Stereocontrolled elaboration of natural (-)-polycavernoside A, a powerfully toxic metabolite of the red alga Polycavernosa tsudai

Article abstract of DOI:10.1021/ja993487o

A stereoselective total synthesis of natural levorotatory polycavernoside A (1) has been achieved. Initial investigations produced the properly activated disaccharide unit 18b via the conjoining of building blocks originating from L-fucose and D-xylose. T

Full text of DOI:10.1021/ja993487o

J. Am. Chem. Soc. 2000, 122, 619-631
619
Stereocontrolled Elaboration of Natural (-)-Polycavernoside A, a
Powerfully Toxic Metabolite of the Red Alga PolycaVernosa tsudai
Leo A. Paquette,* Louis Barriault,† Dmitri Pissarnitski,‡ and Jeffrey N. Johnston§
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed September 27, 1999
Abstract: A stereoselective total synthesis of natural levorotatory polycavernoside A (1) has been achieved.
Initial investigations produced the properly activated disaccharide unit 18b via the conjoining of building
blocks originating from L-fucose and D-xylose. This objective was followed by preparation of the phenylsulfonyl-
substituted tetrahydropyran 23 and aldehyde 30. After proper linking of these key compounds, important
information had to be garnered on the sequence of steps that would ultimately result in successful access to
1. Although oxidation to generate R-diketone 35 and unmasking of the C-13 hydroxyl did give rise efficiently
to lactol 36, this functionality did not pave the way for ensuring macrolactonization. When this sequence of
steps was reversed, it was indeed possible to arrive at the heavily functionalized precursor 44. However,
numerous experiments failed to result in the requisite activation of C-16 for attachment of the trienyl side
chain. However, if the E-vinyl iodide was elaborated in advance of R-diketone generation, glycosidation, and
complete side chain construction, arrival at 1 proceeded without unsurmountable complications to furnish the
targeted marine toxin.
Drawing upon the powerful capabilities of chemical spec-
troscopy, Yasumoto and co-workers were able to define the
gross structural features of polycavernoside A (1) in 1993.1 A
strong sense of urgency surrounded this effort because the
widely consumed red alga PolycaVernosa tsudai, which is the
source of this powerful human toxin, had never previously
induced poisoning and death. For unknown reasons, the onset
of lethal metabolite production proved to be seasonal, occurring
only during the months of April and May.2 Fortunately, this
phenomenon has declined more recently. From 2.6 kg of dried
material collected at Tanguisson Beach on Guam, 400 µg of
the natural product was obtained as a colorless solid. Five
structurally related compounds have subsequently been secured
in lesser amounts.1,3
macrolactone disaccharide fitted with a trienyl side chain.
Detailed inspection of this small group of bioactive marine
toxins reveals significant structural deviation from known
macrolides. The 3,5,7,13,15-pentahydroxy-9,10-dioxotricosanoic
acid carbon backbone is unprecedented, although the smaller
trioxatridecane ring is similar in principle to the trioxadodecane
network present in the aplysiatoxins.4 The presence of an
R-dicarbonyl moiety bears some remote resemblance to the
tricarbonyl immunosuppressive agents rapamycin5 and FK-506.6
Particularly atypical is the lack of unsaturation within the
macrolide ring. The polyene appendage that is conserved among
all congeners may serve as a lipophilic “anchor” for attachment
to a cell membrane.
The high degree of methylation of the disaccharide conforms
to its algal origin. Beyond this, it would seem reasonable to
hypothesize that the structural variants present in the sugar
region may contribute to the heightened toxicity of these algal
metabolites.
Results and Discussion
Deduction of Absolute Stereochemistry. Enantioselective
Synthesis of the Disaccharide Component. For the reasons
discussed above, polycavernoside A (1) emerged as an attractive
target molecule. Preliminary disclosure has, in fact, been made
of completed independent syntheses of 1 by the groups of Murai7
and Paquette.8 Before initiating such an effort, it was mandatory
that the absolute stereochemistry of the entire structure be
Although the absolute configuration of 1 could not be defined
with such small quantities in hand, polycavernoside A was
nevertheless revealed to be a structurally novel 13-membered
† Present address: Department of Chemistry, University of Ottawa, 10
Marie Curie, Ottawa, ON, Canada K1N 6N5.
(4) Kato, Y.; Scheuer, P. J. J. Am. Chem. Soc. 1974, 96, 2245.
(5) (a) Sehgal, S. N.; Baker, H.; Ve´zina, C. J. Antibiot. 1975, 28, 727.
(b) Findlay, J. A.; Radics, L. Can. J. Chem. 1980, 58, 579. (c) Swindells,
D. C. N.; White, P. S.; Findlay, J. A. Can. J. Chem. 1978, 56, 2491.
(6) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto,
T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031.
(7) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am.
Chem. Soc. 1998, 120, 10770.
‡ Present address: Schering Plough Research Institute, 2015 Galloping
Hill Road, Kenilworth, NJ 06033.
§ Present address: Department of Chemistry, Indiana University, Bloom-
ington, IN 47405.
(1) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 1147.
(2) Haddock, R. L.; Cruz, O. L. T. Lancet 1991, 338, 195.
(3) Yotsu-Yamashita, M.; Seki, T.; Paul, V. J.; Naoki, H. Yasumoto, T.
Tetrahedron Lett. 1995, 36, 5563.
(8) Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem. Soc. 1999,
121, 4542.
10.1021/ja993487o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/28/1999

620 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
Scheme 1
Scheme 2
deduced. The Hokkaido University team proceeded to couple
O-methylated derivatives of natural L-fucose, unnatural D-fucose,
and natural D-xylose with synthetic variants of the tetrahydro-
furan (THF) ring9 and to correlate the 1H NMR features of the
diastereoisomers so produced.10 The chemical shifts and splitting
patterns, when compared with those of 1, were diagnostic and
conclusive.
Our approach to this dilemma consisted of comparing the
structural homology of an “unraveled” view of polycavernoside
A with the Celmer model11 of macrolide stereostructure,12,13
and to synthesize the complete disaccharide ready for attachment
to the aglycone from sugars usually found in marine biota. More
specifically, the unique glycosidic building block was elaborated
by linking a 2,3-di-O-methyl-R-L-fucopyranose 1 f 3 to a 2,4-
di-O-methyl-R-D-xylopyranose.14
At the outset, sulfide 6 was considered to be the acceptor
glycoside of choice; therefore, its preparation was explored from
two directions (Scheme 1). Initially, the starting point took the
form of commercially available 1,2-O-isopropylidene-R-D-
xylofuranose (2). After its conversion into 3 by a series of
precedented steps,15,16 subsequent warming in 50% aqueous
acetic acid was used to effect hydrolysis of the isopropylidene
protecting group and allow for equilibration to the pyranose
form 4a. Esterification with acetic anhydride gave rise to 4b
(85% from 3), thereby permitting chemoselective removal of
the benzyl group as in 5 (97%). the thioglycosidation of this
intermediate with phenylthiotrimethylsilane and SnCl4 in dry
benzene according to the directives prescribed by others17,18
made 6 available without complication.
deshielding of H-1, H-2, and H-3 (δ 6.29, 5.44, and 5.25 ppm)
relative to that experienced by H-4 (δ 3.96). The selective
formation of 10 after coupling to 6 in the presence of boron
trifluoride etherate19 requires that C-O bond formation occur
exclusively via axial addition to the oxonium ion intermediate.
Given this initial indication of feasibility, it seemed reasonable
to advance 10 to compound 11 before penultimate O-methyla-
tion. However, this conversion could not be realized satisfac-
torily because saponification of the acetate groups was unavoid-
ably met with migration of the silyl functionality.20 For lack of
a practical solution to this problem, our attention was redirected
toward the acquisition of 15.
This initiative began with peracetylated L-fucose,21 involved
its conversion to the thioglycoside with thiophenol and tin(IV)
chloride,22 and culminated with saponification to deliver 12b
(Scheme 3). The anomers were separated at the 12a stage and
the more dominant â form was singly advanced for reasons of
practicality. Intermediate 12 was transformed into its 3,4-
acetonide, thereby making possible selective O-methylation of
the C-2 carbinol. Hydrolytic removal of the protecting group23
furnished diol 13 in 83% overall yield. Preferential methylation
at C-3 was mediated by the stannylene acetal,24 for which cesium
A more expeditious route to 5 can be realized by taking
advantage of the selectivity with which D-xylose (7) undergoes
acetylation with acetic anhydride in pyridine at -35 °C.19
However, we were unable to improve upon the 21% yield
realized in the developmental stages by the original authors.
Nevertheless, the inexpensive nature of 7 and the ease with
which the C-3 hydroxyl can be differentiated from the other
three equatorial OH groups were adequate compensation.
The process of elaborating a suitable glycosyl donor began
by converting L-fucose (8) into 9. Initial selective acetylation
of the equatorial hydroxyls was followed by silylation of the
lone remaining OH group (Scheme 2). The structural features
of the crystalline R-anomer were clearly apparent on the basis
(17) (a) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J.
Am. Chem. Soc. 1977, 99, 5009. (b) Hanessian, S.; Guindon, Y. Carbohydr.
Res. 1980, 86, C3. (c) Pozsgay, V.; Jennings, H. J. J. Org. Chem. 1988,
53, 4042.
(18) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J.
Am. Chem. Soc. 1988, 110, 4696.
(19) Utille, J. P.; Gagnaire, D. Carbohydr. Res. 1982, 106, 43.
(20) The tendency for acyl and trialkylsilyl groups to migrate is well
precedented: Haines, A. H. AdV. Carbohydr. Chem. Biochem. 1976, 33,
11.
(21) Iselin, B.; Reichstein, T. HelV. Chim. Acta 1944, 27, 1146.
(22) Nicolaou, K. C.; Randall, J. L.; Furst, G. T. J. Am. Chem. Soc.
1985, 107, 5556.
(23) Schuler, H. R.; Slessor, K. N. Can. J. Chem. 1977, 55, 3280.
(24) Review: David, S.; Hanessian, S. Tetrahedron 1985, 41, 643. For
additional specific examples, see also: (a) Kim, S.-H.; Augeri, D.; Yang,
D.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 1766. (b) Nagashima, N.;
Ohno, M. Chem. Lett. 1987, 141. (c) Su, T.-L.; Klein, R. S.; Fox, J. J. J.
Org. Chem. 1982, 47, 1506. (d) El Ashry, E. S. H.; Schuerch, C. Carbohydr.
Res. 1982, 105, 33. (e) Varma, A. J.; Schuerch, C. J. Org. Chem. 1981, 46,
799. (f) Srivastava, V. K.; Schuerch, C. Tetrahedron Lett. 1979, 35, 3269.
(g) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
1
of its H NMR spectrum. One feature was the unmistakable
(9) (a) Hayashi, N.; Mine, T.; Fujiwara, K.; Murai, A. Chem. Lett. 1994,
2143. (b) Fujiwara, K.; Amano, S.; Oka, T.; Murai, A. Chem. Lett. 1994,
2147.
(10) (a) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 191. (b)
Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 855.
(11) Celmer, W. D. Pure Appl. Chem. 1971, 28, 413.
(12) Johnston, J. N. Ph.D. Dissertation, The Ohio State University, 1997.
(13) Paquette, L. A.; Pissarnitski, D.; Barriault, L. J. Org. Chem. 1998,
63, 7389.
(14) Johnston, J. N.; Paquette, L. A. Tetrahedron Lett. 1995, 36, 4341.
(15) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 95.
(16) Ichihara, A.; Ubukata, M.; Sakamura, S. Tetrahedron Lett. 1977,
3473.

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 621
Scheme 3
fluoride served as the activating/cleaving agent of choice. The
substitution pattern present in 14 was corroborated by semise-
lective DEPT-45 experiments.25 Silylation of the axial alcohol
gave the fully protected pyran, which could be converted
uneventfully into fluoride 15 with diethylaminosulfur trifluoride
and N-bromosuccinimide.26
To test our “second generation” approach, 15 was admixed
with 6 under Mukaiyama conditions,27 and disaccharide 16 was
isolated as the only detectable isomer (64%). The coupling
pattern for each of the hydrogens, most notably the anomeric
proton (δ 4.88, J ) 3.4 Hz), was consistent with this structural
assignment. Once 17 was in hand, three-bond-coupling interac-
tion between H-2 and H-4 of the xylose component to the
methoxyl carbons was observed, and H-2 and H-3 in the
furanose ring were similarly correlated. In addition, the full
range of NMR data for 17 corresponded very closely to that of
this subunit in polycavernoside A.1
substantial array of variants. In this study, the specific objective
was to make matters operative by making recourse to a softer
nucleophile. Beyond the added concern for stereoselective
introduction of the multiple stereogenic centers, it was envi-
sioned that the sensitive trienyl functionality be introduced late
in the synthesis. Of the several ploys conceivably adaptable to
elaboration of this polyolefinic appendage, the possibility of
uniting C-17 to C-18 seemed most conveniently workable.
Synthesis of the Sulfonyl-Substituted Tetrahydropyran.
Disconnection of 1 at the lactone site and across the C-9 and
C-10 bond fragments the target into a functionalized tetrahy-
dropyranylacetic acid among other subunits. To be in a position
later to implement the planned nucleophilic addition, the choice
was made to pursue the generation of 23 (Scheme 4). The
acquisition of this phenyl sulfone began with the known lactone
19, whose enantioselective synthesis from L-malic acid was
developed earlier by Fukui and co-workers.28
Given initial indications of potential complications surround-
ing removal of the tert-butyldimethylsilyl protecting group after
glycosidation with 17, it was considered appropriate to make
the p-methoxybenzyl derivative 18b available for use in
subsequent studies (vide infra).
Scheme 4
Retrosynthetic Analysis of the Aglycone Segment. The
polycavernoside A structure offers several major challenges to
anyone contemplating its synthesis. The first is construction of
the 14-membered lactone core, the success of which will depend
critically on attainment by the seco acid precursor of a
conformation properly suited to ring closure. Another key
question surrounds the feasibility of establishing the provocative
R-dicarbonyl linkage across the C-9/C-10 bond. Our initial
investigation contemplated the use of a dithiane subunit as the
To achieve economy in the overall number of synthetic steps,
19 was condensed directly without hydroxyl protection with
excess allylmagnesium bromide at -78 °C. The resulting
sensitive hemiacetal was subjected without delay to chemose-
lective ionic reduction with triethylsilane (TES) in the presence
of stannic chloride.27g This methodology served to orient the
(26) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J.
Am. Chem. Soc. 1984, 106, 4189.
(27) (a) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431.
(b) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A. J.
Am. Chem. Soc. 1986, 108, 2466.
(28) Fukui, M.; Okamoto, S.; Sano, T.; Nakata, T.; Oishi, T. Chem.
Pharm. Bull. Jpn. 1990, 38, 2890. We thank Dr. Tadashi Nakata of RIKEN
for providing us with experimental details for this 10-step procedure.
nucleophilic carbonyl synthon of this union.13 However, favor-
able coupling could not be achieved despite deployment of a
(25) These experiments involved customized INEPT- and DEPT-45 ver-
sions of the selective INEPT experiment introduced by Bax: (a) Bax, A. J.
Magn. Reson. 1984, 57, 314. (b) Bax, A.; Niu, C.-H.; Live, D. J. Am. Chem.
Soc. 1984, 106, 1150. (c) Mu¨ller, N.; Bauer, A. J. Magn. Res. 1989, 82, 400.

