Ring-closing alkyne metathesis. Application to the total synthesis of sophorolipid lactone

Article abstract of DOI:10.1021/jo0012952

The first total synthesis of a major component of the microbial biosurfactant sophorolipid has been achieved. This approach to the 26-membered macrolide 1 containing a Z-configured alkene group in its lipidic tether spanning the sophorose backbone is based on a ring-closing metathesis reaction of diyne 21 catalyzed by Mo[N(t-Bu)(Ar)]₃ (5; Ar = 3,5-dimethylphenyl) activated in situ by CH₂-Cl₂, followed by Lindlar reduction of the resulting cycloalkyne 22. The two β-glycosidic linkages of compound 21 were installed by means of the glucal epoxide method and a modified Koenigs - Knorr reaction promoted by AgOTf/lutidine, respectively.

Full text of DOI:10.1021/jo0012952

8758
J . Org. Chem. 2000, 65, 8758-8762
Rin g-Closin g Alk yn e Meta th esis. Ap p lica tion to th e Tota l
Syn th esis of Sop h or olip id La cton e
Alois Fu¨rstner,* Karin Radkowski, J aroslaw Grabowski, Conny Wirtz, and Richard Mynott
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/ Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received August 28, 2000
The first total synthesis of a major component of the microbial biosurfactant sophorolipid has been
achieved. This approach to the 26-membered macrolide 1 containing a Z-configured alkene group
in its lipidic tether spanning the sophorose backbone is based on a ring-closing metathesis reaction
of diyne 21 catalyzed by Mo[N(t-Bu)(Ar)]3 (5; Ar ) 3,5-dimethylphenyl) activated in situ by CH2-
Cl2, followed by Lindlar reduction of the resulting cycloalkyne 22. The two â-glycosidic linkages of
compound 21 were installed by means of the glucal epoxide method and a modified Koenigs-Knorr
reaction promoted by AgOTf/lutidine, respectively.
In tr od u ction
this mixture.7 All other constituents essentially differ
from these parent compounds in the acylation pattern
of the remaining -OH groups.8
The yeast Candida bombicola is able to grow even on
pure hydrocarbons as the only carbon source. It emulsi-
fies hydrophobic culture media by the production of
extracellular biosurfactants called sophorolipids (SL) that
can be obtained in large amounts by fermentation under
optimized conditions.1 These glycolipids are of growing
commercial interest as biodegradable emulsifiers with
low critical micelle concentrations that can be easily
produced from cheap raw materials as diverse as n-
alkanes, vegetable oils, carbohydrates, and even indus-
trial waste products (yields of 70-135 g of SL per liter
of the fermentation broth can be routinely obtained).2-4
Various applications of SL in the cosmetic industry, for
pharmaceutical formulations, in food production, and
even for technical purposes such as oil pollution abate-
ment of seawater can be envisaged and have been
claimed in the patent literature.2-4
Native SL is a rather complex mixture of up to 14
different compounds.5 Although its composition and
properties strongly depend on both the fermentation
conditions and the carbon sources used as the culture
medium, the sophorose glycoside 26 and the 1′,4′′-lactone
1 derived from it always constitute major components of
(1) (a) Gorin, P. A. J .; Spencer, J . F. T.; Tulloch, A. P. Can. J . Chem.
1961, 39, 846. (b) Tulloch, A. P.; Spencer, J . F. T.; Gorin, P. A. J . Can.
J . Chem. 1962, 40, 1326.
(2) Review: Karanth, N. G. K.; Deo, P. G.; Veenanadig, N. K. Curr.
Sci. 1999, 77, 116.
(3) See the following for leading references and literature cited
therein: (a) Asmer, H.-J .; Lang, S.; Wagner, F.; Wray, V. J . Am. Oil
Chem. Soc. 1988, 65, 1460. (b) Otto, R. T.; Daniel, H.-J .; Pekin, G.;
Mu¨ller-Decker, K.; Fu¨rstenberger, G.; Reuss, M.; Syldatk, C. Appl.
Microbiol. Biotechnol. 1999, 52, 495. (c) Zhou, Q.-H.; Kosaric, N. J .
Am. Oil Chem. Soc. 1995, 72, 67. (d) Daniel, H.-J .; Otto, R. T.; Binder,
M.; Reuss, M.; Syldatk, C. Appl. Microbiol. Biotechnol. 1999, 51, 40.
(e) Inoue, S.; Ito, S. Biotechnol. Lett. 1982, 4, 3. (f) Krivobok, S.;
Guiraud, P.; Seigle-Murandi, F.; Steiman, R. J . Agric. Food Chem.
