The naturally occurring ketene acetal benesudon: Total synthesis and assignment of relative and absolute stereochemistry

Article abstract of DOI:10.1021/jo801028y

(Chemical Equation Presented) The densely functionalized ketene acetal benesudon, which is a bioactive fungal metabolite, was synthesized from D-glucose by a route involving radical cyclization to form the five-membered ring, and oxidative decarboxylation

Full text of DOI:10.1021/jo801028y

The Naturally Occurring Ketene Acetal Benesudon: Total Synthesis
and Assignment of Relative and Absolute Stereochemistry
Derrick L. J. Clive,* Minaruzzaman, and Haikang Yang
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.cliVe@ualberta.ca
ReceiVed May 15, 2008
The densely functionalized ketene acetal benesudon, which is a bioactive fungal metabolite, was synthesized
from D-glucose by a route involving radical cyclization to form the five-membered ring, and oxidative
decarboxylation to generate the key central double bond. The originally suggested stereochemistry for
the quaternary center C(5) must be revised, as both C(5) epimers were prepared and a comparison with
an authentic sample was made. The absolute configuration of benesudon is 4S,5R,6S.
Introduction
methyl group at C(2) instead of the methylene of benesudon,
the noteworthy feature of aigialone is the relative stereochem-
istry, which differs at C(5) from that suggested for benesudon.
The X-ray data also showed that in the solid state the new
metabolite has the two hydroxyl groups and the heptyl chain
pseudoaxial, and nuclear Overhauser data for deuteriochloroform
solutions could be rationalized on the basis of this unusual
conformation. The two compounds 1 and 2 were obtained from
different organisms and, while the X-ray data for 2 suggested
the need for stereochemical revision of structure 1, we did not
regard the evidence as compelling and so we continued with
our route to 1; however, our work showed that revision is indeed
required.3
Benesudon, originally assigned the structure and relative
stereochemistry shown in 1, is a metabolite isolated from an
uncommon terrestrial fungus.1 The substance shows antibacterial
and antifungal activity and has a cytotoxic effect with IC90
values of 1-2 µg/mL.1 Although structure 1 is compact, it still
incorporates several features within its small framework: ketene
acetal, R-methylene ketone, enol ether, and vinylogous ester
subunits are readily discernible and are also interrelated.
Assignment of the gross structure was made by application of
1
appropriate spectroscopic techniques, especially H and 13C
NMR measurements, and the relative stereochemistry shown
was supported by the observed nuclear Overhauser effects.
However, during our synthetic work, the isolation and structure
determination of a related compoundsaigialone 2swas re-
ported.2 This substance, which is a metabolite of a marine
fungus, is crystalline and its relative stereochemistry was
established by X-ray analysis. Apart from the presence of a
The structure type represented by benesudon is rare, not only
among natural products but also in its own right, and an
examination of both the Beilstein and SciFinder Scholar
databases for ketene acetals embedded within bicyclic systems
retrieves very few examples besides benzo-fused compounds
(i.e., chromones) and γ-pyranones. The only relevant substances
we have been able to locate, apart from model compounds made
(1) Thines, E.; Arendholz, W.-R.; Anke, H.; Sterner, O. J. Antibiot. 1997,
50, 13–17.
10.1021/jo801028y CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6743–6752 6743

Clive et al.
SCHEME 1. Bicyclic Ketene Acetals
SCHEME 3. Attempted Acylation of a δ-Lactone
SCHEME 2. Initial Plan
SCHEME 4. Formation of the Five-Membered Ring without
the Central Double Bond
during our own studies, are those shown in Scheme 1. The
ketene acetals 3,4 4,5 5,5 and 66 are totally synthetic products,
while 77 (trichodion) and 88 (cyclogregatin) were isolated from
fungi. The former natural product is an inhibitor of inflammatory
signal transduction pathways,7a and the latter has weak antimi-
crobial, antifungal, and cytotoxic activity. Compounds 3-5, 7,
and 8 were known before we started our synthetic work, while
6, which is formed by a complicated rearrangement, was
reported after9 we had begun. Where the carbonyl group resides
within a six-membered ring, as in the relatively simple struc-
tures 4 and 5, synthetic access by Diels-Alder cycloaddition
is straightforward,5 but the presence of a carbonyl group in the
five-membered ring makes the identification of potential syn-
thetic routes more complicated; no general approaches were
available when we started and, as far as we are aware, the only
such method is that developed in the present investigation.
glucopyranoside as the source of the six-membered ring 9. This
decision implies an arbitrary assumption that benesudon has the
same absolute configuration as D-glucose at the corresponding
asymmetric centers.
With this plan in mind, the diol 11, whose synthesis from
D-glucose is described later, was protected by benzylation and
then oxidized to the lactone 13. Deprotonation with LDA at
-78 °C10 and treatment with ClCH2COCl did effect acylation,
but we were unable to prevent loss of the secondary benzyloxy
group so that the product we isolated was the enone 14. Our
intention had been to explore the pathway 13 f 15 f 16, but
this route was blocked by the ready expulsion of the benzyloxy
group (Scheme 3).
Results and Discussion
Initial Approaches. In our initial studies we underestimated
the difficulties we would encounter in trying to introduce the
central double bond that is characteristic of benesudon. Our first
approach was based on a compound of type 9 onto which we
hoped to build a five-membered ring (9 f 10, Scheme 2). From
that point, methylenation and deprotection would generate the
target. To simplify our work we decided to use methyl R-D-
Our next approach was again based on 12, but this time the
compound was subjected to Vilsmeier-Haack formylation
(Scheme 4, 12 f 17), and the product was exposed to the
action of MeOCH2OCH2Li, generated in situ from
(2) Vongvilai, P.; Isaka, M.; Kittakoop, P.; Srikitikulchai, P.; Kongsaeree,
P.; Thebtaranonth, Y. J. Nat. Prod. 2004, 67, 457–460.
(3) Preliminary communication: Clive, D. L. J.; Minaruzzaman, Org. Lett.
2007, 9, 5315–5317.
(4) McElvain, S. M.; McKay, G. R., Jr J. Am. Chem. Soc. 1955, 77, 5601–
5606.
(5) Sestelo, J. P.; Real, M. M.; Sarandeses, L. A. J. Org. Chem. 2001, 66,
1395–1402.
(6) Schobert, R.; Bieser, A.; Mullen, G.; Gordon, G. Tetrahedron Lett. 2005,
46, 5459–5462.
(7) (a) Erkel, G.; Retner, J.; Anke, T.; Sterner, O. J. Antibiot. 2000, 53, 1401–
1404. (b) Erkel, G. FEBS Lett. 2000, 477, 219–223. (c) Bashyal, B. P.; Wijeratne,
E. M. K.; Faeth, S. H.; Gunatilaka, A. A. L. J. Nat. Prod. 2005, 68, 724–728.
(8) Anke, H.; Casser, I.; Schrage, M.; Steglich, W. J. Antibiot. 1988, 41,
1681–1684.
11
MeOCH2OCH2SnBu3 and BuLi. Oxidation of the resulting
alcohols with TPAP/NMO produced ketone 19, and treatment
with NBS and CF3CO2H generated the cyclized product 20 in
53% yield. While the gross structure of 20 is clear from its NMR
spectra, the ring fusion stereochemistry is a tentative assignment;
cis ring fusion would be expected but whether the bromine is
cis or trans to the adjacent benzyloxy group was not estab-
(10) Cf.: Mckay, C.; Simpson, T. J.; Willis, C. L.; Forrest, A. K.; O’Hanlon,
P. J. Chem. Commun. 2000, 1109–1110.
(11) (a) Danheiser, R. L.; Gee, S. K.; Perez, J. J. J. Am. Chem. Soc. 1986,
108, 806–810. (b) Still, W. K. J. Am. Chem. Soc. 1978, 100, 1481–1487.
(9) Clive, D. L. J.; Minaruzzaman; Yang, H. Org. Lett. 2005, 7, 5581–5583.
6744 J. Org. Chem. Vol. 73, No. 17, 2008

The Naturally Occurring Ketene Acetal Benesudon
SCHEME 5. Potential Routes to the Core Structure 21
SCHEME 6. Potential Methods for Generating the Ketene
Acetal System
lished.12 With the bicyclic skeleton in hand we then tried to
introduce the central double bond, but all attempts to this end
were unsuccessful,13 and we were eventually forced to adopt
the conservative approach of studying a simple model compound
in the hope of being able to devise a robust route to the ketene
acetal core structure characteristic of benesudon. Accordingly,
our target became the model 21 (Scheme 5), which we expected
would be easily convertible into the R-methylene ketene acetal
24.
