Carbohydrate-based synthesis of crocacin: Stereoselective Heck reaction of carbohydrate 5,6-ene- and 5,6-yne-derivatives with aromatic halides

Article abstract of DOI:10.1016/S0040-4039(03)01256-5

The Heck reaction between a carbohydrate 5,6-ene derivative 9 and an aromatic halide exclusively gave rise to the β-carbohydrate-substituted trans-styrene derivative 8; while the corresponding Wittig reaction produced a cis/trans mixture in which the cis-

Full text of DOI:10.1016/S0040-4039(03)01256-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5183–5187
Carbohydrate-based synthesis of crocacin: stereoselective Heck
reaction of carbohydrate 5,6-ene- and 5,6-yne-derivatives with
aromatic halides
Mukund K. Gurjar,* Tushar P. Khaladkar, Ramdas G. Borhade and A. Murugan
National Chemical Laboratory, Pune 411 008, India
Received 3 April 2003; revised 14 May 2003; accepted 20 May 2003
Abstract—The Heck reaction between a carbohydrate 5,6-ene derivative 9 and an aromatic halide exclusively gave rise to the
b-carbohydrate-substituted trans-styrene derivative 8; while the corresponding Wittig reaction produced a cis/trans mixture in
which the cis-isomer predominated. The application of the Heck reaction is described to synthesize the intermediate 5, commonly
used in the synthesis of members of the crocacin family. © 2003 Elsevier Science Ltd. All rights reserved.
The crocacin group of natural products have attracted
unprecedented interest, primarily because of their signifi-
cant biological activities coupled with characteristic struc-
tural features.1 The structures of crocacins (Fig. 1) offer
ample opportunities for synthetic chemists to develop
unique approaches.2 However, carbohydrate based pro-
tocols seem to be missing from the artillery in spite of
variable side chains. The Evans aldol reaction based
synthetic protocols seem to be the most commonly used
approaches for crocacin synthesis.2 We have investigated
for the first time a carbohydrate-based synthesis of 5.
While planning the strategy, we were confronted with a
need to produce the b-carbohydrate-substituted styrene
derivative 8. The most logical approach would be the
Wittig reaction between 5-sugar-carboxylaldehyde 63 and
the fact that chiral centers in D-glucose can be seemingly
transformed to produce the crocacin skeleton, enantiose-
lectively. Crocacins A–D (1–4) possess antifungal and
cytotoxic activities and are regularly found in the extracts
of Chondromyces crocactus and Chondromyces pedicula-
tus. Synthetic efforts2 towards crocacins A–D have been
significantly influenced by the synthesis of the advanced
intermediate 5 (Fig. 1) which is then elaborated to install
benzylidenetriphenylphosphorane
(prepared
from
BnPPh3Br and n-BuLi). The reaction conducted at room
1
temperature gave a product whose H NMR spectrum
revealed the formation of cis/trans-isomers 7 and 8
(84:16), with the unwanted cis isomer being formed
predominantly (Scheme 1).
Figure 1.
* Corresponding author. Tel.: +91-20-5882456; fax: +91-5893614; e-mail: gurjar@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01256-5

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M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 5183–5187
in a 25:75 ratio was observed. All our attempts to
prepare the trans-isomer with acceptable selectivity and
yield via the Wittig reaction were unsuccessful.
The Heck reaction4 between an olefin and an aromatic
halide favors the trans-olefin derivative. However, the
application of this reaction to 5,6-ene derivatives of
sugar substrates, to our knowledge, has not been
reported so far. We attempted a reaction between 1,2-
O-isopropylidine-3-O-methyl-a-D-xylo-hex-5-enofuran-
ose 95 with iodo-benzene in the presence of Pd(OAc)2,
PPh3, Et3N and Bu4NI in DMF at 110°C. In our first
attempt, the requisite trans-isomer 8 was formed almost
exclusively in 54% yield. The starting material 9 was
also recovered in 15% yield. The structure of 8 was
confirmed by the 1H NMR spectrum in which the
olefinic protons appeared at l 6.29 and l 6.73 with a
characteristic-coupling constant (J=16.0 Hz). With a
view to investigating the versatility of this reaction, but
more importantly, to understand the effect of sub-
stituents on the benzene ring, a number of Heck reac-
Scheme 1. Reagents and conditions: (a) PhCH2PPh3Br, n-
BuLi, THF; (b) iodobenzene, Pd(OAc)2, PPh3, Et3N, Bu4NI,
DMF, 110°C.
When the reaction was performed at 0°C, the cis isomer
7 was formed in 95% yield with 5% of the trans-isomer.
Furthermore in refluxing THF, a trans:cis mixture (8/7)
Table 1.

