent-5 in 59% Ausbeute) wurde das Cyclohexanon 28 in
fünf Stufen (54% Ausbeute) erhalten. Leider scheiterte auch
hier die Carbonyladdition. Im schließlich erfolgreichen drit-
ten Versuch wurde ausgehend von Cyclohexanon 43 (8
Stufen aus 5 in 53% Ausbeute) das Gerüst des Wailupemy-
cins B durch hoch diastereoselektive Carbonyladditionen an
C-7 und C-12 aufgebaut. Die Phenylgruppe an C-14 wurde
erst am Ende der Synthesesequenz eingeführt. Vorsichtige
Schutzgruppenmanipulationen erlaubten schließlich die To-
talsynthese des (+)-Wailupemycins B. Durch die Synthese
wurden Relativ- und Absolutkonfiguration des Naturstoffs
einwandfrei bestätigt. Die Gesamtausbeute betrug ausgehend
von (S)-(+)-Carvon (5) 6% über 23 Stufen.
Figure 2. Structures of the two enantiomeric forms 5 and ent-5 of carvone
and of the general building blocks A and B.
isopropenyl substituent can be easily converted into a hy-
droxy group under retention of configuration[8] and the a,b-
unsaturated ketone appeared to be an ideal starting point to
establish functionality in a 1,2,3-pattern. In our synthetic en-
deavour, we followed two major strategies represented by
the general structures A and B (Figure 2, PG = protective
group). One strategy—represented by structure A—fo-
ꢀ
cussed on a C C bond formation at C-7 by carbonyl addi-
tion and by epoxide ring opening at C-13 or vice versa. The
other strategy—represented by structure B—aimed at a suc-
cessive carbonyl addition at C-12 and at C-7. Concerning
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(+)-Wailupemycin B
FULL PAPER
the protective groups PG and PG1 we relied on orthogonal
silyl ethers to protect the hydroxy groups at C-9 and C-11.
The alcohol at C-9 was frequently protected with the robust
tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS)
group, the alcohol at C-11 was often converted into the cor-
responding tert-butyldimethylsilyl (TBDMS) ether. Small
protecting groups were used for the temporary protection of
tertiary alcohols at C-7 and C-12 (Figure 1).
In the following sections we report the results of the indi-
vidual approaches we followed. The study has provided sev-
eral useful details on the reactivity of sterically congested
cyclohexanes. While many of the synthetic approaches to
wailupemycins A and B were performed parallel to each
other they have to be now described in successive order. To
keep this account within a reasonable page limit, several
dead ends cannot be discussed extensively, some are not
even mentioned. The story starts with our initial approaches
according to a bond connection at C-7/C-13 and vice versa
(strategy A). Subsequently, strategy B with a bond connec-
tion C-12/C-7 is discussed. It eventually culminated in a con-
cise synthesis of enantiomerically pure wailupemycin B (2)[9]
which served to unambiguously prove the absolute and rela-
tive configuration of the natural product.
Results and Discussion
Preliminary experiments were conducted to evaluate possi-
ꢀ
ble C C-bond forming reactions at the different positions
mentioned above (Scheme 2). Pyrone formation from differ-
ent aldehydes was possible by addition of ketene acetal 7,[10]
oxidation with the Dess–Martin periodinane (DMP)[11] and
ring closure.[12,13] Isovaleraldyde (6) for example was con-
verted to pyrone 8 in 75% overall yield. Addition of an ace-
tate enolate to a cyclohexanone at C-7 and subsequent re-
duction to an aldehyde would in combination with this
three-step sequence allow for construction of the C-1/C-6
part of the wailupemycins. Alternatively, the direct introduc-
tion of a pyrone was attempted. The best method was found
to be the addition of the dianion derived from 4-hydroxy-6-
methyl-2H-pyran-2-one[14] to an appropriate ketone. Addi-
tion to cyclohexanone (9) and methylation for example
yielded directly the desired pyrone 10.
The epoxide ring opening at carbon atom C-13 with a
benzoyl anion equivalent proceeded favorably by using a
lithiated dithiane.[15] Removal of the dithiane was best ach-
ieved with HgO in the presence of BF3·OEt2. Following this
protocol, epoxide 11 was transformed into phenyl ketone 12
in an overall yield of 69%. An alternative sequence deliver-
ing the alcohol at carbon atom C-12 in protected form was
feasible upon epoxide ring opening with vinyl magnesium
bromide. The same alcohol 13 can of course be obtained by
allyl metal addition to cyclohexanone, which is relevant to
strategy B (see below). Methoxyethoxymethyl (MEM) pro-
tection[16] of alcohol 13 furnished the homoallylic ether 14
which was oxidized to aldehyde 15 and further converted
into the protected b-hydroxyketone 16. The ring opening of
ꢀ
Scheme 2. Test reactions to evaluate possible C C bond formation reac-
tions at C-5, C-7 and C-13 of the wailupemycin skeleton.
epoxide 11 with an a-metalated styrene[17] was not possible
under a variety of conditions.
ꢀ
C C Bond formation at C-7, C-13 and C-5: Reactions at the
double bond (e.g. epoxidation[18]) or at the carbonyl group
(e.g. enolate addition[8a,19]) of carvone (5/ent-5) occur from
the face opposite to the isopropenyl group.[20] Our initial
plan relied on the hydroxy group at C-7 directing the epoxi-
dation at C-11 and C-12 to establish the relative configura-
tion of C-7 and C-12 in wailupemycin A.[21] Since the config-
uration at C-9 can be—after conversion of the isopropenyl
into a hydroxy group—easily inverted (e.g. by a Mitsunobu
reaction)[22] we envisaged a straightforward synthesis of wai-
lupemycin A starting from (R)-(ꢀ)-carvone (ent-5). Enolate
attack at the carbonyl group would establish the correct
configuration at C-7, directed epoxidation would deliver the
desired configuration at C-11 and C-12 and inversion at C-9
would adjust the configuration of the cyclohexane. As de-
picted in Scheme 3, wailupemycin A (1) was retrosyntheti-
cally traced back to the dithiane 17 which in turn was to be
obtained from epoxide 18 by nucleophilic ring opening. Our
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T. Bach and S. F. Kirsch
Scheme 3. Retrosynthetic analysis of wailupemycin A (1) based on a dia-
ꢀ
stereoselective epoxidation and a C C bond disconnection at C-4/C-5
and at C-13/C-14.
method for the construction of the a-pyrone from an alde-
hyde at C-5 (Scheme 2)[13] appeared to be compatible with
the functional groups present in intermediate 17. Epoxide
18 was to be prepared by directed epoxidation via allylic
triol 19 which in turn was expected to evolve from epoxide
20 by elimination. The origin of the relative configuration in
precursor 20 has already been explained (see above).
Indeed, compound 20 had been prepared in an earlier study
which aimed at an optimization of the desired epoxide elim-
ination to an allylic alcohol.[23] It was obtained in eight steps
from (R)-(ꢀ)-carvone (ent-5) with an overall yield of 31%.
The epoxide fragmentation to the desired allylic alcohol
was initiated by treatment of 20 with diethylaluminum
2,2,6,6-tetramethylpiperidide (DATMP).[24] Upon acidic
work-up (1n HCl) triol 19 was obtained (61% yield) and
was selectively TBDMS-protected (TBDMSCl, imidazole in
DMF, RT) at the primary alcohol site (C-5) to yield diol 21
(93%). The relative configuration of triol 19 was proven by
single crystal X-ray crystallography.[23] Directed epoxidation
with meta-chloroperbenzoic acid (MCPBA)[25] in the pres-
ence of NaHCO3 delivered epoxide 22 in quantitative yield
(Scheme 4). Since preliminary experiments had clearly indi-
cated that free hydroxy groups are not compatible with an
attempted nucleophilic epoxide ring opening, a suitable pro-
tection for the alcohols at C-7 and C-11 was looked for.
Even small protecting groups, such as trimethylsilyl (TMS)
or acetyl (Ac), could not be properly installed and we there-
fore had to rely on an acetonide protection of the two axial
hydroxy groups. The formation of the tricyclic product 23
was sluggish (68% yield) but it allowed for an unambiguous
assignment of the relative configuration by 1H NMR
NOESY experiments (Scheme 4). The attempted ring open-
ing with the lithiated 2-phenyl-1,3-dithiane proceeded
smoothly at ꢀ408C.[15] The newly generated hydroxy group,
however, led to unexpected complications upon work-up
and purification. Isomerization to five-membered acetonides
occurred and decomposition was observed. An isomeriza-
tion to a single protected product was impossible and conse-
quently a deprotected tetraol with free hydroxy groups at
Scheme 4. Synthesis of the epoxides 18 and 23 from diol 21, further con-
version of epoxide 18 to aldehyde 25 and major NOESY contacts in ep-
oxide 23.
positions C-5, C-7, C-11 and C-12 was the only product to
be obtained (55% yield) after treatment with 1n HCl and
BF3·OEt2. Given the fact that a further protection would
have been extremely tedious we looked for an alternative
route to intermediates of type 17 (Scheme 3). To this end,
the secondary alcohol at C-11 was benzyl (Bn)-protected
and the resulting alcohol 24 was stereoselectively epoxidized
to the above-mentioned epoxyalcohol 18. Its relative config-
1
uration was proven by H NMR NOESY experiments. Tri-
ethylsilyl (TES) protection was feasible at the C-7 hydroxy
group and the silylated epoxy ether 25 underwent smooth
ring opening to dithiane 17 (PG = TES). Disappointingly,
the projected route could not be successfully completed
from this intermediate. Without mentioning every single ex-
periment we performed the bottom line was that an attack
of the carbonyl group at C-5 with any given nucleophile was
impossible. As an example, the selective deprotection of the
TDBMS group to diol 26 is depicted in Scheme 4. Oxidation
with pyridinium chlorochromate (PCC)[26] gave aldehyde 27
which was inert toward all attempted nucleophilic addition
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(+)-Wailupemycin B
FULL PAPER
reactions. Even the addition of methyl lithium or the reduc-
tion with LiAlH4 did not proceed. Attempts to selectively
attack the aldehyde at C-5 after dithiane deprotection (at C-
14) were not successful, either.
To summarize this section, the hydroxy-directed epoxida-
tion of sterically congested double bonds proved to be a re-
liable method for introducing the stereogenic center at
carbon atom C-12. One axially positioned hydroxy group
was sufficient (cf. alcohol 24) to guarantee high stereocon-
trol. The dithiane moiety could be introduced nicely, but its
steric bulk prohibited further reactions at carbon atom C-5.
The tertiary alcohol at C-7 which was introduced early in
the synthesis by carbonyl addition to carvone caused compli-
cations because it a) was almost impossible to protect and
b) suppressed in unprotected form several straightforward
reactions. We believed that the complete introduction of the
pyrone fragment C-1 to C-6 (Scheme 2) after formation of
the C-13/C-14 bond could be a remedy to avoid these com-
plications.
Figure 3. Structure of the allylic alcohols 30–32 obtained from (R)-(ꢀ)-
carvone (ent-5)[28] and of the epoxidation products 33 of allylic alcohol
31.
with either tert-butyl hydroperoxide (TBHP) and VO(acac)2
(acac = acetyl acetone) as the catalyst[29] or with MCPBA
led to a 1:1 mixture of diastereoisomers 33a and 33b.
In pleasant contrast to the latter observation, the epoxida-
tion of allylic alcohol 30 proceeded with excellent facial dia-
stereoselectivity. MCPBA epoxidation (08C, CH2Cl2) fur-
nished the epoxide 29 as a single diastereoisomer in 71%
yield. The VO(acac)2-catalyzed reaction was even superior
in this instance (Scheme 6) delivering the desired product in
ꢀ
C C Bond formation at C-13 and C-7: We identified ketone
28 as an ideal precursor to test the feasibility of a C-7
ketone addition at a later stage of the synthesis. Irrespective
of the facial diastereoselectivity, both product diols could be
used as intermediates towards the wailupemycins, either as
cis-1,2-diol for the synthesis of wailupemycin A (1) or as
trans-1,2-diol for the synthesis of wailupymycin B (2). As
suitable epoxide for ring opening we planned to employ
compound 29 which in turn was to be formed by directed
epoxidation (Scheme 5).
Scheme 6. Synthesis of ketone 28 from allylic alcohol 30 by diastereose-
Scheme 5. Retrosynthetic analysis of wailupemycin A and B (1/2) based
ꢀ
lective epoxidation and nucleophilic epoxide ring opening.
on a C C bond disconnection at C-13/C-14 and at C-6/C-7.
In selecting the epoxide precursor there was a choice of
allylic alcohol precursors readily available from either enan-
tiomer of carvone. The correct configuration at carbon atom
C-9 was to be based on the use of (R)-(ꢀ)-carvone (ent-5)
as starting material. Following established methodology,[27,28]
the alcohols 30–32 were available in 42–59% overall yield
from ent-5 in six steps (Figure 3). While allylic alcohol 32 is
apparently unsuited for the desired directed epoxidation at
C-12, the two alcohols 30 and 31 both have a directing hy-
droxy group at carbon atom C-7 the relative configuration
of which appeared to be in accord with the desired epoxide
formation at carbon atom C-12. Only alcohol 30, however,
can adopt a single chair conformation in which the hydroxy
group resides in an axial position. Alcohol 31 is conforma-
tionally more flexible and directed reactions were expected
to proceed with less stereocontrol. Indeed, epoxidations
89% yield.[29] TMS protection of the hydroxy group at C-7
proceeded quantitatively and paved the way for the desired
ring opening. Again, lithiated 2-phenyl-1,3-dithiane proved
to be a reliable reagent for the regio- and chemoselective
epoxide ring opening and epoxide 34 was converted into ter-
tiary alcohol 35 and, again, the hydroxy group protection
was required to allow for the reaction. Alcohol 29 did not
react with the lithiated dithiane. TMS deprotection was se-
lectively attained by the use of aqueous acetic acid to yield
secondary alcohol 36. Pfitzner–Moffatt oxidation was the su-
perior method for the oxidation to ketone 28.[30,31] CrVI re-
agents led to glycol cleavage reactions and IV oxidants at-
tacked the dithiane part of the molecule. Attempts to tem-
porarily protect (TMS, MEM, Ac) the sterically congested
tertiary alcohol at C-12 in compounds 28 (after oxidation)
or 35 (prior to oxidation) failed.
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T. Bach and S. F. Kirsch
Disappointingly, the a-hydroxyketone 28 did not react
with a nucleophile to allow for the desired C-6/C-7 bond for-
mation. All synthetic equivalents for an a-metalated 4-me-
thoxy-6-methyl-2H-pyran-2-one, including the dianion de-
rived from 4-hydroxy-6-methyl-2H-pyran-2-one (Scheme 2),
did not attack the carbonyl group. With 10 equivalents of
this reagent elimination to an a,b-unsaturated cyclohexe-
none but no addition was observed. The reasons for the low
electrophilicity of ketone 28 are linked either directly or in-
directly to the steric bulk of the dithiane moiety. Based on
1H NMR NOESY measurements compound 28 adopts a
chair conformation with the silyloxy (C-9, C-11) and oxy (C-
12) groups in equatorial position. The (2-phenyldithian-2-
yl)methyl substituent resides in an axial position prohibiting
the attack to the carbonyl group from the Si face. The Re
face attack is impossible due to 1,3-diaxial interactions and
due to Coulomb repulsion between the alkoxide (C-12) and
the incoming nucleophile. The tertiary alcohol at C-12 in
turn had to remain unprotected because the size of the di-
thiane did not allow a temporary protection.
In other experiments (see below), we noted that cyclohex-
anones which do not populate a chair conformation are
much more difficult to attack by a nucleophile than confor-
mationally restricted cyclohexanones.
As a detour to build the required phenyl ketone, we brief-
ly looked into the vinyl Grignard ring-opening sequence (11
! 16, Scheme 2) and attempted to open epoxide 34 with a
vinyl magnesium reagent rather than with a lithiated di-
thiane. Surprisingly, the major pathway of this reaction was
not the ring opening to homoallylic alcohol 38. Instead, a pi-
nacol-type rearrangement generated a b-hydroxyketone,
which was subsequently trapped by the Grignard reagent to
yield cycloheptanediol 37 (Scheme 7).
tected with HF·py (08C, THF) to yield triol 39, which upon
treatment with HgO and BF3·OEt2 cyclized to the expected
cyclic ketal 40 (Scheme 8). The result nicely illustrated the
high preference for intramolecular ketal formation in triols
of this type and encouraged further work directed towards
the synthesis of wailupemycin B (2).
Scheme 8. Deprotection and intramolecular ketalization of dithiane 39.
ꢀ
C C Bond formation at C-12 and C-7: An analysis of the
consecutive bond-formation steps according to strategy B
(Figure 2) revealed that the trans-1,2-diol found in wailupe-
mycin B is much more readily formed than the cis-1,2-diol
of wailupemycin A. Attack with a reasonably large nucleo-
phile, for example, the dianion derived from 4-hydroxy-6-
methyl-2H-pyran-2-one, on a ketone of general structure C
can only occur as an equatorial attack leading to the axial
alcohol D. Even if R is an allyl or another relatively small
carbon substituent, any attempt to override its preference
for an equatorial position, for example, by enlarging the size
of the O-PG group or by utilizing the relative configuration
of the protected hydroxy groups at C-9 or C-11, appeared
unsensible. On the contrary, it was our notion that a strong
attempt should be made to choose the protected hydroxy
groups at C-9 or C-11 so that a single chair conformation of
an appropriate ketone was strongly preferred. For compari-
son, the open-chain isomer 41 of wailupemycin B is drawn
in Scheme 9.
Scheme 7. Attempted ring opening of epoxide 34 with vinyl magnesium
bromide.