SCHEME 7. Preparation of Acid 38 for Oxidative
Decarboxylation
Synthesis of the Core Structure. In principle, 21 should be
accessible from compounds of type 22 or 23 by a proper choice
of the substituent X. The stereochemical requirements of the
two routes depend on the nature of X. If this group is PhSe,
then X and the adjacent ring fusion hydrogen must be cis, while
if X is a halogen then the ring fusion stereochemistry should
preferably be trans so as to allow for an anti elimination
pathway. However, there is an additional factor in that for
intermediates of type 23 the group X should also have a relative
stereochemistry with respect to the substituent that will be at
C(4) such that elimination toward C(4) is mechanistically
blocked. If X is a heteroatom (e.g., as in SePh) then compounds
of type 22 might be difficult to handle because of their inherent
lability. This disadvantage for routes via 22 is offset, however,
by the fact that 22 requires at most only one stereochemical
restrictionsthe relationship of X to the adjacent ring fusion
hydrogen, while for 23 the stereochemical relationship to two
hydrogenssthose at both C(4) and C(7a)smust be considered.
In the event, our experimental work leading to the model
compound 21 was based exclusively on an approach via 22,
and we decided to set X ) CO2H. This choice would offer the
(12) The chemical shift of the acetal H in 20 is 5.45 ppm. The two reference
compounds i and ii shown below have the indicated chemical shifts for the acetal
H: De Mesmaeker, A.; Hoffmann, P.; Ernst, B. Tetrahedron Lett. 1988, 29, 6585–
6588.
possibility of replacing the carboxyl group by a halogen or by
PhSe (Scheme 6, 25 f 27), using the derived Barton ester, and
might also serve directly for introduction of the C(3a)-C(7a)
double bond by oxidative decarboxylation (Scheme 6, 25 f
26 f 21).
Our route to 25 began with dihydropyran, which was
converted, following a published method,15 into the unsaturated
acid 32 (Scheme 7). Base hydrolysis and esterification then gave
ester 33. Reaction with Br2 formed the dibromides 34 and
addition to a mixture of propargyl alcohol, 4Å molecular sieves,
(13) We also considered hydride abstraction:
16
and AgOCOCF3 provided the bromoethers 35. These are
correctly constituted for radical cyclization, and reaction with
Bu3SnH in the presence of AIBN brought about the desired
5-exo digonal closure (35 f 36). Ozonolysis then gave ketone
37. At this point, we had to hydrolyze the ester group in 37,
Treatment of v with Ph3CBF4 (see ref 14) produced a complex mixture. The
structure of iii was confirmed by X-ray analysis. For preparation of iii, see the
Supporting Information.
(14) Barton, D. H. R.; Magnus, P. D.; Smith, G.; Streckert, G.; Zurr, D.
J. Chem. Soc., Perkin Trans. 1 1972, 542–552.
(15) Hoffmann, H. M. R.; Giesel, K.; Lies, R.; Ismail, Z. M. Synthesis 1986,
548–551.
(16) Paulsen, H.; Wulff, A.; Brenken, M. Liebigs Ann. Chem. 1991, 1127–
1145.
J. Org. Chem. Vol. 73, No. 17, 2008 6745

Clive et al.
SCHEME 8. Formation of the Core Structure of Benesudon
SCHEME 9. Preparation of the Key Glycal
but this initially proved to be troublesome, and experiments with
LiOH in aqueous MeOH were unsuccessful. However, when
(Bu3Sn)2O17 was eventually tried the reaction worked smoothly
(ca. 90%), although the product 38 was not very stable and was
best used within an hour of its isolation.
Having obtained the acid 38 we were now in a position to
examine the replacement of the carboxyl by PhSe, PhS, or a
2-pyridylthio group,18 so that oxidation via a selenoxide or
sulfoxide would generate the crucial C(3a)-C(7a) double bond.
Surprisingly, experiments directed to this end were unpromising
and so we had to investigate the remaining pathway of oxidative
decarboxylation, using Pb(OAc)4 in the presence of a cupric
salt.19 Our first experiment involved treating the acid with
Pb(OAc)4 and Cu(OAc)2 ·H2O in the presence of pyridine under
conditions close to those reported in the literature for oxidative
decarboxylation19a and, although the yield was very low, a small
amount of 21 was indeed isolated (Scheme 8). We then repeated
the experiment a number of times, varying the conditions slightly
in each run, until we found a reliable procedure that gave the
desired product in satisfactory yield (78% from ester 37). In
this optimized method, Cu(OAc)2 ·H2O is added to a solution
of freshly prepared carboxylic acid 38 in dry PhH, followed
after a few minutes by addition at 30 min intervals, and in the
dark, of several portions of Pb(OAc)4; finally, the mixture is
refluxed.
To construct the R-methylene unit, the ketene acetal 21 was
first methylated in the standard way (Scheme 8, LDA, THF,
MeI). The yield in this step was poor because of extensive bis-
methylation, but little effort was made to optimize the conditions
because this reaction was only part of a model study. Phenylse-
lenation of 39 and selenoxide fragmentation then gave 24, the
core structure of benesudon, as a sharp-melting solid. Unlike
its parent acid 38, the complete core structure 24 was easily
handled and did not seem to be noticeably sensitive.
which was then oxidized under Swern conditions (42 f 43).
All the substituents of the ketone are equatorial and there was
little danger of epimerization adjacent to the carbonyl group.
Reaction with MeMgI in Et2O afforded tertiary alcohol 44 with
little of the epimeric alcohol, the ratio of the two being 24:1 in
favor of 44. Later in this work we would need the isomeric
tertiary alcohol and it is fortunate that the stereochemical
outcome of the reaction can be controlled by a proper choice
of reagent (organolithium or Grignard reagent), solvent, and
temperature.21,22 In the present case, the choice of ethereal
MeMgI was made by analogy with the stereochemistry re-
ported21 for reaction of a related ketone differing only in the
nature of the C(2) substituent (CH2OCPh3 instead of C7H15).
The correctness of our stereochemical assignment was estab-
lished by X-ray analysis of a compound made from 44 during
our initial studies.23 Debenzylation by hydrogenolysis (44 f
45) and acetylation led to the tetraacetates 46, and at this stage
the anomeric acetoxy group was replaced by bromine in the
standard way. Finally, Zn reduction produced glycal 48 (Scheme
9). This compound represents the portion of our target (1) onto
which we planned to build the remainder of the ketene acetal,
using methods developed in making the unsubstituted core
structure.
Synthesis of Benesudon: Originally Proposed Stereo-
chemistry. Once we had established a method for constructing
the ketene acetal subunit we returned to the task of making the
natural product and, as stated above, based our approach on
the use of D-glucose. This was converted in four simple steps
by known procedures into the tosylate 41.20 Homologation with
the organocuprate made from n-C6H13MgBr gave alcohol 42,20
In our model study, simple bromine addition and reaction
with CuCN (Scheme 7, 28 f 32) had served to introduce the
nitrile group, but this method did not work when applied to 48
(or to the corresponding bis-O-benzyl analogue), and so a
different approach was needed. Reaction of glycal 48 with NBS
in MeOH gave the expected 2-bromoglucosides 49, and the
(17) Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. J. Org. Chem. 1994, 59,
7259–7266.
(18) (a) Replacement of carboxyl by PhSe or PhS: Barton, D. H. R.; Bridon,
D.; Zard, S. Z. Heterocycles 1987, 25, 449–462. (b) Replacement of carboxyl
by thiopyridyl unit: Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901–3924.
(19) (a) Bacha, J. D.; Kochi, J. K. Tetrahedron 1968, 24, 2215–2226. (b)
Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279–421. (c) Kochi, A. J.;
Bacha, J. D. J. Org. Chem. 1968, 33, 2746–2754. (d) Ogibin, Yu. N.; Katzin,
M. I.; Nikishin, G. I. Synthesis 1974, 889–890.
(20) (a) Toshima, H.; Sato, H.; Ichihara, A. Tetrahedron 1999, 55, 2581–
2590. (b) Davis, N. J.; Flitsch, S. L. J. Chem. Soc., Perkin Trans. 1 1994, 359–
368.
(21) Cf.: Sato, K.; Kubo, K.; Hong, N.; Kodama, H. Bull. Chem. Soc. Jpn.
1982, 55, 938–942.
(22) Cf.: Miljkovic, M.; Gligorijevic, M.; Satoh, T.; Miljkovic, D. J. Org.
Chem. 1974, 39, 1379–1384.
