Total synthesis of (+)-ambruticin S

Article abstract of DOI:10.1016/S0040-4020(03)00370-3

A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh ₂[5(S)-MEPY]₄. Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48, which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4. 3% overall yield.

Full text of DOI:10.1016/S0040-4020(03)00370-3

Tetrahedron 59 (2003) 6819–6832
Total synthesis of (1)-ambruticin S
Stephen M. Berberich, Robert J. Cherney, John Colucci, Christine Courillon, Leo S. Geraci,
*
Thomas A. Kirkland, Matthew A. Marx, Matthias F. Schneider and Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas, 1 University Station A5300, Austin, TX 78712, USA
Received 21 January 2003; revised 10 March 2003; accepted 10 March 2003
Dedicated to Professor K. C. Nicolaou in recognition of his many contributions to organic chemistry and his receipt of the Tetrahedron Prize
Abstract—A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of
intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring
intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the
dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several
inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced
with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the
cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh2[5(S)-MEPY]4. Ring opening of the
resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A-
and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key
intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48,
which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone
49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the
sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various
protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
upon heating at 2408C to give a cycloheptadiene derivative
that showed no biological activity, suggesting that the
divinyl cyclopropane is required for biological activity.4
Ambruticin S (1) is a structurally novel antifungal antibiotic
that was isolated from the fermentation extracts of
Polyangium cellulosum var. fulvum in 1977 by researchers
at Warner–Lambert.1 Ambruticin S was initially considered
an interesting lead compound because of its low toxicity
coupled with its oral activity against several systemic fungal
infections.2 Following its discovery, a combination of
extensive chemical and spectral analysis was first employed
to elucidate the gross structural features of 1. However,
owing to its complexity, it was necessary to determine the
relative stereochemical structure of 1 by X-ray analysis of a
crystalline triformate derivative that was prepared from 1 by
sequential hydride reduction and exhaustive formylation.1
The absolute configuration of 1 was later established
through the independent synthesis of ozonolysis fragments.3
The presence of a divinyl cyclopropane linking two
hydropyranoid fragments in a natural product was unprece-
dented. It has also been shown that this divinyl cyclo-
propane moiety undergoes a sigmatropic rearrangement
Subsequent to their initial report, Connor’s group at
Warner–Lambert isolated the 5-epi-isomer of 1,5 and they
prepared a number of synthetic derivatives to explore the
structure activity relationships of ambruticin analogues.6
More recently, six natural ambruticins possessing quatern-
ary amines in the place of the C5 hydroxyl group were
isolated from P. cellulosum, and these compounds also
exhibited potent in vivo antifungal activity and low
toxicity.7 Taken together, the biological studies demonstrate
that the presence of polar functionality at C1, C5 and C6
was critical to the biological activity of the ambruticins. The
mechanism of action of 1 has recently been studied and
appears to involve interference with osmoregulation.8
However, the narrow spectrum of antifungal activity
exhibited by ambruticin S and its analogues limited the
clinical utility of these compounds.
The shortcomings of its biological profile notwithstanding,
ambruticin S remains an extremely attractive target for total
synthesis because of its unique structural features. Indeed, a
number of groups have developed synthetic approaches
toward ambruticin S.9 The first total synthesis of 1 was
Keywords: oxygen heterocycles; furan; carbohydrates; enantioselective;
rearrangement; ring closing metathesis; Julia coupling.
*
Corresponding author. Tel.: þ1-512-471-3915; fax: þ1-512-471-4180;
e-mail: sfmartin@mail.utexas.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00370-3

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S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
reported by Kende in 1990,10 but three additional syntheses
of 1 have recently been independently reported by
ourselves11 and the groups of Jacobsen12 and Lee.13
enantioselective reduction of 1-furyl-3-hydroxyacetone18
using Baker’s yeast,19 this technique proved rather cumber-
some on large scale, and we found that the Sharpless
dihydroxylation of vinyl furan20 provided an excellent
alternative route to large quantities of 2.21 Oxidation of 2
with singlet oxygen then furnished a mixture of anomeric
pyranones 3, which underwent acid-catalyzed cyclization to
give the bicyclic ketal 4 in 61% yield from 2 (Scheme 2).
Subsequent to our developing this approach to 4, Ogasawara
and co-workers published a closely related synthesis of 4
from 2.22 Reduction of 4 by catalytic hydrogenation
followed by reaction of the enolate of the resultant ketone
with PhNTf2 gave 5, reduction of which with Bu3SnH
provided the bicyclic olefin 6 in 50% overall yield.23,24 The
double bond in 6 was oxidized with m-chloroperbenzoic
acid (MCPBA), and the resulting mixture of a- and
b-epoxides was treated with KOH to give a single
diastereomeric diol that was converted to the dibenzyl
ether 7.25 The stereochemical outcome of the epoxide
opening reaction may be attributed to the preference for
hydroxide to attack the epoxide from an axial direction
irrespective of which diastereomeric epoxide was the
substrate.
Our analysis of the challenges posed by ambruticin S led to
the retrosynthetic analysis outlined in Scheme 1 in which
disconnections at the two disubstituted E-olefins are first
performed. The three fragments obtained from these
disconnections were an A-ring aldehyde A, a bifunction-
alized B-ring cyclopropane B and a C-ring sulfone C. Each
of these fragments has a similar degree of stereochemical
and functional complexity, thereby endowing the approach
with maximal convergency. We originally envisioned that
the central B ring fragment would be accessible via
methodology we had developed in collaboration with the
Doyle group for the enantioselective synthesis of tri-
substituted cyclopropanes via cyclizations of allylic
diazoacetates in the presence of a chiral rhodium catalyst.14
There were a number of options for constructing the
hydropyranoid A and C ring subunits. At the outset,
however, we had a particular prejudice for preparing these
fragments from dihydropyranones that would be prepared
via the oxidation of enantiomerically pure furans according
to strategies that have been under extensive development in
our laboratories.15,16 Carbohydrates were also considered as
potential precursors of the A and C rings. Although a
carbohydrate was ultimately chosen as the starting material
for the A ring, the C ring was eventually most readily
prepared by a ring closing metathesis, a transformation that
has gained considerable importance in natural product
synthesis.17 We now report the details of our studies
directed toward the total synthesis of 1.
Scheme 1.
Scheme 2.
2. Results and discussion
2.1. Approaches to the A-ring
With 7 in hand, it remained to install an acetic acid side
chain at C(3) to complete construction of the A-ring
subunit.26 Although 7 did react with the trimethylsilyl-
and tert-butyldimethylsilylketene acetals derived from
methyl acetate in the presence of Lewis acids,27 the yields
were poor with optimized yields being less than 15%. On
the other hand, reaction of 7 with allyltrimethylsilane in the
presence of TiCl4 provided a mixture (1:4) of the anomeric
C-glycosides 8a,b.28,29 These diastereomers were readily
In our first approach to a protected A-ring subunit, we
explored the use of the dihydropyranone 3, which was
prepared by oxidation of the hydroxy furan 2, as a key
intermediate. We had previously shown that various
dihydropyranones thus obtained admirably served as
intermediates in concise syntheses of highly oxygenated
natural products.16 Although we initially prepared 2 by the

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6821
separable and were independently subjected to ozonolysis
followed by oxidation with Br2 in aqueous methanol to
furnish the esters 9a and 9b. Both 9a and 9b gave H and
13C NMR spectral data that were consistent with those
reported by Donaldson,30 who also showed that 9b could be
readily epimerized to provide exclusively the desired isomer
9a.
trichloroacetimidate and benzyl bromide/silver oxide under
a variety of conditions gave unsatisfactory yields of the
desired dibenzyl ether 14.34,35 Ultimately we found that this
benzylation could be most effectively achieved by reaction
of 13 with benzyl triflate that was prepared in situ to furnish
14 in 51% yield.36
1
Heating 14 with NaOMe in MeOH induced a cascade of
reactions involving cleavage of the cyclic carbonate group,
transesterification of the ethyl ester, and intramolecular
Michael reaction that led to the formation of 9a. If this
reaction was allowed to proceed for short periods of time,
the C(3) epimeric ester 9b could be observed in the mixture.
However, heating the reaction mixture overnight effected
the complete equilibration of any 9b produced into 9a via a
retro-Michael/Michael process, although these conditions
resulted in significant saponification of the methyl ester, a
side reaction that was also observed by Donaldson.30 Hence,
the acid that was produced during this process was esterified
in situ by simply adding an excess of TsOH to the cooled
reaction mixture to deliver 9a in 75% overall yield from 14.
The sequence outlined in Scheme 2 provided a successful
entry to the A-ring subunit of ambruticin S, but we were
interested in developing a stereochemically more efficient
route. After considering a number of possibilities, it
occurred to us that the known aldehyde 10 (Scheme 3),
which could be easily synthesized from commercially
available L-glucono-1,5-lactone,31 might be a suitable
starting material. In the event, stereoselective Wittig
olefination of 10 provided ester 11. The terminal acetonide
moiety was selectively removed by the action of p-TsOH in
aqueous ethanol, and the intermediate diol was reprotected
as a cyclic carbonate.32 The subsequent deprotection of the
internal acetonide of 12 to give 13 proved troublesome, as
the carbonate function was too labile to withstand the
standard acidic conditions required for acetonide cleavage.
Eventually, we discovered that the acetonide group could be
cleanly removed using CuCl2 in acetonitrile to give the diol
13 in good overall yield from 10.33 The instability of the
carbonate to relatively mild acidic conditions served as a
harbinger of the difficulties that would follow as we found
that the cyclic carbonate in 13 was incompatible with a
number of standard conditions that are often employed to
prepare O-benzyl ethers. For example, the use of benzyl
ˆ
After we completed this route to 9a, Genet reported a
similar one-pot equilibration and esterification procedure
for its preparation.9k Oxidation of the primary alcohol group
in 9a using Dess–Martin periodinane37 furnished 15, which
exhibited spectral properties consistent with those pre-
viously reported,9k in seven steps and 18% overall yield
from 10. This stereoselective synthesis of 9a thus
represented a significant improvement over the approach
outlined in Scheme 2 in which 9a was prepared in 11 steps
and 12% overall yield via a sequence that required a
separation of diastereomers.
The route to the A-ring aldehyde 15 summarized in
Scheme 3 was reasonably efficient and was originally
employed to produce the quantities of material that were
needed to explore various model Julia couplings to append
the B ring (vide infra). However, the need to manipulate the
hydroxyl protecting groups was viewed as a serious
drawback to the approach, and so we developed an even
more expeditious synthesis of a suitable A-ring precursor.
Thus, 11 was heated with H2SO4 in MeOH to cleave both
acetonides and provide a complex mixture containing the
Scheme 4.
Scheme 3.