Although the ring opening product could be made the
major product by conducting the epoxide attack in the pres-
ence of CuI (53% yield) we did not further follow this
route. There were several reasons for this decision. First, the
protection of the tertiary alcohol at C-12 would require a la-
borious protection/deprotection strategy if it could be pro-
tected at all. Secondly, the relative configuration of the O-
protected ketone derived from alcohol 38 would not favor a
single chair conformation. Thirdly, access to ketones of this
type was easier to achieve by allyl magnesium addition to a
C-12 ketone (strategy B in Figure 2).
Scheme 9. Facial diastereoselectivity of a nucleophilic approach to cyclo-
hexanone C and structure of the open-chain isomer 41.
Another question to be addressed was related to the con-
figuration at the stereogenic carbon atom C-12. It is defined
in the diastereoselective addition step of a given acetophe-
none enolate equivalent to a chiral C-12 ketone. In our case,
several ketones were available starting from either enantio-
mer of carvone. They are readily prepared from the above-
mentioned alkenes 30–32 (Figure 3) or their enantiomers by
The ketal ring closure to wailupemycin B was modelled in
a final experiment of this series. Ketone 28 was silyl depro-
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Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
TMS protection (C-7) and ozonolytic cleavage.[28] In prelimi-
nary experiments, only two ketones 42 and 43—both pre-
pared from (S)-(+)-carvone (5)—allowed for an unequivocal
attack in favor of the correct absolute configuration at C-12
required for wailupemycin B (Figure 4). The question which
ꢀ
Scheme 10. Retrosynthetic analysis of wailupemycin B (2) based on a C
C bond disconnection at C-12/C-13, at C-6/C-7, and at C-14/C-15.
straightforward based on the facile ketalization we had ear-
lier observed for the model system 40 (Scheme 8).
In a forward direction the synthesis commenced with the
above-mentioned MEM ether 45 which was obtained from
the allyl Grignard addition product 46 by MEM protection
(Scheme 11).[33] The diastereomeric ratio (dr) was deter-
mined after MEM protection to be >95:5. Deprotection of
the TMS ether at C-7 was achieved by treatment of com-
pound 45 with K2CO3 in methanol. The secondary alcohol
47 was oxidized with 2-iodoxybenzoic acid (IBX)[34] to
ketone 48.[35,36] The dianion generated from 4-hydroxy-6-
methyl-2H-pyran-2-one by deprotonation with tert-butyl
lithium added diastereoselectively to this ketone and yielded
the tertiary alcohol 49. In order to achieve a high facial dia-
stereoselectivity, the addition was conducted at low temper-
ature (ꢀ788C), at which the reaction was slow. Even after
2 d it did not go to completion (64% yield) and starting ma-
terial was recovered (22% yield). The unstable hydroxypyr-
anone (dr 93:7) was immediately methylated with dimethyl
sulfate in the presence of K2CO3. Product 50 obtained after
methylation and purification was diastereomerically pure
(dr >95:5).
Originally, we had planned to subsequently remove the
TBDMS group at C-11 and to form the C-11 ketone prior to
inverting the configuration at C-9.[37] While the TBDMS and
MEM deprotection was possible under acidic conditions
(ZnBr2, CeCl3 in MeCN) leaving the TBDPS group un-
touched it turned out that the TBDPS-protecting group at
C-9 was selectively cleaved under standard silyl deprotection
conditions (HF·py in THF). Since the inversion of configu-
ration at C-9 appeared feasible with alcohol 51 it was at-
tempted by an oxidation–reduction sequence. Indeed, oxida-
tion to ketone 52 proceeded smoothly and the subsequent
hydride addition occurred selectively from the equatorial
position if LiHB(sBu)3 (L-selectride) was used as the reduc-
ing agent. NaBH4 gave predominantly the starting material
51 (dr 80:20) approaching the conformationally locked cy-
clohexanone 52 from the axial position. The two axial hy-
droxy groups at C-7 and C-9 could be protected as the cyclic
isopropylidene acetal 54 upon treatment of diol 53 with 2-
methoxy propene in the presence of pyridinium para-tolu-
ene sulfonate (PPTS). At this stage the elaboration of the
terminal olefin to the benzoyl group commenced. The oxi-
dative double bond cleavage was conducted as in the previ-
ous model study (14 ! 15, Scheme 2) by the Lemieux–John-
son method.[38] Grignard addition to aldehyde 44 and imme-
Figure 4. Facial diastereoselectivity of a nucleophilic approach to cyclo-
hexanones 42 and 43 with allyl magnesium bromide and 2-phenylethynyl
lithium.
acetophenone enolate equivalent was to be employed could
also be answered in these studies. Allyl magnesium bromide
gave much higher diastereoselectivities than 2-phenylethynyl
lithium. The observation is in line with previous studies on
the nucleophilic addition to cyclohexanones.[19,20,32] The steri-
cally least congested equatorial trajectory is favored for
large nucleophiles whereas small nucleophiles approach cy-
clohexanones axially. A surprising observation was the fact
that the all-equatorial cyclohexanone 42 reacted with allyl
magnesium bromide in lower yields and with lower diaster-
eoselectivity than cyclohexanone 43.
While it was tempting to introduce the phenyl ring al-
ready with a suitable allyl Grignard reagent, for example,
with 2-phenylallyl magnesium bromide, we discarded this
idea. Previous experience had shown that the substituent at
C-12 should be as small as possible. Based on the prelimina-
ry work (Scheme 2) we were optimistic that the conversion
of the allyl group to a benzoylmethyl substituent would suc-
ceed after MEM protection of the tertiary alcohol. Conse-
quently, we adjusted our retrosyntethic plan aiming at allyl
addition product 45 as initial key intermediate (Scheme 10).
The second key intermediate 44 was certainly not envi-
sioned with this set of protecting groups—they rather ac-
commodated synthetic needs in the real synthesis - but it re-
flects the crucial synthetic steps: a) pyrone addition, b) in-
version of configuration at C-9, c) complete protection of
hydroxy groups and d) ozonolytic cleavage of the double
bond. From intermediate 44 the completion of the synthesis
by carbonyl addition, oxidation at C-14, deprotection and
oxidation at C-11 as well as complete deprotection appeared
Chem. Eur. J. 2005, 11, 7007 – 7023
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7013

T. Bach and S. F. Kirsch
Scheme 11. Total synthesis of wailupemycin B (2) starting from the allyl addition product 46, which in turn was obtained from (S)-(+)-carvone (5) in
nine steps and 53% overall yield.
diate oxidation provided access to ketone 55. The combina-
tion of Dess–Martin periodinane/NaHCO3 was the only oxi-
dant that effected the required oxidation but left the acetal
protecting groups untouched.[39] Swern-,[40] PCC-,[26] and pyr-
idinium dichromate(PDC) oxidation[41] led to concomitant
deprotection reactions whereas IBX,[34–36] tetrapropylammo-
nium perruthenate (TPAP),[42] 2,2,6,6-tetramethylpiperdine
[a]2D0). The relative configuration of intermediates (e.g. 54)
was proven by 1H NMR NOESY studies.[9]
The unexpected higher reactivity of the TBDPS group at
C-9 as compared with the TBDMS group at C-11 in inter-
mediate 50 may raise the question why the protection was
not more conveniently conducted with a twofold TBDMS
protection at C-9 and C-11. The corresponding ketone 57
was quickly prepared in analogy to ketone 48. It failed, how-
ever, to provide the same selectivities in the subsequent ad-
dition step. While the dianion generated from 4-hydroxy-6-
methyl-2H-pyran-2-one added to ketone 48 after 2 d in THF
at ꢀ788C in 64% yield and with a dr 93:7, the addition to
ketone 57 proceeded only in 52% yield and with a dr of
83:17.
The previously mentioned conformational arguments are
important in all addition steps to these sterically congested
cyclohexanones. Ketone 58 may serve as an example
(Figure 5). NOESY studies and analysis of its coupling con-
stants clearly indicated that this ketone does not adopt a
chair conformation. A nucleophilic addition to the carbonyl
group was impossible.
[44]
nitroxyl (TEMPO),[43] or MnO2 did not oxidize the secon-
dary alcohol and starting material was recovered. TBDMS
deprotection at C-11 was impossible under basic conditions
in the presence of the adjacent MEM ether and it was there-
fore decided to attempt the oxidation to the C-11 ketone
after formation of the wailupemycin B skeleton. In the tricy-
clic core the TBDMSO group at C-11 should be in an ex-
posed axial position. The acetal protecting groups could be
completely removed under carefully selected conditions in a
1:2:2:4 mixture of trifluoroacetic acid (TFA), acetic acid,
water, and THFand the cyclic ketal 56 was formed. Tetrabu-
tylammonium fluoride (TBAF) effected the deprotection of
the remaining silyl ether and an IBX oxidation to wailupe-
mycin B (2) completed the synthesis. Conventional IBX oxi-
dation in DMSO with an aqueous work-up and ether extrac-
tion was not favorable due to the low solubility of wailupe-
mycin B in diethyl ether. Instead, the Finney protocol[45] was
followed according to which the IBX oxidation is conducted
in refluxing ethyl acetate.
Overall, the total synthesis proceeded in 23 steps starting
from (S)-(+)-carvone (5) and in 6% overall yield. The iden-
tity of the synthetic material to the natural product was
proven by comparison of the spectroscopic data (NMR,
Figure 5. Structure of the ketones 57 and 58, which were also tested for a
ꢀ
diastereoselective C C bond formation at carbon atom C-7.
7014
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Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
ꢀ
Attempted C C bond formation between C-12 and C-7:
Experimental Section
While strategy B had provided a straightforward entry to
wailupemycin B (2), it appeared to be less suited for the
synthesis of wailupemycin A (1). Since all other approaches
had not led to a feasible synthetic route to 1, either, we at-
tempted as the final strategy a “biomimetic” approach
aiming at a bond construction between carbon atoms C-12
and C-7. MEM deprotection of compound 50 yielded the
diol 59 which could be oxidatively cleaved to diketone 60.
Due to the trans-diaxial relationship of the hydroxy groups
at C-7 and C-12 the yield in the cleavage was not high but
the amount of material was sufficient to attempt a reasona-
ble number of pinacol coupling reactions. None of them,
however, gave a hint on the formation of a diol, be it com-
pound 59 or the desired diastereoisomer (Scheme 12).
General: All reactions involving water-sensitive chemicals were carried
out in flame-dried glass ware with magnetic stirring under Ar. Common
solvents [pentane (P), methanol (MeOH), ethanol (EtOH), ethyl acetate
(EtOAc), tetrahydrofuran (THF), diethyl ether (Et2O), CH2Cl2] were dis-
tilled prior to use. All other reagents and solvents were used as received.
1H and 13C NMR spectra were recorded in CDCl3 unless otherwise
noted. Chemical sifts are reported relative to CHCl3. Apparent multiplets
which occur as a result of accidental equality of coupling constants to
those of magnetically nonequivalent protons are marked as virtual (virt.).
TLC was performed on aluminum sheets (0.2 mm silica gel 60 F254) with
detection by UV (254 nm) or by coloration with ceric ammonium molyb-
date (CAM). Flash chromatography[46] was performed on silica gel 60
(230–400 mesh) (ca. 50 g for 1 g of material to be separated), with the in-
dicated eluent. Compounds 20,[23] 30,[28] and 43[28] were prepared accord-
ing to known procedures.
4-Methoxy-6-[(1-hydroxycyclohexyl)methyl]-2H-pyran-2-one (10): 4-Hy-
droxy-6-methyl-2H-pyran-2-one (630 mg, 5 mmol) was dissolved in THF
(60 mL). The solution was cooled to ꢀ788C, and a solution of tBuLi in
pentane (1.5m; 10 mmol, 6.7 mL) was added dropwise. After stirring the
orange solution for 15 min at ꢀ788C, the mixture was warmed to 08C.
The solution was stirred for 20 min at 08C, then cooled to ꢀ788C. A so-
lution of cyclohexanone (0.15 mL, 147 mg, 1.5 mmol) in THF(5 mL) was
added. The reaction mixture was stirred for additional 20 min at ꢀ788C
and then warmed to RT over a period of 3 h. The reaction was quenched
by addition of sat. aqueous NH4Cl (100 mL). The mixture was acidified
with aqueous H2SO4 (10%) to pH 2. After addition of Et2O (200 mL)
and water (200 mL), the layers were separated. The aqueous layer was
extracted with Et2O (2”150 mL). The combined organic layers were
washed with water (200 mL) and brine (200 mL), dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified by flash
chromatography (P/EA 30:70) to give 4-hydroxy-6-[(1-hydroxycyclohex-
yl)methyl]-2H-pyran-2-one as a yellow oil (205 mg, 0.92 mmol, 61%).
Rf =0.05 (P/EA 50:50) [CAM]; 1H NMR (250 MHz, [D6]DMSO): d=
1.53–1.96 (m, 10H), 2.85 (s, 2H), 3.75 (brs, 1H, OH), 4.72 (brs, 1H,
OH), 5.60 (s, 1H), 6.32 (s, 1H); 13C NMR (90.6 MHz, [D6]DMSO): d=
21.7 (t), 25.4 (t), 37.2 (t), 46.4 (t), 70.0 (s), 88.6 (d), 102.5 (d), 164.0 (s),
164.3 (s), 170.4 (s).
Scheme 12. Preparation of the acyclic diketone 60 from diol 59 by diol
cleavage.
Conclusion
In summary, three approaches to the synthesis of wailupe-
mycins A and B have been described. They were all based
on the use of enantiomerically pure carvone as starting ma-
terial but differed in the chosen bond set. In the first ap-
proach, it was impossible to add a C4 fragment to the alde-
hyde carbon atom C-5 of key intermediate 27. The low reac-
tivity of the electrophile was attributed to the steric shield-
ing of the reaction center by the adjacent dithiane. In the
second approach, attempts to introduce the 4-methoxy-6-ox-
opyran-2-ylmethyl group (C-1 to C-6) by addition to an ap-
propriate ketone (28) were unsuccessful. Besides the steric
bulk of the substituents at the cyclohexanone, the ring con-
formation was found to play a decisive role as to success of
the carbonyl additions. Implementing these observations a
final approach was conducted which aimed at successive
bond formations at carbon atoms C-12 and C-7. By adjust-
ing the configuration of the hydroxy substituents at C-9 and
C-11, cyclohexanones were prepared starting from (S)-(+)-
carvone (5), in which an unequivocal chair conformation
was set up and in which an equatorial nucleophilic approach
was possible. After appropriate protecting and functional
group manipulations the strategy turned out to be successful
and wailupemycin B was synthesized in 23 steps and an
overall yield of 6% starting from (S)-(+)-carvone (5). An
appealing aspect of our synthetic route is the possibility to
replace the peripheral aromatic substituents by other arenes
and hetarenes.
4-Hydroxy-6-[(1-hydroxycyclohexyl)methyl]-2H-pyran-2-one
(180 mg,
0.8 mmol) was dissolved in dry acetone (10 mL) and was stirred with
K2CO2 (300 mg) and dimethyl sulfate (0.15 mL, 202 mg, 1.6 mmol) at RT
for 12 h. The mixture was diluted with Et2O (150 mL) and water
(150 mL), the layers were separated. The organic layer was dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (P/EA 50:50) to give 10 as a colorless oil
(175 mg, 0.74 mmol, 92%). Rf =0.20 (P/EA 50:50) [CAM]; 1H NMR
(250 MHz): d=1.17–1.36 (m, 1H), 1.41–1.55 (m, 9H), 2.14 (brs, 1H,
OH), 2.53 (s, 2H), 3.73 (s, 3H), 5.36 (d, J=2.1 Hz, 1H), 5.84 (d, J=
2.1 Hz, 1H); 13C NMR (62.9 MHz): d=21.9 (t), 25.3 (t), 37.4 (t), 46.3 (t),
55.7 (q), 71.1 (s), 87.7 (d), 102.5 (d), 162.3 (s), 164.8 (s), 171.0 (s); IR
(neat): n˜ =3432 (brs, OH), 2933, 2858 (vs, Csp3-H), 1698 (vs sh, C=O),
1643 (s), 1565 (vs), 1456 (s), 1411 (s), 1249 (vs), 1146 (s), 1035 (s),
984 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 238 (1) [M +], 140 (100), 125 (8),
81 (10); elemental analysis calcd (%) for C13H18O4 (238.28): C 65.53, H
7.61; found: C 65.81, H 7.75.
1-(2-Oxo-2-phenylethyl)cyclohexanol (12): A solution of nBuLi in hex-
anes (1.3m, 2 mmol, 1.6 mL) was added at ꢀ408C to a solution of 2-
phenyl-1,3-dithiane[15a] (392 mg, 2.0 mmol) in dry THF(6 mL). The re-
sulting solution was stirred for 2 h at ꢀ308C. Then the orange solution
was cooled to ꢀ788C.
A
solution of 1-oxaspiro[2.5]octane[47] (11)
(168 mg, 1.5 mmol) in THF(2 mL) was added slowly. The reaction mix-
ture was stirred for 1 h at ꢀ788C. Then the mixture was allowed to stand
for 2 d at ꢀ228C. The reaction was quenched by addition of sat. aqueous
NH4Cl (25 mL). The mixture was extracted with CH2Cl2 (2”50 mL). The
combined organic layers were washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 90:10) to
Chem. Eur. J. 2005, 11, 7007 – 7023
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7015

T. Bach and S. F. Kirsch
give 1-(2-phenyl-1,3-dithian-2-ylmethyl)-1-cyclohexanol as a colorless oil
(370 mg, 1.2 mmol, 80%). Rf =0.59 (P/EA 80:20) [CAM] [UV]; H NMR
(300 MHz): d=1.29–1.63 (m, 10H), 2.02–2.10 (m, 3H), 2.51 (s, 2H),
2.81–2.89 (m, 4H), 7.24–7.39 (m, 1H), 7.46–7.51 (m, 2H), 8.02–8.05 (m,
2H); 13C NMR (50.3 MHz): d=22.3 (t), 25.1 (t), 25.9 (t), 28.3 (t), 39.3 (t),
55.5 (t), 57.2 (s), 73.5 (s), 127.7 (d), 128.9 (d), 129.1 (s), 142.5 (d).
