Total synthesis of tricolorin A

Article abstract of DOI:10.1021/jo971413u

Tricolorin A (1) is a novel tetrasaccharide macrolactone that is a natural herbicide. In this paper is reported a total synthesis of 1. Coupling of hydroxy ester 18 with D-fucosyl trichloroacetimidate 23 gave fucoside 24. Removal of he C-2 pivaloyl group

Full text of DOI:10.1021/jo971413u

8406
J . Org. Chem. 1997, 62, 8406-8418
Tota l Syn th esis of Tr icolor in A
Daniel P. Larson and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received J uly 30, 1997X
Tricolorin A (1) is a novel tetrasaccharide macrolactone that is a natural herbicide. In this paper
is reported a total synthesis of 1. Coupling of hydroxy ester 18 with D-fucosyl trichloroacetimidate
23 gave fucoside 24. Removal of the C-2 pivaloyl group of 24 followed by coupling with D-glucosyl
trichloroacetimidate 29 resulted in isolation of disaccharide 30. Saponification of the ester groups
of 30 and subsequent selective macrolactonization of the acid diol 31 by the Yonemitsu protocol
gave only the desired lactone 32. The key step in the assembly of disaccharide glycosyl
trichloroacetimidate 52 was coupling L-rhamnoside 47 with L-rhamnosyl trichloroacetimidate 43.
Attempts to couple lactone disaccharide 32 with disaccharide 52 were unsuccessful. Using an
alternate plan for assembly of the tetrasaccharide, reaction of disaccharide glycosyl trichloro-
acetimidate 58 with disaccharide 37 gave tetrasaccharide 59. Diester lactone 63 was generated
by selective macrolactonization of tetrasaccharide acid triol 60, again using the Yonemitsu protocol,
followed by addition of the chiral side chain acid to the reaction vessel. Synthetic tricolorin A (1)
was obtained by deprotection of 63. Starting from fucose, glucose, rhamnose, and (S)-1-octyn-3-ol,
the synthesis required 39 steps overall. The longest linear sequence was 14 steps, with an overall
yield for this longest linear sequence of 6%.
Farmers in the southeastern intertropical Mexican
types of protecting groups would result in a reduction of
protecting and deprotecting steps.
state of Morelos use Ipomoea tricolor as a cover crop
during the fallow period in sugar cane fields. An ability
to control weed growth prompted investigation of the
compounds responsible for the biological activity of this
plant. Pereda-Miranda and co-workers1 reported the
isolation of tricolorin A (1) from Ipomoea tricolor in 1993.
This unusual tetrasaccharide macrolactone demonstrated
significant cytotoxic activity against cultured P-388 and
human breast cancer cells. We chose tricolorin A as a
synthetic target because of the unique challenge in
forming the macrolactone in this molecule.
The goal of this project was not necessarily to develop
new synthetic methodology for the synthesis of carbohy-
drates but rather to apply the known chemistry in as
efficient manner as possible. Our plan that would
accomplish this goal can best be described by retrosyn-
thetic analysis of the target molecule. A key disconnec-
tion is the glycosidic linkage between the glucose and
rhamnose rings. This bond would be formed by coupling
a rhamnose-rhamnose disaccharide glycosyl donor 3 with
a lactone disaccharide glycosyl acceptor 2 (Scheme 1). An
important feature of this assembly strategy is that upon
coupling of the two fragments the entire skeleton of
tricolorin A would be intact. This strategy would give a
maximally convergent synthesis. Retrosynthesis of the
lactone disaccharide fragment 2 illustrates how we
planned to use the intrinsic difference in reactivities of
the hydroxyl groups of the molecule to selectively form
some of the carbon-oxygen bonds. Macrolactonization
would occur on an acid diol substrate 4. We believed
lactonization would selectively occur at the C-3 glucose
hydroxyl group due to the steric impediment that the
large substituent at the anomeric position of the glucose
ring would present at the C-2 hydroxyl group. By using
the intrinsic difference in reactivities of these hydroxyl
groups, we could minimize the number of different types
of protecting groups used in the synthesis. Using fewer
Our initial task in the project was to develop an
efficient synthesis of the hydroxy ester portion of the
molecule with a high degree of enantiomeric purity.
Starting from 1-decyne, deprotonation of the akyne
followed by addition of hexanal gave the racemic pro-
pargylic alcohol 6 (Scheme 2). Moffat-Swern oxidation
of the propargylic alcohol to the corresponding acetylenic
ketone 7 and chiral reduction with NB-Enantrane2 gave
an optically active alcohol 8. Derivatization of the alcohol
as the Mosher ester3 revealed that the compound had a
modest enantiomeric purity (81% ee). The remaining
steps of the side chain synthesis were investigated using
the less precious racemic material. Isomerization of the
propargylic alcohol 6 with KNH(CH2)3NH2 (KAPA)4 gave
the terminal alkyne 9 in good yield. Refunctionalization
of the alkyne to the ester was a multistep procedure.
