Free Radical Studies and Solutions to the Synthesis of (+)-Cyclophellitol

Article abstract of DOI:10.1021/jo981211d

D-Xylose serves as a starting material for approaches to the synthesis of the glucosidase inhibitors, (+)-cyclophellitol (1) and (+)-epi-cyclophellitol (2). An investigation of the cyclization of diastereomeric oxiranyl radicals to achieve this goal was m

Full text of DOI:10.1021/jo981211d

7920
J . Org. Chem. 1998, 63, 7920-7930
F r ee Ra d ica l Stu d ies a n d Solu tion s to th e Syn th esis of
(+)-Cyclop h ellitol‡
Frederick E. Ziegler* and Yizhe Wang
Sterling Chemistry Laboratory, Yale University, New Haven, Connecticut 06511-8118
Received J une 22, 1998
D-Xylose serves as a starting material for approaches to the synthesis of the glucosidase inhibitors,
(+)-cyclophellitol (1) and (+)-epi-cyclophellitol (2). An investigation of the cyclization of diaster-
eomeric oxiranyl radicals to achieve this goal was moderately successful with the diastereomer
that would have led to epi-cyclophellitol undergoing cyclization. An alternative route to cyclophellitol
from D-xylose employed Grubbs’ ring closure metathesis and radical transformations to complete
the synthesis.
Ch a r t 1
(+)-Cyclophellitol (1) (Chart 1) was isolated from the
culture broth of the mushroom Phellinus sp. in 1990 by
Umezawa et al.1 and was shown to be a sub-microgram
inhibitor of â-glucosidase.2 These researchers established
the structure and absolute stereochemistry of cycloph-
ellitol by X-ray crystallographic analysis. In the same
year, Tatsuta reported3 the first synthesis of (+)-cyclo-
phellitol from L-glucose.3 Subsequently, syntheses of this
substance have been reported as its racemate4,5 and as
the dextrorotatory enantiomer using nature’s chiral
pool3,6-11 and through asymmetric induction.12 Likewise,
epi-cyclophellitol (2), an inhibitor of R-glucosidase, has
been a target of total synthesis.5,8-10
Our interest in these substances was stimulated by the
opportunity to explore the viability of intramolecular
reactions of oxiranyl radicals in systems wherein an
attendant six-membered ring is formed. We had previ-
ously demonstrated that these cyclizations are effective
when the attendant ring is five-membered.13,14 Because
5-hexenyl radical cyclizes ∼40 times faster than 6-hep-
tenyl radical,15 the success of the larger ring cyclization
was not ensured. Moreover, 6-heptenyl radicals are also
susceptible to allylic abstraction of a hydrogen atom from
C5. On the positive side, Hanessian has demonstrated
that unsaturated esters 3 cyclize in good yield and with
a preference for the formation of the trans stereoisomer
4, a process that proceeds through a chairlike transition
state.16 Herein we describe our efforts to this end using
oxiranyl radicals and we expand upon our communication
on the synthesis of cyclophellitol.11
The strategy for the synthesis of (+)-cyclophellitol
(Scheme 1) was to generate oxiranyl radical 5 of either
oxirane configuration by radical decarboxylation of gly-
cidic acids 6, which would be derived from D-xylose (7).
The three protected oxygens of radical 5 would serve to
anchor the chairlike transition state for cyclization with
three equatorial protected oxygen groups and thereby
lead to the desired stereochemistry of the acetic acid
chain. A related study involving a glucose-derived
ω-bromo-2-octenoate led to a mixture of stereoisomers.17
Starting from the known,18 readily prepared diethyl
thioacetal of D-xylose (Scheme 2), either protected tem-
plate 10 or 11 could be prepared efficiently. These two
substances permitted elaboration on either end of the
termini of the carbon chain of the protected pentose.
Dithioacetal 11, which was prepared in 55% overall yield
from dithioacetal 8a , was employed first in our studies.
Oxidation of primary alcohol 11 to an aldehyde proved
troublesome in the presence of the thioacetal group
‡ In memory of Professor George Bu¨chi. Deceased August 28, 1998.
(1) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.; Nakamura,
H.; Iitaka, Y.; Takeuchi, T. J . Antibiot. 1990, 43, 49.
(2) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K. J . Antibiot.
1990, 43, 1579.
(3) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata, M.
Tetrahedron Lett. 1990, 31, 1171.
(4) Moritz, V.; Vogel, P. Tetrahedron Lett. 1992, 33, 5243.
(5) Acena, J . L.; Arjona, O.; Plumet, J . J . Org. Chem. 1997, 62, 3360.
(6) Akiyama, T.; Shima, H.; Ohnari, M.; Okazaki, T.; Ozaki, S. Bull.
Chem. Soc. J pn. 1993, 66, 3760.
(7) Sato, K.; Bokura, M.; Moriyama, H.; Igarashi, T. Chem. Lett.
1994, 37.
(8) McDevitt, R. E.; Fraser-Reid, B. J . Org. Chem. 1994, 59, 3250.
(9) Shing, T. K. M.; Tai, V. W. F. J . Chem. Soc., Perkin Trans. 1
1994, 2017.
(10) J ung, M. E.; Choe, S. W. T. J . Org. Chem. 1995, 60, 3280.
(11) Ziegler, F. E.; Wang, Y. J . Org. Chem. 1998, 63, 426.
(12) Schlessinger, R. H.; Bergstrom, C. P. J . Org. Chem. 1995, 60,
16.
(13) Ziegler, F. E.; Harran, P. G. Tetrahedron Lett. 1993, 34, 4505.
(14) Ziegler, F. E.; Wang, Y. Tetrahedron Lett. 1996, 37, 6299.
(15) Beckwith, A. J . L.; Moad, G. J . Chem. Soc., Chem. Commun.
1974, 472.
(16) Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J . Chem.
1987, 65, 1859.
(17) Marco-Contelles, J .; Sanchez, B. J . Org. Chem. 1993, 58, 4293.
(18) Rollin, P.; Pougny, J . R. Tetrahedron 1986, 42, 3479.
10.1021/jo981211d CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/06/1998

Synthesis of (+)-Cyclophellitol
Sch em e 1
J . Org. Chem., Vol. 63, No. 22, 1998 7921
Sch em e 4
Sch em e 2
Sch em e 5
Sch em e 3
alcohol 15 with the spectrum of the mixture of epoxy
alcohols 15 and 16 obtained when allylic alcohol 14b was
oxidized with m-CPBA. Glycidic acid 17b, formed by
Lindgren23,24 oxidation of aldehyde 17a and characterized
as its methyl ester 17d , has the correct epoxide stereo-
chemistry to lead ultimately to epi-cyclophellitol 2.
Unfortunately, asymmetric epoxidation of allylic alcohol
14b with L-(+)-DET failed to afford epoxy alcohol 16a .
Rather, an epoxy diol (presumably 16b), as evidenced by
1H NMR and HRMS, was formed consistently in low
yield. This unexpected turn of events precluded access
to cyclophellitol precursors, and an alterative route was
required to obtain the glycidic acid.
The Sharpless asymmetric dihydroxylation (AD) of-
fered itself as a means to gain access to both stereoiso-
mers of radical 5 through the cis-glycidic acids (Scheme
5).22 When unsaturated ester 18 was oxidized with OsO4
(6 mol %) and K3Fe(CN)6 (3 equiv), a 15/1 ratio of â-diol
19/R-diol 20 was obtained without the aid of a chiral
ligand. This high selective reflects inherent substrate
selectivity in the oxidation. This ratio was improved to
20/1 (92% yield) with the inclusion of the â-directing
(DHQD)2PHAL ligand (10 mol %). Initial attempts at
reagent-controlled R-dihydroxylation proved difficult ow-
ing to the inherent substrate selectivity. AD-mixR, in
(Scheme 3). Neither Moffatt-Pfitzner19 nor Doering-
Parikh20 oxidation, both nonmetal-based protocols, proved
effective. However, oxidation with catalytic tetra-n-
propylammonium perruthenate in the presence of N-
methylmorpholine N-oxide led to the desired aldehyde
in 40% yield.21 Subsequent Wittig reactions and forma-
tion of the allylic alcohol 14b proceeded without incident.
In their studies on the synthesis of carbohydrates using
the Sharpless asymmetric epoxidation (SAE), Sharpless
and Masamune22 addressed the epoxidation of benzyloxy
allylic alcohols akin to 14b. Forcing noncatalytic condi-
tions were required to obtain yields in excess of 70%.
Unfortunately, epoxy alcohol 15 was obtained in <50%
crude yield (contaminated with D-(-)-DET). The con-
taminant was removed after Dess-Martin oxidation of
epoxy alcohol 15 to the epoxy aldehyde 17a (Scheme 4).
The diastereoselectivity of the SAE reaction was readily
1
assessed by comparing the H NMR spectrum of epoxy
(19) Pfitzner, K. E.; Moffatt, J . G. J . Am. Chem. Soc. 1965, 87, 5661,
5670.
(20) Parikh, J . R.; Doering, W. E. J . Am. Chem. Soc. 1967, 89, 5505.
(21) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(22) Reed, L. A.; Ito, Y.; Masamune, S.; Sharpless, K. B. J . Am.
Chem. Soc. 1982, 104, 6468.
(23) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(24) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567.

7922 J . Org. Chem., Vol. 63, No. 22, 1998
Ziegler and Wang
Sch em e 6
Sch em e 7
N-Hydroxypyridine-2-thione esters 17c30 and 22c,
prepared in situ from their respective trans- (17b) and
cis- (22b) glycidic acids, were independently photolyzed
(500 W tungsten lamp) in dilute solution in the presence
of n-Bu3SnH to afford consistently a single product of
cyclization in ∼30% yield after chromatography (Scheme
7). A chromatographic fraction contained a mixture of
two additional compounds, which, on the basis of 1H
NMR and past experience, were tentatively assigned as
the product of direct reduction 26a and thiopyridine
derivative 26b. The stereochemistry of the acetic acid
residue in epoxide 25 was tentatively assigned the
â-configuration (equatorial) in accord with the results of
Hanessian (3 f 4). Although the yield of product was
modest, the reaction was relatively clean. The similar
distribution of products in both reactions attests to the
rapid inversion of the oxiranyl radical.
addition to being exceptionally slow as a reagent, afforded
a 1.5:1 ratio of â: R (19:20). AD-mixR in conjunction with
6 mol % of OsO4 and 10 mol % of (DHQ)2PYR led to a
ratio of 3:1 (80%). Substitution of (DHQ)2PYR(OMe)3, a
more effective R-director than (DHQ)2PYR,25 in the
preceding experiment failed to improve the â/R ratio (2.5:
1; 81%) in favor of the R-diol 20. Rewardingly, OsO4 (6%),
(DHQ)2PHAL (10%), and K3Fe(CN)6 (3 equiv) gave rise
to a predominance of the R-diol 20 (â:R ) 1:15) in 88%
yield.
Owing to the wide variation in facial selectivity using
R-selective protocols, diol 20 was degraded to confirm
independently its absolute stereochemistry. Diol 20 was
converted into its acetonide (2,2-dimethoxypropane, PPTS)
and debenzylated (Pd/C, H2) to a crude triol. Exhaustive
oxidation of the triol (RuCl3, NaIO4)26 afforded a crude
carboxylic acid, which, upon esterification with diaz-
omethane, gave the levorotatory acetonide of dimethyl
tartrate derived from natural L-(+)-tartaric acid.
Conversion of the diols 19 and 20 to their respective
cis-glycidates 21 and 23 was dependent upon the
known27-29 selective C2 aryl sulfonation of threo R,â-
dihydroxy esters followed by base treatment (Scheme 6).
This process retains the C3 stereochemistry, which is
necessary in the current study, and effects stereochemical
inversion at C2. Neither diol ester 19 nor 20 could be
sulfonated with p-nitrobenzenesulfonyl chloride (nosyl
chloride, NsCl) in the presence of an amine base as had
been prescribed.29 The diol esters were selectively depro-
tonated (THF, -40 °C) with 1 equiv of NaHMDS prior
to sulfonation with nosyl chloride. Exposure of the
nosylates to K2CO3 in methanol gave rise to their
respective cis-glycidic esters.
With only the cis-glycidate 24a available to test the
diastereomeric oxiranyl radical cyclization, its thiohy-
droxamate ester 24c was photolyzed under identical
conditions. Unfortunately, the reaction mixture was
complex, and although no products of the reaction could
1
be isolated in pure form, the H NMR spectrum of some
chromatographic fractions indicated the possible presence
of the product of cyclization 27. These results were
reproducible, and the difference in the cyclization behav-
ior of the two diastereomeric oxiranyl radicals is unclear.