(360 MHz): d=1.30–1.89 (m, 10H), 2.57 (d, J=2.9 Hz, 2H), 3.37 (s, 3H),
3.51 (t, J=4.6 Hz, 2H), 3.72 (t, J=4.6 Hz, 2H), 4.87 (s, 2H), 9.84 (brs,
1H); 13C NMR (90.6 MHz): d=21.8 (t), 25.2 (t), 35.3 (t), 51.5 (t), 59.0
(q), 67.4 (t), 71.6 (t), 76.3 (s), 89.6 (t), 202.8 (d); IR (neat): n˜ =2932, 2863
(vs, Csp3-H), 1720 (vs, C=O), 1448 (w), 1104 (s), 1036 cmꢀ1 (vs sh); MS
(EI, 70 eV): m/z (%): 230 (1) [M +], 154 (12), 125 (20), 89 (95)
[CH2OCH2CH2OCH3+], 81 (63), 59 (100) [CH3OCH2CH2+]; elemental
analysis calcd (%) for C12H22O4 (230.30): C 62.58, H 9.63; found: C 61.46,
H 9.30.
1
A
solution
of
1-(2-phenyl-1,3-dithian-2-ylmethyl)-1-cyclohexanol
(40.0 mg, 0.13 mmol) in THF(2 mL) was added dropwise to a suspension
of red mercury(ii) oxide (56.3 mg, 0.26 mmol) and BF3·OEt2 (0.07 mL,
36.9 mg, 0.26 mmol) in aqueous THF(2 mL, 15% in water) at RT. The
mixture was stirred at RT for 30 min, diluted with Et2O (10 mL). The
layers were separated. The organic layer was washed with sat. aqueous
NaHCO3 (2”10 mL) and brine (20 mL), dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash chroma-
tography (P/EA 70:30) to give the known compound 12[48] as a colorless
oil (24.3 mg, 0.11 mmol, 86%). Rf =0.28 (P/EA 80:20) [CAM] [UV];
1H NMR (250 MHz, [D6]DMSO): d=1.23–1.78 (m, 10H), 3.04 (s, 2H),
3.35 (brs, 1H, OH), 7.45–7.60 (m, 3H), 7.96–8.00 (m, 2H); 13C NMR
(50.3 MHz, [D6]DMSO): d=21.9, 25.6, 37.8, 47.6, 70.7, 128.7, 128.8,
133.1, 138.6, 200.3.
2-[1-(2-Methoxyethoxymethoxy)cyclohexyl]-1-phenylethanone (16):
A
solution of phenylmagnesium bromide in Et2O (3m; 0.33 mL, 1.0 mmol)
at 08C was added to a solution of aldehyde 15 (200 mg, 0.86 mmol) in
THF(20 mL). The yellow solution was stirred for 1 h at 0 8C. The reac-
tion was quenched by addition of sat. aqueous NH4Cl (150 mL). The mix-
ture was extracted with Et2O (2”200 mL). The combined organic layers
were washed with water (150 mL) and brine (150 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (P/EA 50:50) to give 2-[1-(2-methoxyethox-
ymethoxy)cyclohexyl]-1-phenylethanol as
a
colorless oil (225 mg,
0.73 mmol, 85%). Rf =0.44 (P/EA 50:50) [CAM]; 1H NMR (360 MHz):
d=1.39–1.94 (m, 12H), 3.39 (s, 3H), 3.58 (t, J=4.5 Hz, 2H), 3.80 (t, J=
4.5 Hz, 2H), 4.27 (brs, 1H, OH), 4.92 (s, 2H), 5.02 (dd, J=7.7, 4.5 Hz,
1H), 7.23–7.34 (m, 5H); 13C NMR (90.6 MHz): d=22.6 (t), 25.4 (t), 33.7
(t), 35.5 (t), 58.9 (q), 67.4 (t), 70.5 (d), 71.6 (t), 79.3 (s), 89.1 (t), 125.6 (d),
127.0 (d), 128.2 (d), 142.2 (s).
1-Allylcyclohexanol (13): A solution of vinylmagnesium bromide in THF
(1.0m, 10 mmol, 10 mL) was added at RT to a solution of 1-oxaspiro-
[2.5]octane[47] (11) (1.12 g, 10 mmol) in dry THF(30 mL). The solution
was stirred for 1 h at RT. The reaction was quenched by addition of sat.
aqueous NH4Cl (50 mL) and diluted with water (100 mL). The mixture
was extracted with Et2O (250 mL). The layers were separated. The organ-
ic layer was washed with water (100 mL) and brine (150 mL), dried over
MgSO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (P/EA 80:20) to give 13 as a colorless oil
(1.15 g, 8.2 mmol, 82%). Rf =0.41 (P/EA 80:20) [CAM]. 1H NMR
(360 MHz): d=1.30–1.62 (m, 10H), 1.67 (s, 1H, OH), 2.12 (d, J=7.5 Hz,
2H), 4.98–5.06 (m, 2H), 5.74–5.86 (m, 1H); 13C NMR (90.6 MHz): d=
22.0 (t), 25.6 (t), 37.2 (t), 46.6 (t), 70.7 (s), 118.2 (t), 133.7 (d); IR (neat):
n˜ =3420 (brs, OH), 3077 (m, Csp2-H), 2928 (s, Csp3-H), 636 (s), 1460 (s),
971 (s), 932 cmꢀ1 (vs); MS (EI, 70 eV): m/z (%): 140 (1) [M +], 99 (100)
[M +ꢀC3H5], 81 (95), 55 (64), 41 (28); elemental analysis calcd (%) for
C9H16O (140.22): C 77.09, H 11.50; found: C 76.43, H 11.40.
To
a solution of 2-[1-(2-methoxyethoxymethoxy)cyclohexyl]-1-phenyl-
ethanol (120 mg, 0.39 mmol) in CH2Cl2 was added Dess–Martin periodi-
nane[11] (191 mg, 0.45 mmol) in one portion. The mixture was stirred at
08C. After 2 h, Et2O (100 mL) and sat. aqueous NaHCO3 (100 mL) con-
taining 5% Na2S2O3 were added. The mixture was stirred at RT until the
formation of two clear layers was observed (~30 min). The layers were
separated. The organic layer was washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 80:20) to
give 16 as a colorless oil (112 mg, 0.37 mmol, 94%). Rf =0.51 (P/EA
50:50) [CAM]; 1H NMR (360 MHz): d=1.23–1.88 (m, 10H), 3.22 (s,
3H), 3.30 (s, 2H), 3.41–3.44 (m, 2H), 3.64–3.66 (m, 2H), 4.82 (s, 2H),
7.39–7.53 (m, 3H), 7.92–7.94 (m, 2H); 13C NMR (90.6 MHz): d=22.0 (t),
25.4 (t), 34.9 (t), 46.5 (t), 58.9 (q), 67.2 (t), 71.8 (t), 77.1 (s), 89.8 (t), 128.3
1-(2-Methoxyethoxymethoxy)-1-allylcyclohexane (14):[16] Diisopropyl-
ethylamine (3.6 mL, 21 mmol) and MEM chloride (1.6 mL, 14 mmol)
were added at 08C to a solution of 13 (1.0 g, 7.1 mmol) in 1,2-dichloro-
ethane (20 mL). The solution was stirred for 15 h at RT. The reaction
was quenched by addition of sat. aqueous NaHCO3 (150 mL). The aque-
ous layer was extracted with Et2O (2”150 mL). The layers were separat-
ed. The combined organic layers were washed with water (200 mL) and
brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography (P/EA 90:10)
to give 14 as a colorless oil (1.33 g, 5.8 mmol, 82%). Rf =0.48 (P/EA
(d), 128.4 (d), 132.7 (d), 138.6 (s), 198.8 (s); IR (neat): n˜ =3059 (m, Csp3
-
H), 2930 (vs, Csp3-H), 1675 (vs, C=O), 1448 (vs), 1368 (m), 1208 (m), 1134
(s), 1100 (vs), 1040 (vs sh), 751 (s), 691 cmꢀ1 (vs); MS (EI, 70 eV): m/z
(%): 306 (1) [M +], 200 (50), 105 (100) [OCH2OCH2CH2OCH3+], 89 (91)
[CH2OCH2CH2OCH3+], 59 (94) [CH3OCH2CH2+]; elemental analysis
calcd (%) for C18H26O4 (306.40): C 70.56, H 8.55; found: C 70.66, H 8.55.
(1R,3S,5S)-1-(2-Hydroxyethyl)-5-triisopropysilyloxy-2-methylencyclohex-
ane-1,3-diol (19): A solution of (6R,7S,8S,10S)-7,8-epoxy-2,2,7-trimethyl-
1
10-triisopropylsilyloxy-1,3-dioxaspiro[5.5]undecane
(20)[24]
(1.74 g,
80:20) [CAM]; H NMR (360 MHz): d=1.19–1.71 (m, 10H), 2.27 (dt, J=
7.2, 1.2 Hz, 2H), 3.35 (s, 3H), 3.51 (t, J=5.0 Hz, 2H), 3.72 (t, J=5.0 Hz,
2H), 4.78 (s, 2H), 4.96–5.00 (m, 2H), 5.74–5.83 (m, 1H); 13C NMR
(90.6 MHz): d=22.0 (t), 25.6 (t), 34.8 (t), 42.9 (t), 58.9 (q), 67.2 (t), 71.8
(t), 77.1 (s), 89.4 (t), 117.2 (t), 134.2 (d); IR (neat): n˜ =3071 (m, Csp2-H),
2958, 2922 (vs, Csp3-H), 1470 (vs), 1055 cmꢀ1 (vs br); MS (EI, 70 eV): m/z
(%): 187 (5), 153 (7), 123 (15), 89 (100) [CH2OCH2CH2OCH3+], 81 (32),
59 (98) [CH3OCH2CH2+]; elemental analysis calcd (%) for C13H24O3
(228.33): C 68.38, H 10.59; found: C 68.38, H 10.50.
2-[1-(2-Methoxyethoxymethoxy)cyclohexyl]acetaldehyde (15):[38] Ether
14 (393 mg, 1.72 mmol) was dissolved in THF(10 mL) and water (10 mL)
at RT. To this mixture was added a solution of OsO4 in water (1%;
0.04 mL) and NaIO4 (0.95 g, 4.4 mmol) subsequently. The mixture was
stirred for 3 h at RT. The precipitate was filtered. The residue was
washed with Et2O (50 mL). The filtrate was diluted with Et2O (100 mL)
and water (100 mL). The layers were separated. The aqueous layer was
extracted with Et2O (2”100 mL). The combined organic layers were
washed with sat. aqueous NaHCO3 (200 mL) and brine (200 mL), dried
over Na2SO4, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography (P/EA 80:20) to give 15 as a colorless
oil (285 mg, 1.24 mmol, 72%). Rf =0.24 (P/EA 80:20) [CAM]; 1H NMR
4.5 mmol) in benzene (40 mL) was treated with DATMP [15 mmol; pre-
pared from 2,2,6,6-tetramethylpiperidine (15 mmol), a solution of n-bu-
tyllithium in hexane (2.5m, 15 mmol), a solution of Et2AlCl in toluene
(1.8m, 15 mmol) at 08C] for 45 min at 08C. The reaction was quenched
by addition of saturated aqueous NH4Cl (40 mL). The mixture was acidi-
fied with aqueous HCl (1n, 100 mL) and stirred for 1 h at room tempera-
ture. After dilution with diethyl ether (100 mL), the layers were separat-
ed and extracted with ethyl acetate (2”50 mL). The combined organic
layers were washed with water (100 mL) and brine (100 mL), dried
(Na2SO4), filtered and concentrated. Flash chromatography (CH/EA
50:50) gave triol 19 as a colorless solid (945 mg, 2.75 mmol, 61%). Rf =
0.13 (P/EA 50:50) [CAM]; m.p. 90–968C; [a]2D0 =ꢀ84.6 (c=0.23,
CH2Cl2); 1H NMR (360 MHz): d=1.06 (s, 21H), 1.78–2.01 (m, 5H), 2.21
(d, J=6.1 Hz, 1H), 2.27 (ddd, J=15.0, 5.9, 3.9 Hz, 1H), 2.41 (t, J=
4.6 Hz, 1H), 3.74 (s, 1H), 3.85–3.87 (m, 2H), 4.40 (virt. quint, J ffi 4.9 Hz,
1H), 4.43–4.49 (m, 1H), 5.17 (s, 1H), 5.19 (s, 1H); 13C NMR (90.6 MHz):
d=12.2 (d), 18.1 (q), 18.1 (q), 40.5 (t), 44.5 (t), 47.8 (t), 60.0 (t), 65.4 (d),
70.4 (d), 76.8 (s), 107.0 (t), 153.0 (s); IR (neat): n˜ =3286 (vs br, OH),
2942 (vs), 2866 (s), 1384 (m), 1098 (m), 1058 (s), 914 (m), 674 cmꢀ1 (m);
MS (EI, 70 eV): m/z (%): 301 (43) [M +ꢀiPr], 283 (56), 265 (30), 153
7016
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
(45), 135 (100), 107 (87), 103 (49), 81 (64), 75 (83), 59 (20), 43 (44) [iPr+
]; elemental analysis calcd (%) for C18H36O4Si (344.56): C 62.74, H 10.53;
found: C 62.52, H 10.46.
sept, J ffi 5.4 Hz, 1H); 13C NMR (90.6 MHz): d=ꢀ5.3 [q, (CH3)3CSi-
(CH3)2], ꢀ5.3 [q, (CH3)3CSi(CH3)2], 12.4 [d, Si(CH(CH3)2)3], 18.1 [q, Si-
(CH(CH3)2)3], 18.1 [q, Si(CH(CH3)2)3], 18.3 [s, (CH3)3CSi(CH3)2], 26.0 [s,
(CH3)3CSi(CH3)2], 27.5 (q), 31.0 (q), 36.5 (t), 43.0 (t), 47.5 (t), 48.5 (t),
58.2 (t), 59.6 (s), 65.7 (d), 73.3 (d), 73.8 (s), 97.7 (s); IR (neat): n˜ =2943
(vs), 2866 (s), 1464 (m), 1381 (m), 1369 (m), 1249 (s), 1113 (vs), 1046 (s),
1002 (s), 882 (s), 835 cmꢀ1 (vs); MS (EI, 70 eV): m/z (%): 499 (16) [M +
ꢀCH3], 369 (50), 267 (38), 237 (58), 135 (50), 73 (100); MS (CI): m/z
(%): 515 (40) [M+H+], 457 (100), 439 (80), 325 (29), 283 (65), 253 (20),
151 (40); HRMS of fragment [M +ꢀCH3]: m/z: calcd for C26H51O5Si2:
499.8511; found: 499.8509.
(3S,4R,6S,8S)-4-(2-tert-Butyldimethylsilyloxyethyl)-4,8-dihydroxy-6-(tri-
isopropyl)silyloxy-1-oxaspiro[2.5]octane (22): A solution of tert-butyldi-
methylsilyl chloride in toluene (2.9m; 0.69 mL, 2.0 mmol) at 08C was
added to
a solution of triol 19 (675 mg, 1.96 mmol) and imidazole
(170 mg, 2.5 mmol) in DMF(5 mL). The solution was stirred at RT for
15 h. The solution was diluted with water (150 mL) and Et2O (100 mL).
The layers were separated. The aqueous layer was extracted with Et2O
(2”50 mL). The combined organic layers were washed with water
(100 mL) and brine (150 mL), dried (Na2SO4), filtered and concentrated.
The crude product was purified by flash chromatography (P/EA 80:20)
to give diol 21 as a colorless oil (836 mg, 1.83 mmol, 93%). Rf =0.56 (P/
EA 80:20) [CAM]; 1H NMR (360 MHz): d=0.05 [s, 3H, (CH3)3CSi-
(CH3)2], 0.06 [s, 3H, (CH3)3CSi(CH3)2], 0.90 [s, 9H, (CH3)3CSi(CH3)2],
1.06 [s, 21H, SiCH(CH3)2], 1.72–1.89 (m, 4H), 1.99 (dt, J=12.7, 4.8 Hz,
1H), 2.25 (dt, J=15.2, 4.3 Hz, 1H), 2.40 (d, J=7.1 Hz, 1H, OH), 3.83
(virt. t, J ffi 5.9 Hz, 2H), 4.37–4.40 (m, 2H), 4.85 (s, 1H, OH), 5.17 (s,
2H); 13C NMR (90.6 MHz): d=ꢀ5.7 [q, (CH3)3CSi(CH3)2], ꢀ5.6 [q,
(CH3)3CSi(CH3)2], 12.3 [d, SiCH(CH3)2], 18.0 [q, SiCH(CH3)2], 18.1 [q,
SiCH(CH3)2], 18.1 [s, (CH3)3CSi(CH3)2], 25.8 [q, (CH3)3CSi(CH3)2], 40.0
(t), 44.9 (t), 47.1 (t), 60.9 (t), 65.9 (d), 69.8 (d), 76.5 (s), 106.3 (t), 153.4
(s).