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S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
corresponding open-chain tetraol together with tetrahydro-
furans and tetrahydropyrans derived from the acyclic tetraol
via intramolecular Michael addition reactions (Scheme 4).
Precedent suggested that tetrahydrofurans might be kinetic
products,38 but on the basis of preliminary molecular
mechanics calculations,39 we were seduced into thinking
that the desired tetrahydropyran 16 would be significantly
more stable than the tetrahydrofurans. Gratifyingly, 16 was
isolated in 70% overall yield when this mixture was heated
under reflux in methanolic NaOMe for 24 h and the
resulting reaction mixture was acidified with H2SO4.
2.2. Synthesis of a B-ring subunit
At the outset of our studies we envisioned that suitable
B-ring subunit precursors would be best accessed via an
enantioselective cyclopropanation using a protocol that we
had developed previously.14 Thus, the known diazoacetate
19 was heated in the presence of Rh2[5(S)-MEPY]4 to
provide the bicyclic lactone 20 in 80% yield and 92%
enantiomeric excess (Scheme 5).40 The lactone ring was
opened using morpholine and AlMe3 according to the
Weinreb protocol to give alcohol 21.41 Inasmuch as we
wanted a robust alcohol protecting group to explore various
tactics for coupling the A and B rings (vide infra), the
alcohol 21 was protected as its TIPS ether 22. Base-induced
epimerization of the stereocenter alpha to the carbonyl
group in 22 to give 23 was driven by the conversion of the
more sterically congested all cis-trisubstituted cyclopropane
into a less strained cyclopropane ring in which the
carboxamide group was trans to the other two substituents.
Reduction of the amide moiety to give the requisite primary
alcohol 24 was smoothly effected with the LDA and
borane–ammonia complex reagent reported by Myers.42
Anticipating the union of the A and B subunits via a
standard Julia coupling procedure, the alcohol 24 was
converted into its derived phenyl sulfide that was then
oxidized with MCPBA to give the sulfone 25.43
Transformation of 16 into an A-ring aldehyde then
necessitated protection of the two secondary alcohols.
Toward this objective, the primary alcohol of 16 was first
selectively protected by reaction with TESCl at 08C;
however, several attempts to benzylate the secondary
alcohols to prepare a precursor of 15 were unsuccessful.
Another protecting group for these hydroxyl groups was
thus indicated. Although we were unable to convert these
alcohols cleanly into their TIPS ethers, the corresponding
TBS ethers were readily formed. Indeed, the entire sequence
of protecting the primary alcohol of 16 and then the two
secondary alcohols with TBS groups could be conveniently
performed in a one-pot procedure to provide ester 17 in
nearly quantitative yield. Selective deprotection of the TES
group with TFA followed by oxidation of the resulting
alcohol provided the A-ring aldehyde 18 in five steps and
46% overall yield from 10. This yield represented a
significant improvement over previous routes to similar
compounds.
2.3. Coupling the A-ring and B-ring subunits
Preliminary experiments directed toward joining the A- and
B-ring subunits 15 and 25 via a classic Julia coupling were
fraught with pitfalls (Scheme 6). For example, when 15 was
treated with the carbanion obtained upon deprotonation of
25 with either n-BuLi or NaHMDS, none of the desired
adduct was obtained. Rather sulfone 25 was isolated
together with an unsaturated aldehyde that appeared to
arise from 15 through deprotonation followed by elimin-
ation of benzyl alkoxide. Some years ago, Lythgoe
discovered a solution to this problem and reported that
magnesium, rather than lithium or sodium, salts of sulfones
added cleanly to highly enolizable aldehydes.44 We found,
Scheme 5.
Scheme 6.

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6823
however, that direct deprotonation of 25 with EtMgBr was
sluggish, even at elevated temperature, and provided only
about 50% of the deprotonated sulfone as determined by
quenching of the reaction mixture with CD3OD. On the
other hand, deprotonation of 25 with n-BuLi at 2788C
proceeded quantitatively. The resulting lithiated sulfone
was transmetallated by reaction with ethereal MgBr2·Et2O
prepared according to the procedure of Seebach45 to provide
the corresponding magnesio sulfone,46 which did react with
the aldehyde 15 to furnish a mixture of diastereomeric
hydroxy sulfones 26, albeit in modest yield.
significant quantities of a bisbenzothiazole sulfone, which
was presumably formed through a disproportionation
reaction as described by Kocienski.53 However, when a
solution of 15 and 30 in DMF was treated with NaHMDS,
the desired alkene 27 together with its Z-isomer were
obtained. Although these isomers were inseparable, removal
of the TIPS protecting group provided a separable mixture
of the alcohols 31E and 31Z in a 1.4 to 1 ratio. The 31E thus
1
exhibited H NMR spectral characteristics consistent with
those reported by Kende,10b thus completing a formal total
synthesis of ambruticin S.11a
Despite this success, converting the diastereomeric hydroxy
sulfones 26 into the desired olefin 27 proved to be
problematic. When 26 was subjected to standard conditions
using sodium amalgam to effect reductive elimination, none
of the desired 27 could be detected in the reaction mixture,
and no other identifiable products were isolated. We
speculated that these difficulties might be a consequence
of ring opening of the cyclopropyl carbinyl radical that
would be generated upon homolytic scission of the carbon–
sulfur bond. In one attempt to avoid forming this putative
radical intermediate, 26 was transformed into the xanthate
28, but reaction of 28 with Bu3SnH failed to provide 27.47
Falck had encountered similar difficulties in related
constructions, and he solved his problem by discovering
that cyclopropyl vinyl sulfones could be reduced by electron
transfer to give the corresponding vinyl cyclopropanes.48 In
order to explore this tactic as a possible solution to our
dilemma, we converted several model cyclopropyl hydroxy
sulfones into the corresponding vinyl cyclopropanes by
sequential dehydration using either Tf2O or the Martin
sulfurane49 and reduction of the resultant vinyl sulfone.
However, we were unable to induce efficient elimination of
26 to the vinyl sulfone 29.
We were, of course, interested in improving the E/Z ratio in
this coupling process. Julia,54 Kocienski51 and Charette52 all
reported that the E/Z ratio in their studies was dependent
upon both the solvent and the counterion employed. In
contrast, we found that changing the solvents (THF, DME,
DMF and Et2O) as well as the counterions (Na and K) had
little effect upon the E/Z ratio in this reaction. Use of the
phenyl tetrazole sulfone corresponding to 30 as described by
Kocienski also afforded no advantage.51 Although we
briefly examined the possibility of isomerizing the unde-
sired cis-isomer 31Z using iodine, these experiments were
unavailing, and we therefore had to be content with the
result.
Contemporaneous with the successful coupling of 15 with
30, we developed the improved synthesis of the modified
A-ring precursor 18 that is summarized in Scheme 4. In
planning this approach, ancillary studies suggested that TBS
ethers on the A-ring might not be fully compatible with the
conditions required to remove the TIPS protecting group
from the primary cyclopropyl carbinol in an advanced AB-
ring intermediate. We thus prepared the TBS-protected
benzothiazole sulfone 33 following the procedures pre-
viously developed for the synthesis of 30 (Scheme 8). The
A-ring aldehyde 18 and the sulfone 33 were then coupled
using the previously optimized conditions to give a mixture
(2.6:1) of isomeric E- and Z-alkenes. Although the E/Z ratio
was somewhat higher for this reaction than for the
corresponding coupling of 30 and 15, the overall yield
Given these failures using a phenyl sulfone and the classic
Julia procedure, we turned to modified Julia coupling
methods in which the anion of either a benzothiazole
sulfone50 or a phenyl tetrazole sulfone51 is employed as the
reacting nucleophile. Aldehyde adducts derived from both
of these sulfones were known to eliminate spontaneously in
situ, and Charette had exploited such couplings to form
vinyl cyclopropanes.52 Toward applying this methodology
to solving the problem in our synthesis, the benzothiazole 30
was first prepared from 24 (Scheme 7). The stepwise
procedure of deprotonating 30 followed by adding 15 gave
Scheme 7.
Scheme 8.