622 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
Scheme 5
Scheme 6
allyl group in 20 equatorially in a distinctively diastereoselective
manner. Once the secondary alcohol had been transformed into
a benzyl ether, desilylation to give 21b and the formation of
iodide 22 proceeded very efficiently.29 The latter step was imple-
mented for the purpose of enhancing the response of this build-
ing block to SN2 displacement.30,31 Indeed, the alkylation of lith-
iated methyl phenyl sulfone with 22 proceeded quite effectively.
Elaboration of the Electrophilic Partner. Expecting that
lactone 24 previously synthesized in this laboratory13 would
outperform other chiral precursors to the C-10/C-17 stor of 1,
we set about to reduce it to diol 25a with lithium borohydride
(Scheme 5). Subsequent monoesterification with pivaloyl chlo-
ride and pyridine proceeded almost quantitatively to deliver 25b.
Protection of the secondary hydroxyl moiety with p-methoxy-
benzyl trichloroacetimidate under triflic acid catalysis32 was
followed by fluoride ion-induced desilylation. This sequence
led to terminal carbinol 26b, which on Swern oxidation gave
rise to carboxaldehyde 27a. Because 27a is a nonepimerizable
intermediate, it is not vulnerable to possible deleterious action
by basic reagents. Accordingly, we did not have to exercise
particular care during the ensuing Wittig olefination deployed
to generate the homologated terminal alkene 27b.
reagent-controlled dihydroxylation33 with (DHQ)2PYR proved
ideally suited to the task, affording 28 in 99% yield. Although
it seemed reasonable to conclude that the 15S diastereomer was
in hand, added proof was considered highly desirable. Oxidative
cyclization of 28 to a 1,3-dioxolane would generate the trans
isomer whose anticipated dynamic NMR behavior would only
complicate matters further. This possibility could be countered,
however, by subjecting 27b to dihydroxylation with 2,5-
diphenyl-4,6-pyrimidenediyl hydroquinidine diether ((DHQD)2-
PYR), a chiral ligand recognized to deliver the diol of opposite
absolute configuration.33,34 The strategy is that 31 so formed
would, after regiocontrolled silylation, prove amenable to cycli-
zation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(Scheme 6). The stereodisposition of the substituents in 33 was
certain to favor an all-equatorial disposition as shown in A.
Indeed, nuclear Overhauser effect (NOE) experiments on this
acetal gave the indicated results, thereby confirming that 31
possesses the 15R configuration and, indirectly, that 28 is our
requisite intermediate.
The next transformation in the synthetic pathway was the
fully regioselective introduction of two different silyl protecting
groups as in 29. The pivaloyl group in 29 was cleaved
subsequently with diisobutylaluminum hydride, and the alcohol
so formed was oxidized with tetra-n-proylammonium perruth-
enate (TPAP).35 The fully elaborated aldehyde 30 resulted.
Proper Timing of More Advanced Functionalization. The
Macrolactonization Step. Deprotonation of 23 with n-butyl-
lithium and reaction of this salt with 30 in THF at -78 °C
furnished an alcohol (76% yield) whose oxidation with the
Dess-Martin periodinane reagent36 delivered keto sulfone 34
This option was exercised to permit proper elaboration of
the configuration at C-15. Although other probe experiments
soon revealed that this is no trivial matter, the protocol involving
(29) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866. (b) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem.
Soc. 1987, 109, 6187. (b) Millar, J. G.; Underhill, E. W. J. Org. Chem.
1986, 51, 4726. (c) Marshall, J. A.; Cleary, D. G. J. Org. Chem. 1986, 51,
858. (d) Marshall, J. A.; Grote, J.; Audia, J. E. J. Am. Chem. Soc. 1987,
109, 1186.
(30) Snider, B. B.; Wan, B. Y.-F.; Buckman, B. O.; Foxman, B. M. J.
Org. Chem. 1991, 56, 328.
(31) Lygo, B. Synlett 1992, 793.
(32) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(33) Crispino, G. A.; Jeong, K.-S.; Kolb, H.-C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(34) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 623
Scheme 7
Scheme 8
macrocyclization under modified Yamaguchi conditions.39 An
added benefit to the process was the production of a single C-9
diastereomer of 42, presumably as the direct consequence of
concomitant enolate equilibration. In light of impending chem-
istry that would erase the chirality of this center, no effort was
expended to define the precise configuration.
quantitatively (Scheme 7). After arrival at this coupling product,
it seemed reasonable to attempt to advance by unmasking the
R-dicarbonyl functionality, liberating the C-13 hydroxyl, and
thereby making allowance for intramolecular cyclization to form
a hemiacetal. When 34 was deprotonated with potassium tert-
butoxide and exposed to the Davis oxaziridine,37 oxidative
desulfonylation took place to give 35 exclusively. Of perhaps
greater significance was the finding that subsequent reaction
of 35 with DDQ gave 36 in 83% yield. Exclusive formation of
the five-membered ring lactol, a key step in the overall scheme,
was deduced principally on the basis of the coupling constants
observed for H-13. The doublet of doublets arising from spin-
spin interactions with the C-12 methylene protons (J ) 11.2
and 5.5 Hz) proved to be very similar to the pattern exhibited
by polycavernoside A (J ) 11.6 and 5.3 Hz).1 Later work by
Murai who had witnessed six-membered acetalization revealed
that the magnitudes of the H-13/H-12 coupling constants in that
series were distinctively different (J ≈ 12 and 0-2 Hz).7
We next turned to the possibility of accessing 37 by
chemoselective removal of the triethylsilyl group in 36.
However, attempts ranging from mildly acidic conditions to
various fluoride-promoted methods were unsuccessful. Because
it was plausible that the unprotected lactol was at the root of
this problem, effort was expended to prepare methyl ether 38.
When we were unable to accomplish this step, we decided to
undertake the necessary macrolactonization before chemical
modification of the phenylsulfonyl group.
Arrival at the Target. Having synthesized lactone 42, we
were anxious to determine whether the oxidative desulfonylation
protocol used successfully in Scheme 7 before macrolide
formation would prove equally dependable in a macro-ring
setting. In fact, the R-diketone 43 was smoothly elaborated. This
yellow foamy substance lent itself to efficient DDQ-promoted
removal of the p-methoxybenzyl (PMB) group (Scheme 9). The
resulting carbinol enters readily into intramolecular cyclization,
such that 44 was obtained in 63% yield. The NOE results
recorded for this intermediate (see formula) ensure without
ambiguity the stereochemistry at C-10. Particularly informative
is the rather strong interaction observed between H-8 and H-11
(9.8%). The requisite spatial proximity demanded by this
observation can be realized uniquely in the desired stereoisomer.
Encouraged by the success of this substrate-controlled reac-
tion, we decided to explore in a preliminary way a possible
means for attachment of the trienyl side chain. Because most
options require the involvement of aldehyde 46, it was first
shown that desilylation to provide alcohol 45 was not at all
problematic. However, attempted oxidation of 45 by a variety
of methods failed to afford this advanced intermediate. The
application of several such reagents invariably led to wholesale
destruction of the system. Apparently, the presence of the
hemiacetal renders the macrocycle vulnerable to their latent
oxidizing capability.
In this alternative scenario, removal of the TES substituent
was straightforward (Scheme 8). Once the C-15 hydroxyl had
been deprotected as in 39, the capacity to cleave the allylic
double bond efficiently (85% yield) was most welcome.
Subjection of 40 to chemoselective oxidation with sodium
chlorite38 then provided carboxylic acid 41 in readiness for
Our prior negative experience with lactol protection (e.g., 36
f 38) caused us once again to consider postponement of the
C-9 unveiling. This option required removal of the tert-butyl-
diphenylsilyl protecting group in 42 in advance of conversion
to aldehyde 48 (Scheme 10). The second of these steps was
particularly well served by making recourse to the Dess-
(35) Ley, S. V.; Norman, J.; Griffith, W. P. Marsden, S. P. Synthesis
1994, 639.
(36) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(37) Williams, D. R.; Robinson, L. A.; Amato, G. S.; Osterhout, M. H.
J. Org. Chem. 1992, 57, 3740.
(38) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(39) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Tone, H.; Horita,
K.; Yonemitsu, O. Tetrahedron 1990, 46, 4613.

624 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
Scheme 9
Martin periodinane (90%). The smooth operation of this step
stands in stark contrast to the rapid degradation observed during
the numerous attempts to obtain 46 from 45.
in 77% yield without detectable epimerization at C-15. The
oxidative desulfonylation protocol used previously was suc-
cessful in delivering the corresponding R-diketone as a yellow
foam. Because of the lability of this intermediate, it was treated
immediately with DDQ in wet dichloromethane to provide 50
in 73% overall yield. As before, a single diastereomer was
formed during the transannular cyclization.
Scheme 10
Glycosidation of aglycone 50 with 17 by means of Nicolaou
methodology41 gave 51 in 35% yield. We expected that
subsequent desilylation of 51 would give rise to 53, thereby
providing for completion of the synthesis via a projected Stille
coupling. However, removal of the tert-butyldimethylsilyl (TBS)
group in 51 unexpectedly proved to be very difficult. All
attempts to effect this deprotection maneuver resulted in
extensive degradation. When 18b was brought instead into the
glycosidation step, a 3:1 mixture of 52 and its R-anomer was
produced in 49% yield. After chromatographic separation, the
conversion of 52 into carbinol 53 with DDQ proceeded
uneventfully.
Dienylstannane 54 was readily obtained by iodide-tin ex-
change involving (E,E)-1-iodo-5-methyl-1,3-hexadiene.7 Al-
though 54 was unstable to silica gel, its purification was readily
achieved by reverse-phase chromatography as recommended by
Farina.42 When attempts to accomplish the final cross-coupling
of 53 to 54 with Pd2(dba)3‚CHCl343 or various Cu(I) salts44 were
discovered to be totally ineffective, recourse was made instead
to bis(acetonitrile)dichloropalladium(II) in dimethylformamide
(DMF)45 as catalyst. These conditions were conducive to the
efficient formation of (-)-polycavernoside A (1). The 500 MHz
1H and 125 MHz 13C NMR spectra of the material produced in
this manner (in CD3CN) were compared directly with those of
the natural toxin and corresponded well as expected. In addition,
the negative optical rotation was in close accord to the reported
value.7
In summation, we have devised and executed a highly
convergent total synthesis of (-)-polycavernoside A, thereby
confirming its global structure and absolute configuration. The
macrocyclic framework was assembled by sequential coupling
(40) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(41) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430.
(42) Farina, V. J. Org. Chem. 1991, 56, 4985.
Inspection of the retrosynthetic plan for polycavernoside A
reveals that a one-carbon homologation with incorporation of
C-17 in a way predisposed to establish E geometry across the
C-16/C-17 double bond was now required. Iodovinylation of
48 with the Takai reagent (CrCl2-CHI3)40 gave the desired 49
(43) Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenham, J. M.;
Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237.
(44) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(45) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1. (b) Nicolaou, K. C.; He, Y.; Roschangar, F.; King, N. P.; Vourloumis,
D.; Li, T. Angew. Chem., Int. Ed. Engl. 1998, 37, 84.

