Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents

Article abstract of DOI:10.1021/jo0607562

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.

Full text of DOI:10.1021/jo0607562

Synthesis and Biological Evaluation of Aromatic Analogues of
Conduritol F, L-chiro-Inositol, and Dihydroconduritol F Structurally
Related to the Amaryllidaceae Anticancer Constituents
Artem S. Kireev,†,‡ Oleg N. Nadein,† Vincent J. Agustin,† Nancy E. Bush,†
Antonio Evidente,§ Madhuri Manpadi,† Marcia A. Ogasawara,† Shiva K. Rastogi,†
Snezna Rogelj,‡ Scott T. Shors,‡ and Alexander Kornienko*,†
Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology,
Socorro, New Mexico 87801, and Dipartimento di Scienze del Suolo, della Pianta a dell’Ambiente,
UniVersita` di Napoli Federico II, 80055 Napoli, Italy
akornien@nmt.edu
ReceiVed April 11, 2006
Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited
natural abundance and the stereochemically complex structure undermining practical chemical preparation.
Fifteen aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F that possess four
of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These
compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial
C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides
further insight into pancratistatin’s minimum structural requirements for cytotoxicity, particularly the
criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple
aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology
of these important classes of compounds.
Introduction
compounds possessing a carbon substituent in place of a
hydroxyl group are even more difficult synthetic targets due to
the challenge of creating a carbon-carbon bond with stereo-
control. Such compounds, however, are particularly desirable
from the biological perspective. For example, fungal metabolite
cyclophellitol (1) is a potent inactivator of â-glucosidase and a
Inositols, conduritols, and their numerous derivatives continue
to attract a great deal of attention due to their roles in living
organisms1 and, consequently, diverse biological activities.2 In
addition, synthetic chemists have utilized these classes of
compounds as intermediates in the synthesis of natural products
and other biologically relevant complex structures.3 Cyclitol
preparation is challenging due to the dense stereochemistry of
the hydroxylated carbon cycles. Furthermore, analogues of these
(2) (a) Inositol Lipids in Cell Signalling; Michell, R. H., Drummond, A.
H., Downes, C. P., Eds.; Academic: San Diego, CA, 1989. (b) Powis, G.;
Kozikowski, A. P. Inhibitors of myo-Inositol Signalling. In New Molecular
Targets for Cancer Chemotherapy; Kerr, D. J., Workman, P., Eds.; CRC:
Boca Raton, LA, 1994; pp 81-95. (c) Kozikowski, A.; Fauq, A.; Malaska,
M.; Tuchmantel, W.; Ognyanov, V.; Powis, G. Curr. Med. Chem. 1994, 1,
1-12. (d) Schedler, D. J. A.; Baker, D. C. Carbohydr. Res. 2004, 339,
1585-1595.
† Department of Chemistry, New Mexico Institute of Mining and Technology.
‡ Department of Biology, New Mexico Institute of Mining and Technology.
§ Universita` di Napoli.
(1) (a) Posternak, T. The Cyclitols; Holden-Day: San Francisco, CA,
1962. (b) Anderson, L. The Cyclitols. In The Carbohydrates, 2nd ed.;
Pigman, W., Horton, D., Eds.; Academic: San Diego, CA, 1972; Vol. 1A,
pp 519-579.
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Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetrahedron 1990, 46, 3715-3742. (b)
Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. ReV.
1996, 96, 1195-1220.
10.1021/jo0607562 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/22/2006
5694
J. Org. Chem. 2006, 71, 5694-5707

Synthesis and Anticancer EValuation of Arylcyclitols
in in vitro antiviral (RNA) assays due to reduced toxicity.9 A
number of recent reports demonstrate that pancratistatin is
specifically toxic to cancer cells as opposed to normal ones,
whereas the currently used anticancer drugs, such as taxol and
etoposide, are equally toxic to both cell types.11 Pancratistatin’s
clinical development has been hampered in part by its inadequate
supply and this problem continues to be addressed with total
synthesis12 and biotechnological routes.13
The elucidation of the pancratistatin’s cytotoxic pharmaco-
phore and synthesis of structurally simplified analogues is an
alternative strategy, which is currently pursued by a number of
laboratories.14 All three rings A, B, and C have been targeted
to obtain SAR data. The importance of ring B has been
addressed by Chapleur and co-workers, who showed that
lycoricidine analogues with the open ring B (absent C10a-
C10b bond in 5)14a or the ester group in lieu of the amide (6)14h
were both devoid of anticancer activity. Additionally, Hudlicky
and co-workers synthesized the C10b-epimer of 7-deoxy-
pancratistatin (7) and found that it was inactive.14c,d Thus, it
appears that the configuration at the position C10b is critical
for activity as well.
FIGURE 1. Cyclitol analogues with medicinal promise.
(8) (a) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat.
Prod. 1986, 49, 995-1002. (b) Pettit, G. R.; Pettit, G. R., III; Backhaus,
R. A.; Boyd, M. R.; Meerow, A. W. J. Nat. Prod. 1993, 56, 1682-1687.
(9) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kefauver, D. F.; Pettit,
G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J. J.; Shannon, W. M.; Shubert,
E. M.; Dare, J.; Ugarkar, B.; Ussery, M. A.; Phelan, M. J. J. Nat. Prod.
1992, 55, 1569-1581.
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Meijer, L.; Doerig, C.; Desportes-Livage, I. Antimicrob. Agents Chemother.
2001, 45, 3409-3415.
(11) (a) McLachlan, A.; Kekre, N.; McNulty, J.; Pandey, S. Apoptosis
2005, 10, 619-630. (b) Pandey, S.; Kekre, N.; Naderi, J.; McNulty, J. Artif.
Cells, Blood Substitutes, Biotechnol. 2005, 33, 279-295. (c) Kekre, N.;
Griffin, C.; McNulty, J.; Pandey, S. Cancer Chemother. Pharmacol. 2005,
56, 29-38.
FIGURE 2. Amaryllidaceae constituents with anticancer activity and
their ring B analogues.
(12) Eight total syntheses of pancratistatin have been reported to date:
(a) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829-4837.
(b) Tian, X.; Ko¨nigsberger, K.; Hudlicky, T. J. Am. Chem. Soc. 1995, 117,
3643-3644. (c) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.;
Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752-10765. (d) Trost,
B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143-10144. (e)
Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341-5342. (f)
Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000,
122, 6624-6628. (g) Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard,
S.; Haseltine, J. Tetrahedron 1997, 53, 11153-11170. (h) Pettit, G. R.;
Melody, N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583-2587. (i) Kim,
S.; Ko, H. J.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343-1345. (j) Ko, H.
J.; Kim, E.; Park J. E.; Kim, D.; Kim, S. J. Org. Chem. 2004, 69, 112-
121.
promising anti-HIV agent (Figure 1).4 myo-Inositol cyclic
phosphonate analogue 2 is an inhibitor of phosphatidylinositol-
specific phospholipase C.5 Conduritol F analogues 3 and 4 are
nanomolar inhibitors of S. aureus tyrosyl tRNA synthetase.6
Several amaryllidaceae constituents, including pancratistatin,
narciclasine, and their 7-deoxy congeners, have attracted
considerable interest due to their promising anticancer activities
(Figure 2). These natural products incorporate an arylcyclitol
structural motif and a significant body of synthetic work has
shown that the creation of a C10b-stereocenter renders pan-
cratistatin a more challenging synthetic target than narciclasine,
which lacks this stereocenter.7 Pancratistatin has been found to
exhibit strong in vitro cancer cell growth inhibitory activities
against the U.S. National Cancer Institute (NCI) panel of cancer
cell lines as well as a number of in vivo experimental cancer
systems.8 Powerful antiviral9 and antiparasitic10 activities of
pancratistatin constitute a related area of promise. Although less
potent, 7-deoxypancratistatin exhibits a better therapeutic index
(13) Pettit, G. R.; Pettit, G. R., III; Backhaus, R. A.; Boettner, F. E. J.
Nat. Prod. 1995, 58, 37-43.
(14) (a) Chre´tien, F.; Ibn-Ahmed, S.; Masion, A.; Chapleur, Y. Tetra-
hedron 1993, 49, 7463-7478. (b) McNulty, J.; Mao, J.; Gibe, R.; Mo, R.
W.; Wolf, S.; Pettit, G. R.; Herald, D. L.; Boyd, M. R. Bioorg., Med. Chem.
Lett. 2001, 11, 169-172. (c) Rinner, U.; Siengalewicz, P.; Hudlicky, T.
Org. Lett. 2002, 4, 115-117. (d) Hudlicky, T.; Rinner, U.; Gonzales, D.;
Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J.
Org. Chem. 2002, 67, 8726-8743. (e) Phung, A. N.; Zannetti, M. T.;
Whited, G.; Fessner, W.-D. Angew. Chem., Int. Ed. 2003, 42, 4821-4824.
(f) Rinner, U.; Hillebrenner, H. L.; Adams, D. R.; Hudlicky, T.; Pettit, G.
R. Bioorg. Med. Chem. Lett. 2004, 14, 2911-2915. (g) Rinner, U.; Hudlicky,
T.; Gordon, H.; Pettit, G. R. Angew. Chem., Int. Ed. 2004, 43, 5342-5346.
(h) Ibn-Ahmed, S.; Khaldi, M.; Chre´tien, F.; Chapleur, Y. J. Org. Chem.
2004, 69, 6722-6731. (i) Hudlicky, T.; Rinner, U.; Finn, K. J.; Ghiviriga,
I. J. Org. Chem. 2005, 70, 3490-3499. (j) McNulty, J.; Larichev, V.;
Pandey, S. Bioorg. Med. Chem. Lett. 2005, 15, 5315-5318. (k) Pettit, G.
R.; Melody, N. J. Nat. Prod. 2005, 68, 207-211. (l) Moser, M.; Sun, X.;
Hudlicky, T. Org. Lett. 2005, 7, 5669-5672. (m) Pettit, G. R.; Eastham, S.
A.; Melody, N.; Orr, B.; Herald, D. L.; McGregor, J.; Knight, J. C.; Doubek,
D. L.; Pettit, G. R., III; Garner, L. C.; Bell, J. A. J. Nat. Prod. 2006, 69,
7-13.
(4) For a review on the chemistry and biology of cyclophellitol, see:
Marco-Contelles, J. Eur. J. Org. Chem. 2001, 1607-1618.
(5) Wu, Y.; Zhou, C.; Roberts, M. F. Biochemistry 1997, 36, 356-363.
(6) Jarvest, R. L.; Berge, J. M.; Houge-Frydrych, C. S. V.; Mensah, L.
M.; O’Hanlon, P. J.; Pope, A. J. Bioorg. Med. Chem. Lett. 2001, 11, 2499-
2502.
(7) For recent reviews of synthetic work in this area, see: (a) Polt, R.
Amaryllidaceae alkaloids with antitumor activity. In Organic Synthesis:
Theory and Applications; Hudlicky, T., Ed.; JAI Press: New York, 1997;
Vol. 3, p 109. (b) Rinner, U.; Hudlicky, T. Synlett 2005, 365-387.
J. Org. Chem, Vol. 71, No. 15, 2006 5695

Kireev et al.
SCHEME 1
FIGURE 3. Structures of parent cyclitols and their proposed aromatic
analogue series.
available starting material. The application of two Wittig
olefination reactions to a D-xylose-derived intermediate E would
be expected to provide D.
A crucial element in the proposed synthetic plan is the choice
of a hydroxyl protecting group R. The identity of the group R
is dictated in part by the deprotection conditions necessary to
generate the target series from arylconduritols A. Of particular
concern would be the synthesis of the series 8, because an acidic
milieu could potentially cause the double bond isomerization
into conjugation with the aromatic moiety, while hydrogenolytic
conditions would result in olefin hydrogenation. Additionally,
in the transformation D to C, the hydroxyl protecting group is
also a stereochemistry-controlling moiety facilitating an anti-
selective addition. This process would need not only be highly
diastereoselective to avoid potentially troublesome chromato-
graphic separations of epimers, but also general for structurally
diverse aromatic residues.
Due to these potential impediments, we selected two protect-
ing groups MOM and Bn as suitable candidates for our proposed
synthetic sequence and pursued two independent approaches
with each one. Although prior to the initiation of this work there
had been no examples of a highly anti-selective arylcuprate
conjugate addition process to either γ-MOMO- or γ-BnO-R,â-
enoates, various alkyl- and vinylcuprates had been used with
success in these reactions.17
In the pursuit of the synthetic plan utilizing the MOM
protection, we developed a five-step synthesis of enoate 15 from
D-xylose (Scheme 1). Thus, the anomeric position of D-xylose
was protected as benzyl ether following a method that was
reported by Ireland and co-workers for L-arabinose.18 The
mixture of R- and â-benzyl xylopyranosides was treated with
MOMCl in the presence of Hunig’s base in CH2Cl2 and then
hydrogenolyzed at 40 psi for 10 h over 10% Pd/C. Tri-O-
methoxymethyl-D-xylopyranose (13) was obtained in 38% yield
over the three-step sequence. Disappointingly, each of the three
steps requires a chromatographic purification of the product,
complicating the scale-up. Wittig methylenation at the free
anomeric carbon of 13 was achieved by direct treatment with
2.5 equiv of H2CdPPh3 in THF at 50 °C. Both the product
yield and purification are compromised by the side products,
FIGURE 4. Retrosynthetic analysis of the target arylcyclitols.
In our pursuit of a scalable synthesis of pancratistatin and its
aromatic analogues we have identified a series of aromatic
conduritols F (8, Figure 3) as key intermediates.
These compounds, along with the related L-chiro-inositol and
dihydroconduritol F congeners (9 and 10), possess four of the
six pancratistatin stereocenters and serve as truncated pan-
cratistatin analogues lacking the lactam ring B, but retaining
the crucial C10a-C10b bond with the correct stereochemistry.
In this article we report the synthesis and anticancer evaluation
of arylcyclitols 8, 9, and 10, providing further insight into
pancratistatin’s minimum structural requirements for cyto-
toxicity. Significantly, these series provide rare examples of
simple aromatic conduritol and inositol analogues15 and, there-
fore, this study expands the chemistry and biology of these
important classes of compounds.16
Results and Discussion
The penultimate key intermediates, protected arylconduritols
A (Figure 4), would furnish the target series 8, 9, and 10 by
way of the direct removal of the protecting groups R, olefin
dihydroxylation followed by deprotection, and hydrogenation
with the subsequent deprotection, respectively. Further retro-
synthetic sequence includes ring-closing metathesis of dienes
B, terminal double bond installation in esters C, and a
diastereoselective arylcuprate conjugate addition to enoate D.
The relative stereochemistry of the three oxy-stereocenters in
enoate D points to the potential use of D-xylose as a readily
(17) (a) Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998, 63, 426-427. (b)
Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998, 63, 7920-7930. (c) Hanessian,
S.; Sumi, K. Synthesis 1991, 1083-1089. (d) Hanessian, S.; Wang, W.;
Gai, Y.; Olivier, E. J. Am. Chem. Soc. 1997, 119, 10034-10041. (e) Powell,
S. A.; Tenenbaum, J. M.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124,
12648-12649. (f) Zhu, B.; Panek, J. S. Eur. J. Org. Chem. 2001, 1701-
1714.
(15) We thank a reviewer of this manuscript for bringing to our attention
the following two reports: (a) Sollogoub, M.; Mallet, J.-M.; Sinay¨, P.
Angew. Chem., Int. Ed. 2000, 39, 362-364. (b) Sollogoub, M.; Sinay¨, P.
Molecules 2005, 10, 843-858.
(16) The preliminary communication: Nadein, O. N.; Kornienko, A. Org.
Lett. 2004, 6, 831-834.
(18) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. J. Org. Chem. 1983,
48, 5186-5198.
5696 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
SCHEME 2
SCHEME 4
LiAlH4 in ether gives primary alcohol 19, whose subsequent
conversion to arylselenide and selenoxide elimination affords
diene 20. Ring-closing metathesis, performed with the 1st
generation Grubbs’ catalyst in CH2Cl2 at room temperature,
cleanly provides protected arylconduritol 21. Finally, deprotec-
tion without an accompanying double bond migration was
achieved with a dilute solution of HCl in MeOH at 60 °C with
careful monitoring of the reaction mixture by TLC.