Deprotonation with base followed by addition of TMSCl
gave the bis-silyl compound 10. Hydroboration with
(C6H11)2BH followed by oxidation of the alkylborane
resulted in isolation of the acid 11.5 Finally, the desired
methyl ester 12 was obtained by Fisher esterification of
11.
Although multigram quantities of material could be
moved through this synthesis, which could give enantio-
merically enriched hydroxy ester in 37% overall yield,
the approach had two major flaws. First, the enantio-
meric purity of material generated from this synthesis
would not be sufficient for our needs. Additionally,
oxidative cleavage of the alkyne was unnecessarily labor
intensive and clumsy. Thus, we sought to develop an
improved synthesis of the hydroxy ester.
(2) NB-Enantrane is the reaction product of 9-borabicyclo[3.3.1]-
nonane (9-BBN) and (1R)-(-)-nopol benzyl ether. Midland, M.; Ka-
zubski, A. J . Org. Chem. 1982, 47, 2814. The reagent is commercially
available from the Aldrich Chemical Co., Inc.
(3) Dale, J .; Dull, D.; Mosher, H. J . Org. Chem. 1969, 34, 2543.
(4) (a) Brown, C. A.; Yamashita, A. J . Am. Chem. Soc. 1975, 97,
891. (b) Midland, M. M.; Halterman, R. L.; Brown, C. A.; Yamaichi, A.
Tetrahedron Lett. 1981, 22, 4171.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) Pereda-Miranda, R.; Mata, R.; Anaya, A. L.; Wickramaratne, D.
B. M.; Pezzuto, J . M.; Kinghorn, A. D. J . Nat. Prod. 1993, 56, 571.
(5) Zweifel, G.; Backlund, S. J . Am. Chem. Soc. 1977, 99, 3184.
S0022-3263(97)01413-8 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of Tricolorin A
J . Org. Chem., Vol. 62, No. 24, 1997 8407
Sch em e 1
Sch em e 2a
produced in 79% yield by isomerization of the propargylic
alcohol with KAPA. Protection of the alcohol with tert-
butyldimethylsilyl chloride, followed by oxidative cleav-
age of the alkyne to the corresponding acid,7 and subse-
quent Fisher esterification gave the methyl ester.
Additionally, the acidic esterification reaction conditions
conveniently cleaved the TBS ether to give the desired
hydroxy ester 18. The second generation synthesis gave
the hydroxy ester in 56% yield over five steps, and the
product had a very high degree of enantiomeric purity.
The next task was to synthesize glucose and fucose
glycosyl donors and assemble the aliphatic glycoside of
the fucosyl-glucose unit. We initially investigated use
of the sulfoxide glycosylation method8 to assemble these
fragments but found the glycosyl trichloroacetimidate
method9 to be more successful in forming the glycosidic
linkages that we desired in high yield. As shown in
Scheme 4, the fucose trichloroacetimidate donor synthesis
began with the known benzyl R-D-fucopyranoside (19).10
Selective protection of the C-3 and C-4 hydroxyl groups
as the acetonide followed by protection of the C-2 hy-
droxyl group as the pivaloyl ester gave the fully protected
intermediate 21. The anomeric position was then un-
masked by catalytic hydrogenation of the benzyl ether.
Activation of the fucose derivative for glycoside formation
a
Key: (a) (i) n-BuLi; (ii) hexanal; (b) (COCl)2, DMSO, Et3N; (c)
NB-Enantrane; (d) KAPA; (e) (i) n-BuLi; (ii) Me3SiCl; (f) (i)
(C6H11)2BH; (ii) H2O2, NaOH; (g) MeOH, H2SO4.
Sch em e 3a
11
was achieved by treatment with Cl3CCN and Cs2CO3
to furnish trichloroacetimidate 23. Coupling of hydroxy
ester 18 and the crude trichloroacetimidate occurred
smoothly in CH2Cl2 with catalytic TMSOTf to give 24,
having the desired â-glycosidic linkage, in 79% yield. We
found that use of a pivaloyl protecting group at the C-2
position of the fucose donor resulted in a cleaner coupling
reaction. Use of the acetyl-protected analogue resulted
in significant acyl transfer to the acceptor hydroxyl group.
The C-2 hydroxyl group was exposed by cleavage of the
pivaloyl ester with NaOMe in a MeOH/MeOAc cosolvent
to give coupling partner 25. A large excess of NaOMe
was employed in this reaction to allow the reaction to
proceed at a practical rate. We found that use of MeOAc
in this step greatly minimized saponification of the
a
Key: (a) (i) LiNH2, NH3, -33 °C; (ii) C9H19I, THF, -33 f 25
°C; (b) KAPA, THF; (c) TBSCl, imidazole, DMF; (d) KMnO4,
HOAC, H2O, pentane; (e) MeOH, H2SO4.