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 625
Hz, 1 H), 4.17 (q, J ) 6.7 Hz, 1 H), 3.98 (d, J ) 1.0 Hz, 1 H), 2.13
(s, 3 H), 2.11 (s, 3 H), 1.99 (s, 3 H), 1.28 (d, J ) 6.7 Hz, 3 H) (OH not
observed); 13C NMR (75 MHz, CDCl3) δ 170.2, 169.9, 169.2, 90.0,
of an R-sulfonyl carbanion to an aldehyde, lactonization, and
oxidative desufonylation. The route was punctuated by a
palladium-catalyzed Stille coupling. We note in particular that
the capacity to assemble the several building blocks in the
described manner might well be exploited to produce new
congeners of 1 for biological evaluation. The very late stages
at which the disaccharide and trienyl side chain are introduced
appear notably serviceable for gaining access to specifically
designed analogues.46
70.5, 70.2, 68.4, 66.4, 20.8, 20.8, 20.5, 16.0; HRMS (EI) m/z (M+
-
C2H3O2) calcd 231.0869, obsd 231.0872.
Anal. Calcd for C12H18O8: C, 49.65; H, 6.25. Found: C, 49.68; H,
6.05.
The mixture of triacetates and peracetylated L-fucose was warmed
(60 °C) with imidazole (3.11 g, 45.7 mmol), 4-(N,N-dimethylamino)-
pyridine (0.559 g, 4.58 mmol), and tert-butyldimethylsilyl triflate (10.49
mL, 45.7 mmol) in DMF (14 mL) for 6 h. Dilution of the cooled
solution with saturated NaHCO3 solution and extraction of the mixture
with ether was followed by drying of the organic layers, evaporation
of the solvent under reduced pressure, and chromatography of the
residue (SiO2, elution with 20% ethyl acetate in hexanes) to provide
peracetylated L-fucose (5.86 g, 33%) as an oil and the desired triacetate
9 (9.51 g, 43%); colorless oil; IR (CHCl3, cm-1) 1752, 1372, 1253,
Experimental Section
General. THF and ether were distilled from sodium benzophenone
ketyl under nitrogen just before use. For CH2Cl2 and benzene, the drying
agent was calcium hydride. All reactions were performed under a N2
atmosphere. Analytical thin-layer chromatography was performed on
E. Merck silica gel 60 F254 aluminum-backed plates. All chromato-
graphic purifications were performed on E. Merck silica gel 60 (230-
400 mesh) using the indicated solvent systems. Melting points are
uncorrected. 1H and 13C NMR spectra were recorded on Bruker
instruments at 300 and 75 MHz, respectively, except where noted.
Elemental analyses were performed at Atlantic Microlab, Inc., Norcross,
Georgia. The organic extracts were dried over anhydrous MgSO4. IR
spectra were recorded with a Perkin-Elmer 1320 spectrometer and
optical rotations were measured with a Perkin-Elmer model 241
polarimeter. The high-resolution mass spectra were recorded at The
Ohio State University Campus Chemical Instrumentation Center.
Phenyl 2,4-Di-O-acetyl-1-thio-D-xylopyranoside (6). Triacetate 5
(650 mg, 2.98 mmol) and phenylthiotrimethylsilane (0.85 mL, 4.47
mmol) were stirred in the presence of tin(IV) chloride (0.17 mL, 1.45
1
1240; H NMR (300 MHz, CDCl3) δ 6.29 (d, J ) 4 Hz, 1 H), 5.44
(dd, J ) 11, 4 Hz, 1 H), 5.25 (dd, J ) 11, 2 Hz, 1 H), 4.10 (q, J ) 7
Hz, 1 H), 3.96 (d, J ) 2 Hz, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H), 1.99 (s,
3 H), 1.19 (d, J ) 7 Hz, 3 H), 0.95 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 170.4, 169.9, 169.4, 90.4, 71.8, 70.7,
69.4, 66.5, 25.9 (3 C), 21.2, 21.0, 20.6, 18.3, 17.1, -4.38 (2 C); HRMS
(EI) m/z (M+ - C2H3O2) calcd 345.1733, obsd 345.1737; [R]22D -94.5
(c 0.83, CHCl3).
Phenyl 2,3,4-Tri-O-acetyl-1-thio-L-fucopyranoside (12a). A solu-
tion of L-fucose (5.04 g, 30.7 mmol), acetic anhydride (14.5 mL, 153
mmol), and DMAP (50 mg, 0.41 mmol) in pyridine (12 mL) was stirred
at room temperature for 12 h, diluted with ethyl acetate, and washed
successively with saturated NaHCO3 solution, 10% HCl, and brine.
The organic layer was dried and concentrated in vacuo to provide a
crude oil. This oil was taken up in benzene (30 mL) before being treated
with thiophenol (3.79 mL, 36.8 mmol) and tin(IV) chloride (21.5 mL,
1 M in CH2Cl2, 21.5 mmol). Stirring for 1.5 h was followed by dilution
with ethyl acetate and washing of the organic layer with 10% HCl and
brine. Drying and solvent evaporation left a yellow oil, an aliquot of
which was purified by silica gel chromatography (elution with 35%
ethyl acetate in hexanes) to provide both anomers of 12a as colorless
oils.
•
mmol) for 15 min before the addition of BF3 OEt2 (0.73 mL, 5.96
mmol). After an additional 20 min of stirring, saturated NH4Cl solution
was introduced to give a biphasic mixture that was extracted with ethyl
acetate. The combined organic layers were dried, concentrated, and
purified (SiO2, elution with 50% ethyl acetate in hexanes) to provide
647 mg (66%) of 6.
For the R-anomer: colorless oil; Rf ) 0.28; IR (CHCl3, cm-1) 1746,
1210, 1037; 1H NMR (300 MHz, CDCl3) δ 7.51-7.22 (m, 5 H), 5.79
(d, J ) 5 Hz, 1 H), 4.95-4.84 (m, 2 H), 4.13-4.00 (m, 2 H), 3.91-
3.85 (m, 1 H), 2.17 (s, 3 H), 2.13 (s, 3 H), 1.95 (br s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 170.7, 170.3, 133.3, 131.7, 129.1, 127.6, 85.5,
For the R-anomer: Rf ) 0.38; IR (CHCl3, cm-1) 1750, 1369, 1030;
1H NMR (300 MHz, CDCl3) δ 7.44-7.39 (m, 2 H), 7.33-7.22 (m, 3
H), 5.93 (d, J ) 5 Hz, 1 H), 5.38-5.25 (m, 3 H), 4.61 (q, J ) 7 Hz,
1 H), 2.16 (s, 3 H), 2.09 (s, 3 H), 2.01 (s, 3 H), 1.13 (d, J ) 7 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 170.5, 170.2, 169.9, 133.3, 131.8,
73.4, 71.5, 69.8, 59.8, 20.90, 20.88; [R]23 +141 (c 0.64, CHCl3).
D
1
For the â-anomer: colorless oil; Rf ) 0.21; H NMR (300 MHz,
CDCl3) δ 7.51-7.45 (m, 2 H), 7.33-7.27 (m, 3 H), 4.87-4.80 (m, 2
H), 4.73 (d, J ) 8.7 Hz, 1 H), 4.23 (dd, J ) 11.6, 5.0 Hz, 1 H), 3.78
(dd, J ) 8.3, 8.3 Hz, 1 H), 3.35 (dd, J ) 11.6, 9.0 Hz, 1 H), 2.46 (br
s, 1 H), 2.16 (s, 3 H), 2.09 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
170.6, 170.3, 132.6, 132.4, 129.0, 128.1, 86.2, 73.4, 72.4, 71.3, 65.5,
129.1, 127.5, 85.6, 70.9, 68.6, 68.2, 65.5, 20.8, 20.7, 20.6, 15.9; [R]23
-225 (c 0.47, CHCl3).
D
For the â-anomer: Rf ) 0.30; 1H NMR (300 MHz, CDCl3) δ 7.53-
7.48 (m, 2 H), 7.35-7.28 (m, 3 H), 5.26 (d, J ) 3 Hz, 1 H), 5.20 (d,
J ) 10 Hz, 1 H), 5.05 (dd, J ) 10, 3 Hz, 1 H), 4.70 (d, J ) 10 Hz, 1
H), 3.83 (q, J ) 7 Hz, 1 H), 2.14 (s, 3 H), 2.08 (s, 3 H), 1.97 (s, 3 H),
1.24 (d, J ) 7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.6, 170.1,
169.4, 132.9, 132.4, 128.8, 127.9, 86.5, 73.2, 72.4, 70.4, 67.4, 20.8,
20.8, 20.6, 16.5; HRMS (EI) m/z (M+ - C6H5S) calcd 273.0974, obsd
20.9, 20.8; HRMS (EI) m/z (M+) calcd 326.0824, obsd 326.0825; [R]20
-24.2 (c 1.02, CHCl3).
D
Anal. Calcd for C15H18O6S: C, 55.20; H, 5.56. Found: C, 55.14;
H, 5.56.
1,2,3-Tri-O-acetyl-4-O-(tert-butyldimethylsilyl)-L-fucopyranose (9).
To a solution of L-fucose (8.89 g, 54.2 mmol) and 4-(N,N-dimethy-
lamino)pyridine (DMAP, 0.662 g, 5.43 mmol) in pyridine (50 mL) at
room temperature was added acetic anhydride (15.3 mL, 0.162 mmol)
in two portions. A third equivalent was introduced after 2 h. The
solution was stirred for an additional 1.5 h before dilution with water
and extraction with ether and ethyl acetate. Drying of the organic layers
and concentration in vacuo provided a crude oil that was chromato-
graphed (SiO2, elution with 50% ethyl acetate in hexanes) to remove
undesired partially acetylated starting material. A pure sample of
triacetate was also obtained in this manner and shown to be an epimeric
mixture (R:â ) 4.6:1), the R-anomer of which was characterized:
273.0968; [R]22 -6.72 (c 0.66, CHCl3).
D
Anal. Calcd for C18H22O7S: C, 56.53; H, 5.80. Found: C, 56.41;
H, 5.96.
Phenyl 2-O-Methyl-1-thio-â-L-fucopyranoside (13). The â-anomer
of 12a from above was dissolved in methanol (100 mL) and stirred
with potassium hydroxide (1.03 g, 18.4 mmol) which had been
introduced in aliquots of 0.1 equiv. The resulting turbid mixture was
agitated for an additional 5 h before concentration under reduced
pressure and purification of the oil so obtained by silica gel chroma-
tography (elution with 10% methanol-chloroform) to afford the triol
as a white foam (7.18 g, 91% for three steps).
Zinc(II) chloride (5.85 g, 42.9 mmol) and phosphoric acid (0.05 mL)
in acetone (80 mL) was slowly added to a suspension of the triol (7.18
g, 28.0 mmol) in acetone (80 mL). The resulting solution was stirred
for 10 h before potassium hydroxide (1 g) was added and the mixture
was concentrated in vacuo. The residue was treated with water and
extracted with ethyl acetate. The combined organic layers were washed
with saturated NaHCO3 solution and brine before drying. The solvent
colorless prisms, mp 134.5-135.5 °C (from ether); IR (CHCl3, cm-1
3610, 1750, 1372, 1244; H NMR (300 MHz, CDCl3) δ 6.29 (d, J )
3.7 Hz, 1 H), 5.39 (dd, J ) 10.8, 3.8 Hz, 1 H), 5.26 (dd, J ) 10.8, 3.0
)
1
(46) For application of this coupling to the preparation of analogues of
1, see Barriault, L.; Boulet, S. L.; Fujiwara, K.; Murai, A.; Paquette, L. A.;
Yotsu-Yamashita, M. Bioorg. Med. Chem. Lett. 1999, 9, 2069.

626 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
was removed under reduced pressure, and the residue was chromato-
graphed (SiO2, elution with 40% ethyl acetate in hexanes) to furnish
the acetonide as a colorless oil (6.9 g, 83%).
a colorless oil (170 mg, 88%). The instability of 15 in most solvents
limited its characterization to the R-anomer; colorless oil; Rf ) 0.28;
1H NMR (300 MHz, CDCl3) δ 5.68 (dd, J ) 54.5 Hz, 2.7 Hz, 1 H),
4.03 (q, J ) 6.5 Hz, 1 H), 3.90 (d, J ) 2.2 Hz, 1 H), 3.59 (ddd, J )
25.2, 10.1, 2.7 Hz, 1 H), 3.54 (s, 3 H), 3.47 (s, 3 H), 3.44 (dd, J ) 7.5,
2.6 Hz, 1 H), 1.23 (d, J ) 6.5 Hz, 3 H), 0.93 (s, 9 H), 0.13 (s, 3H),
0.074 (s, 3 H).
A portion of the acetonide (5.80 g, 19.6 mmol) in DMF (55 mL)
was treated with methyl iodide (2.44 mL, 39.1 mmol) and sodium
hydride (704 mg, 29.4 mmol) at 0 °C. The low temperature was
maintained for 30 min before removal of the ice bath. Stirring for an
additional hour was immediately followed by quenching with saturated
NaHCO3 solution and water. After extraction of the mixture with ether,
the combined organic layers were washed with brine, dried, and
concentrated in vacuo to provide a yellow oil.
Phenyl 2,4-Di-O-acetyl-3-O-[4-O-(tert-butyldimethylsilyl)-2,3-di-
O-methyl-r-L-fucopyranosyl)-1-thio-â-D-xylopyranoside (16). A so-
lution of 15 (193 mg, 0.627 mmol) in ether (5 mL) was added to a
vigorously stirred suspension of 6 (170 mg, 0.521 mmol), silver
perchlorate (114 mg, 0.521 mmol), and tin(II) chloride (104 mg, 0.521
mmol) in ether (5 mL). The reaction mixture was stirred for 45 min
before dilution with brine and extraction with ether. The combined ether
layers were dried and concentrated, and the residue was chromato-
graphed (SiO2, elution with 20% ethyl acetate in hexanes) to afford 16
as a white solid, mp 138-140 °C (from ether-hexanes) (207 mg, 64%);
IR (CHCl3, cm-1) 1240, 1236, 1196, 1134; 1H NMR (300 MHz, CDCl3)
δ 7.63-7.59 (m, 2 H), 7.05-6.91 (m, 3 H), 5.27 (dd, J ) 8.4, 8.4 Hz,
1 H), 5.02 (ddd, J ) 8.8, 7.9, 5.1 Hz, 1 H), 4.88 (d, J ) 3.4 Hz, 1 H),
4.64 (d, J ) 8.6 Hz, 1 H), 4.02 (dd, J ) 11.7, 5.0 Hz, 1 H), 3.67 (q,
J ) 6.4 Hz, 1 H), 3.59 (dd, J ) 10.1, 3.3 Hz, 1 H), 3.56 (dd, J ) 7.9,
7.9 Hz, 1 H), 3.44 (d, J ) 0.9 Hz, 1 H), 3.41 (dd, J ) 10.3, 0.9 Hz, 1
H), 3.32 (s, 3 H), 3.24 (s, 3 H), 2.93 (dd, J ) 11.7, 8.8 Hz, 1 H), 1.89
(s, 3 H), 1.75 (s, 3 H), 1.15 (d, J ) 6.5 Hz, 3 H), 1.05 (s, 9 H), 0.21
(s, 3 H), 0.07 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.3, 168.7,
133.4 (2 C), 133.1, 129.1 (2 C), 128.1, 100.0, 86.3, 81.0, 80.1, 78.8,
72.9, 70.5, 70.4, 68.5, 65.4, 58.9, 58.7, 26.4 (3 C), 20.8, 20.7, 18.9,
17.1, -3.71, -4.68; HRMS (EI) m/z (M+ - C6H5S) calcd 505.2469,
The crude oil was warmed to 100 °C in a 50% aqueous AcOH
solution (150 mL) for 2 h. Removal of the solvent under reduced
pressure and filtration of the residue through silica gel (elution with
ethyl acetate) provided 13 as a colorless oil (5.28 g, 99%); IR (CHCl3,
cm-1) 3600-3200, 1463, 1175; 1H NMR (300 MHz, CDCl3) δ 7.55-
7.51 (m, 2 H), 7.32-7.22 (m, 3 H), 4.51 (d, J ) 9.7 Hz, 1 H), 3.75 (br
d, J ) 3.2 Hz, 1 H), 3.64 (s, 3 H), 3.62-3.58 (m, 2 H), 3.27 (dd, J )
9.4 Hz, 1 H), 2.65 (s, 2 H), 1.33 (d, J ) 6.5 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 133.8, 131.7, 128.8, 127.4, 87.2, 79.9, 75.4, 74.4, 71.8,
61.2, 16.6; HRMS (EI) m/z (M+) calcd 270.0926, obsd 270.0928; [R]24
+22.9 (c 1.06, CHCl3).
D
Anal. Calcd for C13H18O4S: C, 57.76; H, 6.71. Found: C, 57.80;
H, 6.85.
Phenyl 2,3-Di-O-methyl-1-thio-â-L-fucopyranoside (14). A solu-
tion of 13 (406 mg, 1.50 mmol) in methanol (6 mL) was refluxed in
the presence of di-n-butyltin oxide (392 mg, 1.58 mmol) for 2 h.
Concentration of the mixture left a white solid to which DMF (3 mL),
methyl iodide (0.47 mL, 7.51 mmol), and cesium fluoride (342 mg,
2.25 mmol) were added. The mixture was stirred for 12 h, at which
point the foamy solution was diluted with 10% HCl (5 mL) and
extracted with ethyl acetate. The combined organic layers were dried
and concentrated to leave a residue which was chromatographed (SiO2,
elution with 60% ethyl acetate in hexanes) to provide 14 as a colorless
oil (424 mg, 99%); IR (CHCl3, cm-1) 3569, 1479, 1440, 1381; 1H NMR
(300 MHz, CDCl3) δ 7.59-7.53 (m, 2 H), 7.32-7.21 (m, 3 H), 4.48
(d, J ) 9.3 Hz, 1 H), 3.85 (dd, J ) 3.1, 1.0 Hz, 1 H), 3.57 (s, 3 H),
3.59-3.52 (m, 1 H), 3.50 (s, 3 H), 3.29 (dd, J ) 9.0, 9.0 Hz, 1 H),
3.22 (dd, J ) 8.8, 3.1 Hz, 1 H), 2.04 (br s, 1 H), 1.36 (d, J ) 6.5 Hz,
3 H); 13C NMR (75 MHz, CDCl3) δ 133.8, 132.0, 128.8, 127.3, 87.2,
85.0, 78.4, 74.2, 68.6, 61.1, 57.6, 16.7; HRMS (EI) m/z (M+) calcd
obsd 505.2467; [R]24 -99.0 (c 0.92, CHCl3).
D
Anal. Calcd for C29H46O10SSi: C, 56.65; H, 7.55. Found: C, 57.07;
H, 7.62.
Phenyl 3-O-[4-O-(tert-butyldimethylsilyl)-2,3-di-O-methyl-r-L-
fucopyranosyl]-2,4-di-O-methyl-1-thio-â-D-xylopyranoside (17). Di-
saccharide 16 (101 mg, 0.164 mmol) was stirred for 15 min in methanol
(5 mL) in the presence of potassium hydroxide (7 mg, 0.125 mmol).
The solvent was evaporated, and the residue was redissolved in DMF
(1 mL), cooled to 0 °C, and treated successively with methyl iodide
(102 µL, 1.64 mmol) and sodium hydride (10 mg, 0.411 mmol). The
ice bath was removed, and after 1 h of stirring, water was carefully
introduced. The mixture was extracted with ether, and the combined
organic layers were dried and concentrated to leave a residue that was
purified by silica gel chromatography (elution with 25% ethyl acetate
in hexanes) to furnish 17 as a colorless oil (77 mg, 84%); IR (CHCl3,
cm-1) 3000, 2933, 2857, 1463, 1365, 1253, 1101, 1028, 970; 1H NMR
(300 MHz, C6D6) δ 7.58-7.55 (m, 2 H), 7.05-6.92 (m, 3 H), 5.46 (d,
J ) 3.6 Hz, 1 H), 4.53 (d, J ) 9.3 Hz, 1 H), 4.23 (q, J ) 6.5 Hz, 1 H),
3.83 (dd, J ) 11.4, 5.1 Hz, 1 H), 3.78 (dd, J ) 8.9, 8.9 Hz, 1 H),
3.75-3.70 (m, 2 H), 3.61 (s, 3 H), 3.54 (dd, J ) 10.1, 2.6 Hz, 1 H),
3.31 (s, 3 H), 3.29 (s, 3 H), 3.27 (dd, J ) 9.1, 9.1 Hz, 1 H), 3.09 (ddd,
J ) 9.4, 9.4, 5.1 Hz, 1 H), 3.00 (s, 3 H), 2.85 (dd, J ) 11.4, 9.6 Hz,
1 H), 1.29 (d, J ) 6.5 Hz, 3 H), 1.09 (s, 9 H), 0.25 (s, 3 H), 0.12 (s,
3 H); 13C NMR (75 MHz, C6D6) δ 135.0, 132.1, 129.0, 127.4, 98.5,
88.6, 83.8, 81.0, 79.9, 78.64, 78.60, 73.0, 67.1, 66.4, 60.4, 59.4, 58.5,
57.4, 26.4, 19.0, 17.4, -3.63, -4.60; HRMS (EI) m/z (M+) calcd
284.1082, obsd 284.1081; [R]25 +9.56 (c 1.13, CHCl3).
D
Phenyl 4-O-(tert-Butyldimethylsilyl)-2,3-di-O-methyl-1-thio-â-L-
fucopyranoside. A warm (80 °C) solution of 14 (3.34 g, 11.7 mmol),
imidazole (1.60 g, 23.5 mmol), and DMAP (287 mg, 2.35 mmol) in
DMF (8 mL) was treated with tert-butyldimethylsilyl triflate (3 mL,
13.1 mmol) in three aliquots at 1-h intervals. Continued heating for 14
h was followed by cooling and quenching of the reaction mixture with
saturated NaHCO3 solution. After extraction with ether, the combined
organic layers were washed with water and saturated NH4Cl solution,
dried, and concentrated. The residue was chromatographed (SiO2,
elution with 15% ethyl acetate in hexanes) to provide the silyl ether of
14 as a colorless oil (3.61 g, 77%); IR (CHCl3, cm-1) 1584, 1472,
1440, 1368, 1250; 1H NMR (300 MHz, CDCl3) δ 7.60-7.55 (m, 2 H),
7.29-7.18 (m, 3 H), 4.41 (d, J ) 9.5 Hz, 1 H), 3.80 (d, J ) 2.6 Hz,
1 H), 3.52 (q, J ) 6.4 Hz, 1 H), 3.46 (s, 3 H), 3.44 (s, 3 H), 3.36 (dd,
J ) 9.4, 9.4 Hz, 1 H), 3.06 (dd, J ) 9.2, 2.7 Hz, 1 H), 1.28 (d, J ) 6.4
Hz, 3 H), 0.92 (s, 9 H), 0.058 (s, 3 H), 0.054 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 133.7, 131.7, 128.6, 126.9, 86.6, 86.3, 77.5, 75.3, 71.2,
60.6, 58.5, 26.0, 18.6, 17.7, -4.13, -4.96; HRMS (EI) m/z (M+) calcd
558.2683, obsd 558.2702; [R]24 -17.1 (c 1.01, CHCl3).
D
Anal. Calcd for C27H46O8SSi: C, 58.03; H, 8.30. Found: C, 57.89;
H, 8.50.
Phenyl 3-O-(2,3-di-O-methyl-r-L-fucopyranosyl)-2,4-di-O-methyl-
1-thio-â-D-xylopyranoside (18a). A solution of 17 (239 mg, 429 µmol)
and tert-butylammonium fluoride (TBAF) (1.28 mL of 1.0 M in THF,
1.28 µmol) in THF (5 mL) was stirred for 48 h and concentrated.
Chromatography of the residue on silica gel (elution with ethyl acetate)
gave 18a as a white foam (181 mg, 95%); IR (film, cm-1) 3482, 1099;
1H NMR (300 MHz, CDCl3) δ 7.50-7.46 (m, 2 H), 7.30-7.22 (m, 3
H), 5.31 (d, J ) 3.0 Hz, 1 H), 4.55 (d, J ) 9.1 Hz, 1 H), 4.24 (q, J )
6.7 Hz, 1 H), 4.14 (dd, J ) 4.5, 11.1 Hz, 1 H), 3.88 (br s, 1 H), 3.68
(t, J ) 8.4 Hz, 1 H), 3.60 (s, 3 H), 3.56-3.50 (m, 2 H), 3.52 (s, 3 H),
3.48 (s, 3 H), 3.35 (s, 3 H), 3.33-3.16 (m, 3 H), 2.33 (br s, 1 H), 1.24
(d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 133.3, 131.3 (2
C), 128.5 (2 C), 127.0, 97.2, 87.7, 82.3, 79.3, 79.0, 77.3, 77.1, 68.7,
398.1947, obsd 398.1939; [R]25 +123 (c 0.50, CHCl3).
D
Anal. Calcd for C20H34O4SSi: C, 60.26; H, 8.60. Found: C, 60.61;
H, 8.69.
4-O-(tert-Butyldimethylsilyl)-2,3-di-O-methyl-L-fucopyranosyl Fluo-
ride (15). To a solution of silylated 14 (250 mg, 0.627 mmol) and
diethylaminosulfur trifluoride (91 µL, 0.690 mmol) in cold (0 °C) CH2-
Cl2 (5 mL) was added N-bromosuccinimide (117 mg, 0.658 mmol).
The orange solution was stirred for 15 min, diluted with triethylamine
(1 mL) and ethyl acetate, washed with water, dried, and concentrated.
The residue was purified by chromatography (SiO2, elution with 15%
ethyl acetate in hexanes containing 1% triethylamine) to provide 15 as