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S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
was slightly lower. This mixture of fully protected
geometric isomers was separable, but the chromatography
was tedious. Because the corresponding primary alcohols
were easy to separate, the mixture of alkenes formed from
the Julia coupling was simply treated with aqueous
CF3CO2H to selectively remove the TBS group from the
primary alcohol function to give 34E and 34Z. Oxidation of
the primary hydroxyl group of 34E using Dess–Martin
periodinane then furnished the aldehyde 35.37
organometallic species or 41 under a wide variety of
conditions. This inability to add organometallic reagents to
lactone 39 necessitated a dramatic change in our approach to
the C-ring subunit of ambruticin S.
Inasmuch as we were concurrently exploiting ring closing
metathesis (RCM) as a key step in several other projects,61 it
occurred to us that such a construction might constitute a
useful entry to the C-ring. Toward this end, we developed an
improved enantioselective synthesis of the known alcohol
4262 in 53% yield and 97% ee by the TADDOL-mediated
addition of Et2Zn to methacrolein.57 This alcohol was then
O-alkylated with tert-butyl bromoacetate under phase
transfer conditions, and the enolate derived from the
resulting ester was alkylated with allyl bromide to provide
diene 43 as a mixture (1:1.3) of diastereomers (Scheme 10).
Although small amounts of each diastereomer could be
obtained through careful chromatography, this procedure
would obviously not be amenable to preparing larger
quantities of material. Hence, the mixture was stirred at
room temperature in the presence of Grubbs’ catalyst63 to
provide the dihydropyran 44, also as a mixture (1:1.3) of
diastereomers. We had originally anticipated that this
mixture could be equilibrated using base to provide the
desired cis-2,6-disubstituted hydropyran exclusively.
Unfortunately, exposing 44 to a variety of bases in different
solvents simply returned the same ratio of C(18) epimers.
2.4. Synthesis of the C-ring
Our initial approach to the C-ring was based on the
oxidative rearrangement of hydroxy furans that we had
previously exploited in our laboratories.16 We first
developed
a
new procedure for preparing the
known enone 3655 via the singlet oxygen oxidation of
(þ)-1-furyl-1-propanol,56 which was synthesized by the
TADDOL-mediated addition of Et2Zn to furfural.57 Silyla-
tion of 36 provided 37a,b as a mixture (3:1) of anomers
(Scheme 9). In principle, each of these anomers could have
been transformed into the lactone 39; however, because the
ensuing 1,4-reduction of 37b was not clean, they were
separated and 37a was used in subsequent experiments. In
order to avoid epimerization of the stereocenter bearing the
ethyl side chain during conjugate reduction, it was
necessary to add 37a to a solution of L-Selectride according
to a protocol developed by Paquette.58 The intermediate
enolate was trapped as its triflate, which was then treated
with Me2CuLi to deliver the trisubstituted olefin 38.59
Removal of the silyl protecting group followed by PCC
oxidation of the resultant lactol provided the lactone 39.
Scheme 10.
Although this study clearly demonstrated the viability of
using a RCM reaction to assemble the C-ring hydropyran
with its trisubstituted double bond, it also revealed the
necessity of correctly establishing the stereocenter at C(18)
prior to ring formation. A different diene was thus required
as a starting material. Toward this goal, the known epoxide
4564 was converted into its tosylate 46 (Scheme 11). The
ring opening of the epoxide moiety of 46 with 42 in the
presence of BF3·Et2O proceeded regioselectively as
expected to give 47,65 and reduction of the tosylate
with LiAlH4 gave the requisite diene 48 in 65%
overall yield from 46. Heating 48 with Grubbs’ catalyst
followed by oxidation of the intermediate alcohol with
catalytic TPAP provided the methyl ketone 49 as a single
diastereomer.
Scheme 9.
We had originally envisioned that addition of an organo-
metallic reagent such as 4160 to lactone 39 followed by
reduction with Et3SiH and BF3·Et2O would provide the
C-ring subunit 40. Unfortunately, this expectation was
overly optimistic as we obtained at best low yields of
adducts from reactions of 39 with either simple vinyl
With ketone 49 in hand, it remained to append the C-14 to
C-17 segment that would be linked to the AB-ring subunit
35. We reasoned that this goal might be best achieved using
a [2,3]-Wittig rearrangement. Toward this end, addition of
propenylmagnesium bromide to 49 proceeded with

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6825
the aldehyde 35 and the C-ring sulfone 52 (Scheme 12). In
the event, deprotonation of 52 with n-BuLi followed by
addition of 35 provided a mixture of diastereomeric hydroxy
sulfones that was not characterized. Rather, the mixture was
treated directly with Na/Hg to provide 53E/Z as an
inseparable mixture (E/Z<10:1) of isomers in 56%
combined yield.70 When the TBS protecting groups were
removed with HF·pyridine, the ambruticin S methyl ester
(54) was isolated in 50% overall yield from 52. The 54 thus
1
obtained exhibited H NMR spectral characteristics con-
sistent with those previously reported.10b Saponification of
54 with LiOH delivered synthetic (þ)-ambruticin S (1),
which was identical with an authentic sample of natural
ambruticin S by TLC, 1H and 13C NMR (including HMQC),
MS and optical rotation.
3. Conclusions
A highly convergent synthesis of ambruticin S (1) was
accomplished in 28 total steps with a 4.3% overall yield for
the longest linear sequence, which comprised only 13 steps
from the cyclopropyl lactone 20. The synthesis featured a
catalytic enantioselective cyclopropanation for the prep-
aration of the B-ring precursor of 1. A RCM reaction and a
stereoselective [2,3]-Wittig rearrangement were utilized to
construct the C-ring subunit, whereas the A-ring subunit
was prepared from a carbohydrate. The synthesis also
highlighted a modified Julia coupling to join the A- and
B-ring fragments and a traditional Julia coupling to
complete the assembly of the skeletal framework.
Scheme 11.
chelation control and with .95% diastereoselectivity to
give the tertiary alcohol 50,66 which was alkylated with
trimethyltinmethyl iodide67 to provide an intermediate
stannane. When this stannane was treated with n-BuLi, a
highly diastereoselective (.20:1) [2,3]-Wittig rearrange-
ment ensued to give the homoallylic alcohol 51,68 which
possessed both the requisite S-configuration at C(15) and the
E-olefin geometry at C(16)–C(17). Transformation of 51
into the sulfone 52 was achieved in 89% overall yield by
sequential reaction with N-thiophenylsuccinimide and
PBu3, followed by oxidation of the intermediate sulfide
with ammonium molybdate/H2O2.69
4. Experimental
4.1. General
All reagents and solvents were used as received, except as
noted below. Tetrahydrofuran (THF), diethyl ether (Et2O),
toluene, dimethylformamide (DMF), and methanol (MeOH)
were purified using solvent columns as described by
Grubbs.71 Dichloromethane (CH2Cl2), diisopropylamine,
and triethylamine (NEt3) were distilled from CaH2. All
moisture sensitive reactions were performed under a
nitrogen or argon atmosphere in oven dried glassware.
Flash chromatography was performed using Merck silica
gel 60 (230–400 mesh ASTM) according to the Still
protocol.72 Percent yields are given for compounds that
The stage was then set for the final assembly of the
ambruticin S framework via the Julia coupling between
1
1
were $95% pure as judged by H NMR spectroscopy. H
and 13C NMR spectra were recorded on 300 or 500-MHz
spectrometers in CDCl3 unless otherwise specified; indi-
vidual peaks are reported as (multiplicity, coupling constant
in Hz, number of hydrogens). Spectral splitting patterns are
designated as: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; comp, complex multiplet; br, broad. Melting
points are uncorrected.
4.1.1. (5S,6R,7S)-5,6;7,8-Diisopropylidene-5,6,7,8-tetra-
hydroxyoct-2-enoic acid, ethyl ester (11). A solution of
aldehyde 1031 (0.10 g, 0.41 mmol) and carboethoxymethyl-
ene triphenylphosphorane (0.21 g, 0.61 mmol) in THF
(3 mL) was stirred at room temperature for 18 h. The
solvent was removed under reduced pressure, and the
Scheme 12.