Our second generation hydroxy ester synthesis (Scheme
3) began with the (S)-propargylic alcohol 13, which was
obtained by resolution of the corresponding racemate.6
Deprotonation of compound 13 with LiNH2 followed by
addition of excess 1-iodononane gave only the C-alklyated
product 14 in 94% yield. Terminal alkyne 15 was
(7) Krapcho, A. P.; Larson, J . R.; Eldridge, J . M. J . Org. Chem. 1977,
42, 3749.
(8) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J . Am. Chem.
Soc. 1989, 111, 6881.
(9) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(10) Heyns, K.; Baron, A. L.; Paulsen, H. Chem. Ber. 1964, 97, 921.
(11) Urban, F. J .; Moore, B. S.; Breitenbach, R. Tetrahedron Lett.
1990, 31, 4421.
(6) Hashimoto, S.; Kase, S.; Suzuki, A.; Yanagiya, Y.; Ikegami, S.
Synth. Commun. 1991, 21, 833.

8408 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
Sch em e 4a
Sch em e 6a
a
Key: (a) 2,2-dimethoxypropane, p-TsOH; (b) t-BuCOCl, pyri-
a
Key: (a) Ac2O (1 equiv), Et3N, DMAP, CH2Cl2; (b) NaOMe,
MeOH, MeOAc.
dine, DMAP, 70 °C; (c) 50 psi H2, Pd(OH)2, EtOAc; (d) Cl3CCN,
Cs2CO3, CH2Cl2; (e) (i) 18; (ii) TMSOTf, CH2Cl2; (f) NaOMe, MeOH,
MeOAc.
CH2Cl2 gave the â-disaccharide 30 in 84% yield. Simul-
taneous saponification of the three ester groups in
disaccharide 30 with LiOH provided the macrolacton-
ization precursor 31. Following the Yonemitsu protocol,15
the dihydroxy acid lactonized at the C-3 hydroxyl position
of the glucose ring with a high degree of selectivity over
the C-2 position to give the target lactone 32 in 71% yield.
Although we expected the macrolactonization reaction
to be selective, we were intrigued by the extremely high
degree of selectivity of this reaction and were curious
about whether the selectivity was due to something
intrinsic to the macrolactonization or common to other
acylations of this substrate type. Also, we wondered if
this was a kinetic or a thermodynamic result. To address
the question of the selectivity of intermolecular acyla-
tions, the acylation of a simple glucose derivative was
first investigated to provide a basis of comparison.
Reaction of diol 33 with 1 equiv of acetic anhydride
resulted in isolation of C-2 and C-3 monoacetate com-
pounds (34 and 35) in a ratio of about 1:1 (Scheme 6).
Conversely, when diol 36 was treated with 1 equiv of
acetic anhydride, the C-3 monoacetate 37 was formed in
80% yield. Only a trace of another compound, presumed
to be the C-2 monoacetate, was observed to be present
Sch em e 5a
a
Key: (a) Ac2O, Et3N, DMAP, CH2Cl2; (b) (i) BnNH2, THF; (ii)
1 N HCl; (c) Cl3CCN, Cs2CO3, CH2Cl2; (d) (i) 25; (ii) AgOTf, CH2Cl2;
(e) LiOH, THF, H2O; (f) 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, benzene.
1
in the H NMR spectrum of the crude reaction product.
Thus, the C-3 glucose hydroxyl group of the disaccharide
diol was found to be much more reactive than the C-2
hydroxyl group in an intermolecular acylation as well as
in the previously discussed intramolecular acylation. It
is likely that the steric bulk of the glucose anomeric
substituent is responsible for the regioselectivity observed
in acylation of 36 and in the intramolecular acylation
observed in 31.
To address the equilibration characteristics of the
reaction substrate, we first examined equilibration of the
simple glucose monosacccharide monoacetates 34 and 35.
To simulate the acylation reaction conditions, each of the
C-2 and C-3 monoacetates was treated with triethylam-
monimum acetate and DMAP in methylene chloride.
Neither compound equilibrated to an observable extent
methyl ester functionality in the molecule by a minor
amount of hydroxide present in the NaOMe reaction
solution.
The glucose unit preparation began by protection of
the known glucopyranose 2612 to form the triacetyl
compound 27 (Scheme 5). Formation of the amino
glycoside by treatment with BnNH2 followed by selective
hydrolysis with dilute aqueous acid13 furnished pyranose
28 in 87% yield. Formation of the corresponding trichlo-
roacetimidate by treatment with Cl3CCN and Cs2CO3
gave glycosyl donor 29. Treatment of alcohol 25 with the
crude trichloroacetimidate and anhydrous AgOTf14 in
(12) Wood, H. B., J r.; Diehl, H. W.; Fletcher, H. G., J r. J . Am. Chem.
Soc. 1957, 79, 1986.
(13) (a) Sim, M. M.; Kondo, H.; Wong, C.-H. J . Am. Chem. Soc. 1993,
115, 2260. (b) Helferich, B.; Portz, W. Chem. Ber. 1953, 86, 604.
(14) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J . J . J . Carbohydr.
Chem. 1993, 12, 131.