SCHEME 3
Thus, the synthetic pathway to the target arylcyclitols has
been developed with use of MOM as a protecting group.
However, we have been frustratingly unsuccessful in our
attempts to scale-up the preparation of enoate 15. In contrast,
our parallel investigation of the synthetic plan based on the Bn
protection had been showing a lot of promise and our initial
concerns over the removal of Bn groups in the presence of the
olefinic functionality in arylconduritols A (see the proposed
synthesis of the series 8 from A in Figure 4) were completely
dispelled after this deprotection had been successfully optimized
with the dissolving metal reduction method. In the remaining
portion of this article we describe the synthesis of the aryl-
cyclitols 8, 9, and 10 using the Bn protection scheme and the
biological evaluation of these compounds.
Enoate 26 had been utilized previously in a total synthesis
of (+)-cyclophellitol and is available from D-xylose via a
synthetic sequence involving eight steps and six chromato-
graphic purifications.17a,b We sought a more practical route,
which could be readily scaled-up. Thus, the mixture of R- and
â-methyl xylosides, prepared by refluxing D-xylose and SOCl2
in methanol, was directly benzylated with inexpensive BnCl/
Bu4NI and NaH (Scheme 4). Hydrolysis of the crude benzylated
anomeric mixture yielded tri-O-benzyl-D-xylopyranose (24),
which was purified by recrystallization from methanol in good
overall yield. This procedure has a significant advantage over
the previously reported methods,20 as it requires neither the
separation of the intermediate xylose anomers nor purification
of the synthetic intermediates. The sequence of Wittig meth-
ylenation at the free anomeric carbon, one-pot Swern oxidation,
and olefination with the commercial Ph3PdCHCO2Me reagent
was significantly higher yielding than the one performed on
the MOM-protected material (Scheme 1). We attribute this
difference in reactivity to the less acidic nature of the R-
benzyloxy position in the aldehyde form of 24 compared to the
R-methyloxymethyl one in the aldehyde form of 13. This high
throughput five-step synthesis involves only one chromato-
graphic purification and it has allowed us to prepare ca. 100 g
of 26.
evidently resulting from the competing deprotonation of the
R-position with the subsequent elimination of the â-methoxy-
methyloxy group. A one-pot Swern oxidation and olefination
with the commercial Ph3PdCHCO2Me reagent, performed
according to a report by Ziegler and co-workers,17a,b gives the
desired enoate 15 in 25% overall yield from 13.
The addition of arylcuprates, derived from the corresponding
aromatic Grignard reagents, to enoate 15 proceeds with exclusive
anti-diastereoselectivities (based on the NMR analysis of crude
and purified reaction mixtures) in acceptable yields (Scheme
2). To confirm the assigned anti-stereochemistry, the addition
product 16a was treated with methanolic HCl to remove the
MOM protection. The resulting triol undergoes lactonization
under the reaction conditions to form 17. Cleavage of the vicinal
diol functionality with NaIO4 followed by treatment of the crude
aldehyde with NaBH4 and Ac2O gives known lactone 18, whose
NMR data are identical with those reported in the literature.19
The completion of the synthetic sequence was investigated
with the arylcuprate addition product 16c. Ester reduction with
(20) (a) Tejima, S.; Ness, R. K.; Kaufman, R. L.; Fletcher, H. G., Jr.
Carbohydr. Res. 1968, 7, 485-490. (b) Tsuda, Y.; Nunozawa, T.;
Yoshimoto, K. Chem. Pharm. Bull. 1980, 28, 3223-3231.
(19) Ha, H.-J.; Yoon, K.-N.; Lee, S.-Y.; Park, Y.-S.; Lim, M.-S.; Yim,
Y.-G. J. Org. Chem. 1998, 63, 8062-8066.
J. Org. Chem, Vol. 71, No. 15, 2006 5697

Kireev et al.
SCHEME 5
SCHEME 6
The reaction of enoate 26 with a broad range of aromatic
organocopper reagents again affords exclusive anti-selectivities
and gives addition products 27a-g in excellent yields (Scheme
5). Similarly to the MOM-based chemistry the sequence
involving ester reduction, selenide formation, selenoxide elimi-
nation, and ring-closing metathesis provides protected aryl-
conduritols 30a-g in good overall yields. Column purification
of 30a-g was made facile by preliminary oxidation of the
ruthenium catalyst with DMSO.21
At this juncture the generation of the target series of
arylcyclitols was attempted. Dihydroxylation of compounds
30a-e with catalytic OsO4 and NMO yields single stereo-
isomeric diols due to much greater steric accessibility of the
R-face of the double bond. These compounds undergo facile
hydrogenolytic cleavage of benzyl ethers when their solutions
in MeOH are stirred under a hydrogen balloon in the presence
of 10% Pd/C catalyst for 2 days, providing the aromatic chiro-
inositol series 9. To generate the series 8, arylconduritols 30a-e
were subjected to the dissolving metal reduction method. To
this end, compounds 30a-e were dissolved in THF and the
resulting mixtures were titrated with a blue solution generated
by the dissolution of chopped Li in liquid ammonia at -78 °C.
After the blue color persisted for 15 s the mixtures were
immediately quenched with solid NH4Cl. Since the benzyl ether
cleavage is faster under these conditions than the reduction of
the aromatic or olefinic moieties, the utilization of this technique
allowed us to avoid overreduction and prepare the aromatic
conduritol F series 8 in consistently good yields. Finally, the
exhaustive hydrogenation of 30a-e over 10% Pd/C removes
the benzyl protection and reduces the olefinic functionality to
afford the aromatic dihydroconduritol F series 10. Unfortunately,
we were unable to deprotect the halogen-containing aryl-
conduritols 30f and 30g without a loss of the halogen atom.
The unsubstituted phenyl group-containing arylcyclitols 8a, 9a,
and 10a were produced from these compounds under both
hydrogenolytic and the Li/NH3 deprotection conditions.
cuprate conjugate addition reactions, we searched for unambigu-
ous proof of stereochemistry through NOE experiments. To this
end arylconduritol 30c was converted to arylinositol derivative
31 by dihydroxylating the double bond, isopropylidenating the
newly introduced cis diol, and thereafter O-debenzylating
(Scheme 6). The cis ring fusion forced the inositol ring into a
boat conformation; the proximity of H1 and H4 could clearly
be detected by NOE difference experiments. Additionally, the
NMR spectra of arylconduritol 8e obtained by using either
MOM-based (Scheme 3) or Bn-based approaches (Scheme 5)
are indistinguishable.
Due to unavailability of pancratistatin, biological evaluation
of the synthesized arylcyclitols was performed with the use of
anticancer amaryllidaceae metabolites lycorine and narciclasine
as positive controls. This choice is justified by the similar
activity profiles and potencies of narciclasine and pancratistatin.8
Since lycorine is the most abundant amaryllidaceae alkaloid,
its isolation from Sternbergia lutea Ker Gawl by using a
procedure reported by Evidente and co-workers22 was straight-
forward and provided 11.22 g/kg of dry bulbs. To obtain
narciclasine various isolation methods and plant sources were
investigated. The base extraction method reported by Evidente
was found to be the most efficient and high yielding.23 When
applied to Narcissus pseudonarcissus King Alfred grown in New
Mexico, it resulted in the isolation yield of 170.4 mg/kg of dry
1
Although H NMR analyses of the cyclized products sup-
ported our original anti-stereochemistry assignment in aryl-
(21) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411-
1413.
(22) Evidente, A.; Iasiello, I.; Randazzo, G. Chem. Ind. 1984, 348-349.
(23) Evidente, A. Planta Med. 1991, 57, 293-295.
5698 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
FIGURE 5. Biological evaluation of the arylcyclitol series. (A) Effect of lycorine (light gray, shaded columns), narciclasine (dark gray, shaded
columns), solvent control (0.1% DMSO in RPMI-1640 10% FBS medium, black column), and any compound from the series 8, 9, or 10 (open
columns) on the survival of Jurkat cells in Trypan Blue dye exclusion assay. (B) Induction of apoptosis in Jurkat cells treated for 20 h with lycorine
(light gray, shaded columns), narciclasine (dark gray, shaded columns), solvent control (0.1% DMSO in RPMI-1640 10% FBS medium, black
column), and any compound from the series 8, 9, or 10 (open columns) in flow cytometric annexin-V/propidium iodide assay. (C) Effect of lycorine
(1 µM, black circle marker), narciclasine (0.05 µM, triangle marker), 8a (300 µM, square marker), and any other compound from the series 8, 9,
or 10 (300 µM, open circle marker) on the growth of Jurkat cells estimated by the Trypan Blue dye exclusion method. Untreated Jurkat cells and
a solution of 0.1% DMSO in RPMI-1640 10% FBS medium were used as controls (open circle marker). (D) Growth inhibitory properties of 8a
toward Jurkat cells in Sulforhodamine B (SRB) assay.
bulbs. To our knowledge, this is the second highest yield
reported for the isolation of this natural product and represents
a 2-fold increase relative to other isolation methods that had
been previously used with this Narcissus species.24
further studies are underway in our laboratories to elucidate the
origin of narciclasine’s anticancer properties.
Conclusions
Arylcyclitol series 8a-e, 9a-e, and 10a-e, along with
lycorine and narciclasine, were assayed for cytotoxic, apoptosis-
inducing, and growth inhibitory properties with use of Jurkat
and HeLa cell lines as models for human T-cell leukemia and
adenocarcinoma, respectively. The results with Jurkat cells are
given in Figure 5. While both lycorine and narciclasine showed
consistent dose-dependent activities in all three assays, almost
all of the synthesized arylcyclitols were inactive in up to 300
µM concentrations. The only exception is weak cell growth
The lack of activity of aromatic analogues of conduritol F,
L-chiro-inositol, and dihydroconduritol F that possess four of
the six pancratistatin stereocenters provides further insight into
pancratistatin’s minimum structural requirements for cyto-
toxicity, particularly the criticality of the intact phenantridone
skeleton. Significantly, these compounds provide rare examples
of simple aromatic conduritol and inositol analogues and,
therefore, this study expands the chemistry and biology of these
important classes of compounds. Another notable finding of this
study involves high anti-selectivities in arylcuprate conjugate
addition reactions to both tri-γ,δ,ꢀ-OMOM-enoate 15 and tri-
γ,δ,ꢀ-OBn-enoate 26. We have studied the origin of these high
diastereoselectivities in detail27 and recently proposed a new
reductive elimination-based stereochemical model27b for this
process.
inhibitory activity of phenylconduritol F analogue 8a (GI50
∼
300 µM, Figure 5C,D). Since none of the oxygenated aromatic
conduritol F analogues, whose structures more closely resemble
those of the potent natural products (especially 8c, 8d, and 8e),
exhibit any growth inhibitory properties, this activity is likely
due to a different mode of action. Notably, narciclasine, which
is considerably more potent than lycorine, induces apoptosis in
Jurkat cells in submicromolar concentrations. Although it is
generally accepted that narciclasine is a potent cytotoxic natural
product and a promising anticancer drug,25 its mechanism of
action is still poorly understood.26 On the basis of these findings,
(24) Piozzi, F.; Marino. M. L.; Fuganti, C.; Di Martino, A. Phytochem-
istry 1969, 8, 1745-1748.
(25) See: Pettit, G. R.; Melody, N.; Simpson, M.; Thompson, M.; Herald,
D. L.; Knight, J. C. J. Nat. Prod. 2003, 66, 92-96 and references therein.
(26) (a) Carrasco, L.; Fresno, M.; Vazquez, D. FEBS Lett. 1975, 52,
236-239. (b) Jimenez, A.; Sanchez, L.; Vazquez, D. FEBS Lett. 1975, 55,
53-56. (c) Jimenez, A.; Santos, A.; Alonso, G.; Vasquez, D. Biochim.
Biophys. Acta 1976, 425, 342-348.
J. Org. Chem, Vol. 71, No. 15, 2006 5699

Kireev et al.
76.3, 76.2, 64.5, 61.1, 56.2, 56.0, 55.9, 55.7, 55.6; HRMS m/z (ESI)
calcd for C11H22O8Na (M + Na)+ 305.1207, found 305.1216.
(2R,3R,4S)-2,3,4-Tri(methoxymethyloxy)-5-hexene-1-ol (14).
To a stirred suspension of methyltriphenylphosphonium bromide
(15.8 g, 44.3 mmol) in THF (50 mL) was added BuLi (17.7 mL of
2.5 M solution in hexanes, 44.3 mmol) dropwise at 0 °C. The
mixture was stirred for 2 h at room temperature. To the above red
solution was added 13 (5.0 g, 17.7 mmol) in THF (50 mL) dropwise
at 45-50 °C with continued stirring overnight at this temperature.
NH4Cl (1 M, 50 mL) was added at room temperature to the reaction
mixture and the latter was extracted with ether (3 × 100 mL). The
organic extracts were combined, washed with brine, and dried
(MgSO4). After removal of the solvent under reduced pressure, the
residue was adsorbed on silica gel and purified by chromatography
with gradients: 40%, 50%, 60% EtOAc/hexanes, to obtain 3.02 g
Thus, we showed that a single γ-alkoxy stereocenter is
sufficient to attain very high anti-selectivities, and that if a group
R is sterically demanding then the transition state leading to
the anti-product is favored on the basis of both stereoelectronic
and steric considerations. In this study we found that the identity
of the γ-alkoxy group (MOMO vs BnO) is inconsequential and
the δ- and ꢀ-alkoxy groups are unlikely to contribute to the
control of stereochemistry. These observations are fully con-
sistent with our proposed model.
Finally, we provided a recommendation for a convenient
isolation of narciclasine and reported its potent apoptosis
inducing properties. This work is expected to encourage further
efforts to understand the mechanism of action of these natural
products and develop their active structurally simplified ana-
logues for clinical investigations.
1
(60.8%) of 14; Rf 0.23 (50% EtOAc/hexanes); H NMR (CDCl3)
δ 5.70 (ddd, J ) 17.9, 10.2, 8.0 Hz, 1H), 5.31-5.25 (m, 2H), 4.85
(d, J ) 6.6 Hz, 1H), 4.69 (d, J ) 6.6 Hz, 1H), 4.65 (d, J ) 6.9 Hz,
1H), 4.64 (d, J ) 6.6 Hz, 1H), 4.57 (d, J ) 6.9 Hz, 1H), 4.51 (d,
J ) 6.6 Hz, 1H), 4.27 (app t, J ) 7.2 Hz, 1H), 3.75-3.65 (m, 3H),
3.38 (s, 3H), 3.36 (s, 3H), 3.31 (s, 3H); 13C NMR (CDCl3) δ 134.4,
119.8, 98.9, 98.1, 94.1, 81.4, 79.9, 77.9, 62.8, 56.5, 56.1, 55.8;
HRMS m/z (ESI) calcd for C12H24O7Na (M + Na)+ 303.1444, found
303.1419.
Experimental Section
Mixture of R- and â-Benzyl D-Xylopyranosides (11). To
stirring benzyl alcohol (50 mL) was added acetyl chloride (2 mL)
followed by D-xylose (10 g, 66.7 mmol) and the resulting mixture
was stirred for 24 h at 50 °C. The cold reaction mixture was then
dissolved in 500 mL of CH2Cl2, and the solution was run through
a silica gel pad. After the solution was washed with CH2Cl2 (500
mL), R- and â-benzyl D-xylopyranosides were eluted with 10%
MeOH/CH2Cl2 solution (500 mL). The solvent was removed under
reduced pressure to give virtually pure residue (11.8 g, yield 73.8%),
which was used in the next step without additional purification.