6826
S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
resulting paste was filtered through a plug of silica gel using
Et2O (75 mL). The filtrate was concentrated under reduced
pressure, and the resulting yellow oil was purified by flash
chromatography over silica gel eluting with EtOAc/hexanes
(15:85) to provide 110 mg (85%) of 11 as a clear colorless
3.09 (ddd, J¼9.0, 5.0, 2.1 Hz, 1H), 2.56 (dd, J¼15.4,
7.4 Hz, 1H), 2.35 (dd, J¼15.3, 5.8 Hz, 1H), 1.97 (ddd,
J¼12.7, 4.8, 1.8 Hz, 1H), 1.32 (q, J¼12.6 Hz, 1H), 0.93 (t,
J¼8.0 Hz, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.54 (q,
J¼8.1 Hz, 6H), 0.07 (s, 3H), 0.06 (s, 9H); 13C NMR d
171.5, 81.3, 74.8, 72.8, 71.4, 62.5, 51.5, 40.7, 40.6, 26.4,
26.2, 18.4, 18.1, 6.7, 4.6, 22.8, 22.9, 23.9, 24.7; IR (neat)
2956, 2359, 1748, 1471, 1255 cm21; MS (CI) m/z 563.3622
[C27H59O6Si3 (Mþ1) requires 563.3620] (base), 533, 505,
431, 299.
1
oil: H NMR d 7.04 (dt, J¼15.7, 7.2 Hz, 1H), 5.94 (dt,
J¼15.7, 1.2 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 4.15–3.90
(comp, 4H), 3.57 (t, J¼8.0 Hz, 1H), 2.73 (dddd, J¼16.8,
8.2, 3.4, 1.6 Hz, 1H), 2.50 (dddd, J¼15.3, 8.9, 7.7, 1.6 Hz,
1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H),
1.29 (t, J¼7.1 Hz, 3H); 13C NMR d 166.3, 144.4, 123.6,
110.0, 109.3, 80.5, 78.8, 77.1, 67.8, 60.2, 35.8, 27.1, 26.9,
26.7, 25.2, 14.2; IR (neat) 2986, 2874, 1746, 1658, 1455,
1372 cm21; MS (CI) m/z 315.1809 [C16H27O6 (Mþ1)
requires 315.1808] (base), 275, 257, 217.
4.1.4. [2,3-Bis-O-tert-butyldimethylsilyl-4,6-dideoxy-6-
(methoxycarbonyl)-D-gluco-b-C-pyranosyl]methanol. A
solution of 17 (36 mg, 0.064 mmol) and trifluoroacetic acid
(0.049 mL, 0.64 mmol) in THF (2 mL) and H2O (0.1 mL)
was stirred for 3 h at room temperature. Saturated aqueous
NaHCO3 (4 mL) and Et2O (4 mL) were added, and the
layers were separated. The aqueous layer was extracted with
Et2O (2£2 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The
resulting clear oil was purified by flash chromatography
over silica gel eluting with EtOAc/hexanes (1:4) to provide
23 mg (81%) of alcohol as a clear colorless oil: 1H NMR d
3.93–3.88 (m, 1H), 3.81 (dd, J¼11.4, 2.8 Hz, 1H), 3.75–
3.69 (m, 1H) 3.72 (s, 3H), 3.60 (dd, J¼11.4, 6.2 Hz, 1H),
3.34 (t, J¼7.8 Hz, 1H), 3.25 (ddd, J¼9.1, 6.2, 2.8 Hz, 1H),
2.58 (dd, J¼15.5, 7.7 Hz, 1H), 2.44 (dd, J¼15.5, 5.3 Hz,
1H), 2.02 (ddd, J¼12.9, 4.8, 1.9 Hz, 1H), 1.58 (br s, 1H),
1.42 (q, J¼12.9 Hz, 1H), 0.92 (s, 9H), 0.91 (s, 9H), 0.12 (s,
3H), 0.11 (s, 6H), 0.10 (s, 3H); 13C NMR (CDCl3,
125 MHz) d 171.1, 80.4, 74.4, 73.2, 71.7, 62.6, 51.7, 40.6,
40.4, 26.3, 26.1, 18.3, 18.0, 22.8, 22.9, 24.1, 24.6; IR
(neat) 3506, 2964, 2353, 2334, 1745, 1467 cm21; MS (CI)
m/z 449.2751 [C21H45O6Si2 (Mþ1) requires 449.2755]
(base), 433, 391, 317, 301.
4.1.2. [4,6-Dideoxy-6-(methoxycarbonyl)-D-gluco-b-C-
pyranosyl]methanol (16). A solution of H2SO4 (0.1 M in
MeOH, 0.57 mL) was added to a solution of 11 (90 mg,
0.29 mmol) in anhydrous MeOH (3 mL), and this mixture
was heated under reflux for 3 h. The reaction was cooled to
room temperature and the solvent removed in vacuo. The
resultant white solid was redissolved in MeOH (3 mL), and
the solution heated under reflux for 3 h; this process was
repeated an additional time. The reaction was then stirred
for 16 h at room temperature, at which time NaOMe (0.5 M
in MeOH, 0.86 mL) was added. This mixture was heated
under reflux for an additional 24 h. The solution was then
cooled to room temperature and H2SO4 (0.1 M in MeOH)
was added until the solution was strongly acidic (pH<1).
The reaction was stirred for 2 h at room temperature, and
saturated aqueous NaHCO3 was added until the mixture was
neutral. The insoluble salts were removed by filtration, and
the filtrate was concentrated under reduced pressure. The
resulting yellow oil was purified by flash chromatography
over silica gel eluting with MeOH/CH2Cl2 (1:9) to provide a
white solid. This was recrystallized using EtOAc/hexanes
(2:1) to provide 44 mg (70%) of 16 as a white solid: mp
4.1.5. [2,3-Bis-O-tert-butyldimethylsilyl-4,6-dideoxy-6-
(methoxycarbonyl)-D-gluco-b-C-pyranosyl] aldehyde
(18). A suspension of alcohol from the preceding experi-
ment (14 mg, 0.031 mmol) and Dess–Martin periodinane
(27 mg, 0.062 mmol) in CH2Cl2 (0.5 mL) was stirred for 1 h
at room temperature. A solution of 1 M aqueous NaOH
(1 mL) was added, and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (1£2 mL), and the
combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure. The resulting clear oil was
purified by flash chromatography over silica gel eluting with
EtOAc/hexanes (1:4) to provide 13.5 mg (96%) of 18 as a
1
114–1158C; H NMR (CD3OD) d 3.92–3.77 (comp, 2H),
3.66 (s, 3H), 3.64–3.50 (comp, 2H), 3.17 (d, J¼1.8 Hz, 1H),
3.15 (s, 1H), 2.59 (dd, J¼15.6, 7.7 Hz, 1H), 2.48 (dd,
J¼15.6, 5.5 Hz, 1H), 2.00 (ddd, J¼12.7, 5.1, 1.9 Hz, 1H),
1.33 (q, J¼11.5 Hz, 1H); 13C NMR (CD3OD) d 173.2, 81.6,
73.5, 73.1, 73.0, 62.9, 52.2, 41.1, 39.9; MS (CI) m/z
221.1020 [C9H17O6 (Mþ1) requires 221.1025], 185 (base),
171, 129.
4.1.3. [1-O-Triethylsilyl-2,3-bis-O-tert-butyldimethyl-
silyl-4,6-dideoxy-6-(methoxycarbonyl)-D-gluco-b-C-pyr-
anosyl]methanol (17). To a solution of 16 (50 mg,
0.23 mmol) and 2,6-lutidine (0.29 mL, 2.49 mmol) in
CH2Cl2 (2.5 mL) at 08C was added TESCl (0.057 mL,
0.34 mmol), and the mixture was stirred for 30 min at 08C.
Freshly distilled TBSOTf (0.21 mL, 0.91 mmol) was then
added, and stirring was continued for another 30 min at 08C.
Saturated aqueous NaHCO3 (2 mL) was added, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (2£2 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
The resulting clear oil was purified by flash chromatography
over silica gel eluting with EtOAc/hexanes (5:95) to provide
1
clear, colorless oil: H NMR d 9.61 (d, J¼1.8 Hz, 1H),
4.01–3.90 (m, 1H), 3.80–3.74 (m, 1H), 3.73 (dd, J¼8.5,
1.9 Hz, 1H) 3.67 (s, 3H), 3.52 (t, J¼8.3 Hz, 1H), 2.67 (dd,
J¼15.8, 7.3 Hz, 1H), 2.44 (dd, J¼15.8, 5.8 Hz, 1H), 2.04
(ddd, J¼13.2, 4.8, 2.5 Hz, 1H), 1.42 (q, J¼12.1 Hz, 1H),
0.88 (s, 9H), 0.86 (s, 9H), 0.08 (s, 6H), 0.07 (s, 3H), 20.04
(s, 3H); 13C NMR d 198.4, 171.0, 84.1, 73.4, 72.9, 71.3,
51.7, 40.3, 39.5, 26.2, 25.9, 18.2, 17.9, 23.3, 23.4, 24.4,
24.5; IR (neat) 3473, 2962, 2486, 2334, 1750, 1725 cm21
;
MS (CI) m/z 447.2597 [C21H43O6Si2 (Mþ1) requires
447.2598] (base), 431, 389, 315, 299.
4.1.6. (1R,2S,3R)-2-Hydroxymethyl-3-methyl-1-(mor-
pholino)carbonylcyclopropane (21). To a solution of
morpholine (0.23 mL, 2.7 mmol) in CH2Cl2 (10 mL) was
1
126 mg (99%) of 17 as a clear colorless oil: H NMR d
3.82–3.61 (comp, 4H), 3.66 (s, 3H), 3.33 (t, J¼8.9 Hz, 1H),