(1R,3S,5S)-1-(2-tert-Butyldimethylsilyloxyethyl)-3-benzyloxy-5-triisopro-
pysilyloxy-2-methylencyclohexan-1-ol (24): Sodium hydride (60% in oil;
120 mg, 3 mmol) was added at 08C to a solution of diol 21 (1.26 g,
2.75 mmol) and benzyl bromide (0.36 mL, 513 mg, 3 mmol) in DMF
(15 mL). The mixture was stirred for 20 min at 08C and then warmed to
RT. After stirring for 1 h at RT, the mixture was diluted with Et2O
(150 mL) and water (200 mL). The layers were separated. The aqueous
layer was extracted with Et2O (3”50 mL). The combined organic layers
were washed with water (150 mL) and brine (150 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (P/EA 90:10) to give 24 as a yellow oil
(1.30 g, 2.37 mmol, 86%). Rf =0.62 (P/EA 90:10) [CAM]; [a]2D0 =ꢀ52.4
(c=0.25, CHCl3); 1H NMR (500 MHz): d=0.06 [s, 6H, (CH3)3CSi-
(CH3)2], 0.90 [s, 9H, (CH3)3CSi(CH3)2], 1.04 [s, 21H, SiCH(CH3)2], 1.67–
1.74 (m, 2H), 1.94 (ddd, J=14.9, 9.5, 5.1 Hz, 1H), 2.03 (dt, J=11.0,
2.8 Hz, 1H), 2.16 (dt, J=12.6, 4.4 Hz, 1H), 2.30 (dt, J=14.9, 3.5 Hz, 1H),
3.69–3.78 (m, 2H), 4.12 (dd, J=11.0, 4.4 Hz, 1H), 4.33–4.37 (m, 1H),
4.56 (d, J=12.0 Hz, 1H), 4.71 (d, J=12.0 Hz, 1H), 4.78 (s, 1H, OH), 5.32
(s, 1H), 5.38 (s, 1H), 7.25–7.34 (m, 5H); 13C NMR (90.6 MHz): d=ꢀ5.7
[q, (CH3)3CSi(CH3)2], ꢀ5.6 [q, (CH3)3CSi(CH3)2], 12.2 [d, SiCH(CH3)2],
18.1 [q, SiCH(CH3)2], 18.1 [q, SiCH(CH3)2], 18.1 [s, (CH3)3CSi(CH3)2],
25.8 [q, (CH3)3CSi(CH3)2], 40.7 (t), 42.5 (t), 47.3 (t), 60.9 (t), 66.4 (d),
71.2 (t), 74.7 (d), 76.3 (s), 106.5 (t), 127.5 (d), 127.5 (d), 128.4 (d), 138.6
(s), 151.3 (s); IR (neat): n˜ =3486 (brs, OH), 2943 (vs), 2866 (vs), 1463
(m), 1255 (s), 1051 (vs br), 911 (vs), 837 cmꢀ1 (vs); MS (EI, 70 eV): m/z
(%): 530 (1) [M +ꢀH2O], 397 (18), 383 (19), 209 (15), 91 (100) [C7H7+];
elemental analysis calcd (%) for C31H56O4Si2 (548.94): C 67.83, H 10.28;
found C 67.41, H 10.06.
3-Chloroperbenzoic acid (444 mg, 1.8 mmol) and NaHCO3 (210 mg,
2.5 mmol) were added at 08C to a solution of 21 (662 mg, 1.45 mmol) in
CH2Cl2 (10 mL). The mixture was stirred for 2 h at 08C. The mixture was
filtered and diluted with sat. aqueous NaHCO3 (20 mL) and CH2Cl2
(20 mL). The layers were separated. The aqueous layer was extracted
with CH2Cl2 (2”10 mL). The combined organic layers were washed with
sat. aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified by flash
chromatography (P/EA 80:20) to give 22 as a colorless oil (680 mg,
1.43 mmol, 99%; dr
> =
95:5). Rf =0.41 (P/EA 80:20) [CAM]; [a]D20
1
ꢀ32.9 (c=0.52, CHCl3); H NMR (500 MHz): d=0.03 [s, 6H, (CH3)3CSi-
(CH3)2], 0.84 [s, 9H, (CH3)3CSi(CH3)2], 1.04 [s, 21H, SiCH(CH3)2], 1.74
(virt. t, J ffi 12.9 Hz, 1H), 1.81–1.92 (m, 3H), 2.02 (dt, J=12.9, 4.7 Hz,
1H), 2.22 (virt. quint, J ffi 6.8 Hz, 1H, -OH), 3.00 (d, J=5.0 Hz, 1H),
3.03 (d, J=5.0 Hz, 1H), 3.79–3.89 (m, 2H), 4.03–4.08 (m, 1H, + OH),
4.32–4.34 (m, 2H); 13C NMR (90.6 MHz): d=ꢀ5.7 [q, (CH3)3CSi(CH3)2],
ꢀ5.6 [q, (CH3)3CSi(CH3)2], 12.2 [d, Si(CH(CH3)2)3], 17.9 [q, Si-
(CH(CH3)2)3], 18.0 [s, (CH3)3CSi(CH3)2], 18.1 [s, (CH3)3CSi(CH3)2], 25.7
[s, (CH3)3CSi(CH3)2], 38.8 (t), 41.4 (t), 44.1 (t), 47.2 (t), 59.9 (t), 64.3 (s),
65.7 (d), 65.7 (d), 72.5 (s); IR (neat): n˜ =3345 (vs br, OH), 2941 (vs),
2866 (s), 1386 (m), 1252 (m), 1095 (m), 1058 (s), 912 (m), 674 cmꢀ1 (m);
MS (EI, 70 eV): m/z (%): 431 (10) [M +ꢀC3H7], 399 (18), 299 (30), 255
(38), 151 (61), 105 (67), 75 (100) [C2H7SiO+]; MS (CI): m/z (%): 475
(48) [M+H+], 457 (66), 439 (27), 325 (100), 283 (52), 151 (25); elemental
analysis calcd (%) for C24H50O5Si2 (474.82): C 60.71, H 10.61; found: C
60.42, H 10.55.
(3S,4R,6S,8S)-4-(2-tert-Butyldimethylsilyloxyethyl)-8-benzyloxy-4-tri-
ethylsilyloxy-6-(triisopropyl)silyloxy-1-oxaspiro[2.5]octane (25): 3-Chlor-
operbenzoic acid (370 mg, 1.5 mmol) and NaHCO3 (210 mg, 2.5 mmol)
were added at 08C to a solution of 24 (554 mg, 1.01 mmol) in CH2Cl2
(10 mL). The mixture was stirred for 2 h at 08C. The mixture was filtered
and diluted with sat. aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL).
The layers were separated. The aqueous layer was extracted with CH2Cl2
(2”10 mL). The combined organic layers were washed with sat. aqueous
NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by flash chroma-
tography (P/EA 90:10) to give 18 as
a colorless oil in (536 mg,
0.95 mmol, 94%). The obtained product was dissolved in CH2Cl2
(10 mL). To this solution were added triethylamine (0.28 mL, 202 mg,
2 mmol) and triethylsilyl trifluoromethanesulfonate (0.34 mL, 396.5 mg,
1.5 mmol) at 08C. The reaction mixture was stirred for 2 h at 08C. The
mixture was diluted with Et2O (150 mL). The layers were separated. The
organic layer was washed with sat. aqueous NaHCO3 (100 mL) and brine
(100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 98:2) to give
25 as a colorless oil (631 mg, 0.93 mmol, 98%) which decomposed slowly
at RT. Rf =0.62 (P/EA 90:10) [CAM]; 1H NMR (500 MHz): d=0.00 [s,
3H, (CH3)3CSi(CH3)2], 0.01 [s, 3H, (CH3)3CSi(CH3)2], 0.55 [q, J=7.9 Hz,
6H, Si(CH2CH3)3], 0.86 [s, 9H, (CH3)3CSi(CH3)2], 0.92 [t, J=7.9 Hz, 9H,
Si(CH2CH3)3], 1.03 [s, 21H, SiCH(CH3)2], 1.83 (virt. td, J ffi 12.6, 2.9 Hz,
1H), 1.86 (ddd, J=14.5, 9.5, 4.7 Hz, 1H), 1.90 (dd, J=12.9, 3.8 Hz, 1H),
1.92 (virt. dt, J=12.9 Hz, J ffi 2.5 Hz, 1H), 2.09 (dddd, J=12.6, 4.4, 3.1,
2.5 Hz, 1H), 2.52 (ddd, J=14.5, 9.5, 6.3 Hz, 1H), 2.90 (d, J=6.3 Hz, 1H),
3.00 (d, J=6.3 Hz, 1H), 3.62–3.70 (m, 2H), 4.11 (dd, J=11.7, 4.4 Hz,
1H), 4.28 (virt. quin, J=3.1 Hz, 1H), 4.50 (s, 2H), 7.21–7.28 (m, 5H);
13C NMR (90.6 MHz): d=ꢀ5.3 [q, (CH3)3CSi(CH3)2], ꢀ5.2 [q, (CH3)3CSi-
(3S,4R,6S,8S)-4-(2-tert-Butyldimethylsilyloxyethyl)-4,8-(dimethyl)methy-
lendioxy-6-(triisopropyl)silyloxy-1-oxaspiro[2.5]octane (23): Molecular
sieves (4 ; 300 mg), 2-methoxypropene (1.00 mL, 757 mg, 10.5 mmol)
and a catalytic amount of PPTS (~15 mg) were added successively at RT
to a solution of diol 22 (500 mg, 1.05 mmol) in dry DMF(15 mL). The
mixture was stirred at RT for 14 h, filtered and diluted with Et2O
(150 mL) and sat. aqueous NaHCO3 (150 mL). The layers were separat-
ed. The aqueous layer was extracted with Et2O (2”50 mL). The com-
bined organic layers were washed with water (150 mL) and brine
(150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 90:10) to
give 23 as a colorless oil (368 mg, 0.71 mmol, 68%). Rf =0.68 (P/EA
80:20) [CAM]; [a]2D0 =ꢀ60.2 (c=0.20, CHCl3); 1H NMR (500 MHz): d=
0.02 [s, 6H, (CH3)3CSi(CH3)2], 0.86 [s, 9H, (CH3)3CSi(CH3)2], 1.05 [s,
21H, SiCH(CH3)2], 1.34 (s, 3H), 1.32–1.41 (m, 2H), 1.52–1.59 (m, 1H),
1.57 (s, 3H), 1.77 (ddd, J=13.7, 8.2, 5.4 Hz, 1H), 2.33–2.38 (m, 1H), 2.45
(ddd, J=12.9, 5.4, 2.2 Hz, 1H), 2.59 (d, J=4.3 Hz, 1H), 2.84 (d, J=
4.3 Hz, 1H), 3.67 (dd, J=4.1, 1.6 Hz, 1H), 3.73–3.82 (m, 2H), 4.51 (virt.
Chem. Eur. J. 2005, 11, 7007 – 7023
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7017

T. Bach and S. F. Kirsch
(CH3)2], 6.9 [t, Si(CH2CH3)3], 7.1 [q, Si(CH2CH3)3], 12.1 [d, SiCH-
(CH3)2], 18.1 [q, SiCH(CH3)2], 18.2 [q, SiCH(CH3)2], 18.3 [s, (CH3)3CSi-
(CH3)2], 25.9 [q, (CH3)3CSi(CH3)2], 37.3 (t), 44.4 (t), 44.5 (t), 46.4 (t),
59.0 (t), 63.7 (s), 66.5 (d), 70.1 (d), 72.0 (t), 74.1 (s), 127.5 (d), 127.6 (d),
128.3 (d), 138.4 (s).
(90.6 MHz): d=ꢀ5.2 (q, MeSiCH3), ꢀ5.1 (q, H3CSiMe), 18.1 [s, SiC-
(CH3)3], 19.1 [s, SiC(CH3)3], 25.7 [q, SiC(CH3)3], 27.0 [q, SiC(CH3)3],
40.8 (t), 44.1 (t), 48.5 (t), 63.2 (d), 63.8 (s), 65.9 (d), 72.5 (d), 127.6 (d),
127.7 (d), 129.6 (d), 129.7 (d), 134.2 (s), 134.3 (s), 135.7 (d), 135.7 (d); IR
(neat): n˜ =3444 (vs br, OH), 3071 (m, Csp2-H), 2929, 2857 (vs, Csp3-H),
1472 (m), 1428 (s), 1388 (m sh), 1250 (s), 1112 (vs sh), 1028 (vs), 940 (s),
886 (s), 837 (vs), 780 (s), 739 (vs), 702 cmꢀ1 (vs); MS (EI, 70 eV): m/z
(%): 497 (1) [M +ꢀCH3], 455 (8) [M +ꢀtBu], 437 (10), 313 (15), 271 (22),
209 (31), 199 (100), 135 (60), 125 (35), 75 (38).
2-{(1S,2S,3S,5S)-3-Benzyloxy-1-triethylsilyloxy-5-(triisopropyl)silyloxy-2-
hydroxy-2-[(2-phenyl-1,3-dithian-2-yl)methyl]cyclohexyl}acetaldehyde
(27): A solution of nBuLi in hexanes (2.5m, 1.36 mL, 3.4 mmol) at
ꢀ408C was added to a solution of 2-phenyl-1,3-dithiane[15a] (654 mg,
3.33 mmol) in dry THF(40 mL). The resulting orange solution was stir-
red for 2 h at ꢀ408C. A solution of epoxide 25 (1.25 g, 1.85 mmol) in
THF(30 mL) was added slowly. The reaction mixture was stirred for 6 h
at ꢀ408C. Then the mixture was allowed to warm to RT and stirring was
continued for 30 min. The reaction was quenched by addition of sat.
aqueous NH4Cl (100 mL). The mixture was extracted with Et2O (2”
80 mL). The combined organic layers were washed with water (100 mL)
and brine (100 mL), dried over Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography (P/EA
99:1) to give 17 as a colorless oil (1.51 g, 1.72 mmol, 93%). Dithiane 17
could not be completely separated from the excess of 2-phenyl-1,3-di-
thiane and was directly used in the next step. To a solution of dithiane 17
in THF(20 mL) was added pyridine (20 mL) and HF·py (3 mL) at 0 8C
subsequently. The solution was stirred at 08C for 5 h. The reaction was
quenched by addition of sat. aqueous NaHCO3 (200 mL) (caution: gas
evolution). After stirring for 30 min at RT, Et2O (100 mL) was added and
the layers were separated. The aqueous layer was extracted with Et2O
(2”80 mL). The combined organic layers were washed with water
(150 mL) and brine (150 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. The crude product was purified by flash chromatography
(P/EA 85:15) to give the primary alcohol 26 (524 mg, 0.69 mmol, 40%)
which was directly used in the next step.
(3R,4R,6R,8R)-8-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenylsilyl-
oxy)-4-(trimethylsilyloxy)-1-oxaspiro[2.5]octane (34): Trimethylsilyl chlo-
ride (1.3 mL, 1.09 g, 10 mmol) was added at 08C to a solution of triol 30
(4.8 g, 9.4 mmol) and imidazole (884 mg, 13 mmol) in DMF(15 mL). The
solution was stirred at RT for 3 h. The solution was diluted with water
(200 mL) and Et2O (200 mL). The layers were separated. The aqueous
layer was extracted with Et2O (2”100 mL). The combined organic layers
were washed with water (200 mL) and brine (200 mL), dried (MgSO4),
filtered and concentrated. The crude product was purified by flash chro-
matography (P/EA 98:2) to give 34 as a colorless oil (5.4 g, 9.3 mmol,
99%). Rf =0.70 (P/EA 98:2) [CAM]; [a]2D0 =ꢀ33.7 (c=1.49, CHCl3);
1H NMR (360 MHz): d=ꢀ0.06 (s, 3H, MeSiCH3), ꢀ0.05 (s, 3H,
H3CSiMe), ꢀ0.02 [s, 9H, Si(CH3)3], 0.81 [s, 9H, SiC(CH3)3], 1.07 [s, 9H,
SiC(CH3)3], 1.50–1.62 (m, 2H), 1.95 (dddd, J=11.9, 5.5, 4.8, 1.4 Hz, 1H),
2.10–2.17 (m, 1H), 2.36 (d, J=5.7 Hz, 1H), 2.95 (d, J=5.7 Hz, 1H), 3.41
(dd, J=3.6, 2.3 Hz, 1H), 3.99 (dd, J=11.6, 4.8 Hz, 1H), 4.27 (virt. tt, J ffi
10.9 Hz,
J
ffi
4.7 Hz, 1H), 7.35–7.44 (m, 6H), 7.66–7.69 (m, 4H);
13C NMR (90.6 MHz): d=ꢀ5.2 (q, MeSiCH3), ꢀ5.1 (q, H3CSiMe), 0.0 [q,
Si(CH3)3], 18.1 [s, SiC(CH3)3], 19.1 [s, SiC(CH3)3], 25.7 [q, SiC(CH3)3],
27.0 [q, SiC(CH3)3], 42.7 (t), 44.3 (t), 47.1 (t), 63.2 (d), 63.4 (s), 66.2 (d),
73.0 (d), 127.5 (d), 127.5 (d), 129.6 (d), 129.6 (d), 134.4 (s), 134.5 (s),
135.7 (d), 135.8 (d); IR (neat): n˜ =3073 (m, Csp2-H), 2974, 2879 (vs, Csp3
-
H), 1436 (m), 1378(vs), 1267 (m), 1252 (m), 1193 (s), 1162 (s), 1101 (vs),
1050 (s), 979 (vs), 889 (vs), 812 cmꢀ1 (vs); MS (EI, 70 eV): m/z (%): 237
(32), 177 (43), 135 (30), 119 (50), 97 (30), 68 (45), 43 (100); elemental
analysis calcd (%) for C32H52O4Si3 (585.01): C 65.70, H 8.96; found: C
65.40, H 8.64.