To ascertain the complete stereochemistry of cyclized
epoxide 25 and epoxide 27, if it indeed did exist in the
reaction mixture, an independent route to these sub-
stances through cyclohexene 29 was undertaken. Alde-
hyde 10 was converted into the (Z)-vinyl bromide 28 by
adaptation of the method of Stork (Scheme 8).31 When
the vinyl bromide was reduced with n-Bu3SnH in dilute
solution, the desired cyclohexene 29 was not obtained but
1
rather a product was isolated in ∼30% yield whose H
NMR spectrum displayed a vinyl group and the absence
of enoate vinyl protons. These data coupled with a
HRMS molecular ion consistent with C30H32O5 suggested
structure 31 in which only three stereocenters could be
defined with certainty. The initially generated vinyl
radical apparently abstracts a hydrogen atom from the
proximate benzyl group followed by benzyl radical cy-
clization into the R,â-unsaturated ester.
(25) Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993, 34,
5575.
(26) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3937.
(27) Denis, J . N.; Correa, A.; Greene, A. E. J . Org. Chem. 1990, 55,
1957.
A successful route to the desired cyclohexene 29
employed the ring closure metathesis reaction (RCM).
(28) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .; J ackson,
W. R.; Gountzos, H.; Matthews, B. R. J . Chem. Soc., Chem. Commun.
1990, 1018.
(30) The N-hydroxypyridine-2-thione ester 17c of acid 17b was
prepared in situ as described in the Experimental Section for the
esterification of acid 22b (preparation of 25).
(29) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56, 2869.
(31) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.

Synthesis of (+)-Cyclophellitol
Sch em e 8
J . Org. Chem., Vol. 63, No. 22, 1998 7923
Sch em e 9
epoxide was identical with the epoxide formed from the
radical cyclization of thiohydroxamates 17c and 22c.
Realizing that the oxiranyl radical cyclization to form
six-membered rings was inefficient in this instance, we
nonetheless sought to exploit the R-epoxide 25, which had
been formed in modest yield, as a substrate for the
synthesis of epi-cyclophellitol (2). Whereas â-epoxide 27
underwent saponification to form cleanly the epoxy acid,
saponification of R-epoxy ester 25 with K2CO3/aqueous
MeOH led to the dihydroxy acid 34 (Scheme 9). The
stereochemistry of the latter compound was confirmed
Methylenation of aldehyde 10 under standard Wittig
conditions proved too basic as products of elimination of
the aldehyde were prevalent. Tebbe’s reagent32 proved
to be an effective alternative for the formation of olefin
30a . At the outset, the formation of divinyl ester 33 by
conjugate addition proved to be troublesome. The addi-
tion of lithium cuprates to γ-alkoxy-R,â-unsaturated
esters had been shown to be stereoselective,33,34 proceed-
ing through a nonchelation, vinylogous Felkin-Anh
transition state.35,36 A number of instances of the addi-
tion lithium vinyl cuprates have been reported35,36 and
on occasion were found to perform inconsistently, an
observation that is in accord with our own experience.
Different protocols for employing magnesium-based vinyl
cuprates in 1,4-additions to γ-alkoxy-R,â-unsaturated
esters have been advanced by Auge´37 and Hanessian.38
The latter procedure was more amenable and reproduc-
ible (90% yield) when applied to unsaturated ester 32.
Cyclohexene 29 was formed readily from dienic ester 33
using Grubbs’ RCM protocol.39 At this juncture the
stereochemical relationship of the acetic acid residue and
the proximate benzyloxy group had been established as
a result of the stereoselective vinyl cuprate addition.
Epoxidation of cyclohexene 29 with urea-hydrogen
peroxide complex/trifluoroacetic anhydride40 led to a 3:1
mixture of epoxides 27 and 25, respectively. The major
epoxide 27 was detected in the reaction mixture from the
ill-fated cyclization of thiohydroxamate 24c; the minor
1
through the H NMR spectrum of the diacetoxy methyl
ester 35. The dihedral coupling constant, J ) ∼3.2 Hz,
between the two acetoxy methine hydrogens (triplets)
indicated that the two acetoxy groups were diaxial
assuming that the four other substituents occupy equato-
rial positions in a chair cyclohexane. Two mechanisms
present themselves for the formation of the dihydroxy
acid: direct opening of the epoxide by hydroxide or
carboxylate participation. Although no definitive distinc-
tion between the two mechanisms could be established,
the possibility that carboxylate participation was oper-
able was confirmed by first conversion of dihydroxy acid
34 to hydroxy lactone 36. The lactone was readily
converted into the dihydroxy acid under mild conditions
in the presence of K2CO3/aqueous MeOH, demonstrating
that lactone 36 could have been generated during the
saponification and rapidly consumed.
Not only did cyclohexene 29 serve as a means of
establishing the stereochemistry of the oxiranyl radical
cyclization, but it also presented itself as an attractive
entry toward the synthesis of cyclophellitol.11 Saponifi-
cation and iodolactonization of ester 29 lead to iodolac-
tone 37 (92%), which, upon exposure to methanolic
K2CO3, afforded the â-epoxide 27 (Scheme 10). Given the
mechanism of iodolactonization, the formation of the
â-epoxide confirmed the stereochemical relationship be-
tween the epoxide and the acetic acid residue.
(32) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J . Am. Chem. Soc.
1978, 100, 3611.
(33) Ziegler, F. E.; Gilligan, P. J . J . Org. Chem. 1981, 46, 3874.
(34) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J . Am. Chem. Soc.
1982, 104, 2027.
(35) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B. M.;
Chong, W. K. M.; Harris, D. J . J . Am. Chem. Soc. 1989, 111, 2984.
(36) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J . Am. Chem. Soc. 1992, 114, 7652.
(37) Auge, C.; Gautheron, C.; David, S.; Malleron, A.; Cavaye, B.;
Bouxom, B. Tetrahedron 1990, 46, 201.
Epoxy ester 27, available stereoselectively through
iodolactonization and less so by direct epoxidation of
cyclohexene 29, required oxidative decarboxylation to
realize cyclophellitol. As noted earlier, this ester could
be saponified without difficulty to acid 41a (Scheme 11).
Its Barton ester 41b,41 upon photolysis in the presence
(38) Hanessian, S.; Gai, Y. H.; Wang, W. G. Tetrahedron Lett. 1996,
37, 7473.
(39) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
(40) Cooper, M. S.; Heaney, H.; Newbold, A. J .; Sanderson, W. R.
Synlett 1990, 533.
(41) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083.

7924 J . Org. Chem., Vol. 63, No. 22, 1998
Ziegler and Wang
Sch em e 10
Sch em e 12
42.50 Although both of these compounds were useful for
our ultimate goal, we chose to maximize the formation
of alcohol 42.
Sch em e 11
The nucleophilic approach was abandoned in favor of
a radical solution. Exposure of diiodoformate 39 to KOH
in aqueous THF led to iodo epoxide 40 without elimina-
tion. Alkyl bromides and iodides have been converted
to alcohols with n-Bu3SnH in the presence of O2.51-53
Accordingly, iodo epoxide 40 was converted into epoxy
alcohol 42 (70%) along with the formation of epoxy diol
45a (10%) (Scheme 12). The position of the secondary
hydroxyl group in the diol was ascertained through the
formation of cyclic carbonate 44. The coupling pattern
J ab ) J bc )10.2 Hz and J ae ) 10.3 Hz in the 1H NMR
spectrum reaffirmed the trans relationship of the acetic
acid moiety to the proximate benzyloxy groups. The
formation of epoxy diol 45 probably arises through an
ionic process in which iodide ion cleaves the proximate
benzyl group, which is activated as a stannyl complex
(46). Finally, the mixture of epoxy alcohol 42 and epoxy
diol 45 was hydrogenated to afford (+)-cyclophellitol
identical with the sample prepared earlier.
of O2,42 afforded alcohol 42 in modest yield 30% with an
equal amount of acid 41a being recovered. However,
oxidative degradation in the presence of Sb(SPh)3 raised
the yield of 42 to 60%.43 Hydrogenolysis of the benzyl
ethers in 42 in the presence Pd(OH)2/C gave rise to (+)-
cyclophellitol (1), whose 500 MHz 1H NMR spectrum was
identical with that of an enantiomerically pure synthetic
sample provided by Professor Tatsuta.
Iodolactone 37 provided an additional route to cyclo-
phellitol in which degradation preceded epoxide forma-
tion (Scheme 10). Efforts to degrade the lactone via
oxidative cleavage of enol lactone derivatives were un-
successful as was alkoxy hydroperoxide rearrange-
ment.44,45 However, Sa´urez radical fragmentation46,47 of
lactol 38 with PhI(OAc)2/I2 readily provided the diodo-
formate 39.48 Attempts to substitute the primary iodide
of 39 with hydroxide (KOH, aqueous DMF) at room
temperature led to exclusive formation of olefin 43, which
had previously been converted to benzylated cyclophel-
litol 42.49 An improvement in selectivity was seen when
KO2 gave a 1:1 mixture of olefin 43 and epoxy alcohol
Exp er im en ta l Section
Unless otherwise stated, all reactions were carried out in
flame-dried glassware, under N2. Ether (Et2O) and tetrahy-
drofuran (THF) were distilled from sodium benzophenone ketyl
under N2. Methylene chloride (CH2Cl2), benzene, toluene,
diisopropylamine (i-Pr2NH), and hexanes were distilled from
CaH2. Other solvents (ACS photometric grade) were used
without further purification. Commercially available reagents
were used as received. Alkyllithiums were titrated by the
method of Lipton.54 Flash chromatography employed J . T.
Baker 40 µm silica gel. Workup means drying over MgSO4,
filtration, and concentration in vacuo.
(42) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J . Chem. Soc.,
Chem. Commun. 1984, 242.
(43) Barton, D. H. R.; Bridon, D.; Zard, S. Z. J . Chem. Soc., Chem.
Commun. 1985, 1066.
(44) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363.
(45) Ziegler, F. E.; Kneisley, A.; Thottathil, J . K.; Wester, R. T. J .
Am. Chem. Soc. 1988, 110, 5434.
(46) Sua´rez, E.; Freire, R.; Marrero, J . J .; Rodriguez, M. S. Tetra-
hedron Lett. 1986, 27, 383.
(47) Sua´rez, E.; Armas, P.; Francisco, C. G. Angew. Chem., Int. Ed.
Engl. 1992, 31, 772.
(48) For a related case, see: Oh, J . Tetrahedron Lett. 1997, 38, 3249.
(49) Letellier, P.; Ralainirina, R.; Beaupere, D.; Uzan, R. Tetrahe-
dron Lett. 1994, 35, 4555.
(50) Corey, E. J .; Nicoloau, K. C.; Shibasaki, M.; Machida, Y.; Shiner,
C. S. Tetrahedron Lett. 1975, 37, 3183.
(51) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J . Am. Chem.
Soc. 1991, 113, 8980.
(52) Prandi, J .; Moutel, S. Tetrahedron Lett. 1994, 35, 8163.
(53) Prandi, J .; Mayer, S. Tetrahedron Lett. 1996, 37, 3117.
(54) Lipton, M. F.; Sorensen, C. M.; Sadler, A. C.; Shapiro, R. H. J .
Organomet. Chem. 1980, 186, 155.

Synthesis of (+)-Cyclophellitol
J . Org. Chem., Vol. 63, No. 22, 1998 7925
Melting points are uncorrected. Optical rotations were
recorded in CHCl3 containing 1% EtOH at 20 °C. FT-IR were
recorded in CDCl3 or CHCl3. NMR spectra were recorded as
follows unless stated otherwise: 1H NMR (300 MHz; CDCl3,
δ ) 7.26 ppm) and 13C NMR (75 MHz, δ ) 77.0 ppm). Low-
resolution mass spectra were recorded in either chemical
ionization (CI, 2-methylpropane as a reagent gas) or electron
ionization (EI) mode. High-resolution mass spectra (HRMS;
CI or FAB; (1 ppm) were recorded at the Mass Spectrometry
Laboratory, University of Illinois, Urbana-Champaign, IL.
Combustion analyses were determined by Atlantic Microlab,
Inc., Norcross, GA.
