Enantiodivergent formal synthesis of (+)-and (-)-cyclophellitol from D-xylose based on the latent symmetry concept

Article abstract of DOI:10.1021/jo048459p

(Chemical Equation Presented) Formal synthesis of (+)- and (-)-cyclophellitol from D-xylose has been accomplished through utilization of the latent plane of chirality present in the starting carbohydrate. The synthetic pathway is suitable for preparation

Full text of DOI:10.1021/jo048459p

ring chiral molecules are usually abundant in practical
quantities only in one enantiomeric form. Notwithstand-
ing this limitation, a number of enantiodivergent ap-
proaches to complex chiral structures starting from one
enantiomeric form of a “chiral pool” molecule have been
reported.5 These routes are particularly effective when
the chiral source possesses a latent plane of symmetry,5a
and simple chemical manipulation of the existing func-
tionalities allows crossover from one enantiomeric do-
main to the other. Such strategies are devoid of the
drawbacks associated with enzymatic or chemical asym-
metric catalysis6 and can be rather straightforward.
Enantiodivergent Formal Synthesis of (+)-
and (-)-Cyclophellitol from D-Xylose Based
on the Latent Symmetry Concept
Artem S. Kireev, August T. Breithaupt, William Collins,
Oleg N. Nadein, and Alexander Kornienko*
Department of Chemistry, New Mexico Institute of Mining
and Technology, Socorro, New Mexico 87801
akornien@nmt.edu
Received September 1, 2004
(5) (a) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem.
Soc. 1990, 112, 9439. (b) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna,
H.; Andersen, C.; Price, J. D. Isr. J. Chem. 1991, 31, 229. (c) Hudlicky,
T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55, 4683. (d)
Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. Tetrahedron Lett. 1989,
30, 4053. (e) Hudlicky, T.; Price, J. Synlett 1990, 159. (f) Nakashima,
H.; Sato, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2000,
41, 2639. (g) Popsavin, V.; Krstic, I.; Popsavin, M. Tetrahedron Lett.
2003, 44, 8897. (h) Akai, S.; Tsujino, T.; Fukuda, N.; Lio, K.; Takeda,
Y.; Kawaguchi, K.; Naka, T.; Higuchi, K.; Kita, Y. Org. Lett. 2001, 3,
4015.
(6) For recent discussion of the factors that contribute to the slow
development of commercial-scale catalytic asymmetric processes, see:
Rouhi, A. M. Chem. Eng. News 2004, 82 (24), 47.
Formal synthesis of (+)- and (-)-cyclophellitol from D-xylose
has been accomplished through utilization of the latent plane
of chirality present in the starting carbohydrate. The
synthetic pathway is suitable for preparation and biological
evaluation of cyclophellitol analogues in both enantiomeric
series.
(7) The term “pro-enantiotopic functionality” has been introduced
by Hudlicky and co-workers (ref 5a) to specify functional groups whose
differences in reactivity are responsible for the latency of symmetry.
(8) The amaryllidaceae alkaloid (+)-pancratistatin exhibits potent
anti-cancer and anti-viral activities and it is currently undergoing
preclinical development as a new anti-cancer drug. For recent discus-
sion, see: Pettit, G. R.; Melody, N.; Herald, D. L. J. Nat. Prod. 2004,
67, 322.
Development of efficient chemical pathways that allow
the preparation of both enantiomers of compounds of
biological and medicinal significance is an important goal
of synthetic organic chemistry. Enantiomers of biologi-
cally active natural products very often exhibit improved
potencies or even novel activities altogether. For example,
the unnatural (-)-enantiomer of the antitumor antibiotic
roseophilin is 2 to 10 times more potent than the natural
(+)-isomer in cytotoxicity assays.1 (-)-Quinine is an
antimalarial compound, while its quasienantiomer (+)-
quinidine is an antiarrhythmic.2 (-)-Gossypol, the enan-
tiomer of the predominant natural (+)-isomer, has anti-
cancer, male-contraceptive, and anti-HIV activities.3 In
addition, the switch from racemic to single enantiomer
chiral pharmaceuticals is important for managing prod-
uct life cycles and increasing efficacy.4 Such processes
require efficient preparation and pharmacological testing
of either enantiomer of a chiral drug or drug candidate
individually.
