Rapid synthesis of cyclodepsipeptides containing a sugar amino acid or a sugar amino alcohol by a sequence of a multicomponent reaction and acid-mediated macrocyclization

Article abstract of DOI:10.1021/jo0621874

Cyclodepsipeptides incorporating a sugar amino acid (alcohol) have been synthesized. A three-component reaction of a sugar amino acid (SAA) derivative, an aldehyde, and a dipeptide isonitrile in refluxing methanol afforded the corresponding 5-aminooxazole

Full text of DOI:10.1021/jo0621874

of designed hybrid structure. Kessler and co-workers were the
first to study and to demonstrate the potential of such molecules
as peptidomimetics and artificial receptors for host-guest
chemistry.7 Since then, several types of cyclic oligomers
incorporating open-chain,8 pyranoid,9 furanoid sugar amino
acid10 and oxetane units11 have been synthesized and their
conformational properties were thoroughly examined.9-11 It has
been demonstrated that incorporation of SAAs into the peptidic
backbone can broaden the dynamic spectrum and widen the
conformational space of the peptide, increasing consequently
the potency as well as the specificity of the given bioactive
compounds. Indeed, potent antitumor agents12 and inhibitors of
P-selectines13 have been discovered from these studies indicating
the potential of this approach in drug development.
Rapid Synthesis of Cyclodepsipeptides Containing
a Sugar Amino Acid or a Sugar Amino Alcohol
by a Sequence of a Multicomponent Reaction and
Acid-Mediated Macrocyclization
Carine Bughin, Ge´raldine Masson, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
ReceiVed October 20, 2006
A synthesis allowing one to systematically modify the amino
acid and the carbohydrate residues, as well as the size of the
macrocycle, is highly needed to fully exploit the potential of
such hybride structures in searching for new active compounds.
Previously, most of the cyclic SAAs have been synthesized by
stepwise amide bond formation followed by macrolactamiza-
tion.8-11,14 We report herein an alternative and highly efficient
(5) (a) Nicolaou, K. C.; Flo¨rke, H.; Egan, M. G.; Barth, T.; Estevez,
V. A. Tetrahedron Lett. 1995, 36, 1775. (b) Goodnow, R. A., Jr.; Richou,
A.-R.; Tam, S. Tetrahedron Lett. 1997, 38, 3195. (c) Goodnow, R. A., Jr.;
Tam, S.; Pruess, D. L.; McComas, W. W. Tetrahedron Lett. 1997, 38, 3199.
(6) Smith, M. D.; Claridge, T. D. W.; Tranter, G. E.; Sansom, M. S. P.;
Fleet, G. W. J. J. Chem. Soc., Chem. Commun. 1998, 2041.
Cyclodepsipeptides incorporating a sugar amino acid (alco-
hol) have been synthesized. A three-component reaction of
a sugar amino acid (SAA) derivative, an aldehyde, and a
dipeptide isonitrile in refluxing methanol afforded the
corresponding 5-aminooxazole which, after saponification,
underwent a trifluoroacetic acid promoted macrocyclization
to furnish the cyclic sugar amino acids.
(7) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed. 1994, 33,
687.
(8) (a) Mayes, B. A.; Stetz, R. J. E.; Ansell, C. W. G.; Fleet, G. W. J.
Tetrahedron Lett. 2004, 45, 153. (b) Mayes, B. A.; Simon, L.; Watkin,
D. J.; Ansell, C. W. G.; Fleet, G. W. J. Tetrahedron Lett. 2004, 45, 157.
(9) (a) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.;
Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156. (b) Lohof, E.; Planker,
E.; Mang, C.; Bukhart, F.; Dechantsreiter, M. A.; Haubner, R.; Wester,
H.-J.; Schwaiger, M.; Ho¨lzemann, G.; Goodman, S. L.; Kessler, H. Angew.
Chem., Int. Ed. 2000, 39, 2761. (c) Locardi, E.; Sto¨ckle, M.; Gruner,
S. A. W.; Kessler, H. J. Am. Chem. Soc. 2001, 123, 8189. (d) Sto¨ckle, M.;
Voll, G.; Gunther, R.; Lohof, E.; Locardi, E.; Gruner, S. A. W.; Kessler,
H. Org. Lett. 2002, 4, 2501. (e) Gruner, S. A. W.; Truffault, V.; Voll, G.;
Locardi, E.; Sto¨ckle, M.; Kessler, H. Chem.-Eur. J. 2002, 4365. (f) Van
Well, R.; Marinelli, L.; Erkelens, K.; van der Marel, G. A.; Lavecchia, A.;
Overkleeft, H.; van Boom, J.; Kessler, H.; Overhand, M. Eur. J. Org. Chem.