(15) (a) Evans, D. A., Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc.
1993, 115, 11446. (b) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu,
O. Tetrahedron Lett. 1990, 31, 6367.

Total Synthesis of Tricolorin A
J . Org. Chem., Vol. 62, No. 24, 1997 8409
Sch em e 7
Sch em e 8a
a
Key: (a) BnBr, Bu4NI, NaH, DMF; (b) (i) t-BuOK, DMSO, 100
°C; (ii) 1 N HCl, acetone, reflux; (c) Cl3CCN, Cs2CO3, CH2Cl2; (d)
(EtO)3CMe, p-TsOH, CH2Cl2; (e) Ac2O, Et3N, DMAP, CH2Cl2; (f)
HOAc, H2O.
treatment with Cl3CCN and Cs2CO3 gave glycosyl donor
43. For synthesis of the rhamnose acceptor, 40 was
transformed into the 2,3 ortho ester by reaction with
triethyl orthoacetate and catylatic acid. The acid-labile
ortho ester was immediately subjected to standard acyla-
tion conditions to give the fully protected rhamnoside 45.
Brief exposure of the ortho ester to aqueous acetic acid
resulted in transformation to a 7:1 mixture of 2,4-acetyl
(46) and 3,4-acetyl (47) derivatives.18 Although the
isomers were not separable by chromatography, recrys-
tallization two times resulted in isolation of pure 46. The
overall yield of 46 by this sequence was 77%, based on
compound 40.
In the coupling of the two rhamnose sugars, we were
concerned that the Lewis acidic reaction conditions might
catalyze acetyl migration between the cis-oriented C-2
and C-3 positions of the acceptor 46. Addition of either
BF3 etherate or TMSOTf to a solution of donor 43 and
acceptor 46 failed to give the desired disaccharide
coupling product. Instead, a small amount of a C1-O-
C1 glycosyl acetal dimer of 43 and good recovery of the
acceptor resulted. Although we were disappointed that
coupling failed, we were pleased that the anticipated
problem with acetyl migration did not manifest itself. The
dimerization of the donor was a strong indication of its
unstable nature. We hypothesize that during the workup
of the trichloroacetimidate formation reaction a small
amount of the trichloroacetimidate decomposes back to
the reducing sugar 42. When this mixture is activated
with the Lewis acid, the donor rapidly reacts with the
reducing sugar and also decomposes before it can couple
with the relatively unreactive acceptor. To minimize the
exposure of the donor to the Lewis acidic reaction
solution, a solution of donor 43 was slowly added by
syringe pump to a solution of the acceptor 46 and Lewis
acid. Thus, the ratio of acceptor to activated donor in
the reaction solution would be relatively high, which
under these conditions after 48 h. In contrast, the C-2
monoacetate 34 rapidly equilibrated to a 1:1.3 ratio of
34 and 35 when reacted with a catalytic amount of NaH
(Scheme 7). Reaction of the C-3 monoacetate 35 with
catalytic NaH resulted in generation of a similar ratio of
monoacetates. Disaccharide monoacetate 37 behaved in
the same manner, equilibrating to a 1.3:1 ratio of C-3
monoacetate 37 and a new compound when treated with
catalytic NaH. Although the new compound was chro-
matographically inseparable from isomer 37, the 1H NMR
spectrum of the mixture was consistent with the new
compound being the C-2 monoacetate 38. When macro-
lactone 32 was subjected to the equilibration conditions,
a 5.8:1 ratio of 32 and a new compound resulted. Again,
the new compound could not be cleanly isolated, but the
1H NMR spectrum of the impure material was consistent
with the major component being the C-2 isomer 39.
Thus, the observed acylation selectivity appears to be
kinetic. Interestingly though, even under thermody-
namic conditions, the desired C-3 macrolactone is favored
substantially.
With a good route to 32 in hand, we turned our
attention to the rhamnose disaccharide glycosyl donor.
Since the trichloroacetimidate glycosylation method had
worked so well in the assembly of the glycosidic linkages
in the lactone disaccharide subunit, we decided to employ
this method in the formation of the remaining glycosidic
linkages in the natural product. The rhamnose donor
synthesis began from the known allyl rhamnoside 40
(Scheme 8).16 Benzylation of the hydroxyl groups, fol-
lowed by isomerization of the allyl group with t-BuOK
and DMSO and acid hydrolysis of the resulting enol
ether, gave the tribenzylrhamnose 42 in high yield.17
Formation of the corresponding trichloroacetimidate by
(16) Aspinall, G.; Crane, A.; Gammon, D.; Ibrahim, I.; Khare, N.;
Chatterjee, D.; Rivoire, B.; Brennan, P. Carbohydr. Res. 1991, 216,
337.
(17) (a) Gigg, J .; Gigg, R. J . Chem. Soc. 1966, 82. (b) Gigg, R.;
Warren, C. J . Chem. Soc. 1965, 2205.