(9) (+)-Cyclophellitol and its various analogues are potent glycosi-
dase inhibitors. Potential therapeutic applications of these compounds
include treatments for HIV infection and the cancer metastatic process.
For discussion, see: Marco-Contelles, J. Eur. J. Org. Chem. 2001, 1607.
(10) For total syntheses of pancratistatin see: (a) Danishefsky, S.;
Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X.; Hudlicky,
T.; Ko¨nigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643. (c) Hudlicky,
T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan, B. J. Am.
Chem. Soc. 1996, 118, 10752. (d) Trost, B. M.; Pulley, S. R. J. Am.
Chem. Soc. 1995, 117, 10143. (e) Magnus, P.; Sebhat, I. K. J. Am.
Chem. Soc. 1998, 120, 5341. (f) Magnus, P.; Sebhat, I. K. Tetrahedron
1998, 54, 15509. (g) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J.
Am. Chem. Soc. 2000, 122, 6624. (h) Doyle, T. J.; Hendrix, M.;
VanDerveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53,
11153. (i) Pettit, G. R.; Melody, N.; Herald, D. L. J. Org. Chem. 2001,
66, 2583. (j) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343.
(k) Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J. Org. Chem. 2004,
69, 112.
(11) For total syntheses of cyclophellitol see: (a) Tatsuta, K.; Niwata,
Y.; Umezawa, K.; Toshima, K.; Nakata, M. Tetrahedron Lett. 1990,
31, 1171. (b) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.;
Nakata, M. Carbohydr. Res. 1991, 222, 189. (c) Akiyama, T.; Ohnari,
T.; Shima, H.; Ozaki, S. Synlett 1991, 831. (d) Moritz, V.; Vogel, P.
Tetrahedron Lett. 1992, 33, 5243. (e) Akiyama, T.; Shima, H.; Ohnari,
M.; Okazaki, T.; Ozaki, S. Bull. Chem. Soc. Jpn. 1993, 66, 3760. (f)
Shing, T. K. M.; Tai, V. W.-F. J. Chem. Soc., Chem. Commun. 1993,
995. (g) Shing, T. K. M.; Tai, V. W.-F. J. Chem. Soc., Perkin Trans. 1
1994, 2017. (h) McDevitt, R. E.; Fraser-Reid, B. J. Org. Chem. 1994,
59, 3250. (i) Sato, K.; Bokura, M.; Moriyama, H.; Igarashi, T. Chem.
Lett. 1994, 37. (j) Jung, M. E.; Choe, S. W. T. J. Org. Chem. 1995, 60,
3280. (k) Schlessinger, R. H.; Bergstrom, C. P. J. Org. Chem. 1995,
60, 16. (l) Acena, J. L.; deAlba, E.; Arjona, O.; Plumet, J. Tetrahedron
Lett. 1996, 37, 3043. (m) Letellier, P.; Ralainairina, R.; Beaupere, D.;
Uzan, R. Synthesis 1997, 925. (n) Acena, J. L.; Arjona, O.; Plumet, J.
J. Org. Chem. 1997, 62, 3360 (o) Takahashi, H.; Iimori, T.; Ikegami,
S. Tetahedron Lett. 1998, 39, 6939. (p) Ziegler, F. E.; Wang, Y. J. Org.
Chem. 1998, 63, 426. (q) Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998,
63, 7920. (r) Trost, B. M.; Hembre, E. J. Tetrahedron Lett. 1999, 40,
219. (s) Trost, B. M.; Patterson, D. E.; Hembre, E. J. Chem. Eur. J.
2001, 7, 3768. (t) Ishikawa, T.; Shimizu, Y.; Kudoh, T.; Saito, S. Org.
Lett. 2003, 5, 3879.