Mixture of R- and â-Benzyl 2,3,4-Tri-O-methoxymethyl-D-
xylopyranosides (12). To a stirred solution of R- and â-benzyl
D-xylopyranosides (15 g, 62.5 mmol) in dichloromethane (250 mL)
at room temperature were added diisopropylethylamine (97.8 mL,
0.56 mol) and methoxymethyl chloride (28.5 mL, 0.38 mol) over
a 10 min period. The reaction mixture was stirred for 12 h. Saturated
aqueous NH4Cl solution (100 mL) was then added. The organic
layer was separated, washed with 0.2 M HCl (2 × 200 mL), water
(200 mL), and brine (100 mL), dried with anhydrous MgSO4, and
concentrated under reduced pressure. The residue was adsorbed on
silica gel and eluted with gradients: 10%, 30% EtOAc/hexanes
(500 mL) to obtain 19 g (82%) of 12; Rf 0.70 (50% EtOAc/hexanes);
1H NMR (CDCl3) δ 7.39-7.23 (m, 5H), 4.92 (d, J ) 3.6 Hz, 1H),
4.84 (d, J ) 6.6 Hz, 1H), 4.77 (d, J ) 6.3 Hz, 1H), 4.76 (d, J )
6.9 Hz, 1H), 4.74 (d, J ) 12.1 Hz, 1H), 4.72 (d, J ) 6.9 Hz, 1H),
4.64 (d, J ) 6.9 Hz, 1H), 4.61 (d, J ) 6.6 Hz, 1H), 4.51 (d, J )
12.1 Hz, 1H), 3.91 (app t, J ) 9.1 Hz, 1H), 3.75 (dd, J ) 16.5,
11.8 Hz, 1H), 3.62-3.56 (m, 2H), 3.75 (dd, J ) 9.6, 3.6 Hz, 1H),
3.39 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H); 13C NMR (CDCl3) δ 137.1,
128.4, 128.3, 127.9, 98.0, 97.4, 96.7, 78.6, 77.2, 77.1, 76.7, 69.1,
60.7, 55.9, 55.6, 55.4; HRMS m/z (ESI) calcd for C18H28O8Na (M
+ Na)+ 395.1676, found 395.1690.
2,3,4-Tri-O-methoxymethyl-D-xylopyranose (13). A solution
of 12 (6.5 g, 17.5 mmol) in THF (100 mL) underwent hydro-
genolysis (40 psi) in the presence of 10% Pd/C catalyst (10 mol
%) for 12 h. The resulting solution was filtered from the catalyst,
concentrated under reduced pressure, presorbed on silica gel, and
purified by chromatography with gradients: 30% EtOAc/hexanes,
50% EtOAc/hexanes to recover unreacted 12 followed by 5% and
10% MeOH/CH2Cl2 to obtain 13 (3.02 g, 61.3%); Rf 0.28 (50%
EtOAc/hexanes); 1H NMR (CDCl3) δ 5.21 (m, 1H), 4.89-4.71 (m,
5H), 4.65 (d, J ) 6.6 Hz, 1H), 4.55 (app t, J ) 3.4 Hz, 1H), 4.41
(m, 1H), 4.19 (dd, J ) 9.6, 3.6 Hz, 1H), 3.89 (app t, J ) 7.2 Hz,
1H), 3.79 (m, 1H), 3.70-3.49 (m, 2H), 3.47 (s, 3H), 3.41 (s, 3H),
3.36 (s, 3H), 3.27 (m, 1H), 3.09 (m, 1H); 13C NMR (CDCl3) δ
98.4, 97.8, 97.7, 97.6, 97.2, 97.1, 96.6, 92.4, 82.6, 78.9, 78.4, 76.6,
Methyl (2E,4R,5R,6S)-4,5,6-Tri(methoxymethyloxy)-2,7-octa-
dienoate (15). To oxalyl chloride (11.9 mL of 2 M in CH2Cl2,
23.7 mmol) in dry CH2Cl2 (50 mL) at -78 °C was added DMSO
(3.5 mL, 49.6 mmol) in CH2Cl2 (20 mL) over 10 min and the
mixture was stirred for 20 min. Alcohol 14 (3.02 g, 10.8 mmol) in
CH2Cl2 (20 mL) was added over 10 min and the mixture was stirred
for an additional 10 min period. Triethylamine (14.5 mL, 96 mmol)
in CH2Cl2 (20 mL) was added over 10 min and the white slurry
was stirred for 20 min at -78 °C. To the cold reaction mixture
was added methyl (triphenylphosphoranylidene)acetate (7.2 g, 21.6
mmol) in one portion, and the resulting mixture was stirred for 10
h while it was allowed to warm to room temperature. Water (200
mL) was added to the reaction mixture, the two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
100 mL). The combined organic layers were dried (MgSO4) and
evaporated under reduced pressure. The residual oil was presorbed
on silica gel and purified by chromatography with gradients: 25%,
30%, 35% EtOAc/hexanes to afford enoate 15 (1.48 g, 41.1%) as
a colorless oil; Rf 0.50 (50% EtOAc/hexanes); 1H NMR (CDCl3) δ
7.02 (dd, J ) 18.7, 6.1 Hz, 1H), 6.08 (dd, J ) 15.7, 1.4 Hz, 1H),
5.84 (ddd, J ) 17.6, 10.5, 7.4 Hz, 1H), 5.38-5.32 (m, 2H), 4.84
(d, J ) 6.9 Hz, 1H), 4.78 (d, J ) 6.9 Hz, 1H), 4.69 (d, J ) 6.9 Hz,
1H), 4.64 (s, 2H), 4.57 (d, J ) 6.9 Hz, 1H), 4.45 (m, 1H), 4.27 (m,
1H), 3.74 (s, 3H), 3.65 (app t, J ) 5.0 Hz, 1H), 3.38 (s, 3H), 3.36
(s, 3H), 3.31 (s, 3H); 13C NMR (CDCl3) δ 166.5, 145.5, 134.7,
122.7, 119.5, 98.4, 95.7, 94.4, 81.3, 77.1, 75.9, 56.5, 56.3, 56.1,
51.8; HRMS m/z (ESI) calcd for C15H26O8Na (M + Na)+ 357.1520,
found 357.1516.
General Procedure for Arylcuprate Addition (16). A 1 mL
aryl bromide (15 mmol) solution in THF (30 mL) was added to
magnesium turnings (0.36 g, 15 mmol). Magnesium was crushed
in the flask with a glass rod and the solution started to turn yellowish
and warm. The rest of the aryl bromide solution was added dropwise
to maintain gentle boiling of the stirred reaction mixture. After the
solution was cooled to room temperature Grignard reagent was
transferred to a slurry of CuI (1.43 g, 7.5 mmol) in THF (10 mL)
at -20 °C via cannula. The resulting mixture was stirred at -20
°C for 30 min, then treated with TMSCl (1.63 g, 15 mmol) at -78
°C, followed by the addition of enoate 6 (0.50 g, 15 mmol) in THF
(20 mL). Stirring was continued overnight, while the mixture was
allowed to warm to room temperature. The reaction mixture was
quenched with a mixture of concentrated NH4OH-saturated NH4Cl
(1:9, 50 mL), diluted with ether, and separated. The aqueous layer
was extracted with ether (3 × 100 mL) and the combined organic
layers were washed with brine, dried (MgSO4), and concentrated
(27) (a) Manpadi, M.; Kornienko, A. Tetrahedron Lett. 2005, 46, 4433-
4437. (b) Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org. Chem. 2006,
71, 2630-2640.
5700 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
under reduced pressure. The residue was presorbed on silica gel
and purified by column chromatography (25%, 30%, 35%, 40%
EtOAc/hexanes) to afford exclusively anti-addition products 16a-
c.
was stirred for 28 h. The organic layer was separated, and the
aqueous fraction was extracted with ether (3 × 5 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. The residue was dissolved
in absolute EtOH (2 mL). To this solution at 0 °C was added NaBH4
(0.15 g, 3.9 mmol) in one portion and glacial acetic acid (0.3 mL).
Stirring was continued for 12 h, and then the reaction mixture was
quenched with a mixture of concentrated NH4OH-saturated NH4Cl
(1:8, 90 mL). The aqueous phase was extracted with EtOAc (5 ×
100 mL). The combined organic layers were washed with saturated.
NH4Cl (2 × 100 mL) and brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was dried by coevaporating
with toluene (5 × 1 mL) and dissolved in anhydrous pyridine (3
mL). To this solution at 0 °C was added acetic anhydride (0.196 g,
1.92 mmol). The resulting mixture was allowed to warm to room
temperature and the reaction mixture was stirred for 5 h. The
mixture was extracted with ether (3 × 12 mL). The combined
organic layers were washed with water (10 mL), dried (MgSO4),
and evaporated. The residue was presorbed on silica gel and purified
by column chromatography (5-10% EtOAc/hexanes) to afford
lactone 1819 (42 mg, 91%).
Methyl (3S,4R,5R,6S)-3-Phenyl-4,5,6-tri(methoxymethoxy)-
7-octaenoate (16a). 46.0%; Rf 0.51 (50% EtOAc/hexanes); 1H
NMR (CDCl3) δ 7.31-7.17 (m, 5H), 5.56 (ddd, J ) 18.2, 10.7,
7.4 Hz, 1H), 5.27-5.32 (m, 2H), 5.26 (br d, J ) 4.1 Hz, 1H), 5.22
(br d, J ) 10.5 Hz, 1H), 4.78 (d, J ) 6.9 Hz, 1H), 4.73 (d, J ) 6.9
Hz, 1H), 4.72 (d, J ) 6.9 Hz, 1H), 4.63 (d, J ) 6.9 Hz, 1H), 4.60
(d, J ) 6.6 Hz, 1H), 4.49 (d, J ) 6.6 Hz, 1H), 4.10 (app t, J ) 7.0
Hz, 1H), 3.85 (dd, J ) 8.8, 3.0 Hz, 1H), 3.59 (m, 1H), 3.52 (s,
3H), 3.50 (s, 3H), 3.43 (dd, J ) 6.9, 3.0 Hz, 1H), 3.38 (s, 3H),
3.30 (s, 3H), 2.98 (dd, J ) 15.7, 5.0 Hz, 1H), 2.65 (dd, J ) 15.7,
10.2 Hz, 1H); 13C NMR (CDCl3) δ 172.9, 141.3, 134.7, 128.6,
127.0, 119.5, 98.7, 98.6, 94.1, 80.9, 79.2, 77.7, 56.4, 56.4, 55.7,
51.4, 44.4, 37.5; HRMS m/z (ESI) calcd for C21H32O8Na (M +
Na)+ 435.1989, found 435.1986.
Methyl (3S,4R,5R,6S)-3-(Benzo[d][1,3]dioxol-6-yl)-4,5,6-tri-
(methoxymethoxy)-7-octaenoate (16b). 61.4%; Rf 0.43 (50%
1
EtOAc/hexanes); H NMR (CDCl3) δ 6.75 (s, 1H), 6.71 (s, 2H),
5.92 (s, 2H), 5.58 (ddd, J ) 18.4, 11.0, 7.4 Hz, 1H), 5.29 (br s,
2H), 5.24 (br d, J ) 8.5 Hz, 1H), 4.80 (d, J ) 6.9 Hz, 1H), 4.73
(d, J ) 6.9 Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 4.62 (d, J ) 6.9 Hz,
2H), 4.51 (d, J ) 6.9 Hz, 1H), 4.14 (app t, J ) 7.2 Hz, 1H), 3.76
(dd, J ) 8.8, 3.0 Hz, 1H), 3.53 (m, 1H), 3.54 (s, 3H), 3.49 (s, 3H),
3.44 (dd, J ) 6.9, 3.0 Hz, 1H), 3.39 (s, 3H), 3.32 (s, 3H), 2.94 (dd,
J ) 15.4, 4.7 Hz, 1H), 2.57 (dd, J ) 15.4, 10.2 Hz, 1H); 13C NMR
(CDCl3) δ 172.9, 147.8, 146.5, 135.1, 134.7, 121.8, 119.7, 108.9,
108.4, 101.0, 98.8, 98.7, 94.2, 81.1, 79.3, 77.9, 56.5, 56.4, 55.7,
51.5, 44.1, 37.6; HRMS m/z (ESI) calcd for C22H32O10Na (M +
Na)+ 479.1887, found 479.1865.
(3S,4R,5R,6S)-3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-4,5,6-tri-
(methoxymethoxy)-7-octaen-1-ol (19). To a solution of ester 16c
(0.153 g, 0.32 mmol) in ether (15 mL) cooled to 0 °C was added
LiAlH4 (0.024 g, 0.63 mmol) in one portion. The reaction mixture
was stirred for 3 h while it was allowed to warm to room
temperature. Careful quenching with saturated NH4Cl (10 mL) was
followed by extraction with ether (3 × 50 mL). Organic layers
were combined, dried (MgSO4), and concentrated under reduced
pressure to afford primary alcohol 19 (0.130 g, 90.2%) as a colorless
oil; Rf 0.05 (50% EtOAc/hexanes); 1H NMR (CDCl3) δ 6.43 (d, J
) 1.4 Hz, 1H), 6.40 (d, J ) 1.4 Hz, 1H), 5.91 (s, 2H), 5.58 (m,
1H), 5.26 (m, 2H), 4.76 (d, J ) 6.9 Hz, 1H), 4.73 (d, J ) 6.9 Hz,
1H), 4.72 (d, J ) 6.9 Hz, 1H), 4.65 (d, J ) 6.9 Hz, 1H), 4.61 (d,
J ) 6.6 Hz, 1H), 4.50 (d, J ) 6.6 Hz, 1H), 4.14 (app t, J ) 7.2 Hz,
1H), 3.85 (s, 3H), 3.73 (dd, J ) 8.5, 3.0 Hz, 1H), 3.49 (m, 1H),
3.43 (s, 3H), 3.40 (s, 3H), 3.31 (s, 3H), 3.06 (m, 1H), 2.16 (m,
1H), 1.76 (m, 1H), 1.22 (m, 2H); 13C NMR (CDCl3) δ 149.0, 143.6,
136.5, 134.8, 133.9, 119.5, 108.4, 102.3, 101.4, 98.8, 94.2, 81.7,
79.8, 77.9, 61.2, 56.6, 56.5, 56.2, 55.7, 44.7, 34.6, 29.7; HRMS
m/z (ESI) calcd for C22H34O10Na (M + Na)+ 481.2044, found
481.2033.
6-((3S,4R,5R,6S)-4,5,6-Tri(methoxymethoxy)octa-1,7-dien-3-
yl)-4-methoxybenzo[d][1,3]dioxole (20). To a solution of alcohol
19 (0.130 g, 0.28 mmol) and o-nitrophenylselenocyanate (0.097 g,
0.43 mmol) in THF (10 mL) was added tributylphosphine (0.086
g, 0.43 mmol) at room temperature. The reaction mixture im-
mediately turned deep brown and TLC showed complete disap-
pearance of the starting material. The mixture was quenched with
1 M NaOH (5 mL) and stirred for 30 min. The mixture was diluted
with water (20 mL) and extracted with ether (3 × 50 mL). Organic
layers were combined, dried (MgSO4), and concentrated under
reduced pressure. The yellow residue was dissolved in THF (10
mL) and cooled to 0 °C, and 30% H2O2 (0.48 g, 4.3 mmol) was
added to the solution. After an overnight stirring at room temper-
ature the reaction mixture was quenched with NaHSO3 and extracted
with ether (3 × 50 mL). Organic layers were combined, dried
(MgSO4), and concentrated under reduced pressure. The residue
was presorbed on silica gel and purified by column chromatography
(20%, 25%, 30% EtOAc/hexanes) to afford pure diene 20 (0.066
g, 52.8%) as a colorless oil; Rf 0.54 (50% EtOAc/hexanes); 1H NMR
(CDCl3) δ 6.44 (s, 1H), 6.43 (s, 1H), 6.10 (m, 1H), 5.91 (s, 2H),
5.71 (m, 1H), 5.31 (m, 2H), 5.12 (m, 2H), 4.76 (s, 2H), 4.66 (d, J
) 6.9 Hz, 1H), 4.65 (d, J ) 6.9 Hz, 1H), 4.56 (d, J ) 6.9 Hz, 1H),
4.55 (d, J ) 6.9 Hz, 1H), 4.14 (app t, J ) 6.7 Hz, 1H), 3.91 (dd,
J ) 7.2, 4.1 Hz, 1H), 3.86 (s, 3H), 4.62 (app t, J ) 8.3 Hz, 1H),
3.48 (dd, J ) 6.3, 1.9 Hz, 1H), 3.45 (s, 3H), 3.36 (s, 3H), 3.27 (s,
3H); 13C NMR (CDCl3) δ 149.0, 143.6, 138.2, 136.4, 135.0, 133.8,
119.3, 117.4, 107.9, 102.4, 101.4, 98.8, 98.5, 94.2, 80.4, 80.0, 77.4,
Methyl (3S,4R,5R,6S)-3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-
4,5,6-tri(methoxymethoxy)-7-octaenoate (16c). 76.0%; Rf 0.39
1
(50% EtOAc/hexanes); H NMR (CDCl3) δ 6.47 (d, J ) 1.1 Hz,
1H), 6.42 (d, J ) 1.1 Hz, 1H), 5.91 (s, 2H), 5.56 (m, 1H), 5.29 (br
s, 1H), 5.23 (br d, J ) 6.9 Hz, 1H), 4.81 (d, J ) 6.9 Hz, 1H), 4.74
(d, J ) 6.9 Hz, 1H), 4.70 (d, J ) 6.9 Hz, 1H), 4.62 (d, J ) 6.9 Hz,
1H), 4.61 (d, J ) 6.6 Hz, 1H), 4.50 (d, J ) 6.6 Hz, 1H), 4.13 (app
t, J ) 7.3 Hz, 1H), 3.85 (s, 3H), 3.73 (dd, J ) 8.8, 2.8 Hz, 1H),
3.54 (s, 3H), 3.53 (m, 1H), 3.49 (s, 3H), 3.43 (dd, J ) 6.9, 2.8 Hz,
1H), 3.38 (s, 3H), 3.31 (s, 3H), 2.94 (dd, J ) 15.7, 5.0 Hz, 1H),
2.58 (dd, J ) 15.7, 10.5 Hz, 1H); 13C NMR (CDCl3) δ 172.9, 148.9,
143.5, 135.8, 134.7, 134.1, 119.8, 108.3, 102.2, 101.4, 98.8, 98.7,
94.1, 81.1, 79.3, 77.9, 56.5, 56.5, 56.4, 55.7, 51.5, 44.4, 37.6; HRMS
m/z (ESI) calcd for C23H34O11Na (M + Na)+ 509.1993, found
509.1996.