(23) See ref 13. Compound iii, whose structure was confirmed by X-ray
analysis, was made from 44. Hence the stereochemistry of 44 at the quaternary
carbon is established.
6746 J. Org. Chem. Vol. 73, No. 17, 2008

The Naturally Occurring Ketene Acetal Benesudon
SCHEME 10. Elaboration of Glycal 48
SCHEME 11. Formation of the Originally Proposed
Structure of Benesudon
in the usual way proceeded without incident, as did the
subsequent oxidation and fragmentation of the selenoxide,
bringing the route to 62, a protected version of the target.
Removing the silicon protecting groups was troublesome and
use of Bu4NF in THF with or without AcOH was unsuccessful;
it appears that the desired product 1 is sensitive to fluoride ion.
Use of HF-pyridine was the most promising method and gave
1 in 29% yield. We did not optimize these conditions mainly
because the NMR spectra, especially the 13C NMR spectrum,
of 1 differed significantly from those reported for natural
benesudon. There was no doubt about the gross structure
assigned to benesudon, and so only a stereochemical alteration
was necessary, and the most likely candidate was 63 with a
relative stereochemistry analogous to that of aigialone (2).
anomeric methoxy group was then replaced by reaction with
Me3SiCN in the presence of BF3 ·OEt2.24 Base treatment now
caused elimination to the unsaturated nitrile 51. As in the model
study, this was hydrolyzed with aqueous KOH and the resulting
acid was methylated.
We initially intended to protect both hydroxyls of 52 as their
tert-butyldimethylsilyl ethers, but only the secondary hydroxyl
could be protected; the remaining tertiary hydroxyl was therefore
masked as its triethylsilyl ether (52 f 53 f 54; Scheme 10).
Next, to attach the acetylenic side chain we tried the method
that had been successful in the preparation of the core structure,
but this procedure did not work in the present case. However,
after several trial experiments we were able to find conditions
that did allow conversion of 54 into 55; these involved use of
propargyl alcohol and NBS in CH2Cl2. Likewise, the conditions
previously used for the radical cyclization in making the core
structure were also unsuccessful, but when we tried Bu3SnH
and Et3B in the presence of air,25 cyclization occurred satis-
factorily (74%). Finally, ozonolysis took us to the point where
the next critical step was introduction of the central double bond
and, for this reaction (Scheme 11), both the tin oxide-mediated
ester hydrolysis and the oxidative decarboxylation occurred
satisfactorily under the conditions established in our route to
the core structure. Methylation of ketone 59 under standard
conditions then provided compound 60 as a single isomer whose
stereochemistry at C(2) was not established. Phenylselenation
Synthesis of Benesudon. In principle, the route we had used
to make 1 should be applicable to 63 because, as mentioned
earlier, the stereochemical outcome of the addition of organo-
metallic reagents to ketone 43 can be controlled, and this should
be the only step that requires alteration. In the event, matters
were not nearly so simple; conversion of ketone 43 to the tertiary
alcohol with stereochemistry corresponding to 63 was readily
achieved, but this stereochemical alteration exerted a profound
influence on other reactions so that appreciable modification of
the subsequent route was necessary. Moreover, the structure 63
appeared to be even more sensitive to fluoride ion than 1 and,
although we were able to reach 64,26 it was impossible to
remove the t-BuMe2Si group without destroying the material.
Consequently, we had to repeat the whole sequence with a more
labile protecting group for the C(4) hydroxyl and we selected
(24) (a) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2005, 127, 528–529. (b) Sato, K.; Sasaki, M. Org. Lett. 2005,
7, 2441–2444.
J. Org. Chem. Vol. 73, No. 17, 2008 6747

Clive et al.
SCHEME 13. Silylation of Diol 72
Et3Sisa choice that proved just satisfactory. For this route
(Scheme 12) we treated ketone 43 with MeLi in Et2O and
obtained 65 with opposite stereochemistry21,22 to that produced
by the action of MeMgI in the same solvent (cf. Scheme 9). As
before, the benzyl groups were removed by hydrogenolysis, and
then peracetylation, followed by treatment with HBr-AcOH
gave the bromide 68. This was converted into glycal 69 by
reaction with Zn.
SCHEME 14. Elaboration of Glycal 72
SCHEME 12. Preparation of the Key Glycal with Revised
Stereochemistry
At this point our expectations that the route would follow
closely what we had done before were quickly dispelled.
Compound 69 was converted into methoxy bromides 7027 (as
we had done in the series leading to 1) but we were unable to
replace the anomeric methoxy group by cyanide, using Me3SiCN
in the presence of Lewis acids. It could be replaced by an
acetoxy group (to form 7128), but even an acetoxy substituent
at the anomeric position could not be replaced by cyanide in
acceptable yield. We assume that there is a stereoelectronic
effect exerted by the C(3) oxygen function that deactivates the
anomeric position. Such effects have been observed before and
studied extensively.29 Their magnitude is strongest when the
C(3) oxygen substituent is equatorial, which we assume to be
the case with 70 and 71.
69 was hydrolyzed and we tried to prepare 73 (Scheme 13),
but obtained mainly 74. The tertiary hydroxyl of 74 was
therefore protected as its triethylsilyl ether (75), but with this
compound also we could not introduce a nitrile group at C(6),
using methods we had tried with the acetylated analogue 69.
It was clear that a different procedure had to be developed
to ultimately introduce an ester group at C(6). This was
eventually achieved, starting from 75, and we were then able
to reach 64, which, as mentioned earlier, could not be depro-
tected without destroying the compound. This experience caused
us to select Et3Si as the protecting group for both hydroxyls of
72. The bis-silylation was easily achieved with Et3SiOSO2CF3
(Scheme 14, 72 f 76) and we then subjected 76 to the same
procedures we had developed in making 64.
Protection of both hydroxyl groups in 72 as triethylsilyl ethers
has the added advantage that both hydroxyls are masked at the
(25) Cf.: Yamazaki, O.; Yamaguchi, K.; Yokoyama, M.; Togo, H. J. Org.
Chem. 2000, 65, 5440–5442.
(26) See the Supporting Information for a flow chart summarizing the route.
(27) Compound 70 was a mixture of isomers (two major isomers in a ratio
of 3.5:1).
(28) Compound 71 was a mixture of two isomers (2:1).
(29) Cf.: (a) Jensen, H. H.; Bols, M. Acc. Chem. Res. 2006, 39, 259–265.
(b) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419–3421.
Our earlier system (49) presumably has this oxygen axial, and
so is free from a large deactivating effect at C(6). In the present
case the deactivation was sufficiently strong to thwart further
progress in our intended route. We wondered if replacement of
the acetyl group on the C(3) oxygen by a siloxy unit would
result in a smaller degree of deactivation; accordingly, diacetate
6748 J. Org. Chem. Vol. 73, No. 17, 2008

The Naturally Occurring Ketene Acetal Benesudon
same time. Oxidation with PCC then produced lactone 7730 in
acceptable yield. We did not detect, but did not specifically look
for, the product arising by elimination of the C(4) OSiEt3 group
and, in fact, lactone 77 was a stable and well-behaved
compound. When the lactone was treated at a low temperature
with (Me3Si)2NK and then with the Comins’ reagent 2-[N,N-
bis(trifluoromethylsulfonylamino]pyridine31 it was possible to
isolate the desired enol triflate in good yield. Formation of an
enolate from a ꢀ-oxygenated δ-lactone without loss of the
oxygen substituent is unusual, and only a few cases appear to
have been reported.10,32,33 Palladium-mediated carbonylation34
of 78 in the presence of MeOH then served to introduce the
ester group, bringing the synthesis to 79, which corresponds to
54 (Scheme 10) but has different forms of hydroxyl protection
and the opposite stereochemistry at C(5). Introducing the
propargyl unit at C(2) by bromoetherification, as had been done
earlier in our route to 55 (Scheme 10), proved to be very
troublesome until we recognized that a large excess of propargyl
alcohol must be present and the best conditions involved the
use of 1:1 propargyl alcohol-dichloromethane in the presence
of NBS and powdered 4Å molecular sieves. Under these
conditions the reaction worked well (79 f 80, 98%). Radical
cyclization (80 f 81) under the same conditions used to make
56 (Bu3SnH, Et3B, air, EtOAc, room temperature), followed
by ozonolysis, gave the keto ester 82.