2003, 2303. (g) Raunkjaer, M.; El Oualid, F.; van der Marel, G. A.;
Overkleeft, H.; Overhand, M. Org. Lett. 2004, 6, 3167. (h) Me´nand, M.;
Blais, J.-C.; Hamon, L.; Vale´ry, J.-M.; Xie, J. J. Org. Chem. 2005, 70,
4423. (i) Billing, J. F.; Nilsson, U. J. Tetrahedron 2005, 61, 863.
(10) (a) Van Well, R.; Overkleeft, H.; Overhand, M.; Vang Carstenen,
E.; van der Marel, G. A.; van Boom, J. Tetrahedron Lett. 2000, 41, 9331.
(b) Van Well, R.; Marinelli, L.; Altona, C.; Erkelens, K.; Siegal, G.; van
Raaij, M.; Llamas-Saiz, A. L.; Kessler, H.; Novellino, E.; Lavecchia, A.;
van Boom, J.; Overhand, M. J. Am. Chem. Soc. 2003, 125, 10822. (c)
Grotenberg, G. M.; Timmer, M. S. M.; Llamas-Saiz, A. L.; Verdoes, M.;
van der Marel, G. A.; van Raaij, M.; Overkleeft, H.; Overhand, M. J. Am.
Chem. Soc. 2004, 126, 3444. (d) Grotenberg, G. M.; Buizert, A. E. M.;
Llamas-Saiz, A. L.; Spalburg, E.; van Hooft, P. A. V.; de Neeling, A. J.;
Noort, D.; van Raaij, M.; van der Marel, G. A.; Overkleeft, H.; Overhand,
M. J. Am. Chem. Soc. 2006, 128, 7559. (e) Chakraborty, T. K.; Ghosh, S.;
Jayaprakash, S. Curr. Med. Chem. 2002, 9, 421. (f) Chakraborty, T. K.;
Srinivasu, P.; Bikshapathy, E.; Nagaraj, R.; Vairamani, M.; Kiran Kumar,
S.; Kunwar, A. C. J. Org. Chem. 2003, 68, 6257.
Amino acids and sugars are two major building blocks from
which the biopolymers of life are formed in nature. The sugar
amino acids (SAAs), defined as sugars containing at least one
amino and at least one carboxyl group, also exist in nature.1
For example, the sialic acid, responsible for many inter- and
intracellular recognition events, is found in all living organisms
with the exception of certain bacteria.2 Glucosaminuronic acid
is found in A-40926, a structurally complex glycopeptide of
the vancomycine family of antibiotics.3 Synthetic linear oligo-
mers of SAAs, first introduced by Fuchs and Lehmann in mid
1970s,4 have been proposed to mimic oligosaccharides and
oligonucleotides5 and have been shown to adopt well-defined
three-dimensional structures.6 On the other hand, cyclic peptides
incorporating sugar amino acids belong to a relatively new type
* To whom correspondence should be addressed. Fax: Int. code + 33 1
69077247.
(1) (a) Gervay-Hague, J.; Weathers, T. M. J. Carbohydr. Chem. 2002,
21, 867. (b) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem.
ReV. 2002, 102, 491. (c) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41,
230. (d) Chakraborty, T. K.; Jayaprakash, S. Curr. Med. Chem. 2002, 9,
421.
(2) Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; Wong, C.-H.
Chem. ReV. 1998, 98, 833.
(3) (a) Waltho, J. P.; Williams, D. H.; Selva, E.; Ferrari, P. J. Chem.
Soc., Perkin Trans. I 1987, 2103. (b) Zhu, J. Expert Opin. Ther. Pat. 1999,
9, 1005. (c) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2096.
(4) (a) Fuchs, E. F.; Lehmann, J. Chem. Ber. 1975, 108, 2254. (b) Fuchs,
E. F.; Lehmann, J. Carbohydr. Res. 1976, 49, 267. (c) St Hilaire, P. M.;
Meldal, M. Angew. Chem., Int. Ed. 2000, 39, 1162.