These demands can be addressed through enantiose-
lective synthesis in which the pathway is adjusted to the
production of either enantiomer of a chiral target by
changing the absolute asymmetry of a chiral catalyst or
auxiliary. By contrast, it has been pointed out11s that
chemical routes emanating from “chiral pool” compounds
are unsuited for this purpose, since the naturally occur-
(1) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515.
(2) Grace, A. A.; Camm, J. N. Engl. J. Med. 1998, 338, 35.
(3) Vander Jagt, D. L.; Deck, L. M.; Royer, R. E. Curr. Med. Chem.
2000, 7, 479.
(4) Rouhi, A. M. Chem. Eng. News 2003, 81(18), 56.
10.1021/jo048459p CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/22/2004
742
J. Org. Chem. 2005, 70, 742-745

enation, Swern oxidation, and reaction of the resulting
aldehyde with Ph3PdCHCO2Me (Scheme 1).16 We ex-
SCHEME 1
FIGURE 1. “Latent symmetry” approach for the synthesis of
pancratistatin and cyclophellitol enantiomers.
While investigating novel synthetic approaches to natural
cyclitols such as pancratistatin and cyclophellitol, we
noticed that the starting carbohydrate, D-xylose, has a
latent plane of symmetry. Therefore, both enantiomers
of the cyclitol targets can be reached by exploiting the
differences in chemical reactivity of the aldehyde and
hydroxyl functional groups (Figure 1).7
plored the possibility of obtaining ent-1 by directly
reversing the order of the two olefination steps. Although
carbohydrate derivatives free at the anomeric position
react with stabilized Wittig reagents to give R,â-enoates
and enones, such reactions usually suffer from the
formation of cyclized C-glycoside products and lack of
E-selectivity.17 We found that performing Wittig olefina-
tion in a concentrated solution in refluxing benzene with
the incremental addition of Ph3PdCHCO2Me suppresses
the formation of the cyclized products and gives hydroxy-
enoate 2 in excellent yield and E-selectivity (∼15:1 E/Z).
Swern oxidation of 2 to give aldehyde 3 proceeds without
complications. However, reaction of 3 with CH2dPPh3
results in complex mixtures of products under a variety
of experimental conditions, possibly because of the elec-
trophilic nature of the enoate moiety. The best experi-
mental protocol, which provides a low (20%) yield of the
desired enoate ent-1, involves a dropwise addition of an
exact stoichiometric amount of the Wittig reagent to
aldehyde 3 in THF. Disappointingly, the use of nonbasic
titanium-based methylenation reagents18 did not improve
the outcome.
To circumvent the enoate reactivity problem, the
anomeric position of tri-O-benzyl-D-xylose was protected
to form ethyl thioacetal 4 (Scheme 2).11q,19 Swern oxida-
tion of the primary hydroxyl in 4 was followed by the
immediate treatment of the crude aldehyde with Ph3Pd
CH2 to give a good yield of terminal olefin 5. Unmasking
the latent aldehyde in 5 with NBS/CdCO3 and subjecting
the crude material to reaction with Ph3PdCHCO2Me
cleanly provides the desired enantiomeric enoate ent-1
in excellent yield. Although this sequence involves ad-
ditional protection/deprotection steps, it is high yielding
and scalable.
The potent and diverse biological activities as well as
promising medicinal applications of natural (+)-pancrat-
istatin8 and (+)-cyclophellitol9 have led to a large body
of synthetic effort culminating in many total syntheses
of these targets and their analogues.10,11 In addition, a
synthesis of (-)-cyclophellitol has been accomplished by
Trost and co-workers via the application of a dynamic
kinetic asymmetric transformation process.11s To our
knowledge, the biology of (-)-cyclophellitol or its ana-
logues has not been investigated, despite potent glycosi-
dase inhibitory activities found with (+)-cyclophellitol
analogues in which three of the six stereocenters origi-
nally present in the natural product are inverted.12 While
(-)-pancratistatin has not been synthesized in enantio-
merically pure form, the ongoing synthetic work toward
this antipode has been disclosed13 and the synthesis of
(-)-7-deoxypancratistatin has been achieved by Hudlicky
and co-workers.14 Biological testing of the latter com-
pound revealed activity similar in scope to its natural
enantiomer, although of reduced magnitude.15 These
intriguing observations warrant further exploration of
chemistry and biology of the above natural cyclitols and
their analogues in both antipodal series. In this paper
we wish to report a formal synthesis of (+)- and (-)-
cyclophellitol based on the “latent symmetry” approach.