(2R,3S,4R)-2,3,4-Tr is(ben zyloxy)-5,5-bis(eth ylth io)p en -
ta n -1-ol (11). To a solution of silyl ether 9 (2.0 g, 3.1 mmol)
in THF (12 mL), was added n-Bu4N+F- (1.0 M in THF, 4.3
mL, 4.3 mmol) at 0 °C, and the resulting solution was warmed
to room temperature and stirred for 2 h. The mixture was
then treated with saturated NH4Cl, diluted with H2O, and
extracted with EtOAc. The combined organic layers were
washed with brine and worked up. The residue was chro-
matographed with 20-45% EtOAc/hexanes to afford alcohol
11 (1.45 g, 88%) as a light yellow oil: [R]D -4.2 (c 1.55, CHCl3);
1
IR 3581 cm-1; H NMR δ 7.29-7.41 (m, 15H), 4.59-4.95 (m,
6H), 4.19 (t, J ) 5.1 Hz, 1H), 4.07 (dd, J ) 5.6, 4.1 Hz, 1H),
3.99 (d, J ) 4.0 Hz, 1H), 3.84 (m, 1H), 3.66-3.72 (m, 2H), 2.70
(q, J ) 7.4 Hz, 2H), 2.57-2.64 (m, 2H), 2.10 (m, 1H), 1.21 (t,
J ) 7.4 Hz, 6H); 13C NMR δ 14.57, 25.30, 25.44, 53.41, 61.63,
72.17, 74.91, 75.13, 78.46, 80.24, 82.31, 127.63, 127.94, 127.99,
128.19, 128.37, 128.53, 128.59, 138.04, 138.27, 138.53. Anal.
Calcd for C30H38O4S2: C, 68.41; H, 7.27. Found: C, 68.48; H,
7.28.
Compound names were generated by ACD/Name (Advanced
Chemistry Development, Inc.) according to IUPAC guidelines.
(2R,3S,4R)-5-{[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxy}-1,1-
bis(eth ylth io)p en ta n e-2,3,4-tr iol (8b). A solution of dithio-
acetal 8a (15 g, 58.6 mmol) in CH2Cl2 (60 mL) was treated
with imidazole (5.2 g, 76.2 mmol). After 5 min, (TBDMS)Cl
(10.6 g, 70.3 mmol) was added and the resulting white slurry
was stirred for 3 h. Saturated NH4Cl was added, and the
mixture was partitioned between H2O and CH2Cl2. The
combined organic extracts were washed with brine and worked
up. Flash chromatography with 20-50% EtOAc/hexanes
afforded silyl ether 8b (16.9 g, 78%) as a white solid: mp 62
Meth yl (E,4R,5S,6R)-4,5,6-Tr is(ben zyloxy)-7,7-bis(eth -
ylth io)-2-h ep ten oa te (12). To a solution of alcohol 11 (0.5
g, 0.95 mmol) in CH2Cl2/CH3CN (4:1, 12 mL) at room temper-
ature was added 4-methylmorpholine N-oxide (0.23 g, 1.9
mmol) and powdered 4 Å molecular sieves (0.47 g). After the
mixture was stirred for 15 min, n-Pr4N+RuO4- (TPAP) (17 mg,
0.05 mmol) was added in one portion. The dark green mixture
turned black after 5 min, and the reaction mixture was stirred
for another 45 min until the reaction was complete (TLC). The
solvent was removed in vacuo. The residue was taken up in
CH2Cl2 (1 mL), filtered through a short silica gel column, and
further eluted with pure EtOAc. The combined filtrate was
concentrated to afford a crude aldehyde which was used
directly in the next step.
1
°C; [R]D +32.9 (c 1.0, CHCl3); IR 3552 cm-1; H NMR δ 4.15
(bd, J ) 6.6 Hz, 1H), 4.11 (d, J ) 8.9 Hz, 1H), 3.83 (m, 1H),
3.75 (d, J ) 5.5 Hz, 2H), 3.65 (d, J ) 8.0 Hz, 1H), 3.50 (bs,
1H), 3.10 (bs, 1H), 2.82 (m, 1H), 2.78-2.67 (m, 4H), 1.30 (t, J
) 7.4 Hz, 6H), 0.93 (s, 9H), 0.11 (s, 6H); 13C NMR δ -5.36,
14.53, 14.66, 18.32, 23.90, 25.79, 25.92, 55.26, 64.11, 69.10,
73.69, 74.60. Anal. Calcd for C15H34O4SiS2: C, 48.61; H, 9.25.
Found: C, 48.67; H, 9.21.
ter t-Bu tyl(d im eth yl){[(2R,3S,4R)-2,3,4-tr is(ben zyloxy)-
5,5-bis(eth ylth io)p en tyl]oxy}sila n e (9). To a THF (1 mL)
suspension of NaH (95%, 27 mg, 1.08 mmol) at 0 °C was added
a solution of triol 8b (100 mg, 0.27 mmol) in THF (0.5 mL),
and the mixture was stirred at room temperature for 1.5 h.
After cooling of the mixture to 0 °C, benzyl bromide (0.15 mL,
1.26 mmol) and n-Bu4N+I- (10 mg, 0.03 mmol) were added.
The white slurry was stirred for 8 h at room temperature. A
solution of saturated NH4Cl (2 mL) was slowly added at 4 °C,
and the mixture was partitioned between H2O and Et2O. The
combined organic extracts were washed with brine and worked
up. Flash chromatography with 0-10% EtOAc/hexanes af-
forded tribenzyl ether 9 (0.14 g, 80%) as a light yellow oil: [R]D
-7.5 (c 4.0, CDCl3); 1H NMR δ 7.24-7.39 (m, 15H), 4.57-4.92
(m, 6H), 4.07-4.15 (m, 2H), 3.77-3.82 (m, 3H), 3.62 (m, 1H),
2.70 (q, J ) 7.4 Hz, 2H), 2.55 (qd, J ) 7.3, 1.6 Hz, 2H), 1.20 (t,
J ) 7.0 Hz, 3H), 1.18 (t, J ) 7.0 Hz, 3H), 0.90 (s, 9H), 0.04 (d,
J ) 4.5 Hz, 6H); 13C NMR δ -5.26, 14.53, 18.28, 25.11, 25.37,
26.01, 53.80, 63.02, 72.59, 75.25, 75.30, 79.32, 80.16, 83.07,
127.38, 127.62, 127.74, 128.25, 128.32, 128.44, 138.51, 138.74.
Anal. Calcd for C36H52O4SiS2: C, 67.45; H, 8.18. Found: C,
67.55; H, 8.19.
A solution of the crude, intermediate aldehyde and methyl
(triphenylphosphoranylidene)acetate (0.6 g, 1.80 mmol) in CH2-
Cl2 (20 mL) was stirred at room temperature for 6 h. The
reaction was quenched with saturated NH4Cl and diluted with
H2O, and the two layers were separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic layers
were washed with brine and worked up. Chromatography
with 5-20% EtOAc/hexanes afforded unsaturated ester 12
(0.24 g, 40%) as a light yellow oil: [R]D -12.9 (c 1.7, CHCl3);
1
IR 1720 cm-1; H NMR δ 7.27-7.29 (m, 15H), 7.08 (dd, J )
15.9, 5.4 Hz, 1H), 6.12 (dd, J ) 16.1, 1.1 Hz, 1H), 4.61-4.89
(m, 5H), 4.41 (d, J ) 11.9 Hz, 1H), 4.15 (m, 1H), 4.09 (dd, J )
6.4, 4.1 Hz, 1H), 3.96 (dd, J ) 6.4, 4.0 Hz, 1H), 3.83 (d, J )
4.0 Hz, 1H), 3.76 (s, 3H), 2.62 (q, J ) 7.4 Hz, 2H), 2.55 (m,
2H), 1.20 (t, J ) 7.5 Hz, 3H), 1.17 (t, J ) 7.6 Hz, 3H); 13C
NMR δ 14.44, 14.58, 25.19, 25.47, 51.71, 53.39, 71.55, 75.20,
75.25, 77.63, 81.30, 82.52, 122.60, 127.42, 127.64, 127.74,
127.80, 128.09, 128.24, 128.38, 128.53, 128.59, 137.37, 138.10,
138.65, 145.61, 166.37. Anal. Calcd for C33H40O5S2: C, 68.24;
H, 6.94. Found: C, 68.25; H, 6.90.
Meth yl (E,4R,5S,6R)-4,5,6-Tr is(ben zyloxy)-7-oxo-2-h ep -
ten oa te (13). A mixture of dithioacetal 12 (1.85 g, 3.18 mmol)
and HgO (1.73 g, 7.99 mmol) in 95% aqueous acetone (34 mL)
was heated at reflux. A suspension of mercuric chloride (2.16
g, 6.37 mmol) in acetone (6 mL) was added dropwise over 30
min. After 5 h the hot solution was filtered and the filtrate
was treated with NaHCO3 (0.66 g in 2 mL of H2O). The
mixture was evaporated, and the residue was taken up in
CHCl3. The mixture was washed successively with H2O,
aqueous KI (10% w/v; 150 mL), and brine. After workup, the
crude residue was chromatographed (25% EtOAc/hexanes) to
afford aldehyde 13 (1.29 g, 85%) as a light yellow oil: [R]D +5.6
(2R,3S,4R)-2,3,4-Tr is(ben zyloxy)-5-{[1-(ter t-bu tyl)-1,1-
d im eth ylsilyl]oxy}p en ta n a l (10). A mixture of dithioacetal
9 (1 g, 2.19 mmol) and mercuric oxide (0.85 g, 3.92 mmol) in
95% aqueous acetone (18 mL) was heated to reflux at which
time a suspension of mercuric chloride (1.06 g, 3.90 mmol) in
acetone (4 mL) was added dropwise over a period of 40 min.
After 5 h the hot solution was filtered and the filtrate was
treated with NaHCO3 (0.33 g in 1 mL of H2O). The mixture
was evaporated, and the residue was taken up in CHCl3. The
mixture was washed with H2O, aqueous KI (10% w/v; 70 mL),
and brine. After workup, the crude residue was chromato-
graphed (25% EtOAc/hexanes) to afford aldehyde 10 (0.63 g,
77%) as a light yellow oil: [R]D +13.6 (c 1.0, CHCl3); IR 1727
1
(c 0.71, CHCl3); IR 2871, 1726 cm-1; H NMR δ 9.56 (s, 1H),
7.11-7.27 (m, 15H), 6.79 (dd, J ) 15.8, 6.0 Hz, 1H), 5.93 (dd,
J ) 15.6, 0.9 Hz, 1H), 4.64 (d, J ) 11.8 Hz, 1H), 4.50 (m, 2H),
4.40 (d, J ) 12.0 Hz, 2H), 4.29 (d, J ) 11.4 Hz, 1H), 4.18 (td,
J ) 4.6, 1.0 Hz, 1H), 3.79 (d, J ) 4.4 Hz, 1H), 3.72 (t, J ) 4.4
Hz, 1H), 3.65 (s, 3H); 13C NMR δ 51.76, 72.09, 73.40, 74.37,
80.78, 81.78, 123.21, 128.00, 128.20, 128.30, 128.39, 128.55,
128.64, 136.96, 137.10, 137.15, 144.62, 166.29; HRMS (CI)
calcd for C29H31O6 (M + H)+ m/e 475.2121, found m/e 475.2120.
1
cm-1; H NMR δ 9.73 (s, 1H), 7.24-7.34 (m, 15H), 4.48-4.80
(m, 6H), 3.97 (m, 1H), 3.89 (d, J ) 5.3 Hz, 1H), 3.67 (m, 2H),
3.55 (m, 1H), 0.87 (s, 9H), 0.00 (d, J ) 1.8 Hz, 6H); 13C NMR
δ -5.33, 18.24, 25.98, 61.67, 73.01, 73.28, 74.23, 78.26, 78.80,
81.30, 127.79, 128.09, 128.27, 128.37, 128.50, 137.44, 137.76,
138.12, 200.83; HRMS (FAB) calcd for C32H43O5Si (M + H)+
m/e 535.2880, found m/e 535.2882.

7926 J . Org. Chem., Vol. 63, No. 22, 1998
Ziegler and Wang
Meth yl (2E,4R,5R,6S,7E)-4,5,6-Tr is(ben zyloxy)-9-oxo-
2,7-n on a d ien oa te (14a ). A solution of aldehyde 13 (0.86 g,
1.81 mmol) and triphenylphosphoranylideneacetaldehyde (0.78
g, 2.56 mmol) in benzene (30 mL) was heated at reflux for 12
h. The reaction mixture was cooled to room temperature,
quenched with saturated NH4Cl, and diluted with H2O. The
layers were separated, and the aqueous layer was further
extracted with EtOAc. The combined organic layers were
washed with brine and worked up. The crude residue was
chromatographed with 10-25% EtOAc/hexanes to afford
unsaturated aldehyde 14a (0.53 g, 58%) as an orange oil: [R]D
residue was chromatographed with 10-30% EtOAc/hexanes
to afford epoxy aldehyde 17a (16 mg, 30% from allylic alcohol
14b) as a colorless oil: [R]D -10.0 (c 0.7, CHCl3); IR 1728 cm-1
;
1H NMR δ 8.84 (d, J ) 6.0 Hz, 1H), 7.25-7.39 (m, 15H), 6.94
(dd, J ) 15.9, 6.0 Hz, 1H), 6.06 (dd, J ) 16.1, 1.0 Hz, 1H),
4.39-4.76 (m, 6H), 4.27 (m, 1H), 3.76 (s, 3H), 3.63 (m, 2H),
3.34 (m, 2H); 13C NMR δ 51.79, 55.91, 57.46, 71.98, 73.94,
74.92, 76.12, 78.03, 80.62, 122.95, 128.12, 128.57, 128.64,
137.35, 137.47, 144.72, 166.32, 197.60; HRMS (CI) Calcd for
C
31H33O7 (M + H)+ m/e 517.2226, found m/e 517.2228.