(4S,5R)-4,5-Dihydro-5-((1R,2S)-1,2-dihydroxybut-3-enyl)-4-
phenyl-2(3H)-furanone (17). To the solution of the addition
product 16a (0.158 g, 0.34 mmol) in MeOH (26 mL) were added
4-6 drops of concentrated HCl. The reaction mixture was stirred
for 3 h at 60 °C, cooled to room temperature, quenched with 7
drops of concentrated NH4OH, and evaporated under reduced
pressure. The residue was dried by coevaporating with acetone (20
mL) and purified by column chromatography (40%, 45%, 50%
EtOAc/hexanes) to afford lactone 17 (60 mg, 70%); Rf 0.41 (50%
1
EtOAc/hexanes); H NMR (CDCl3) δ 7.39-7.23 (m, 5H), 5.77
(ddd, J ) 17.3, 10.5, 6.9 Hz, 1H), 5.39 (d, J ) 17.3 Hz, 1H), 5.24
(d, J ) 10.2 Hz, 1H), 4.50 (d, J ) 6.3 Hz, 1H), 4.28 (app t, J )
7.0 Hz, 1H), 3.85 (dd, J ) 16.0, 7.2 Hz, 1H), 3.52 (d, J ) 6.3 Hz,
1H), 3.08 (dd, J ) 17.9, 9.4 Hz, 1H), 2.67 (dd, J ) 17.9, 8.5 Hz,
1H), 1.25 (br s, 2H); 13C NMR (CDCl3) δ 176.7, 140.0, 136.1,
129.3, 127.8, 127.2, 119.0, 86.1, 74.1, 73.5, 42.8, 36.9, 29.8; HRMS
m/z (ESI) calcd for C14H16O4Na (M + Na)+ 271.0940, found
271.0951.
(4R,5S)-5-Acetoxymethyl-4-phenyl-4,5-dihydro-2(3H)-fura-
none (18).19 To a solution of lactone 17 (0.05 g, 0.2 mmol) in ether
(2 mL) at 0 °C was added NaIO4 (53 mg, 0.25 mmol). To the
resulting suspension was added water (1 mL). The resulting mixture
J. Org. Chem, Vol. 71, No. 15, 2006 5701

Kireev et al.
56.6, 56.4, 56.3, 55.8, 52.2; HRMS m/z (ESI) calcd for C22H32O9Na
(M + Na)+ 463.1944, found 463.1963.
methanol gave 2,3,4-tri-O-benzyl-D-xylose as white needles (50.7
g, 71%); mp 137-138 °C (lit.20 mp 139-142 °C); Rf 0.45 (33%
EtOAc/hexanes).
6-((1S,4S,5R,6R)-4,5,6-Tri(methoxymethoxy)cyclohex-2-enyl)-
4-methoxybenzo[d][1,3]dioxole (21). To a solution of diene 20
(0.066 g, 0.15 mmol) in dry CH2Cl2 (10 mL) was added (Cy3P)2-
(PhCHd)RuCl2 (0.012 g, 0.015 mmol). After the solution was
stirred overnight DMSO (0.059 g, 0.75 mmol) was added and the
reaction mixture was stirred for an additional 6 h. The mixture was
concentrated under reduced pressure and the residue was presorbed
on silica gel and purified by column chromatography (30%, 35%,
40% EtOAc/hexanes) to afford pure olefin 21 (0.060 g, 97.1%) as
a colorless oil; Rf 0.73 (50% EtOAc/hexanes); 1H NMR (CDCl3) δ
6.47 (d, J ) 1.4 Hz, 1H), 6.43 (d, J ) 1.4 Hz, 1H), 5.93 (s, 2H),
5.90 (ddd, J ) 10.2, 3.0, 1.7 Hz, 1H), 5.31 (ddd, J ) 10.2, 3.9, 1.7
Hz, 1H), 4.84 (d, J ) 6.9 Hz, 1H), 4.77 (d, J ) 6.9 Hz, 1H), 4.72
(br s, 2H), 4.66 (d, J ) 6.9 Hz, 1H), 4.49 (d, J ) 6.9 Hz, 1H), 4.15
(m, 1H), 3.90 (app t, J ) 4.7 Hz, 1H), 3.69 (m, 1H), 3.43 (s, 3H),
3.38 (s, 3H), 3.28 (s, 3H); 13C NMR (CDCl3) δ 148.7, 143.2, 134.2,
133.8, 129.3, 127.6, 109.5, 104.1, 101.4, 97.2, 96.7, 96.4, 76.5,
76.3, 75.8, 56.7, 56.0, 55.8, 55.6, 44.6; HRMS m/z (ESI) calcd for
C20H28O9Na (M + Na)+ 435.1625, found 435.1615.
(2R,3R,4S)-2,3,4-Tri(benzyloxy)-5-hexene-1-ol (25).17b,28 To a
stirred suspension of methyltriphenylphosphonium bromide (42 g,
0.1 mol) in THF (150 mL) was added BuLi (50 mL of 2 M solution
in pentane, 0.1 mol) dropwise at 0 °C. The mixture was stirred for
2 h at room temperature. To the above red solution was added tri-
O-benzylxylopyranose (20 g, 0.048 mol) in THF (150 mL) dropwise
at 0 °C. The reaction mixture was stirred overnight at room
temperature and then at reflux for 2 h. NH4Cl (1 M, 200 mL) was
added at room temperature to the reaction mixture and the latter
was extracted with ether (3 × 200 mL). The organic extracts were
combined, washed with brine, and dried (MgSO4). After the removal
of the solvent, the residue was passed through a short column of
silica gel with gradients: 15%, 35% EtOAc/hexanes, to obtain 16
g (80%) of the enol product; Rf 0.38 (33% EtOAc/hexanes).
Methyl (2E,4R,5R,6S)-4,5,6-Tri(benzyloxy)-2,7-octadienoate
(26).17b To oxalyl chloride (27 mL of 2M in CH2Cl2, 54 mmol) in
dry CH2Cl2 (100 mL) at -78 °C was added DMSO (7.8 mL, 110
mmol) in CH2Cl2 (40 mL) over 20 min and the mixture was stirred
for 40 min. The above alcohol (10 g, 24 mmol) in CH2Cl2 (40
mL) was added over 30 min and the mixture was stirred for an
additional 1 h. Triethylamine (20 mL, 133 mmol) in CH2Cl2 (40
mL) was added over 20 min and the white slurry was stirred for
30 min at -78 °C. To the cold reaction mixture was added methyl
(triphenylphosphoranylidene)acetate (18 g, 54 mmol) in one portion,
and the resulting mixture was stirred for 10 h while it was allowed
to warm to room temperature. Water (300 mL) was added to the
reaction mixture, the two layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 200 mL). The combined
organic layers were washed with brine, dried (MgSO4), and
evaporated under reduced pressure. The residual oil was split into
two fractions, which were presorbed on silica gel and purified by
chromatography with gradients: 5%, 15% EtOAc/hexanes to afford
enoate 26 (9.7 g, 84%) as a colorless oil; Rf 0.55 (25% EtOAc/
hexanes).
(1R,2R,3S,6R)-6-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-4-cyclo-
hexene-1,2,3-triol (8e). To a solution of 21 (0.025 g, 0.06 mmol)
in MeOH (10 mL) was added 1-2 drops of concentrated HCl. After
the reaction mixture was stirred for 3 h at 60 °C it was cooled to
room temperature, quenched with 3 drops of concentrated NH4OH,
and evaporated under reduced pressure. Acetone (20 mL) was added
and evaporated again to remove traces of water. The residue was
adsorbed on a preparative TLC plate and separated chromatographi-
cally with 5% MeOH/CH2Cl2 to obtain 13 mg of 8e (76%); Rf 0.04
1
(50% EtOAc/hexanes); H NMR (CDCl3) δ 6.43 (s, 1H), 6.39 (s,
1H), 5.92 (s, 1H), 5.91 (s, 1H), 5.77 (d, J ) 9.9 Hz, 1H), 5.67 (dd,
J ) 9.9, 3.6 Hz, 1H), 4.02 (br s, 1H), 3.88 (s, 3H), 3.60-3.48 (m,
3H); 13C NMR (CDCl3) δ 148.9, 143.3, 134.6, 131.7, 130.0, 128.0,
110.3, 104.4, 101.6, 73.5, 72.8, 70.6, 56.9, 47.2; HRMS m/z (ESI)
calcd for C14H16O6Na (M + Na)+ 303.0839, found 303.0829.
Mixture of R- and â-Methyl D-Xylopyranosides (22). A
methanolic solution of 1% HCl was prepared by a careful addition
of SOCl2 (5 mL, 0.069 mol) to stirred dry MeOH (250 mL) at 0
°C. d-Xylose (25 g, 0.17 mol) was added in one portion and the
resulting solution was refluxed for 4 h. The reaction mixture was
allowed to cool to room temperature, neutralized by the addition
of solid NaHCO3 (17.5 g, 0.21 mol), and concentrated under
reduced pressure. The residue was dissolved in EtOH (200 mL),
the solution was concentrated to one-half of the original volume,
toluene (100 mL) was added, and the mixture was concentrated to
dryness. The residual viscous oil was used without purification in
the next step.
General Procedure for the Arylcuprate Addition. One milli-
liter of a required aryl bromide (7.03 mmol) solution in THF was
added to crushed Mg turnings (0.17 g, 7.03 mmol) in THF (10
mL) under nitrogen atmosphere. Once the reaction started the
solution warmed and slightly darkened. The rest of the aryl bromide
was added dropwise to allow a gentle reaction. The reaction mixture
was allowed to cool to room temperature and then cannulated to a
slurry of CuI (0.67 g, 3.52 mmol) in THF (10 mL) at -78 °C. The
mixture was stirred at -78 °C for 40 min. Me3SiCl (0.76 g, 7.03
mmol) and the enoate (0.703 mmol in 10 mL of THF) were added
sequentially at -78 °C. The yellow-brown suspension was stirred
overnight while slowly warming up to room temperature. The
reaction mixture was quenched with a mixture of concentrated
NH4OH and saturated NH4Cl (1:9, 30 mL) and extracted with ether
(3 × 30 mL). The combined organic layers were washed with brine,
dried with MgSO4, and concentrated under reduced pressure. The
residue was absorbed on silica gel and purified by column
chromatography (5-30% EtOAc/hexanes) to yield corresponding
addition products 27a-g as an oil.
Methyl (3S,4R,5R,6S)-3-Phenyl-4,5,6-tri(benzyloxy)-7-octa-
enoate (27a). 97%; Rf 0.66 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.46-7.23 (m, 20H), 6.01 (m, 1H), 5.44 (br d, J ) 9.4
Hz, 1H), 5.39 (br d, J ) 17.1 Hz, 1H), 4.90 (d, J ) 11.6 Hz, 1H),
4.89 (d, J ) 11.3 Hz, 1H), 4.74 (d, J ) 11.8 Hz, 1H), 4.67 (d, J )
11.6 Hz, 1H), 4.57 (d, J ) 11.3 Hz, 1H), 4.44 (d, J ) 11.8 Hz,
1H), 4.11 (app t, J ) 5.8 Hz, 1H), 4.04 (dd, J ) 6.9, 5.2 Hz, 1H),
3.80 (m, 1H), 3.55 (m, 1H), 3.54 (s, 3H), 3.09 (dd, J ) 15.7, 4.4
Hz, 1H), 2.86 (dd, J ) 15.7, 10.2 Hz, 1H); 13C NMR (CDCl3) δ
173.1, 141.9, 139.1, 139.0, 138.4, 135.6, 128.7, 128.6, 128.5, 128.3,
Mixture of R- and â-Methyl 2,3,4-Tri-O-benzyl-D-xylopyrano-
sides (23). To NaH 60% suspension in mineral oil (34 g, 0.85 mol)
in a 1 L flask was added a solution of methyl xylosides from the
previous step in DMF (500 mL) in 100 mL portions at 0 °C with
vigorous stirring. After the hydrogen evolution was complete the
mixture was treated with Bu4NI (11 g, 0.03 mol) and BnCl (70
mL, 0.61 mol) and stirred for 30 min at 0 °C and then overnight at
room temperature. The reaction mixture was carefully quenched
with a cold aqueous solution of 10% NH4Cl (130 g). Water (400
mL) was added to the mixture and the aqueous layer was extracted
with ether (3 × 200 mL). The combined organic extracts were
washed with water (2 × 300 mL), then dried (MgSO4) and
concentrated under reduced pressure. The residual oil (about 250
mL) was subjected to the next step without purification.
2,3,4-Tri-O-benzyl-D-xylopyranose (24).20a,b The crude mixture
of xylosides from the previous step was heated under reflux for 10
h with 1 M H2SO4 (210 mL), AcOH (240 mL), and dioxane (220
mL). After allowing the mixture to cool to room temperature,
hexane (100 mL) and water (800 mL) were added with intense
stirring. The separated precipitate was collected by filtration, washed
with hexane (2 × 250 mL), and air-dried. Recrystallization from
(28) Kornienko, A.; d’Alarcao, M. Tetrahedron Lett. 1997, 38, 6497-
6500.
5702 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
128.0, 127.9, 127.8, 127.6, 127.6, 127.0, 119.2, 82.4, 82.3, 81.5,
75.0, 73.4, 70.9, 51.6, 43.6, 36.7; HRMS m/z (ESI) calcd for
C36H39O5 (M + H)+ 551.2798, found 551.2795.
1H), 3.81 (app t, J ) 6.0 Hz, 1H), 3.60-3.51 (m, 1H), 3.45 (s,
3H), 3.39 (m, 1H), 2.89 (dd, J ) 15.7, 4.4 Hz, 1H), 2.68 (dd, J )
15.7, 10.7 Hz, 1H); 13C NMR (CDCl3) δ 172.9, 138.7, 137.5, 137.4,
135.4, 129.8, 129.7, 128.4, 128.3, 128.2, 127.9, 127.7, 127.5, 127.4,
115.4, 115.2, 82.3, 82.2, 81.0, 74.7, 73.4, 70.8, 51.4, 42.6, 35.9;
HRMS m/z (ESI) calcd for C36H37O5FNa (M + Na)+ 591.2523,
found 591.2507.