To a solution of 26 (524 mg, 0.69 mmol) in CH2Cl2 (15 mL) were added
anhydrous sodium acetate (164 mg, 2 mmol) and pyridinium chlorochro-
mate (323 mg, 1.5 mmol) at RT. After stirring for 60 min at RT, the mix-
ture was filtered and concentrated. The residue was purified by flash
chromatography (P/EA 90:10) to give the aldehyde 27 as a yellow oil
(340 mg, 0.45 mmol, 65%). Rf =0.71 (P/EA 90:10) [CAM]; [a]2D0 =ꢀ32.6
(c=0.78, CHCl3); 1H NMR (360 MHz): d=0.49 [q, J=7.9 Hz, 6 H], 0.79
[t, J=7.9 Hz, 9 H], 0.96 [s, 21 H], 0.94–1.03 (m, 1H), 1.59 (dd, J=13.7,
9.8 Hz, 1H), 1.83–1.99 (m, 3H), 2.02 (dd, J=9.8, 2.5 Hz, 1H), 2.20 (d, J=
15.0 Hz, 1H), 2.41 (d, J=15.0 Hz, 1H), 2.50 (dd, J=15.0, 4.0 Hz, 1H),
2.55 (d, J=15.0 Hz, 1H), 2.61–2.71 (m, 3H), 2.75–2.78 (m, 1H), 3.73
(brs, 1H, OH), 3.89–3.92 (m, 1H), 4.20 (virt. sept, J ffi 4.8 Hz, 1H), 4.32
(d, J=11.4 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 7.16–7.29 (m, 8H), 7.88 (d,
J=7.5 Hz, 2H), 9.86 (virt. d, J ffi 4.0 Hz, 1H); 13C NMR (90.6 MHz): d=
6.9 [t, Si(CH2CH3)3], 7.1 [q, Si(CH2CH3)3], 12.3 [d, SiCH(CH3)2], 18.1 [q,
SiCH(CH3)2], 18.1 [q, SiCH(CH3)2], 24.6 (t), 28.0 (t), 28.1 (t), 35.3 (t),
45.0 (t), 48.0 (t), 52.9 (t), 57.9 (s), 63.9 (d), 73.3 (t), 77.2 (s), 78.4 (d), 82.0
(s), 126.9 (d), 127.7 (d), 128.1 (d), 128.5 (d), 128.9 (d), 129.3 (d), 138.3 (s),
142.6 (s), 201.7 (d); IR (neat): n˜ =3504 (s sh, OH), 2944 (vs), 2862 (vs),
1715 (vs, C=O), 1455 (m), 1097 (s), 909 (s), 734 cmꢀ1 (vs); MS (EI,
70 eV): m/z (%): 758 (9) [M +], 715 (4) [M +ꢀiPr], 607 (8), 385 (28), 195
(100) [C10H11S2+], 91 (92) [C7H7+].
(1R,2R,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphenylsilyl-
oxy)-1-[(2-phenyl-1,3-dithian-2-yl)methyl]-6-(trimethylsilyloxy)-cyclohex-
an-1-ol (35): A solution of nBuLi in hexanes (2.5m, 1.80 mL, 4.5 mmol)
was added at ꢀ408C to a solution of 2-phenyl-1,3-dithiane[15a] (882 mg,
4.5 mmol) in dry THF(20 mL). The resulting orange solution was stirred
for 2 h at ꢀ408C. Then the orange solution was cooled to ꢀ788C. A solu-
tion of 34 (1.75 g, 3 mmol) in THF(20 mL) was added slowly. The reac-
tion mixture was stirred for 1 h at ꢀ788C. Then the mixture was allowed
to warm to ꢀ458C over 45 min. The reaction was quenched by addition
of sat. aqueous NH4Cl (100 mL). The mixture was extracted with Et2O
(3”100 mL). The combined organic layers were washed with brine
(200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 98:2) to give
35 as a colorless oil (90%, 2.11 g, 2.7 mmol). Rf =0.58 (P/EA 98:2)
[CAM]; [a]2D0 =ꢀ38.5 (c=1.26, CHCl3); 1H NMR (360 MHz): d = ꢀ0.18
[s, 9H, Si(CH3)3], ꢀ0.15 (s, 3H, MeSiCH3), ꢀ0.06 (s, 3H, H3CSiMe), 0.81
[s, 9H, SiC(CH3)3], 1.01 [s, 9H, SiC(CH3)3], 1.35–1.45 (m, 2H), 1.52–1.55
(m, 1H), 1.70–1.74 (m, 1H), 1.84–1.95 (m, 2H), 2.05 (s, 1H, OH), 2.23
(d, J=15.4 Hz, 1H), 2.60–2.81 (m, 4H), 2.89 (d, J=15.4 Hz, 1H), 3.42
(dd, J=12.3, 4.5 Hz, 1H), 3.61 (brs, 1H), 3.89–3.97 (m, 1H), 7.19–7.37
(m, 9H), 7.56–7.64 (m, 4H), 7.93–7.95 (m, 2H); 13C NMR (90.6 MHz):
d=ꢀ4.8 (q, MeSiCH3), ꢀ4.6 (q, H3CSiMe), 0.1 [q, Si(CH3)3], 18.1 [s, SiC-
(CH3)3], 19.0 [s, SiC(CH3)3], 24.9 (t), 25.9 [q, SiC(CH3)3], 26.9 [q, SiC-
(CH3)3], 27.9 (t), 28.0 (t), 38.8 (t), 41.3 (t), 42.9 (t), 57.6 (s), 66.0 (d), 71.5
(d), 72.6 (d), 77.1 (s), 126.7 (d), 127.5 (d), 127.5 (d), 128.2 (d), 128.9 (d),
129.5 (d), 129.5 (d), 134.4 (s), 134.5 (s), 135.7 (d), 135.7 (d), 142.4 (s); IR
(neat): n˜ =3564 (m sh, OH), 3070 (m, Csp2-H), 2953, 2856 (vs, Csp3-H),
1484 (m), 1428 (m), 1251 (s), 1075 (vs br), 927 (s), 838 (s sh), 777 (m),
740 (m), 701 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 780 (10) [M +], 723 (90)
[M +ꢀtBu], 633 (18), 513 (70), 397 (12), 195 (100), 135 (63), 73 (92); ele-
mental analysis calcd (%) for C42H64O4S2Si3 (781.34): C 64.56, H 8.26;
found: C 64.56, H 8.25.
(3R,4R,6R,8R)-8-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenylsilyl-
oxy)-1-oxaspiro[2.5]octan-4-ol (29): VO(acac)2 (67 mg, 0.25 mmol) and a
solution of tert-butylhydroperoxide in decane (5m; 3.4 mL, 17.2 mmol)
was added at 08C to a solution of 30[28] (4.3 g, 8.6 mmol) in CH2Cl2
(25 mL). The dark red solution was stirred for 15 h at RT. After addition
of dimethylsulfide (0.5 mL), the mixture was stirred for additional 10 min
at RT, then concentrated in vacuo. The crude product was purified by
flash chromatography (P/EA 90:10) to give 29 as sole diastereoisomer
(3.92 g, 7.56 mmol, 89%; dr
> 95:5). Rf =0.28 (P/EA 90:10) [CAM];
[a]2D0 =ꢀ17.2 (c=0.50, CHCl3); 1H NMR (500 MHz): d=ꢀ0.11 (s, 3H,
MeSiCH3), ꢀ0.09 (s, 3H, H3CSiMe), 0.77 [s, 9H, SiC(CH3)3], 1.06 [s, 9H,
SiC(CH3)3], 1.50 (virt. q, J ffi 11.7 Hz, 1H), 1.63–1.68 (m, 1H), 1.99–2.03
(m, 1H, +OH), 2.16–2.20 (m, 1H), 2.46 (d, J=5.4 Hz, 1H), 3.04 (d, J=
5.4 Hz, 1H), 3.48 (brs, 1H), 3.95 (dd, J=11.7, 4.7 Hz, 1H), 4.19–4.27 (m,
1H), 7.34–7.42 (m, 6H), 7.67 (virt. t,
J
ffi
8.2 Hz, 4H); 13C NMR
7018
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
(1R,2R,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphenylsilyl-
oxy)-1-[(2-phenyl-1,3-dithian-2-yl)methyl]-cyclohexan-1,6-diol (36): Di-
thiane 35 (1.05 g, 1.35 mmol) was dissolved in a mixture of THF(21 mL),
water (7 mL) and acetic acid (7 mL). The mixture was stirred at RT for
14 h. To this mixture was added water (300 mL) and Et2O (300 mL). The
layers were separated; the organic layer was carefully washed with sat.
aqueous NaHCO3 (2”200 mL) and brine (150 mL), dried over MgSO4,
filtered and concentrated in vacuo. The crude product was purified by
flash chromatography (P/EA 90:10) to give 36 as a colorless oil (768 mg,
1.11 mmol, 82%). Due to the instability of the compound, an analytical
sample was not obtained. Rf =0.29 (P/EA 90:10) [CAM]; 13C NMR
(90.6 MHz): d=ꢀ4.7 (q, MeSiCH3), ꢀ4.6 (q, H3CSiMe), 18.0 [s, SiC-
(CH3)3], 19.1 [s, SiC(CH3)3], 24.5 (t, SCH2CH2CH2S), 25.9 [q, SiC(CH3)3],
27.0 [q, SiC(CH3)3], 27.7 (t), 28.1 (t), 36.9 (t), 40.7 (t), 42.4 (t), 57.4 (s),
65.8 (d), 71.1 (d), 71.6 (d), 77.2 (s), 127.3 (d), 127.3 (d), 127.5 (d), 128.6
(d), 128.7 (d), 129.5 (d), 129.5 (d), 134.2 (s), 134.5 (s), 135.7 (d), 135.7 (d),
142.1 (s).
(8) [M +ꢀtBu], 465 (22), 405 (22), 327 (18), 267 (25), 209 (42), 199 (96),
135 (100), 107 (32), 73 (88); elemental analysis calcd (%) for C31H48O4Si2
(540.88): C 68.84, H 8.94; found: C 68.94, H 9.06.
Diol 37 was obtained as major product (75 mg, 0.14 mmol, 48%). Rf =
0.24 (P/EA 80:20) [CAM]; 1H NMR (500 MHz): d=ꢀ0.11 (s, 3H,
MeSiCH3), ꢀ0.07 (s, 3H, H3CSiMe), 0.81 [s, 9H, SiC(CH3)3], 1.04 [s, 9H,
SiC(CH3)3], 1.56 (brs, 1H, OH), 1.60 (dd, J=14.2, 9.2 Hz, 1H), 1.78–1.82
(m, 1H), 1.83–1.87 (m, 1H), 1.91–1.97 (m, 1H), 2.04 (virt. dt, J ffi
14.2 Hz, J ffi 3.5 Hz, 1H), 2.08 (dd, J=14.2, 3.5 Hz, 1H), 2.69 (brs, 1H,
OH), 3.47 (dd, J=9.8, 3.5 Hz, 1H), 4.00 (brs, 1H), 4.13–4.16 (m, 1H),
5.15 (d, J=10.8 Hz, 1H), 5.32 (d, J=17.3 Hz, 1H), 6.09 (dd, J=17.3,
10.8 Hz, 1H), 7.34–7.42 (m, 6H), 7.63–7.66 (m, 4H); 13C NMR
(90.6 MHz): d=ꢀ5.0 (q, MeSiCH3), ꢀ4.3 (q, H3CSiMe), 17.9 [s, SiC-
(CH3)3], 19.1 [s, SiC(CH3)3], 25.8 [q, SiC(CH3)3], 27.0 [q, SiC(CH3)3],
43.0 (t), 43.8 (t), 45.3 (t), 65.6 (d), 66.6 (d), 75.9 (d), 76.3 (s), 114.2 (t),
127.6 (d), 127.7 (d), 129.6 (d), 129.7 (d), 134.2 (s), 134.2 (s), 135.8 (d),
135.9 (d), 140.3 (d).
(2S,3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxy)-2-
(1R,2S,4S,6S)-1-Allyl-2-(tert-butyldimethylsilyloxy)-4-(tert-butyldiphenyl-
silyloxy)-6-trimethylsilyloxycyclohexanol (46): A stirred solution of 43[28]
(5.0 g, 8.8 mmol) in THF(150 mL) was cooled to ꢀ208C and allylmagne-
sium chloride (1m in Et2O; 13.2 mL, 13.2 mmol) was added dropwise.
The clear solution was stirred for 1 h at ꢀ788C. The reaction was
quenched by the addition of saturated aqueous NH4Cl solution (300 mL),
and allowed to warm to ambient temperature. The mixture was diluted
with Et2O (300 mL). After separation, the aqueous layer was extracted
with Et2O (2”200 mL). The organic extracts were combined, washed
with water (400 mL) and brine (300 mL), dried (Na2SO4), filtered, and
concentrated to give the crude product (dr 90:10, determined by
1H NMR) as a yellow oil. The residue was purified by flash chromatogra-
phy (P/EA 98:2) to yield 46 and its epimer as inseparable mixture of dia-
stereoisomers (5.4 g, 8.8 mmol, quant.; dr 90:10, determined by
[(2-phenyl-1,3-dithian-2-yl)methyl]-2-hydroxycyclohexan-1-one
(28):[30]
DMSO (3 mL), pyridine (0.04 mL, 41 mg, 0.53 mmol), trifluoroacetic acid
(15 mL, 24 mg, 0.21 mmol) and dicyclohexylcarbodiimide (289 mg,
1.4 mmol) were added successively to a stirred solution of alcohol 36
(250 mg, 0.35 mmol) in benzene (3 mL). The mixture was stirred for 1 d
at RT and filtered. The filtrate was diluted with Et2O (20 mL) and water
(20 mL). The layers were separated. The organic layer was washed with
brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography (P/EA 95:5) to
give 28 as a colorless oil (228 mg, 0.322 mmol, 92%). Rf =0.49 (P/EA
90:10) [CAM]; [a]2D0 =ꢀ61.8 (c=1.21, CHCl3); 1H NMR (360 MHz): d=
ꢀ0.17 (s, 3H, MeSiCH3), ꢀ0.03 (s, 3H, H3CSiMe), 0.82 [s, 9H, SiC-
(CH3)3], 1.03 [s, 9H, SiC(CH3)3], 1.72–1.99 (m, 4H), 2.31 (ddd, J=12.5,
5.2, 2.0 Hz, 1H), 2.44 (virt. t, J ffi 12.5 Hz, 1H), 2.59–2.75 (m, 5H), 2.95
(dd, J=11.6, 5.2 Hz, 1H), 3.13 (d, J=15.4 Hz, 1H), 3.46–3.57 (m, 1H),
3.52 (s, 1H, OH), 7.19–7.39 (m, 9H), 7.51–7.59 (m, 4H), 7.83–7.86 (m,
2H); 13C NMR (90.6 MHz): d=ꢀ5.3 (q, MeSiCH3), ꢀ4.7 (q, H3CSiMe),
18.1 [s, SiC(CH3)3], 19.0 [s, SiC(CH3)3], 24.7 (t, SCH2CH2CH2S), 25.8 [q,
SiC(CH3)3], 26.8 [q, SiC(CH3)3], 27.7 (t), 28.2 (t), 41.5 (t), 46.0 (t), 47.6
(t), 57.0 (s), 66.3 (d), 75.8 (d), 83.2 (s), 127.4 (d), 127.7 (d), 127.7 (d),
128.4 (d), 129.7 (d), 129.9 (d), 129.9 (d), 133.3 (s), 133.5 (s), 135.6 (d),
1H NMR); Rf =0.65 (P/EA 90:10); [a]2D0
= 10.5 (c=0.94, CHCl3);
1H NMR (360 MHz): d=ꢀ0.11 (s, 3H), ꢀ0.06 (s, 12H), 0.85 (s, 9H), 1.05
(s, 9H), 1.63–1.78 (m, 2H), 1.83 (virt d, J ffi 13.1 Hz, 1H), 1.97 (virt dt, J
ffi 1.9 Hz, J ffi 13.1 Hz, 1H), 2.06 (s, 1H, OH), 2.21 (dd, J=14.2, 8.0 Hz,
1H), 2.38 (dd, J=14.2, 6.2 Hz, 1H), 3.49 (dd, J=10.7, 5.4 Hz, 1H), 3.86
(virt. s, 1H), 3.98 (virt. sept, J ffi 6.0 Hz 1H), 5.02–5.09 (m, 2H), 5.84–
5.95 (m, 1H), 7.34–7.40 (m, 6H), 7.63–7.69 (m, 4H); 13C NMR
(90.6 MHz): d=ꢀ5.0 (q), ꢀ4.2 (q), 0.28 (q), 17.9 (s), 19.1 (s), 25.8 (q),
26.9 (q), 37.7 (t), 39.2 (t), 40.1 (t), 65.8 (d), 70.9 (d), 71.0 (d), 74.0 (s),
117.6 (t), 127.5 (d), 127.5 (d), 129.5 (d), 129.6 (d), 134.2 (s), 134.3 (s),
134.6 (d), 135.8 (d); IR (neat): n˜ =3572 (m, sh), 3072 (m), 2954, 2856 (s),
1471 (s), 1428 (s), 1379 (m), 1361 (m), 1251 (s), 1068 (s, br), 941 (s), 838
(s), 776 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 571 (5) [M +ꢀC3H5], 465
(50), 339 (52), 209 (48), 135 (65), 73 (100); elemental analysis calcd (%)
for C34H56O4Si3 (612.349): C 66.61, H 9.21; found: C 66.27, H 9.17.