SCHEME 15. Formation of ent-Benesudon
The ester group was hydrolyzed, using (Bu3Sn)2O, and the
central double bond was formed by the oxidative decarboxy-
lation that had been optimized for this task. In the present case,
the yield from 82 was very satisfactory (74%). With ketene
acetal 84 in hand, we had only to attach the exo methylene and
remove the silyl groups. The first of these tasks proved more
difficult than anticipated, because methylation of 84 led to
extensive bis-methylation, and attempts to phenylselenate the
monomethylated product that we were able to isolate gave very
low yields (<20%). Therefore, we reversed the order of these
two steps, but found initially that phenylselenation of 84 resulted
in extensive bis-phenylselenation. This outcome is understand-
able by virtue of the fact that the first phenylseleno group
facilitates proton exchange so as to generate a furanoid system.
Fortunately, this difficulty could be largely suppressed by
quenching the enolate derived from 84 with Me3SiCl, followed
by addition of PhSeCl. By this means it was possible to convert
84 into 85 in 39% yield together with what we assume to be
the corresponding bis-phenylselenated product. The latter was
converted back into 84 by treatment with Ph3P in wet CH2Cl2,
the overall yield of 85 then being 66% after correction for
recovered 84.
The 1H and 13C NMR spectra of 63 showed slight differences
from the reported1 data. Fortunately, the original sample of the
natural product had been preserved at a low temperature and
we were able to obtain this material. When we measured the
spectra on our own instruments the results were identical with
those obtained with synthetic 63. However, the optical rotation
of the two samples was different, the synthetic material being
dextrorotatory with [R]D +124.2 (c 0.11, CHCl3) and the natural
compound being levorotatory with [R]D -120.5 (c 0.1, CHCl3).
Accordingly, natural benesudon has the 4S,5R,6S configuration
shown in 88, and the compound we had made is ent-benesudon.
Conclusion
Our synthesis of ent-benesudon establishes the relative and
absolute stereochemistry of the natural product. The method
we have developed for constructing the unusual ketene acetal
subunit is probably general.
Once the phenylseleno group was in place, methylation
worked well, as did the selenoxide elimination (86 f 87).
Finally, application of the HF-pyridine method for desilylation
gave the target structure 63 (Scheme 15).
Experimental Section
(3aR,7aR)-rel-Hexahydro-3-oxo-7aH-furo[2,3-b]pyran-7a-car-
boxylic Acid (38). (Bu3Sn)2O (0.97 mL, 1.94 mmol) was added to
a solution of 37 (96 mg, 0.48 mmol) in dry PhH (7.5 mL), and the
solution was refluxed under N2 for 5 h. The solvent was evaporated
and EtOAc (10 mL) was added to the residue. The EtOAc solution
was extracted with saturated aqueous NaHCO3 (2 × 10 mL), and
the aqueous extract was acidified to pH 1 (pH paper) with ice-cold
2 N hydrochloric acid and extracted with EtOAc (4 × 5 mL). The
combined organic extracts were dried (Na2SO4) and evaporated at
room temperature. The crude acid 38 (80.4 mg, ca. 90%) was used
immediately, without further purification: FTIR (CH2Cl2, cast)
3500-2500, 1766 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.43-1.54
(m, 2 H), 1.90-2.01 (m, 1 H), 2.16-2.26 (m, 1 H), 2.89 (dd, J )
(30) Rollin, P.; Sina|Ady, P. Carbohydr. Res. 1981, 98, 139–142.
(31) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(32) Cf.: (a) Mlynarski, J.; Banaszek, A. Tetrahedron 1999, 55, 2785–2794.
(b) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang, Z. J. Am.
Chem. Soc. 1997, 119, 5467–5468.
(33) (a) For use of Me3SiOSO2CF3/Et3N to prepare a ketene acetal from a
δ-lactone with a ꢀ-siloxy group, see: Chao, Y.-s.; Hartman, G. D.; Halczenko,
W.; Duggan, M. E.; Imagire, J. S.; Smith, R. L.; Pitzenberger, S. M.; Fitzpatrick,
S. L.; Alberts, A. W.; Bostedor, R.; Germershausen, J. I.; Gilfillan, J. L.; Hunt,
V. J. Med. Chem. 1992, 35, 3813–3821. (b) For use of an unprotected hydroxyl
ꢀ to the carbonyl, see: Yakura, T.; Kitano, T.; Ikeda, M.; Uenishi, J. Heterocycles
2003, 59, 347–358. (c) Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.;
Reddy, M. V. R. J. Org. Chem. 2004, 69, 6294–6304.
(34) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109–
1112.
J. Org. Chem. Vol. 73, No. 17, 2008 6749

Clive et al.
6.3, 3.4 Hz, 1 H), 2.6-3.4 (br, 1 H), 3.70-3.77 (m, 1 H), 3.94-4.02
(m, 1 H), 4.27 (AB q, ∆νAB ) 25.2 Hz, J ) 16.6 Hz, 2 H); 13C
NMR (CDCl3, 100.6 MHz) δ 19.9 (t), 21.0 (t), 47.0 (d), 65.0 (t),
70.5 (t), 101.8 (s), 169.5 (s), 210.5 (s); exact mass (electrospray)
m/z calcd for C8H11O5 (M + H) 187.0601, found 187.0603.
5,6-Dihydro-4H-furo[2,3-b]pyran-3(2H)-one (21). Cu(OAc)2 ·
H2O (56 mg, 0.28 mmol) was added to a stirred solution of the
above crude acid 38 in dry PhH (2.5 mL) (N2 atmosphere), and
stirring was continued for 5 min. The flask was then wrapped in
aluminum foil and Pb(OAc)4 (118 mg, 0.27 mmol) was tipped in.
Stirring was continued for 30 min, and another portion of Pb(OAc)4
(55 mg, 0.13 mmol) was added, followed by PhH (1.5 mL). Stirring
was again continued for 30 min and a further portion of Pb(OAc)4
(88 mg, 0.20 mmol) was then added, followed by PhH (1 mL) and
dry DMF (0.4 mL). The flask was fitted with a reflux condenser
and flushed well with N2 for 30 min (in some experiments, the
apparatus was evacuated with the house vacuum and then filled
with N2, and the process was repeated twice more). The mixture
was refluxed for 11 h (oil bath at 84 °C). The aluminum foil was
removed, and refluxing was continued for 1 h. The resulting green
solution was cooled to room temperature and evaporated to a thick
oil, which was applied directly to a flash chromatography column
made up with silica gel (1.5 × 26 cm). Flash chromatography, using
1:1 EtOAc-hexane and then pure EtOAc, gave 21 (52 mg, 78%
over two steps) as a white solid: mp 60-62 °C; FTIR (CH2Cl2,
cast) 1705, 1600 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.91-1.99
(m, 2 H), 2.33 (t, J ) 6.2 Hz, 2 H), 4.47 (apparent t, J ) 5.1 Hz,
2 H), 4.52 (s, 2 H); 13C NMR (CDCl3, 100 MHz) δ 15.5 (t), 21.2
(t), 71.5 (t), 74.2 (t), 88.9 (s), 182.8 (s), 194.1 (s); exact mass m/z
calcd for C7H8O3 140.0474, found 140.0473.
(d, J ) 5.3 Hz, 1 H), 6.26 (d, J ) 6.1 Hz, 1 H); 13C NMR (CDCl3,
125.7 MHz) δ 14.0 (q), 20.9 (q), 21.7 (q), 21.8(q), 22.6 (t), 26.4
(t), 26.9 (t), 29.2 (t), 29.4 (t), 31.8 (t), 67.2 (d), 78.2 (s), 79.4 (d),
98.3 (d), 143.9(d), 169.5 (s), 169.9 (s); exact mass (electrospray)
m/z calcd for C17H28NaO5 (M + Na) 335.1829, found 335.1828.