(11) Fleet, G. W. J.; Johnson, S. W.; Jones, J. H. J. Pept. Sci. 2006, 12,
559.
(12) (a) Gruner, S. A. W.; Ke´ri, G.; Schwab, R.; Venetianer, A.; Kessler,
H. Org. Lett. 2001, 3, 3723. (b) Haubner, R.; Gratias, R.; Diefenbach, B.;
Goodman, S. L.; Jonczyk, A.; Kessler, J. J. Am. Chem. Soc. 1996, 118,
7461.
(13) Tsai, C.-Y.; Huang, X.; Wong, C.-H. Tetrahedron Lett. 2000, 41,
9499.
10.1021/jo0621874 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/25/2007
1826
J. Org. Chem. 2007, 72, 1826-1829

SCHEME 1
SCHEME 2a
synthesis of cyclic SAAs by a multicomponent reaction/
postfunctionalization strategy.15 The reaction sequence we
envisaged is shown in Scheme 1. A three-component reaction
of a sugar amino acid derivative 1, an aldehyde 2, and an
isocyanoacetamide 3 would provide the functionalized oxazole
4.16 Saponification of methyl ester followed by acidic treatment
should afford the macrocycle according to the chemistry
developed previously in this laboratory.17
The preparation of the furanoids 1a-c is outlined in Scheme
2. The D-ribose (6) is converted to â-C-furanoside (7) in four
conventional steps involving acetalization, Wittig reaction,
mesylation, and SN2 displacement of the mesylate by sodium
azide.9g,18 Saponification of the methyl ester afforded the
carboxylic acid 8, and the synthesis is diverged at this stage.
Reduction of acid via the mixed anhydride intermediate followed
by hydrogenolysis of the azide furnished the amino alcohol 1a.
On the other hand, EDC-mediated coupling of the acid 8 with
1,2-aminoalcohol followed by the reduction of azide afforded
the SAA derivative 1b in 57% overall yield. In parallel,
reduction of azido ester 7 gave the amino ester 9 that was
coupled with azido acid 8 to afford compound 10. Finally,
reduction of the ester and the azide functions provided the
dimeric SAA derivative 1c in 34% overall yield.
a Reagents and conditions : (a) LiOH‚H2O, H2O/THF, rt, 15 h, 93%;
(b) ClCO2Et, Et3N, THF, 0 °C, 1 h; then NaBH4, H2O, rt, 4 h, 68%; (c) H2,
Pd/C 10%, MeOH, rt, 2 h; (d) 1,2-aminoethanol, EDCI, CH2Cl2, rt, 24 h,
57%; (e) 9, EDCI, CH2Cl2, rt, 24 h, 79%.
SCHEME 3
Heating to reflux a methanol solution of amino alcohol 1a,
heptanal (2a), and isonitrile 3a,19 according to our previously
developed conditions,16 afforded the desired 5-aminooxazole 4a
in 83% yield as a mixture of two diastereoisomers (dr ) 1:1)
(Scheme 3). Apparently, the chiral environment of the chiral
amino alcohol 1a is not sufficient to induce the diastereoselec-
tivity in the key C-C bond-forming step. Nevertheless, the low
diastereoselectivity observed in this 3CR is in accordance with
the general trends of isonitrile-based MCRs and reflects the
complexity of the reaction mechanism.20 By varying the
structure of the aldehyde, SAA, and isonitrile compounds, we
synthesized five other 5-aminooxazoles 4b-f, and their struc-
tures were listed in Figure 1.
With compounds 4a-f in hand, we next investigated the key
macrolactonization using the 5-aminooxazole as an internal
activator of the terminal carboxylic acid. Saponification of the
methyl ester 4a (LiOH, THF-H2O) gave the corresponding
lithium salt, which after evaporation of the solvents was used
directly for the next step without further purification. Gratify-
ingly, simply stirring an acetonitrile solution (0.001 M) of the
so-obtained lithium salt in the presence of trifluoroacetic acid
(50 equiv) at room temperature provided the macrocycle 5a in
59% yield (Scheme 4). Two diastereoisomers were separable
at this step by preparative TLC. However, the presence of
rotamers due to the presence of the tertiary amide in the peptide
backbone significantly complicated the 1H NMR spectrum;
therefore, the relative stereochemistry of the two chiral centers
was not assigned. In DMSO-d6, the NMR spectrum of 5a
(14) For synthesis of a symmetric cyclic dimer by staudinger Aza-Wittig
reaction, see: Me´nand, M.; Blais, J.-C.; Hamon, L.; Vale´ry, J.-M.; Xie, J.