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 627
65.9, 64.8, 59.8, 59.4, 57.4, 56.8, 15.6; HRMS (EI) m/z (M+) calcd
MHz, CDCl3) δ 7.78-7.69 (m, 4 H), 7.49-7.27 (m, 11 H), 6.00-
5.89 (m, 1 H), 5.52-5.02 (m, 2 H), 4.68 (d, J ) 11.6 Hz, 1 H), 4.46
(d, J ) 11.6 Hz, 1 H), 3.80 (dd, J ) 5.5, 10.4 Hz, 1 H), 3.66 (dd, J )
5.0, 10.4 Hz, 1 H), 3.52-3.43 (m, 1 H), 3.16 (td, J ) 6.0, 10.4 Hz, 1
H), 3.09 (ddd, J ) 2.9, 7.0, 9.9 Hz, 1 H), 2.46 (dm, J ) 12.0 Hz, 1 H),
2.29-2.17 (m, 2 H), 1.55-1.46 (m, 1 H), 1.31 (q, J ) 11.6 Hz, 1 H),
1.09 (s, 9 H), 0.99 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 138.7, 135.7 (4 C), 135.2, 133.8 (2 C), 129.6 (2 C), 128.3 (2 C),
127.7 (2 C), 127.6 (5 C), 116.2, 80.7, 80.4, 76.0, 70.4, 67.1, 41.1, 37.3,
33.5, 26.8 (3 C), 19.3, 13.0; HRMS (EI) m/z (M+ - C4H9) calcd
444.1818, obsd 444.1830; [R]20 -70.4 (c 2.26, CHCl3).
D
Anal. Calcd for C21H32O8S: C, 56.73; H, 7.26. Found: C, 56.88;
H, 7.30.
Phenyl 3-O-[4-O-(p-methoxybenzyl)-2,3-di-O-methyl-r-L-fucopy-
ranosyl]-2,4-di-O-methyl-1-thio-â-D-xylopyranoside (18b). A solution
of 18a (57 mg, 128 mmol) and THF (3 mL) was treated with sodium
iodide (212 mg, 1.28 µmol), sodium hydride (19.2 mg of 80% in oil,
641 µmol), and p-methoxybenzyl chloride (60 mg, 384 µmol), heated
at 65 °C for 30 min, and allowed to cool to room temperature. The
reaction mixture was quenched with saturated NH4Cl solution (5 mL)
and extracted with ether (three times). The combined organic layers
were dried and concentrated to leave a residue which was purified by
flash chromatography (SiO2, elution with 50% ethyl acetate in hexanes)
to provide 18b as a colorless oil (69 mg, 96%); IR (film, cm-1) 1612,
1098; 1H NMR (300 MHz, CDCl3) δ 7.50 (dd, J ) 1.9, 7.9 Hz, 2 H),
7.35-7.24 (m, 5 H), 6.86 (d, J ) 7.9 Hz, 2 H), 5.34 (d, J ) 3.8 Hz,
1 H), 4.86 (d, J ) 11.4 Hz, 1 H), 4.59 (d, J ) 11.1 Hz, 1 H), 4.58 (d,
J ) 9.2 Hz, 1 H), 4.16-4.11 (m, 2 H), 3.79 (s, 3 H), 3.77-3.66 (m,
3 H), 3.60 (s, 3 H), 3.60-3.56 (m, 1 H), 3.56 (s, 3 H), 3.51 (s, 3 H),
3.34 (s, 3 H), 3.30-3.16 (m, 3 H), 1.08 (d, J ) 6.5 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 159.1, 133.8, 131.7 (2 C), 130.8, 129.9 (2
C), 128.8 (2 C), 127.4, 113.5 (2 C), 98.5, 97.6, 88.0, 82.6, 81.3, 78.9,
78.0, 77.7, 75.7, 74.1, 66.2, 66.1, 60.1, 59.6, 57.9, 55.2, 16.6; HRMS
457.2199, obsd 457.2201; [R]21 +34.0 (c 1.04, CHCl3).
D
Anal. Calcd for C33H42O3Si: C, 77.00; H, 8.22. Found: C, 77.18;
H, 8.29.
(2S,4S,5R,6S)-6-Allyl-4-(benzyloxy)tetrahydro-5-methyl-2H-py-
ran-2-methanol (21b). A solution of 10.96 g (21.3 mmol) of 21a in
80 mL of THF was treated with 31.9 mL (31.9 mmol) of a 1 M solution
of TBAF in THF. The reaction mixture was stirred for 1.5 h before
dilution with ether and aqueous workup. The combined organic phases
were dried and concentrated, and the residue was purified by column
chromatography on silica gel (gradient elution with 20-40% ether in
petroleum ether) to furnish 5.78 g (98%) of 21b as a colorless oil; IR
(film, cm-1) 3442, 1454, 1072; 1H NMR (300 MHz, CDCl3) δ 7.37-
7.27 (m, 5 H), 5.96-5.82 (m, 1 H), 5.11-5.03 (m, 2 H), 4.66 (d, J )
11.5 Hz, 1 H), 4.43 (d, J ) 11.5 Hz, 1 H), 3.63-3.53 (m, 2 H), 3.49-
3.41 (m, 1 H), 3.22-3.08 (br m, 2 H), 2.47 (dm, J ) 14.7 Hz, 1 H),
2.26-2.17 (m, 2 H), 2.03 (ddd, J ) 1.9, 4.6, 12.3 Hz, 1 H), 1.76-
1.42 (m, 1 H), 1.31 (q, J ) 11.4 Hz, 1 H), 0.99 (d, J ) 6.5 Hz, 3 H);
13C NMR (75 MHz, CDCl3) δ 138.5, 134.8, 128.4 (2 C), 127.7 (2 C),
127.6, 116.6, 80.5, 80.0, 75.6, 70.5, 66.0, 41.2, 37.2, 32.8, 12.9; HRMS
(EI) m/z (M+) calcd 276.1725, obsd 276.1715; [R]20D +75.41 (c 1.11,
CHCl3).
(EI) molecular ion too fleeting for accurate mass measurement; [R]20
-150.6 (c 2.25, CHCl3).
D
Anal. Calcd for C29H40O9S: C, 61.68; H, 7.14. Found: C, 61.94; H,
7.28.
(2S,3R,4S,6S)-2-Allyl-6-[(tert-butyldiphenylsiloxy)methyl]tetra-
hydro-3-methyl-2H-pyran-4-ol (20). A solution of 15.00 g (37.6
mmol) of 1928 in 200 mL of THF was treated at -78 °C with 112.9
mL (112.9 mmol) of 1 M allylmagnesium bromide in ether, stirred for
5 min, quenched with 100 mL of saturated NH4Cl solution, and allowed
to warm to room temperature. The product was extracted into ether
(ca. 50 mL of 1 M HCl was added to break the emulsion), and the
combined organic phases were washed with brine, dried, and concen-
trated. The residual yellowish hemiacetal was dried at high vacuum
for 2 h, admixed with 42.60 g (376.3 mmol) of triethylsilane dissolved
in 200 mL of CH2Cl2, cooled to -78 °C, and treated with 41.4 mL
(41.4 mmol) of a 1 M solution of tin tetrachloride in CH2Cl2. The
reaction mixture was allowed to warm gradually to -20 °C for 80 min
and quenched with 100 mL of water and 50 mL of 1 M HCl. The
product was extracted into CH2Cl2 and ether, and the combined organic
phases were dried and concentrated. The residue was purified by
chromatography (SiO2, elution with 15% ether in petroleum ether) to
furnish 11.43 g (71%) of 20 as a colorless oil; IR (film, cm-1) 3355,
1113; 1H NMR (300 MHz, CDCl3) δ 7.72-7.66 (m, 4 H), 7.45-7.34
(m, 6 H), 6.00-5.87 (m, 1 H), 5.11-5.00 (m, 2 H), 3.76 (dd, J ) 5.4,
10.3 Hz, 1 H), 3.61 (dd, J ) 5.1, 10.3 Hz, 1 H), 3.55-3.47 (m, 1 H),
3.37 (td, J ) 4.6, 10.4 Hz, 1 H), 3.06 (ddd, J ) 3.0, 7.0, 9.9 Hz, 1 H),
2.44 (dm, J ) 14.0 Hz, 1 H), 2.21 (m, 1 H), 2.04 (ddd, J ) 1.9, 4.7,
12.3 Hz, 1 H), 1.51 (br, 1 H), 0.56-0.40 (m, 2 H), 1.06 (s, 9 H), 0.98
(d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 135.7 (4 C), 135.7,
133.7 (2 C), 129.5 (2 C), 127.6 (4 C), 116.3, 80.4, 76.0, 73.6, 66.9,
43.1, 37.6, 37.1, 26.8 (3 C), 19.3, 12.6; FAB MS m/z (M+ + H) calcd
Anal. Calcd for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.62; H,
8.71.
(2S,3R,4S,6R)-2-Allyl-4-(benzyloxy)-6-iodomethyltetrahydro-3-
methyl-2H-pyran (22). A solution of 1.00 g (3.62 mmol) of alcohol
21b, 1.42 g (5.42 mmol) of triphenylphosphine, and 0.37 g (5.4 mmol)
of imidazole in 50 mL of benzene was cooled to 10 °C and treated
with 1.38 g (5.42 mmol) of iodine (added in portions for 10 min) with
vigorous magnetic stirring. The cooling bath was removed and stirring
was continued for an additional 1.5 h, during which time an amorphous
precipitate that originally deposited on the walls of the flask was
transformed into a suspension. The reaction mixture was quenched with
10 mL of 25% sodium thiosulfate solution, and the product was
extracted into ether. The combined organic phases were washed with
brine, dried, and concentrated. Chromatographic purification of the
residue on silica gel (elution with 3% ether in petroleum ether) afforded
1
1.31 g (94%) of 22 as a colorless oil; IR (film, cm-1) 1354, 1074; H
NMR (300 MHz, CDCl3) δ 7.36-7.27 (m, 5 H), 6.05-5.91 (m, 1 H),
5.12-5.04 (m, 2 H), 4.67 (d, J ) 11.5 Hz, 1 H), 4.44 (d, J ) 11.5 Hz,
1 H), 3.41-3.32 (m, 1 H), 3.24-3.06 (m, 4 H), 2.49-2.33 (m, 2 H),
2.27-2.18 (m, 1 H), 1.57-1.41 (m, 1 H), 1.26 (q, J ) 11.4 Hz, 1 H),
0.98 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 138.4, 135.0,
128.4 (2 C), 127.7 (2 C), 127.6, 116.4, 81.0, 79.9, 74.8, 70.6, 40.9,
37.2, 36.7, 12.8, 9.0; HRMS (EI) m/z (M+ - C3H5) calcd 345.0351,
obsd 345.0309; [R]20 +57.52 (c 1.33, CHCl3).
D
425.25, obsd 425.19; [R]21 -25.3 (c 0.79, CHCl3).
Anal. Calcd for C17H23IO2: C, 52.86; H, 6.00. Found: C, 52.65; H,
D
Anal. Calcd for C26H36O3Si: C, 73.54; H, 8.54. Found: C, 73.81;
6.06.
H, 8.59.
(2S,3R,4S,6S)-2-Allyl-4-(benzyloxy)tetrahydro-3-methyl-6-[2-(phe-
nylsulfonyl)ethyl]-2H-pyran (23). A solution of 5.07 g (32.5 mmol)
of methyl phenyl sulfone in 70 mL of THF was cooled to -78 °C and
treated with 21.0 mL (32.5 mmol) of a 1.5 M solution of n-butyllithium
in hexanes. The reaction mixture was stirred for 25 min before the
addition of 1.88 mL of hexamethylphosphoric triamide (HMPA) and a
solution of 4.18 g (10.8 mmol) of 22 in 70 mL of THF. The reaction
mixture was allowed to warm gradually to room temperature and stirred
for an additional 8 h before aqueous workup and extraction with ether.
The combined organic phases were dried and concentrated, and the
residue was purified by chromatography (SiO2, elution with 30% ether
in petroleum ether) to furnish 3.09 g (69%) of 23 as a white solid, mp
57 °C (from ether-petroleum ether); IR (film, cm-1) 1450, 1357, 1305,
1137, 1075; 1H NMR (300 MHz, CDCl3) δ 7.97-7.89 (m, 2 H), 7.69-
[[(2S,4S,5R,6S)-6-Allyl-4-(benzyloxy)tetrahydro-5-methyl-2H-py-
ran-2-yl]methoxy]-tert-butyldiphenylsilane (21a). A suspension of
80% sodium hydride in mineral oil (2.40 g, 80.1 mmol) was placed in
a 250-mL flask, washed once with 20 mL of THF, and treated with a
solution of 20 (11.33 g, 26.7 mmol) in 80 mL of THF followed by
12.0 g (80.1 mmol) of flame-dried sodium iodide. The reaction mixture
was refluxed for 5 min, treated with 9.1 g (53.0 mmol) of benzyl
bromide, and refluxed for an additional 20 min before cooling, dilution
with 200 mL of ether, quenching with water, and extraction with ether.
The combined organic layers were washed with brine, dried, and
concentrated. The residue was chromatographed (SiO2, gradient elution
with 2-5% ether in petroleum ether) to furnish 11.93 g (87%) of 21a
as a colorless oil; IR (film, cm-1) 1454, 1428, 1113; H NMR (300
1