Our enantiodivergent strategy relies on the synthesis
of both enantiomeric forms of enoate 1 from D-xylose. We
have previously reported a straightforward preparation
of 1 from tri-O-benzyl-D-xylose by way of Wittig methyl-
(12) (a) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata,
M. J. Antibiot. 1991, 44, 912. (b) Tai, V. W.-F.; Fung, P.-H.; Wong,
Y.-S.; Shing, T. K. M. Tetrahedron: Asymmetry 1994, 5, 1353.
(13) Hudlicky, T. Chem. Rev. 1996, 96, 3.
(14) Akgu¨n, H.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3081.
(15) Hudlicky, T.; Rinner, U.; Gonzales, D.; Akgun, H.; Schilling,
S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002,
67, 8726.
(16) Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831.
(17) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(18) Pine, S. H. Org. React. 1993, 43, 1.
(19) (a) Herczegh, P.; Zsely, M.; Szilagyi, L.; Batta, G.; Bajza, I.;
Bognar, R. Tetrahedron 1989, 45, 2793. (b) Agocs, A.; Gunda, T. E.;
Batta, G.; Kovacs-Kulyassa, A.; Herczegh, P. Tetrahedron: Asymmetry
2001, 12, 469.
J. Org. Chem, Vol. 70, No. 2, 2005 743

reported by Trost and co-workers,11r,s this pathway
constitutes a formal synthesis of the natural product. In
addition to providing access to both enantiomers of
cyclophellitol, the synthesis is scalable and we have
performed it on a gram quantity without compromising
its efficiency. These advantages make the synthetic
pathway suitable for preparation of cyclophellitol ana-
logues in both enantiomeric series for biological evalua-
tion.
SCHEME 2
In conclusion, the application of the latent symmetry
principle to D-xylose has resulted in enantiodivergent
synthesis of (+)- and (-)-cyclophellitol and studies are
ongoing to utilize this strategy for the synthesis of each
pancratistatin enantiomer. Being the second most abun-
dant sugar after D-glucose,22 D-xylose has been exten-
sively utilized as a convenient and inexpensive “chiral
pool” resource in multistep syntheses of various chiral
targets. However, L-xylose is rather expensive and,
therefore, it is not commonly included in synthetic
planning. We hope that the chemistry described here
provides a partial solution to this problem and serves as
an impetus for further exploitation of the latent sym-
metry elements contained in the structures of “chiral
pool” molecules.