(2S,3R)-3-[(1R,2S,3R,4E)-1,2,3-Tr is(ben zyloxy)-6-m eth -
1
-13.3 (c 0.75, CHCl3); IR 2871, 1720, 1690 cm-1; H NMR δ
oxy-6-oxo-4-h exen yl]oxir a n e-2-ca r boxylic a cid (17b). To
a CH3CN (1.3 mL) solution of aldehyde 17a (65 mg, 0.126
mmol), at 0 °C was added NaH2PO4 (9.3 mg, 0.08 mmol) in
H2O (0.6 mL) and H2O2 (73 µL of 30% solution, 1.21 mmol).
After 5 min a solution of sodium chlorite (45 mg, 0.50 mmol)
in H2O (1.2 mL) was slowly added over 40 min, and the
resulting mixture was stirred for 1 h at 0 °C and 3 h at room
temperature.58 The solvent was removed in vacuo without
heating, and the residue was diluted with H2O. The mixture
was carefully acidified to pH 4 with 1 N HCl, and the mixture
was extracted with Et2O. The combined ether layers were
concentrated in vacuo, and the residue was redissolved in CH2-
Cl2. The organic layer was washed with brine and worked up
to afford acid 17b (51 mg, 76%) as a colorless oil, which was
used directly in the oxiranyl radical cyclization experiment.
A sample of this sensitive acid was characterized as its methyl
ester.
9.31 (d, J ) 7.9 Hz, 1H), 7.25-7.39 (m, 15H), 6.90 (dd, J )
15.9, 6.0 Hz, 1H), 6.60 (d, J ) 15.8, 5.3 Hz, 1H), 6.23 (dd, J )
15.4, 7.7 Hz, 1H), 6.05 (dd, J ) 15.3, 0.8 Hz, 1H), 4.54-4.74
(m, 4H), 4.38 (t, J ) 11.9 Hz, 2H), 4.22 (q, J ) 4.6 Hz, 2H),
3.77 (s, 3H), 3.55 (t, J ) 4.9 Hz, 1H); 13C NMR δ 51.79, 71.81,
72.34, 75.05, 77.96, 78.29, 81.87, 123.21, 128.04, 128.16,
128.32, 128.37, 128.49, 128.61, 128.84, 132.82, 137.18, 137.26,
144.82, 153.84, 166.29, 193.37. Anal. Calcd for C31H32O6: C,
74.38; H, 6.44. Found: C, 74.30; H, 6.48.
Met h yl (2E,4R,5R,6S,7E)-4,5,6-Tr is(b en zyloxy)-9-h y-
d r oxy-2,7-n on a d ien oa te (14b). To a solution of unsaturated
aldehyde 14a (0.53 g, 1.06 mmol) in MeOH (16 mL) at 0 °C
was added NaBH4 (40 mg, 1.05 mmol) in two portions, and
the resulting mixture was stirred for 40 min. Saturated NH4-
Cl was slowly added to the reaction mixture. The mixture was
diluted with H2O (16 mL) and extracted with Et2O, and the
combined organic layers were washed with brine and worked
up. The crude residue was chromatographed with 30-60%
EtOAc/hexane to afford allylic alcohol 14b (0.42 g, 80%) as a
white solid: mp 93.5 °C; [R]D +10.3 (c 1.32, CHCl3); IR 3611,
1719 cm-1; 1H NMR δ 7.27-7.33 (m, 15H), 6.88 (dd, J ) 15.8,
6.2 Hz, 1H), 6.03 (dd, J ) 15.6, 1.0 Hz, 1H), 5.74 (td, J ) 15.7,
5.0 Hz, 1H), 5.58 (dd, J ) 15.8, 7.5 Hz, 1H), 4.75 (dd, J ) 16.3,
11.6 Hz, 2H), 4.59 (dd, J ) 11.6, 9.1 Hz, 2H), 4.36 (dd, J )
13.5, 11.7 Hz, 2H), 4.26 (td, J ) 5.8, 0.9 Hz, 1H), 3.97-4.02
(m, 3H), 3.76 (s, 3H), 3.47 (t, J ) 5.1 Hz, 1H); 13C NMR δ 51.70,
62.83, 70.85, 71.79, 75.22, 79.01, 79.62, 83.22, 122.83, 127.64,
127.78, 127.87, 128.15, 128.22, 128.27, 128.37, 128.47, 128.89,
133.59, 137.81, 138.16, 138.24, 145.52, 166.52; HRMS calcd
for C31H35O6 (M + H)+ m/e 503.2434, found m/e 503.2427.
Meth yl (E,4R,5S,6R)-4,5,6-Tr is(ben zyloxy)-6-[(2S,3R)-
3-for m yloxir a n -2-yl]-2-h exen oa te (17a ). To a mixture of
D-(-)-diethyl tartrate (74 mg, 0.36 mmol) and 4 Å molecular
sieves (30 mg) in CH2Cl2 (4 mL) at -23 °C was added titanium
tetraisopropoxide (92 µL, 0.31 mmol) followed by anhydrous
tert-butyl hydroperoxide (0.12 mL of 3 M solution in isooctane,
0.36 mmol). After 30 min of stirring at -23 °C, allylic alcohol
14b (52 mg, 0.10 mmol) in 0.6 mL of CH2Cl2 was added
dropwise to the mixture. After 30 h at -20 °C (freezer), the
cold mixture was quickly filtered through a pad of Celite to
remove the sieves and the filtrate was recooled to -23 °C. A
mixture of saturated Na2S2O3 and NaHCO3 solution (5 mL)
was then added to the reaction flask, and the mixture was
allowed to warm gradually to room temperature. After dilu-
tion with H2O, the mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine and worked
up. The residue was chromatographed with 30-55% EtOAc/
hexanes to afford epoxy alcohol 15 (∼27 mg, 50%) as an oil
which was contaminated with D-(-)-diethyl tartrate.
To a solution of acid 17b in Et2O at 0 °C was slowly added
diazomethane in Et2O until the solution became yellow.
A
small amount of AcOH was added to destroyed the residual
diazomethane. The organic layer was washed successively
with saturated NaHCO3, H2O and brine. Workup and chro-
matography afforded methyl glycidate 17d as a colorless oil:
[R]D +20.0 (c 0.35, CHCl3); IR 1744, 1722 cm-1 1H NMR δ
;
7.25-7.36 (m, 15H), 6.92 (dd, J ) 15.8, 6.0 Hz, 1H), 6.04 (dd,
J ) 15.6, 1.1 Hz, 1H), 4.40-4.75 (m, 6H), 4.36 (td, J ) 5.9, 1.1
Hz, 1H), 3.73 (s, 3H), 3.66 (s, 3H), 3.62 (m, 1H), 3.56 (t, J )
4.2 Hz, 1H), 3.48 (t, J ) 1.8 Hz, 1H), 3.39 (dd, J ) 4.3, 2.0 Hz,
1H); 13C NMR δ 51.63, 51.73, 52.48, 57.32, 71.88, 73.78, 74.96,
76.24, 78.28, 80.73, 122.82, 127.80, 127.86, 127.97, 128.09,
128.47, 137.57, 137.66, 144.82, 166.36, 169.07; HRMS (CI)
calcd for C32H35O8 (M + H)+ m/e 547.2332, found m/e 547.2323.
Meth yl (E,4S,5R,6R)-4,5,6-Tr is(ben zyloxy)-7-{[1-(ter t-
bu tyl)-1,1-dim eth ylsilyl]oxy}-2-h epten oate (18). To a CH2-
Cl2 (200 mL) solution of aldehyde 10 (9.6 g, 18.0 mmol) was
added methyl (triphenylphosphoranylidene)acetate (12 g, 39.4
mmol), and the resulting mixture, was stirred for 10 h. Water
was added to the reaction mixture and the two layers were
separated. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were washed with brine and
worked up. The residue was chromatographed with 5-20%
EtOAc/hexanes to afford unsaturated ester 18 (9.2 g, 86%) as
a colorless oil: [R]D +5.4 (c 1.3, CHCl3); IR 1718, 1096 cm-1
;
1H NMR δ 7.27-7.37 (m, 15H), 6.93 (dd, J ) 15.8, 6.0 Hz,
1H), 6.01 (d, J ) 15.7 Hz, 1H), 4.51-4.57 (m, 5H), 4.41 (d, J
) 11.7 Hz, 1H), 4.25 (td, J ) 5.8, 1.1 Hz, 1H), 3.74 (s, 3H),
3.59-3.77 (m, 4H), 0.87 (s, 9H), 0.00 (d, J ) 1.9 Hz, 6H); 13C
NMR δ -5.36, 18.25, 25.95, 51.63, 62.43, 71.85, 73.08, 74.99,
78.79, 79.53, 80.06, 122.21, 127.61, 127.71, 127.78, 127.83,
128.04, 128.09, 128.33, 128.47, 128.58, 137.81, 138.30, 138.61,
145.85, 166.58. Anal. Calcd for C35H46O6Si: C, 71.15; H, 7.85.
Found: C, 71.23; H, 7.82.
To a CH2Cl2 (1.0 mL) solution of Dess-Martin period-
inane55-57 (33 mg, 0.08 mmol) at room temperature was added
crude alcohol 15 (27 mg, 0.05 mmol) in CH2Cl2 (0.2 mL), and
the resulting white slurry was stirred for another 40 min. The
reaction mixture was diluted with Et2O and poured into
saturated NaHCO3 containing a 7-fold excess of Na2S2O3. The
mixture was stirred until two clear layers appeared. After
separation, the aqueous layer was extracted with Et2O. The
combined organic layers were washed successively with satu-
rated NaHCO3, H2O, and brine. After workup, the crude
Met h yl (2S,3S,4S,5S,6R)-4,5,6-Tr is(b en zyloxy)-7-{[1-
(t er t -b u t yl)-1,1-d im e t h ylsilyl]oxy-2,3-d ih yd r oxyh e p -
ta n oa te (19). To a well-stirred mixture of (DHQD)2-PHAL
(0.5 g, 0.64 mmol), K3Fe(CN)6 (6.4 g, 19.43 mmol), K2CO3 (2.6
g, 19.3 mmol), and CH3SO2NH2 (0.61 g, 6.42 mmol) in 1:1
t-BuOH-H2O (76 mL) at 0 °C was added OsO4 (2.5 mL of 4%
aqueous solution, 0.4 mmol). After 15 min, R,â-unsaturated
ester 18 (3.8 g, 6.44 mmol) in t-BuOH was added over 20 min
and the mixture was stirred for another 36 h at 0 °C. Solid
(55) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(56) Ireland, R. E.; Liu, L. B. J . Org. Chem. 1993, 58, 2899.
(57) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(58) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567.

Synthesis of (+)-Cyclophellitol
J . Org. Chem., Vol. 63, No. 22, 1998 7927
sodium sulfite (20 g) was added, and the mixture was stirred
for 30 min at 0 °C and allowed to warm to room temperature.
EtOAc was added, and the layers were separated. The
aqueous layer was further extracted with EtOAc. The com-
bined organic phases were worked up and chromatographed
with 20-35% EtOAc/hexanes to afford diol 19 (3.8 g, 92%; 19:
20, 20:1) as a colorless oil: [R]D -13.5 (c 2.0, CHCl3); IR 3543,
1743 cm-1; 1H NMR δ 7.30-7.37 (m, 15H), 4.58-4.77 (m, 6H),
4.46 (d, J ) 8.4 Hz, 1H), 4.21 (m, 1H), 3.87-3.95 (m, 2H),
3.76-3.78 (m, 2H), 3.75 (s, 3H), 3.52 (d, J ) 2.9 Hz, OH, 1H),
3.02 (d, J ) 2.9 Hz, OH, 1H), 0.91 (s, 9H), 0.06 (s, 6H); 13C
NMR δ -5.32, 18.29, 25.79, 25.98, 52.54, 61.98, 70.99, 73.11,
73.45, 73.75, 74.70, 78.79, 127.78, 127.97, 128.06, 128.23,
128.28, 128.39, 128.51, 137.64, 137.86, 137.99, 174.22. Anal.