628 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
7.54 (m, 3 H), 7.38-7.27 (m, 5 H), 5.87-5.73 (m, 1 H), 5.06-4.99
(m, 2 H), 4.62 (d, J ) 11.5 Hz, 1 H), 4.40 (d, J ) 11.5 Hz, 1 H),
3.37-3.27 (m, 2 H), 3.21 (dd, J ) 5.8, 9.9 Hz, 1 H), 3.17-3.04 (m,
1 H), 2.95 (ddd, J ) 2.8, 7.6, 10.1 Hz, 1 H), 2.42-2.33 (m, 1 H),
2.16-1.99 (m, 2 H), 1.99-1.77 (m, 2 H), 1.46-1.32 (m, 1 H), 1.20
(q, J ) 11.3 Hz, 1 H), 0.93 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 139.2, 138.4, 135.0, 133.6, 129.3 (2 C), 128.4 (2 C), 128.0
(2 C), 127.7 (2 C), 127.6, 116.4, 80.6, 80.0, 72.9, 70.6, 52.8, 41.2,
37.2, 37.0, 29.2, 12.9; HRMS (EI) m/z (M+ - C3H5) calcd 341.1575,
135.8 (4 C), 133.7 (2 C), 131.4, 129.6 (2 C), 128.8 (4 C), 127.6 (2 C),
113.6 (2 C), 80.2, 74.3, 70.4, 69.9, 55.2, 41.1, 38.8, 34.6, 29.9, 27.2 (3
C), 27.0 (3 C), 21.8, 20.2, 19.4, 16.5; HRMS (EI) molecular ion too
fleeting for accurate mass measurement; [R]20D +10.1 (c 0.99, CHCl3).
Anal. Calcd for C38H54O5Si: C, 73.74; H, 8.80. Found: C, 73.85;
H, 8.70.
(2R,4R)-6-Hydroxy-4-[(p-methoxybenzyl)oxy]-2,5,5-trimethyl-
hexyl Pivalate (26b). A solution of 26a (239 mg, 372 µmol) and tetra-
n-butylammonium fluoride (1.16 mL of 0.1 M in THF, 1.16 mmol) in
THF (4 mL) was stirred for 3 days. After concentration, the brown
residue was purified by flash chromatography (SiO2, elution with 50%
ether in hexanes) to afford 26b as a colorless oil (133 mg, 94%); IR
obsd 341.1517; [R]20 +51.2 (c 0.215, CHCl3).
D
Anal. Calcd for C24H30O4S: C, 69.53; H, 7.29. Found: C, 69.40;
H, 7.30.
1
(2R,4R)-6-(tert-Butyldiphenylsiloxy)-4-hydroxy-2,5,5-trimethyl-
hexyl Pivalate (25b). A cold (0 °C), magnetically stirred solution of
2413 (1.26 g, 3.07 mmol) in ether (30 mL) was treated with methanol
(148 mg, 4.61 mmol) and lithium borohydride (100 mg, 4.61 mmol),
stirred at room temperature for 30 min, and quenched with saturated
NH4Cl solution. The product was extracted into ether (three times),
and the combined organic layers were dried and concentrated. The
residue was purified by flash chromatography (SiO2, elution with 50%
ethyl acetate in hexanes) to provide 25a as a colorless oil (1.13 g, 93%);
IR (film, cm-1) 3346, 1589, 1111; 1H NMR (300 MHz, C6D6) δ 7.79-
7.72 (m, 4 H), 7.24-7.20 (m, 6 H), 3.69 (dd, J ) 1.3, 10.2 Hz, 1 H),
3.58 (d, J ) 9.8 Hz, 1 H), 3.51 (d, J ) 9.8 Hz, 1 H), 3.60-3.43 (m,
1 H), 3.36 (dd, J ) 7.3, 10.6 Hz, 1 H), 1.89-1.84 (m, 1 H), 1.52-
1.32 (m, 1 H), 1.29-1.27 (m, 1 H), 1.13 (s, 9 H), 0.89 (s, 3 H), 0.86
(d, J ) 6.5 Hz, 3 H), 0.75 (s, 3 H) (two OH not observed); 13C NMR
(75 MHz, C6D6) δ 136.1 (2 C), 136.0 (2 C), 133.5, 133.4, 130.2, 130.1,
128.1 (4 C), 76.7, 72.9, 68.9, 39.4, 37.3, 34.9, 27.0 (3 C), 21.9, 19.5;
HRMS (EI) m/z (M+ + H) calcd 414.2590, obsd 414.2687; [R]20D +16.6
(c 1.50, CHCl3).
(film, cm-1) 3473, 1726, 1513, 1465; H NMR (300 MHz, CDCl3) δ
7.24 (d, J ) 8.5 Hz, 2 H), 6.81 (d, J ) 8.5 Hz, 2 H), 4.54 (s, 2 H),
3.91 (d, J ) 6.2 Hz, 2 H), 3.78 (s, 3 H), 3.60 (d, J ) 10.8 Hz, 1 H),
3.40 (dd, J ) 9.3, 2.0 Hz, 1 H), 3.30 (d, J ) 10.8 Hz, 1 H), 2.72 (br
s, 1 H), 2.07-2.00 (m, 1 H), 1.74-1.65 (m, 1 H), 1.34-1.26 (m, 1
H), 1.20 (s, 9 H), 1.02 (s, 3 H), 0.96 (d, J ) 6.7 Hz, 3 H), 0.84 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 178.5, 159.5, 130.5, 129.2 (2 C),
113.8 (2 C), 84.0, 74.4, 70.4, 69.6, 55.2, 39.6, 38.8, 35.0, 30.2, 27.2 (3
C), 23.1, 20.7, 16.5; HRMS (EI) m/z (M+) calcd 380.2563, obsd
380.2549; [R]20 +5.4 (c 1.1, CHCl3).
D
(2R,4R)-5-Formyl-4-[(p-methoxybenzyl)oxy]-2,5-dimethylhexyl Piv-
alate (27a). Oxalyl chloride (7.39 g, 57.6 mmol) dissolved in CH2Cl2
(140 mL) was cooled to -78 °C, treated with dimethyl sulfoxide
(DMSO) (9.0 g, 115 mmol), and stirred for 10 min. A solution of 26b
(18.37 g, 48 mmol) was introduced via cannula at this temperature,
and the reaction mixture was stirred for 1 h before the addition of
triethylamine (19.4 g, 192 mmol) and gradual warming to 0 °C. After
stirring had been maintained for 30 min, the mixture was poured into
saturated NH4Cl solution (200 mL) and extracted with CH2Cl2 (three
times). The combined organic phases were washed with saturated
NaHCO3 solution and brine, dried, and concentrated. Purification of
the residue by flash chromatography on silica gel (elution with 20%
ether in hexanes) gave 27a as a colorless oil (18.13 g, 99%); IR (film,
cm-1) 1728, 1613, 1514, 1249; 1H NMR (300 MHz, CDCl3) δ 9.61 (s,
1 H), 7.21 (d, J ) 8.6 Hz, 2 H), 6.84 (d, J ) 8.6 Hz, 2 H), 4.49 (s, 2
H), 3.90 (d, J ) 6.2 Hz, 2 H), 3.77 (s, 3 H), 3.64 (dd, J ) 9.6, 2.2 Hz,
1 H), 2.08-1.90 (m, 1 H), 1.70-1.60 (m, 1 H), 1.25-1.20 (m, 1 H),
1.19 (s, 9 H), 1.11 (s, 3 H), 1.04 (s, 3 H), 0.96 (d, J ) 6.7 Hz, 3 H);
13C NMR (75 MHz, CDCl3) δ 206.1, 178.3, 159.1, 134.7, 129.1 (2 C),
113.7 (2 C), 80.4, 73.4, 69.3, 55.1, 51.1, 38.8, 35.0, 29.8, 27.1 (3 C),
19.1, 17.6, 16.3; HRMS (EI) m/z (M+) calcd 378.2406, obsd 378.2394;
Anal. Calcd for C25H38O3Si: C, 72.41; H, 9.24. Found: C, 72.55;
H, 9.28.
This material was dissolved in CH2Cl2 (30 mL) and treated
sequentially with pyridine (1.35 g, 17.0 mmol) and pivaloyl chloride
(515 mg, 4.26 mmol) at 25 °C. After overnight stirring, saturated NH4-
Cl solution was introduced, the product was extracted into CH2Cl2 (three
times), and the combined organic phases were washed with 2 N HCl,
saturated NaHCO3 solution, and brine before drying. The solvent was
removed under reduced pressure and the residue was chromatographed
(SiO2, elution with 30% ether in hexanes) to afford 25b (1.36 g, 96%)
1
as a colorless oil; IR (film, cm-1) 3506, 1728, 1478, 1427; H NMR
(300 MHz, CDCl3) δ 7.68-7.65 (m, 4 H), 7.45-7.27 (m, 6 H), 4.00
(dd, J ) 10.6, 5.5 Hz, 1 H), 3.90 (dd, J ) 10.6, 6.8 Hz, 1 H), 2.67 (d,
J ) 9.5 Hz, 1 H), 3.53 (d, J ) 10.0 Hz, 1 H), 3.47 (d, J ) 10.0 Hz,
1 H), 3.19 (br s, 1 H), 2.21-2.04 (m, 1 H), 1.55-1.42 (m, 1 H), 1.26-
1.17 (m, 1 H), 1.20 (s, 9 H), 1.07 (s, 9 H), 0.98 (d, J ) 6.7 Hz, 3 H),
0.87 (s, 3 H), 0.83 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 178.5, 135.7
(2 C), 135.6 (2 C), 132.7 (2 C), 129.9 (2 C), 129.8 (2 C), 127.8 (2 C),
75.4, 73.3, 70.1, 38.8, 38.7, 35.0, 29.5, 27.2 (3 C), 26.9 (3 C), 22.3,
19.2, 19.1, 16.1; HRMS (EI) m/z (M+ - C9H18O2) calcd 340.1858,
[R]20 +5.2 (c 1.30, CHCl3).
D
(2R,4R)-4-[(p-Methoxybenzyl)oxy]-2,5,5-trimethyl-6-heptenyl Piv-
alate (27b). To a suspension of methyltriphenylphosphonium iodide
(29.1 g, 72 mmol) in THF (450 mL) was added potassium hexameth-
yldisilazide (144 mL of 0.5 M in toluene, 72 mmol) at 0 °C. After 20
min of stirring, a solution of 27a (18.13 g, 48 mmol) in THF (50 mL)
was introduced via cannula, and the reaction mixture was stirred at 0
°C for an additional 20 min before being quenched with saturated NH4-
Cl solution. The product was extracted into ether (three times), and
the combined organic phases were dried and concentrated. The residue
was chromatographed on silica gel (elution with 10% ether in hexanes)
to provide 27b as a colorless oil (16.02 g, 89%); IR (film, cm-1) 1728,
1248, 1162; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J ) 8.6 Hz, 2 H),
6.86 (d, J ) 8.6 Hz, 2 H), 5.91 (dd, J ) 16.8, 10.5 Hz, 1 H), 5.02-
4.96 (m, 2 H), 4.58 (d, J ) 10.8 Hz, 1 H), 4.51 (d, J ) 10.8 Hz, 1H),
3.88 (dd, J ) 5.8, 5.0 Hz, 2 H), 3.79 (s, 3 H), 3.20 (dd, J ) 9.7, 2.0
Hz, 1 H), 2.00-1.95 (m, 1 H), 1.58-1.49 (m, 1 H), 1.27-1.20 (m, 1
H), 1.19 (s, 9 H), 1.06 (s, 3 H), 1.04 (s, 3 H), 0.93 (d, J ) 7.6 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 178.4, 159.0, 146.0, 131.2, 129.1 (2
C), 113.7 (2 C), 111.7, 84.2, 74.6, 69.7, 55.2, 42.4, 38.8, 35.4, 29.9,
27.2 (3 C), 24.1, 22.8, 16.5; HRMS (EI) m/z (M+) calcd 377.2692,
obsd 340.1891; [R]20 +19.1 (c 0.98, CHCl3).
D
Anal. Calcd for C30H46O4Si: C, 72.24; H, 9.30. Found: C, 72.12;
H, 9.30.
(2R,4R)-6-(tert-Butyldiphenylsiloxy)-4-[(p-methoxybenzyl)oxy]-
2,5,5-trimethylhexyl Pivalate (26a). A solution of 25b (945 mg, 1.89
mmol) in ether (20 mL) was treated successively with p-methoxybenzyl
trichloroacetimidate (1.36 g, 4.73 mmol) and triflic acid (189 µL of
0.1 M in ether, 18.9 mmol) at room temperature. After the reaction
mixture had been stirred for 1 h, saturated NaHCO3 solution was
introduced and the product was extracted into ethyl acetate. The
combined organic phases were washed with brine, dried, and freed of
solvent. Flash chromatography of the residue (SiO2, elution with 10%
ether in hexanes) gave 953 mg (81%) of 26a as a colorless oil; IR
obsd 377.2731; [R]20 +17.6 (c 1.83, CHCl3).
1
(film, cm-1) 1728, 1513, 1247, 1160; H NMR (300 MHz, CDCl3) δ
D
Anal. Calcd for C23H36O4: C, 73.35; H, 9.64. Found: C, 73.20; H, 9.51.
(2R,4R,6S)-6,7-Dihydroxy-4-[(p-methoxybenzyl)oxy]-2,5,5-tri-
methylheptyl Pivalate (28). To a well stirred mixture of (DHQ)2PYR
(6.3 mg, 7.2 µmol), osmium tetraoxide (45 µL of 0.16 M in THF, 7.17
µmol), potassium ferricyanide (707 mg, 2.15 mmol), and K2CO3 (296
mg, 2.15 mmol) in tert-butyl alcohol-water (1:1, 8 mL) was added 27b
7.69-7.66 (m, 4 H), 7.50-7.40 (m, 6 H), 7.14 (d, J ) 8.4 Hz, 2 H),
6.83 (d, J ) 8.4 Hz, 2 H), 4.54 (s, 2 H), 4.00-3.86 (m, 2 H), 3.81 (s,
3 H), 3.63 (d, J ) 10.1 Hz, 1 H), 3.58 (d, J ) 9.8 Hz, 1 H), 3.41 (d,
J ) 9.8 Hz, 1 H), 2.08-2.02 (m, 1 H), 1.66-1.57 (m, 1 H), 1.32-
1.19 (m, 1 H), 1.21 (s, 9 H), 1.12 (s, 9 H), 1.01 (d, J ) 6.6 Hz, 3 H),
0.91 (s, 3 H), 0.89 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 178.5, 158.9,