With the synthetic pathways to 1 and ent-1 available
we demonstrated the feasibility of accessing each cyclo-
phellitol enantiomer by completing the synthesis of the
(+)-antipode (Scheme 3). Addition of a vinylcopper re-
SCHEME 3
Experimental Section
Methyl (2E,4S,5R,6R)-4,5,6-Tri(benzyloxy)-7-hydroxy-2-
heptenoate (2). A mixture of 2,3,4-tri-O-benzyl-D-xylopyranose
(2.10 g, 5 mmol) and methyl (triphenylphosphoranylidene)-
acetate (3.34 g, 10 mmol) in benzene (50 mL) was heated under
reflux for 8 h. One more equivalent of methyl (triphenylphos-
phoranylidene)acetate (1.67 g, 5 mmol) was added and reflux
was continued for 4 h. After the mixture cooled to room
temperature it was evaporated under reduced pressure. The
residue was presorbed on silica gel and purified by column
chromatography with gradients from 20% to 40% EtOAc/hexanes
to afford enoate 2 (2.19 g, 92.0%) as a colorless oil; Rf 0.55 (5%
MeOH/CH2Cl2); [R]25 -1.8 (c 1, CHCl3); 1H NMR (CDCl3) δ
D
7.37-7.28 (m, 15H), 6.96 (dd, J ) 15.9, 5.8 Hz, 1H), 6.07 (dd, J
) 15.9, 1.4 Hz, 1H), 4.69 (s, 2H), 4.60 (d, J ) 11.6 Hz, 1H), 4.59
(s, 2H), 4.39 (d, J ) 11.6 Hz, 1H), 4.25 (m, 1H), 3.74 (s, 3H),
3.70-3.66 (m, 2H), 3.63-3.58 (m, 2H); 13C NMR (CDCl3) δ 166.5,
145.2, 138.2, 137.9, 137.5, 128.7, 128.6, 128.6, 128.2, 128.1, 127.9,
122.8, 80.7, 79.4, 78.3, 74.9, 73.0, 71.9, 61.4, 51.8; HRMS m/z
(EI) calcd for C29H32O6 (M)+ 476.2199, found 476.2205.
agent to enoate 1, which has been reported previously
by Ziegler and co-workers in their synthesis of (+)-
cyclophellitol based on radical methodology,11q provides
ester 8 in excellent yield and exclusive anti selectivity.
Treating the potassium enolate of ester 8 with Davis
oxaziridine20 gives a 1:1 mixture of R-hydroxylated
derivatives 9, which is reduced to diols 10 in good yield.
Cleavage of the vicinal diol functionality with NaIO4
followed by treatment of the crude aldehyde with NaBH4
gives alcohol 11 in excellent overall yield. Finally, ring-
closing metathesis of unprotected alcohol 11 with the first
generation Grubbs’ ruthenium catalyst results in condu-
ritol analogue 12, whose chromatographic purification
was greatly facilitated by preliminary oxidation of the
ruthenium catalyst with DMSO.21 Since the transforma-
tion of 12 to (+)-cyclophellitol by way of directed epoxi-
dation and hydrogenolytic deprotection was previously
Methyl (2E,4S,5R,6S)-4,5,6-Tri(benzyloxy)-7-oxo-2-hep-
tenoate (3). To oxalyl chloride (2.3 mL of 2 M in CH2Cl2, 4.6
mmol) in dry CH2Cl2 (10 mL) at -78 °C was added DMSO (0.69
mL, 9.7 mmol) in CH2Cl2 (5 mL) over 10 min and the mixture
was stirred for 30 min. Hydroxyenoate 2 (1.0 g, 2.1 mmol) in
CH2Cl2 (10 mL) was added over 10 min and the mixture was
stirred for an additional 1 h. Triethylamine (1.74 mL, 11.6 mmol)
in CH2Cl2 (10 mL) was added over 10 min and the white slurry
was stirred for 30 min at -78 °C. The resulting mixture was
allowed to warm to -20 °C. Water (50 mL) was added to the
reaction mixture, the two layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. The residual oil was
presorbed on silica gel and purified by column chromatography
with gradients from 5%-20% EtOAc/hexanes to afford oxoenoate
3 (0.96 g, 96%) as a colorless oil; Rf 0.49 (25% EtOAc/hexanes);
1H NMR (CDCl3) δ 9.65 (s, 1H), 7.36-7.20 (m, 15H), 6.88 (dd, J
) 16.0, 6.1 Hz, 1H), 6.02 (dd, J ) 16.0, 1.4 Hz, 1H), 4.72 (d, J )
11.6 Hz, 1H), 4.62 (d, J ) 11.6 Hz, 1H), 4.55 (d, J ) 11.8 Hz,
1H), 4.49 (m, 2H), 4.38 (d, J ) 11.6 Hz, 1H), 4.27 (m, 1H), 3.88
(20) (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (b)
Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. 1987,
66, 203.
(22) Lachke, A. Resonance-J. Sci. Ed. (Ind. Acad. Sci.) 2002, May,
50.