(18) (a) Garegg, P.; Hultberg, H. Carbohydr. Res. 1979, 72, 276. (b)
Lemieux, R.; Driguez, H. J . Am. Chem. Soc. 1975, 97, 4069.
(19) Schmidt, R.; Toepfer, A. Tetrahedron Lett. 1991, 32, 3353.

8410 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
Sch em e 10a
Sch em e 9a
a
Key: (a) (i) BF3‚Et2O, CH2Cl2; (ii) 43, CH2Cl2; (b) NaOMe,
MeOH; (c) (S)-2-methylbutyric acid, DCC, DMAP, CH2Cl2; (d) (i)
(Ph3P)3RhCl, EtOH, H2O, reflux; (ii) HgO, HgCl2, acetone, H2O;
(e) Cl3CCN, Cs2CO3, CH2Cl2.
would favor the cross-coupling reaction.19 By employing
this strategy, the desired disaccharide 48 was obtained
in 91% yield (Scheme 9). The synthesis of the disaccha-
ride donor was continued by removing the acetate groups
and installing the chiral side chains. The anomeric
position was unmasked by isomerization of the allyl
group with Wilkinson’s catalyst and cleavage of the
resulting enol ether with HgO and HgCl2. The resulting
lactol was converted to the corresponding glycosyl trichlo-
roacetimidate 52.
a
Key: (a) TMSOTf, CH2Cl2; (b) Cl3CCN, Cs2CO3, CH2Cl2; (c)
(i) 32; (ii) TMSOTf, CH2Cl2.
With both disaccharides in hand, the final task was to
couple the fully elaborated disaccharide donor 52 with
the lactone disaccharide acceptor 32. Unfortunately, this
coupling failed. We investigated many reaction condi-
tions using either AgOTf or TMSOTf as a catalyst. In
retrospect, it is not especially surprising that this reaction
was unsuccessful, as both the glycosyl donor and acceptor
are sterically congested at their respective reaction sites.
Donor 52 is probably deactivated by the R-branched ester
adjacent to the anomeric position, and acceptor 32 may
be hindered by the bulky anomeric substituent and the
macrolactone at the sites adjacent to the C-2 hydroxyl
group. To test this theory, two model couplings were
performed. In the first of these test reactions, donor 52
was coupled to the less sterically hindered glucoside 35,
giving trisaccharide 53 in good yield (Scheme 10). Ad-
ditionally, macrolactone 32 was successfully coupled with
a simplified rhamnose donor 55, providing a compound
that was spectroscopically consistent with trisaccharide
56 in good yield.
On the basis of the foregoing model studies, our
synthetic approach to tricolorin A was modified to permit
coupling of less congested donor and acceptor disaccha-
rides. To this end, allyl glycoside 48 was isomerized by
a newly developed rhodium catalyst, formed by reaction
of (Ph3P)3RhCl and n-butyllithium (Scheme 11).20 Cleav-
age of the enol ether was effected by HgO and HgCl2,
and the lactol was converted to the trichloroacetimidate
58. Reaction of donor 58 with monoacetate 37 (see
Scheme 6) in the presence of TMSOTf gave the tetrasac-
charide 59 in 75% yield. In preparation for macrolac-
tonization, the four ester groups were saponified to give
the acid triol 60.
Macrolactonization with DCC, DMAP, and DMAP-
21
TFA as activating agents in refluxing CHCl3 resulted
in formation of the desired C-3 glucose lactone 61,
accompanied by a compound spectroscopically consistent
with C-2 rhamnose lactone 62, each in about 25% yield.
However, use of the Yonemitsu lactonization protocol
gave varying ratios of 61 and 62, depending on the
reaction conditions (Scheme 12). A reaction time of 16
h gave the best yield of 61% for the desired lactone 61,
with only about 1-2% of the isomeric lactone 62. Shorter
reaction times led to incomplete reaction, and longer
reaction times led to lower yields of the desired lactone
61 and slightly higher yields of 62, accompanied by
general decomposition. We believe that the desired
lactone is a kinetic reaction product and that the isomeric
lactone 62 results from subsequent acyl migration.
However, we were not able to validate this hypothesis
experimentally. Attempts to equilibrate either 61 or 62
by treatment with 2,4,6-trichlorobenzoyl chloride, Et3N,
and DMAP or catalytic NaH were inconclusive. Only
decomposition products were observed to result from
these reactions.
Acylation of 61 with (S)-2-methylbutyric acid, DCC,
and DMAP resulted in smooth installation of the two
chiral side chains. Since the lactonization employed a
(20) Boons, G.-J .; Burton, A.; Isles, S. Chem. Commun. 1996, 141.
(21) Boden, E.; Keck, G. J . Org. Chem. 1985, 50, 2394.