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6827
added AlMe3 (1.3 mL, 2.0 M in hexanes) over 15 min. This
solution was stirred for 15 min, and 2040 (100 mg,
0.89 mmol) was added. After stirring for 72 h, the reaction
was cooled to 08C, and 1N HCl (10 mL) was slowly added.
The resulting heterogeneous mixture was stirred for 1 h at
room temperature, and then the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3£10 mL). The
combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure. The resulting oil was purified
by flash chromatography over silica gel eluting with EtOAc
solution of i-Pr2NH (0.10 mL, 0.74 mmol) in THF (2 mL)
at 08C was added n-BuLi (0.55 mL, 1.35 M in hexanes), and
the solution was stirred for 5 min. BH3·NH3 (26 mg,
0.74 mmol) was added, and the cloudy suspension was
stirred for 15 min at 08C and 15 min at room temperature. A
solution of amide from the preceding experiment (58 mg,
0.19 mmol) in THF (1 mL) was added, and the reaction was
stirred for 90 min at 08C. A solution of 1 M HCl (2 mL) was
then added dropwise until the mixture was neutral. H2O
(2 mL) and Et2O (6 mL) were then added, and the layers
were separated. The aqueous layer was extracted with Et2O
(2£2 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography over silica gel
eluting with NEt3/EtOAc/hexanes (2:23:75) to provide
1
to provide 165 mg (93%) of 21 as a clear, colorless oil: H
NMR d 4.07 (br s, 1H), 3.88 (dd, J¼12.0, 6.2 Hz, 1H),
3.80–3.45 (comp, 9H), 1.71 (t, J¼8.8 Hz, 1H), 1.57–1.34
(comp, 2H), 1.05 (d, J¼6.5 Hz, 3H); 13C NMR d 169.5,
66.8, 58.7, 46.1, 41.9, 23.1, 22.8, 16.0, 9.4; IR (CHCl3)
3540–3040, 2965, 2915, 2875, 1625, 1480 cm21; MS (CI)
m/z 199.1219 [C10H17NO3 (M) requires 199.1208] (base),
182, 168, 114.
1
37 mg (86%) of 32 as a clear, colorless oil: H NMR d
3.67 (dd, J¼10.9, 6.4 Hz, 1H), 3.56 (dd, J¼10.9, 7.3 Hz,
1H), 3.50 (dd, J¼11.1, 6.7 Hz, 1H), 3.36 (dd, J¼11.1,
7.3 Hz, 1H), 1.72 (br s, 1H), 1.07 (d, J¼6.0 Hz, 3H), 0.95–
0.77 (comp, 2H), 0.86 (s, 9H), 0.73–0.62 (m, 1H), 0.03 (s,
6H); 13C NMR d 66.5, 62.3, 27.3, 26.0, 23.8, 18.3, 15.5,
12.7, 25.2; IR (neat) 3356, 2955, 2857, 1472, 1391,
1255 cm21; MS (CI) m/z 231.1785 [C12H27O2Si (Mþ1)
requires 231.1780], 213 (base), 194, 186, 182.
4.1.7. (1R,2S,3R)-3-Methyl-1-(morpholino)carbonyl-2-
(tert-butyldimethylsilyloxy)methylcyclopropane. To
a
solution of 21 (38 mg, 0.19 mmol) and 2,6-lutidine
(0.089 mL, 0.76 mmol) in CH2Cl2 (2 mL) at 08C was
added freshly distilled TBSOTf (0.066 mL, 0.29 mmol),
and the solution was stirred for 30 min at 08C. Saturated
aqueous NaHCO3 (4 mL) was added, and the layers were
separated. The aqueous layer was extracted with CH2Cl2
(2£2 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure to
provide 58 mg (97%) of protected alcohol as a clear,
4.1.10. (1S,2S,3S)-1-[(Benzothiazolo)thio]methyl-2-
methyl-3-(tert-butyldimethylsilyloxy)methyl cyclopro-
pane. A solution of 32 (71 mg, 0.31 mmol), 2-mercapto-
benzothiazole (62 mg, 0.37 mmol), Ph3P (97 mg,
0.37 mmol), and DEAD (0.058 mL, 0.37 mmol) in THF
(3 mL) was stirred at room temperature for 18 h. The
solvent was removed under reduced pressure, and the
residue was purified by flash chromatography over silica gel
eluting with CH2Cl2/hexanes (1:4) to provide 116 mg (99%)
1
colorless oil that was used without further purification: H
NMR d 3.95 (dd, J¼11.5, 5.4 Hz, 1H), 3.79 (dd, J¼11.5,
8.1 Hz, 1H), 3.61–3.38 (comp, 8H), 1.62 (t, J¼9.0 Hz, 1H),
1.41–1.12 (comp, 2H), 1.08 (d, J¼6.2 Hz, 3H), 0.82 (s, 9H),
20.02 (s, 6H); 13C NMR d 169.3, 67.0, 59.1, 46.2, 41.8,
26.0, 24.1, 21.1, 18.2, 15.7, 8.3, 25.2; IR (neat) 2953, 2851,
1
of sulfide as a clear, colorless oil: H NMR d 7.84 (ddd,
J¼8.1, 1.1, 0.6 Hz, 1H), 7.72 (ddd, J¼8.0, 1.2, 0.6 Hz, 1H),
7.38 (ddd, J¼8.1, 7.3, 1.2 Hz, 1H), 7.26 (ddd, J¼8.4, 7.3,
1.2 Hz, 1H), 3.75 (dd, J¼11.0, 6.0 Hz, 1H), 3.50 (dd, J¼8.1,
11.0 Hz, 1H) 3.35 (dd, J¼12.8, 7.3 Hz, 1H), 3.30 (dd,
J¼12.9, 7.3 Hz, 1H), 1.13–1.05 (m, 1H), 1.08 (d, J¼6.3 Hz,
3H), 1.00–0.93 (m, 1H), 0.87 (s, 9H), 0.85–0.80 (m, 1H),
0.03 (s, 3H), 0.02 (s, 3H); 13C NMR d 167.2, 153.4, 135.3,
126.0, 124.1, 120.9, 62.1, 38.6, 26.9, 26.0, 23.4, 18.8, 18.3,
12.6, 25.2, 25.3; IR (neat) 2956, 2928, 2856, 1428, 1428,
1251 cm21; MS (CI) m/z 380.1542 [C19H30NOSiS2 (Mþ1)
requires 380.1538] (base), 364, 322, 248, 213.
2364, 1659, 1462 cm21
;
MS (CI) m/z 314.2149
[C16H32NO3Si (Mþ1) requires 314.2151] (base), 298,
256, 182.
4.1.8. (1S,2S,3R)-3-Methyl-1-(morpholino)carbonyl-2-
(tert-butyldimethylsilyloxy)methylcyclopropane (23). To
a solution of preceding cyclopropane amide (159 mg,
0.51 mmol) in THF at 08C was added NaHMDS (0.56 mL,
1.0 M in THF), and the solution was stirred for 90 min at
08C. Saturated aqueous NH4Cl (2 mL) and Et2O (4 mL)
were then added, and the layers were separated. The
aqueous layer was extracted with Et2O (2£2 mL), and the
combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure. The resulting yellow oil was
purified by flash chromatography over silica gel eluting with
EtOAc/hexanes (35:65) to provide 146 mg (92%) of
4.1.11. (1S,2S,3S)-1-[(Benzothiazolo)sulfonyl]methyl-2-
methyl-3-(tert-butyldimethylsilyloxy)methylcyclopro-
pane (33). A suspension of sulfide from the preceeding
experiment (54 mg, 0.14 mmol), MCPBA (50 mg,
0.29 mmol) and NaHCO3 (60 mg, 0.72 mmol) in CH2Cl2
(2 mL) was stirred for 24 h at room temperature. Saturated
aqueous NaHCO3 (2 mL) and Na2S2O3 (2 mL) were added
and the layers separated. The aqueous layer was extracted
with CH2Cl2 (2£2 mL), and the combined organic layers
were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography
over silica gel eluting with EtOAc/hexanes (1:9) to provide
48 mg (82%) of 33 as a white solid: mp 84–868C; 1H NMR
d 8.20–8.16 (m, 1H), 8.01–7.97 (m, 1H), 7.64–7.52 (comp,
2H), 3.61 (dd, J¼11.0, 5.3 Hz, 1H), 3.54 (dd, J¼14.7,
6.6 Hz, 1H), 3.40 (dd, 14.7, 7.5 Hz, 1H), 3.31 (dd, J¼10.9,
1
epimerized amide as a clear, colorless oil: H NMR d 3.69
(dd, J¼11.0, 4.4 Hz, 1H), 3.68–3.48 (comp, 9H), 1.57–1.52
(comp, 2H), 1.31 (t, J¼4.7 Hz, 1H), 1.08 (d, J¼6.2 Hz, 3H),
0.81 (s, 9H), 20.02 (s, 6H); 13C NMR d 171.3, 66.7, 61.0,
45.8, 42.3, 28.1, 25.7, 24.5, 19.4, 18.1, 12.0, 25.4; IR (neat)
2951, 2857, 1647, 1466 cm21; MS (CI) m/z 314.2144
[C16H32NO3Si (Mþ1) requires 314.2151] (base), 298, 256,
182.
4.1.9. (1S,2S,3S)-1-Hydroxymethyl-3-methyl-2-(tert-
butyldimethylsilyloxy)methylcyclopropane (32). To a