M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 5183–5187
5185
1
trans-styrene derivative 18. In the H NMR spectrum
of 18, the characteristic olefinic protons were located at
6.07 and 6.63 ppm (J=16.2 Hz). Treatment of 18 with
methanol and Amberlyst IR120 gave the methyl fura-
noside 19 and simultaneously exposed the 2-OH group
which was blocked as methyl ether 20. The methyl
glycosidic bond was hydrolyzed to give 21 with 20%
AcOH in H2O and then treated with MeMgCl in THF
to afford the diol 22. The sterically hindered OH group
at C-5 was exploited to selectively protect the C-2-OH
group using TBSOTf to give 23. The Mitsunobu reac-
tion of 23 with p-nitrobenzoic acid, PPh3-DEAD fol-
lowed by hydrolysis with LiOH in MeOH gave 24. A
comparison of the 1H NMR spectra of 23 and 24
clearly indicated that inversion had indeed occurred.
Next the free OH group was methylated to afford
di-O-methyl derivative 25.
tions were examined as shown in Table 1. In all the
cases studied, exclusive formation of the trans-isomer
was observed. The reaction (entry 6) involving the
coupling of the sugar with a L-phenylalanine residue is
indeed interesting from a synthetic point of view. In
general, electron-donating substituents on benzene rings
favor the Heck reaction with good yields (Table 1).
We also investigated the Heck reaction with 5,6-yne
derivative 106 and were gratified to observe that it
worked efficiently. The structure of 11 was confirmed
by spectroscopic and elemental analysis. Table 2 shows
reactions of sugar 5,6-yne derivative 10 with aryl
halides. It is pertinent to mention that compounds of
type 11 are difficult to synthesize other than by the
Heck reaction (Scheme 2).
Having successfully developed a new protocol to pre-
pare b-carbohydrate-substituted trans-styrene deriva-
tives, we directed our efforts to apply this method to
prepare the common intermediate 5 for crocacin
The next critical reaction was the introduction of the
methyl group at C-2 (cf. 5) for which a route involving
(Scheme 3). 1,2:5,6-Di-O-cyclohexylidene-D-glucofura-
nose 12 was successively7 subjected to (i) oxidation
(PDC, MS, Ac2O, DCM) to 3-ulose 13; (ii) Wittig
reaction with Ph3PꢀCH2 to the exo-methylene deriva-
tive 14 and (iii) catalytic reduction to 3-C-methyl-3-
deoxy derivative 15. The conversion of 15 into 5,6-ene
17 by standard reaction pathways, was accomplished in
three steps.8 The Heck reaction of 17 with iodobenzene
under the conditions reported above furnished the
Scheme 2. Reagents and conditions: iodobenzene, Pd(PPh3)4,
piperidine, rt.
Table 2.