(21) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411.
744 J. Org. Chem., Vol. 70, No. 2, 2005

(m, 1H), 3.82 (ψt, J ) 4.4 Hz, 1H), 3.74 (s, 3H); 13C NMR (CDCl3)
δ 201.3, 166.3, 144.7, 137.2, 137.1, 137.0, 128.6, 128.5, 128.4,
128.2, 128.1, 127.9, 123.2, 81.9, 80.8, 74.4, 73.4, 72.1, 51.7;
HRMS m/z (EI) calcd for C29H30O6 (M)+ 474.2042, found 474.2051.
Methyl (2E,4S,5S,6R)-4,5,6-Tri(benzyloxy)-2,7-octadi-
enoate (ent-1). Method 1: To a stirred suspension of methyl-
triphenylphosphonium bromide (0.36 g, 1 mmol) in THF (15 mL)
was added BuLi (0.4 mL of 2.5 M solution in pentane, 1 mmol)
dropwise at 0 °C. The mixture was stirred for 1 h at room
temperature. The resulting red solution was transferred drop-
wise to the solution of oxoenoate 3 (0.47 g, 1 mmol) in THF (10
mL) at 0 °C. The reaction mixture was stirred for 3 h at room
temperature. The reaction mixture was quenched with 1 M NH4-
Cl (10 mL) and extracted with ether (3 × 20 mL). The organic
extracts were combined, washed with brine, dried (MgSO4), and
evaporated under reduced pressure. The residual oil was pre-
sorbed on silica gel and purified by column chromatography with
gradients from 10%-20% EtOAc/hexanes to afford enoate ent-1
(0.096 g, 20%) as a colorless oil; Rf 0.56 (25% EtOAc/hexanes);
[R]25D -4.16 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.40-7.18 (m, 15H),
6.86 (dd, J ) 9.6, 6.3 Hz, 1H), 6.00 (dd, J ) 16.0, 1.4 Hz, 1H),
5.81 (m, 1H), 5.21 (m, 2H), 4.71 (s, 2H), 4.57 (d, J ) 11.5 Hz,
1H), 4.55 (d, J ) 11.5 Hz, 1H), 4.34 (d, J ) 11.5 Hz, 1H), 4.32
(d, J ) 11.5 Hz, 1H), 4.21 (ψt, J ) 5.2 Hz, 1H), 3.97 (dd, J ) 5.2
Hz, 2.5 Hz, 1H), 3.72 (s, 3H), 3.46 (t, J ) 5.2 Hz, 1H); 13C NMR
(CDCl3) δ 166.6, 145.5, 138.3, 138.2, 137.7, 135.3, 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 122.8, 118.9, 83.5, 80.8,
79.1, 75.3, 71.8, 70.7, 51.6; HRMS m/z (EI) calcd for C30H32O5
(M)+ 472.2256, found 472.2265.
ether (3 × 150 mL). The combined organic layers were washed
with brine, dried (MgSO4), and evaporated under reduced
pressure. The residue was presorbed on silica gel and purified
by column chromatography (30, 50% EtOAc/hexanes) to afford
a mixture of epimeric diols 10 (1.12 g, 70%) as a colorless oil; Rf
0.6 (50% EtOAc/hexanes); selected 1H NMR (CDCl3) δ 7.60-7.25
(m, 15 H), 5.93 (m, 2H), 5.34 (m, 2H), 5.14-5.05 (m, 2H), 4.82-
4.54 (m, 5H), 4.37 (d, J ) 11.8 Hz, 1H), 4.02 (ψt, J ) 4.6 Hz,
1H), 3.94-3.84 (m, 1H), 3.6-3.2 (m, 3H), 2.39 (m, 1H), 2.30 (m,
1H), 1.94 (m, 1H); 13C NMR (CDCl3) δ 138.5, 138.3, 137.8, 135.4,
135.0, 128.5, 128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 119.2, 118.4,
83.4, 82.7, 80.1, 75.4, 75.0, 71.0, 70.7, 65.5, 46.3; HRMS m/z (EI)
calcd for C31H36O5 (M)+ 488.2563, found 488.2570.