1994, 42, 1247. (g) Cooper, D. G.; Paddock, D. A. Appl. Environ.
Microbiol. 1984, 47, 173.
Little is known about the (physico)chemical and, in
particular, the biological properties of the individual
compounds such as 1 and 2, although this information
may be crucial for future applications. While SL is
generally considered to be a nontoxic biodetergent,3e
(6) Sophorose is the trivial name for the disaccharide 2-O-(â-D-
glucopyranosyl)-D-glucopyranose.
(7) Structure elucidation: Tulloch, A. P.; Hill, A.; Spencer, J . F. T.
Can. J . Chem. 1968, 46, 3337. For
a more recent NMR study
confirming the earlier results, see ref 3a.
(4) For a particularly efficient production see: Marchal, R.; Lemal,
J .; Sulzer, C. U.S. Patent 5,616,479.
(5) For investigations into the composition of native SL and the
determination of individual components see: (a) Davila, A. M.;
Marchal, R.; Monin, N.; Vandecasteele, J . P. J . Chromatogr. 1993, 648,
139. (b) de Koster, C. G.; Heerma, W.; Pepermans, H. A. M.; Groe-
newegen, A.; Peters, H.; Haverkamp, J . Anal. Biochem. 1995, 230, 135.
(8) (a) Derivatives of lactone 1 bearing acetyl groups at the 6′- and/
or the 6′′-OH of the sophorose backbone are particularly abundant in
native SL. It is known, however, that they are converted into 1 upon
enzymatic hydrolysis without concomitant opening of the lactone
ring.3a,b (b) For a brief study of the inhibitory effects of lactone 6′,6′′-
diacetate on the growth of various yeasts see: Ito, S.; Kinta, M.; Inoue,
S. Agric. Biol. Chem. 1980, 44, 2221.
10.1021/jo0012952 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

Total Synthesis of Sophorolipid Lactone
J . Org. Chem., Vol. 65, No. 25, 2000 8759
Sch em e 1
recent reports indicate that purified samples display
significant cytotoxic effects (LC50 15 mg L-1) that are
greater than those of the native product mixture.3b SL
also inhibits the activity of phospholipid- and Ca2+
-
dependent protein kinase9 and can induce cell dif-
ferentiation of the human promyelocytic leucemia cell
lines HL 60 into monocytes.9 Moreover, it is well-known
that many glycolipids elicit a strong immune response
in humans,10 an aspect that has not been addressed with
regard to SL. In view of these preliminary results, it is
certainly called for to map the biological profile of the
major constituents of SL in more detail prior to potential
applications in food, cosmetics, or pharmaceutical for-
mulations. Given the difficulties in obtaining analytically
pure samples by conventional separation techniques, we
were prompted to develop a concise preparative route to
the parent sophorolipid lactone 1, from which acid 2 can
also be obtained upon simple hydrolysis. Rather than
relying on a conservative macrolactonization strategy,11
however, we considered the intricate structure of this
target as a testing ground for probing new methodology.
The results of this investigation are summarized below.
Resu lts a n d Discu ssion
Sch em e 2
Str a tegy a n d Retr osyn th etic An a lysis. In recent
work, we have outlined an efficient entry into bioactive
resin glycosides produced by higher plants based on the
excellent application profile of various ruthenium cata-
lysts for ring-closing olefin metathesis (RCM).12 One of
the products formed by this route was the disaccharide
lactone 4, a key building block for the total synthesis of
tricolorin A (Scheme 1). Although this compound bears
considerable resemblance to sophorolipid lactone, sug-
gesting that RCM could also be employed en route to
1,13,14 a more detailed assessment of the projected case
calls for a revised strategy.
RCM of diene 3 invariably delivered lactone 4 as a
mixture of stereoisomers (E:Z ≈ 3:1) at the newly formed
double bond independent of the catalyst used.15 This
outcome is characteristic for RCM-based macrocycliza-
tions in which the (E)-alkene is (strongly) favored in most
of the recorded cases.13-16 In view of this compelling
precedence, a stereoselective synthesis of 1 containing a
Z-configured alkene moiety in its lipidic tether based on
conventional RCM cannot be expected.