Methyl (3S,4R,5R,6S)-3-(4-Methoxyphenyl)-4,5,6-Tri(benzyl-
oxy)-7-octaenoate (27b). 95%; Rf 0.54 (25% EtOAc/hexanes); 1H
NMR (CDCl3) δ 7.41-7.36 (m, 15H), 7.09 (d, J ) 8.5 Hz, 2H),
6.83 (d, J ) 8.5 Hz, 2H), 5.95 (m, 1H), 5.39 (br d, J ) 9.5 Hz,
1H), 5.34 (br d, J ) 17.9 Hz, 1H), 4.85 (d, J ) 11.6 Hz, 1H), 4.83
(d, J ) 11.3 Hz, 1H), 4.68 (d, J ) 11.8 Hz, 1H), 4.61 (d, J ) 11.6
Hz, 1H), 4.54 (d, J ) 11.3 Hz, 1H), 4.39 (d, J ) 11.8 Hz, 1H),
4.06 (app t, J ) 6.1 Hz, 1H), 3.93 (dd, J ) 7.4, 5.2 Hz, 1H), 3.82
(s, 3H), 3.68 (m, 1H), 3.51 (s, 3H), 3.49 (m, 1H), 3.00 (dd, J )
15.4, 4.4 Hz, 1H), 2.75 (dd, J ) 15.4, 10.5 Hz, 1H); 13C NMR
(CDCl3) δ 173.2, 158.5, 139.1, 139.0, 138.4, 135.6, 133.7, 129.4,
128.5, 128.4, 128.2, 127.9, 127.8, 127.7, 127.5, 119.1, 114.0, 82.4,
81.6, 75.0, 73.2, 70.8, 55.3, 51.5, 42.8, 36.9; HRMS m/z (ESI) calcd
for C37H41O6 (M + H)+ 581.2903, found 581.2910.
Methyl (3S,4R,5R,6S)-3-(Benzo[d][1,3]dioxol-6-yl)-4,5,6-tri-
(benzyloxy)-7-octaenoate (27c). 95%; 1H NMR (CDCl3) δ 7.38-
7.33 (m, 15H), 6.70 (d, J ) 8.0 Hz, 1H), 6.64 (br s, 1H), 6.59 (br
d, J ) 8.0 Hz, 1H), 5.93 (s, 2H), 5.92 (m, 1H), 5.38 (br d, J ) 5.2
Hz, 1H), 5.34 (br d, J ) 13.7 Hz, 1H), 4.83 (d, J ) 11.8 Hz, 1H),
4.78 (d, J ) 11.3 Hz, 1H), 4.65 (d, J ) 11.6 Hz, 1H), 4.59 (d, J )
11.6 Hz, 1H), 4.50 (d, J ) 11.3 Hz, 1H), 4.37 (d, J ) 11.8 Hz,
1H), 4.07 (app t, J ) 6.1 Hz, 1H), 3.86 (dd, J ) 6.9, 5.2 Hz, 1H),
3.60 (m, 1H), 3.51 (s, 3H), 3.47 (app t, J ) 5.2 Hz, 1H), 2.93 (dd,
J ) 15.7, 4.4 Hz, 1H), 2.69 (dd, J ) 15.7, 10.5 Hz, 1H); 13C NMR
(CDCl3) δ 173.0, 147.7, 146.4, 138.9, 138.8, 138.2, 135.5, 135.4,
128.5, 128.4, 128.2, 127.9, 127.8, 127.7, 127.5, 121.6, 119.2, 108.6,
108.3, 101.0, 82.3, 82.2, 81.5, 74.9, 73.2, 70.8, 51.5, 43.0, 36.7;
HRMS m/z (ESI) calcd for C37H38O7 (M)+ 594.2618, found
594.2612.
Methyl (3S,4R,5R,6S)-3-(3,4-Dimethoxyphenyl)-4,5,6-tri(ben-
zyloxy)-7-octaenoate (27d). 78%; Rf 0.59 (25% EtOAc/hexanes);
[R]22D 37.7 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.48-7.21 (m, 15H),
6.70 (d, J ) 8.8 Hz, 1H), 6.62 (br d, J ) 6.8 Hz, 2H), 5.95-5.83
(m, 1H), 5.32 (d, J ) 3.0 Hz, 1H), 5.28 (br d, J ) 9.6 Hz, 1H),
4.76 (dd, J ) 11.8, 4.4 Hz, 2H), 4.60 (d, J ) 11.8 Hz, 1H), 4.51
(d, J ) 11.8 Hz, 1H), 4.40 (d, J ) 11.8 Hz, 1H), 4.32 (d, J ) 11.8
Hz, 1H), 4.00 (t, J ) 6.0 Hz, 1H), 3.86 (dd, J ) 12.1, 7.4 Hz, 1H),
3.83 (s, 3H), 3.58 (s, 3H), 3.46 (s, 3H), 3.44 (m, 1H), 2.90 (dd, J
) 15.7, 4.4 Hz, 1H), 2.71 (dd, J ) 15.7, 10.5 Hz, 1H); 13C NMR
(CDCl3) δ 173.1, 148.8, 147.8, 138.9, 138.3, 135.5, 134.3, 128.4,
128.3, 128.0, 127.6, 127.5, 127.4, 120.1, 118.9, 111.6, 111.2, 82.5,
82.4, 81.5, 74.8, 73.1, 70.8, 55.8, 55.6, 51.5, 42.8, 36.5; HRMS
m/z (ESI) calcd for C38H42O7Na (M + Na)+ 633.2822, found
633.2831.
Methyl (3S,4R,5R,6S)-3-(4-Chlorophenyl)-4,5,6-tri(benzyloxy)-
7-octaenoate (27g). 91%; Rf 0.46 (25% EtOAc/hexanes); [R]22
D
43.3 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.48-7.04 (m, 15H), 6.98
(d, J ) 8.2 Hz, 2H), 6.74 (d, J ) 8.8 Hz, 2H), 5.94-5.82 (m, 1H),
5.35-5.20 (m, 2H), 4.73 (dd, J ) 11.8, 3.8 Hz, 2H), 4.62 (d, J )
11.8 Hz, 1H), 4.52 (d, J ) 11.8 Hz, 1H), 4.32 (dd, J ) 11.8, 7.7
Hz, 2H), 4.00 (app t, J ) 6.0 Hz, 1H), 3.80 (app t, J ) 6.0 Hz,
1H), 3.60-3.51 (m, 1H), 3.45 (s, 3H), 3.39 (m, 1H), 2.89 (dd, J )
15.7, 4.4 Hz, 1H), 2.72 (dd, J ) 15.7, 10.7 Hz, 1H); 13C NMR
(CDCl3) δ 173.1, 140.5, 138.6, 138.5, 135.2, 132.6, 129.7, 129.5,
128.6, 128.4, 128.2, 127.5, 127.9, 127.7, 127.6, 127.5, 119.1, 116.7,
82.2, 80.9, 74.8, 73.6, 70.8, 51.6, 42.7, 36.3; HRMS m/z (ESI) calcd
for C36H37O5ClNa (M + Na)+ 607.2227, found 607.2222.
General Procedure for Ester Reduction. A solution of a desired
ester 27 (1.5 mmol) in ether (25 mL) was cooled to 0 °C, and
LiAlH4 was added (0.23 g, 6 mmol) in one portion. The reaction
mixture was stirred for 3 h while slowly warming up to room
temperature. Careful quenching with saturated NH4Cl (10 mL) was
followed by extraction with ether (3 × 25 mL). Organic layers
were combined, dried with MgSO4, and concentrated under reduced
pressure to afford the corresponding primary alcohols as viscous
colorless oils. Reduction products 28a-g were used without
purification in the next step. A small portion of each crude alcohol
was purified (35% EtOAc/hexanes) for characterization.
(3S,4R,5R,6S)-3-Phenyl-4,5,6-tri(benzyloxy)-7-octaen-1-ol (28a).
Rf 0.30 (25% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.35-7.12 (m,
20H), 5.91 (m, 1H), 5.36 (br d, J ) 8.8 Hz, 1H), 5.31 (br d, J )
16.5 Hz, 1H), 4.78 (d, J ) 11.4 Hz, 1H), 4.77 (d, J ) 11.2 Hz,
1H), 4.64 (d, J ) 11.8 Hz, 1H), 4.54 (d, J ) 11.4 Hz, 1H), 4.47
(d, J ) 11.2 Hz, 1H), 4.36 (d, J ) 11.8 Hz, 1H), 4.05 (app t, J )
5.5 Hz, 1H), 3.88 (dd, J ) 6.6, 5.4 Hz, 1H), 3.49 (app t, J ) 6.2
Hz, 1H), 3.46 (m, 1H), 3.22 (m, 1H), 3.20 (m, 1H), 2.18 (m, 1H),
2.00 (m, 1H), 1.35 (br s, 1H); 13C NMR (CDCl3) δ 142.4, 139.1,
138.2, 135.5, 128.7, 128.5, 128.4, 128.4, 127.9, 127.8, 127.5, 127.4,
126.7, 119.0, 83.2, 82.7, 81.3, 74.9, 73.4, 70.8, 61.2, 43.4, 33.7;
HRMS m/z (ESI) calcd for C35H39O4 (M + H)+ 523.2848, found
523.2848.
(3S,4R,5R,6S)-3-(4-Methoxyphenyl)-4,5,6-tri(benzyloxy)-7-
octaen-1-ol (28b). Rf 0.33 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.38-7.29 (m, 15H), 7.04 (d, J ) 8.5 Hz, 2H), 6.81 (d,
J ) 8.5 Hz, 2H), 5.91 (m, 1H), 5.36 (br d, J ) 8.8 Hz, 1H), 5.32
(br d, J ) 16.0 Hz, 1H), 4.80 (d, J ) 11.6 Hz, 1H), 4.77 (d, J )
11.0 Hz, 1H), 4.65 (d, J ) 11.8 Hz, 1H), 4.55 (d, J ) 11.6 Hz,
1H), 4.50 (d, J ) 11.0 Hz, 1H), 4.37 (d, J ) 11.8 Hz, 1H), 4.06
(app t, J ) 5.8 Hz, 1H), 3.84 (dd, J ) 6.6, 5.2 Hz, 1H), 3.80 (s,
3H), 3.49 (app t, J ) 5.2 Hz, 1H), 3.46 (m, 1H), 3.32 (m, 1H),
3.16 (m, 1H), 2.16 (m, 1H), 1.95 (m, 1H), 1.58 (br s, 1H); 13C
NMR (CDCl3) δ 158.4, 139.1, 138.2, 135.5, 134.3, 129.6, 128.5,
128.4, 128.4, 127.9, 127.8, 127.7, 127.5, 127.4, 119.0, 114.0, 83.3,
82.7, 81.3, 74.9, 73.4, 70.8, 61.2, 55.3, 42.6, 33.9; HRMS m/z (ESI)
calcd for C36H41O5 (M + H)+ 553.2954, found 553.2947.
(3S,4R,5R,6S)-3-(Benzo[d][1,3]dioxol-6-yl)-4,5,6-tri(benzyloxy)-
7-octaen-1-ol (28c). Rf 0.12 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.38-7.29 (m, 15H), 6.71 (d, J ) 7.9 Hz, 1H), 6.65 (d,
J ) 1.5 Hz, 1H), 6.56 (dd, J ) 8.0, 1.5 Hz, 1H), 5.93 (s, 2H), 5.92
(m, 1H), 5.39 (br d, J ) 3.2 Hz, 1H), 5.34 (br d, J ) 10.5 Hz, 1H),
4.81 (d, J ) 11.6 Hz, 1H), 4.77 (d, J ) 11.0 Hz, 1H), 4.65 (d, J )
11.8 Hz, 1H), 4.56 (d, J ) 11.6 Hz, 1H), 4.51 (d, J ) 11.0 Hz,
1H), 4.38 (d, J ) 11.8 Hz, 1H), 4.09 (app t, J ) 5.8 Hz, 1H), 3.81
(app t, J ) 5.4 Hz, 1H), 3.52 (app t, J ) 5.4 Hz, 1H), 3.48 (m,
1H), 3.32 (m, 1H), 3.12 (m, 1H), 2.13 (m, 1H), 1.90 (m, 1H), 1.40
(m, 1H); 13C NMR (CDCl3) δ 147.9, 146.3, 139.1, 139.0, 138.2,
Methyl (3S,4R,5R,6S)-3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-
4,5,6-tri(benzyloxy)-7-octaenoate (27e). 97%; Rf 0.42 (25%
1
EtOAc/hexanes); H NMR (CDCl3) δ 7.36-7.28 (m, 15H), 6.33
(s, 1H), 6.32 (s, 1H), 5.94 (br s, 2H), 5.93 (m, 1H), 5.38 (s, 1H),
5.34 (br d, J ) 6.6 Hz, 1H), 4.84 (d, J ) 11.8 Hz, 1H), 4.78 (d, J
) 11.3 Hz, 1H), 4.65 (d, J ) 11.6 Hz, 1H), 4.56 (d, J ) 11.6 Hz,
1H), 4.46 (d, J ) 11.3 Hz, 1H), 4.37 (d, J ) 11.8 Hz, 1H), 4.08
(app t, J ) 5.8 Hz, 1H), 3.86 (dd, J ) 6.3, 5.5 Hz, 1H), 3.65 (s,
3H), 3.59 (m, 1H), 3.51 (s, 3H), 3.48 (app t, J ) 5.5 Hz, 1H), 2.90
(dd, J ) 15.7, 4.7 Hz, 1H), 2.70 (dd, J ) 15.7, 10.5 Hz, 1H); 13C
NMR (CDCl3) δ 173.0, 148.9, 143.5, 139.0, 138.9, 138.2, 136.4,
135.4, 134.0, 128.5, 128.4, 128.1, 127.7, 127.6, 127.5, 119.1, 107.8,
102.1, 101.4, 82.5, 82.4, 81.5, 74.9, 73.2, 70.9, 56.4, 51.6, 43.2,
36.4; HRMS m/z (ESI) calcd for C38H40O8 (M)+ 624.2723, found
624.2715.
Methyl (3S,4R,5R,6S)-3-(4-Fluorophenyl)-4,5,6-tri(benzyloxy)-
7-octaenoate (27f). 88%; Rf 0.78 (25% EtOAc/hexanes); [R]22
D
53.1 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.42-7.23 (m, 15H), 7.01
(dd, J ) 8.5, 5.5 Hz, 2H), 6.88 (app t, J ) 8.8 Hz, 2H), 5.94-5.82
(m, 1H), 5.33 (br d, J ) 8.8 Hz 1H), 5.27 (br d, J ) 8.8 Hz, 1H),
4.74 (d, J ) 11.8 Hz, 2H), 4.62 (d, J ) 11.8 Hz, 1H), 4.53 (d, J )
11.8 Hz, 1H), 4.33 (t, J ) 12.1 Hz, 2H), 3.98 (app t, J ) 6.0 Hz,
J. Org. Chem, Vol. 71, No. 15, 2006 5703

Kireev et al.
136.2, 135.4, 128.5, 128.4, 127.8, 127.5, 127.4, 121.8, 119.0, 108.7,
108.3, 101.0, 83.3, 82.6, 81.3, 74.9, 73.5, 70.8, 61.1, 43.0, 33.8;
HRMS m/z (ESI) calcd for C36H38O6 (M)+ 566.2668, found
566.2663.
solution (wt 35%) of hydrogen peroxide (0.56 g, 5 mmol) was
added. After overnight stirring at room temperature, the reaction
mixture was quenched with dry NaHSO3 and extracted with ether
(3 × 100 mL). Organic layers were combined, dried (MgSO4), and
concentrated under reduced pressure. The residue was presorbed
on silica gel and purified by column chromatography (1-2%,
EtOAc/hexanes) to afford pure dienes 29a-g as a colorless oil.
1-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)octa-1,7-dien-3-yl)ben-
zene (29a). 75% (3 steps); Rf 0.73 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.44-7.21 (m, 20H), 6.40 (m, 1H), 6.01 (m, 1H), 5.39
(br d, J ) 8.5 Hz, 1H), 5.36 (br d, J ) 17.3 Hz, 1H), 5.20 (br d,
J ) 10.5 Hz, 1H), 5.00 (br d, J ) 17.1 Hz, 1H), 4.77 (d, J ) 11.3
Hz, 1H), 4.74 (d, J ) 11.8 Hz, 1H), 4.68 (d, J ) 10.7 Hz, 1H),
4.67 (d, J ) 11.3 Hz, 1H), 4.44 (d, J ) 11.8 Hz, 1H), 4.27 (d, J )
10.7 Hz, 1H), 4.11 (m, 2H), 3.59 (dd, J ) 9.4, 5.2 Hz, 1H), 3.52
(app t, J ) 5.0 Hz, 1H); 13C NMR (CDCl3) δ 142.6, 139.1, 138.1,
137.8, 136.1, 128.8, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.5,
127.4, 126.5, 119.0, 117.4, 83.5, 83.1, 80.0, 75.4, 74.2, 70.4, 51.2;
HRMS m/z (ESI) calcd for C35H37O3 (M + H)+ 505.2743, found
505.2757.