Acetic Acid (2R,3S,4S)-4-Acetoxy-5-bromo-2-heptyltetrahydro-
6-methoxy-3-methylpyran-3-yl Ester (49). A solution of 48 (0.250
g, 0.60 mmol) in dry MeOH (6 mL) was added dropwise to a stirred
and cooled (-50 °C) solution of NBS (0.106 g, 0.60 mol) in dry
MeOH (4 mL). The cooling bath was left in place but not recharged
and stirring was continued for 19 h. Most of the MeOH was
evaporated and the residue was diluted with Et2O (20 mL). The
resulting solution was washed with 10% aqueous Na2S2O3 (15 mL)
and water (15 mL), dried (Na2SO4), and evaporated. Flash chro-
matography of the residue over silica gel (2.5 × 22 cm), using
20% EtOAc-hexanes, gave 49 (0.339 g, 99%) as a mixture of
isomers. The more polar isomer had the following: FTIR (neat)
1
2956, 2927, 2857, 1749, 1466, 1370, 1236, 1129, 1066 cm-1; H
NMR (CDCl3, 400 MHz) δ 0.87 (t, J ) 7.0 Hz, 3 H), 1.22-1.36
(m, 10 H), 1.58-1.67 [m, including a singlet at δ 1.52 (3 H), 4 H
in all], 1.75-1.83 (m, 1 H), 2.09 (s, 3 H), 2.13 (s, 3 H), 3.41 (s, 2
H), 3.58 (s, 1 H), 3.73 (dt, J ) 10.7, 1.2 Hz, 1 H), 4.13 (t, J ) 3.7
Hz, 1 H), 4.95 (d, J ) 3.5 Hz, 1 H), 5.30 (d, J ) 4.0 Hz, 1 H); 13
C
NMR (CDCl3, 125 MHz) δ 14.1 (q), 20.3 (q), 20.8 (q), 22.4 (q),
22.6 (t), 26.3 (t), 27.6 (t), 29.3 (t), 29.4 (t), 31.8 (t), 46.8 (d), 55.7
(q), 71.3 (d), 75.9 (d), 80.0 (s), 100.6 (d), 169.6 (s), 169.7 (s); exact
mass (electrospray) m/z calcd for C18H3179BrNaO6 445.11962, found
445.11978.
Acetic Acid (2R,3S,4S)-4-Acetoxy-5-bromo-6-cyano-2-heptyl-
tetrahydro-3-methylpyran-3-yl Ester (50). Me3SiCN (2.90 mL, 20.7
mmol), followed by BF3 ·OEt2 (2.90 mL, 20.7 mmol), was added
dropwise to a stirred and cooled (-78 °C) solution of bromoacetal
49 (1.30 g, 3.07 mmol) in dry CH2Cl2 (12 mL). The cold bath was
left in place but not recharged and stirring was continued for 35 h.
The mixture was diluted with CH2Cl2 (15 mL) and washed with
saturated aqueous NaHCO3 (2 × 15 mL) and water (2 × 20 mL),
dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (4 × 28 cm), using 1:6 EtOAc-hexanes,
gave 50 (0.636 g, 64%) as a yellow oil, which was a mixture of
two isomers: FTIR (CHCl3, cast) 2956, 2928, 2857, 1754, 1466,
(2R,3S,4R,5R,6S)-4,5-Bis(benzyloxy)-2-heptyltetrahydro-6-meth-
oxy-3-methyl-2H-pyran-3-ol (44). A solution of 43 (13.51 g, 30.71
mmol) in Et2O (26 mL) was added dropwise over about 40 min to
a stirred and cooled (-78 °C) mixture of MeMgI (3.0 M in Et2O,
21.0 mL) in Et2O (100 mL). Stirring at -78 °C was continued for
2.5 h. The mixture was diluted with saturated aqueous NH4Cl (32
mL) and extracted with Et2O (2 × 50 mL). The combined organic
extracts were washed with brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (5 × 25 cm),
using 1:5 EtOAc-hexane, gave 44 (13.0 g, 93%) as a yellow oil:
[R]D +45.4 (c 1.0, CHCl3); FTIR (CHCl3, cast) 3500, 3063, 3030,
1
1437, 1368, 1231, 1202, 1140, 1094, 1050, 1016 cm-1; H NMR
1
2953, 2925 cm-1; H NMR (CDCl3, 400 MHz) δ 0.86 (t, J ) 6.9
(CDCl3, 400 MHz) δ 0.84-0.90 (m, 3 H), 1.23-1.36 (m, 10 H),
1.40-1.51 (m, 1 H), 1.59 (s, 2 H), 1.62-1.66 (m, 1 H), 1.74 (s, 1
H), 1.98 (s, 1 H), 2.07 (s, 2 H), 2.14 (s, 3 H), 3.72 (dd, J ) 9.7,
2.2 Hz, 1 H), 4.30 (dd, J ) 11.1, 5.8 Hz, 1 H), 5.04 (d, J ) 5.8
Hz, 1 H), 5.22 (d, J ) 11.1 Hz, 1 H); exact mass m/z calcd for
C16H2581BrNO4 (M - C2H3O) 376.09464, found 376.09484.
Acetic Acid (2R,3S,4R)-4-Acetoxy-6-cyano-2-heptyl-3,4-dihy-
dro-3-methyl-2H-pyran-3-yl Ester (51). DBU (0.250 mL, 1.85
mmol) was added dropwise to a stirred and cooled (0 °C) solution
of bromonitrile 50 (0.636 g, 1.24 mmol) in dry THF (20 mL). The
ice bath was left in place but not recharged and stirring was
continued for 3 h, by which time the solution had reached room
temperature. Evaporation of the solvent and flash chromatography
of the residue over silica gel (3.5 × 15 cm), using 1:6
EtOAc-hexane, gave unsaturated nitrile 51 (0.480 g, 94%) as an
oil: [R]D -46.3 (c 0.38, CHCl3); FTIR (CH2Cl2, cast) 2970, 2928,
Hz, 3 H), 1.14 (s, 3 H), 1.18-1.68 (m, 12 H), 2.18 (d, J ) 1.6 Hz,
1 H), 3.36 (s, 3 H), 3.47 (d, J ) 10.1 Hz, 1 H), 3.56 (d, J ) 9.7
Hz, 1 H), 3.81 (dd, J ) 9.6, 3.7 Hz, 1 H), 4.63 (d, J ) 3.2 Hz, 1
H), 4.64 (d, J ) 11.3 Hz, 1 H), 4.67 (AB q, J ) 12.0 Hz, ∆νAB
)
46.7 Hz, 2 H), 5.01 (d, J ) 10.9 Hz, 1 H), 7.24-7.37 (m, 10 H);
13C NMR (CDCl3, 100.6 MHz) δ 14.0 (q), 22.1 (q), 22.6 (t), 26.4
(t), 27.6 (t), 29.2 (t), 29.6 (t), 31.8 (t), 55.1(q), 72.7 (d), 73.1 (t),
74.3 (s), 76.2 (t), 78.1 (d), 80.9 (d), 98.0 (d), 127.8 (d), 128.1 (d),
128.2 (d), 128.3 (d), 128.4 (d), 138.3 (s); exact mass (electrospray)
m/z calcd for C28H40NaO5 (M + Na) 479.2768, found 479.2771.
Acetic Acid (2R,3S,4R)-3-Acetoxy-2-heptyl-3-methyl-3,4-dihy-
dro-2H-pyran-4-yl Ester (48). Zn dust (9.33 g) was tipped into a
stirred solution of AcONa (11 g) and AcOH (15.6 mL) in water
(22 mL), and saturated aqueous CuSO4 (3 mL) was then added.
The blue color disappeared, and a solution of 47 (1.32 g, 2.93 mmol)
in Ac2O (6 mL) was added at a fast dropwise rate. Stirring was
continued for 2 h and the mixture was diluted with CH2Cl2 (25
mL) and filtered. The aqueous phase was extracted with CH2Cl2
(2 × 15 mL), and the combined organic extracts were washed with
saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (5 × 16 cm), using 1:6 EtOAc-hexane, gave 48 (0.76 g,
83%) as a yellow oil: [R]D -106.0 (c 1.0, CHCl3); FTIR (CHCl3,
1
2858, 2237, 1752, 1645, 1373, 1241, 1161, 1029 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.90 (t, J ) 7.5 Hz, 3 H), 1.24-1.40 (m, 10
H), 1.60 (s, 3 H), 1.64-1.73 (m, 1 H), 1.74-1.90 (m, 1 H), 2.045
(s, 3 H), 2.054 (s, 3 H), 4.19 (dt, J ) 10.7, 1.8 Hz, 1 H), 5.49 (dd,
J ) 5.0, 1.4 Hz, 1 H), 5.76 (d, J ) 4.9 Hz, 1 H); 13C NMR (CDCl3,
100 MHz) δ 13.9 (q), 20.5 (q), 21.3 (q), 21.5 (q), 22.5 (t), 25.9 (t),
26.4 (t), 29.0 (t), 29.1 (t), 31.6 (t), 66.2 (d), 81.5 (d), 112.2 (d),
113.4 (s), 129.2 (s), 169.2 (s), 169.4 (s); exact mass m/z calcd for
C18H27NO5 337.1889, found 337.1891.