(2R,3R,4R,5S)-3,4,5-Tri(benzyloxy)-2-vinyl-6-heptene-1-
ol (11). To a solution of diols 10 (1.0 g, 2.0 mmol) in ether (20
mL) at 0 °C was added NaIO4 (534 mg, 2.5 mmol). To the
resulting suspension was added water (13 mL). The resulting
mixture was stirred for 28 h. The organic layer was separated,
and the aqueous fraction was extracted with ether (3 × 50 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and evaporated under reduced pressure. The residue
was dissolved in abs. EtOH (15 mL). To this solution at 0 °C
was added NaBH4 (1.5 g, 39.6 mmol) in one portion and glacial
acetic acid (3 mL). Stirring was continued for 12 h, and then
the reaction mixture was quenched with a mixture of concen-
trated NH4OH-sat. NH4Cl (1:8, 90 mL). The aqueous phase was
extracted with EtOAc (5 × 100 mL). The combined organic layers
were washed with sat. NH4Cl (2 × 100 mL) and brine, dried
(MgSO4), and concentrated under reduce pressure. The residue
was presorbed on silica gel and purified by column chromatog-
raphy (8%, 12%, and 50% EtOAc/hexanes) to give 11 as a
colorless oil (0.95 g) in quantitative yield; Rf 0.53 (25% EtOAc/
Method 2: A solution of 519 (1 g, 1.92 mmol) in acetone (10
mL) and water (1 mL) was treated with cadmium carbonate (2.6
g, 15.1 mmol) and N-bromosuccinimide (0.739 g, 4.1 mmol). The
suspension was stirred for 40 min at 40 °C, filtered, and
evaporated. The crude product was taken up in ether and
washed with sat. NaHCO3 solution and brine, dried (MgSO4),
and evaporated, giving a yellowish oil. To a solution of the crude
aldehyde (0.76 g, 1.92 mmol) in CH2Cl2 (50 mL) at -78 °C was
added methyl (triphenylphosphoranylidene)acetate (1.28 g, 3.8
mmol) in one portion, and the resulting mixture was stirred for
10 h while it was allowed to warm to room temperature. Water
(100 mL) was added to the reaction mixture, the two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3
× 50 mL). The combined organic layers were washed with brine,
dried (MgSO4), and evaporated under reduced pressure. The
residue was presorbed on silica gel and purified by chromatog-
raphy with gradients from 5%, 15% EtOAc/hexanes to afford
enoate ent-1 (0.77 g, 86%) as a colorless oil.
Methyl (2R+S,3R,4R,5R,6S)-4,5,6-Tri(benzyloxy)-2-hy-
droxy-3-vinyl-7-octenoate (9). To a solution of 811q (2.05 g,
4.1 mmol) in THF (80 mL) was added KHMDS (0.5 M in toluene,
11.36 mL, 5.65 mmol) at -78 °C. The resulting mixture was
stirred for 30 min and a solution of the Davis oxaziridine
reagent20 (2.89 g, 11.1 mmol) in THF (20 mL) was added. The
reaction was continued for 3 h at -78 °C and quenched with
saturated NH4Cl (100 mL). The mixture was extracted with
EtOAc (3 × 100 mL) and the combined organic extracts were
washed with saturated NH4Cl and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was presorbed
on silica gel and purified by column chromatography (5, 12%
EtOAc/hexanes) to give 9 as an oil (1.74 g, 82%); Rf 0.36 (25%
EtOAc/hexanes). Selected 1H NMR (CDCl3) δ 7.60-7.28 (m,
15H), 5.90 (m, 1H), 5.72 (m, 1H), 5.45-5.09 (m, 4H), 5.0-4.56
(m, 5H), 4.44 (d, J ) 11.8 Hz, 1H), 4.26 (t, J ) 7.1 Hz, 1H), 3.93
(m, 1H), 3.79 (m, 1H), 3.72 (s, 3H), 3.67 (m, 1H), 3.55 (s, 1H),
3.11 (m 1H); selected 13C NMR (CDCl3) δ 173.1, 138.5, 138.3,
137.8, 136.2 135.2, 128.4, 128.3, 128.0, 127.8, 127.7, 119.2, 118.3,
82.8, 82.5, 80.8, 74.9, 74.7, 71.7, 70.8, 65.2, 49.1, 46.3; HRMS
m/z (MALDI) calcd for C32H36O6 (M + Na)+ 539.2409, found
539.2402.