In contrast, ring-closing metathesis of diynes consti-
tutes a more promising strategy that allows the stereo-
chemical issue to be geared to the cyclization event. In
combination with a Lindlar-type reduction of the result-
ing cycloalkynes, this method opens a convenient and
stereoselective entry into macrocyclic (Z)-alkenes (Scheme
2)17 and may therefore constitute the method of choice
for the total synthesis of sophorolipid lactone 1. Alkyne
metathesis, however, is still in its infancy as compared
with alkene metathesis, which over the past decade has
evolved into a mature tool for advanced organic synthe-
sis.13,18 Although no application of alkyne metathesis to
(9) Isoda, H.; Kitamoto, D.; Shinmoto, H.; Matsumura, M.; Naka-
hara, T. Biosci. Biotechn. Biochem. 1997, 61, 609.
(10) For a general review on glycolipids see: Li, Y.-T.; Li, S.-C. Adv.
Carbohydr. Chem. Biochem. 1982, 40, 235.
(11) A recent report on an enzyme-catalyzed macrocyclization of acid
2 did not afford lactone 1 but resulted in esterification with the primary
alcohol groups of the sophorose, i.e., with either the 6′-OH or the 6′′-
OH position, respectively. Cf.: Bisht, K. S.; Gross, R. A.; Kaplan, D.
L. J . Org. Chem. 1999, 64, 780.
(12) (a) Fu¨rstner, A.; Mu¨ller, T. J . Am. Chem. Soc. 1999, 121, 7814.
(b) Fu¨rstner, A.; Mu¨ller, T. J . Org. Chem. 1998, 63, 424. (c) Lehmann,
C. W.; Fu¨rstner, A.; Mu¨ller, T. Z. Kristallogr. 2000, 215, 114.
(13) For the most recent review on alkene and alkyne metathesis
see: Fu¨rstner, A. Angew. Chem. 2000, 112, 3140; Angew. Chem., Int.
Ed. 2000, 39, 3012.
(14) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Fu¨rstner, A. Top. Catal. 1997, 4, 285. (c) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 37. (e) Ivin, K. J .; Mol, J . C. Olefin
Metathesis and Methathesis Polymerization, 2nd ed.; Academic Press:
New York, 1997.
(15) The choice of the catalyst had no appreciable effect on the E:Z
ratio, although their structures are substantially different; the follow-
ing three RCM catalysts have been employed en route to 4. (a)
Cl2(PCy3)2RudCHCHdCPh2: Nguyen, S. T.; Grubbs, R. H.; Ziller, J .
W. J . Am. Chem. Soc. 1993, 115, 9858. (b) (p-cymene)(PCy3)RuCl2/hν:
Fu¨rstner, A.; Ackermann, L. Chem. Commun. 1999, 95. (c) [(p-cymene)-
(PCy3)RuCl(dCdCdCPh2)]+PF6-: Fu¨rstner, A.; Picquet, M.; Bruneau,
C.; Dixneuf, P. H. Chem. Commun. 1998, 1315. Fu¨rstner, A.; Liebl,
M.; Lehmann, C. W.; Picquet, M.; Kunz, R.; Bruneau, C.; Touchard,
D.; Dixneuf, P. H. Chem. Eur. J . 2000, 6, 1847.
(16) Further examples of RCM-based macrocyclizations from our
laboratory in which the E isomer largely dominates or is even the only
product formed: (a) Fu¨rstner, A.; Grabowski, J .; Lehmann, C. W. J .
Org. Chem. 1999, 64, 8275. (b) Fu¨rstner, A.; Gastner, T.; Weintritt,
H. J . Org. Chem. 1999, 64, 2361. (c) Fu¨rstner, A.; Seidel, G.; Kindler,
N. Tetrahedron 1999, 55, 8215. (d) Fu¨rstner, A.; Langemann, K. J .
Am. Chem. Soc. 1997, 119, 9130. (e) Fu¨rstner, A.; Langemann, K. J .
Org. Chem. 1996, 61, 3942. (f) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J . Org. Chem., in press.
(17) Fu¨rstner, A.; Seidel, G. Angew. Chem. 1998, 110, 1758; Angew.
Chem., Int. Ed. Engl. 1998, 37, 1734.

8760 J . Org. Chem., Vol. 65, No. 25, 2000
Fu¨rstner et al.
Sch em e 3a
a target as densely functionalized as 1 has been reported
to date, the known examples19-24 are highly promising
and encouraged us to implement this emerging method-
ology into the present study. Among the catalysts pres-
ently available, a molybdenum species formed in situ
from Mo[N(t-Bu)(Ar)]3 (5; Ar ) 3,5-dimethylphenyl) and
CH2Cl2 seems to be the most promising with regard to
efficiency and tolerance toward polar functional groups
in the substrate.20,21,25
Another important issue en route to 1 concerns the
choice of the proper protecting groups. They must be
cleaved in the final step of the sequence without com-
promising the integrity of the unsaturated lactone ring.