1
cast) 2926, 2857, 1747, 1458, 1230 cm-1; H NMR (CDCl3, 500
MHz) δ 0.86 (t, J ) 6.9 Hz, 3 H), 1.20-1.66 [m, including a singlet
(3 H) at δ 1.58, 14 H in all], 1.83-1.93 (m, 1 H), 1.99 and 2.00 (s,
6 H), 4.08 (d, J ) 10.9 Hz, 1 H), 4.90 (t, J ) 10.2 Hz, 1 H), 5.38
(2R,3R,4R)-2-Heptyl-3,4-dihydro-3,4-dihydroxy-3-methyl-2H-py-
ran-6-carboxylic Acid Methyl Ester (52). KOH (4.0 g, 71.3 mmol)
was added to a stirred solution of 51 (0.429 g) in water (62 mL)
6750 J. Org. Chem. Vol. 73, No. 17, 2008

The Naturally Occurring Ketene Acetal Benesudon
and the mixture was refluxed (oil bath at 105-110 °C), the
disappearance of the starting material being monitored by TLC
(silica, 1:1 EtOAc-hexane). After 24 h another portion of KOH
(0.385 g, 6.86 mmol) was added and refluxing was continued for
11 h (oil bath at 120-130 °C). At this stage the reaction was
complete. The mixture was cooled to room temperature and then
in an ice bath, and acidified to pH 1 with hydrochloric acid (2 N).
The solution was saturated with solid NaCl and extracted with Et2O
(3 × 15 mL). The combined ether extracts were treated with ethereal
CH2N2 until a yellow color persisted. Evaporation of the solvent
and flash chromatography of the residue over silica gel (2.25 × 22
cm), using 1:1 EtOAc-hexanes, gave unsaturated ester 52 (0.366
g, 100%) as a yellow oil: [R]D +130.6 (c 0.19, CHCl3); FTIR
(CH2Cl2, cast) 3446, 2954, 2926, 2857, 1733, 1653, 1438, 1373,
(4S,5S,6R)-3-Bromo-4-[(tert-butyldimethylsilyl)oxy]-6-heptyltet-
rahydro-5-methyl-2-prop-2-ynyloxy-5-[(triethylsilyl)oxy]-2H-pyran-
2-carboxylic Acid Methyl Ester (55). A solution of 54 (24.5 mg,
0.05 mmol) in CH2Cl2 (1 mL) was added dropwise over 1 h to a
stirred and cooled (-40 °C) solution of NBS (0.0123 g, 0.06 mmol)
and 2-propyn-1-ol (0.07 mL, 1.20 mmol) in CH2Cl2 (1 mL). The
bath temperature was raised to -20 °C by addition of acetone and
stirring was continued for 2 h at -20 °C. The cold bath was left in
place but not recharged and stirring was continued for 21 h. The
mixture was diluted with CH2Cl2 (10 mL) and washed with 5%
aqueous Na2S2O3 (10 mL). The organic layer was washed with
water (10 mL), dried (Na2SO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (2 × 30 cm), using 1:6
EtOAc-hexanes, gave the bromo ester 55 (28.3 mg, 93%) as a
single isomer: [R]D +4.23 (c 0.31, CHCl3); FTIR (CHCl3, cast)
3313, 2954, 2930, 2876, 2858, 2126, 1761, 1463, 1255 1160, 1110
1
1267, 1140, 1102 cm-1; H NMR (CDCl3, 500 MHz) δ 0.89 (t, J
) 6.9 Hz, 3 H), 1.24-1.38 (m, including a singlet, 11 H),
1.38-1.44 (m, 1 H), 1.64-1.74 (m, 2 H), 1.76-1.86 (m, 1 H), 2.0
(s, 1 H), 2.31 (d, J ) 10.4 Hz, 1 H), 3.73 (dd, J ) 10.0, 1.9 Hz,
1 H), 3.80 (s, 3 H), 4.04 (dd, J ) 10.3, 2.4 Hz, 1 H), 5.95 (d, J )
2.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 14.1 (q), 20.8 (q),
22.6 (t), 25.7 (t), 27.6 (t), 29.2 (t), 29.5 (t), 31.8 (t), 52.3 (q), 68.4
(s), 69.3 (d), 82.3 (d), 112.9 (d), 144.1 (s), 162.7 (s); exact mass
m/z calcd for C15H26O5 286.1780, found 286.1783.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.13 (s, 3 H), 0.24 (s, 3 H),
0.62-0.71 (m, 6 H), 0.86 (t, J ) 7 Hz, 3 H), 0.93-1.00 (m, 18
H), 1.18 (s, 3 H), 1.22-1.31 (m, 10 H), 1.40-1.48 (m, 1 H),
1.511.52 (m, 1 H), 2.41 (t, J ) 2.4 Hz, 1 H), 3.53 (dd, J ) 10.1,
1.8 Hz, 1 H), 3.75 (s, 3 H), 3.81 (d, J ) 10.3 Hz, 1 H), 4.28 (dd,
J ) 15.7, 2.5 Hz, 1 H), 4.59 (d, J ) 10.4 Hz, 1 H), 4.63 (dd, J )
15.8, 2.5 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ -3.4 (q), -2.0
(q), 6.8 (t), 7.0 (q), 14.1 (q), 19.1 (s), 22.6 (t), 22.7 (q), 26.1 (t),
27.0 (q), 28.5 (t), 29.2 (t), 29.8 (t), 31.9 (t), 52.0 (t), 52.7 (d), 53.3
(q), 74.0 (s), 76.0 (d), 78.8 (s), 79.0 (d), 100.4 (s), 167.2 (s); exact
mass m/z calcd for C28H5279BrO6Si2 (M - C2H5) 621.2465, found
621.2457.
(4R,5S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-6-heptylhexahydro-
5-methyl-3-methylene-5-[(triethylsilyl)oxy]-7aH-furo[2,3-b]pyran-
7a-carboxylic Acid Methyl Ester (56). Et3B in THF (21 µL, 1 M
in hexanes) was added to a stirred mixture of 55 (20 mg, 0.03 mmol)
and Bu3SnH (14 µL, 0.047 mmol) in EtOAc (1 mL) in a flask open
to the air. Stirring was continued for 3.5 h, and the mixture was
diluted with Et2O (5 mL), washed with brine, and dried (Na2SO4).
Evaporation of the solvent and flash chromatography of the residue
over silica gel (1.75 × 22 cm), using 1:6 EtOAc-hexanes, gave
56 (13 mg, 74%) as a colorless oil: [R]D -12.9 (c 0.04, CHCl3);
FTIR (CHCl3, cast) 2953, 2929, 2875, 2857, 1754, 1462, 1252,
1228, 1175, 1093 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.00 (s, 3
H), 0.06 (s, 3 H), 0.63-0.73 (m, 6 H), 0.88 (t, J ) 7 Hz, 3 H),
0.93-1.01 (m, 18 H), 1.13 (s, 3 H), 1.23-1.34 (m, 9 H), 1.44-1.64
(m, 3 H), 3.04 (d, J ) 10 Hz, 1 H), 3.41 (d, J ) 9.6 Hz, 1 H), 3.57
(dd, J ) 10.0, 2.4 Hz, 1 H), 3.71 (s, 3 H), 4.37 (dt, J ) 12.5, 1.7
Hz, 1 H), 4.51 (d, J ) 12.5 Hz, 1 H), 5.00 (s, 1 H), 5.20 (t, J ) 2.3
Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ -3.4 (q), -2.5 (q), 6.9
(q), 7.1 (t), 14.1 (q), 18.5 (s), 22.0 (q), 22.7 (t), 26.0 (t), 26.5 (q),
28.6 (t), 29.2 (t), 29.6 (t), 31.8 (t), 49.0 (d), 52.3 (q), 68.7 (t), 74.3
(s), 75.6 (d), 78.8 (d), 105.1 (s), 111.5 (s), 144.1 (s), 169.2 (s);
exact mass m/z calcd for C28H53O6Si2 (M - C2H5) 541.3381, found
541.3384.