Calcd for C35H48O8Si: C, 67.28; H, 7.74. Found: C, 67.18; H,
7.77.
Met h yl (2R,3R,4S,5S,6R)-4,5,6-Tr is(b en zyloxy)-7-{[1-
(t er t -b u t yl)-1,1-d im e t h ylsilyl]oxy}-2,3-d ih yd r oxyh e p -
t a n oa t e (20). Diol 20 was prepared from R,â-unsaturated
ester 18 (4 g, 6.8 mmol) by the same procedure used for the
preparation of diol 19. After chromatography with 20-35%
EtOAc/hexanes, diol 20 (3.75 g, 88%; 20:19, 15:1) was obtained
as a colorless oil: [R]D -16.8 (c 1.35, CHCl3); IR 3550, 1741,
1096 cm-1; 1H NMR δ 7.31-7.37 (m, 15H), 4.53-4.83 (m, 6H),
4.28 (dd, J ) 5.5, 2.7 Hz, 1H), 4.09 (bm, 1H), 3.76-3.93 (m,
2H), 3.73 (bs, 3H), 3.61 (s, 3H), 3.06 (d, J ) 5.6 Hz, OH, 1H),
2.92 (d, J ) 7.3 Hz, OH, 1H), 0.89 (m, 9H), 0.02 (bs, 6H); 13C
NMR δ -5.31, 18.25, 25.99, 52.57, 62.54, 71.61, 73.14, 74.23,
74.53, 77.65, 78.34, 78.80, 78.97, 127.72, 127.88, 127.96,
128.10, 128.22, 128.41, 128.49, 128.54, 138.06, 138.14, 138.46,
stirred for 20 min. A solution of alcohol 21b (0.4 g, 0.81 mmol)
in CH2Cl2 (2 mL) was added dropwise over 10 min. After 40
min of stirring at -78 °C, Et3N (0.56 mL, 4.01 mmol) was
added, and the resulting white slurry was stirred for another
15 min and allowed to warm slowly to -30 °C. To the reaction
mixture at -30 °C was added methyl (triphenylphosphora-
nylidene)acetate (0.57 g, 1.79 mmol) in one portion, and the
resulting mixture was stirred for 6 h while it was allowed to
warm gradually to room temperature. Water was added, and
the two layers were separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic phases were
washed with brine and worked up. The residue was chro-
matographed with 10-30% EtOAc/hexanes to afford unsatur-
ated ester 22a (0.39 g, 88%) as a colorless oil: [R]D -4.3 (c
1
3.1, CHCl3); IR 1721, 1280, 1070 cm-1; H NMR δ 7.23-7.33
(m, 15H), 6.91 (dd, J ) 15.7, 6.0 Hz, 1H), 5.99 (dd, J ) 15.7,
1.1 Hz, 1H), 4.81 (d, J ) 11.4 Hz, 1H), 4.74 (d, J ) 11.4 Hz,
1H), 4.46-4.58 (m, 3H), 4.27-4.32 (m, 2H), 3.83 (dd, J ) 6.4,
3.0 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.64 (t, J ) 3.7 Hz, 1H),
3.59 (d, J ) 4.0 Hz, 1H), 3.48 (dd, J ) 7.3, 4.1 Hz, 1H); 13C
NMR δ 51.62, 52.39, 53.30, 56.51, 71.94, 72.59, 74.14, 75.23,
78.67, 81.23, 122.56, 127.78, 127.90, 127.95, 128.03, 128.42,
128.54, 137.51, 137.86, 138.00, 145.06, 166.42, 168.49. Anal.
Calcd for C32H34O8: C, 70.31; H, 6.27. Found: C, 70.37; H,
6.29.
Met h yl (2S,3R)-3-((1R,2S,3R)-1,2,3-Tr is(ben zyloxy)-4-
{[1-(ter t-b u t yl)-1,1-d im et h ylsilyl]oxy}b u t yl)oxir a n e-2-
ca r boxyla te (23a ). To a THF (6.5 mL) solution of diol ester
20 (0.4 g, 0.64 mmol) at -78 °C was added sodium bis-
(trimethylsilyl)amide (0.71 mL of 1.0 M THF solution, 0.71
mmol) over 10 min. After another 10 min, p-nitrosulfonyl
chloride (0.16 g, 0.71 mmol) was added and the resulting
yellow-brown mixture was stirred for 50 min while gradually
warming to -40 °C. Saturated NH4Cl solution was added
slowly to the reaction mixture. The layers were separated,
and the aqueous layer was extracted with Et2O. The combined
organic phases were washed with brine and worked up to
afford crude nosylate as a syrup that was used directly in the
next step.
173.66. Anal. Calcd for
Found: C, 67.03; H, 7.81.
C35H48O8Si: C, 67.28; H, 7.74.
Met h yl (2R,3S)-3-((1R,2S,3R)-1,2,3-Tr is(ben zyloxy)-4-
{[1-(ter t-b u t yl)-1,1-d im et h ylsilyl]oxy}b u t yl)oxir a n e-2-
ca r boxyla te (21a ). Glycidate 21a was prepared from diol
ester 19 (3 g, 4.8 mmol) as described for the preparation of
glycidate 23a (vide infra). After flash chromatography with
10-20% EtOAc/hexanes, cis-glycidate 21a (1.96 g, 67%) was
obtained as a colorless oil: [R]D -8.0 (c 0.65, CHCl3); IR 1751,
1090 cm-1; 1H NMR δ 7.28-7.40 (m, 15H), 4.73 (bs, 4H), 4.51
(d, J ) 11.3 Hz, 1H), 4.42 (d, J ) 11.3 Hz, 1H), 3.76-3.79 (m,
4H), 3.68 (m, 1H), 3.65 (s, 3H), 3.59 (d, J ) 4.6 Hz, 1H), 3.48
(dd, J ) 6.8, 4.2 Hz, 1H), 0.88 (bs, 9H), 0.01 (bs, 6H); 13C NMR
δ -5.30, 18.28, 26.00, 52.33, 52.93, 56.87, 62.89, 72.92, 73.18,
74.86, 74.99, 79.19, 79.80, 127.46, 127.73, 127.82, 128.02,
128.26, 128.32, 128.40, 137.89, 138.34, 138.99, 168.56. Anal.
Calcd for C35H46O7Si: C, 69.28; H, 7.64. Found: C, 69.02; H,
7.58.
The nosylate in CH3OH (7 mL) at 0 °C was treated with
K2CO3 (0.35 g, 2.57 mmol), and the mixture was stirred for
1.5 h at 0 f 25 °C. Saturated NH4Cl solution was added, and
the mixture was carefully acidified to pH 4 with 1 N HCl. The
mixture was extracted with Et2O, and the combined organic
phases were washed with brine and worked up. The crude
residue was chromatographed with 10-20% EtOAc/hexanes
to afford cis-glycidate 23a (0.27 g, 70%) as a colorless oil: [R]D
1
+26.1 (c 0.65, CHCl3); IR 1747, 1093 cm-1; H NMR δ 7.32-
Met h yl (2R,3S)-3-[(1R,2S,3R)-1,2,3-Tr is(b en zyloxy)-4-
h yd r oxybu tyl]oxir a n e-2-ca r boxyla te (21b). To a solution
of silyl ether 21a (2.5 g, 4.1 mmol) in CH3CN (55 mL) at -20
°C was added dropwise a solution of HF (6.1 mL of 48%
solution, 146.4 mmol) in CH3CN (37 mL) via a polyethylene
syringe. After 2.5 h of stirring at -20 f -10 °C, NaHCO3
(13 g, 155 mmol) in H2O (200 mL) was carefully added and
the resulting mixture was vigorously stirred at room temper-
ature for 40 min. (Note: It is critical that the mixture is basic.)
The mixture was extracted with Et2O, and the combined
organic phases were washed with brine and worked up. The
residue was purified 20-50% EtOAc/hexanes to afford alcohol
21b (1.8 g, 88%) as a colorless oil: [R]D -5.0 (c 1.6, CHCl3); IR
3587, 1750 cm-1; 1H NMR δ 7.26-7.35 (m, 15H), 4.77 (s, 2H),
4.75 (d, J ) 10.4 Hz, 1H), 4.61 (d, J ) 11.6 Hz, 1H), 4.57 (d,
J ) 11.5 Hz, 1H), 4.37 (d, J ) 11.6 Hz, 1H), 3.94 (dd, J ) 6.3,
3.1 Hz, 1H), 3.83 (m, 1H), 3.68-3.79 (m, 2H), 3.70 (s, 3H), 3.57
(t, J ) 5.7 Hz, 1H), 3.51 (dd, J ) 7.4, 4.0 Hz, 1H), 2.00 (t, J )
6.4 Hz, 1H); 13C NMR δ 52.50, 53.26, 56.60, 61.78, 72.49, 73.08,
73.92, 74.92, 79.42, 79.51, 127.82, 127.94, 128.00, 128.05,
128.49, 137.44, 138.05, 138.35, 168.53. Anal. Calcd for
7.45 (m, 15H), 4.54-4.95 (m, 6H), 3.88 (m, 1H), 3.83 (dd, J )
7.6, 3.1 Hz, 1H), 3.72 (dd, J ) 11.2, 3.8 Hz, 2H), 3.59 (s, 3H),
3.50-3.65 (m, 2H), 3.27 (d, J ) 4.7 Hz, 1H), 0.89 (bs, 9H),
0.02 (m, 6H); 13C NMR δ -5.31, 18.34, 26.01, 50.31, 52.29,
58.94, 63.24, 72.33, 73.22, 74.07, 75.13, 78.30, 79.65, 94.10,
127.53, 127.73, 127.81, 127.90, 128.04, 128.32, 128.39, 128.43,
128.51, 128.57, 137.92, 137.98, 138.78, 168.28. Anal. Calcd
for C35H46O7Si: C, 69.28; H, 7.64. Found: C, 69.36; H, 7.68.
Met h yl (2S,3R)-3-[(1R,2S,3R)-1,2,3-Tr is(ben zyloxy)-4-
h yd r oxybu tyl]oxir a n e-2-ca r boxyla te (23b). Alcohol 23b
was prepared from silyl ether 23a (2.4 g, 3.96 mmol) as
described for the preparation of alcohol 21b. After flash
chromatography with 20-50% EtOAc/hexanes alcohol 23b (1.6
g, 82%) was obtained as a colorless oil: [R]D +49.7 (c 2.35,
1
CHCl3); IR 3587, 1749, 1710 cm-1; H NMR δ 7.34-7.37 (m,
15H), 4.55-4.91 (m, 6H), 3.78 (m, 1H), 3.65 (m, 1H), 3.62 (s,
3H), 3.52-3.59 (m, 2H), 3.43 (dd, J ) 7.6, 4.7 Hz, 1H), 3.16-
3.23 (m, 2H), 1.86 (t, J ) 4.9 Hz, 1H); 13C NMR δ 49.92, 52.54,
58.58, 61.01, 72.11, 73.17, 74.73, 78.83, 79.77, 127.91, 127.98,
128.06, 128.43, 128.56, 128.79, 137.41, 137.83, 168.26. Anal.
Calcd for C29H32O7: C, 70.71; H, 6.55. Found: C, 70.58; H,
6.52.
C
29H32O7: C, 70.71; H, 6.55. Found: C, 70.61; H, 6.57.
Meth yl (2R,3S)-3-[(1R,2S,3R,4E)-1,2,3-Tr is(ben zyloxy)-
Meth yl (2S,3R)-3-[(1R,2S,3R,4E)-1,2,3-Tr is(ben zyloxy)-
6-m eth oxy-6-oxo-4-h exen yl]oxir a n e-2-ca r boxyla te (24a ).
Unsaturated ester 24a was prepared from alcohol 23b (0.5 g,
1.01 mmol) as described above for unsaturated ester 22a .
After chromatography with 10-30% EtOAc/hexanes, methyl
6-m eth oxy-6-oxo-4-h exen yl]oxir a n e-2-ca r boxyla te (22a ).