135.6 (d), 140.9 (s), 208.1 (s); IR (neat): n˜ =3478 (m, OH), 3071 (w, Csp2
-
H), 2953, 2857 (vs, Csp3-H), 1712 (s, C=O), 1471 (m), 1428 (m), 1250 (m),
1105 (vs sh), 909 (s), 837 (s), 824 (s), 734 (vs), 702 cmꢀ1 (vs); MS (EI,
70 eV): m/z (%): 706 (8) [M +], 649 (10) [M +ꢀtBu], 255 (22), 209 (84),
195 (100), 135 (25), 103 (28); elemental analysis calcd (%) for
C39H54O4S2Si2 (707.15): C 66.24, H 7.70; found: C 66.39, H 7.80.
(1R,2R,4R,6R)-1-Allyl-2-(tert-butyldimethylsilyloxy)-4-(tert-butyldiphe-
nylsilyloxy)-cyclohexan-1,6-diol (38): A solution of vinylmagnesium bro-
mide in THF(1.0 m, 1 mmol, 1 mL) was added at RT to a solution of 34
(150 mg, 0.29 mmol) in dry THF(5 mL). The solution was stirred for
12 h at RT. The reaction was quenched by addition of sat. aqueous
NH4Cl (20 mL) and diluted with Et2O (20 mL). The layers were separat-
ed. The organic layer was washed with water (10 mL) and brine (10 mL),
dried over Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (P/EA 90:10) to give 38 as a color-
less oil (34.5 mg, 0.064 mmol, 22%). Rf =0.30 (P/EA 90:10) [CAM];
[a]2D0 =ꢀ5.0 (c=0.31, CHCl3); 1H NMR (360 MHz): d=ꢀ0.13 (s, 3H,
MeSiCH3), ꢀ0.07 (s, 3H, H3CSiMe), 0.83 [s, 9H, SiC(CH3)3], 1.06 [8s,
9H, SiC(CH3)3], 1.49 (virt. q, J ffi 11.6 Hz, 1H), 1.58–1.64 (m, 1H), 1.74–
1.82 (m, 1H), 2.06–2.11 (m, 1H), 2.12 (s, 1H, OH), 2.21 (dd, J=14.8,
8.8 Hz, 1H), 2.36 (brs, 1H, OH), 2.57 (dd, J=14.8, 6.1 Hz, 1H), 3.72 (dd,
J=12.2, 4.5 Hz, 1H), 3.79 (virt. t, J ffi 3.0 Hz, 1H), 4.15 (virt. septett, J ffi
4.9 Hz, 1H), 5.04–5.12 (m, 2H), 5.80–5.91 (m, 1H), 7.34–7.40 (m, 6H),
7.63–7.69 (m, 4H); 13C NMR (90.6 MHz): d=ꢀ5.0 (q, MeSiCH3), ꢀ4.5
(q, H3CSiMe), 17.9 [s, SiC(CH3)3], 19.1 [s, SiC(CH3)3], 25.8 [q, SiC-
(CH3)3], 27.0 [q, SiC(CH3)3], 35.7 (t), 36.9 (t), 40.9 (t), 62.2 (d), 70.9 (d),
71.4 (d), 75.9 (s), 118.3 (t), 127.6 (d), 127.6 (d), 129.6 (d), 129.7 (d), 133.7
(d), 134.2 (s), 134.5 (s), 135.7 (d), 135.7 (d); IR (neat): n˜ =3563 (brs,
OH), 3072 (m, Csp2-H), 2932 (s, Csp3-H), 1471 (s), 1428 (s), 1385 (m), 1254
(m), 1112 cmꢀ1 (s br); MS (EI, 70 eV): m/z (%): 499 (4) [M +ꢀC3H5], 483
(1R,2S,4S,6S)-1-Allyl-1-(2-methoxyethoxymethoxy)-2-(tert-butyldime-
thylsilyloxy)-4-(tert-butyldiphenylsilyloxy)-6-trimethylsilyloxycyclohexane
(45): A solution of tertiary alcohol 46 (5.4 g, 8.8 mmol) in 1,2-dichloro-
ethane (40 mL) was treated with N,N-diisopropylethylamine (2.3 mL,
1.7 g, 13.2 mmol) and MEMCl (1.0 mL, 1.0 g, 8.8 mmol) at 08C. After
stirring for 4 h at 708C, N,N-diisopropylethylamine (2.3 mL, 1.7 g,
13.2 mmol) and MEMCl (1.0 mL, 1.0 g, 8.8 mmol) were added to the
orange-colored solution. The reaction mixture was stirred for additional
4 h at 708C, cooled to room temperature, and diluted with CH2Cl2
(100 mL) and saturated aqueous NH4Cl solution (100 mL). The aqueous
layer was extracted with CH2Cl2 (100 mL), the combined organic layers
were washed with water (100 mL) and brine (100 mL), dried (Na2SO4),
filtered, and concentrated. Purification by flash chromatography (P/EA
98:2) gave 45 (4.9 g, 7.0 mmol, 80%) as a yellow oil. Rf =0.47 (P/EA
90:10); [a]2D0 = 6.8 (c=1.10, CHCl3); 1H NMR (500 MHz): d=ꢀ0.15 (s,
3H), ꢀ0.08 (s, 3H), ꢀ0.07 (s, 9H), 0.84 (s, 9H), 1.06 (s, 9H), 1.73 (virt.
dt, J ffi 11.8, 4.6 Hz, 1H), 1.75–1.86 (m, 2H), 2.04 (virt. dt, J ffi 2.2,
11.1 Hz, 1H), 2.13 (dd, J=15.5, 7.9 Hz, 1H), 2.80 (dd, J=15.5, 6.0 Hz,
1H), 3.44 (s, 3H), 3.52 (dd, J=12.0, 4.6 Hz, 1H), 3.62 (t, J=5.4 Hz, 2H),
3.74–3.86 (m, 3H), 3.97 (virt. sept, J ffi 4.6 Hz, 1H), 5.03–5.13 (m, 4H),
5.86–5.95 (m, 1H), 7.34–7.40 (m, 6H), 7.61–7.69 (m, 4H); 13C NMR
(90.6 MHz): d=ꢀ5.3 (q), ꢀ4.6 (q), 0.27 (q), 17.8 (s), 19.1 (s), 25.7 (q),
Chem. Eur. J. 2005, 11, 7007 – 7023
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7019

T. Bach and S. F. Kirsch
26.9 (q), 32.7 (t), 37.5 (t), 40.1 (t), 59.0 (q), 66.6 (d), 67.6 (t), 71.1 (d, C2),
71.6 (d, C4), 71.8 (t), 78.9 (s, C1), 90.8 (t), 117.5 (t), 127.4 (d), 127.5 (d),
129.4 (d), 129.5 (d), 133.6 (d), 134.3 (s), 134.7 (s), 135.7 (d); IR (neat):
n˜ =3072 (m), 2955, 2893, 2857 (s), 1472 (s), 1427 (s), 1379 (m), 1361 (m),
1251 (vs), 1112 (vs), 1070 (vs, br), 1024 (vs), 914 (s), 838 cmꢀ1 (s); MS
(EI, 70 eV): m/z (%): 443 (6) [M +ꢀtBu], 553 (5), 463 (9), 369 (20), 339
(30), 257 (64), 213 (18), 133 (100), 89 (54), 59 (48) [CH3OCH2CH2+]; ele-
mental analysis calcd (%) for C38H64O6Si3 (700.401): C 65.09, H 9.20;
found: C 65.13, H 9.21.
one (334 mg, 2.65 mmol) was dissolved in THF(60 mL). The solution
was cooled to ꢀ788C, and
a solution of tBuLi in pentane (1.5m;
5.83 mmol, 3.89 mL) was added dropwise. After stirring the orange solu-
tion for 15 min at ꢀ788C, the mixture was warmed to 08C. The dark red
solution was stirred for 20 min at 08C, then cooled to ꢀ788C. A solution
of 48 (665 mg, 1.06 mmol) in THF(10 mL) was added dropwise. The re-
action mixture was stirred for 2 d at ꢀ788C. The reaction was quenched
by addition of sat. aqueous NH4Cl (100 mL). The mixture was acidified
with aqueous H2SO4 (10%) to pH 2. After addition of Et2O (200 mL)
and water (200 mL), the layers were separated. The aqueous layer was
extracted with Et2O (2”150 mL). The combined organic layers were
washed with water (200 mL) and brine (200 mL), dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified by flash
chromatography (P/EA 30:70) to give the title compound as a yellow oil
(510 mg, 0.68 mmol, 64%; dr 93:7; 82% based on recovered starting ma-
terial). The starting material 48 was recovered as a pure compound
(144 mg, 0.23 mmol). The product 49 showed limited stability at RT and
was directly methylated. Rf =0.13 (P/EA 60:40) [CAM]; [a]2D0 = 13.5 (c=
0.22, MeOH); 1H NMR (360 MHz): d=ꢀ0.06 (s, 3H, MeSiCH3), ꢀ0.05
(s, 3H, H3CSiMe), 0.84 [s, 9H, SiC(CH3)3], 1.03 [s, 9H, SiC(CH3)3], 1.46
(dd, J=12.9, 4.5 Hz, 1H), 1.75–1.88 (m, 3 H + OH), 2.08 (brs, 1H, OH),
2.55 (dd, J=14.7, 9.5 Hz, 1H), 2.79 (d, J=14.3 Hz, 1H), 2.90 (d, J=
14.3 Hz, 1H), 3.02 (dd, J=14.7, 4.8 Hz, 1H), 3.41 (s, 3H), 3.59–3.68 (m,
3H), 3.81–3.94 (m, 3H), 4.86 (d, J=6.3 Hz, 1H), 5.00–5.19 (m, 2H), 5.23
(d, J=5.9 Hz, 1H), 5.60 (d, J=1.8 Hz, 1H), 5.82–5.89 (m, 2H), 7.28–7.39
(1S,2R,3S,5S)-2-Allyl-3-(tert-butyldimethylsilanyl-oxy)-5-(tert-butyldiphe-
nylsilyloxy)-2-(2-methoxyethoxymethoxy)cyclohexanol
(47):
K2CO3
(1.8 g) was added at 08C to a solution of 45 (4.9 g, 7.0 mmol) in MeOH
(60 mL). The mixture was allowed to warm to room temperature. After
12 h saturated aqueous NH4Cl solution (400 mL) and CH2Cl2 (400 mL)
were added. The aqueous layer was separated and extracted with CH2Cl2
(300 mL). The organic extracts were combined, washed with water
(400 mL) and brine (400 mL), dried over Na2SO4, filtered and concen-
trated. The crude product was purified by flash chromatography (P/EA
90:10) to give 47 as a colorless oil (4.2 g, 6.7 mmol, 95%). Rf = 0.17 (P/
1
EA 90:10); [a]2D0 =ꢀ0.4 (c=2.02, CHCl3); H NMR (360 MHz): d=ꢀ0.12
(s, 3H), ꢀ0.07 (s, 3H), 0.84 (s, 9H), 1.07 (s, 9H), 1.41 (brd, J=4.3 Hz,
1H, OH), 1.63–1.74 (m, 2H), 1.80 (virt. q, J ffi 11.4 Hz, 1H), 1.96 (ddd,
J=14.8, 11.4, 2.9 Hz, 1H), 2.08 (dd, J=15.5, 9.3 Hz, 1H), 2.86 (dd, J=
15.5, 5.0 Hz, 1H), 3.42 (s, 3H), 3.51–3.58 (m, 3H), 3.62–3.68 (m, 1H),
3.71–3.75 (m, 1H), 3.76–3.82 (m, 1H), 3.99 (virt. sept, J ffi 4.8 Hz, 1H),
4.89 (d, J=6.1 Hz, 1H), 5.03–5.12 (m, 2H), 5.18 (d, J=6.1 Hz, 1H), 5.93–
6.09 (m, 1H), 7.33–7.40 (m, 6H), 7.61–7.71 (m, 4H); 13C NMR
(90.6 MHz): d=ꢀ5.1 (q), ꢀ4.5 (q), 17.8 (s), 19.1 (s), 25.8 (q), 26.9 (q),
34.7 (t), 37.3 (t), 40.1 (t), 59.0 (q), 66.6 (d), 67.5 (t), 70.7 (d), 71.9 (t), 72.3
(d), 78.8 (s), 91.1 (t), 117.4 (t), 127.5 (d), 127.5 (d), 129.5 (d), 129.5 (d),
134.5 (d), 134.6 (s), 134.8 (s), 135.7 (d), 135.8 (d); IR (neat): n˜ =3478 (m,
br), 3071 (m), 2955, 2930, 2892, 2857 (s), 1472 (s), 1427 (m), 1374 (m),
1361 (m), 1251 (s), 1111 (vs), 1061 (vs, br), 1025 (vs), 835 (s), 702 cmꢀ1
(s); MS (EI, 70 eV): m/z (%): 587 (1) [M +ꢀC3H5], 571 (5) [M +ꢀtBu],
495 (8), 465 (10), 297 (18), 257 (100), 133 (68), 89 (52), 59 (58)
[CH3OCH2CH2+]; elemental analysis calcd (%) for C35H56O6Si2
(628.362): C 66.83, H, 8.97; found: C 66.78, H 8.97.
(m, 6H), 7.58–7.70 (m,
4
Hr); 13C NMR (90.6 MHz): d=ꢀ5.0 (q,
MeSiCH3), ꢀ4.0 (q, H3CSiMe), 17.9 [s, SiC(CH3)3], 19.0 [s, SiC(CH3)3],
25.8 [q, SiC(CH3)3], 27.0 [q, SiC(CH3)3], 33.2 (t), 39.6 (t), 40.8 (t), 41.5
(t), 59.0 (q), 66.3 (d), 67.7 (t), 70.4 (d), 71.9 (t), 78.3 (s), 80.9 (s), 90.4 (d),
91.3 (t), 104.0 (d), 117.6 (t), 127.5 (d), 127.5 (d), 129.6 (d), 129.8 (d),
134.1 (s), 134.4 (s), 135.6 (d), 135.6 (d), 135.7 (d), 163.8 (s), 166.8 (s),
171.1 (s); IR (neat): n˜ =3426 (brs, OH), 3072 (m, Csp2-H), 2955 (s), 2857
(s, Csp3-H), 1694 (s sh, C=O), 1567 (s), 1472 (m), 1428 (m), 1254 (s), 1112
(vs), 1072 (s), 1028 (s), 872 (m), 836 cmꢀ1 (s); MS (EI, 70 eV): m/z (%):
695 (1) [M +ꢀtBu], 651 (20), 347 (42), 257 (100), 199 (18), 133 (85), 89
(40) [CH2OCH2CH2OCH3+], 73 (32); elemental analysis calcd (%) for
C41H60O9Si2 (753.08): C 65.39, H 8.03; found: C 65.40, H 8.00.
4-Methoxy-6-([(1R,2S,3S,5R)-2-allyl-3-(tert-butyldimethylsilyloxy)-5-
(tert-butyldiphenylsilyloxy)-1-hydroxy-2-(2-methoxyethoxymethoxy)cy-
clohexyl]methyl)-2H-pyran-2-one (50): Pyranone 49 (410 mg, 0.54 mmol)
was dissolved in dry acetone (20 mL) and was stirred with K2CO2
(500 mg) and dimethyl sulfate (0.11 mL, 151 mg, 1.2 mmol) at RT for
12 h. After 12 h, methanol (1 mL) and sodium acetate (200 mg) were
added to the mixture and stirring was continued for 20 min. The mixture
was diluted with Et2O (250 mL) and water (250 mL), the layers were sep-
arated. The organic layer was dried over Na2SO4, filtered and concentrat-
ed in vacuo. The crude product was purified by flash chromatography (P/
EA 50:50) to give 50 as a colorless oil (377 mg, 0.50 mmol, 92%). Rf =
(2S,3S,5R)-2-Allyl-3-(tert-butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyl-
oxy)-2-(2-methoxyethoxymethoxy)cyclohexanone (48): Alcohol 47 (4.1 g,
6.5 mmol) was dissolved in DMSO (30 mL), and IBX[34] (3.6 g, 13 mmol)
was added in one portion. The resulting solution was stirred for 12 h at
room temperature, then poured into a mixture of Et2O (300 mL) and sa-
turated aqueous NaHCO3 solution (300 mL). The layers were separated,
the aqueous layer was extracted with Et2O (150 mL). The combined or-
ganic layers were washed with water (2”400 mL), dried over Na2SO4, fil-
tered, and concentrated. Flash chromatography (P/EA 95:5) of the crude
oil gave the title compound 48 (4.0 g, 6.4 mmol, 98%) as a colorless oil.