This precludes basic (saponification) as well as acidic
conditions (acyl migration), while hydrogenolysis is obvi-
ously incompatible with the double bond in the octade-
cenoic acid tether. With these stringent criteria in mind,
we have designed a synthesis that converges to p-
methoxybenzyl (PMB) ethers as the only residual pro-
tecting groups for the -OH functions in the penultimate
step. The oxidative conditions used for their deprotection
should be tolerated by the sensitive target.26
Tota l Syn th esis of Sop h or olip id La cton e. Our
synthesis of sophorolipid lactone 1 requires enantiomeri-
cally pure alcohol 8 (ee g 99.5%) for the first glycosylation
step, which was conveniently obtained by a Cu(I)-
catalyzed ring-opening reaction of (S)-propenoxide 727
with the Grignard reagent 6 derived from 1-bromo-6-
octyne in THF according to a procedure previously
reported by our laboratory.28 The other starting material
is commercially available D-glucal 9 that was protected
as tri-O-PMB ether 10 under conventional conditions
(Scheme 3). These two components were then glycosyl-
ated using Danishefsky’s glycal epoxide methodology.29
Thus, substrate 10 was treated with a slight excess of
dimethyldioxirane in CH2Cl2 at -25 °C,30 all volatiles
a
Legend: [a] CuCl(COD) (10 mol %), THF, -78 °C f room
temperature, 63%; [b] p-MeOC6H4CH2Cl, NaH, (n-Bu)4NI cat.,
DMF, 0 °C f room temperature, 76%; [c] dimethyldioxirane,
CH2Cl2, -25 °C; [d] alcohol 8, ZnCl2, THF, -78 °C f room
temperature, 42%.
were stripped off in vacuo, and the resulting epoxide 11
was reacted with alcohol 8 in THF in the presence of
ZnCl2 (2 equiv) as the Lewis-acidic promoter. Although
this reaction afforded the desired â-configured product
12 in only 42% isolated yield, other conceivable ap-
proaches to this building block bearing an unprotected
-OH group at C-2 require more steps.31,32
The assembly of the second sugar building block
(Scheme 4) starts with a routine transacetalization of
p-methoxybenzaldehyde dimethylacetal with D-glucose in
the presence of p-TsOH‚H2O as the catalyst, delivering
the fairly sensitive 4,6-O-p-methoxybenzylidene acetal 13
on a multigram scale.33 Peracetylation followed by selec-
tive deprotection of the anomeric center of product 14
using benzylamine as the nucleophile delivers the reduc-
ing sugar 15 in good yield. To preserve its labile acetal
function, this compound was converted into glycosyl
bromide 16 under essentially neutral conditions using
Br2 activated by P(OPh)3 in CH2Cl2 as the reagent of
choice.34 Product 16 was stable enough to be purified by
(18) For a short review on alkyne metathesis see: Bunz, U. H. F.;
Kloppenburg, L. Angew. Chem., Int. Ed. 1999, 38, 478. A more detailed
and updated discussion is found in ref 13.
(19) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J . Am. Chem. Soc.
1999, 121, 11108.
(20) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J . Am. Chem. Soc.
1999, 121, 9453.
(21) Fu¨rstner, A.; Grela, K. Angew. Chem. 2000, 112, 1292; Angew.
Chem., Int. Ed. 2000, 39, 1234.
(29) (a) Halcomb, R. L.; Danishefsky, S. J . J . Am. Chem. Soc. 1989,
111, 6661. (b) Review: Danishefsky, S. J .; Bilodeau, M. T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1380.
(30) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(31) Compound 12 can also be prepared via an ortho ester as the
key intermediate by essentially following the approach used for the
synthesis of caloporoside described in ref 28. Although the yields of
all six individual steps are good to excellent, the overall efficiency is
not higher than that of the glycal epoxidation route described herein.
(32) For a discussion of our strategic goals see: Fu¨rstner, A. Synlett
1999, 1523.
(33) Prepared in analogy to the procedure described by: Barili, P.
L.; Berti, G.; Catelani, G.; Cini, C.; D’Andrea, F.; Mastrorilli, E.
Carbohydr. Res. 1995, 278, 43.
(22) Fu¨rstner, A.; Rumbo, A. J . Org. Chem. 2000, 65, 2608.