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 629
(270 mg, 717 µmol) dissolved in the same solvent system (3 mL at 0
°C). The mixture was stirred overnight at this temperature, treated with
sodium sulfite (1.2 g), and after 20 min extracted several times with
CH2Cl2. The combined organic layers were dried and concentrated.
Flash chromatography of the residue on silica gel (gradient elution with
50% ethyl acetate in hexanes to 100% ethyl acetate) gave 28 as a
colorless, oily mixture (>25:1) of diastereomers (293 mg, 99%); IR
(film, cm-1) 3440, 1727, 1514, 1248, 1171; 1H NMR (300 MHz, CDCl3)
δ 7.22 (d, J ) 8.5 Hz, 2 H), 6.85 (d, J ) 8.5 Hz, 2 H), 4.55 (s, 2 H),
3.90 (d, J ) 6.2 Hz, 2 H), 3.70 (s, 3 H), 3.71 (dd, J ) 3.0, 7.8 Hz, 1
H), 3.61-3.51 (m, 2 H), 3.36 (dd, J ) 1.6, 9.3 Hz, 1 H), 2.03-1.95
(m, 1 H), 1.79-01.73 (m, 1 H), 1.39-1.32 (m, 1 H), 1.18 (s, 9 H),
1.03 (s, 3 H), 0.94 (d, J ) 6.7 Hz, 3 H), 0.83 (s, 3 H) (two OH not
observed); 13C NMR (75 MHz, CDCl3) δ 178.3, 159.3, 129.9, 129.1
(2 C), 113.8 (2 C), 94.4, 86.2, 75.8, 74.8, 63.2, 55.1, 40.5, 38.7, 34.8,
30.2, 27.1 (3 C), 21.7, 20.9, 16.3; HRMS (EI) m/z (M+) calcd 410.2668,
µmol), N-methylmorpholine N-oxide (NMO) (26 mg, 225 µmol), and
powdered 4-Å molecular sieves (75 mg), stirred for 1 h, and
concentrated. The black residue was purified by flash chromatography
on silica gel (elution with 20% ether in hexanes) to provide 30 as a
colorless gum (90 mg, 89%); IR (film, cm-1) 1723, 1513, 1247, 1107;
1H NMR (300 MHz, CDCl3) δ 9.44 (d, J ) 2.9 Hz, 1 H), 7.71-7.67
(m, 4 H), 7.46-7.36 (m, 6 H), 7.21 (d, J ) 8.6 Hz, 2 H), 6.83 (d, J )
8.6 Hz, 2 H), 4.45 (d, J ) 10.5 Hz, 1 H), 4.37 (d, J ) 10.5 Hz, 1 H),
3.84-3.76 (m, 2 H), 3.80 (s, 3 H), 3.60 (dd, J ) 4.8, 9.9 Hz, 1 H),
3.50 (dd, J ) 2.5, 10.5 Hz, 1 H), 2.38-2.34 (m, 1 H), 2.07-1.98 (m,
1 H), 1.42 (ddd, J ) 2.5, 6.5, 9.0 Hz, 1 H), 1.11 (s, 9 H), 1.02-0.92
(m, 15 H), 0.85 (s, 3 H), 0.68-0.51 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ 204.6, 159.0, 136.0 (4 C), 133.6, 133.5, 131.0, 129.9 (2 C),
129.1 (4 C), 127.9 (2 C), 113.8 (2 C), 82.4, 78.8, 74.3, 66.9, 55.4,
44.6, 43.9, 33.4, 27.2 (3 C), 20.7, 20.5, 19.3, 14.3, 7.3 (3 C), 5.6 (3
C); HRMS m/z (M+ - C6H15Si) calcd 618.3741, obsd 618.3779; [R]20
D
obsd 410.2669; [R]20 +15.3 (c 1.00, CHCl3).
+14.8 (c 1.02, CHCl3).
D
(2R,4R,6S)-7-(tert-Butyldiphenylsiloxy)-4-[(p-methoxybenzyl)-
oxy]-2,5,5-trimethyl-6-(triethylsiloxy)heptyl Pivalate (29). A solution
of 28 (293 mg, 717 µmol), tert-butyldiphenylsilyl chloride (295 mg,
1.07 mmol), and imidazole (195 mg, 2.87 mmol) in THF (15 mL) was
stirred for 5 h, quenched with saturated NH4Cl solution, and extracted
with ether (three times). The combined organic phases were dried and
concentrated to leave a residue, purification of which by flash
chromatography (SiO2, elution with 20% ether in hexanes) afforded
636 mg of a colorless oil.
(4R,6R,8S)-1-[(2S,4S,5R,6S)-6-Allyl-4-(benzyloxy)tetrahydro-5-
methyl-2H-pyran-2-yl]-9-(tert-butyldiphenylsiloxy)-8-hydroxy-6-[(p-
methoxybenzyl)oxy]-4,7,7-trimethyl-2-(phenylsulfonyl)-3-nona-
none (39). A solution of 34 (232 mg, 213 µmol) and p-toluenesulfonic
acid (4 mg, 21.3 µmol) in methanol (5 mL) was stirred for 1 h, quenched
with saturated NaHCO3 solution (5 mL), and concentrated. After
extraction with CH2Cl2 (three times), the combined organic layers were
dried and freed of solvent under reduced pressure. The residue was
purified by flash chromatography on silica gel (elution with 50% ether
in hexanes) to provide 39 as a white foam (201 mg, 97%); IR (film,
This oil was dissolved in DMF (10 mL), treated in turn with
triethylsilyl chloride (324 mg, 2.15 mmol), DMAP (87 mg, 717µmol),
and imidazole (195 mg, 2.86 mmol), stirred for 5 h, quenched with
saturated NH4Cl solution, and extracted with 1:1 ether-hexanes (three
times). The combined organic layers were processed in the predescribed
manner to furnish 439 mg (81% over two steps) of 29 as a colorless
oil; IR (film, cm-1) 1729, 1109; 1H NMR (300 MHz, CDCl3) δ 7.71-
7.67 (m, 4 H), 7.44-7.34 (m, 6 H), 7.22 (d, J ) 8.6 Hz, 2 H), 6.83 (d,
J ) 8.6 Hz, 2 H), 4.49 (s, 2 H), 3.89 (dd, J ) 1.6, 5.9 Hz, 2 H),
3.86-3.80 (m, 2 H), 3.80 (s, 3 H), 3.63-3.58 (m, 1 H), 3.48 (dd, J )
2.0, 9.4 Hz, 1 H), 2.05-1.90 (m, 1 H), 1.70-1.60 (m, 1 H), 1.35-
1.25 (m, 1 H), 1.21 (s, 9 H), 1.09 (s, 9 H), 1.06-0.85 (m, 15 H), 0.79
(s, 3 H), 0.72-0.60 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 178.4,
158.8, 135.8 (2 C), 135.7 (2 C), 133.6, 133.5, 131.5, 129.6 (2 C), 129.5
(2 C), 128.5 (2 C), 127.6 (2 C), 113.6 (2 C), 81.2, 78.9, 73.9, 69.8,
66.8, 55.2, 43.4, 38.8, 34.8, 30.3, 27.2 (3 C), 26.9 (3 C), 20.3 (2 C),
19.1, 16.4, 7.1 (3 C), 5.5 (3 C); FAB MS m/z (M+ + H) calcd 763.47
1
cm-1) 3566, 1715, 1612, 1308, 1111; H NMR (300 MHz, CDCl3) δ
7.78-7.26 (m, 22 H), 5.88 (m, 2 H), 5.83-5.60 (m, 1 H), 5.03-4.87
(m, 2 H), 4.79-4.59 (m, 3 H), 4.35 (m, 1 H), 3.79 (s, 3 H), 3.78-3.43
(m, 4 H), 3.20-2.75 (m, 4 H), 2.31-2.29 (m, 1 H), 2.20-1.80 (m 4
H), 1.70-1.50 (m, 2 H), 1.40-1.20 (m, 2 H), 1.16-0.75 (m, 20 H),
0.70 and 0.65 (2 s, 3 H); 13C NMR (75 MHz, CDCl3) δ 205.5, 205.2,
159.1, 159.0, 138.4, 138.3, 137.0, 136.9, 135.5, 135.4, 134.5, 134.0,
133.9, 133.1, 133.0, 132.9, 129.3, 129.2, 127.9, 127.6, 127.5, 116.9,
116.6, 113.8, 91.9, 81.7, 80.2, 79.9, 79.7, 79.6, 75.1, 74.7, 74.5, 72.7,
70.9, 70.4, 70.3, 69.9, 69.6, 64.9, 64.7, 60.2, 55.1, 45.3, 44.5, 40.9,
40.5, 40.2, 37.1, 36.9, 34.3, 33.6, 32.9, 32.4, 26.8, 20.9, 19.2, 19.1,
19.0, 18.9, 18.8, 15.3, 14.3, 14.1, 12.6, 12.5; FAB MS m/z (M+
-
OH) calcd 957.33, obsd 957.43; [R]20 +10.7 (c 2.01, CHCl3).
D
(2S,3R,4S,6S)-4-(Benzyloxy)-6-(4R,6R,8S)-9-(tert-butyldiphenyl-
siloxy)-8-hydroxy-6-[(p-methoxybenzyl)oxy]-4,7,7-trimethyl-3-oxo-
2-(phenylsulfonyl)nonyl]tetrahydro-3-methyl-2H-pyran-2-acetalde-
hyde (40). A solution of 39 (452 mg, 464 µmol), osmium tetraoxide
(11.8 mg, 46.4 µmol), and N-methylmorpholine N-oxide (109 mg, 927
µmol) in THF-water (5:1, 6 mL) was stirred for 4 h, at which point
sodium periodate (298 mg, 1.39 µmol) was introduced and agitation
was continued for another 3 h. The reaction mixture was quenched
with saturated sodium sulfite solution (3 mL), stirred for 30 min, and
extracted with ether (three times). The usual workup including flash
chromatography on silica gel (elution with 30% ethyl acetate in hexanes)
furnished 403 mg (89%) of 40 as a white foam; IR (film, cm-1) 3430,
obsd 763.41; [R]20 +13.7 (c 2.06, CHCl3).
D
Anal. Calcd for C45H70O6Si2: C, 70.82; H, 9.25. Found: C, 70.64;
H, 9.11.
(2R,4R,6S)-7-(tert-Butyldiphenylsiloxy)-4-[(p-methoxybenzyl)-
oxy]-2,5,5-trimethyl-6-(triethylsiloxy)heptanal (30). A solution of 29
(509 mg, 667 µmol) in THF (10 mL) was cooled to -78 °C, treated
with diisobutylaluminum hydride (2.67 mL of 1.0 M in hexanes, 2.67
mmol), warmed to -40 °C, stirred for 1 h at this temperature, and
quenched slowly with acetone (1 mL) and tartaric acid (10 mL of 1 M
in water). The reaction mixture was stirred for 1 h at room temperature
before extraction with ether (three times). The combined organic phases
were washed with brine, dried, and freed of solvent to leave a residue
that was purified by flash chromatography on silica gel (elution with
50% ether in hexanes). Obtained was 357 mg (79%) of the primary
alcohol as a colorless gum; IR (film, cm-1) 3358, 1110; 1H NMR (300
MHz, CDCl3) δ 7.67 (m, 4 H), 7.43-7.32 (m, 6 H), 7.15 (d, J ) 8.6
Hz, 2 H), 6.80 (d, J ) 8.6 Hz, 2 H), 4.42-4.36 (m, 2 H), 3.85 (dd, J
) 10.8, 2.8 Hz, 1 H), 3.78 (s, 3 H), 3.70 (dd, J ) 6.3, 2.8 Hz, 1 H),
3.55 (dd, J ) 10.8, 6.2 Hz, 1 H), 3.48-3.41 (m, 3 H), 1.80-1.75 (m,
1 H), 1.66 (br s, 1 H), 1.60-1.45 (m, 1 H), 1.30-1.18 (m, 1 H), 1.07
(s, 9 H), 1.05-0.88 (m, 12 H), 0.86 (s, 3 H), 0.76 (s, 3 H), 0.73-0.60
(m, 6 H); 13C NMR (75 MHz, CDCl3) δ 158.8, 135.8 (2 C), 135.7 (2
C), 133.5, 133.4, 131.1, 129.6, 129.5, 128.2 (2 C), 127.6 (4 C), 113.6
(2 C), 81.4, 79.8, 74.6, 69.2, 67.2, 55.2, 43.4, 34.8, 33.2, 26.9 (3 C),
1
1719, 1079; H NMR (300 MHz, CDCl3) δ 9.71 and 9.61 (m, 1 H),
7.79-7.25 (m, 22 H), 6.93-6.88 (m, 2 H), 4.73-4.55 (m, 3 H), 4.42-
4.32 (m, 1 H), 3.82-3.40 (m, 8 H), 3.30-2.80 (m, 3 H), 2.65-2.23
(m, 2 H), 2.15-1.80 (m, 3 H), 1.75-1.55 (m, 2 H), 1.50-0.60 (m, 25
H); 13C NMR (75 MHz, CDCl3) δ 205.0, 200.7, 159.2, 159.1, 138.2,
138.1, 136.7, 135.5, 135.4, 134.2, 134.1, 133.2, 133.1, 133.0, 131.0,
130.8, 129.8, 129.7, 129.3, 127.5, 113.9, 113.8, 113.6, 82.1, 82.0, 79.3,
79.1, 76.8, 76.6, 75.2, 74.8, 74.8, 74.5, 72.9, 71.5, 70.6, 70.4, 69.6,
64.9, 64.8, 55.2, 47.0, 46.7, 45.3, 44.3, 41.6, 41.4, 41.0, 37.1, 37.0,
33.9, 33.7, 33.1, 32.4, 26.8, 19.3 (2 C), 19.1, 19.0, 15.4, 14.4, 14.1,
12.9, 12.7; FAB MS m/z (M+) calcd 976.45, obsd 976.35; [R]20D -2.6
(c 1.53, CHCl3).
(2S,3R,4S,6S)-4-(Benzyloxy)-6-(4R,6R,8S)-9-(tert-butyldiphenyl-
siloxy)-8-hydroxy-6-[(p-methoxybenzyl)oxy]-4,7,7-trimethyl-3-oxo-
2-(phenylsulfonyl)nonyl]tetrahydro-3-methyl-2H-pyran-2-acetic Acid
(41). To a mixture of 40 (395 mg, 404 µmol), monobasic sodium
phosphate hydrate (557 mg, 4.04 mmol), and â-isoamylene (2.8 g, 40
mmol) in tert-butyl alcohol-water (3:1, 4 mL) was added a solution
of sodium chlorite (219 mg, 2.42 mmol) in the same medium (4 mL)
20.4 (2 C), 19.1, 16.9, 7.1 (3 C), 5.4 (3 C); HRMS (EI) m/z (M+
-
C4H9OH) calcd 604.3585, obsd 604.3589; [R]20D -0.5 (c 1.88, CHCl3).
The alcohol above (102 mg, 150 µmol) was dissolved in CH2Cl2 (2
mL), treated with tetra-n-propylammonium perruthenate (2.6 mg, 7.5