Rf =0.34 (P/EA 90:10); [a]D20
=
10.1 (c=0.98, CHCl3); 1H NMR
0.36 (P/EA 50:50) [CAM]; [a]D20
=
18.2 (c=0.16, CHCl3); 1H NMR
(500 MHz): d=ꢀ0.12 (s, 3H), ꢀ0.10 (s, 3H), 0.85 (s, 9H), 1.07 (s, 9H),
1.86 (ddt, J=11.9, 1.7, 4.4 Hz, 1H), 2.30 (virt. q, J ffi 11.9 Hz, 1H), 2.49
(dd, J=14.2, 7.3 Hz, 1H), 2.52 (ddd, J=12.8, 5.2, 1.7 Hz, 1H), 2.77 (dd,
J=14.2, 6.6 Hz, 1H), 3.17 (dd, J=12.8, 11.2 Hz, 1H), 3.29 (dd, J=11.9,
4.4 Hz, 1H), 3.41 (s, 3H), 3.57 (t, J=4.6 Hz, 2H), 3.69 (virt. sept, J ffi
4.9 Hz, 1H), 3.72–3.82 (m, 2H), 4.92 (d, J=6.3 Hz, 1H), 4.94 (d, J=
6.3 Hz, 1H), 5.03 (dd, J=10.2, 1.9 Hz, 1H), 5.12 (dd, J=17.3, 1.9 Hz,
1H), 5.64–5.73 (m, 1H), 7.33–7.42 (m, 6H), 7.59–7.68 (m, 4H); 13C NMR
(90.6 MHz): d=ꢀ4.9 (q), ꢀ4.0 (q), 17.9 (s), 19.0 (s), 25.8 (q), 26.9 (q),
32.8 (t), 39.1 (t), 47.5 (t), 58.9 (q), 65.9 (d), 67.7 (t), 71.1 (d), 71.7 (t), 83.9
(s), 91.3 (t), 118.2 (t), 127.7 (d), 127.7 (d), 129.8 (d), 129.8 (d), 133.4 (d),
133.5 (s), 133.8 (s), 135.6 (d), 135.7 (d), 205.7 (s); IR (neat): n˜ =3072 (m),
2931, 2857 (s), 1721 (s), 1472 (s), 1427 (s), 1377 (m), 1255 (s), 1113 (vs),
1021 (vs), 837 (s), 703 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 626 (1) [M +],
569 (5) [M +ꢀC(CH3)3], 493 (2), 370 (10), 281 (15), 257 (48), 199 (32),
133 (46), 89 (100), 59 (80) [CH3OCH2CH2+]; elemental analysis calcd
(%) for C35H54O6Si2 (626.346): C 67.05, H 8.68; found: C 66.90, H 8.73.
(500 MHz): d=ꢀ0.08 (s, 3H, MeSiCH3), ꢀ0.07 (s, 3H, H3CSiMe), 0.83 [s,
9H, SiC(CH3)3], 1.03 [s, 9H, SiC(CH3)3], 1.44 (dd, J=12.9, 5.2 Hz, 1H),
1.80–1.98 (m, 3H), 2.04 (s, 1H, OH), 2.55 (dd, J=15.1, 9.6 Hz, 1H), 2.79
(d, J=14.4 Hz, 1H), 2.88 (d, J=14.4 Hz, 1H), 3.03 (dd, J=15.1, 5.7 Hz,
1H), 3.40 (s, 3H), 3.59 (t, J=4.6 Hz, 2H), 3.65–3.71 (m, 1H), 3.80–3.96
(m, 6H), 4.86 (d, J=6.6 Hz, 1H), 5.07 (d, J=10.2 Hz, 1H), 5.17 (d, J=
17.0 Hz, 1H), 5.24 (d, J=6.6 Hz, 1H), 5.43 (d, J=2.3 Hz, 1H), 5.74 (d,
J=2.3 Hz, 1H), 5.84–5.95 (m, 1H), 7.28–7.39 (m, 6H), 7.58–7.70 (m,
4H); 13C NMR (90.6 MHz): d=ꢀ5.0 (q, MeSiCH3), ꢀ4.1 (q, H3CSiMe),
17.9 [s, SiC(CH3)3], 19.0 [s, SiC(CH3)3], 25.8 [q, SiC(CH3)3], 27.0 [q, SiC-
(CH3)3], 33.2 (t), 39.6 (t), 40.7 (t), 41.1 (t), 55.7 (q), 59.1 (q), 66.3 (d),
67.7 (t), 70.3 (d), 71.9 (t), 78.2 (s), 80.7 (s), 87.9 (d), 91.2 (t), 102.8 (d),
117.4 (t), 127.4 (d), 127.5 (d), 129.5 (d), 129.5 (d), 134.3 (s), 134.4 (s),
135.6 (d), 135.7 (d), 135.7 (d), 162.4 (s), 164.4 (s), 170.7 (s); IR (neat): n˜ =
3538 (m sh, OH), 3072 (m, Csp2-H), 2930 (s), 2857 (s, Csp3-H), 1724 (s sh,
C=O), 1648 (s), 1567 (s), 1456 (m), 1410 (m), 1249 (s), 1112 (vs), 1071
(s), 1033 (s), 872 (m), 835 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 766 (1)
[M +], 709 (100) [M +ꢀtBu], 616 (40), 589 (39), 257 (50), 199 (73), 135
(88), 73 (92); elemental analysis calcd (%) for C42H62O9Si2 (767.11): C
65.76, H 8.15; found: C 65.70, H 8.48.
4-Hydroxy-6-([(1R,2S,3S,5R)-2-allyl-3-(tert-butyldimethylsilyloxy)-5-
(tert-butyldiphenylsilyloxy)-1-hydroxy-2-(2-methoxyethoxymethoxy)cy-
clohexyl]methyl)-2H-pyran-2-one (49): 4-Hydroxy-6-methyl-2H-pyran-2-
7020
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
4-Methoxy-6-([(1R,2S,3S,5R)-2-allyl-3-(tert-butyldimethylsilyloxy)-1,5-di-
hydroxy-2-(2-methoxyethoxymethoxy)cyclohexyl]methyl)-2H-pyran-2-
one (51): TBDPS ether 50 (402 mg, 0.52 mmol) was dissolved in THF
(8 mL). To this solution were added pyridine (0.5 mL) and HF·py (1 mL)
at 08C. The mixture was allowed to warm to RT and stirred for 12 h
(until TLC analysis indicated complete conversion). The mixture was
cooled to 08C and diluted with EtOAc (50 mL) and sat. aqueous
NaHCO3. Stirring was continued at RT until gas evolution stopped. The
layers were separated, the aqueous layer was extracted with EtOAc (2”
50 mL). The combined organic layers were washed with sat. aqueous
NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (P/EA 50:50) to give the title compound as
a colorless oil (257 mg, 0.49 mmol, 94%). Rf =0.12 (P/EA 50:50) [CAM];
H2O2 (30%; 0.6 mL) were added subsequently. The mixture was warmed
to 08C. After stirring for 30 min at 08C, the mixture was diluted with
water (50 mL) and Et2O (50 mL). The layers were separated and the
aqueous layer was extracted with Et2O (50 mL). The combined organic
layers were washed with water (70 mL) and brine (70 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (CH2Cl2/MeOH 95:5) to give the title com-
pound as a colorless oil (175 mg, 0.33 mmol, 97%). Rf =0.26 (CH2Cl2/
MeOH 95:5) [CAM]; [a]D20
=
56.3 (c=0.90, CHCl3); 1H NMR
(360 MHz): d=0.07 (s, 3H, MeSiCH3), 0.07 (s, 3H, H3CSiMe), 0.86 [s,
9H, SiC(CH3)3], 1.51 (dd, J=14.3, 2.9 Hz, 1H), 1.90–1.95 (m, 2H), 2.04
(dd, J=14.3, 3.4 Hz, 1H), 2.61 (dd, J=14.8, 8.4 Hz, 1H), 2.79–2.85 (m,
2H), 3.11 (dd, J=14.8, 5.9 Hz, 1H), 3.39 (s, 3H), 3.52 (brs, 1H, OH),
3.53 (t, J=3.9 Hz, 2H), 3.58–3.61 (m, 1H), 3.77 (s, 1H), 3.78–3.83 (m,
1H), 3.84 (s, 1H, OH), 4.07–4.09 (m, 1H), 4.37 (brs, 1H), 4.84 (d, J=
6.6 Hz, 1H), 5.07–5.18 (m, 3H), 5.36 (d, J=2.3 Hz, 1H), 5.86 (d, J=
2.3 Hz, 1H), 6.02 (brs, 1H); 13C NMR (90.6 MHz): d=ꢀ5.0 (q,
MeSiCH3), ꢀ4.1 (q, H3CSiMe), 17.9 [s, SiC(CH3)3], 25.8 [q, SiC(CH3)3],
32.9 (t), 36.1 (t), 37.8 (t), 40.7 (t), 55.7 (q), 58.9 (q), 67.1 (d), 67.7 (t), 68.2
(d), 71.7 (t), 80.1 (s), 81.9 (s), 87.6 (d), 91.2 (t), 103.2 (d), 116.8 (t), 135.6
(d), 162.7 (s), 165.0 (s), 171.1 (s); IR (neat): n˜ =3398 (brs, OH), 3070 (w,
Csp2-H), 2928 (s, Csp3-H), 1693 (s sh, C=O), 1644 (s), 1565 (vs), 1458 (s),
1411 (m), 1249 (s), 1033 (s sh), 837 cmꢀ1 (s); MS (EI, 70 eV): m/z (%):
528 (5) [M +], 471 (12) [M +ꢀtBu], 395 (20), 365 (28), 289 (38), 133 (62),
125 (75), 89 (95) [CH2OCH2CH2OCH3+], 59 (100) [CH3OCH2CH2+]; el-
emental analysis calcd (%) for C26H44O9Si (528.71): C 59.06, H 8.39;
found: C 58.67, H 8.48.
[a]2D0
=
28.0 (c=0.51, CHCl3); 1H NMR (360 MHz): d=0.09 (s, 3H,
MeSiCH3), 0.11 (s, 3H, H3CSiMe), 0.88 [s, 9H, SiC(CH3)3], 1.61–1.81 (m,
4H), 2.00–2.04 (m, 1H), 2.37 (s, 1H, OH), 2.59 (dd, J=14.8, 9.7 Hz, 1H),
2.85 (d, J=14.3 Hz, 1H), 2.96 (d, J=14.3 Hz, 1H), 3.11 (dd, J=14.8,
5.0 Hz, 1H), 3.39 (s, 3H), 3.56 (t, J=4.7 Hz, 2H), 3.62–3.67 (m, 1H), 3.78
(s, 1H), 3.79–3.88 (m, 2H), 4.18 (dd, J=11.4, 4.3 Hz, 1H), 4.87 (d, J=
6.6 Hz, 1H), 5.13–5.29 (m, 3H), 5.41 (d, J=2.3 Hz, 1H), 5.82 (d, J=
2.3 Hz, 1H), 5.90–5.95 (m, 1H); 13C NMR (90.6 MHz): d=ꢀ4.9 (q,
MeSiCH3), ꢀ3.9 (q, H3CSiMe), 17.9 [s, SiC(CH3)3], 25.8 [q, SiC(CH3)3],
33.2 (t), 39.2 (t), 40.6 (t), 41.2 (t), 55.7 (q), 59.0 (q), 65.0 (d), 67.8 (t), 70.5
(d), 71.9 (t), 78.3 (s), 80.8 (s), 87.9 (d), 91.2 (t), 103.1 (d), 117.8 (t), 135.5
(d), 162.4 (s), 164.6 (s), 170.9 (s); IR (film): n˜ =3414 (m br, OH), 3070
(w, Csp2-H), 2929 (m), 2855 (m, Csp3-H), 1702 (s sh, C=O), 1641 (m), 1565
(s), 1457 (m), 1411 (m), 1249 (s), 1115 (s br), 1070 (s), 1035 (s sh), 874
(m), 837 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 528 (5) [M +], 471 (12) [M +
ꢀtBu], 395 (20), 365 (30), 211 (22), 133 (84), 125 (70), 89 (95)
[CH2OCH2CH2OCH3+], 59 (100) [CH3OCH2CH2+]; elemental analysis
calcd (%) for C26H44O9Si (528.71): C 59.06, H 8.39; found: C 59.02, H
8.31.
4-Methoxy-6-([(1R,2S,3S,5S)-2-allyl-3-(tert-butyldimethylsilyloxy)-2-(2-
methoxyethoxymethoxy)-1,5-(dimethyl)methylendioxycyclohexyl]-
methyl)-2H-pyran-2-one (54): Diol 53 (175 mg, 0.33 mmol) was dissolved
in 1,2-dichloroethane (10 mL). At 08C, a catalytic amount of PPTS (<
2 mg) was added followed by a slow addition of 2-methoxypropene
(67 mL, 50 mg). The solution was stirred for 15 min at 08C, then warmed
to RT. After 3 h at RT, triethylamine (0.6 mL) was added at once. The
mixture was diluted with Et2O (100 mL) and sat. aqueous NaHCO3
(100 mL). The layers were separated and the aqueous layer was extracted
with Et2O (50 mL). The combined organic layers were washed with water
(100 mL) and brine (100 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. The crude product was purified by flash chromatography
(P/EA 50:50) to give the title compound as a colorless oil (169 mg,
0.29 mmol, 90%). Rf =0.28 (P/EA 50:50) [CAM]; [a]2D0 = 76.7 (c=0.97,
CHCl3); 1H NMR (400 MHz): d=0.09 (s, 3H, MeSiCH3), 0.09 (s, 3H,
H3CSiMe), 0.89 [s, 9H, SiC(CH3)3], 1.17 (s, 3H), 1.27 (s, 3H), 1.67 (ddd,
J=12.5, 11.1, 1.6 Hz, 1H), 1.96–2.03 (m, 1H), 2.27 (dd, J=15.0, 1.8 Hz,
1H), 2.31 (ddd, J=15.0, 4.5, 2.0 Hz, 1H), 2.55 (dd, J=15.4, 7.0 Hz, 1H),
2.83 (d, J=13.9 Hz, 1H), 2.85 (d, J=13.9 Hz, 1H), 3.03 (dd, J=15.4,
7.3 Hz, 1H), 3.37 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.62 (dt, J=10.7,
4.8 Hz, 1H), 3.76–3.81 (m, 1H), 3.79 (s, 1H), 4.20–4.28 (m, 1H), 4.33 (dd,
J=11.1, 5.0 Hz, 1H), 4.86 (d, J=6.5 Hz, 1H), 4.97 (dd, J=10.2, 1.6 Hz,
1H), 5.08 (dd, J=17.0, 1.6 Hz, 1H), 5.20 (d, J=6.5 Hz, 1H), 5.41 (d, J=
2.1 Hz, 1H), 5.82 (d, J=2.1 Hz, 1H), 6.02 (dddd, J=17.0, 10.2, 7.3,
7.0 Hz, 1H); 13C NMR (90.6 MHz): d=ꢀ4.8 (q, MeSiCH3), ꢀ3.9 (q,
H3CSiMe), 18.0 [s, SiC(CH3)3], 25.9 (t, C8), 26.0 [q, SiC(CH3)3], 31.4 (q,
H3CCCH3), 31.8 (q, H3CCCH3), 33.5 (t), 38.7 (t), 40.3 (t), 55.8 (q), 59.0
(q), 66.5 (d), 67.7 (t), 70.3 (d), 71.9 (t), 79.2 (s), 81.9 (s), 87.8 (d), 91.5 (t),
98.2 (s), 104.0 (d), 115.3 (t), 135.5 (d), 162.5 (s), 164.9 (s), 170.9 (s); IR
(neat): n˜ =3078 (m, Csp2-H), 2930 (vs), 2857 (vs, Csp3-H), 1728 (s, C=O),
1649 (s), 1569 (vs), 1457 (s), 1411 (s), 1248 (vs), 1197 (m), 1028 (s sh),
1098 (s), 1073 (s), 1026 (vs), 992 (s), 836 cmꢀ1 (s); MS (EI, 70 eV): m/z
(%): 568 (4) [M +], 511 (10) [M +ꢀtBu], 421 (18), 221 (15), 133 (34), 125
(37), 89 (100) [CH2OCH2CH2OCH3+], 59 (68) [CH3OCH2CH2+]; ele-
mental analysis calcd (%) for C29H48O9Si (568.772): C 61.24, H 8.51;
found: C 61.07, H 8.55.
4-Methoxy-6-([(1S,2S,3S)-2-allyl-3-(tert-butyldimethylsilyloxy)-1-hydroxy-
2-(2-methoxyethoxymethoxy)-5-oxocyclohexyl]methyl)-2H-pyran-2-one
(52): IBX[34] (178 mg, 0.63 mmol) at RT was added to a solution of alco-
hol 51 (224 mg, 0.42 mmol) in DMSO (3 mL). After stirring for 4 h at
RT, the solution was diluted with Et2O (50 mL) and water (50 mL). The
layers were separated, the aqueous layer was extracted with Et2O (2”
30 mL). The combined organic layers were washed with sat. aqueous
NaHCO3 (2”80 mL) and brine (100 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by flash chroma-
tography (P/EA 60:40) to give the title compound as a colorless oil
(214 mg, 0.41 mmol, 96%). Rf =0.29 (P/EA 50:50) [CAM]; [a]2D0 = 85.2
(c=0.25, CHCl3); 1H NMR (360 MHz): d=0.07 (s, 3H, MeSiCH3), 0.08
(s, 3 H3CSiMe), 0.87 [s, 9H, SiC(CH3)3], 2.08 (dd, J=14.8, 1.6 Hz, 1H),
2.52–2.56 (m, 1H), 2.64–2.73 (m, 2 H + OH), 2.85–2.89 (m, 1H), 2.89 (d,
J=14.3 Hz, 1H), 2.99 (d, J=14.3 Hz, 1H), 3.20 (dd, J=15.2, 5.0 Hz, 1H),
3.36 (s, 3H), 3.53–3.56 (m, 2H), 3.62–3.68 (m, 1H), 3.76 (s, 1H), 3.80–
3.84 (m, 1H), 4.44 (dd, J=10.5, 5.5 Hz, 1H), 4.92 (d, J=6.8 Hz, 1H),
5.16 (virt. d, J ffi 10.0 Hz, 1H), 5.23 (virt. d, J ffi 16.7 Hz, 1H), 5.30 (d, J=
6.8 Hz, 1H), 5.39 (d, J=2.1 Hz, 1H), 5.80 (d, J=2.1 Hz, 1H), 5.90–5.96
(m, 1H); 13C NMR (90.6 MHz): d=ꢀ5.0 (q, MeSiCH3), ꢀ4.2 (q,
H3CSiMe), 17.8 [s, SiC(CH3)3], 25.7 [q, SiC(CH3)3], 33.2 (t), 40.4 (t), 46.8
(t), 48.1 (t), 55.8 (q), 59.0 (q), 67.9 (t), 70.9 (d), 71.7 (t), 78.5 (s), 80.8 (s),
88.1 (d), 91.5 (t), 103.3 (d), 118.3 (t), 134.4 (d), 161.1 (s), 164.2 (s), 170.6
(s), 206.4 (s); IR (neat): n˜ =3416 (m br, OH), 3070 (w, Csp2-H), 2926 (s,
Csp3-H), 1721 (vs sh, C=O), 1649 (m), 1567 (vs), 1459 (m), 1412 (m), 1250
(s sh), 1107 (s br), 1018 (s sh), 837 (s), 828 (m), 777 cmꢀ1 (m); MS (EI,
70 eV): m/z (%): 526 (3) [M +], 469 (12) [M +ꢀtBu], 133 (60), 125 (40),
89 (100) [CH2OCH2CH2OCH3+], 59 (78) [CH3OCH2CH2+]; elemental
analysis calcd (%) for C26H42O9Si (526.69): C 59.29, H 8.04; found: 59.31,
H 7.92.