(23) Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463.
(24) Fu¨rstner, A.; Seidel, G. J . Organomet. Chem. 2000, 606, 75.
(25) (a) Complex 5 is prepared as described in: Laplaza, C. E.;
Odom, A. L.; Davis, W. M.; Cummins, C. C.; Protasiewicz, J . D. J . Am.
Chem. Soc. 1995, 117, 4999. (b) See also: Cummins, C. C. Chem.
Commun. 1998, 1777.
(26) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991.
(27) (S)-7 is commercially available or can be conveniently prepared
on a large scale in optically active form using J acobsen’s excellent
resolution method, cf.: (a) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.;
J acobsen, E. N. Science 1997, 277, 936. (b) Furrow, M. E.; Schaus, S.
E.; J acobsen, E. N. J . Org. Chem. 1998, 63, 6776.
(34) (a) Mani, N. S.; Kanakamma, P. P. Synth. Commun. 1992, 22,
2175. (b) See also: Spencer, R. P.; Cavallaro, C. L.; Schwartz, J . J .
Org. Chem. 1999, 64, 3987.
(28) (a) Fu¨rstner, A.; Konetzki, I. J . Org. Chem. 1998, 63, 3072. (b)
Fu¨rstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071.

Total Synthesis of Sophorolipid Lactone
J . Org. Chem., Vol. 65, No. 25, 2000 8761
Sch em e 4a
Sch em e 5a
a
Legend: [a] Mo[N(t-Bu)(Ar)]3 (Ar ) 3,5-dimethylphenyl), 5 (10
mol %), CH2Cl2/toluene, 80 °C, 78%; [b] H2 (1 atm), Lindlar catalyst
(Pd, 5% w/w, on CaCO3 poisoned with Pb), quinoline, CH2Cl2, room
temperature, quantitative; [c] DDQ, CH2Cl2/MeOH (18/1), room
temperature, 8 h, 93% (containing only trace impurities; analyti-
cally pure sample after preparative HPLC: 64%).
respectable 89% yield. Promoters other than AgOTf gave
largely inferior results.37 After having served the purpose
of guiding the glycosylation in a â-selective way, the
acetyl groups were cleaved off under standard conditions
and the resulting diol 18 was converted into the corre-
sponding PMB ether derivative 19 on treatment with
NaH and p-methoxybenzyl chloride in the presence of
catalytic amounts of n-Bu4NI. Reductive cleavage of the
4,6-O-p-methoxybenzylidene acetal in 19 by means of a
large excess of NaBH3CN and F3CCOOH took the ex-
pected regioselective course,38 delivering the desired
product 20 in 88% yield together with trace amounts of
the wrong regioisomer having a free 6′′-OH group (<5%);
this byproduct was readily removed by flash chromatog-
raphy. Esterification of pure 20 with 9-undecynoic acid19
in the presence of DCC and DMAP afforded compound
21, thereby setting the stage for the crucial diyne
metathesis reaction.
Gratifyingly, this key transformation performed very
well using a catalyst formed in situ from Mo[N(t-Bu)-
(Ar)]3 (5; Ar ) 3,5-dimethylphenyl) and CH2Cl2 in toluene
at 80 °C as previously described (Scheme 5).20 The desired
cycloalkyne 22 was obtained in 78% yield, thus providing
further evidence that alkyne metathesis is a reliable
a
Legend: [a] p-MeOC6H4CH(OMe)2, p-TsOH‚H2O cat., DMF,
51%; [b] Ac2O, pyridine, room temperature, 95%; [c] benzylamine,
THF, room temperature, 76%; [d] Br2, P(OPh)3, CH2Cl2/pyridine,
0 °C f room temperature, 60%; [e] alcohol 12, AgOTf, 2,6-di-tert-
butylpyridine, MS 4 Å, -5 °C, 89%; [f] NaOMe, MeOH, room
temperature, 99%; [g] p-MeOC6H4CH2Cl, NaH, (n-Bu)4NI cat.,
DMF, 0 °C f room temperature, 91%; [h] NaBH3CN (10 equiv),
F3CCOOH (25 equiv), MS 4 Å, DMF, 0 °C f room temperature,
88%; [i] 9-undecynoic acid, DCC, DMAP cat., 93%.
(35) Reviews: (a) Paulsen, H. Angew. Chem. 1982, 94, 184; Angew.
Chem., Int. Ed. Engl. 1982, 21, 155. (b) Schmidt, R. R. In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, U.K., 1991; Vol. 6, p 33. (c) Toshima, K.; Tatsuta, K. Chem.