6828
S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
8.3 Hz, 1H), 0.94 (d, J¼5.9 Hz, 3H), 0.98–0.67 (comp, 3H),
0.78 (s, 9H), 20.09 (s, 6H); 13C NMR d 166.1, 152.8, 136.7,
127.9, 127.6, 125.3, 122.3, 61.4, 59.2, 25.8, 25.2, 18.1, 17.4,
16.4, 12.1, 25.5; IR (CH2Cl2) 2956, 2929, 2856, 1473,
1333, 1270, 1090 cm21; MS (CI) m/z 412.1432 [C19H30-
NO3S2Si (Mþ1) requires 412.1436], 354, 280 (base), 256.
J¼13.0, 8.2, 4.8 Hz, 1H), 3.65 (s, 3H), 3.53 (dd, J¼11.4,
8.6 Hz, 1H), 3.26 (t, J¼8.4 Hz, 1H), 2.62 (dd, J¼15.7,
6.8 Hz, 1H), 2.39 (dd, J¼15.9, 6.2 Hz, 1H), 2.01 (ddd,
J¼12.8, 4.8, 1.8 Hz, 1H), 1.40 (q, J¼12.6 Hz, 1H),
1.31–1.26 (m, 1H), 1.15 (d, J¼6.4 Hz, 3H), 1.13–1.10
(m, 1H), 1.01–0.96 (m, 1H), 0.89 (s, 9H), 0.83 (s, 9H), 0.08
(s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR d
171.3, 138.5, 126.6, 76.9, 76.7, 74.5, 71.5, 61.9, 51.6, 40.7,
40.5, 28.1, 26.3, 26.2, 23.9, 19.8, 18.3, 18.0, 12.3, 22.8,
22.9, 23.5, 24.1; IR (neat) 3444, 2956, 2925, 2883, 2857,
4.1.12. Methyl (8E,10S,11S,12S)-2,3-di-O-tert-butyl-
dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-hydroxy-
methylcyclopropylethenyl]-D-glucoheptopyranuronate
(34E) and methyl (8Z, 10S,11S,12S)-2,3-di-O-tert-butyl-
dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-hydroxy-
methylcyclopropylethenyl]-D-glucoheptopyranuronate
(34Z). To a solution of aldehyde 18 (35 mg, 0.078 mmol)
and sulfone 33 (48 mg, 0.12 mmol) in DMF (0.5 mL) at
2608C was added a solution of NaHMDS (22 mg,
0.12 mmol) in DMF (1.5 mL). The reaction was stirred for
1 h at 2608C, the cold bath was removed, and the reaction
was stirred at room temperature for 30 min. Saturated
aqueous NH4Cl (5 mL) and Et2O (6 mL) were added, and
the layers were separated. The aqueous layer was extracted
with Et2O (3£4 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
The resulting yellow-brown oil was purified by flash
chromatography over silica gel eluting with EtOAc/NEt3/
hexanes (4:2:94) to provide 28 mg of the desired adduct as a
clear, colorless oil that was a mixture of inseparable olefin
1732, 1660, 1463 cm21
; MS (CI) m/z 529.3380
[C27H53O6Si2 (Mþ1) requires 529.3381], 511, 379, 265,
243 (base).
4.1.13. Methyl (8E,10S,11S,12S)-2,3-di-O-tert-butyl-
dimethylsilyl-1,4-dideoxy-1b-[11-methyl-12-formyl-
cyclopropylethenyl]-D-glucoheptopyranuronate (35). A
suspension of 34E (26 mg, 0.049 mmol) and Dess–Martin
periodinane (42 mg, 0.098 mmol) in CH2Cl2 (1 mL) was
stirred at room temperature for 90 min. A solution of 1 M
aqueous NaOH (2 mL) was added, and the layers were
separated. The aqueous layer was extracted with CH2Cl2
(1£2 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure to
provide 24 mg (92%) of 35 as a clear, colorless oil which
1
was used without further purification: H NMR d 9.46 (d,
J¼4.6 Hz, 1H), 5.56 (dd, J¼15.3, 7.2 Hz, 1H), 5.19 (ddd,
J¼15.3, 9.0, 0.6 Hz, 1H), 3.82 (dtd, J¼11.6, 6.6, 2.0 Hz,
1H), 3.67–3.61 (m, 1H), 3.65 (s, 3H), 3.49 (dt, J¼8.6,
0.8 Hz, 1H), 3.16 (t, J¼8.4 Hz, 1H), 2.59 (dd, J¼15.5,
6.8 Hz, 1H), 2.38 (dd, J¼15.5, 6.0 Hz, 1H), 2.10 (ddd,
J¼10.8, 6.4, 4.4 Hz, 1H), 1.99 (ddd, J¼13.0, 4.8, 2.0 Hz,
1H), 1.97–1.94 (m, 1H), 1.56–1.51 (m, 1H), 1.38 (q,
J¼12.8 Hz, 1H), 1.26 (d, J¼6.2 Hz, 3H), 0.88 (s, 9H),
0.85 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.01 (s, 3H);
13C NMR d 199.6, 171.3, 133.5, 129.3, 81.4, 76.5, 74.3,
71.5, 51.7, 40.7, 40.4, 36.5, 32.9, 26.5, 26.3, 26.1, 18.3,
18.0, 12.5, 22.9, 23.0, 23.7, 24.2; IR (neat) 2954, 2929,
1
isomers. Integration of the appropriate signals in the H
NMR spectrum of this mixture revealed the ratio of E- and
Z-isomers to be 2.6:1.
A solution of the mixture of olefins (28 mg, 0.044 mmol)
and trifluoroacetic acid (0.034 mL, 0.44 mmol) in THF/H2O
(1 mL/0.1 mL) was stirred at room temperature for 3 h.
Saturated aqueous NaHCO3 (2 mL) and Et2O (5 mL) were
added and the layers were separated. The aqueous layer was
extracted with Et2O (2£2 mL), and the combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure. The resulting clear oil was purified by flash
chromatography over silica gel eluting with Et2O/CH2Cl2
(1:9) to first provide 6 mg (14%) of the Z-isomer 34Z as a
clear, colorless oil followed by 15 mg (37%) of the
E-isomer 34E as a clear, colorless oil:
2857, 1738, 1698 cm21
;
MS (CI) m/z 527.3202
[C27H51O6Si2 (Mþ1) requires 527.3224], 395, 263, 243
(base).
4.1.14. (2S,3S)-1-p-Toluenesulfoxy-2,3-epoxy-5-hexene
(46). To a solution of alcohol 4564 (5.0 g, 44 mmol) and
pyridine (6.5 mL, 80 mmol) in CH2Cl2 (44 mL) at 08C was
added p-toluenesulfonyl chloride (9.6 g, 50 mmol). The
solution was then stirred at room temperature for 16 h,
whereupon H2O (100 mL) was added. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(2£100 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography over
silica gel eluting with Et2O/hexanes (3:7) to provide 10.0 g
For 34Z. 1H NMR d 5.38 (dd, J¼15.3, 7.8 Hz, 1H), 5.18 (dd,
J¼15.3, 8.7 Hz, 1H), 3.81 (dtd, J¼11.6, 6.5, 1.8 Hz, 1H),
3.76 (dd, J¼11.5, 6.4 Hz, 1H), 3.65 (s, 3H), 3.64–3.60 (m,
1H), 3.50 (dd, J¼11.5, 8.6 Hz, 1H), 3.49–3.44 (m, 1H),
3.16 (t, J¼8.5 Hz, 1H), 2.61 (dd, J¼15.6, 6.6 Hz, 1H), 2.38
(dd, J¼15.6, 6.5 Hz, 1H), 1.99 (ddd, J¼12.9, 4.8, 1.9 Hz,
1H), 1.38 (q, J¼12.8 Hz, 1H), 1.29–1.23 (m, 1H), 1.22–
1.15 (m, 1H), 1.12 (d, J¼6.0 Hz, 3H), 1.00–0.91 (m, 1H),
0.89 (s, 9H), 0.85 (s, 9H), 0.062 (s, 3H), 0.061 (s, 3H), 0.056
(s, 3H), 0.02 (s, 3H); 13C NMR d 171.3, 137.5, 126.6, 82.0,
76.5, 74.3, 71.4, 62.1, 51.7, 40.8, 40.5, 31.6, 27.9, 27.3,
26.3, 26.2, 18.3, 18.0, 12.4, 22.9, 23.0, 23.6, 24.2; IR
(neat) 3432, 2959, 2925, 2880, 1746, 1642 cm21; MS (CI)
m/z 529.3355 [C27H53O6Si2 (Mþ1) requires 529.3381],
511, 379, 265, 243 (base).
1
(85%) of 46 as a clear, colorless oil: H NMR d 7.81 (d,
J¼8.2 Hz, 2H), 7.37 (d, J¼8.0 Hz, 2H), 5.76 (ddt, J¼17.1,
13.2, 6.6 Hz, 1H), 5.17–4.92 (comp, 2H), 4.21 (dd, J¼11.2,
3.2 Hz, 1H), 4.01 (dd, J¼11.2, 5.7 Hz, 1H), 3.01 (ddd, 5.7,
3.9, 2.0 Hz, 1H), 2.90 (td, J¼5.5, 2.0 Hz, 1H), 2.47 (s, 3H),
2.36–2.28 (m, 1H); 13C NMR d 145.0, 132.4, 132.0, 129.8,
127.7, 117.9, 69.8, 55.2, 53.8, 35.0, 21.5; IR (neat) 3079,
2981, 2926, 1637, 1598, 1448, 1363, 1190 cm21; MS (CI)
m/z 269.0843 [C13H17O4S (Mþ1) requires 269.0848], 215,
173, 155 (base).
For 34E. 1H NMR d 5.27 (t, J¼9.6 Hz, 1H), 5.06 (t,
J¼10.2 Hz, 1H), 3.95 (t, J¼8.8 Hz, 1H), 3.89 (dtd, J¼11.4,
6.8, 1.8 Hz, 1H), 3.79 (dd, J¼11.4, 6.2 Hz, 1H), 3.70 (ddd,