4-Methoxy-6-([(1R,2S,3S,5S)-2-allyl-3-(tert-butyldimethylsilyloxy)-2-(2-
methoxyethoxymethoxy)-1,5-dihydroxycyclohexyl]methyl)-2H-pyran-2-
one (53): A solution of L-selectride in THF(1 m; 0.34 mL, 0.34 mmol)
dropwise at ꢀ788C was added to a solution of ketone 52 (180 mg,
0.34 mmol) in THF(7 mL). The solution was stirred at ꢀ788C for 2 h.
Then, methanol (0.6 mL), aqueous NaOH (2m; 0.6 mL) and aqueous
2-{(1S,2R,4S,6S)-6-(tert-Butyldimethylsilyloxy)-2,4-(dimethyl)methylen-
dioxy-1-(2-methoxyethoxymethoxy)-2-[(4-methoxy-6-oxopyran-2-yl)me-
thyl]cyclohexyl}acetaldehyde (44): Acetonide 54 (700 mg, 1.24 mmol)
was dissolved in THF(20 mL) and an aqueous solution of sodium acetate
in water (1.5 g in 20 mL) at RT. To this mixture was added a solution of
OsO4 in water (1%; 0.08 mL) and NaIO4 (1.07 g, 5 mmol) subsequently.
Chem. Eur. J. 2005, 11, 7007 – 7023
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7021

T. Bach and S. F. Kirsch
The mixture was stirred for 3 h at RT. The precipitate was filtered off.
The residue was washed with Et2O (80 mL). The filtrate was diluted with
Et2O (150 mL) and water (150 mL). The layers were separated. The
aqueous layer was extracted with Et2O (2”100 mL). The combined or-
ganic layers were washed with sat. aqueous NaHCO3 (250 mL) and brine
(250 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (P/EA 50:50) to
give 44 as a colorless oil (605 mg, 1.06 mmol, 85%). Rf =0.21 (P/EA
[CH2OCH2CH2OCH3+], 59 (80) [CH3OCH2CH2+]; elemental analysis
calcd (%) for C34H50O10Si (646.84): C 63.13, H 7.79;found: C 63.15, H
7.84.
6-{(1R,3S,4S,6S,8R)-[4-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-phenyl-
9,10-dioxatricyclo[4.3.1.0][3,8]dec-8-yl]methyl}-4-methoxy-2H-pyran-2-
one (56): A mixture of water (10 mL), acetic acid (10 mL) and trifluoro-
acetic acid (5 mL) was added to a solution of ketone 55 (350 mg,
0.54 mmol) in THF(20 mL). The resulting mixture was stirred at RT for
1 h, and then the mixture was poured into ice-cold sat. aqueous NaHCO3
(200 mL). The mixture was neutralized with K2CO3 and diluted with
Et2O (200 mL) and water (100 mL). The layers were separated. The
aqueous layer was extracted with Et2O (2”100 mL). The combined or-
ganic layers were washed with water (300 mL) and brine (300 mL), dried
over Na2SO4, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography (P/EA 50:50) to give 56 as a colorless
50:50) [CAM]; [a]D20
=
94.0 (c=1.58, CH2Cl2); 1H NMR (360 MHz,
[D6]benzene]: d=0.06 (s, 3H, MeSiCH3), 0.11 (s, 3H, H3CSiMe), 0.90 [s,
9H, SiC(CH3)3], 1.22 (s, 6H), 1.62 (ddd, J=12.3, 11.0, 1.6 Hz, 1H), 1.99–
2.07 (m, 1H), 2.13 (dd, J=15.0, 1.6 Hz, 1H), 2.48 (ddd, J=15.0, 4.8,
2.0 Hz, 1H), 2.89 (d, J=13.9 Hz, 1H), 2.96 (dd, J=13.2, 4.8 Hz, 1H),
2.98 (s, 3H), 3.04 (d, J=13.9 Hz, 1H), 3.23 (s, 3H), 3.40 (dd, J=13.2,
2.0 Hz, 1H), 3.41–3.44 (m, 2H), 3.51–3.55 (m, 1H), 3.76–3.84 (m, 1H),
4.02–4.06 (m, 1H), 4.67 (dd, J=11.0, 5.0 Hz, 1H), 4.88 (d, J=7.0 Hz,
1H), 5.31 (d, J=2.3 Hz, 1H), 5.46 (d, J=7.0 Hz, 1H), 5.82 (d, J=2.3 Hz,
1H), 10.00 (dd, J=4.8, 2.0 Hz, 1H); 13C NMR (90.6 MHz, [D6]benzene]):
d=ꢀ4.7 (q, MeSiCH3), ꢀ4.1 (q, H3CSiMe), 18.2 [s, SiC(CH3)3], 26.1 (t),
26.1 [q, SiC(CH3)3], 31.2 (q), 31.8 (q), 38.8 (t), 41.0 (t), 43.9 (t), 55.0 (q),
58.8 (q), 66.4 (d), 68.2 (t), 71.2 (d), 72.3 (t„ 79.1 (s), 83.0 (s), 88.2 (d),
92.3 (t), 99.2 (s), 103.9 (d), 162.0 (s), 163.4 (s), 170.5 (s), 197.4 (d): IR
(neat): n˜ =3072 (m, Csp2-H), 2930 (s, Csp3-H), 1726 (s sh, C=O), 1649 (s),
1565 (s), 1456 (s), 1410 (s), 1248 (s), 1028 (s), 1095 (s), 1073 (s),
1026 cmꢀ1 (s); MS (EI, 70 eV): m/z (%): 570 (2) [M +], 555 (6) [M +
ꢀCH3], 513 (9) [M +ꢀtBu], 423 (10), 349 (28), 221 (25), 133 (24), 125
(52), 89 (100) [CH2OCH2CH2OCH3+], 59 (55) [CH3OCH2CH2+], 44
(28).
oil (185 mg, 0.37 mmol, 69%). Rf =0.58 (P/EA 50:50) [CAM]; [a]D20
=
88.9 (c=0.24, CHCl3); 1H NMR (360 MHz, [D6]benzene]): d=ꢀ0.05 (s,
3H, MeSiCH3), 0.00 (s, 3H, H3CSiMe), 0.91 [s, 9H, SiC(CH3)3], 1.69 (dd,
J=15.7, 5.9 Hz, 1H), 2.28–2.38 (m, 3H), 2.35 (d, J=12.9 Hz, 1H), 2.51 (s,
1H, OH), 2.52 (d, J=12.9 Hz, 1H), 2.63 (d, J=14.5 Hz, 1H), 2.83 (s,
3H), 3.14 (d, J=14.5 Hz, 1H), 4.11 (d, J=6.4 Hz, 1H), 4.20–4.24 (m,
1H), 5.16 (d, J=2.3 Hz, 1H), 5.92 (d, J=2.3 Hz, 1H), 7.19–7.28 (m, 3H),
7.82–7.87 (m, 2H); 13C NMR (90.6 MHz, [D6]benzene]): d=ꢀ4.9 (q,
MeSiCH3), ꢀ4.6 (q, H3CSiMe), 18.1 [s, SiC(CH3)3], 26.0 [q, SiC(CH3)3],
34.9 (t), 39.0 (t), 40.8 (t), 52.3 (t), 54.8 (q), 68.7 (d), 73.7 (d), 81.4 (s), 83.3
(s), 88.2 (d), 102.4 (d), 103.7 (s), 125.7 (d), 127.6 (d), 128.4 (d), 141.0 (s),
162.2 (s), 163.4 (s), 170.6 (s); IR (neat): n˜ =3455 (m br, OH), 3072 (w,
Csp2-H), 2928 (s, Csp3-H), 1699 (s sh, C=O), 1645 (s), 1567 (s), 1456 (s),
1412 (m), 1360 (m), 1251 (s), 1093 (vs sh), 1019 (s), 922 (m), 828 cmꢀ1
(m); MS (EI, 70 eV): m/z (%): 500 (5) [M +], 443 (40) [M +ꢀtBu], 343
(18), 292 (22), 105 (100) [C7H5O+], 73 (30), 40 (28); elemental analysis
calcd (%) for C27H36O7Si (500.66): C 64.77, H 7.25; found: C 64.79, H
7.20.
2-{(1S,2R,4S,6S)-6-(tert-Butyldimethylsilyloxy)-2,4-(dimethyl)methylen-
dioxy-1-(2-methoxyethoxymethoxy)-2-[(4-methoxy-6-oxopyran-2-yl)me-
thyl]cyclohexyl}-1-phenylethanone (55): A solution of phenylmagnesium
bromide in Et2O (3m; 0.43 mL, 1.3 mmol) at ꢀ788C was added to a solu-
tion of aldehyde 44 (580 mg, 1.02 mmol) in THF(50 mL). The yellow so-
lution was stirred for 1 h at ꢀ788C. The cold reaction mixture was
quenched by addition of sat. aqueous NH4Cl (200 mL). The mixture was
extracted with Et2O (2”200 mL). The combined organic layers were
washed brine (400 mL), dried over Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography (P/EA
50:50) to give the secondary alcohol as a mixture of epimers (588 mg,
0.91 mmol, 89%; dr 4:1 according to 1H NMR). The epimeric mixture
(588 mg, 0.91 mmol) was dissolved in CH2Cl2 (30 mL). To this solution
were added NaHCO3 (1 g) and Dess–Martin periodinane (678 mg,
1.6 mmol) subsequently. The mixture was stirred at RT. After 3 h, Et2O
(100 mL) and sat. aqueous NaHCO3 (100 mL) containing 5% Na2S2O3
were added. The biphasic mixture was stirred at RT until the formation
of two clear layers was observed (~30 min). The layers were separated.
The organic layer was washed with water (100 mL) and brine (100 mL),
dried over Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (P/EA 50:50) to give 55 as a color-
(7R,9R,12R,14R)-(+)-Wailupemycin B (2): A solution of TBAFin THF
(1m; 0.3 mL, 0.3 mmol) at 08C was slowly added to a solution of 56
(102 mg, 0.20 mmol) in THF(15 mL). Stirring was continued at 0 8C for
20 min, and then sat. aqueous NH4Cl (150 mL) and EtOAc (150 mL)
were added. The layers were separated. The aqueous layer was extracted
with EtOAc (100 mL). The combined organic layers were washed with
water (200 mL) and brine (200 mL), dried over Na2SO4, filtered and con-
centrated in vacuo. The crude product was directly used in the next step.
The crude alcohol was dissolved in EtOAc (10 mL). To this solution was
added IBX (280 mg, 1 mmol). The mixture refluxed for 4 h, cooled to
RT, filtered and concentrated in vacuo. The crude product was purified
by flash chromatography (P/EA 50:50) to give wailupemycin B (2) as a
colorless oil (54 mg, 0.14 mmol, 70%). Rf =0.22 (P/EA 50:50) [CAM];
[a]D20 = 79.0 (c=0.09, MeOH); natural product:[1] [a]2D0 = 77.7 (c=0.07,
1
MeOH); H NMR (600 MHz): d=1.62 (d, J=13.3 Hz, 1H, C8HaH), 2.41
(ddd, J=13.3, 5.0, 2.6 Hz, 1H, C8HHb), 2.55 (d, J=13.6 Hz, 1H,
C13HaH), 2.73 (dd, J=18.7, 5.3 Hz, 1H, C10HaH), 2.76 (d, J=13.6 Hz,
1H, C13HHb), 2.85 (d, J=14.9 Hz, 1H, C6HbH), 3.03 (d, J=14.9 Hz,
1H, C6HHb), 3.14 (br d, J=18.7 Hz, 1H, C10HHb), 3.80 (s, 3H, OCH3),
4.01 (br s, 1H, OH), 4.76 (virt. t, J ffi 5.0 Hz, 1H, H9), 5.43 (d, J=2.3 Hz,
1H, H2), 6.02 (d, J=2.0 Hz, 1H, H4), 7.36–7.41 (m, 3H, HAr), 7.59 (d,
J=7.5 Hz, 2H, HAr); 13C NMR (90.6 MHz): d=36.1 (t, C8), 38.7 (t, C6),
43.7 (t, C10), 54.7 (t, C10), 55.8 (q, OCH3), 69.0 (d, C9), 85.0 (s, C12),
85.4 (s, C7), 88.2 (d, C2), 103.2 (d, C4), 106.0 (s, C14), 125.0 (d), 128.3
(d), 128.9 (d), 138.5 (s), 160.5 (s, C5), 164.3 (s, C1), 171.0 (s, C3), 208.9 (s,
C11); IR (neat): n˜ =3450 (brs, OH), 3072 (m), 3013 (m, Csp2-H), 2957 (s,
Csp3-H), 1723 (s sh, C=O), 1647 (s), 1567 (vs), 1456 (s), 1411 (m), 1328
(m), 1248 (s), 1119 (s), 1072 (m), 1020 (m), 943 (m), 758 cmꢀ1 (vs); MS
(EI, 70 eV): m/z (%): 384 (15) [M +], 356 (50), 209 (52), 140 (100), 125
(48), 105 (90) [C7H5O+], 77 (32), 40 (20); HRMS: m/z: calcd for
C21H20O7: 384.1209, found 384.1206.
less oil (536 mg, 0.83 mmol, 91%). Rf =0.23 (P/EA 50:50) [CAM]; [a]D20
=
101.2 (c=1.06, CHCl3); 1H NMR (360 MHz, [D6]benzene]): d=0.37 (s,
3H, MeSiCH3), 0.40 (s, 3H, H3CSiMe), 1.01 [s, 9H, SiC(CH3)3], 1.07 (s,
3H), 1.33 (s, 3H), 1.72 (ddd, J=12.5, 11.1, 1.6 Hz, 1H), 2.16 (dd, J=15.0,
1.6 Hz, 1H), 2.16–2.23 (m, 1H), 2.58 (ddd, J=15.0, 4.8, 2.3 Hz, 1H), 2.77
(s, 3H), 2.86 (d, J=13.9 Hz, 1H), 2.94 (d, J=13.9 Hz, 1H), 3.16 (s, 3H),
3.36–3.43 (m, 1H), 3.48–3.56 (m, 2H), 3.61 (d, J=12.7 Hz, 1H), 3.90–3.96
(m, 1H), 4.06 (d, J=12.7 Hz, 1H), 4.11 (tt, J=4.8, 1.6 Hz, 1H), 4.84 (d,
J=2.3 Hz, 1H), 4.92 (d, J=7.3 Hz, 1H), 5.21 (d, J=2.3 Hz, 1H), 5.26
(dd, J=11.1, 5.0 Hz, 1H), 5.83 (d, J=7.3 Hz, 1H), 7.24–7.27 (m), 8.00–
8.03 (m); 13C NMR (90.6 MHz, [D6]benzene]): d=ꢀ4.5 (q, MeSiCH3),
ꢀ4.3 (q, H3CSiMe), 18.4 [s, SiC(CH3)3], 26.3 [q, SiC(CH3)3], 26.5 (t), 30.3
(q), 31.9 (q), 35.6 (t), 39.4 (t), 40.6 (t), 54.8 (q), 58.8 (q), 66.5 (d), 67.8 (t),
70.5 (d), 72.5 (t), 79.0 (s), 84.8 (s), 88.1 (d), 92.2 (t), 99.5 (s), 103.5 (d),
128.8 (d), 129.0 (d), 132.0 (d), 141.0 (s), 162.3 (s), 163.4 (s), 170.4 (s),
198.1 (s); IR (neat): n˜ =3072 (m, Csp2-H), 2928 (s, Csp3-H), 1731 (vs sh, C=
O), 1681 (s), 1649 (s), 1568 (s), 1454 (s), 1412 (s), 1336 (s), 1249 (s), 1195
(s), 1027 (s sh), 1018 (s), 931 (s), 836 cmꢀ1 (s); MS (EI, 70 eV): m/z (%):
646 (1) [M +], 555 (2) [M +ꢀCH3], 513 (18) [M +ꢀtBu], 499 (22), 483
(20), 425 (42), 221 (23), 125 (68), 105 (100) [C7H5O+], 89 (94)
7022
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7007 – 7023

(+)-Wailupemycin B
FULL PAPER
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Acknowledgements
This work was supported by Bayer AG (Wuppertal) and by the Fonds
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Received: June 6, 2005
Published online: September 6, 2005
Chem. Eur. J. 2005, 11, 7007 – 7023
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