(3S,4R,5R,6S)-3-(3,4-Dimethoxyphenyl)-4,5,6-tri(benzyloxy)-
7-octaen-1-ol (28d). Rf 0.32 (25% EtOAc/hexanes); [R]22D 26.6 (c
1, CHCl3); 1H NMR (CDCl3) δ 7.50-7.21 (m, 15H), 6.73 (br d, J
) 7.9 Hz, 1H), 6.66 (br d, J ) 9.0 Hz, 1H), 6.63 (br d, J ) 8.2 Hz,
1H), 5.97-5.85 (m, 1H), 5.33 (br d, J ) 11.2 Hz, 1H), 5.31 (br d,
J ) 5.5 Hz, 1H), 4.77 (dd, J ) 11.5, 4.9 Hz, 2H), 4.62 (d, J )
11.8 Hz, 1H), 4.51 (d, J ) 11.5 Hz, 1H), 4.42 (d, J ) 11.8 Hz,
1H), 4.35 (d, J ) 11.5 Hz, 1H), 4.06 (app t, J ) 6.6 Hz, 1H), 3.84
(s, 3H), 3.57 (s, 3H), 3.52 (m, 2H), 3.37-3.26 (m, 1H), 3.15-
3.08 (m, 1H), 2.17-2.03 (m, 1H), 2.01-1.91 (m, 1H); 13C NMR
(CDCl3) δ 149.0, 147.7, 139.2, 139.0, 138.2, 135.5, 135.0, 128.4,
128.3, 128.2, 127.7, 127.6, 127.4, 127.3, 120.5, 118.8, 111.5, 111.2,
83.5, 82.8, 81.2, 74.8, 73.4, 70.8, 61.2, 55.9, 55.6, 42.8, 33.5; HRMS
m/z (ESI) calcd for C37H42O6Na (M + Na)+ 605.2873, found
605.2860.
(3S,4R,5R,6S)-3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-4,5,6-tri-
(benzyloxy)-7-octaen-1-ol (28e). Rf 0.30 (25% EtOAc/hexanes);
1H NMR (CDCl3) δ 7.35-7.28 (m, 15H), 6.33 (s, 1H), 6.32 (s,
1H), 5.94 (s, 2H), 5.93 (m, 1H), 5.39 (m, 1H), 5.35 (br d, J ) 5.2
Hz, 1H), 4.83 (d, J ) 11.6 Hz, 1H), 4.79 (d, J ) 11.3 Hz, 1H),
4.65 (d, J ) 11.8 Hz, 1H), 4.55 (d, J ) 11.6 Hz, 1H), 4.48 (d, J )
11.3 Hz, 1H), 4.38 (d, J ) 11.8 Hz, 1H), 4.11 (app t, J ) 5.5 Hz,
1H), 3.82 (app t, J ) 5.8 Hz, 1H), 3.65 (s, 3H), 3.54 (app t, J )
5.5 Hz, 1H), 3.49 (m, 1H), 3.34 (m, 1H), 3.12 (m, 1H), 2.11 (m,
1H), 1.92 (m, 1H), 1.38 (br s, 1H); 13C NMR (CDCl3) δ 149.0,
143.6, 139.1, 138.2, 137.1, 135.4, 133.9, 128.5, 128.4, 128.3, 127.8,
127.6, 127.5, 127.4, 119.0, 107.9, 102.3, 101.4, 83.4, 82.8, 81.3,
74.9, 73.4, 70.8, 61.1, 56.4, 43.2, 33.7; HRMS m/z (ESI) calcd for
C37H40O7 (M)+ 596.2774, found 596.2775.
1-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)octa-1,7-dien-3-yl)-4-
methoxybenzene (29b). 84% (3 steps); Rf 0.69 (25% EtOAc/
1
hexanes); H NMR (CDCl3) δ 7.36-7.18 (m, 15H), 7.07 (d, J )
8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 6.31 (m, 1H), 5.95 (m, 1H),
5.34 (br d, J ) 8.5 Hz, 1H), 5.30 (br d, J ) 15.4 Hz, 1H), 5.13
(dd, J ) 10.5, 1.7 Hz, 1H), 4.93 (dd, J ) 17.1, 1.7 Hz, 1H), 4.72
(d, J ) 11.3 Hz, 1H), 4.68 (d, J ) 11.8 Hz, 1H), 4.63 (d, J ) 11.0
Hz, 1H), 4.60 (d, J ) 11.3 Hz, 1H), 4.38 (d, J ) 11.8 Hz, 1H),
4.27 (d, J ) 11.0 Hz, 1H), 4.06 (dd, J ) 7.2, 4.7 Hz, 1H), 3.98
(app t, J ) 5.8 Hz, 1H), 3.80 (s, 3H), 3.50 (dd, J ) 9.4, 5.5 Hz,
1H), 3.45 (app t, J ) 6.1 Hz, 1H); 13C NMR (CDCl3) δ 158.2,
139.1, 138.1, 136.1, 134.7, 129.3, 128.7, 128.5, 128.3, 128.2, 128.0,
127.9, 127.4, 127.3, 118.9, 117.0, 113.9, 83.4, 83.0, 80.2, 75.4,
74.1, 70.4, 55.3, 50.3; HRMS m/z (ESI) calcd for C36H38O4 (M)+
534.2770, found 534.2757.
(3S,4R,5R,6S)-3-(4-Fluorophenyl)-4,5,6-Tri(benzyloxy)-7-
octaen-1-ol (28f). Rf 0.66 (25% EtOAc/hexanes); [R]22 55.9 (c
D
1
1, CHCl3); H NMR (CDCl3) δ 7.48-7.16 (m, 15H), 7.03 (app t,
5-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)octa-1,7-dien-3-yl)benzo-
[d][1,3]dioxole (29c). 77% (3 steps); Rf 0.69 (25% EtOAc/hexanes);
1H NMR (CDCl3) δ 7.35-7.17 (m, 15H), 6.70 (d, J ) 7.9 Hz,
1H), 6.64 (d, J ) 1.5 Hz, 1H), 6.57 (dd, J ) 7.9, 1.5 Hz, 1H), 6.25
(m, 1H), 5.93 (m, 1H), 5.92 (s, 2H), 5.33 (dd, J ) 8.4, 1.9 Hz,
1H), 5.29 (br d, J ) 13.5 Hz, 1H), 5.11 (dd, J ) 10.3, 1.9 Hz,
1H), 4.92 (dd, J ) 17.2, 1.9 Hz, 1H), 4.71 (d, J ) 11.4 Hz, 1H),
4.66 (d, J ) 11.8 Hz, 1H), 4.62 (d, J ) 10.9 Hz, 1H), 4.60 (d, J )
11.4 Hz, 1H), 4.36 (d, J ) 11.8 Hz, 1H), 4.29 (d, J ) 10.9 Hz,
1H), 4.04 (dd, J ) 7.5, 4.7 Hz, 1H), 3.94 (app t, J ) 5.8 Hz, 1H),
3.44 (m, 2H); 13C NMR (CDCl3) δ 147.6, 146.0, 139.0, 138.1,
137.9, 136.5, 136.0, 128.7, 128.5, 128.3, 128.2, 128.0, 127.9, 127.5,
127.4, 121.3, 118.9, 117.2, 108.8, 108.3, 100.9, 83.3, 83.0, 80.1,
75.4, 74.2, 70.4, 50.7; HRMS m/z (ESI) calcd for C36H36O5 (M)+
548.2563, found 548.2562.
4-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)-1,7-octadien-3-yl)-1,2-
dimethoxybenzene (29d). 83%; Rf 0.66 (25% EtOAc/hexanes);
[R]22D 20.8 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.50-7.13 (m,15H),
6.75 (br d, J ) 8.0 Hz, 1H), 6.66 (br d, J ) 7.7 Hz, 2H), 6.36-
6.24 (m, 1H), 6.01-5.89 (m, 1H), 5.32 (br d, J ) 10.2 Hz, 1H),
5.30 (br d, J ) 17.3 Hz, 1H), 5.13 (dd, J ) 10.2, 1.7 Hz, 1H), 4.94
(dd, J ) 17.3, 1.1 Hz, 1H), 4.68 (br t, J ) 11.3 Hz, 2H), 4.63 (dd,
J ) 11.0, 4.1 Hz, 2H), 4.35 (d, J ) 11.8 Hz, 1H), 4.20 (d, J )
11.0 Hz, 1H), 4.05 (dd, J ) 7.4, 4.4 Hz, 1H), 3.98 (dd, J ) 6.6,
5.0 Hz, 1H), 3.84 (s, 3H), 3.62 (s, 3H), 3.50-3.43 (m, 2H); 13C
NMR (CDCl3) δ 148.8, 147.5, 139.0, 138.9, 138.1, 137.8, 136.0,
135.3, 128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.4, 127.3, 120.1,
118.8, 117.1, 111.5, 111.2, 83.5, 83.2, 80.1, 75.4, 74.1, 70.4, 55.9,
55.6, 50.6; HRMS m/z (ESI) calcd for C37H40O5Na (M + Na)+
587.2767, found 587.2786.
J ) 5.8 Hz, 2H), 6.91 (app t, J ) 6.6 Hz, 2H), 6.01-5.85 (m, 1H),
5.33 (br d, J ) 9.6 Hz, 1H), 5.29 (br d, J ) 8.5 Hz, 1H), 4.74 (d,
J ) 11.6 Hz, 2H), 4.63 (d, J ) 11.6 Hz, 1H), 4.53 (d, J ) 11.6
Hz, 1H), 4.35 (dd, J ) 11.8, 3.3 Hz, 2H), 4.02 (app t, J ) 6.3 Hz,
1H), 3.78 (app t, J ) 5.8 Hz, 1H), 3.55-3.39 (m, 2H), 3.32-3.15
(m, 1H), 3.14-3.08 (m, 1H), 2.20-2.03 (m, 1H), 2.02-1.89 (m,
1H); 13C NMR (CDCl3) δ 138.9, 138.8, 138.0, 135.3, 130.0, 129.9,
128.5, 128.4, 128.3, 127.8, 127.7, 127.5, 127.4, 118.9, 115.4, 115.2,
83.3, 82.6, 80.9, 74.8, 73.7, 70.8, 60.9, 42.4, 33.3; HRMS m/z (ESI)
calcd for C35H38O4F (M)+ 541.2754, found 541.2750.
(3S,4R,5R,6S)-3-(4-Chlorophenyl)-4,5,6-tri(benzyloxy)-7-
octaen-1-ol (28g). Rf 0.16 (25% EtOAc/hexanes); [R]22 45.3 (c
D
1, CHCl3); 1H NMR (CDCl3) δ 7.48-7.23 (m, 15H), 7.19 (d, J )
8.0 Hz, 2H), 7.0 (d, J ) 8.2 Hz, 2H), 5.99-5.83 (m, 1H), 5.35 (br
d, J ) 9.6 Hz, 1H), 5.32 (br d, J ) 8.5 Hz, 1H), 4.74 (d, J ) 11.6
Hz, 2H), 4.63 (d, J ) 11.6 Hz, 1H), 4.53 (d, J ) 11.6 Hz, 1H),
4.35 (dd, J ) 11.8, 3.3 Hz, 2H), 4.04 (app t, J ) 6.3 Hz, 1H), 3.78
(app t, J ) 5.8 Hz, 1H), 3.55-3.39 (m, 2H), 3.35-3.18 (m, 1H),
3.15-3.08 (m, 1H), 2.18-2.03 (m, 1H), 2.02-1.89 (m, 1H); 13C
NMR (CDCl3) δ 140.9, 138.8, 138.7, 135.2, 132.3, 129.9, 128.6,
128.5, 128.4, 128.3, 127.9, 127.7, 127.5, 127.4, 118.9, 83.1, 82.5,
80.8, 74.8, 73.8, 70.8, 67.1, 60.8, 42.4, 33.0; HRMS m/z (ESI) calcd
for C35H38O4Cl (M)+ 557.2459, found 557.2463.
General Procedure for the Terminal Double Bond Installation
by Selenoxide Elimination. Tributylphosphine (0.51 g, 2.5 mmol)
was added to the solution of an appropriate alcohol 28 (0.5 mmol)
and o-nitrophenylselenocyanate (0.56 g, 2.5 mmol) in THF (30 mL).
The reaction went to completion immediately and was quenched
with 1 M NaOH solution (15 mL) for 30 min. The resulting mixture
was diluted with water (100 mL) and extracted with ether (3 ×
100 mL). Organic layers were combined, dried with MgSO4, and
concentrated under reduced pressure. The yellow residue was
dissolved in THF (30 mL) and cooled to 0 °C, and an aqueous
6-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)octa-1,7-dien-3-yl)-4-
methoxybenzo[d][1,3]dioxole (29e). 84% (3 steps); Rf 0.65 (25%
1
EtOAc/hexanes); H NMR (CDCl3) δ 7.39-7.19 (m, 15H), 6.36
(d, J ) 1.4 Hz, 1H), 6.34 (d, J ) 1.4 Hz, 1H), 6.28 (m, 1H), 5.98
5704 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
(m, 1H), 5.94 (s, 2H), 5.37 (br d, J ) 3.3 Hz, 1H), 5.32 (br d, J )
10.5 Hz, 1H), 5.16 (dd, J ) 10.2, 1.9 Hz, 1H), 4.97 (dd, J ) 17.3,
1.9 Hz, 1H), 4.75 (d, J ) 11.6 Hz, 1H), 4.69 (d, J ) 11.8 Hz, 1H),
4.67 (d, J ) 10.7 Hz, 1H), 4.63 (d, J ) 11.6 Hz, 1H), 4.39 (d, J )
11.8 Hz, 1H), 4.30 (d, J ) 10.7 Hz, 1H), 4.08 (dd, J ) 7.4, 4.4
Hz, 1H), 3.97 (dd, J ) 6.6, 5.0 Hz, 1H), 3.69 (s, 3H), 3.49 (dd, J
) 6.6, 4.4 Hz, 1H), 3.45 (dd, 1H); 13C NMR (CDCl3) δ 148.8,
143.5, 139.0, 138.1, 137.6, 137.3, 136.0, 133.7, 128.6, 128.5, 128.3,
128.2, 127.9, 127.8, 127.4, 127.3, 118.9, 117.4, 107.6, 102.4, 101.3,
83.5, 83.1, 80.1, 75.4, 74.2, 70.4, 56.4, 51.0; HRMS m/z (ESI) calcd
for C37H38O6 (M)+ 578.2668, found 578.2677.
2.4, 1.3 Hz, 1H), 5.73 (ddd, J ) 10.1, 4.7, 1.9 Hz, 1H), 4.79-4.64
(m, 6H), 4.16 (m, 1H), 3.81 (m, 2H), 3.73 (app t, J ) 4.5 Hz, 1H);
13C NMR (CDCl3) δ 147.6, 146.7, 139.0, 138.8, 132.5, 129.1, 128.6,
128.4, 128.1, 128.0, 127.8, 127.7, 127.6, 123.5, 110.9, 107.9, 101.1,
80.1, 80.0, 79.2, 74.8, 73.1, 72.5, 45.6; HRMS m/z (ESI) calcd for
C34H32O5 (M)+ 520.2250, found 520.2265.
4-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)-1,2-
dimethoxybenzene (30d). 81%; Rf 0.58 (25% EtOAc/hexanes);
1
[R]22 -93.7 (c 1, CHCl3); H NMR (CDCl3) δ 7.60-7.19 (m,
D
15H), 6.81 (d, J ) 11.8 Hz, 3H), 5.91 (dd, J ) 9.9, 2.5 Hz, 1H),
5.79 (ddd, J ) 9.9, 4.7, 1.6 Hz, 1H), 4.90-4.61 (m, 6H), 4.17 (m,
1H), 3.88 (s, 3H), 3.82 (m, 3H), 3.75 (s, 3H); 13C NMR (CDCl3)
δ 148.4, 148.0, 138.9, 138.8, 138.7, 131.0, 129.3, 128.4, 128.3,
128.0, 127.9, 127.7, 127.5, 122.1, 113.9, 110.7, 79.9, 79.8, 79.5,
74.5, 73.0, 72.1, 55.9, 55.8, 45.2; HRMS m/z (ESI) calcd for
C36H36O5Na (M + Na)+ 559.2454, found 559.2459.