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M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 5183–5187
,
Scheme 3. Reagents and conditions: (a) (i) PDC, 4 A MS, Ac2O, DCM, rt, 12 h, 78%; (ii) PPh3ꢀCH2, THF, −10°C, 0.5 h, 67%;
(b) 10% Pd–C, H2, 50 psi., 3 h, 97%; (c) 0.8% H2SO4, MeOH, 24 h, 83%; (d) (i) MsCl, NEt3, DCM, 0°C–rt, 2 h, 95%; (ii)
EtCOMe, NaI, reflux, 6 h, 74%; (e) Ph–I, Pd(OAc)2, PPh3, NEt3, TBAI, DMF, 110°C, 6 h, 63%; (f) Amberlyst IR-120 (H+) resin,
MeOH, reflux, 8 h, 82%; (g) NaH, MeI, THF, rt, 3 h, 95%; (h) 20% aq. CH3CO2H, cat. H2SO4, 80°C, 6 h, 79%; (i) MeMgCl,
THF, rt, 2.5 h, 75%; (j) TBSOTf, 2,6-lutidine, DCM, −78°C, 1.5 h, 86%; (k) (i) DEAD, TPP, 4-nitrobenzoic acid, THF, rt, 5 h,
66%; (ii) LiOH, MeOH, rt, 2 h, 62%; (l) KH, MeI, THF, rt, 3.5 h, 96%; (m) TBAF, THF, rt, 36 h, 93%; (n) Dess–Martin-Peri-
odinane, DCM, rt, 2 h, 91%; (o) Ph3PꢀCH2, THF, −10°C, 8 h, 85%; (p) 9-BBN, THF, rt, 2 h, CH3COONa, H2O2, 0°C–rt, 7 h,
64%.
stereoselective hydroboration–oxidation of the 2-iso-
propene functionality was planned. Thus compound 25
was first desilylated with TBAF in THF, oxidized to
ketone 27 and then subjected to a Wittig reaction to
give 28. The stereochemical outcome of the hydrobora-
tion–oxidation of a terminal 2-isopropylene with an
adjacent chiral hydroxyl substituent giving rise to the
syn product has been reported in the presence of
Wilkinson’s catalyst,9 whilst the uncatalysed hydrobo-
ration–oxidation provides the anti-product. Indeed, the
reaction of compound 28 with 9-BBN followed by
oxidation with H2O2 in the presence of sodium acetate
gave exclusively the required product 5. The structure
of 5 was confirmed by spectroscopic and analytical
data10 which were identical with reported values.2
In conclusion, we have shown that Heck reaction of
carbohydrate based olefins and acetylene derivatives
occurs smoothly. This reaction has been utilized to
prepare a common intermediate for crocacin synthesis.
Acknowledgements
T.P.K. thanks UGC and R.G.B. thanks CSIR for
assistance in the form of fellowships.