To a solution of oxalyl chloride (0.12 mL, 1.38 mmol) in dry
CH2Cl2 (5 mL) at -78 °C was added DMSO (0.22 mL, 3.10
mmol) in CH2Cl2 (0.5 mL) over 10 min, and the mixture was

7928 J . Org. Chem., Vol. 63, No. 22, 1998
Ziegler and Wang
ester 24a (0.42 g, 76%) was isolated as a colorless oil: [R]D
+57.2 (c 0.75, CHCl3); IR 1723 cm-1; 1H NMR δ 7.31-7.36 (m,
15H), 6.64 (dd, J ) 15.8, 6.4 Hz, 1H), 5.91 (d, J ) 5.7 Hz, 1H),
4.85 (d, J ) 11.7 Hz, 1H), 4.78 (d, J ) 11.8 Hz, 1H), 4.58 (m,
3H), 4.42 (d, J ) 11.5 Hz, 1H), 4.33 (d, J ) 6.3 Hz, 1H), 3.72
(s, 3H), 3.60 (s, 3H), 3.58 (d, J ) 2.2 Hz, 1H), 3.42 (dd, J )
7.5, 4.9 Hz, 1H), 3.36 (dd, J ) 6.5, 2.3 Hz, 1H), 3.17 (d, J )
4.7 Hz, 1H); 13C NMR δ 50.04, 51.67, 52.38, 58.56, 71.92, 72.15,
74.75, 75.12, 78.87, 80.69, 123.28, 127.87, 128.06, 128.39,
128.52, 128.65, 128.85, 137.52, 137.61, 137.70, 144.37, 166.16,
168.16; HRMS (CI) Calcd for C32H35O8 (M + H)+ m/e 547.2332,
found m/e 547.2318.
Meth yl 2-[(1aS,2R,3R,4S,5R,5a S)-3,4,5-Tr is(ben zyloxy)-
p er h yd r o-1-ben zoxir en -2-yl]a ceta te (25). To a THF (3 mL)
solution of diester 22a (0.18 g, 0.33 mmol) at 10 °C was added
a 0.2 M LiOH solution (2.5 mL, 0.49 mmol), and the resulting
mixture was stirred for 2 h while gradually warming to room
temperature. Another two portions of LiOH (2 × 0.6 mL, 0.24
mmol) were added over 2 h to complete the reaction. The
mixture was diluted with H2O (8 mL), carefully acidified to
pH 4 with 1 N HCl, and extracted with Et2O. The combined
organic layers were washed with brine and worked up as usual
to afford a crude acid 22b (0.15 g, 85%) as a thick oil which
was used directly in the next step.
(0.06 g, 0.08 mmol) was added in two portions over the next
36 h. The reaction mixture was quenched by exposure to air
(turns greenish black after 3 h), concentrated, and chromato-
graphed with 5-20% EtOAc/hexanes to afford cyclohexene 29
(0.89 g, 94%) as an oil: [R]D +109.8 (c 1.5, CHCl3); IR 1733
1
cm-1; H NMR δ 7.33-7.40 (m, 15H), 5.73 (dt, J ) 10.2, 2.3
Hz, 1H), 5.61 (dt, J ) 10.1, 1.5 Hz, 1H), 5.06 (d, J ) 11.1 Hz,
1H), 4.96 (d, J ) 1.7 Hz, 2H), 4.75 (s, 2H), 4.64 (d, J ) 11.1
Hz, 1H), 4.3 (m, 1H), 3.88 (dd, J ) 9.9, 7.8 Hz, 1H), 3.65 (s,
3H), 3.51 (t, J ) 9.7 Hz, 1H), 2.88 (m, 1H), 2.66 (dd, J ) 15.3,
5.1 Hz, 1H), 2.34 (dd, J ) 15.3, 5.0 Hz, 1H); 13C NMR δ 36.35,
40.34, 51.66, 72.07, 75.20, 75.33, 76.68, 80.97, 81.29, 85.17,
126.70, 127.64, 127.71, 127.90, 127.99, 128.45, 129.43, 138.48,
138.77, 172.62; LRMS (CI) (M + H)+ m/e 473. Anal. Calcd
for C30H32O5: C, 76.25; H, 6.83. Found: C, 74.29; H, 6.72.
ter t-Bu tyl(d im eth yl){[(2R,3S,4R)-2,3,4-tr i(ben zyloxy)-
5-h exen yl]oxy}sila n e (30a ). To a solution of aldehyde 10
(0.020 g, 0.04 mmol) and pyridine (2 µL) in 3:1 toluene/THF
(0.8 mL) was added Tebbe’s reagent ((µ-chloro)(µ-methylene)-
[bis(cyclopentadienyl)titanium]dimethylaluminum, 0.51 M in
toluene, 0.11 mL, 0.06 mmol) at -78 °C over 5 min. The
mixture was vigorously stirred and allowed to warm to -15
°C over 2 h. The reaction mixture was quenched with 15%
NaOH (0.1 mL), diluted with H2O, and extracted with EtOAc.
The combined organic layers were washed with brine and
worked up. The residue was chromatographed with 0-5%
EtOAc/hexanes to afford olefin 30a (0.017 g, 80%) as a light
yellow oil: [R]D +7.6 (c 1.05, CHCl3); 1H NMR δ 7.25-7.35 (m,
15H), 5.81 (ddd, J ) 17.4, 10.2, 7.4 Hz, 1H), 5.22-5.29 (m,
2H), 4.83 (d, J ) 11.4 Hz, 1H), 4.70 (d, J ) 11.8 Hz, 2H), 4.62
(d, J ) 11.7 Hz, 1H), 4.56 (d, J ) 11.7 Hz, 1H), 4.41 (d, J )
11.6 Hz, 1H), 4.15 (t, J ) 6.8 Hz, 1H), 3.62-3.71 (m, 4H), 0.88
(s, 9H), 0.00 (s, 6H); 13C NMR δ -5.35, 18.22, 25.95, 62.76,
70.76, 73.11, 75.23, 80.13, 81.15, 81.66, 118.75, 127.96, 128.07,
128.20, 128.25, 128.36, 128.46, 135.79, 138.55, 138.93, 139.00;
LRMS (CI) (M + H)+ m/e 533. Anal. Calcd for C33H44O4Si:
C, 74.39; H, 8.32. Found: C, 74.19; H, 8.35.
(2R,3R,4S)-2,3,4-Tr is(ben zyloxy)-5-h exen -1-ol (30b). To
a solution of silyl ether 30a (1.65 g, 3.1 mmol) in THF (12 mL)
at 0 °C was added n-Bu4N+F- (1.0 M in THF, 4.2 mL, 4.2
mmol), and the resulting solution was allowed to warm to room
temperature and stir for 2 h. The mixture was treated with
saturated NH4Cl (10 mL), diluted with H2O, and extracted
with EtOAc. The combined organic layers were washed with
brine and worked up. The residue was chromatographed with
20-45% EtOAc/hexanes to afford unsaturated alcohol 30b (1.1
g, 88%) as a light yellow oil: [R]D +5.7 (c 1.4, CHCl3); IR 3581
cm-1; 1H NMR δ 7.29-7.33 (m, 15H), 5.90 (ddd, J ) 17.7, 10.0,
7.52 Hz, 1H), 5.35-5.30 (m, 2H), 4.37-4.75 (m, 6H), 4.1 (dd,
J ) 7.2, 3.55 Hz, 1H), 3.65-3.75 (m, 3H), 3.57 (m, 1H), 2.16
(t, J ) 6.2, 5.7 Hz, 1H); 13C NMR δ 61.53, 70.78, 72.88, 74.88,
79.58, 80.48, 81.74, 118.98, 127.77, 127.87, 127.97, 128.10,
128.44, 128.50, 135.15, 138.02, 138.32, 138.47. LRMS (CI) (M
+ H)+ m/e 419. Anal. Calcd for C27H30O4: C, 77.48; H, 7.22.
Found: C, 77.38; H, 7.29.
To a solution of isobutyl chloroformate (38 µL, 0.29 mmol)
in THF (3 mL) at -23 °C was added dropwise a precooled THF
(1.5 mL) solution of acid 22b (0.15 g, 0.28 mmol) and N-
methylmorpholine (34 µL, 0.31 mmol) via a cannulating
needle. After 5 min, sodium thiopyridone N-oxide (46 mg, 0.31
mmol) was added and the resulting mixture was stirred for 3
h at -23 °C in the dark. The cold mixture was filtered rapidly
through a pad of Celite, diluted to 0.015 M with THF (18 mL
in total), and degassed in the dark. Tri-n-butyltin hydride (23
µL, 0.08 mmol) was added to the resulting bright yellow
solution and irradiated with a 500 W tungsten lamp at 5 °C
while the remaining portion of the n-Bu3SnH (91 µL, 0.33
mmol) was added over 15 min. The entire irradiation took
about 30 min. Solvent was removed in vacuo without heating,
and the residue was purified on silica gel packed with 1% Et3N/
hexane. The column was first eluted with pentane and then
with 10-20% EtOAc/hexanes (gradient) to afford epoxide 25
(38 mg, 30%) as a light yellow solid: [R]D +35.9 (c 0.5, CHCl3);
1
IR 1731 cm-1; H NMR δ 7.27-7.44 (m, 15H), 4.81-4.94 (m,
5H), 4.52 (d, J ) 11.1 Hz, 1H), 3.94 (dd, J ) 8.5, 1.6 Hz, 1H),
3.72-3.78 (m, 1H), 3.61 (s, 3H), 3.29-3.38 (m, 2H), 3.05 (d, J
) 3.9 Hz, 1H), 2.61 (dd, J ) 16.5, 4.7 Hz, 1H), 2.51 (dd, J )
16.6, 6.2 Hz, 1H), 2.38-2.43 (m, 1H); 13C NMR δ 34.23, 38.69,
51.76, 55.28, 72.95, 75.20, 75.82, 77.28, 77.34, 79.93, 82.33,
127.67, 127.80, 127.94, 128.02, 128.13, 128.30, 128.42, 128.48,
138.28, 138.66, 172.31. HRMS (CI) for C30H33O6 (M + H)+ m/e
489.2277, found m/e 489.2259.
Meth yl 2-[(1a R,2R,3R,4S,5R,5a R)-3,4,5-Tr is(ben zylox-
y)p er h yd r o-1-ben zoxir en -2-yl]a ceta te (27). A solution of
iodolactone 37 (0.2 g, 0.34 mmol) and Na2CO3 (0.22 g, 2.07
mmol) in methanol (4 mL) at room temperature was stirred
for 8 h. The mixture was filtered through a pad of Celite, and
the solid was further rinsed with EtOAc. The combined
filtrate was concentrated, and the residue was chromato-
graphed with 30% EtOAc/hexanes to afford epoxy ester 27
(0.16 g, 98%) as a colorless solid: mp 65 °C; [R]D +77.0 (c 1.4,
CHCl3); IR 1732 cm-1; 1H NMR δ 7.25-7.37 (m, 15H), 4.95 (d,
J ) 11.1 Hz, 1H), 4.81 (m, 4H), 4.50 (d, J ) 11.1 Hz, 1H), 3.87
(d, J ) 8.1 Hz, 1H), 3.64 (s, 3H), 3.58 (app t, J ) 9.2 Hz, 1H),
3.37 (d, J ) 3.2 Hz, 1H), 3.22 (d, J ) 8.1 Hz, 2H), 3.19 (d, J )
8.2 Hz, 1H), 2.77 (dd, J ) 11.9, 2.1 Hz, 1H), 1.56-2.55 (m,
2H); 13C NMR δ 33.97, 38.95, 51.80, 54.65, 56.62, 73.16, 75.48,
79.87, 84.88, 127.68, 127.74, 127.90, 128.01, 128.42, 128.62,
137.69, 138.28, 138.57, 172.73. Anal. Calcd for C30H32O6: C,
73.75; H, 6.60. Found: C, 73.72; H, 6.57.
Meth yl (2E,4R,5R,6S)-4,5,6-Tr is(ben zyloxy)-2,7-octa d i-
en oa te (32). To a solution of oxalyl chloride (0.23 mL, 2.64
mmol) in dry CH2Cl2 (7 mL) at -78 °C was added DMSO (0.39
mL, 5.50 mmol) in CH2Cl2 (2 mL) over 10 min, and the mixture
was stirred for 20 min. A solution of alcohol 30b (0.5 g, 1.20
mmol) in CH2Cl2 (2 mL) was added dropwise over 10 min. After
40 min of stirring at -78 °C, Et3N (0.91 mL, 6.65 mmol) was
added, and the resulting white slurry was stirred for another
15 min and allowed to warm slowly to -30 °C.