1-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)-1,7-octadien-3-yl)-4-
chlorobenzene (29f). 79%; Rf 0.59 (25% EtOAc/hexanes); [R]22
D
106.0 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.53-7.15 (m,15H), 7.09
(dd, J ) 8.8, 5.5 Hz, 2H), 6.95 (t, J ) 8.8 Hz, 2H), 6.44-6.26 (m,
1H), 6.11-5.86 (m, 1H), 5.36 (br d, J ) 10.4 Hz, 1H), 5.33 (br d,
J ) 17.9 Hz, 1H), 5.17 (d, J ) 10.1 Hz, 1H), 4.92 (d, J ) 17.3
Hz, 1H), 4.71 (d, J ) 11.0 Hz, 2H), 4.64 (dd, J ) 10.7, 5.0 Hz,
2H), 4.39 (d, J ) 12.1 Hz, 1H), 4.19 (d, J ) 10.7 Hz, 1H), 4.06
(dd, J ) 7.4, 4.4 Hz, 1H), 3.97 (dd, J ) 6.9, 4.6 Hz, 1H), 3.56-
3.42 (m, 2H); 13C NMR (CDCl3) δ 138.8, 138.4, 138.0, 137.3,
135.9, 129.7, 129.6, 128.7, 128.5, 128.3, 128.2, 128.0, 127.9, 127.8,
127.5, 127.3, 118.9, 117.5, 115.2, 114.9, 83.4, 83.0, 79.7, 75.3,
74.4, 70.3, 50.2; HRMS m/z (ESI) calcd for C35H35O3FNa (M +
Na)+ 545.2468, found 545.2469.
6-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)-4-
methoxybenzo[d][1,3]dioxole (30e). 96%; Rf 0.57 (25% EtOAc/
1
hexanes); H NMR (CDCl3) δ 7.42-7.31 (m, 15H), 6.54 (d, J )
1.4 Hz, 1H), 6.47 (d, J ) 1.4 Hz, 1H), 5.98 (s, 2H), 5.93 (ddd, J
) 9.9, 2.8, 1.1 Hz, 1H), 5.78 (ddd, J ) 9.9, 4.7, 1.7 Hz, 1H), 4.80-
4.68 (m, 6H), 4.18 (m, 1H), 3.85 (m, 2H), 3.83 (s, 3H), 3.73 (app
t, J ) 4.7 Hz, 1H); 13C NMR (CDCl3) δ 148.6, 143.1, 138.9, 138.8,
134.3, 133.2, 129.1, 128.5, 128.4, 128.0, 127.9, 127.7, 127.6, 127.5,
110.0, 104.4, 101.5, 79.9, 79.8, 79.3, 74.6, 73.2, 72.2, 56.6, 45.7;
HRMS m/z (ESI) calcd for C35H34O6 (M)+ 550.2355, found
550.2356.
1-((3S,4R,5R,6S)-4,5,6-Tri(benzyloxy)-1,7-octadien-3-yl)-4-
fluorobenzene (29g). 71%; Rf 0.78 (25% EtOAc/hexanes); [R]22
D
109.1 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.53-7.12 (m, 15H), 7.25
(d, J ) 8.0 Hz, 2H), 7.05 (d, J ) 8.5 Hz, 2H), 6.36-6.24 (m, 1H),
6.09-5.94 (m, 1H), 5.35 (br d, J ) 8.5 Hz, 1H), 5.33 (br d, J )
17.9 Hz, 1H), 5.16 (d, J ) 12.1 Hz, 1H), 4.91 (d, J ) 17.3 Hz,
1H), 4.70 (d, J ) 12.6 Hz, 2H), 4.64 (dd, J ) 10.7, 3.8 Hz, 2H),
4.38 (d, J ) 11.8 Hz, 1H), 4.18 (d, J ) 10.7 Hz, 1H), 4.04 (dd, J
) 7.1, 3.8 Hz, 1H), 3.96 (dd, J ) 6.9, 4.6 Hz, 1H), 3.56-3.38 (m,
2H); 13C NMR (CDCl3) δ 141.2, 138.8, 138.0, 137.0, 135.9, 132.1,
129.7, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.5,
127.4, 118.9, 117.8, 83.4, 82.9, 79.6, 75.4, 74.5, 70.3, 50.4; HRMS
m/z (ESI) calcd for C35H35O3ClNa (M + Na)+ 561.2172, found
561.2167.
1-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)-4-fluoro-
benzene (30f). 73%; Rf 0.68 (25% EtOAc/hexanes); [R]22D -53.0
1
(c 1, CHCl3); H NMR (CDCl3) δ 7.61-7.25 (m, 15H), 7.07 (t, J
) 8.5 Hz, 4H), 5.97 (dd, J ) 10.1, 2.5 Hz, 1H), 5.79 (ddd, J )
10.1, 4.7, 1.6 Hz, 1H), 4.90-4.65 (m, 6H), 4.23 (m, 1H), 4.06-
3.78 (m, 3H); 13C NMR (CDCl3) δ 138.7, 131.8, 131.7, 128.8,
128.6, 128.4, 128.1, 128.0, 127.8, 127.6, 115.0, 114.7, 79.8, 79.7,
79.0, 74.6, 73.0, 72.5, 45.0; HRMS m/z (ESI) calcd for C33H31O3FNa
(M + Na)+ 517.2155, found 517.2147.
1-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)-4-chloro-
benzene (30g). 77%; Rf 0.51 (25% EtOAc/hexanes); [R]22D -130.8
1
(c 1, CHCl3); H NMR (CDCl3) δ 7.56-7.05 (m, 19H), 5.92 (dd,
General Procedure for Ring-Closing Metathesis. An appropri-
ate diene 29 (0.3 mmol) was dissolved in dry CH2Cl2 (16 mL)
followed by the addition of the Grubbs’ catalyst (Cy3P)2(PhCHd)-
RuCl2 (11 mg, 11.4 µmol). After 12 h, DMSO (0.11 g, 1.4 mmol)
was added, and the reaction mixture was stirred for an additional
6 h. The mixture was then concentrated under reduced pressure.
The residue was presorbed on silica gel and purified by column
chromatography (1-4% EtOAc/hexanes) to afford pure conduritol
analogues 30a-g as an oil.
J ) 9.9, 2.5 Hz, 1H), 5.73 (ddd, J ) 9.9, 4.7, 1.6 Hz, 1H), 4.98-
4.56 (m, 6H), 4.15 (m, 1H), 3.90-3.71 (m, 3H); 13C NMR (CDCl3)
δ 138.8, 138.6, 138.5, 137.2, 132.8, 131.6, 128.7, 128.5, 128.4,
128.1, 127.9, 127.8, 79.7, 79.6, 78.8, 74.6, 73.0, 72.5, 45.1; HRMS
m/z (ESI) calcd for C33H31O3ClNa (M + Na)+ 533.1859, found
533.1860.
Compound 31. To a solution of 30c (0.114 g, 0.22 mmol) in 5
mL of a mixture of acetone-H2O (9:1) was added NMO (0.036 g,
0.26 mmol) and 2.5% OsO4 in tert-butyl alcohol (0.224 g solution,
0.022 mmol). The mixture was stirred overnight, then quenched
with 10% NaHSO3 (1 g), diluted with water (20 mL), extracted
with ether (3 × 20 mL), and dried (MgSO4). After the removal of
the solvent the crude diol was dissolved in DMF (5 mL).
2,2-Dimethoxypropane (0.046 g, 0.44 mmol) and TsOH (0.0023
g, 0.022 mmol) were added and the reaction mixture was stirred
for 3 h at room temperature. The mixture was diluted with water
(30 mL), extracted with ether (3 × 30 mL), and dried (MgSO4).
After the removal of the solvent the residue was chromatographed
(25% EtOAc/hexanes). The pure acetonide (0.090 g) was dissolved
in MeOH (10 mL) and hydrogenolyzed overnight (50 psi H2, 10%
Pd/C). The resulting solution was filtered through a layer of Celite
and the solvent was removed to give pure 31 (0.049 g, 69% from
((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)benzene
1
(30a). 92%; Rf 0.66 (25% EtOAc/hexanes); H NMR (CDCl3) δ
7.48-7.30 (m, 20H), 5.99 (dd, J ) 10.1, 2.0 Hz, 1H), 5.85 (ddd,
J ) 10.1, 4.3, 1.9 Hz, 1H), 4.86-4.68 (m, 6H), 4.25 (br s, 1H),
3.91 (br s, 3H); 13C NMR (CDCl3) δ 138.9, 138.8, 138.7, 130.4,
129.0, 128.5, 128.3, 128.3, 128.0, 127.8, 127.7, 127.5, 127.4, 127.0,
79.9, 79.8, 79.1, 74.6, 72.8, 72.4, 45.8; HRMS m/z (ESI) calcd for
C33H33O3 (M + H)+ 477.2430, found 477.2423.
1-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)-4-meth-
oxybenzene (30b). 89%; Rf 0.63 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.42-7.28 (m, 15H), 7.24 (d, J ) 8.7 Hz, 2H), 6.90 (d,
J ) 8.7 Hz, 2H), 5.97 (ddd, J ) 9.9, 2.4, 0.9 Hz, 1H), 5.78 (ddd,
J ) 9.9, 4.5, 1.7 Hz, 1H), 4.81-4.64 (m, 6H), 4.19 (m, 1H), 3.83
(s, 3H), 3.80 (m, 3H); 13C NMR (CDCl3) δ 158.7, 139.0, 138.9,
138.8, 131.3, 130.6, 129.3, 128.5, 128.4, 128.0, 127.9, 127.8, 127.5,
113.5, 80.2, 80.0, 79.3, 74.7, 72.9, 72.4, 55.3, 45.1; HRMS m/z
(EI) calcd for C34H34O4 (M)+ 506.2457, found 506.2446.
5-((1S,4S,5R,6R)-4,5,6-Tri(benzyloxy)cyclohex-2-enyl)benzo-
[d][1,3]dioxole (30c). 94%; Rf 0.59 (25% EtOAc/hexanes); 1H NMR
(CDCl3) δ 7.41-7.28 (m, 15H), 6.81 (m, 1H), 6.78 (br s, 1H),
6.75 (dd, J ) 8.1, 1.5 Hz, 1H), 5.96 (s, 2H), 5.88 (ddd, J ) 10.1,
1
30c); H NMR (CDCl3) δ 6.82 (d, J ) 1.4 Hz, 1H), 6.79 (d, J )
8.0 Hz, 1H), 6.73 (dd, J ) 8.0, 1.4 Hz, 1H), 5.93 (s, 2H), 4.58 (dd,
J ) 6.6, 6.1 Hz, 1H), 4.31 (dd, J ) 6.9, 6.1 Hz, 1H), 3.94 (dd, J
) 5.5, 3.9 Hz, 1H), 3.81 (dd, J ) 8.0, 6.9 Hz, 1H), 3.66 (dd, J )
8.0, 5.5 Hz, 1H), 3.30 (dd, J ) 6.6, 3.9 Hz, 1H), 1.48 (s, 3H), 1.34
1
(s, 3H); H NMR (D2O, 45 °C) δ 7.17 (d, J ) 1.7 Hz, 1H), 7.15
(d, J ) 8.0 Hz, 1H), 7.09 (dd, J ) 8.0, 1.7 Hz, 1H), 6.21 (s, 2H),
5.02 (dd, J ) 8.5, 7.2 Hz, 1H), 4.58 (dd, J ) 8.5, 7.2 Hz, 1H),
J. Org. Chem, Vol. 71, No. 15, 2006 5705

Kireev et al.
4.14 (dd, J ) 4.4, 4.1 Hz, 1H), 4.00 (dd, J ) 9.1, 8.8 Hz, 1H),
3.82 (dd, J ) 9.1, 4.1 Hz, 1H), 3.44 (dd, J ) 8.8, 4.4 Hz, 1H),
1.72 (s, 3H), 1.62 (s, 3H); 13C NMR (CDCl3) δ 148.1, 147.0, 131.4,
122.3, 109.6, 109.1, 108.5, 101.2, 78.7, 75.9, 75.1, 74.3, 74.0, 46.5,
28.0, 25.5; HRMS m/z (ESI) calcd for C16H20O7 (M)+ 324.1209,
found 324.1215.
tert-butyl alcohol (0.224 g solution, 0.022 mmol). The mixture was
stirred at room temperature for 48 h, and then quenched with 10%
NaHSO3 (5 mL), diluted with water (20 mL), extracted with ether
(3 × 20 mL), and dried (MgSO4). After the solvent was removed,
the crude diol was dissolved in MeOH (8 mL), and 10% Pd/C (75
mg, 0.06 mmol) was added. The suspension was stirred for 48 h
with an H2 balloon. The catalyst was filtered off with a Celite pad
and solution was concentrated under reduced pressure. Redissolution
of the material in H2O followed by lyophilization gave pure
compounds 9a-e as powders.
General Procedure for the Preparation of the (1R,2R,3S,6R)-
6-Aryl-4-cyclohexene-1,2,3-triol (8a-e). NH3 gas was liquefied
at -78 °C in two 50 mL flasks. The first flask was charged with
chopped Li (0.2 g, 28 mmol), while compound 30a-e (0.1 mmol)
in THF (5 mL) was added to the second one. After the complete
dissolution of Li, the deep blue solution was added dropwise via
cannula to the compound 30a-e until the blue color persisted for
15 s. The reaction mixture was quenched with dry NH4Cl (0.2 g,
3.7 mmol) and allowed to stand at room temperature until the
complete evaporation of NH3. The residue was diluted with water
(20 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine and dried with MgSO4. The
solvent was removed, and residue was dissolved in dry methanol.
Activated carbon was added to the solution. After the solution was
stirred for 5 min, the carbon was filtered off with a Celite pad and
solution was concentrated under reduced pressure. Lyophilization
of its aqueous solution affords pure compounds 8a-e as powders.
(1R,2R,3S,6R)-6-Phenyl-4-cyclohexene-1,2,3-triol (8a). 85%;
Rf 0.36 (20% MeOH/EtOAc); [R]28D -304.0 (c 1, MeOH); 1H NMR
(D2O) δ 7.47-7.24 (m, 5H), 5.89-5.73 (m, 2H), 4.21 (dd, J )
7.4, 1.6 Hz 1H), 3.95 (dd, J ) 10.7, 6.6 Hz, 1H), 3.84 (app t, J )
6.0 Hz, 1H), 3.55 (dd, J ) 10.7, 7.7 Hz, 1H); 13C NMR (D2O) δ
138.0, 130.6, 129.1, 128.6, 128.5, 127.5, 72.8, 72.7, 70.7, 47.5;
HRMS m/z (ESI) calcd for C12H14O3Na (M + Na)+ 229.0835, found
229.0834.
(1R,2R,3R,4S,5R,6R)-6-Phenylcyclohexane-1,2,3,4,5-pentaol (9a).
1
77%; Rf 0.21 (2% MeOH/EtOAc); [R]25 42.8 (c 1, MeOH); H
D
NMR (D2O) δ 7.50-7.28 (m, 5H), 4.28-3.50 (m, 6H); 13C NMR
(D2O) δ 137.7, 130.0, 128.8, 127.4, 74.0, 73.2, 72.2, 71.6, 71.2;
HRMS m/z (ESI) calcd for C12H16O5Na (M + Na)+ 263.0889, found
263.0891.
(1R,2R,3R,4S,5R,6R)-6-(4-Methoxyphenyl)cyclohexane-1,2,3,4,5-
pentaol (9b). 95%; Rf 0.35 (10% MeOH/EtOAc); [R]28D 35.5 (c 1,
MeOH); 1H NMR (D2O) δ 7.34 (d, J ) 8.5 Hz, 2H), 7.00 (d, J )
8.5 Hz, 2H), 4.17 (m, 1H), 4.10 (d, J ) 6.6 Hz, 1H), 3.98 (d, J )
8.0 Hz, 1H), 3.91 (d, J ) 11.6 Hz, 1H), 3.89-3.76 (m, 1H), 3.84
(s, 3H), 3.53 (m, 1H); 13C NMR (D2O) δ 157.9, 131.3, 130.1, 114.2,
74.0, 73.2, 71.5, 71.2, 55.5; HRMS m/z (ESI) calcd for C13H18O6Na
(M + Na)+ 293.0995, found 293.1008.