Total Synthesis of Tricolorin A
Sch em e 11a
J . Org. Chem., Vol. 62, No. 24, 1997 8411
flask fitted with a dry ice condenser. Upon addition of
approximately 5 mg of lithium to the refluxing NH3, the
reaction solution became dark blue. Addition of 10 mg of Fe-
(NO3)3‚9H2O resulted in a sudden change of the reaction
solution to brownish gray after 2-3 min. Lithium (total of
190 mg, 27.4 mmol) was then added in several portions, and
the solution was stirred until the brownish gray color per-
sisted. (3S)-1-Octyn-3-ol (1.00 mL, 6.85 mmol) was added
dropwise, and the resulting grayish suspension was stirred
for 20 min. 1-Iodononane (4.06 mL, 20.6 mmol) in 30 mL of
THF was added dropwise, and the reaction mixture was stirred
at NH3 reflux temperature for 30 min. The reaction mixture
was warmed to room temperature over 90 min and then stirred
for 90 min. After careful addition of 10 mL of H2O, the reaction
mixture was diluted with 1:1 EtOAc/hexanes and washed with
1 N HCl, saturated NaHCO3, 10% Na2S2O3, and brine. The
organic layer was dried over Na2SO4, concentrated, and
purified by chromatography on silica gel with 510% EtOAc in
hexanes as eluent to give 1.62 g (94%) of a clear, colorless oil:
1H NMR (CDCl3, 400 MHz) δ 0.86-0.91 (m, 6H), 1.03-1.75
(m, 22H), 2.19 (dt, 2H, J ) 1.9, 7.1), 4.34 (tt, 1H, J ) 1.9, 6.6);
13C NMR (CDCl3, 100 MHz) δ 14.0, 14.1, 18.7, 22.6, 22.7, 24.9,
28.7, 28.8, 29.1, 29.3, 29.5, 31.5, 31.9, 38.2, 62.8, 81.3, 85.5;
IR (thin film) 3349 cm-1; [R]D -1 (c ) 0.68, CH2Cl2). Anal.
Calcd for C17H32O: C, 80.89; H, 12.78. Found: C, 80.76; H,
12.87.
(12S)-12-Hyd r oxy-1-h ep ta d ecyn e (15). A dry flask was
charged with 3.51 g (30.7 mmol) of a 35% (weight) oil
dispersion of KH that was rinsed with pentane. The last of
the pentane was removed under a stream of argon. 1,3-
Diaminopropane (16.7 mL, 200 mmol) was added dropwise and
stirred for 90 min to give a homogeneous brown solution.
Propargylic alcohol 14 (1.50 g, 5.94 mmol) in 8 mL of THF
was added dropwise and stirred for 90 min. The viscous
reddish brown mixture was quenched with 10 mL of H2O and
extracted with CH2Cl2. The organic layer was dried over Na2-
SO4, concentrated, and purified by chromatography on silica
gel with 58% EtOAc in hexanes as eluent to give 1.18 g (79%)
a
Key: (a) (i) (Ph3P)3RhCl, n-BuLi, THF, reflux; (ii) HgO, HgCl2,
acetone, H2O; (b) Cl3CCN, Cs2CO3, CH2Cl2; (c) (i) 37; (ii) TMSOTf,
CH2Cl2; (d) LiOH, THF, H2O.
vast excess of activating agent, we thought that these
two steps could be successfully combined into a one-pot
procedure. This tandem process turned out to work very
well. After the lactonization had proceeded for 16 h,
excess (S)-2-methylbutyric acid was introduced. After an
additional 2.5 h, the reaction mixture was worked up in
the normal manner to afford the fully elaborated tet-
rasaccharide 63 in 61% yield. Global deprotection was
accomplished by catalytic hydrogenation under acidic
conditions to give tricolorin A (1) in good yield. The
synthetic material was found to be identical in all
respects (13C NMR, 1H NMR, mp, and TLC mobility) with
an authentic sample provided by Dr. Pereda-Miranda.
In summary, we have developed an efficient synthesis
of the natural product tricolorin A. Starting from fucose,
glucose, rhamnose, and (S)-1-octyn-3-ol, the synthesis
required 39 steps overall. The longest linear sequence
was 14 steps, with an overall yield for this longest linear
sequence of 6%.
1
of a white solid: mp 37-38 °C; H NMR (CDCl3, 400 MHz) δ
0.88 (t, 3H, J ) 6.9), 1.28-1.55 (m, 24H), 1.92 (t, 1H, J ) 2.6),
2.17 (dt, 2H, J ) 2.6, 7.1), 3.57 (br m, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.0, 18.4, 22.6, 25.3, 25.6, 28.5, 28.7, 29.0, 29.4,
29.5, 29.7, 31.9, 37.4, 37.4, 68.0, 72.0, 84.7; IR (KBr) 3308,
3233, 2143 cm-1; [R]D +0.8 (c ) 0.37, CH2Cl2). Anal. Calcd
for C17H32O: C, 80.89; H, 12.78. Found: C, 81.20; H, 12.77.