630 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Paquette et al.
at 0 °C. After 10 min of stirring, saturated NaHSO3 solution and brine
were introduced, and the product was extracted into ethyl acetate (five
times). The combined organic phases were dried and concentrated, and
the residue was purified by flash chromatography (SiO2, elution with
50% ethyl acetate in hexanes) to give 41 as a white foam (353 mg,
bicyclo[11.3.1]heptadecane-5-carboxaldehyde (48). To a solution of
47 (77 mg, 109 µmol) in CH2Cl2 (2 mL) was added the Dess-Martin
periodinane (60.2 mg, 141 µmol). The reaction mixture was stirred for
30 min, quenched with saturated NaHCO3 solution (5 mL) and solid
sodium thiosulfate (100 mg), stirred for 20 min, and worked up in the
usual manner. After chromatography on silica gel (elution with 50%
ethyl acetate in hexanes), there was isolated 69 mg (90%) of 48 as a
1
88%); IR (film, cm-1) 3572-2784, 1717, 1308, 1111; H NMR (300
MHz, CDCl3) δ 7.85-7.20 (m, 22 H), 7.00-6.85 (m, 2 H), 4.88-
4.55 (m, 3 H), 4.45-4.30 (m, 1 H), 3.90-3.57 (m, 7 H),3.50-3.30
(m, 1 H), 3.30-2.75 (m, 4 H), 2.68-2.50 (m, 1 H), 2.40-0.60 (series
of m, 29 H) (two OH not observed); 13C NMR (75 MHz, CDCl3) δ
205.6, 172.0, 159.8, 138.2, 137.0, 135.6, 134.0, 133.1, 133.0, 130.1,
130.0, 129.9, 129.8, 129.7, 129.5, 128.6, 128.3, 127.8, 127.7, 127.6,
114.2, 113.9, 83.3, 79.2, 78.7, 75.4, 74.4, 70.8, 70.6, 70.4, 69.9, 64.6,
55.2, 44.3, 41.3, 40.5, 39.0, 38.7, 37.5, 33.2, 32.9, 26.8, 26.7, 19.8,
19.4, 19.1, 14.9, 12.9; FAB MS m/z (M+ - OH) calcd 975.56, obsd
1
white foam; IR (film, cm-1) 1724, 1513, 1250, 1083; H NMR (300
MHz, CDCl3) δ 9.36 (d, J ) 1.7 Hz, 1 H), 7.69-7.60 (m, 3 H), 7.51-
7.45 (m, 2 H), 7.38-7.24 (m, 7 H), 6.93 (d, J ) 8.7 Hz, 2 H), 4.80
(dd, J ) 2.7, 12.5 Hz, 1 H), 4.61 (d, J ) 10.2 Hz, 1 H), 4.59 (d, J )
11.6 Hz, 1 H), 4.46 (d, J ) 10.8 Hz, 1 H), 4.43 (d, J ) 1.7 Hz, 1 H),
4.34 (d, J ) 11.6 Hz, 1 H), 3.78 (s, 3 H), 3.40-3.24 (m, 3 H), 3.01
(dt, J ) 4.5, 10.6 Hz, 1 H), 2.86 (br t, J ) 10.8 Hz, 1 H), 2.72 (dd, J
) 1.5, 18.2 Hz, 1 H), 2.58 (dd, J ) 8.8, 18.2 Hz, 1 H), 2.49 (t, J )
12.7 Hz, 1 H), 2.16 (t, J ) 12.6 Hz, 1 H), 2.05-1.99 (m, 1 H), 1.88-
1.79 (m, 1 H), 1.42 (s, 3 H), 1.38-1.11 (m, 3 H), 1.08 (d, J ) 6.2 Hz,
3 H), 1.02 (s, 3 H), 0.92 (d, J ) 6.4 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 205.1, 194.7, 170.5, 159.5, 138.1, 137.0, 134.1, 130.2 (2 C),
129.2 (2 C), 129.1, 129.0 (2 C), 128.4, 127.7 (4 C), 113.9 (2 C), 85.3,
83.0, 78.9, 77.3, 76.6, 71.6, 70.3, 69.2, 55.3, 45.4, 44.6, 41.3, 39.5,
37.1, 33.7, 32.9, 26.5, 23.8, 13.6, 12.5; FAB MS m/z (M+ + H) calcd
975.38; [R]20 -12.2 (c 1.73, CHCl3).
D
(1S,5S,7R,9R,13S,15S,16R)-15-(Benzyloxy)-5-[(tert-butyldiphenyl-
siloxy)methyl]-7-[(p-methoxybenzyl)oxy]-6,6,9,16-tetramethyl-11-
(phenylsulfonyl)-4,17-dioxabicyclo[11.3.1]heptadecane-3,10-dione (42).
A solution of hydroxy acid 41 (555 mg, 0.56 mmol) in THF (1 mL)
was treated with 2,4,6-trichlorobenzoyl chloride (409 mg, 1.67 mmol)
and triethylamine (282 mg, 2.79 mmol), stirred for 4 h, filtered through
a cotton plug, and diluted with toluene (10 mL). This solution of the
mixed anhydride was introduced via a syringe pump during a 2-h period
into a solution of DMAP (409 mg, 3.35 mmol) in toluene (102 mL) at
110 °C. The syringe was rinsed with toluene (1 mL) and heating was
continued for an additional 30 min. The cooled reaction mixture was
diluted with saturated sodium bisulfite solution (10 mL) and extracted
with ether (three times). After the combined organic phases had been
dried and evaporated, the residue was subjected to flash chromatography
(SiO2, elution with 20% ethyl acetate in hexanes) to provide 42 as a
735.32, obsd 735.32; [R]20 -93.9 (c 1.65, CH2Cl2).
D
(1S,5R,7R,9R,13S,15S,16R)-15-(Benzyloxy)-5-[(E)-2-iodovinyl]-7-
[(p-methoxybenzyl)oxy]-6,6,9,16-tetramethyl-11-(phenylsulfonyl)-4,-
17-dioxabicyclo[11.3.1]heptadecane-3,10-dione (49). Chromium dichlo-
ride (603 mg, 4.91 mmol) was added to a solution of 48 (69 mg, 98
µmol) and iodoform (579 mg, 1.47 mmol) in THF (5 mL) at 0 °C. The
dark solution was stirred for 3 h, diluted with water (3 mL) and saturated
sodium thiosulfate solution (3 mL), and extracted with ether (three
times). The combined organic phases were dried and concentrated. The
residue was subjected to flash chromatography on silica gel (gradient
elution with 10-40% ethyl acetate in hexanes) to give 49 as a yellow
diastereomerically pure white foam (445 mg, 82%); IR (film, cm-1
)
1733, 1248; 1H NMR (300 MHz, CDCl3) δ 7.70-7.23 (m, 20 H), 7.06
(d, J ) 8.6 Hz, 2 H), 6.69 (d, J ) 8.6 Hz, 2 H), 5.04 (dd, J ) 2.0, 9.3
Hz, 1 H), 4.91 (dd, J ) 3.5, 10.9 Hz, 1 H), 4.60 (d, J ) 11.6 Hz, 1 H),
4.40 (d, J ) 10.6 Hz, 1 H), 4.35 (d, J ) 11.6 Hz, 1 H), 4.30 (d, J )
10.6 Hz, 1 H), 4.10 (dd, J ) 9.1, 11.6 Hz, 1 H), 3.85 (dd, J ) 2.1,
11.6 Hz, 1 H), 3.82-3.72 (m, 4 H), 3.15-2.95 (m, 4 H), 2.61-2.43
(m, 2 H), 2.15-1.95 (m, 2 H), 1.40-0.85 (series of m, 23 H), 0.80 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 205.8, 171.5, 159.2, 138.3, 136.8,
135.7 (4 C), 135.5 (2 C), 134.1, 133.7, 133.6, 130.3, 129.7 (2 C), 129.2
(2 C), 129.0 (2 C), 128.7, 128.3 (2 C), 127.6 (2 C), 126.7 (4 C), 113.7
(2 C), 84.4, 81.3, 79.3, 79.2, 75.7, 71.4, 70.4, 68.4, 64.2, 55.2, 44.7,
42.0, 41.9, 40.7, 37.2, 33.4, 33.3, 26.7 (3 C), 24.3, 24.1, 19.0, 13.5,
13.2; FAB MS m/z (M+ + H) calcd 975.45, obsd 975.37; [R]20D -25.9
(c 1.08, CHCl3).
foam (54 mg, 77% based on 12 mg of recovered 48); IR (film, cm-1
)
1725, 1240, 1092; 1H NMR (300 MHz, CDCl3) δ 7.73-7.44 (m, 6 H),
7.37-7.21 (m, 6 H), 6.95 (d, J ) 9.6 Hz, 2 H), 6.79 (dd, J ) 8.7, 16.4
Hz, 1 H), 6.33 (d, J ) 14.5 Hz, 1 H), 5.00 (d, J ) 8.6 Hz, 1 H), 4.81
(dd, J ) 3.1, 11.2 Hz, 1 H), 4.60 (d, J ) 11.6 Hz, 1 H), 4.47 (s, 2 H),
4.34 (d, J ) 11.6 Hz, 1 H), 3.80 (s, 3 H), 3.78-3.65 (m, 1 H), 3.29-
3.12 (m, 3 H), 3.01-2.96 (m, 2 H), 2.56-2.40 (m, 3 H), 2.24-2.15
(m, 1 H), 2.04-1.89 (m, 2 H), 1.69-1.60 (m, 1 H), 1.30-1.25 (m, 1
H), 1.14 (s, 3 H), 1.10 (d, J ) 6.4 Hz, 3 H), 0.93 (d, J ) 6.4 Hz, 3 H),
0.89 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 205.8, 170.6, 159.2, 142.1,
138.2, 134.1, 130.5, 129.3 (2 C), 129.2 (2 C), 129.1, 129.0 (2 C), 128.8
(2 C), 128.4, 128.3, 127.7 (2 C), 114.0 (2 C), 84.1, 80.3, 79.2, 78.2,
75.8, 71.5, 70.3, 68.7, 55.3, 45.0, 42.5, 41.6, 40.4, 37.1, 33.7, 33.2,
25.1, 23.7, 13.5 (2 C); FAB MS m/z (M+) calcd 858.23, obsd 858.41;
(1S,5S,7R,9R,13S,15S,16R)-15-(Benzyloxy)-5-(hydroxymethyl)-7-
[(p-methoxybenzyl)oxy]-6,6,9,16-tetramethyl-11-(phenylsulfonyl)-4,-
17-dioxabicyclo[11.3.1]heptadecane-3,10-dione (47). A solution of
42 (167 mg, 171 µmol) in THF (1 mL) was treated with the HF-pyri-
dine complex (400 µL) in THF-pyridine (1:3, 3 mL) at 0 °C, stirred
for 5 h at room temperature, quenched with saturated NaHCO3 solu-
tion (20 mL), and extracted with ether (three times). After drying and
solvent evaporation, the residue was chromatographed on silica gel
(elution with 50% ethyl acetate in hexanes) to deliver 47 as a color-
[R]20 -72.1 (c 0.9, CHCl3).
D
(1S,4R,5R,7R,9R,13S,14R,15S)-4,15-Dihydroxy-9-[(E)-2-iodovinyl]-
5,8,8,14-tetramethyl-10,17,18-trioxatricyclo[11.3.1.14,7]octadecane-
3,11-dione (50). A solution of 49 (24 mg, 28 µmol) in THF (4 mL)
was treated with potassium tert-butoxide (33.5 µL in 1.0 M in tert-
butyl alcohol, 33.5 µmol) at 0 °C and stirred for 30 min at this
temperature before the addition of the Davis oxaziridine (14.4 mg, 55.8
µmol) in THF (1 mL) via cannula. After an additional 1 h of agitation
at 0 °C, the reaction mixture was quenched with saturated NH4Cl
solution (10 mL) and extracted several times with ether. The combined
organic phases were dried and concentrated to leave an oil that was
dissolved in CH2Cl2 and water (18:1, 4 mL), treated with DDQ (190
mg, 840 µmol), and stirred for 20 h. After saturated NaHCO3 solution
had been introduced, the product was extracted into CH2Cl2 (three
times), dried, and concentrated. The residue was purified by flash
chromatography on silica gel (elution with 70% ethyl acetate in hexanes)
to furnish 50 as a colorless solid (10.6 mg, 73%); IR (film, cm-1) 3482,
1
less foam (77 mg, 64%); IR (film, cm-1) 3469, 1718, 1309, 1251; H
NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 7.4 Hz, 2 H), 7.62-7.46 (m,
4 H), 7.37-7.24 (m, 6 H), 6.92 (d, J ) 7.4 Hz, 2 H), 5.10 (dd, J ) 2.4,
11.9 Hz, 1 H), 4.67-4.53 (m, 4 H), 4.33 (d, J ) 11.6 Hz, 1 H), 4.15-
3.69 (series of m, 3 H), 3.80 (s, 3 H), 3.42-3.32 (m, 2 H), 3.15 (br dt,
J ) 1.2, 9.4 Hz, 1 H), 2.99 (dt, J ) 3.8, 10.2 Hz, 1 H), 2.87 (dq, J )
0.6, 10.3 Hz, 2 H), 2.63-2.58 (m, 2 H), 2.23 (t, J ) 12.3 Hz, 1 H),
2.00-1.90 (m, 1 H), 1.85-1.80 (m, 1 H), 1.27-1.19 (m, 3 H), 1.22
(s, 3 H), 1.15 (d, J ) 6.3 Hz, 3 H), 0.94 (s, 3 H), 0.92 (d, J ) 6.4 Hz,
3 H); 13C NMR (75 MHz, CDCl3) δ 205.3, 170.9, 159.6, 138.2, 137.1,
134.0, 129.6 (2 C), 129.1 (5 C), 128.3 (2 C), 127.7 (2 C), 127.6, 114.2
(2 C), 83.8, 82.1, 79.1, 77.4, 76.7, 71.9, 70.2, 67.5, 59.4, 55.2, 44.6,
42.4, 41.3, 40.1, 36.7, 33.5, 32.4, 26.1, 24.6, 13.6, 12.9; FAB MS m/z
(M+ - OH) calcd 719.32, obsd 719.38; [R]20D -81.9 (c 2.14, CHCl3).
(1S,5S,7R,9R,13S,15S,16R)-15-(Benzyloxy)-7-[(p-methoxybenzyl)-
oxy]-6,6,9,16-tetramethyl-3,10-dioxo-11-(phenylsulfonyl)-4,17-dioxa-
1
1719, 1162; H NMR (300 MHz, CDCl3) δ 6.47 (dd, J ) 7.1, 14.4
Hz, 1 H), 6.40 (d, J ) 14.4 Hz, 1 H), 5.12 (d, J ) 7.1 Hz, 1 H), 4.48
(s, 1 H), 4.15 (dd, J ) 5.2, 11.4 Hz, 1 H), 3.79 (br t, J ) 10.6 Hz, 1
H), 3.44-3.36 (m, 3 H), 3.05 (dd, J ) 9.2, 13.4 Hz, 1 H), 2.76-2.71
(m, 1 H), 2.56 (dd, J ) 2.5, 12.5 Hz, 1 H), 2.24 (t, J ) 11.8 Hz, 1 H),
2.07-1.97 (m, 3 H), 1.69 (q, J ) 11.6 Hz, 1 H), 1.38 (q, J ) 11.6 Hz,
1 H), 0.98 (d, J ) 6.4 Hz, 3 H), 0.97 (d, J ) 6.3 Hz, 3 H), 0.89 (s, 3