M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 5183–5187
5187
References
J=16.0 Hz), 7.3 (m, 5H); 13C NMR (CDCl3, 50 MHz)—
l 26.1, 26.7, 58.1, 81.2, 82.2, 86.1, 104.7, 111.4, 123.1,
126.6, 127.3, 128.4, 133.8, 136.5. Anal. calcd for
C16H20O4: C, 69.56; H, 7.24. Found: C, 70.30; H, 7.10.
1. (a) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1994, 47, 881–886; (b) Jansen, R.; Washausen,
P.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org.
Chem. 1999, 5, 1085–1089.
1
Spectroscopic data of 11: H NMR (CDCl3, 200 MHz)—
l 1.33 (s, 3H), 1.52 (s, 3H), 2.28 (brs, 1H), 4.25 (d, 1H,
J=4.0 Hz), 4.64 (d, 1H, J=4.0 Hz), 5.11 (d, 1H, J=4.0
Hz), 6.01 (d, 1H, J=4.0 Hz), 7.2–7.6 (m, 5H); 13C NMR
(CDCl3, 50 MHz)—l 26.0, 26.7, 72.8, 76.1, 81.6, 84.0,
104.8, 111.8, 121.5, 128.2, 128.9, 131.9, 159.7. Anal. calcd
for C15H16O4: C, 69.23; H, 6.15. Found: C, 68.80; H,
6.80. Spectroscopic data of 18: 1H NMR (500 MHz,
CDCl3)—l 1.07 (d, 3H, J=6.5 Hz), 1.2–1.85 (m, 11H),
4.26 (t, 1H, J=8.1 Hz), 4.57 (t, 1H, J=3.2 Hz), 5.85 (d,
1H, J=3.2 Hz), 6.07 (dd, 1H, J=16.2, 8.1 Hz), 6.63 (d,
1H, J=16.2 Hz), 7.2–7.4 (m, 5H); 13C NMR (125 MHz,
CDCl3)—l 9.0, 23.7, 24.0, 25.1, 36.1, 36.4, 44.7, 82.1,
83.6, 104.6, 111.9, 126.6, 127.0, 127.8, 128.5, 133.1, 136.6.
Anal. calcd for C19H24O3: C, 76.00; H, 8.00. Found: C,
76.44; H, 8.30. Spectroscopic data of 28: 1H NMR (500
MHz, CDCl3)—l 0.75 (d, 3H, J=7.1 Hz), 1.60 (s, 3H),
1.69 (m, 1H), 3.22 (s, 3H), 3.34 (s, 3H), 3.49 (d, 1H,
J=10.1 Hz), 4.20 (dd, 1H, J=6.7, 3.3 Hz), 4.92 (s, 1H),
4.99 (s, 1H), 6.17 (dd, 1H, J=16.1, 6.7 Hz), 6.57 (d, 1H,
J=16.1 Hz), 7.2–7.4 (m, 5H); 13C NMR (125 MHz,
CDCl3)—l 9.7, 15.9, 41.0, 55.9, 57.3, 80.7, 87.0, 115.8,
126.5, 127.4, 128.6, 130.0, 131.3, 137.2, 143.1. Anal. calcd
for C17H24O2: C, 78.46; H, 9.23. Found: C, 78.03; H,
9.52. Spectroscopic data of 5: 1H NMR (500 MHz,
CDCl3)—l 0.90 (d, 3H, J=7.0 Hz), 1.20 (d, 3H, J=7.0
Hz), 1.86 (m, 2H), 2.77 (brs, 1H), 3.27 (dd, 1H, J=9.5,
2.7 Hz), 3.31 (s, 3H), 3.51 (dd, 1H, J=11.2, 4.3 Hz), 3.54
(s, 3H), 3.82 (dd, 1H, J=11.2, 3.4), 4.05 (dd, 1H, J=7.2,
2.0 Hz), 6.16 (dd, 1H, J=16.3, 7.2 Hz), 6.56 (d, 1H,
J=16.3 Hz), 7.2–7.4 (m, 5H); 13C NMR (125 MHz,
CDCl3)—l 10.5, 16.4, 36.1, 42.5, 56.4, 61.6, 64.6, 81.2,
88.6, 126.5, 127.7, 128.6, 129.4, 132.3, 136.9. Anal. calcd
for C17H26O3: C, 73.38; H, 9.35. Found: C, 73.92; H,
8.97.
2. (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org.
Lett. 2000, 2, 3365–3367; (b) Chakraborty, T. K.;
Jayaprakash, S. Tetrahedron Lett. 2001, 42, 497–499; (c)
Chakraborty, T. K.; Jayaprakash, S.; Laxman, P. Tetra-
hedron 2001, 57, 9461–9467; (d) Dias, L. C.; de Oliveira,
L. G. Org. Lett. 2001, 3, 3951–3954; (e) Feutrill, J. T.;
Lilly, M. J.; Rizzacasa, M. A. Org. Lett. 2002, 4, 525–
527.
3. Sueda, N.; Ohrui, H.; Kuzuhara, H. Tetrahedron Lett.
1979, 20, 2039–2042.
4. (a) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetra-
hedron 2001, 57, 7449–7476; (b) Crisp, G. T. Chem. Soc.
Rev. 1998, 27, 427–436; (c) Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009–3066.
5. Josan, J. S.; Eastwood, F. W. Carbohydr. Res. 1968, 7,
161–166.
6. Yadav, J. S.; Chander, M. C.; Rao, C. S. Tetrahedron
Lett. 1989, 30, 5455–5458.
7. Rosenthal, A.; Sprinzl, M. Can. J. Chem. 1969, 47,
3941–3945.
8. Jones, J. K. N.; Thompson, J. L. Can. J. Chem. 1957, 35,
955–959.
9. (a) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983,
105, 2487–2489; (b) Burgess, K.; Cassidy, J.; Ohlmeyer,
M. J. J. Org. Chem. 1991, 56, 1020–1027; (c) Burgess, K.;
Ohlmeyer, M. J. Tetrahedron Lett. 1989, 30, 5861–5864;
(d) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am.
Chem. Soc. 1988, 110, 6917–6918; (e) Burgess, K.;
Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179–1191.
1
10. Spectroscopic data of 8: H NMR (CDCl3, 200 MHz)—l
1.34 (s, 3H), 1.54 (s, 3H), 3.42 (s, 3H), 3.68 (d, 1H, J=3.5
Hz), 4.62 (d, 1H, J=3.5 Hz), 4.75 (m, 1H), 5.94 (d, 1H,
J=3.5 Hz), 6.29 (dd, 1H, J=8.0, 16.0 Hz), 6.73 (d, 1H,