Rev. 1993, 93, 1503.
(36) Hanessian, S.; Banoub, J . Carbohydr. Res. 1977, 53, C13. In
this procedure, the use of AgOTf in combination with tetramethylurea
is recommended; in our hands, however, tetramethylurea gave rather
low yields of the expected disaccharide, whereas lutidine as the base
led to excellent and reproducible results.
(37) The use of Ag2CO3 or AgNO3 deposited on silica/alumina led to
marginal conversions only.
(38) (a) J ohansson, R.; Samuelsson, B. J . Chem. Soc., Perkin Trans.
1 1984, 2371. (b) Garegg, P. J . In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; p 53.
flash chromatography prior to use in the subsequent
glycosylation reaction, which was carried out under
slightly modified Koenigs-Knorr conditions.35 Specifi-
cally, reaction of this bromide with alcohol 12 promoted
by an excess of AgOTf (1.8 equiv)36 and lutidine (3.2
equiv) in CH2Cl2 at -5 °C in the presence of molecular
sieves yielded the desired sophorose glycoside 17 in a

8762 J . Org. Chem., Vol. 65, No. 25, 2000
Fu¨rstner et al.
and efficient reaction even if applied to fairly elaborate
natural products. The fact that neither the acid-labile
PMB ethers nor the glycosidic linkages were damaged
by the Lewis acidic metal center of the catalyst adds two
more important examples to the rapidly growing list of
functional groups that are compatible with this system.
Cycloalkyne 22 exhibits two sets of signals in the high
field (600 MHz) NMR spectra recorded at ambient
temperature. Extensive investigations, however, have
shown beyond doubt that the connectivities of both
components are identical. Therefore, this phenomenon
is due to rotamers and is by no means caused by the
presence of isomeric products formed prior or during
alkyne metathesis. Similarly, two components are found
in the NMR spectra of the Lindlar reduction product 23,
whereas the deprotected sophorolipid lactone 1 itself
gives only the expected single set of resonances. An
unambiguous assignment of all signals to the individual
rotamers has been achieved by means of 1D and 2D
correlation experiments, the results of which are sum-
marized in the Supporting Information.
Lindlar hydrogenation of cycloalkyne 22 under stan-
dard conditions in CH2Cl2 as the reaction medium
proceeded uneventfully, delivering fully protected sophoro-
lipid lactone 23. In line with our expectations, the final
deprotection of this compound using an excess of DDQ
in CH2Cl2/H2O (18:1)39 afforded the targeted product 1.
In view of the amphiphilic character of this compound,
however, its purification was somewhat delicate. Al-
though the material collected after conventional flash
chromatography (93%) was essentially pure, it did not
give correct combustion analyses. Therefore, a sample
was subjected to preparative HPLC; lactone 1 thus
obtained in 64% yield fully meets all criteria of purity
and integrity. In particular, its high-resolution NMR
spectra (600 MHz) are perfectly in agreement with the
proposed structure (cf. Experimental Section).
Con clu sion s. This work completes the first total
synthesis of a major component of the microbial biosur-
factant sophorolipid and constitutes the first application
of ring-closing alkyne metathesis17 to the carbohydrate
series. Together with previous syntheses reported from
our laboratory dealing with alkaloids,19,22 prostaglan-
dins,21 acetogenins,23 and perfume ingredients,19,24 this
example further illustrates the wide scope of this trans-
formation and the excellent compatibility of the available
catalysts17-20 with a host of polar functional groups, even
if these are grouped in dense arrays. A comparison of our
recent RCM approach to the glycolipidic segment 4 of
tricolorin A (Scheme 1)12 with this synthesis of glycolipid
1 shows that “conventional” RCM and the emerging
alkyne metathesis are essentially equipotent in prepara-
tive terms, with the latter offering the additional advan-
tage of providing a stereoselective entry into macrocyclic
products.13 Further applications corroborating these ad-
vantageous features are underway and will be reported
in due course.
Ack n ow led gm en t. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz award
to A.F.) and by the Fonds der Chemischen Industrie is
acknowledged with gratitude. We thank Mr. A. Deege
and Mrs. H. Hinrichs for performing the preparative
HPLC separation.
Su p p or tin g In for m a tion Ava ila ble: Text giving full
experimental details, appropriate characterization of all new
compounds, and an unambiguous assignment of the NMR
signals of all disaccharidic products described. This material
is available free of charge via the Internet at http://pubs.acs.org.
(39) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
J O0012952