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6829
4.1.15. [2S,3R,3(3R)]-3-(4-Methyl-4-penten-3-oxy)-5-
hexen-2-ol (48). To a solution of epoxide 46 (8.28 g,
30.9 mmol) and alcohol 4262 (4.5 g, 45.0 mmol) in CH2Cl2
(62 mL) was added BF3·Et2O (0.38 mL, 3.0 mmol). After
stirring at room temperature for 16 h, the solvent was
removed under reduced pressure. The resulting paste of 47
was dissolved in Et2O (50 mL) and added via cannula to a
slurry of LiAlH4 (3.8 g, 100 mmol) in Et2O (100 mL) at
08C. The mixture was stirred for 3 h at 08C, and then H2O
(4 mL) was added dropwise. A solution of 6 M aqueous
NaOH (4 mL) and H2O (8 mL) were added, and the
resulting slurry was stirred for 2 h and then filtered through
a pad of Celite. The pad was washed with Et2O (2£100 mL)
and the combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The resulting oil was
purified by flash chromatography over silica gel eluting with
Et2O/hexanes (3:7) to provide 4.0 g (65%) of 48 as a clear,
(Na2SO4) and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography over
silica gel eluting with Et2O/hexanes (1:9) to provide 189 mg
(75%) of 50 as a clear, colorless oil: 1H NMR d 5.60–5.35
(comp, 3H), 4.08 (br s, 1H), 3.46 (dd, J¼10.7, 3.2 Hz, 1H),
2.64 (br s, 1H), 2.19–2.09 (m, 1H), 1.89 (dd, J¼7.1, 1.1 Hz,
1H), 1.82–1.71 (m, 1H), 1.60 (t, J¼1.1 Hz, 3H), 1.57–1.44
(comp, 2H), 1.29 (s, 3H), 0.90 (t, J¼7.3 Hz, 3H); 13C NMR
d 135.0, 134.1, 127.0, 120.6, 79.0, 78.5, 74.9, 25.6, 25.3,
18.8, 14.3, 8.5; IR (neat) 3568, 2967, 2934, 2875, 1719,
1654, 1458, 1375, 1329, 1292, 1116, 1056 cm21; MS (CI)
m/z 211.1699 [C13H23O2 (Mþ1) requires 211.1698], 194,
193 (base), 169, 151.
4.1.18. [2R,6R,2(20S,30E)]-2-(1-Hydroxy-2-methyl-3-pen-
ten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran (51). A sus-
pension of alcohol 50 (0.22 g, 1.1 mmol), 18-crown-6
(0.28 g, 1.1 mmol), and KH (150 mg of 35% dispersion in
mineral oil, 1.3 mmol) in THF (10 mL) was stirred at 08C
for 5 min, whereupon trimethylstannyl methyliodide (3.2 g,
11 mmol) was added. The solution was allowed to warm to
room temperature and stirred for 3 h. H2O (10 mL) was then
added, and the layers were separated. The aqueous layer was
extracted with Et2O (4£5 mL), and the combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure. The resulting oil was purified by flash chroma-
tography over silica gel eluting with Et2O to provide crude
trimethylstannylmethyl ether that was not purified but
dissolved in THF (10 mL). The solution was cooled to
2788C, n-BuLi (1.6 M in hexanes, 1.0 mL) was added
slowly, and the reaction was stirred for 2 h at 2788C. The
reaction was then warmed to room temperature, and H2O
(10 mL) was added. The layers were separated, and the
aqueous layer was extracted with Et2O (4£5 mL). The
combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure. The resulting oil was purified
by flash chromatography over silica gel eluting with Et2O/
hexanes (1:1) to provide 162 mg (70%) of 51 as a clear,
1
colorless oil: H NMR d 5.80 (ddt, J¼17.1, 14.1, 7.1 Hz,
1H), 5.10–4.86 (comp, 4H), 3.96 (dq, J¼6.5, 3.2 Hz, 1H),
3.71 (dd, J¼7.1, 6.8 Hz, 1H), 3.32 (ddd, J¼8.4, 5.2, 3.2 Hz,
1H), 2.40–2.10 (comp, 2H), 2.08 (br s, 1H), 1.66 (d,
J¼0.9 Hz, 3H), 1.66–1.40 (comp, 2H), 1.15 (d, J¼6.5 Hz,
3H), 0.87 (t, J¼7.5 Hz, 3H); 13C NMR d 144.6, 135.7,
116.5, 114.1, 84.4, 79.6, 67.2, 33.8, 26.3, 17.5, 16.4, 10.2;
IR (neat) 3474, 2963, 2933, 2874, 1647, 1598, 1458, 1369,
1190 cm21; MS (CI) m/z 199.1695 [C12H23O2 (Mþ1)
requires 199.1698], 181, 177, 163, 127, 117, 115, 100
(base).
4.1.16. (2R,6R)-Methyl-(6-ethyl-5-methyl-3,6-dihydro-
solution of 48 (2.0 g,
pyran-2-yl)ketone (49).
A
10.0 mmol) in CH2Cl2 (100 mL) containing dichlorobis-
(tricyclohexylphosphine)ruthenium benzylidene (0.82 g,
1.0 mmol) was heated under reflux for 16 h. The mixture
was cooled, and the solvent was removed under reduced
pressure. The resulting brown oil was purified by flash
chromatography over silica gel eluting with Et2O/hexanes
(1:9) to provide the desired dihydropyran as a brown oil.
The crude alcohol thus obtained was dissolved in CH2Cl2
1
colorless oil: H NMR d 5.58 (d, J¼4.8 Hz, 1H), 5.23 (d,
˚
(20 mL) containing 4 A molecular sieves (5 g). NMO
J¼9.6 Hz, 1H), 4.11 (br s, 1H), 3.86 (dd, J¼10.5 Hz,
3.0 Hz, 1H), 3.49 (dd, J¼10.5, 6.1 Hz, 1H), 3.38 (dd,
J¼10.2, 7.7 Hz, 1H), 2.73–2.61 (m, 1H), 2.18–2.06 (m,
1H), 1.99–1.88 (m, 1H), 1.84–1.72 (m, 1H), 1.72 (d,
J¼1.1 Hz, 3H), 1.64–1.48 (comp, 2H) 1.61 (d, J¼1.1 Hz,
3H), 0.98 (d, J¼6.8 Hz, 3H), 0.92 (t, J¼7.3 Hz, 3H); 13C
NMR d 138.4, 135.1, 127.0, 120.7, 78.0, 77.5, 67.8, 35.0,
30.3, 25.6, 18.9, 16.9, 13.0, 8.3; IR (neat) 3382, 2935, 2854,
1712, 1667, 1453, 1374, 1350, 1266, 1204 cm21; MS (CI)
m/z 225.1857 [C14H25O2 (Mþ1) requires 225.1855] (base),
207, 129, 117, 109.
(1.4 g, 12.0 mmol) and TPAP (0.18 g, 0.5 mmol) were
added, and the solution was stirred at room temperature for
2 h. The black solution was then filtered through a pad of
silica gel, and the filtrate was concentrated under reduced
pressure. The resulting yellow oil was purified by flash
chromatography over silica gel eluting with Et2O/hexanes
(1:9) to provide 1.0 g (60%) of 49 as a clear, colorless oil:
1H NMR d 5.57 (br s, 1H), 4.11 (br s, 1H), 3.93 (dd, J¼10.5,
4.6 Hz, 1H), 2.26 (s, 3H), 2.21–2.08 (m, 1H), 1.89–1.76
(m, 1H), 1.62 (d, J¼0.9 Hz, 3H), 1.60–1.40 (comp, 2H),
0.96 (t, J¼7.5 Hz, 3H); 13C NMR d 210.0, 135.6, 119.6,
78.8, 78.3, 27.3, 25.7, 25.6, 18.9, 8.6; MS (CI) m/z 169.1229
[C10H17O2 (Mþ1) requires 169.1229].
4.1.17. [2R,6R,2(20R)]-2-[20-Hydroxy-30-penten-20(Z)-yl]-
5-methyl-6-ethyl-3,6-dihydropyran (50). To a solution of
ketone 49 (0.20 g, 1.2 mmol) in THF (10 mL) at 2788C was
slowly added dropwise cis-propenylmagnesium bromide
(1.0 M in THF, 5.0 mL), and the mixture was stirred for 1 h
at 2788C. The reaction was warmed to 08C and poured into
saturated aqueous NH4Cl (10 mL), and the layers were
separated. The aqueous layer was extracted with Et2O
(4£5 mL), and the combined organic layers were dried
4.1.19. [2R,6R,2(20S,30E)]-2-(1-Phenylthioxy-2-methyl-3-
penten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran. To a
solution of N-phenylthiosuccinimide (62 mg, 0.30 mmol)
in C6H6 (2 mL) was added PBu3 (0.075 mL, 0.30 mmol).
After stirring for 5 min, a solution of alcohol 51 (50 mg,
0.22 mmol) in C6H6 (1 mL) was added, and the reaction was
stirred for 1 h. The solution was concentrated under reduced
pressure, and the residue was purified by flash chromato-
graphy over silica gel eluting with Et2O/hexanes (1:4) to
provide 63 mg (91%) of sulfide as a clear, colorless oil: 1H
NMR d 7.36–7.14 (comp, 5H), 5.58 (d, J¼4.6 Hz, 1H), 5.31
(d, J¼9.1 Hz, 1H), 4.11 (br s, 1H), 3.85 (dd, J¼10.9, 3.2 Hz,