J. Org. Chem. 2006, 71, 3295.
(15) (a) Marcaccini, S.; Torroba, T. Post-condensation Modifications of
the Passerini and Ugi Reactions in Multicomponent Reactions; Zhu, J.,
Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005; p 33. (b) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51. (c) Zhu, J. Eur. J. Org. Chem.
2003, 1133. (d) Wessjohann, L. A.; Ruijter, E. Mol. DiVersity 2005, 9, 159.
(e) Do¨mling, A. Chem. ReV. 2006, 106, 17.
(16) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.; Zhu, J. Org. Lett.
2001, 3, 877. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem.
Soc. 2002, 124, 2560. (c) Fayol, A.; Housseman, C.; Sun, X.; Janvier, P.;
Bienayme´, H.; Zhu, J. Synthesis 2005, 161.
(17) (a) Zhao, G.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem. Soc.
2001, 123, 6700. (b) Bughin, C.; Zhao, G.; Bienayme´, H.; Zhu, J. Chem.-
Eur. J. 2006, 12, 1174.
(18) (a) Ohrui, H.; Jones, G. H.; Moffatt, J. G.; Maddox, M. L.;
Christensen, A. T.; Byram, S. K. J. Am. Chem. Soc. 1975, 97, 4602. (b)
McDevitt, J. P.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118, 3818.
(19) Zhao, G.; Bughin, C.; Bienayme´, H.; Zhu, J. Synlett 2003, 1153.
(20) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Asymmetric Isocyanide-
based MCRs in Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 1.
J. Org. Chem, Vol. 72, No. 5, 2007 1827

FIGURE 2. Cyclic sugar amino acids synthesized.
novel macrolactonization process, the oxazole served as an
internal activator of the terminal carboxylic acid and became
an integral part of the peptide backbone after cyclization. The
cyclization worked equally well in toluene. However, the
structure of acids can significantly influence the reaction
efficiency and only a trace amount of macrolactone was isolated
when the cyclization was performed in the presence of para-
toluenesulfonic acid.
Figure 2 lists macrocyclic SAAs synthesized from the
corresponding linear oxazolo-SAAs. Although yields remained
moderate to good, the cyclization seems to be quite general
because the representative 16-membered and 19-membered rings
are readily accessed. In the case of 5c wherein a new chiral
center was generated, four diastereomers were produced with
an overall yield of 61%. However, only one of them was
separated from the diastereomeric mixture. We emphasize that
the present synthesis is highly step-efficient because only two
operations are required for the synthesis of these structurally
complex macrocycles from readily accessible starting materials
(1-3).21 Furthermore, an amino acid is created in the course of
the three-component reaction thus facilitating the incorporation
of a non-proteinogenic amino acid unit into the cyclic SAAs.
In conclusion, we have developed a new synthesis of highly
functionalized cyclic sugar amino acids that allows us to access
macrocycles in two steps from simple starting materials. In this
two-step process, only two molecules of water are lost, whereas
lithium hydroxide and trifluoroacetic acid are the only reagents
used to mediate the formation of these macrocycles.
FIGURE 1. 5-Amino oxazoles synthesized by a three-component
reaction.
SCHEME 4
recorded at 297 K was well resolved and two sets of peaks were
identified. Particularly, two broad triplets that appeared at δ )
8.39 and 8.13 ppm were attributed to the amide NH proton of
the two rotamers by a COSY spectrum. These two peaks
Experimental Section
General Procedure for the Three-Component Synthesis of
5-Aminooxazole. A solution of amino sugar 1 (1.1 equiv) and
aldehyde 2 (1.1 equiv) in dry methanol (0.1 mol/L) was stirred at
room temperature for 15 min, and isocyanide 3 (1.0 equiv) was
1
coalesced at δ ) 8.05 ppm when the H NMR spectrum was
recorded at 353 K (cf. Supporting Information).