(2R,3S,4R)-4-[(tert-Butyldimethylsilyl)oxy]-2-heptyl-3,4-dihydro-
3-hydroxy-3-methyl-2H-pyran-6-carboxylic Acid Methyl Ester
(53). t-BuMe2SiOSO2CF3 (140 mL, 0.607 mmol) was added
dropwise to a stirred and cooled (0 °C) solution of diol 52 (100
mg, 0.3 mmol) and 2,6-lutidine (0.180 mL, 1.55 mmol) in CH2Cl2
(5 mL). Stirring at 0 °C was continued for 1 h, the ice bath was
removed, and stirring was continued for 4 h. The mixture was
diluted with CH2Cl2 (5 mL) and washed with saturated aqueous
NaHCO3 (5 mL). The organic phase was separated and the aqueous
layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic
extracts were dried (Na2SO4) and evaporated. Flash chromatography
of the residue over silica gel (1.75 × 20 cm), using 1:1
EtOAc-hexanes, gave 53 (140.2 mg, 100%) as a colorless oil: [R]D
-0.8 (c 0.73, CHCl3); FTIR (CHCl3, cast) 3546, 2954, 2929, 2858,
1734, 1653, 1260 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.15 (s, 3
H), 0.18 (s, 3 H), 0.86-0.94 (m, 12 H), 1.19 (s, 3 H), 1.22-1.39
(m, 9 H), 1.62-1.74 (m, 2 H), 1.84-1.97 (m, 1 H), 2.72 (s, 1 H),
3.73 (d, J ) 10 Hz, 1 H), 3.8 (s, 3 H), 4.07 (dd, J ) 3.0, 0.8 Hz,
1 H), 5.79 (d, J ) 3.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ
-5.1 (q), -4.2 (q), 14.0 (q), 17.9 (s), 22.5 (t), 23.0 (q), 25.6 (q),
26.0 (t), 27.3 (t), 29.0 (t), 29.4 (t), 31.7 (t), 52.1 (q), 68.0 (s), 69.5
(d), 81.6 (d), 110.1 (d), 143.6 (s), 162.9 (s); exact mass (electro-
spray) m/z calcd for C21H40NaO5Si (M + Na) 423.2537, found
423.2536.
(2R,3S,4R)-4-[(tert-Butyldimethylsilyl)oxy]-2-heptyl-3,4-dihydro-
3-methyl-3-[(triethylsilyl)oxy]-2H-pyran-6-carboxylic Acid Meth-
yl Ester (54). Et3SiOSO2CF3 (1 mL, 4.5 mmol) was added dropwise
to a stirred and cooled (0 °C) solution of ester 53 (269 mg, 0.78
mmol) and 2,6-lutidine (0.7 mL, 6 mmol) in CH2Cl2 (25 mL). The
ice bath was left in place but not recharged and stirring was
continued for 18 h. The mixture was diluted with CH2Cl2 (15 mL)
and washed with saturated aqueous NaHCO3 (15 mL) and brine,
dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (3.5 × 25 cm), using hexanes, gave 54 (345
mg, 100%) as a colorless oil: [R]D -1.9 (c 0.76, CHCl3); FTIR
(CHCl3, cast) 2955, 2930, 2875, 2858, 1745, 1656, 1462, 1438,
1258 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.13 (s, 6 H), 0.54-0.69
(m, 6 H), 0.86-0.95 (m, 21 H), 1.20 (s, 3 H), 1.25-1.32 (m, 9 H),
1.59-1.67 (m, 2 H), 1.80-1.91 (m, 1 H), 3.71 (d, J ) 10.5 Hz, 1
H), 3.77 (s, 3 H), 4.10 (br s, 1 H), 5.76 (d, J ) 2.6 Hz, 1 H); 13C
NMR (CDCl3, 100 MHz) δ -4.56 (q), -4.46 (q), 4.9 (t), 6.5 (t),
6.6 (t), 6.8 (q), 7.0 (q), 14.1 (q), 18.4 (s), 22.6 (t), 23.1 (q), 26.0
(q), 26.3 (t), 27.7 (t), 29.2 (t), 29.6 (t), 31.8 (t), 52.1 (q), 71.3 (d),
71.4 (s), 82.9 (d), 112.3 (d), 142.5 (s), 163.2 (s); exact mass
(electrospray) m/z calcd for C27H54NaO5Si2 (M + Na) 537.3402,
found 537.3405.
(4R,5S,6R)-[4-(tert-Butyldimethylsilyl)oxy]-6-heptylhexahydro-
5-methyl-3-oxo-5-[(triethylsilyl)oxy]-7aH-furo[2,3-b]pyran-7a-car-
boxylic Acid Methyl Ester (57). An O3-O2 stream was passed
through a stirred and cooled (-78 °C) solution of 56 (197 mg,
0.35 mmol) in dry CH2Cl2 (10 mL) for 12 min. The solution was
purged with O2 for 15 min, and then Ph3P (142 mg, 0.54 mmol)
was added. The cooling bath was removed and stirring was
continued for 7 h. Evaporation of the solvent and flash chroma-
tography of the residue over silica gel (1.75 × 22 cm), using 1:6
EtOAc-hexanes, gave keto ester 57 (158 mg, 80%) as a colorless
oil: [R]D +34.3 (c 0.02, CHCl3); FTIR (CHCl3, cast) 2954, 2929,
1
2876, 2857, 1770, 1739, 1463, 1258, 1231, 1141 cm-1; H NMR
(CDCl3, 500 MHz) δ -0.02 (s, 3 H), 0.07 (s, 3 H), 0.58-0.68 (m,
6 H), 0.89 (t, J ) 7 Hz, 3 H), 0.92-0.98 (m, 18 H), 1.17 (s, 3 H),
1.24-1.36 (m, 9 H), 1.48-1.54 (m, 1 H), 1.58-1.74 (m, 2 H),
2.76 (d, J ) 9.4 Hz, 1 H), 3.61 (d, J ) 9.5 Hz, 1 H), 3.64 (dd, J
) 9.9, 2.5 Hz, 1 H), 3.76 (s, 3 H), 4.21 (AB q, J ) 16.5 Hz, ∆νAB
) 80.1 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) (small impurity
J. Org. Chem. Vol. 73, No. 17, 2008 6751

Clive et al.
signals at 130-136 ppm) δ -4.6 (q), -2.7 (q), 6.9 (t), 7.0 (q),
14.1 (q), 18.5 (s), 21.6 (q), 22.7 (t), 26.0 (t), 26.4 (q), 28.5 (t), 29.2
(t), 29.5 (t), 31.8 (t), 51.9 (q), 52.7 (d), 70.6 (t), 73.6 (s), 74.6 (d),
78.9 (d), 102.7 (s), 168.5 (s), 209.4 (s); exact mass m/z calcd for
C27H51O7Si2 (M - C2H5) 543.3173, found 543.3191.
and a solution of PhSeCl (0.023 g, 0.12 mmol) in THF (0.1 mL) was
then added dropwise. Stirring at -78 °C was continued for 4 h and
the mixture was quenched with saturated aqueous NH4Cl (2 mL) and
diluted with Et2O (5 mL). The organic layer was washed with water,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1.75 × 22 cm), using 1:8 EtOAc-hexanes, gave the
unsaturated ketone 61 (39 mg, 70%) as a yellow oil: FTIR (CH2Cl2,
cast) 2955, 2928, 2876, 2857, 1709, 1603, 1454, 1248, 1199, 1167,
(4R,5S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-6-heptyl-5,6-dihydro-
5-methyl-5-[(triethylsilyl)oxy]-4H-furo[2,3-b]pyran-3(2H)-one (59).
(Bu3Sn)2O (3.5 mL, 6.8 mmol) was added to a stirred solution of
57 (158 mg, 0.28 mmol) in PhH (9 mL) and the mixture was
refluxed at 85 °C for 23 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel (2.75 × 10 cm), using
1:1 EtOAc-hexanes, gave the acid 58, which was used immediately.
Cu(OAc)2 ·H2O (0.34 g, 1.7 mmol) was added to a stirred
solution of the freshly prepared acid in PhH (9.5 mL) (N2
atmosphere). Dry pyridine (0.1 mL) was added, and stirring was
continued for 50 min. The flask was then wrapped with aluminum
foil, and Pb(OAc)4 (0.8 g, 1.83 mmol) was tipped in. Stirring was
continued for 50 min, and another portion of Pb(OAc)4 (0.9 g, 2.06
mmol) was added, followed by dry DMF (0.9 mL). The flask was
fitted with a reflux condenser and flushed well with N2. The mixture
was refluxed for 11 h (oil bath at 88 °C). PhH (4 mL) was added
and refluxing was continued for 1 h. The resulting solution was
cooled to room temperature, evaporated to a small volume, and
applied directly to a flash chromatography column (27 × 2.75 cm)
made up with silica gel in 1:20 EtOAc-hexane. Flash chromatog-
raphy, using 1:20 to 1:6 EtOAc-hexanes, gave 59 (88 mg, 61%)
as a yellow oil: [R]D +6.8 (c 0.10, CHCl3); FTIR (CH2Cl2, cast)
1
1138, 1089, 1063, 1005 cm-1; H NMR (CDCl3, 400 MHz) δ 0.13
(s, 6 H), 0.51-0.64 (m, 7 H), 0.08-0.98 (m, 22 H), 1.23-1.35 (m,
10 H), 1.50-1.60 (br s, 1 H), 1.77 (s, 3 H), 1.83-1.97 (br s, 1 H),
1.98-2.11 (m, 1 H), 3.84-4.0 (m, 2 H), 7.24-7.29 (m, 2 H), 7.34
(tt, J ) 7.3, 1.0 Hz, 1 H), 7.66 (d, J ) 7.8 Hz, 2 H); 13C NMR (CDCl3,
125.3 MHz) δ -4.6, 6.8, 7.1, 14.1, 18.3, 22.7, 23.0, 24.7, 27.0, 27.4,
29.1, 29.3, 31.8, 66.3, 73.0, 90.6, 91.7, 94.0, 125.2, 129.0, 129.5, 137.8,
177.5, 193.1; exact mass m/z calcd for C33H55O580SeSi2 (M - CH3)
667.27533, found 667.27426.