(1R,2R,3R,4S,5R,6R)-6-(Benzo[d][1,3]dioxol-5-yl)cyclohexane-
1,2,3,4,5-pentaol (9c). 95%; Rf 0.42 (10% MeOH/EtOAc); [R]28
D
1
38.6 (c 1, MeOH); H NMR (D2O) δ 6.89 (s, 1H), 6.85 (s, 2H),
5.93 (s, 2H), 4.17 (m, 1H), 4.07 (app t, J ) 8.0 Hz, 1H), 3.92 (m,
2H), 3.79 (app t, J ) 8.0 Hz, 1H), 3.45 (dd, J ) 10.5, 5.2 Hz, 1H);
13C NMR (D2O) δ 147.3, 146.0, 131.5, 123.3, 110.4, 108.6, 101.2,
73.8, 73.2, 71.8, 71.4; HRMS m/z (ESI) calcd for C13H16O7Na (M
+ Na)+ 307.0788, found 307.0793.
(1R,2R,3S,6R)-6-Methoxyphenyl-4-cyclohexene-1,2,3-triol (8b).
85%; Rf 0.27 (20% MeOH/EtOAc); [R]23 -220.0 (c 1, MeOH);
D
(1R,2R,3R,4S,5R,6R)-6-(3,4-Dimethoxyphenyl)cyclohexane-
1H NMR (D2O) δ 7.25 (d, J ) 8.0 Hz, 2H), 7.02 (d, J ) 8.0 Hz,
2H), 5.89-5.73 (m, 2H), 4.23 (d, J ) 7.2, Hz 1H), 3.93 (m, 2H),
3.85 (s, 3H), 3.78-3.53 (m, 1H); 13C NMR (D2O) δ 158.2, 131.7,
130.5, 128.9, 113.9, 72.9, 72.7, 70.8, 55.6, 46.7; HRMS m/z (ESI)
calcd for C13H16O4Na (M + Na)+ 259.0940, found 259.0936.
(1R,2R,3S,6R)-6-(Benzo[d][1,3]dioxol-5-yl)-4-cyclohexene-1,2,3-
1,2,3,4,5-pentaol (9d). 93%; Rf 0.46 (10% MeOH/EtOAc); [R]23
D
44.7 (c 1, MeOH); 1H NMR (D2O) δ 7.04-6.96 (m, 3H), 4.22 (br
s, 1H), 4.11 (app t, J ) 6.6 Hz, 1H), 3.99-3.78 (m, 3H), 3.87 (s,
3H), 3.85 (s, 3H), 3.52 (m, 1H); 13C NMR (D2O) δ 148.0, 147.3,
130.8, 122.4, 114.3, 111.9, 73.9, 73.2, 71.6, 71.4, 55.9; HRMS m/z
(ESI) calcd for C14H20O7Na (M + Na)+ 323.1101, found 323.1095.
triol (8c). 61%; Rf 0.39 (10% MeOH/CH2Cl2); [R]23 -274.3 (c
D
(1R,2R,3R,4S,5R,6R)-6-(4-Methoxybenzo[d][1,3]dioxol-5-yl)-
cyclohexane-1,2,3,4,5-pentaol (9e). 95%; Rf 0.47 (10% MeOH/
EtOAc); [R]28D 47.2 (c 1, MeOH); 1H NMR (D2O) δ 6.69 (s, 2H),
6.01 (s, 2H), 4.27 (s, 1H), 4.14 (m, 1H), 3.99-3.85 (m, 3H), 3.96
(s, 3H), 3.53 (m, 1H); 13C NMR (D2O) δ 148.6, 142.9, 133.9, 132.5,
110.1, 104.2, 101.8, 73.8, 73.2, 71.9, 71.6, 56.9; HRMS m/z (ESI)
calcd for C14H18O8Na (M + Na)+ 337.0893, found 337.0882.
1, MeOH); 1H NMR (D2O) δ 6.90 (d, J ) 8.0 Hz, 1H), 6.83 (br s,
1H), 6.79 (br d, J ) 8.0 Hz, 1H), 5.98 (s, 2H), 5.85-5.75 (m, 2H),
4.20 (br d, J ) 7.4 Hz, 1H), 3.92 (app t, J ) 8.8 Hz, 1H), 3.78 (m,
1H), 3.57 (app t, J ) 8.8, Hz, 1H); 13C NMR (D2O) δ 147.2, 146.4,
131.9, 129.1, 128.8, 123.9, 110.9, 108.3, 101.2, 72.9, 72.7, 70.7,
47.2; HRMS m/z (ESI) calcd for C13H14O5Na (M + Na)+ 273.0733,
found 273.0735.
General Procedure for the Preparation of the (1S,2R,3R,4R)-
4-Arylcyclohexane-1,2,3-triol (10a-e). To a stirred solution of
olefin 30a-e (0.1 mmol) in THF-MeOH (9:1, 5 mL) was added
10% Pd/C (50 mg, 0.04 mmol). The suspension was stirred for 48
h with an H2 balloon. The catalyst was filtered off with a Celite
pad and solution was concentrated under reduced pressure. The
residue was dissolved in ether (30 mL), washed with water (3 ×
20 mL) and brine, dried (MgSO4), and evaporated under reduced
pressure. Redissolution of the material in H2O followed by
lyophilization gave pure compounds 10a-e as powders.
(1R,2R,3S,6R)-6-(3,4-Dimethoxyphenyl)-4-cyclohexene-1,2,3-
triol (8d). 72%; Rf 0.45 (10% MeOH/CH2Cl2); [R]23 -221.2 (c
D
1, MeOH); 1H NMR (D2O) δ 7.03 (d, J ) 8.2 Hz, 1H), 6.90 (br s,
1H), 6.87 (br d, J ) 8.5, Hz 1H), 5.90-5.71 (m, 2H), 4.22 (d, J )
6.3 Hz, 1H), 4.03-3.73 (m, 2H), 3.86 (s, 6H), 3.65-3.52 (m, 1H);
13C NMR (D2O) δ 147.8, 147.5, 131.1, 129.1, 128.7, 123.1, 114.4,
111.7, 72.7, 70.7, 55.9, 47.0; HRMS m/z (ESI) calcd for C14H18O5Na
(M + Na)+ 289.1046, found 289.1052.
(1R,2R,3S,6R)-6-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-4-cyclo-
hexene-1,2,3-triol (8e). 93%; Rf 0.32 (10% MeOH/CH2Cl2); [R]23
D
-199.6 (c 1, MeOH); 1H NMR (D2O) δ 6.49 (s, 1H), 6.39 (s, 1H),
5.93 (s, 2H), 5.80 (d, J ) 9.3 Hz, 1H), 5.75-5.65 (m, 1H), 4.18
(br d, J ) 7.4 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 1H), 3.73 (m, 1H),
3.55 (dd, J ) 18.2, 8.2 Hz, 1H); 13C NMR (D2O) δ 160.0, 156.7,
148.3, 142.7, 141.0, 134.0, 132.7, 129.3, 128.5, 128.3, 110.4, 110.2,
108.6, 104.7, 101.7, 100.4, 72.7, 70.5, 56.7, 55.5, 47.5, 47.4; HRMS
m/z (ESI) calcd for C14H16O6Na (M + Na)+ 303.0839, found
303.0829.
(1S,2R,3R,4R)-4-Phenylcyclohexene-1,2,3-triol (10a). 90%; Rf
1
0.85 (20% MeOH/EtOAc); [R]26 145.4 (c 1, MeOH); H NMR
D
(D2O) δ 7.46-7.33 (d, J ) 4.4 Hz, 4H), 5.32-5.23 (m, 1H), 3.84-
3.92 (m, 2H), 3.79-3.71 (m, 1H), 3.28-3.21 (m, 1H), 2.18-1.64
(m, 4H); 13C NMR (D2O) δ 142.5, 129.1, 128.6, 126.7, 74.5, 73.2,
71.4, 43.4, 27.6, 22.3; HRMS m/z (ESI) calcd for C12H16O3Na (M
+ Na)+ 231.0991, found 231.0990.
(1S,2R,3R,4R)-4-(4-Methoxyphenyl)cyclohexene-1,2,3-triol (10b).
1
General Procedure for the Preparation of the (1R,2R,3R,4S,
5R,6R)-6-Arylcyclohexane-1,2,3,4,5-pentaol (9a-e). To a solution
of olefin 30a-e (0.22 mmol) in 5 mL of acetone-H2O (9:1) was
added NMO (0.036 g, 0.26 mmol) and a 2.5% solution of OsO4 in
95%; Rf 0.48 (10% MeOH/EtOAc); [R]28 48.0 (c 1, MeOH); H
D
NMR (D2O) δ 7.51 (d, J ) 8.5 Hz, 2H), 7.15 (d, J ) 8.8 Hz, 2H),
4.04 (m, 2H), 3.99 (s, 3H), 3.95 (m, 1H), 3.38 (m, 1H), 2.29-1.89
(m, 4H); 13C NMR (D2O) δ 157.7, 135.3, 130.4, 114.3, 74.7, 73.5,
5706 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis and Anticancer EValuation of Arylcyclitols
71.7, 55.8, 42.7, 27.8, 22.7; HRMS m/z (ESI) calcd for C13H18O4Na
(M + Na)+ 261.1097, found 261.1093.
at 2200 rpm (400G) for 2 min. Supernatant was discarded and the
remaining pellet was resuspended in 400 µL of Annexin Binding
Buffer (ABB: Heinz-Hepes Buffer (HHB: 30 mM HEPES; 110
mM NaCl; 10 mM KCl; 10 mM glucose; 1 mM MgCl2; pH 7.4)
plus 9 mM CaCl2) and centrifuged for 2 min at 2200 rpm. The
supernatant was removed and the remaining pellet was resuspended
in 200 µL of Annexin Binding Buffer (ABB). Then, cells in ABB
were placed into an ice-cold bath and simultaneously fluorescently
labeled with both 1 µL of propidium iodide (a 1 mg/mL stock
solution in ABB was kept at -20 °C) and 2 µL of annexin-V FITC.
After being incubated at 37 °C for 15 min, each labeled sample
was transferred to a Falcon tube. Values of relative fluorescence
intensity were measured and analyzed. The results were then
calculated and tabulated as the percentage of apoptotic or necrotic
cells.
Sulforhodamine B (SRB) Assay. A laboratory test measures
cell growth inhibition. Jurkat cells in RPMI-1640 10% FBS were
inoculated into 96 well plates in 100 µL and incubated for 24 h.
Then, one plate was fixed in situ with 50 µL of 50% (w/v)
trichloroacetic acid (TCA), to represent a measurement of the cell
population at the time of drug addition. Jurkat cells in another plate
were treated in triplicate with ether solvent (DMSO, 0.1% (v/v)
final concentration) or with one of our compounds at the indicated
final concentration (0.01, 0.1, 1, 10, 50, 100, 300, and 600 µM).
Following drug addition, plates were incubated for an additional
48 h. After that, cells were fixed in situ by layering 50 µL of cold
50% (w/v) TCA directly on top of the incubation medium and
incubated for an hour at 4 °C. The supernatant was discarded, and
plates were washed five times with tap water and air-dried.
Sulforhodamine B solution (200 µL) at 0.4% (w/v) in 1% acetic
acid was added to each well, and plates were incubated for 30 min
at room temperature. After staining, unbound dye was removed by
washing five times with 1% acetic acid, and plates were air-dried.
Bound stain was subsequently solubilized with 200 µL/well of 10
mM Tris buffer, pH 10.5, and absorbance was read on an automated
plate reader at a wavelength of 490 nm.
(1S,2R,3R,4R)-4-(Benzo[d][1,3]dioxol-5-yl)cyclohexene-1,2,3-
triol (10c). 84%; Rf 0.55 (10% MeOH/EtOAc); [R]28 41.9 (c 1,
D
MeOH); 1H NMR (D2O) δ 6.98 (s, 1H), 6.92 (s, 2H), 5.99 (s, 2H),
4.12-4.75 (m, 3H), 3.21 (m, 1H), 2.21-1.62 (m, 4H); 13C NMR
(D2O) δ 147.2, 145.6, 136.7, 122.1, 109.6, 108.4, 101.1, 74.6, 72.9,
71.2, 42.8, 27.7, 22.0; HRMS m/z (ESI) calcd for C13H16O5Na (M
+ Na)+ 275.0889, found 275.0896.
(1S,2R,3R,4R)-4-(3.4-Dimethoxyphenyl)cyclohexene-1,2,3-
triol (10d). 76%; Rf 0.46 (10% MeOH/EtOAc); [R]22 29.7 (c 1,
D
MeOH); 1H NMR (D2O) δ 6.96 (s, 3H), 4.20-3.73 (m, 3H), 3.85
(s, 3H), 3.83 (s, 3H), 3.19 (m, 1H), 2.22-1.62 (m, 4H); 13C NMR
(D2O) δ 147.9, 146.8, 135.8, 121.4, 113.1, 111.9, 74.5, 73.1, 71.3,
55.9, 42.8, 27.7, 22.3; HRMS m/z (ESI) calcd for C14H20O5Na (M
+ Na)+ 291.1203, found 291.1191.
(1S,2R,3R,4R)-4-(Methoxybenzo[d][1,3]dioxol-6-yl)cyclohex-
ene-1,2,3-triol (10e). 95%; Rf 0.61 (10% MeOH/EtOAc); [R]28
D
1
44.1 (c 1, MeOH); H NMR (D2O) δ 6.72 (s, 2H), 5.99 (s, 2H),
4.12-3.82 (m, 3H), 3.96 (s, 3H), 3.16 (m, 1H), 2.21-1.61 (m,
4H); 13C NMR (D2O) δ 148.4, 142.9, 137.8, 133.4, 108.5, 103.2,
101.6, 74.6, 72.6, 71.0, 56.8, 42.9, 27.8, 21.6; HRMS m/z (ESI)
calcd for C14H18O6Na (M + Na)+ 305.0995, found 305.0983.
Cell Culture. A human T cell leukemia cell line (Jurkat cells,
Clone E6-1) was cultivated in RPMI-1640 medium supplemented
with 10% (v/v) fetal bovine serum (FBS), 100 mg/L penicillin G,
100 mg/L streptomycin, 1.0 mM sodium pyruvate, 1.5 g/L sodium
bicarbonate, and 4.5 g/L glucose at 37 °C in a humidified
atmosphere with 10% CO2. Cells were diluted at a ratio of 1:5 every
2-3 days.
Drugs. All compounds undergoing the drug screening were
dissolved at 0.3 M dimethyl sulfoxide as a stock solution and diluted
in DMSO just before use. The maximum final concentration of
DMSO in medium was smaller than 0.1% (v/v).
Cell Counts. Jurkat control or drug treated cells were cultivated
in a 24-well tissue culture plate. To examine the viability of treated
Jurkat cells after appropriate culture for 20 h, 50 µL of 0.4% Trypan
Blue stain was added to 50 µL of a sample cell suspension. Using
a hemacytometer, both dead (Trypan Blue-positive) and live cells
were counted four times. The results were then calculated and
tabulated as percentage of dead cells. To examine the anti-
proliferative effect of the tested compounds, growth curves were
determined by a manual count method. After appropriate culture,
viable cells were counted for up to 5 days by the Trypan Blue dye
exclusion method.
Acknowledgment. We thank Professor Patrick S. Mariano
for his help with the preparation of the manuscript and the
University of New Mexico Mass Spectrometry Facility for MS
analyses. N.E.B. wishes to thank Anna Andolfi and Michele
Fiore for their assistance with narciclasine isolation. This work
is supported by the U.S. National Institutes of Health (RR-16480
and CA-99957) under the BRIN/INBRE and AREA programs.
Flow Cytometric Annexin-V/Propidium Iodide Assay. Flow
cytometry was used to quantitatively measure apoptotic and necrotic
rates. After being cultivated with medium alone (RPMI-1640
10%FBS) or medium containing 0.1% (v/v) DMSO, or one of the
tested compounds at the indicated final concentration (0.5, 5, 15,
50, 100, and 300 µM) for 20 h, 3 × 105 Jurkat cells were centrifuged
Supporting Information Available: General methods paragraph
and copies of 1H and 13C NMR of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO0607562
J. Org. Chem, Vol. 71, No. 15, 2006 5707