To the above mixture at -30 °C was added methyl (triph-
enylphosphoranylidene) acetate (0.84 g, 2.64 mmol) in one
portion, and the resulting mixture was stirred for 6 h while it
was allowed to warm gradually to room temperature. Water
was added, and the layers were separated. The aqueous layer
was further extracted with CH2Cl2, and the combined organic
phases were washed with brine and worked up. The residue
was chromatographed with 10-30% EtOAc/hexanes to afford
unsaturated ester 32 (0.50 g, 88%) as a colorless oil: [R]D +3.0
Meth yl 2-[(1S,4S,5R,6R)-4,5,6-Tr is(ben zyloxy)-2-cyclo-
h exen yl]a ceta te (29). To a CH2Cl2 solution of divinyl ester
33 (1.0 g, 2 mmol) under N2 was added 0.1 equiv of bis-
(tricyclohexylphosphine)benzylideneruthenium dichloride (0.17
g, 0.2 mmol; Strem Inc.) at room temperature. The dark red
solution was stirred for 24 h. Another 0.04 equiv of catalyst
1
(c 1.0, CHCl3); IR 1719 cm-1; H NMR δ 7.27-7.31 (m, 15H),
6.87 (dd, J ) 15.8, 6.2 Hz, 1H), 6.02 (dd, J ) 15.8, 1.1 Hz,

Synthesis of (+)-Cyclophellitol
J . Org. Chem., Vol. 63, No. 22, 1998 7929
1H), 5.83 (m, 1H), 5.27 (s, 1H), 5.22 (d, J ) 2.9 Hz, 1H), 4.73
(s, 2H), 4.58 (dd, J ) 11.6, 7.2 Hz, 2H), 4.35 (dd, J ) 11.5, 8.7
Hz, 2H), 4.22 (dt, J ) 5.8, 1.1 Hz, 1H), 3.99 (dd,J ) 7.5, 4.9
Hz, 1H), 3.74 (s, 3H), 3.48 (t, J ) 5.0 Hz, 1H); 13C NMR δ 51.66,
70.72, 71.86, 75.37, 79.13, 80.78, 83.51, 119.04, 122.79, 127.62,
127.71, 127.81, 128.07, 128.17, 128.26, 128.41, 128.58, 135.34,
137.83, 138.15, 138.25, 145.57, 166.49; HRMS (CI) calcd for
CO, 1H), 2.47 (d, J ) 7.3 Hz, CH(O)CO, 1H); LRMS (CI) (M +
H)+ m/e 475.
(3a R,4R,5S,6R,7R,7a R)-4,5,6-Tr is(ben zyloxy)-7-iod op -
er h yd r oben zo[b]fu r a n -2-on e (37). To a THF (40 mL)
solution of ester 29 (0.89 g, 1.9 mmol) was added LiOH (0.46
g, 19.2 mmol) in H2O (30 mL), and the resulting mixture was
stirred for 4 h. The reaction mixture was carefully neutralized
with concentrated HCl and then treated with KHCO3 (1.13 g,
11.3 mmol) and KI (0.78 g, 4.7 mmol). After 5 min, I2 (2.1 g,
8.3 mmol) was added, and the mixture was stirred for another
6 h. Saturated Na2S2O3 (30 mL) was added, and the mixture
was extracted with Et2O. The combined organic layers were
washed with brine and worked up. The crude residue was
chromatographed with 5-20% EtOAc/hexanes to afford iodo
lactone 37 (1.01 g, 92%) as a white solid: mp 138 °C; [R]D +29.9
C
30H33O5 (M + H)+ m/e 473.2328, found m/e 473.2294.
Meth yl (3S,4R,5R,6S)-4,5,6-Tr is(ben zyloxy)-3-vin yl-7-
octen oa te (33). To a slurry of CuI (3.2 g, 16.3 mmol), which
was weighed in a glovebox, in THF (100 mL) at -78 °C was
added vinylmagnesium bromide (1.0 M in THF, 33 mL, 32.6
mmol) via an addition funnel. The resulting mixture was
stirred for 40 min and treated with chlorotrimethylsilane (4.4
mL, 35 mmol) followed by the addition of unsaturated ester
32 (1.1 g, 2.3 mmol) in THF (4 mL) at -78 °C. Stirring was
continued for 2 h, and then the reaction mixture was treated
with concentrated NH4OH and saturated NH4Cl (200 mL) at
-78 °C. After being warmed to room temperature, the reaction
mixture was diluted with ether and the layers were separated.
The aqueous layer was extracted with ether, and the combined
organic layers were washed with brine and worked up. The
residue was chromatographed with 5-15% EtOAc/hexanes to
afford divinyl ester 33 (1.06 g, 90%) as an oil: [R]D +32.3 (c
2.1, CHCl3); IR 1729 cm-1; 1H NMR δ 7.26-7.40 (m, 15H), 5.90
(m, 1H), 5.74 (m, 1H), 5.35 (s, 1H), 5.30 (d, J ) 4.2 Hz, 1H),
5.01 (m, 2H), 4.35-4.82 (m, 6H), 4.07 (t, J ) 6.5 Hz, 1H), 3.70
(t, J ) 5.5 Hz, 1H), 3.57-3.61 (m, 1H), 3.58 (s, 3H), 2.98 (m,
1H), 2.63 (dd, J ) 15.2, 4.1 Hz, 1H), 2.41 (dd, J ) 15.3, 9.8
Hz, 1H); 13C NMR δ 35.27, 42.05, 51.50, 70.68, 73.46, 74.99,
81.16, 82.55, 116.71, 119.08, 127.46, 127.51, 127.66, 128.09,
128.17, 128.31, 128.38, 135.46, 138.26, 138.68, 138.78, 138.82,
173.17. Anal. Calcd for C32H36O5: C, 76.77; H, 7.25. Found:
C, 76.72; H, 7.29.
Meth yl 2-[(1R,2R,3R,4R,5S,6R)-2,3-Di(a cetyloxy)-4,5,6-
tr i(ben zyloxy)cycloh exyl]a ceta te (35). A mixture of ester
25 (8.1 mg, 0.017 mmol) and K2CO3 (40 mg, 0.28 mmol) in
25% aqueous MeOH (1.0 mL) at room temperature was stirred
for 20 h. The mixture was diluted with H2O, acidified to pH
4 with 1 N HCl, and extracted with EtOAc. The combined
organic layers were washed with brine and worked up as usual
to afford crude dihydroxy acid 34 (6.4 mg, 78%) as a semisolid.
The crude acid was esterified with ethereal diazomethane and
used without purification.
To a solution of the dihydroxy ester in CH2Cl2 (0.4 mL) at
room temperature was added pyridine (10 µL, 0.12 mmol) and
acetic anhydride (10 mL, 0.11 mmol) followed by a catalytic
amount of DMAP (“one crystal”). After being stirred for 1 h,
the mixture was treated with H2O and extracted with CH2Cl2
(3 × 3 mL). Workup afforded diacetate 35 (4.0 mg, 40% from
25) as a colorless oil: 1H NMR δ 7.29-7.34 (m, 15H), 5.43 (t,
J ) 3.5 Hz, CHOAc, 1H), 5.12 (t, J ) 3.0 Hz, CHOAc, 1H),
5.03 (d, J ) 11.0 Hz, 1H), 4.96 (d, J ) 10.6 Hz, 1H), 4.78 (d,
J ) 10.6 Hz, 1H), 4.73 (d, J ) 11.1 Hz, 1H), 4.57 (d, J ) 8.6
Hz, 1H), 4.54 (d, J ) 8.9 Hz, 1H), 3.90 (t, J ) 9.3 Hz, 1H),
3.76 (dd, J ) 9.3, 3.1 Hz, 1H), 3.54 (s, CH3O, 3H), 3.48 (m,
1H), 2.56-2.69 (m, 2H), 2.16-2.23 (m, 1H), 2.17 (s, OC(O)-
CH3, 3H), 2.05 (s, OC(O)CH3, 3H); HRMS (CI) calcd for
C34H39O9 (M + H)+ m/e 591.2594, found m/e 591.2594.
1
(c 1.4, CHCl3); IR 1785 cm-1; H NMR δ 7.30-7.48 (m, 15H),
4.96 (m, 2H), 4.88 (d, J ) 11.0 Hz, 1H), 4.76 (m, 2H), 4.69 (m,
2H), 4.62 (d, J ) 11.1 Hz, 1H), 3.99 (t, J ) 7.2 Hz, 1H), 3.43
(dd, J ) 10.1, 8.4 Hz, 1H), 3.34 (m, 1H), 2.98 (m, 1H), 2.70
(dd, J ) 17.1, 7.3 Hz, 1H), 2.53 (d, J ) 17.6 Hz, 1H); 13C NMR
δ 28.14, 35.03, 39.13, 72.77, 74.24, 75.28, 78.78, 79.67, 83.36,
83.85, 128.10, 128.18, 128.58, 128.67, 137.31, 137.79, 174.90.
LRMS (CI) (M + H)+ m/e 585. Anal. Calcd for C29H29O5I: C,
59.60; H, 5.00. Found: C, 59.53; H, 5.06.
(3a R,4R,5S,6R,7R,7a R)-4,5,6-Tr is(ben zyloxy)-7-iod op -
er h yd r oben zo[b]fu r a n -2-ol (38). To a solution of lactone
37 (0.35 g, 0.60 mmol) in ether (5 mL) and CH2Cl2 (2 mL) at
-78 °C was added dropwise DIBAL-H (0.12 mL, 0.67 mmol)
in hexane (0.6 mL) over a period of 20 min. After 40 min,
precooled methanol (0.3 mL) was added slowly, and the
reaction mixture was allowed to warm to room temperature.
Rochelle’s salt solution (15 mL of 30% aqueous sodium
potassium tartrate) was added, and the mixture was stirred
until two clear layers appeared. The organic layer was
separated and washed with another 10 mL of Rochelle’s salt
solution. The combined aqueous portions were extracted with
Et2O, and the organic phases were combined, washed with
brine, and worked up. The crude residue was chromato-
graphed with 20-40% EtOAc/hexanes to afford lactols 38 (0.30
g, 85%) as an oil: [R]D +34.5 (c 1.3, CHCl3); IR 3597 cm-1; 1H
NMR: major δ 7.41-7.27 (m, 15H), 5.53 (m, 1H), 4.54-4.95
(m, 8H), 3.96 (m, 1H), 3.33 (t, J ) 9.4 Hz, 1H), 3.25 (dd, J )
7.0, 3.3 Hz, 1H), 2.74 (bm, 1H), 2.62 (bm, 1H), 2.16 (m, 1H),
minor (partial) δ 4.07 (dd, J ) 11.1, 8.2 Hz, 1H); 3.52 (m, 1H);
1.91-2.00 (m, 2H); 13C NMR: mixture δ 31.12, 32.69, 37.11,
38.60, 40.66, 42.04, 72.26, 72.41, 73.86, 74.64, 75.17, 79.00,
80.24, 81.00, 81.56, 81.61, 84.32, 84.50, 84.62, 98.44, 98.96,
127.77, 127.93, 128.02, 128.13, 128.18, 128.53, 137.80, 137.86,
138.28, 138.41. Anal. Calcd for C29H31O5I: C, 59.39; H, 5.33.
Found: C, 59.51; H, 5.33.
(1R,2R,3R,4S,5R,6R)-3,4,5-Tr is(ben zyloxy)-2-iod o-6-(io-
d om eth yl)cycloh exyl for m a te (39). A solution of iodolactol
38 (0.30 g, 0.51 mmol) in dry cyclohexane (34 mL) containing
iodobenzene diacetate (0.20 g, 0.62 mmol) and I2 (0.15 g, 0.59
mmol) was irradiated with a 500 W tungsten lamp at 4-20
°C for 2 h. To the reaction mixture was added saturated
aqueous Na2S2O3 (20 mL) and H2O (30 mL). The two layers
were separated, and the aqueous layer was extracted with
EtOAc/hexanes (1:4) and worked up. The residue was chro-
matographed with 0-20% EtOAc/hexanes to afford diiodo
formate 39 (0.2 g, 78%) as a colorless oil: [R]D +31.3 (c 0.77,
(3a R,4R,5S,6S,7R,7a R)-4,5,6-Tr is(ben zyloxy)-7-h yd r ox-
yp er h yd r oben zo[b]fu r a n -2-on e (36). A solution of acid 34
(3 mg, 0.006 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimide hydrochloride (3 mg, 0.014 mmol), and i-Pr2NEt (1
drop) in CH2Cl2 (0.4 mL) was stirred for 1 h. The reaction
mixture was diluted with CH2Cl2 and washed with H2O and
brine. Workup and chromatography with 10-30% EtOAc/
hexanes afforded lactone 36 (1.5 mg, 52%) as an oil: IR 3690,
1
CHCl3); IR 1733 cm-1; H NMR δ 7.98 (s, 1H), 7.29-7.40 (m,
15H), 5.60 (bs, 1H), 4.96 (dd, J ) 10.7, 2.8 Hz, 2H), 4.80 (d, J
) 11.1 Hz, 1H), 4.70 (d, J ) 11.1 Hz, 1H), 4.61-4.56 (m, 2H),
3.94 (t, J ) 9.2 Hz, 1H), 3.51-3.60 (m, 1H), 2.97 (dd, J ) 9.2,
4.2 Hz, 1H), 2.91 (m, 2H); 13C NMR δ 2.90, 30.28, 42.93, 71.99,
75.19, 75.79, 76.81, 80.27, 84.55, 127.78, 128.02, 128.05,
128.11, 128.16, 128.54, 128.59, 159.18; HRMS (FAB) calcd for
1
1786 cm-1; H NMR δ 7.32-7.43 (m, 15H), 4.97 (d, J ) 11.4
C
29H29O5I2 (M - H)+ m/e 711.0105, found m/e 711.0104.