hexanes); [R]25 32.81 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.60-
D
7.28 (m, 15H), 5.90 (m, 1H), 5.76 (m, 1H), 5.36-5.07 (m, 4H),
4.85-4.56 (m, 5H), 4.36 (d, J ) 11.8 Hz, 1H), 4.06 (ψt, J ) 5.8
Hz, 1H), 3.81 (t, J ) 5.8 Hz, 1H), 3.76-3.63 (m, 3H), 2.65-2.57
(m, 1H), 2.31-2.27 (br t, J ) 5.0 Hz, 1H); 13C NMR (CDCl3) δ
138.7, 138.5, 138.1, 137.4, 135.3, 128.4, 128.3, 128.16, 128.10,
127.8, 127.7, 127.68, 127.6, 119.1, 117.8, 82.7, 81.5, 80.9, 75.0,
74.3, 70.6, 63.3, 47.2; HRMS m/z (EI) calcd for C30H34O4 (M)+
458.2457, found 458.2463.
(3R,4R,5R,6S)-4,5,6-Tri(benzyloxy)-3-hydroxymethylcy-
clohexene (12).11s To a solution of diene 11 (0.95 g, 2.0 mmol)
in dry CH2Cl2 (100 mL) was added (Cy3P)2(PhCHd)RuCl2 (0.082
g, 0.1 mmol). The reaction mixture soon turned dark. After
overnight stirring DMSO (0.72 mL, 10.0 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 and 50% EtOAc/hexanes) to afford pure 12
(0.77 g, 87%) as a colorless oil; Rf 0.25 (25% EtOAc/hexanes);
1
[R]25 96.4 (c 1, CHCl3); H NMR (CDCl3) δ 7.6-7.3 (m, 15 H),
D
5.76 (dd, J ) 10.2, 2.7 Hz, 1H), 5.56 (dd, J ) 10.2, 1.9 Hz, 1H),
5.0 (d, J ) 11.3 Hz, 1H), 4.95 (s, 2H), 4.75 (s, 2H), 4.70 (d, J )
11.3 Hz, 1H), 4.25 (m, 1H), 3.86 (dd, J ) 10.2, 7.7 Hz, 1H), 3.67
(m, 3H), 2.50 (m, 1H), 1.56 (m, 1H); 13C NMR (CDCl3) δ 138.8,
138.5, 138.4, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7,
85.2, 80.9, 78.6, 75.4, 75.2, 72.2, 63.3, 45.8.
Acknowledgment. We thank Professors Marc
d’Alarcao, Patrick S. Mariano, and Willem A. L. van
Otterlo for insightful discussions. This work is sup-
ported by the National Institutes of Health (1-R15-
CA099957-01).
Supporting Information Available: Copies of 1H and 13
C
(2R+S,3R,4R,5R,6S)-4,5,6-Tri(benzyloxy)-3-vinyl-7-octene-
1,2-diol (10). To a solution of epimeric hydroxyesters 9 (1.7 g,
3.3 mmol) in ether (20 mL) was added 95% LiAlH4 (0.32 g, 8.5
mmol) in one portion at 0 °C. After 10 h at 0 °C the reaction
mixture was quenched with 1 M HCl (80 mL) and extracted with
NMR spectra for compounds ent-1, 2, 3, 8, 1, and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048459P
J. Org. Chem, Vol. 70, No. 2, 2005 745