(-)-PolycaVernoside A, Metabolite of P. tsudai
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 631
H), 0.88 (s, 3 H) (OH not observed); 13C NMR (75 MHz, CDCl3) δ
206.1, 171.2, 140.9, 102.8, 83.0, 82.0, 79.4, 78.9, 74.0, 72.7, 43.4, 42.1,
41.6, 39.5, 39.3, 39.1, 33.5, 19.3, 17.7, 13.3, 12.6; HRMS m/z (M+)
58.4, 57.7, 42.5, 42.4, 41.4, 40.0, 39.7, 39.5, 33.9, 19.7, 18.1, 16.5,
13.7, 12.9; FAB MS m/z (M+ + H) calcd 857.28, obsd 857.13; [R]20
D
-85.4 (c 0.75, CHCl3).
calcd 522.1114, obsd 522.1112; [R]20 -47.0 (c 0.29, CHCl3).
Polycavernoside A (1). To a solution of (E,E)-1-iodo-5-methyl-
1,3-hexadiene7,47 (128 mg, 576 µmol) in dry THF (5 mL) cooled to
-78 °C was added tert-butyllithium (699 µL of 1.65 M in pentane,
1.15 mmol). After 30 min of stirring, tributyltin chloride (170 mg, 523
µmol) was introduced and agitation was maintained for another 30 min
before warming to room temperature. Thirty minutes later, water (10
mL) was added and the product was extracted into ether (3 × 10 mL).
The combined organic phases were concentrated, the residue was taken
up in ether (5 mL), and this solution was stirred for 30 min with
potassium fluoride (1 g in 10 mL of water). This mixture was stirred
for 20 min and filtered to remove the tin fluoride precipitate. The
separated ethereal phase was dried and concentrated. A portion of the
residue was purified by reverse-phase chromatography on plates (elution
with 10% CH2Cl2 in acetonitrile, two elutions) to give 54 as a colorless
D
(1S,4R,5R,7R,9R,13S,14S,15S)-4-Hydroxy-9-[(E)-2-iodovinyl]-15-
[[3-O-[4-O-(p-methoxybenzyl)-2,3-di-O-methyl-r-L-fucopyranosyl]-
2,4-di-O-methyl-â-D-xylopyranosyl]oxy]-5,8,8,14-tetramethyl-10,-
17,18-trioxatricyclo[11.3.1.14,7]octadecane-3,11-dione (52). Reaction
of 50 (32 mg, 361 µmol) with 18b (68.8 mg, 122 µmol), N-bromo-
succinimide (43.4 mg, 244 µmol), and pulverized 4-Å molecular sieves
(160 mg) in the predescribed manner afforded 21.3 mg (36%) of 52 as
an amorphous white solid together with 7.4 mg (13% of the R-anomer.
1
For 52: IR (film, cm-1) 1731, 1095; H NMR (300 MHz, CDCl3)
δ 7.59 (d, J ) 2.0 Hz, 1 H), 7.31 (dd, J ) 1.9, 8.4 Hz, 1 H), 7.27 (br
s, 1 H), 6.86 (d, J ) 8.4 Hz, 1 H), 6.51 (dd, J ) 7.1, 14.4 Hz, 1 H),
6.43 (d, J ) 14.4 Hz, 1 H), 5.38 (d, J ) 3.7 Hz, 1 H), 5.12 (d, J ) 7.1
Hz, 1 H), 4.84 (d, J ) 11.5 Hz, 1 H), 4.55 (d, J ) 11.5 Hz, 1 H), 4.48
(br s, 1 H), 4.28 (d, J ) 7.7 Hz, 1 H), 4.20-4.10 (m, 2 H), 4.00 (dd,
J ) 5.0, 11.0 Hz, 1 H), 3.89 (s, 3 H), 3.78-3.70 (m, 4H), 3.56 (s, 3
H), 3.55 (s, 3 H), 3.51 (s, 3 H), 3.43-3.38 (m, 2 H), 3.35 (s, 3 H),
3.34-3.30 (m, 2 H), 3.28-3.08 (m, 2 H), 3.03 (dd, J ) 4.0, 13.4 Hz,
1 H), 2.80-2.60 (m, 1 H), 2.55 (dd, J ) 2.7, 12.6 Hz, 1 H), 2.23 (t, J
) 11.4 Hz, 1 H), 2.17-2.10 (m, 1 H), 2.04-1.97 (m, 2 H), 1.69 (q, J
) 12.0 Hz, 1 H), 1.50 (q, J ) 11.9 Hz, 1 H), 1.45-1.30 (m, 2 H), 1.12
(d, J ) 6.5 Hz, 3 H), 1.00 (d, J ) 6.7 Hz, 6 H), 0.89 (s, 3 H), 0.88 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 206.2, 171.2, 133.4, 132.5, 128.7,
113.6, 105.9, 102.8, 97.2, 84.2, 82.9, 82.3, 81.9, 80.9, 80.8, 79.4, 78.1,
77.8, 74.1, 73.6, 66.1, 65.9, 63.1, 60.4, 59.1, 58.0, 56.3, 55.3, 42.1,
41.9, 41.0, 39.6, 39.3, 39.1, 33.5, 19.3, 17.6, 16.6, 13.3, 12.6; FAB
MS m/z (M+) calcd 976.33, obsd 976.34; [R]20D -69.1 (c 1.19, CHCl3).
For the R-anomer: IR (film, cm-1) 1714, 1258; 1H NMR (500 MHz,
CDCl3) δ 7.59 (s, 1 H), 7.32 (d, J ) 7.2 Hz, 1 H), 7.26 (s, 1 H), 6.87
(d, J ) 8.4 Hz, 1 H), 6.48 (dd, J ) 7.7, 14.4 Hz, 1 H), 6.40 (d, J )
14.4 Hz, 1 H), 5.36 (d, J ) 3.6 Hz, 1 H), 5.12 (d, J ) 7.7 Hz, 1 H),
5.05 (d, J ) 3.5 Hz, 1 H), 4.83 (d, J ) 11.6 Hz, 1 H), 4.57 (d, J ) 11.6
Hz, 1 H), 4.39 (s, 1 H), 4.20-4.10 (m, 3 H), 3.89 (s, 3 H), 3.84 (t, J
) 9.3 Hz, 1 H), 3.76-3.73 (m, 2 H), 3.69 (dd, J ) 3.6, 13.9 Hz, 1 H),
3.67 (s, 1 H), 3.58-3.47 (m, 2 H), 3.53 (s, 3 H), 3.51 (s, 3 H), 3.45-
3.21 (m, 3 H), 3.41 (s, 3 H), 3.36 (s, 3 H), 3.05 (dd, J ) 9.2, 13.4 Hz,
1 H), 2.74-2.69 (m, 1 H), 2.57 (dd, J ) 2.2, 12.6 Hz, 1 H), 2.24 (t, J
) 11.8 Hz, 1 H), 2.07-1.99 (m, 3 H), 1.67 (q, J ) 11.8 Hz, 1 H),
1.50-1.46 (m, 1 H), 1.31 (q, J ) 11.8 Hz, 1 H), 1.13 (d, J ) 6.4 Hz,
3 H), 0.98 (d, J ) 6.5 Hz, 3 H), 0.97 (d, J ) 6.2 Hz, 3 H), 0.89 (s, 3
H), 0.88 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 206.1, 171.3, 140.9,
144.3, 132.5, 128.6, 111.6, 102.8, 96.8, 91.7, 82.9, 82.2, 80.6 (2 C),
79.3, 79.1, 78.1, 77.8, 76.6, 75.9, 75.0, 73.8, 73.5, 65.8, 59.7, 58.1 (2
C), 57.7, 56.2, 42.3, 40.9, 39.6, 39.3, 39.1, 36.9, 33.5, 19.3, 17.6, 16.6,
13.3, 13.2 (3 carbons not observed); HRMS (molecular ion too fleeting
1
oil that was used directly; H NMR (300 MHz, C6D6) δ 6.77 (d, J )
9.7, 18.7 Hz, 1 H), 6.26 (d, J ) 18.7 Hz, 1 H), 6.14 (dd, J ) 9.7, 14.8
Hz, 1 H), 5.59 (dd, J ) 6.9, 14.8 Hz, 1 H), 2.24-2.17 (m, 1 H), 1.64-
1.51 (m, 8 H), 1.43-1.26 (m, 8 H), 1.10-0.80 (m, 17 H); 13C NMR
(75 MHz, C6D6) δ 148.2, 141.0, 131.5, 130.5, 31.0 (2 C), 29.9 (3 C),
28.1 (3 C), 15.5, 13.9 (3 C), 9.8 (3 C).
A solution of 53 (1.2 mg, 1.4 µmol) and 54 (5.8 mg, 14 µmol) in
previously degassed DMF (0.5 mL) was treated with bis(acetonitrile)-
dichloropalladium(II) (42 µL of 0.01 M in DMF, 0.42 µmol), stirred
in the dark for 5 h, diluted with water, and extracted with ether-hexanes
(1:1, 3 × 10 mL). The combined organic phases were dried, filtered,
and concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate) to give 1 as an amorphous
white solid (1.0 mg, 87%); 1H NMR (500 MHz, CD3CN, CHD2CN as
1.90 ppm) δ 6.19-6.10 (m, 3 H), 6.03 (dd, J ) 10.5, 15.6 Hz, 1 H),
5.69 (dd, J ) 6.9, 15.6 Hz, 1 H), 5.58 (dd, J ) 7.7, 15.0 Hz, 1 H),
5.21 (d, J ) 3.3 Hz, 1 H), 5.00 (d, J ) 7.7 Hz, 1 H), 4.59 (s, 1 H),
4.31 (d, J ) 7.7 Hz, 1 H), 4.13 (br q, J ) 6.5 Hz, 1 H), 4.05 (dd, J )
4.9, 11.4 Hz, 1 H), 3.93 (dd, J ) 4.6, 10.8 Hz, 1 H), 3.79 (br s, 1 H),
3.64 (br t, J ) 10.8 Hz, 1 H), 3.48 (s, 3 H), 3.43 (t, J ) 8.8 Hz, 1 H),
3.38 (s, 3 H), 3.37 (br d, J ) 10.1 Hz, 1 H), 3.35 (dd, J ) 3.3, 10.1
Hz, 1 H), 3.34 (s, 3 H), 3.32 (m, 1 H), 3.31 (s, 3 H), 3.29 (m, 1 H),
3.13 (ddd, J ) 4.5, 8.4, 10.4 Hz, 1 H), 3.08 (dd, J ) 10.4, 10.9 Hz, 1
H), 2.96 (dd, J ) 9.0, 13.8 Hz, 1 H), 2.87 (t, J ) 9.0 Hz, 1 H), 2.80-
2.73 (m, 1 H), 2.70 (d, J ) 3.1 Hz, 1 H), 2.52 (dd, J ) 2.7, 12.6 Hz,
1 H), 2.30 (m, 1 H), 2.14 (dd, J ) 11.2, 12.7 Hz, 1 H), 2.10 (m, 1 H),
2.05 (m, 1 H), 1.99 (ddd, J ) 5.3, 6.8, 11.5 Hz, 1 H), 1.56 (br q, J )
11.5 Hz, 1 H), 1.36 (br q, J ) 11.5 Hz, 1 H), 1.27 (m, 1 H), 1.07 (d,
J ) 6.5 Hz, 3 H), 0.95 (d, J ) 6.6 Hz, 6 H), 0.92 (d, J ) 6.4 Hz, 3 H),
0.89 (d, J ) 6.5 Hz, 3 H), 0.79 (s, 3 H), 0.77 (s, 3 H); 13C NMR (125
MHz, CD3CN, CD313CN as 118.2 ppm) δ 207.3, 172.1, 143.7, 135.3,
134.8, 130.6, 128.7, 128.1, 106.1, 103.8, 97.8, 85.4, 83.6, 82.6, 79.8
(2 C), 79.2, 78.8 (2 C), 78.1, 74.8, 69.2, 66.0, 63.5, 60.8, 58.7, 58.4,
56.9, 43.1, 42.7, 41.5, 40.4, 40.1, 39.4, 34.3, 31.9, 22.3 (2 C), 19.3,
for accurate mass measurement); [R]20 -34.7 (c 0.47, CHCl3).
D
(1S,4R,5R,7R,9R,13S,14S,15S)-15-[[3-O-(2,3-Di-O-methyl-r-L-fu-
copyranosyl)-2,4-di-O-methyl-â-D-xylopyranosyl]oxy]-4-hydroxy-9-
[(E)-2-iodovinyl]-5,8,8,14-tetramethyl-10,17,18-trioxatricyclo-
[11.3.1.14,7] octadecane-3,11-dione (53). A solution of 52 (17 mg, 17
µmol) in CH2Cl2-water (18:1, 1 mL) was treated with DDQ (19.7
mg, 87 µmol), stirred overnight, and poured into saturated NaHCO3
solution (2 mL). The product was extracted into CH2Cl2, dried,
evaporated, and chromatographed on silica gel (elution with ethyl
17.8, 16.4, 13.6, 12.7; [R]25 -34.5 (c 0.09, CH3CN).
D
Acknowledgment. We thank the National Institutes of
Health and Eli Lilly and Company for their financial support
of this research effort. L.B. is the recipient of a postdoctoral
fellowship from the Ministe`re de l’Enseignement Supe´rieure et
de la Science (FCAR, Que´bec, Canada). J.N.J. served as a
GAANN (1992-1996) and Wyeth-Ayerst Fellow (1997). The
authors are indebted to Dr. Kurt Loening for his assistance with
nomenclature.
acetate) to give 53 as a white solid (11.3 mg, 76%); IR (film, cm-1
)
1
3431, 1736, 1707, 1093; H NMR (300 MHz, CDCl3) δ 6.51-6.38
(m, 2 H), 5.36 (d, J ) 3.0 Hz, 1 H), 5.12 (d, J ) 7.1 Hz, 1 H), 4.48
(s, 1 H), 4.29-4.21 (m, 2 H), 4.16 (d, J ) 5.1, 11.3 Hz, 1 H), 4.01
(dd, J ) 4.9, 11.4 Hz, 1 H), 3.90 (s, 1 H), 3.74 (br t, J ) 10.1 Hz, 1
H), 3.62-3.50 (m, 4 H), 3.57 (s, 3 H), 3.54 (s, 3 H), 3.51 (s, 3 H),
3.48-3.37 (m, 1 H), 3.37 (s, 3 H), 3.34-3.22 (m, 2 H), 3.16-3.08
(m, 2 H), 3.01 (dd, J ) 9.1, 13.5 Hz, 1 H), 2.77-2.69 (m, 1 H), 2.55
(dd, J ) 2.6, 12.5 Hz, 1 H), 2.23 (t, J ) 15.2 Hz, 1 H), 2.17-2.11 (m,
1 H), 2.04-1.99 (m, 2 H), 1.69 (q, J ) 11.6 Hz, 1 H), 1.50 (q, J ) 1
2.0 Hz, 1 H), 1.44-1.29 (m, 1 H), 1.26 (d, J ) 6.5 Hz, 3 H), 0.98 (d,
J ) 6.6 Hz, 6 H), 0.89 (s, 3 H), 0.87 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 206.5, 171.6, 141.4, 106.3, 103.2, 97.6, 84.6, 83.4, 82.8, 82.4,
79.8, 79.7, 79.6, 78.7, 78.5, 77.8, 74.5, 69.5, 65.4, 63.5, 60.8, 59.6,
Supporting Information Available: Experimental details
for the preparation of those intermediates associated with
unsuccessful alternative routes to 1, viz. 3-5, 10, 32-36, 43-
45, and 51, along with copies of the 400 MHz 1H NMR spectra
of natural and synthetic 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA993487O
(47) Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990,
31, 7257.