A possible reaction sequence leading to the macrocycle 5a
is depicted in Scheme 4.17b Thus, protonation of the C-4 carbon
of the oxazole would provide the iminium intermediate 11 that
would be trapped by the vicinal carbonyl oxygen to afford the
spirolactone 12. The intramolecular nucleophilic addition of the
tethered hydroxy group to the lactone followed by fragmentation
then provided the observed macrocycle 5a. In this conceptually
(21) For recent examples of one-step multicomponent synthesis of
macrocycles, see: (a) Wessjohann, L. A.; Voigt, B.; Rivera, D. G. Angew.
Chem., Int. Ed. 2005, 44, 4785. (b) Rivera, D. G.; Wessjohann, L. A.
J. Am. Chem. Soc. 2006, 128, 7122. (c) Kreye, O.; Westermann, B.; Rivera,
D. G.; Johnson, D. V.; Orru, R. V. A.; Wessjohann, L. A. QSAR Comb.
Sci. 2006, 5-6, 461. (e) Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8,
4145.
1828 J. Org. Chem., Vol. 72, No. 5, 2007

then added to the solution. The reaction was heated at 70 °C, and
the progress of the reaction was followed by TLC. When isocyanide
was fully consumed, the solvent was removed under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (CH2Cl2/MeOH 95:5) to give the aminooxazole 4.
Compound 4a: yield 83%; Rf (heptane/AcOEt 4:1) 0.19; IR
(CHCl3) ν 1076, 1158, 1263, 1383, 1455, 1496, 1581, 1616, 1746,
2852, 2932, 3532 cm-1; NMR 1H (CDCl3, 300 MHz, 293 K, ppm)
two diastereoisomers, 1:1 ratios δ 0.83 (t, J ) 7.9 Hz, 3H), 1.09-
1.28 (m, 9H), 1.49 (s, 3H), 1.61-1.88 (m, 4H), 2.07 (brs, 1H),
2.51-2.75 (m, 2H), 3.64 (t, J ) 7.8 Hz, 1H), 3.67 (s, 3H), 3.69-
3.75 (m, 2H), 3.80 (s, 2H), 3.94-4.03 (m, 2H), 4.35-4.53 (m,
1H), 4.38 (s, 2H), 4.45-4.53 (m, 1H), 5.88 (s, 1H), 7.20-7.31
(m, 5H); NMR 13C (CDCl3, 75 MHz, 293 K, ppm) two diastere-
oisomers 1:1 ratios δ 14.0, 22.6 (25.5), 25.9 (27.3), 29.0, 31.7, 34.3,
35.7, 49.1, 50.0, 52.0, 54.6, 56.8, 60.5, 83.9-83.6, 84.9, 101.5,
114.5, 127.9-128.3 (2C), 129.0 (2C), 136.2, 114.5, 156.8, 156.9,
170.3; MS (IE) (m/z) 559 [M]+, 474 [M - C6H13]+; HRMS (ESI)
calcd for [M + Na]+ ) 582.3155; m/z found 582.3169.
General Procedure for the Acid-Promoted Macrolactoniza-
tion. A solution of 5-aminooxazole and LiOH‚H2O (1.05 equiv)
in THF/H2O (3:1) was stirred at room temperature for 3 h and
evaporated to dryness in vacuo. The residue obtained was dissolved
in MeCN (10-3 M), and TFA (50 equiv) was added under a stream
of argon. The reaction mixture was stirred at room temperature
and followed by TLC. When the reaction was completed, the
volatile was evaporated under reduced pressure. The crude product
was diluted with ethyl acetate and washed with a saturated aqueous
solution of sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered, and evaporated to dryness. Purification
by preparative TLC afforded the desired macrocycle. Compound
5a: yield 59%; reaction was performed at 0.1 mmol scale.