6830
S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
1H), 2.93 (dd, J¼12.5, 6.6 Hz, 1H), 2.82 (dd, J¼12.3,
7.3 Hz, 1H), 2.76–2.64 (m, 1H), 2.19–2.04 (m, 1H), 2.00–
1.70 (comp, 3H), 1.65–1.50 (comp, 6H), 1.12 (d, J¼6.6 Hz,
3H), 0.92 (t, J¼7.3 Hz, 3H); 13C NMR d 137.2, 136.4,
135.0, 129.1, 128.9, 128.7, 125.6, 120.8, 77.8, 77.7, 41.0,
31.9, 30.1, 25.6, 20.1, 18.9, 12.4, 8.2; IR (neat) 2935, 2852,
1576, 1475, 1440, 1084 cm21; MS (CI) m/z 317.1945
[C20H29OS (Mþ1) requires 317.1939] (base), 299, 275,
221, 207.
of 53E and its Z-isomer 53Z as a clear, colorless oil. For
1
.53E. H NMR d 5.56–5.53 (m, 1H), 5.41 (dd, J¼15.7,
6.8 Hz, 1H), 5.35 (dd, J¼15.3, 8.0 Hz, 1H), 5.22 (dt, J¼9.0,
1.2 Hz, 1H), 5.17 (dd, J¼15.3, 9.2 Hz, 1H), 5.05 (ddd,
J¼1.2, 8.8, 15.3 Hz, 1H), 4.07 (br s, 1H), 3.81 (dd, J¼11.3,
3.4 Hz, 1H), 3.82–3.77 (m, 1H), 3.67 (m, 1H), 3.65 (s, 3H),
3.47 (t, J¼7.0 Hz, 1H), 3.16 (t, J¼8.4 Hz, 1H), 3.07–3.00
(m, 1H), 2.62 (dd, J¼15.7, 6.4 Hz, 1H), 2.38 (dd, J¼15.5,
6.6 Hz, 1H), 2.12–1.97 (m, 1H), 1.99 (ddd, J¼12.8, 4.8,
1.8 Hz, 1H), 1.89–1.81 (m, 1H), 1.62 (d, J¼1.2 Hz, 3H),
1.57 (br s, 3H), 1.52–1.44 (comp, 2H), 1.43–1.37 (m, 1H),
1.04–0.96 (comp, 2H), 1.03 (d, J¼6.4 Hz, 3H), 1.02 (d,
J¼6.8 Hz, 3H), 0.89–0.85 (m, 3H), 0.88 (s, 9H), 0.86 (s,
9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR d
171.3, 138.1, 135.4, 135.0, 129.8, 126.1, 125.3, 121.0, 82.3,
78.1, 77.8, 76.5, 74.3, 71.3, 51.6, 40.8, 40.5, 35.0, 30.9,
30.2, 28.5, 26.3, 26.2, 25.6, 21.2, 20.7, 18.9, 18.3, 18.0,
13.0, 12.1, 8.2, 22.8, 23.0, 23.6, 24.2; IR (CH2Cl2) 2958,
2929, 2857, 1763, 1463, 1114, 837 cm21; MS (CI) m/z
717.4942 [C41H73O6Si2 (Mþ1) requires 717.4946] (base),
585, 453, 243 (base).
4.1.20. [2R,6R,2(20S,3E)]-2-(1-Phenylsulfonyl-2-methyl-
3-penten-4-yl)-5-methyl-6-ethyl-3,6-dihydropyran (52).
A solution of ammonium molybdate tetrahydrate (0.12 g,
0.10 mmol) in 30% aqueous H2O2 (2 mL) was added
dropwise to a solution of the preceding sulfide (80 mg,
0.25 mmol) in EtOH (2 mL) at 2108C, and the reaction was
stirred for 30 min. Saturated aqueous NaHCO3 (5 mL) and
Et2O (5 mL) were added and the layers separated. The
aqueous layer was extracted with Et2O (3£20 mL), and the
combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure. The resulting oil was purified
by flash chromatography over silica gel eluting with Et2O/
hexanes (1:4) to provide 85 mg (98%) of 52 as a clear,
colorless oil: 1H NMR d 7.90–7.48 (comp, 5H), 5.53–5.46
(m, 1H), 5.13 (d, J¼8.7 Hz, 1H), 4.03–3.95 (m, 1H), 3.67
(dd, J¼10.0, 2.7 Hz, 1H), 3.12–2.96 (comp, 3H), 2.01–1.87
(m, 1H), 1.87–1.65 (m, 1H), 1.56 (d, J¼1.1 Hz, 3H), 1.52
(d, J¼1.1 Hz, 3H), 1.52–1.41 (comp, 2H), 1.12 (d,
J¼6.4 Hz, 3H), 0.84 (t, J¼7.3 Hz, 3H); 13C NMR d 139.9,
136.6, 135.0, 133.4, 129.1, 127.8, 127.1, 120.5, 77.8, 77.0,
62.4, 29.9, 27.7, 25.5, 20.8, 18.8, 12.5, 8.3; IR (neat) 3063,
2935, 2848, 1586, 1447, 1374, 1305, 1149, 1085 cm21; MS
(CI) m/z 349.1837 [C20H29O3S (Mþ1) requires 349.1837]
(base), 331, 253, 241.
4.1.22. Methyl 5b,6a-dihydroxypolyangioate (54). A
solution of the preceding mixture of 53E/Z (16 mg,
0.022 mmol) in THF (1 mL) and HF·pyridine (0.2 mL)
was stirred for 16 h at room temperature. Saturated aqueous
NaHCO3 (4 mL) and CH2Cl2 (4 mL) were added, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3£2 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
The resulting oil was purified by flash chromatography over
silica gel eluting with EtOAc/hexanes (35:65) followed by
HPLC using two m-porasil columns and eluting with
EtOAc/hexanes (50:50) to provide 9 mg (89%) of 54 as a
clear colorless oil. The 1H NMR spectrum of 54 was
consistent with that reported.1,10b 1H NMR (500 MHz,
CDCl3) d 5.56–5.54 (m, 1H), 5.44 (ddd, J¼15.5, 6.0,
0.6 Hz, 1H), 5.41–5.39 (comp, 2H), 5.23 (dt, J¼8.8, 1.2 Hz,
1H), 5.06 (ddd, J¼15.3, 8.8, 1.4 Hz, 1H), 4.08 (br s, 1H),
3.92–3.87 (m, 1H), 3.70–3.65 (m, 1H), 3.67 (s, 3H),
3.53–3.50 (m, 1H), 3.11 (t, J¼8.8 Hz, 1H), 3.07–3.02
(m, 1H), 2.64 (dd, J¼15.7, 6.8 Hz, 1H), 2.43 (dd, J¼15.7,
6.2 Hz, 1H), 2.33 (br s, 1H), 2.14–2.02 (comp, 2H), 1.91
(br s, 1H), 1.87–1.82 (m, 1H), 1.80–1.72 (m, 1H), 1.62
(d, J¼1.4 Hz, 3H), 1.57 (m, 3H), 1.55–1.40 (comp, 3H),
1.20–1.05 (comp, 2H), 1.04 (comp, 6H), 0.88 (t, J¼7.2 Hz,
3H).
4.1.21. Methyl 5b,6a-di-tert-butyldimethylsilyloxy-
polyangioates (53E/Z). A solution of 1.25 M n-BuLi in
hexanes (0.08 mL, 0.1 mmol) was added to a solution of
sulfone 52 (34 mg, 0.097 mmol) in THF (0.2 mL) at 2788C,
and the resulting solution was stirred for 30 min. A solution
of aldehyde 35 (17 mg, 0.032 mmol) in THF (0.25 mL) was
then added, and the solution was stirred at 2788C for an
additional 2 h. Saturated aqueous NH4Cl (2 mL) and
CH2Cl2 (6 mL) were added, and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2£2 mL),
and the combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The residual oil was
purified by flash chromatography over silica gel eluting first
with CH2Cl2/hexanes (1:3) and then with EtOAc/CH2Cl2
(1:9) to provide 15 mg of recovered 52 and 31 mg of
hydroxy sulfones as a mixture of diastereomers. The
hydroxy sulfones (31 mg, 0.035 mmol) were dissolved in
MeOH (1.5 mL) containing Na2HPO4 (0.25 g, 1.8 mmol) at
2308C, and sodium amalgam (1.0 g, 2.1 mmol Na) was
added. The mixture was stirred for 3 h at 2308C, whereupon
saturated aqueous NH4Cl (10 mL) and CH2Cl2 (8 mL) were
added. The supernatant was decanted, and the layers were
separated. The aqueous layer was extracted with CH2Cl2
(2£2 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure, and
the resulting oil was purified by flash chromatography over
silica gel eluting with PhCH3/hexanes (1:1) to provide
13 mg (56% from 35) of an inseparable mixture (E/Z<10:1)
4.1.23. Ambruticin S (1). A solution of diol 54 (6 mg,
0.12 mmol) in THF (1 mL) containing 0.3 M aqueous LiOH
(0.21 mL) was stirred for 3.5 h at room temperature. A
solution of 1N HCl (4 mL) and CHCl3 (6 mL) were added,
and the layers were separated. The aqueous layer was
extracted with CHCl3 (3£2 mL), and the combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure to provide 5 mg (95%) of (þ)-ambruticin S (1) as
an off-white gum. The synthetic sample was identical with
an authentic sample of natural ambruticin S by TLC, 1H and
13C NMR (including HMQC), MS, and optical rotation. 1H
NMR (CDCl3) d 5.55 (dd, J¼6.2, 1.6 Hz, 1H), 5.48–5.41
(comp, 3H), 5.23 (dt, J¼8.8, 1.2 Hz, 1H), 5.06 (ddd,
J¼15.3, 8.8, 1.4 Hz, 1H), 4.08 (br s, 1H), 3.92–3.87 (m,
1H), 3.82 (dd, J¼10.6, 3.0 Hz, 1H), 3.69 (ddd, J¼13.7, 8.6,

S. M. Berberich et al. / Tetrahedron 59 (2003) 6819–6832
6831
1988, 44, 3953–3973. (e) Davidson, A. H.; Eggleton, N.;
Wallace, I. H. J. Chem. Soc., Chem. Commun. 1991, 378–380.
´
(f) Marko, I. E.; Bayston, D. J. Tetrahedron 1994, 50,
5.0 Hz, 1H), 3.56 (dd, J¼9.0, 6.0 Hz, 1H), 3.15 (t,
J¼9.0 Hz, 1H), 3.09–3.03 (m, 1H), 2.65 (dd, J¼16.1,
7.6 Hz, 1H), 2.53 (dd, J¼16.1, 5.0 Hz, 1H), 2.13–2.07
(comp, 2H), 1.89–1.80 (m, 1H), 1.78–1.68 (m, 1H), 1.63
(d, J¼1.2 Hz, 3H), 1.57 (br s, 3H), 1.56–1.45 (comp, 3H),
1.12–1.06 (comp, 2H), 1.05 (br s, 3H), 1.03 (d, J¼7.0 Hz,
3H), 0.88 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3) d 173.2,
140.1, 135.8, 135.2, 135.1, 129.5, 125.0, 123.3, 120.9, 80.9,
78.0, 77.9, 75.6, 72.0, 71.6, 40.1, 38.0, 35.0, 30.4, 30.2,
29.2, 25.6, 21.7, 21.1, 18.9, 13.0, 12.3, 8.2; MS (CI) m/z
475.3053 [C28H43O6 (Mþ1) requires 475.3060];
[a]D22¼þ328 (c 0.11, CHCl3); {lit.10b for synthetic 1,
[a]D22¼þ378 (c 0.10, CHCl3); for natural 1, [a]2D2¼þ428 (c
0.22, CHCl3)}.
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´
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Acknowledgements
We thank the National Institutes of Health, the Robert
A. Welch Foundation, Pfizer, Inc., Merck Research
Laboratories, and the Alexander von Humboldt Stiftung
for their generous support of this research. M. F. S.
gratefully acknowledges a Feodor-Lynen postdoctoral
fellowship from the Alexander von Humboldt Foundation,
and M. A. M is grateful for an NRSA Postdoctoral
Fellowship from the National Institutes of Health. We also
thank Pfizer, Inc. (Ann Arbor Laboratories) for a sample of
natural ambruticin and Professor Andrew Kende
12. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
10772–10773.
13. Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min,
S. J.; Son, S. H.; Lim, S. M.; Jang, W. S. Angew. Chem. Int. Ed.
2002, 41, 176–178.
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Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.;
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1
(University of Rochester) for providing us with H NMR
spectra of ambruticin and an advanced intermediate in his
synthesis. We are also most grateful to Dr David E. Kaelin,
Jr. for invaluable assistance in characterizing advanced
intermediates and synthetic ambruticin S.
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