(1a R,2R,3R,4S,5R,5a R)-2,3,4-Tr is(b en zyloxy)-5-(iod o-
Hz, 1H), 4.88 (d, J ) 11.0 Hz, 1H), 4.82 (d, J ) 11.5 Hz, 1H),
4.78 (d, J ) 11.2 Hz, 1H), 4.73 (d, J ) 11.5 Hz, 1H), 4.63 (d,
J ) 10.9 Hz, 1H), 4.61 (d, J ) 5.1 Hz, CHOC(O), 1H), 4.32
(dd, J ) 6.4, 3.0 Hz, CHOH, 1H), 3.95 (t, J ) 7.9 Hz, 1H),
3.77 (dd, J ) 7.3, 3.0 Hz, 1H), 3.38 (d, J ) 9.9, 8.7 Hz, 1H),
2.71-2.81 (m, CHCH2, 1H), 2.65 (dd, J ) 17.7, 7.4 Hz, CH(O)-
m eth yl)p er h yd r o-1-ben zoxir en e (40). To a solution of
diiodoformate 39 (0.32 g, 0.45 mmol) in THF (4.4 mL) and H2O
(1.2 mL) was added KOH (76 mg, 1.36 mmol). After being
stirred for 3 h, the reaction mixture was diluted with H2O and
neutralized with 1 N HCl. The mixture was diluted with H 2O

7930 J . Org. Chem., Vol. 63, No. 22, 1998
Ziegler and Wang
and Et2O. The combined extracts were washed with brine and
worked up. The residue was chromatographed with 0-15%
EtOAc/hexanes to yield iodo epoxide 40 (0.19 g, 76%) as a white
solid: mp 83 °C; [R]D +60.9 (c 0.95, CHCl3); 1H NMR δ 7.26-
7.36 (m, 15H), 4.94 (d, J ) 11.0 Hz, 1H), 4.71-4.89 (m, 4H),
4.55 (d, J ) 10.9 Hz, 1H), 3.92 (d, J ) 8.2 Hz, 1H), 3.49-3.60
(m, 3H), 3.19-3.28 (m, 3H), 2.29 (m, 1H); 13C NMR δ 4.79,
44.29, 53.80, 56.94, 73.22, 75.47, 75.85, 79.69, 84.88, 127.74,
127.89, 128.04, 128.10, 128.46, 128.61, 137.60, 138.02, 138.48;
HRMS (FAB) calcd for C28H30O4I M+ m/e 557.1189, found m/e
557.1188.
2-[(1a R,2R,3R,4S,5R,5a R)-3,4,5-Tr is(ben zyloxy)p er h y-
d r o-1-ben zoxir en -2-yl]a cetic Acid (41a ). To a solution of
ester 27 (0.10 g, 0.20 mmol) in THF (6 mL) was added a 0.2 M
LiOH solution (4.2 mL, 0.84 mmol) in 3 portions over 5 h, and
the resulting mixture was stirred overnight. The mixture was
concentrated in vacuo, diluted with H2O, acidified to pH 4 with
1 N HCl, and extracted with EtOAc. The combined organic
layers were washed with brine and worked up to afford crude
acid 41b (95 mg, 94%) as a colorless semisolid: [R]D +74.1 (c
1.05, CHCl3); IR 3511-3069 (b), 1712 cm-1; 1H NMR δ 7.27-
7.37 (m, 15H), 4.95 (d, J ) 11.0 Hz, 1H), 4.87 (d, J ) 11.0 Hz,
1H), 4.84 (d, J ) 11.4 Hz, 1H), 4.82 (d, J ) 11.6 Hz, 1H), 4.73
(d, J ) 11.4 Hz, 1H), 4.51 (d, J ) 11.1 Hz, 1H), 3.88 (d, J )
8.2 Hz, 1H), 3.58 (dd, J ) 9.1, 8.7 Hz, 1H), 3.35 (d, J ) 3.3 Hz,
1H), 3.22 (d, J ) 7.0 Hz, 1H), 3.19 (d, J ) 8.8 Hz, 1H), 2.73-
2.80 (m, 1H), 2.46-2.56 (m, 2H); 13C NMR δ 34.15, 38.81,
54.71, 56.55, 73.17, 75.52, 76.75, 79.83, 84.87, 127.74, 127.84,
127.91, 127.96, 128.07, 128.46, 128.51, 128.64, 137.70, 138.18,
138.54, 178.49; HRMS (CI) calcd for C29H29O6 (M - H)+ m/e
473.1964, found m/e 473.1955.
[(1aR,2R,3R,4S,5R,5aR)-3,4,5-Tr is(ben zyloxy)per h ydr o-
1-ben zoxir en e-2-yl]m eth a n ol (42) fr om 41a . A round-
bottomed flask containing a solution of acid 41a (16 mg, 0.034
mmol) in CH2Cl2 (1 mL) was wrapped with Al foil. To the
solution at 0 °C was added dithiobis(pyridine N-dioxide) (12
mg, 0.048 mmol) followed by the addition of tri-n-butylphos-
phine (10.2 µL, 0.041 mmol). The reaction mixture was stirred
for 15 min at 0 °C and 2 h at room temperature. The Al foil
was removed, and the reaction mixture was treated with tris-
(phenylthio)antimony (20 mg, 0.043 mmol). After the flask
was purged with oxygen for about 2 min, the mixture was
stirred and exposed to air for 2 h. The mixture was diluted
with CH2Cl2 and washed with 5% NaHCO3 and brine. After
workup, the crude residue was chromatographed with 20-40%
EtOAc/hexanes to afford alcohol 42 (9 mg, 60%) as a colorless
solid. See below for analytical data.
3.18 (d, J ) 3.6 Hz, 1H), 2.20 (m, 1H), 1.95 (dd, J ) 8.0, 3.1
Hz, 1H); 13C NMR δ 44.00, 53.02, 55.96, 62.86, 73.24, 75.44,
75.62, 79.87, 85.00, 127.68, 127.87, 128.03, 128.25, 128.44,
128.61, 137.64, 138.60; HRMS (FAB) calcd for C28H31O5 M+
m/e 447.2171, found m/e 447.2172.
Further elution with 50% EtOAc/hexanes afforded diol 45
(5 mg, 7%) as a white semisolid: 1H NMR δ 7.31-7.40 (m,
10H), 4.97 (d, J ) 11.3 Hz, 1H), 4.83 (d, J ) 10.5 Hz, 1H),
4.68 (t, J ) 10.7 Hz, 2H), 4.04 (dd, J ) 10.8, 6.9 Hz, 1H), 3.93
(dd, J ) 10.8, 4.8 Hz, 1H), 3.84 (d, J ) 7.9 Hz, 1H), 3.51 (t, J
) 9.9 Hz, 1H), 3.41 (t, J ) 9.9 Hz, 1H), 3.29 (bs, 1H), 3.18 (d,
J ) 3.6 Hz, 1H), 2.19 (m, 1H); LRMS (EI) (M - C7H7)+ m/e
265.
(1a R ,2R ,3R ,3a R ,7a S ,7b R )-2,3-Bis(b e n zyloxy)p e r h y-
d r ooxir en o[2′,3′:3,4]ben zo[d ][1,3]d ioxin -5-on e (44). To a
solution of diol 45 (4 mg, 0.01 mmol) and pyridine (9.1 µL,
0.11 mmol) in CH2Cl2 (0.7 mL) at room temperature was added
triphosgene (3.3 mg, 0.01 mmol), and the mixture was stirred
for 2 h. Buffer (pH7) was added, and the aqueous layer was
extracted with CH2Cl2. The combined organic phases were
washed with brine and worked up. The crude residue was
chromatographed with 30% EtOAc/hexanes to afford carbonate
1
44: IR 1760, 1601 cm-1; H NMR δ 7.30-7.40 (m, 10H), 4.97
(d, J ) 11.1 Hz, 1H), 4.76 (s, 1H), 4.74 (d, J ) 9.9 Hz, 1H),
4.63 (dd, J ) 10.3, 5.2 Hz, 1H), 4.47 (t, J ) 11.3 Hz, 1H), 4.26
(t, J ) 10.1 Hz, 1H), 3.97 (d, J ) 6.5 Hz, 1H), 3.68 (dd, J )
10.1, 6.9 Hz, 1H), 3.27 (m, 2H), 2.58 (m, 1H); MS (EI) (M -
C7H7)+ m/e 291.
(1a S,2R,3S,4R,5R,5a R)-5-(Hyd r oxym eth yl)p er h yd r o-1-
ben zoxir en e-2,3,4-tr iol [(+)-Cyclop h ellitol] (1). A solution
of tribenzyl ether 42 (23 mg, 0.05 mmol) in CH3OH (1.5 mL)
containing Pd(OH)2/C (12 mg, 50% w/w) was purged with H2
for 2 min, and the mixture was stirred under atmospheric
hydrogen for 10 h. The suspension was filtered through a pad
of Celite and rinsed with CH3OH (5 mL). The filtrate was
concentrated in vacuo, and the residue was chromatographed
with 10-30% CH3OH/CHCl3 to afford (+)-cyclophellitol (1) (7.8
mg, 85%) as a white solid: [R]D +97.0 (c 0.35, H2O), lit.1 [R]27
D
+103 (c 0.5, H2O); 1H NMR (500 MHz, D2O, DOH at δ 4.80) δ
4.02 (dd, J ) 11.2, 3.8 Hz, 1H), 3.84 (dd, J ) 11.2, 7.5 Hz,
1H), 3.80 (d, J ) 8.5 Hz, 1H), 3.54 (br m, 1H) 3.37-3.41 (m,
1H), 3.25-3.28 (m, 2H), 2.08-2.18 (br m,1H).
Ack n ow led gm en t. This work was supported by
grants from the National Science Foundation and the
Institute of General Medical Sciences of the National
Institutes of Health. We are grateful to Professor
Hanessian (University of Montreal) for experimental
details regarding cuprate preparation, Professor Tatsuta
(Waseda University) for spectra and a sample of syn-
thetic (+)-cyclophellitol, and Professor K. B. Sharpless
(Scripps) for a sample of (DHQ)2PYR(OMe)3.
[(1aR,2R,3R,4S,5R,5aR)-3,4,5-Tr is(ben zyloxy)per h ydr o-
1-ben zoxir en e-2-yl]m eth a n ol (42) a n d (1a R,2R,3R,4S,5R,
5a R)-4,5-Bis(ben zyloxy)-2-(h yd r oxym eth yl)p er h yd r o-1-
ben zoxir en -3-ol (45) fr om 41a. Oxygen was bubbled through
a solution of iodo epoxide 40 (110 mg, 0.20 mmol), n-Bu3SnH
(0.2 mL, 0.74 mmol), and AIBN (36 mg, 0.22 mmol) in toluene
(3 mL) at 60 oC for 1 h. Another portion of n-Bu3SnH (0.05
mL, 0.19 mmol) and AIBN (10 mg, 0.06 mmol) was added as
oxygen was passed through the solution for another 2 h at 60
°C. The reaction mixture was cooled, transferred onto a
column of SiO2, and eluted with hexanes to remove tin
residues. Further elution with 10-45% EtOAc/hexanes (gra-
dient) afforded epoxy alcohol 42 (62 mg, 70%) as a white
solid: mp 92-93 °C; [R]D +71.0 (c 0.9, CHCl3); IR 3690, 3628
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of compounds 10, 13, 14b, 17a ,d , 24a , 25, 28
and precursor, 31, 32, 35, 36, 39, 40, 41a , 42, 44 and 45, which
are lacking combustion analyses, and comparison 1H NMR
spectra of 1 and text describing complete experiments for the
formation of 28 and 31 from aldehyde 10 (21 pages). This
material is contained in libraries on microfiche, immediately
following this article in the microfilm version of the journal,
and can be ordered from the ACS; see any current masthead
for ordering information.
cm-1 1H NMR δ 7.28-7.37 (m, 15H), 4.94 (d, J ) 10.9 Hz,
;
1H), 4.88 (d, J ) 2.0 Hz, 2H), 4.79 (q, J ) 11.5 Hz, 2H), 4.56
(d, J ) 10.9 Hz, 1H), 3.97 (m, 1H), 3.89 (m, 2H), 3.61(t, J )
9.1 Hz, 1H), 3.48 (t, J ) 9.9 Hz, 1H), 3.36 (d, J ) 2.3 Hz, 1H),
J O981211D