Diastereoisomer A: white solid; yield 26%; Rf (CH2Cl2/ MeOH
3.75-3.82 (m, 1H), 3.83-4.00 (m, 2H), 4.05-4.20 (m, 1H), 4.29
(d, J ) 18.0 Hz, 1H), 4.27-4.35 (m, 4H), 4.36-4.52 (m, 1H),
4.75 (4.88) (d, J ) 15.9 (14.1) Hz, 1H), 7.23-7.38 (m, 1H), 8.01
(7.88) (brs, 1H); NMR 13C (CDCl3, 75 MHz, 293 K) two rotamers
1:3 ratio δ 14.0, 22.5, 25.5 (25.6), 26.0 (27.3), 29.1 (29.4), 29.2
(29.7), 31.7 (32.5), 34.1, 40.9 (40.1), 49.9 (49.7), 51.8 (50.8), 51.8
(52.6) (2C), 61.6 (62.7), 64.5 (63.3), 82.2 (81.5), 82.4, 82.7 (83.5),
83.3 (84.3), 115.0 (115.7), 127.1 to 129.1-135.2 (136.0), 168.7
(168.1), 170.1 (169.6), 175.4; MS (ESI) (m/z) 546.4 [M + 1], 568.2
[M + Na]+; MS (HRMS) m/z calcd for [M + 1]+ ) 546.3179;
m/z found 546.3166; calcd for [M + Na]+ ) 568.2999; m/z found
568.2974. Diastereoisomer B: white solid; yield 33%; Rf (CH2-
1
Cl2/ MeOH 95:5) 0.54; NMR H (CDCl3, 500 MHz, 293 K) two
rotamers 2:1 ratio δ 0.80 (t, J ) 7.8 Hz, 3H), 1.08-1.75 (m, 10H),
1.32 (1.33) (s, 3H), 1.49 (1.50) (s, 3H), 1.80-2.09 (m, 1H), 2.49-
2.53 (m, 2H), 2.88-2.91 (m, 1H), 2.91-3.02 (m, 1H), 3.23 (d,
J ) 13.6 Hz, 1H), 3.38 (3.41) (d, J ) 15.9 (15.1) Hz, 1H), 3.55-
3.61 (m, 1H), 3.65-4.02 (m, 2H), 4.08 (4.49) (d, J ) 14.7 (16.6)
Hz, 1H), 4.12-4.30 (m, 3H), 4.56 (dd, J ) 15.9 Hz, 8.7 Hz, 1H),
5.06 (4.75) (d, J ) 14.7 (16.6) Hz, 1H), 7.10-7.29 (m, 5H), 8.02
(7.73) (brs, 1H); NMR 13C (CDCl3, 75 MHz, 293 K) two rotamers
2:1 ratio δ 14.0, 22.5, 26.1 (25.6), 27.6 (27.3), 29.4 (29.3), 31.6
(31.1), 34.5 (33.5), 39.3 (40.9), 49.7 (49.3), 50.5 (51.3), 52.6 (52.9),
53.8 (55.0), 61.8 (62.5), 65.2 (63.1), 80.5, 82.8 (82.7), 83.1 (84.7),
85.9, 116.3 (115.4) 127.1-129.1, 136.2 (135.6), 167.9 (168.6),
171.2 (170.3), 175.6 (175.1); MS (ESI) (m/z) 546.3 [M + 1], 568.3
[M + Na]+; MS (HRMS) m/z calcd for [M + 1]+ ) 546.3179,
m/z found 546.3162; calcd for [M + Na]+ ) 568.2999, m/z found
568.2982.
Acknowledgment. We thank CNRS and our institute for
financial support. C.B. thanks Ministe`re de l’Enseignement
Supe´rieur et de la Recherche for a doctoral fellowship.
95:5) 0.62; IR (CHCl3) ν 1062, 1716, 1672, 1643, 1737, 3324 cm-1
;
Supporting Information Available: Syntheses, physical data
of 1a-c, 4a-f, and 5a-f, and copies of 1H NMR of 1a-c, 4a-f,
and 5a-e. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
NMR H (CDCl3, 300 MHz, 293 K, ppm) two rotamers 1:3 ratio
δ 0.85-0.88 (m, 3H), 1.03-1.50 (m, 10H), 1.37 (1.39) (s, 3H),
1.54 (1.58) (s, 3H), 1.58-1.85 (m, 1H), 1.95-2.03 (m, 1H), 2.75
(dd, J ) 14.1 Hz, 4.7 Hz, 1H), 2.90 (2.88) (dd, J ) 14.1 Hz, 8.4
Hz, 1H), 3.04-3.07 (3.12) (m, 1H), 3.53 (d, J ) 18.0 Hz, 1H),
JO0621874
J. Org. Chem, Vol. 72, No. 5, 2007 1829