(4R,5S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-6-heptyl-5,6-dihydro-
5-methyl-2-methylene-5-[(triethylsilyl)oxy]-4H-furo[2,3-b]pyran-
3(2H)-one (62). H2O2 (30%, 0.05 mL, 0.57 mmol) was added to a
stirred solution of 61 (39 mg, 0.06 mmol) in THF (1.4 mL) and
water (0.3 mL) (flask open to the air). Stirring was continued for
1.5 h, and the mixture was diluted with THF (3 mL) and water (2
mL), and extracted with Et2O (3 × 5 mL). The combined organic
extracts were dried (Na2SO4) and evaporated. Flash chromatography
of the residue over silica gel (2.75 × 24 cm), using 1:10
t-BuOMe-hexanes, gave 62 (29.6 mg, 76%) as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 0.17 (s, 6 H), 0.60-0.72 (m, 6 H),
0.82-1.03 (m, 21 H), 1.25-1.36 (m, 13 H), 1.55-1.60 (m, 1 H),
1.98-2.12 (m, 1 H), 4.14-4.24 (m, 1 H), 4.25-4.32 (m, 1 H),
5.08 (d, J ) 2.4 Hz, 1 H), 5.49 (d, J ) 2.7 Hz, 1 H).
(4R,5R,6R)-6-Heptyl-5,6-dihydro-4,5-dihydroxy-5-methyl-2-me-
thylene-4H-furo[2,3-b]pyran-3(2H)-one (1). HF-pyridine (70%
w/w, 34 µL) was added to a stirred and cooled (0 °C) solution of
62 (12.3 mg, 0.04 mmol) in dry THF (1 mL) (Ar atmosphere).
Stirring was continued for 25 min, the ice bath was removed, and
another portion of HF-pyridine (0.2 mL) was added. The progress
of the reaction was monitored by TLC (silica, 1:1 EtOAc-hexanes).
After 1.5 h, the reaction flask was placed in an ice bath and the
mixture was diluted with Et2O (2 mL) and quenched with saturated
aqueous NaHCO3 until CO2 evolution stopped. The organic phase
was dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1 × 18 cm), using 1:1 EtOAc-hexanes,
gave 1 (2 mg, 29%) as a colorless oil: [R]D +124.2 (c 0.11, CHCl3);
FTIR (CH2Cl2, cast) 3382, 2956, 2927, 2857, 1695, 1595, 1478,
1306, 1033 cm-1; 1H NMR (CD3OD, 400 MHz) δ 0.91 (t, J ) 7.2
Hz, 3 H), 1.29 (s, 3 H), 1.31-1.41 (m, 7 H), 1.41-1.52 (m, 2 H),
1.66-1.80 (m, 2 H), 1.92-1.96 (m, 1 H), 4.08 (s, 1 H), 4.46 (dd,
J ) 10.9, 2.3 Hz, 1 H), 5.27 (d, J ) 3.1 Hz, 1 H), 5.52 (d, J ) 3.0
Hz, 1 H); 13C NMR (CD3OD, 125.3 MHz, 50 °C) δ 14.8, 22.5,
24.1, 27.0, 29.2, 30.7, 30.8, 33.4, 67.3, 72.6, 87.5, 95.0, 97.6, 155.5,
181.0, 183.3; exact mass m/z calcd for C16H24O5 296.1624, found
296.1612.
1
2956, 2928, 2877, 2857, 1707, 1604, 1467, 1249 cm-1; H NMR
(CDCl3, 400 MHz, 60 °C) δ 0.18 (s, 6 H), 0.62-0.74 (m, 6 H),
0.89-1.02 (m, 21 H), 1.26-1.37 (m, 12 H), 1.44-1.65 (m, 1 H),
2.01-2.06 (m, 2 H), 4.11 (dd, J ) 7.1, 3.8 Hz, 1 H), 4.26 (s, 1 H),
4.50 (AB q, J ) 15.7 Hz, ∆νAB ) 27.0 Hz, 2 H); 13C NMR (CDCl3,
100.58 MHz, 50 °C) δ -4.7, 6.89, 6.99, 14.0, 18.3, 22.7, 24.8,
26.1, 27.1, 29.1, 29.4, 31.8, 67.6, 73.4, 75.6, 90.0, 92.6, 181.4,
192.8; exact mass m/z calcd for C26H49O5Si2 (M - CH3) 497.3119,
found 497.3128.
(4R,5S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-6-heptyl-5,6-dihydro-
2,5-dimethyl-5-[(triethylsilyl)oxy]-4H-furo[2,3-b]pyran-3(2H)-
one (60). n-BuLi (2.5 M in hexanes, 0.1 mL, 0.23 mmol) was added
to a stirred and cooled (-78 °C) solution of i-Pr2NH (0.05 mL, 0.32
mmol) in dry THF (0.8 mL) and stirring was continued for 40 min. A
solution of 59 (105.0 mg, 0.21 mmol) in THF (0.2 mL) was then added
dropwise and stirring at -78 °C was continued for 1 h. Freshly distilled
HMPA (0.03 mL, 0.17 mmol) was added rapidly followed immediately
by MeI (25 µL, 0.40 mmol), which was also added quickly, and stirring
at -78 °C was continued for 18 h. Then the cold bath was removed
and the solution was allowed to reach room temperature. The mixture
was quenched with water (2 mL) and diluted with Et2O (5 mL). The
organic layer was washed with water, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel (2 × 15 cm), using
1:6 EtOAc-hexane, gave 60 (80 mg, 75%) as a yellow oil: [R]D +71.2
(c 0.20, CHCl3); FTIR (CH2Cl2, cast) 2956, 2929, 2877, 2857, 1706,
1
1602, 1467, 1249, 1086 cm-1; H NMR (CDCl3, 400 MHz) δ 0.14
(s, 6 H), 0.0.56-0.71 (m, 6 H), 0.82-1.00 (m, 21 H), 1.21-1.35 (m,
13 H), 1.43 (d, J ) 7.0 Hz, 3 H), 1.56-1.60 (m, 1 H), 1.97-2.04 (br
s, 1 H), 4.08 (d, J ) 4.9 Hz, 1 H), 4.20 (t, J ) 4.3 Hz, 1 H), 4.63-4.67
(br s, 1 H); 13C NMR (CDCl3, 125.7 MHz, 60 °C) δ -4.6, 7.0, 14.0,
16.2, 18.4, 22.7, 23.0, 26.2, 27.2, 29.1, 29.2, 29.4, 31.6, 31.8, 67.5,
73.5, 84.0, 89.9, 91.4, 179.9, 195.8; exact mass m/z calcd for
C26H49O5Si2 (M - C2H5) 497.3119, found 497.3113.
(4R,5S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-6-heptyl-5,6-dihydro-
2,5-dimethyl-2-(phenylseleno)-5-[(triethylsilyl)oxy]-4H-furo[2,3-
b]pyran-3(2H)-one (61). n-BuLi (2.5 M in hexanes, 41 µL, 0.1
mmol) was added to a stirred and cooled (-0 °C) solution of i-Pr2NH
(0.016 g, 0.16 mmol) in dry THF (0.3 mL). After 15 min the solution
was cooled to -78 °C and 60 (43 mg, 0.08 mmol) in THF (0.3 mL)
was added dropwise. Stirring at -78 °C was continued for 40 min
Acknowledgment. We thank Crompton Co. and NSERC for
financial support, S. Ardelean and D. Song for assistance, and
Dr. R. McDonald for the X-ray structure determination. We are
extremely grateful to Professors O. Sterner (Lund University,
Sweden) and H. Anke (University of Kaiserslautern, Germany)
for their sample of natural benesudon.
Supporting Information Available: Experimental proce-
dures and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org. The X-ray data have been
deposited with the Cambridge Crystallographic Data Centre and
assigned the registry number CCDC 684303.
JO801028Y
6752 J. Org. Chem. Vol. 73, No. 17, 2008