(12S )-12-[(t er t -Bu t yld im e t h ylsilyl)oxy]-1-h e p t a d e c-
yn e (16). A solution of alcohol 15 (1.12 g, 4.44 mmol), tert-
butyldimethylsilyl chloride (1.00 g, 6.66 mmol), and imidazole
(605 mg, 8.88 mmol) in 3 mL of DMF was stirred overnight at
room temperature. The reaction solution was diluted with 75
mL of Et2O and washed with H2O, 1 N HCl, saturated
NaHCO3, and brine. The organic layer was dried over MgSO4,
concentrated, and purified by chromatography on silica gel
with 05% EtOAc in hexanes as eluent to give 1.59 g (98%) of
a clear, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.03 (s,
6H), 0.87-0.90 (m, 12H), 1.27-1.40 (m, 22H), 1.52 (m, 2H),
1.93 (t, 1H, J ) 2.7), 2.18 (dt, 2H, J ) 2.7, 7.1), 3.61 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ -4.4, 14.1, 18.2, 18.4, 22.7, 25.0,
25.3, 25.9, 28.5, 28.8, 29.1, 29.4, 29.6, 29.8, 32.1, 37.1, 37.1,
68.0, 72.4, 84.7; IR (thin film) 3314, 2136, 1057 cm-1; [R]D
-0.05 (c ) 5.60, CH2Cl2). Anal. Calcd for C23H46OSi: C, 75.33;
H, 12.64. Found: C, 75.31; H, 12.84.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, starting ma-
terials were obtained from commercial suppliers and used as
received. All reactions were carried out under an argon
atmosphere, unless otherwise stated. Tetrahydrofuran (THF)
was distilled under nitrogen from sodium/benzophenone im-
mediately prior to use. Benzene, CH2Cl2, and Et3N were
distilled under nitrogen from CaH2 immediately prior to use.
Silica gel chromatography was performed according to the
method of Still.22 All melting points are uncorrected. Coupling
constants (J ) are reported in Hz.
(11S)-11-[(ter t-Bu t yld im et h ylsilyl)oxy]h exa d eca n oic
Acid (17). A solution of KMnO4 (3.08 g, 19.5 mmol) in 20 mL
of H2O was cooled in an ice bath. In one portion a solution of
alkyne 16 (1.43 g, 3.90 mmol), 6 mL of HOAc, and 5 drops of
Aliquat 336 in 15 mL of pentane was added. Without
replenishing the ice in the cooling bath, the reaction mixture
was stirred for 24 h. After cooling in an ice bath, 5 g of Na2-
SO3 and 10 mL of 6 N HCl were carefully added to the viscous
black reaction mixture. After the mixture was stirred for 10
min, a white precipitate formed as the reaction mixture
became colorless. The reaction mixture was diluted with 50
mL of H2O and extracted with hexanes. The combined organic
layers were dried over Na2SO4 and concentrated to give 1.46
(6S)-6-Hyd r oxy-7-h ep ta d ecyn e (14). Approximately 50
mL of NH3 was condensed into a three-necked round-bottomed
(22) Still, W. C.; Kahn, M., Mitra, A. J . Org. Chem. 1978, 43, 2923.

8412 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
Sch em e 12a
a
Key: (a) DCC, DMAP, DMAP‚TFA, CHCl3, reflux (28% for 61, 24% for 62); (b) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, benzene
(61% for 61); (c) (i) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, benzene; (ii) (S)-2-methylbutyric acid; (d) Pd(OH)2, H2, HCl, MeOH.
g of slightly yellowish oil. The product was used in the
following step without further purification.
25.9, 27.7, 64.1, 69.3, 69.7, 75.6, 76.1, 96.9, 109.2, 127.9, 128.5,
128.5, 137.2; IR (thin film) 3466, 1071 cm-1; [R]D +140 (c )
0.56, CH2Cl2). Anal. Calcd for C16H22O5: C, 65.29; H, 7.53.
Found: C, 65.10; H, 7.69.
Meth yl (11S)-11-Hyd r oxyh exa d eca n oa te (18). A solu-
tion of crude acid 17 (1.46 g) and 0.5 mL of H2SO4 in 50 mL
MeOH was heated at reflux for 2 h. After the solution was
cooled to room temperature, 1 g of NaHCO3 was added in small
portions. The resulting slurry was concentrated, diluted with
75 mL of H2O, and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4, concentrated, and
purified by chromatography on silica gel with 5 f 20% EtOAc
in hexanes as eluent to give 835 mg (75%) of a white solid:
Ben zyl 3,4-O-Isop r op ylid en e-2-O-p iva loyl-r-D-fu cop y-
r a n osid e (21). A solution of benzyl fucoside 20 (3.08 g, 10.5
mmol) and pivaloyl chloride (6.47 mL, 52.5 mmol) in 50 mL of
pyridine was stirred at 70 °C for 18 h. The reaction solution
was then diluted with 200 mL of Et2O and washed with 1 N
HCl, saturated NaHCO3, and brine. The organic layer was
dried over MgSO4, concentrated, and purified by chromatog-
raphy on silica gel with 10 f 20% EtOAc in hexanes as eluent
to give 3.81 g (96%) of a clear, colorless oil: 1H NMR (CDCl3,
400 MHz) δ 1.20 (s, 9H), 1.35 (s, 3H), 1.36 (d, 3H, J ) 6.7),
1.52 (s, 3H), 4.08 (dd, 1H, J ) 2.5, 5.4), 4.17 (dq, 1H, J ) 2.4,
6.6), 4.36 (dd, 1H, J ) 5.4, 8.0), 4.49 (d, 1H, J ) 12.2), 4.69 (d,
1H, J ) 12.2), 4.91 (dd, 1H, J ) 3.7, 8.0), 4.97 (d, 1H, J ) 3.7),
7.28-7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 16.3, 26.4,
27.1, 28.0, 38.8, 63.5, 69.5, 71.4, 73.6, 76.1, 95.5, 109.3, 127.7,
127.8, 128.4, 137.3, 178.0; IR (thin film) 1732 cm-1; [R]D +165
(c ) 1.18, CH2Cl2). Anal. Calcd for C21H30O6: C, 66.65; H,
7.99. Found: C, 66.77; H, 8.01.
3,4-O-Isop r op ylid en e-2-O-p iva loyl-r-D-fu cop yr a n ose
(22). In a Parr hydrogenation bottle, benzyl fucoside 21 (3.54
g, 9.35 mmol) and 1.0 g of Pd(OH)2 were combined with 50
mL of EtOAc. The bottle was then evacuated and back-filled
with H2 three times. The reaction mixture was shaken under
50 psi of H2 for 5 days and filtered through a pad of Celite
and the pad washed with MeOH. The combined filtrate was
concentrated and purified by chromatography on silica gel with
20 f 30% EtOAc in hexanes as eluent to give 2.26 g (84%) of
1
mp 44-45 °C; H NMR (CDCl3, 400 MHz) δ 0.88 (t, 3H, J )
6.8), 1.27-1.47 (m, 22H), 1.60 (br m, 2H), 2.29 (t, 2H, J ) 7.6),
3.56 (br m, 1H), 3.65 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
14.0, 22.6, 24.9, 25.3, 25.6, 29.1, 29.2, 29.3, 29.5, 29.6, 31.9,
34.1, 37.4, 37.4, 51.4, 72.0, 174.3; IR (KBr) 3343, 1746, 1175
cm-1; [R]D +0.8 (c ) 0.51, CH2Cl2). Anal. Calcd for C17H34O3:
C, 71.28; H, 11.96. Found: C, 71.51; H, 12.05.
Ben zyl 3,4-O-Isop r op ylid en e-r-D-fu cop yr a n osid e (20).
Benzyl fucoside 19 (3.07 g, 12.1 mmol) and p-TsOH‚H2O (228
mg, 1.2 mmol) were combined with 25 mL of reagent grade
acetone and 25 mL of 2,2-dimethoxypropane. After the reac-
tion solution stirred for 19 h, 1 mL of Et3N was added and the
reaction solution was concentrated. The oily residue was
purified by chromatography on silica gel with 20 f 40% EtOAc
in hexanes as eluent to give 3.08 g (87%) of a clear, colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 1.31 (d, 3H, J ) 6.7), 1.35
(s, 3H), 1.51 (s, 3H), 3.82 (dd, 1H, J ) 4.0, 6.4), 4.06 (dd, 1H,
J ) 2.3, 6.1), 4.16 (dq, 1H, J ) 2.2, 6.7), 4.23 (t, 1H, J ) 6.3),
4.57 (d, 1H, J ) 11.8), 4.79 (d, 1H, J ) 11.8), 4.94 (d, 1H, J )
3.9), 7.30-7.39 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 16.2,

Total Synthesis of Tricolorin A
J . Org. Chem., Vol. 62, No. 24, 1997 8413
a white solid: mp 140.5-141.5 °C; R:â (CDCl3) ) 1:1; 1H NMR
(CDCl3, 400 MHz) δ 1.22 (s, 4.5H), 1.23 (s, 4.5H), 1.33-1.34
(m, 4.5H), 1.41 (d, 1.5H, J ) 6.6), 1.50 (s, 1.5H), 1.53 (s, 1.5H),
3.91 (dq, 0.5H, J ) 2.1, 6.6), 4.04 (dd, 0.5H, J ) 2.1, 5.6), 4.07
(dd, 0.5H, J ) 2.3, 5.7), 4.21 (dd, 0.5H, J ) 5.6, 7.1), 4.34-
4.37 (m, 1H), 4.53 (d, 0.5H, J ) 7.4), 4.79 (t, 0.5H, J ) 7.4),
4.91 (dd, 0.5H, J ) 3.6, 7.2), 5.28 (d, 0.5H, J ) 3.6); 13C NMR
(CDCl3, 100 MHz) δ 16.4, 16.5, 26.1, 26.1, 27.0, 27.1, 27.6, 27.7,
38.8, 38.9, 63.7, 68.9, 71.0, 73.1, 75.0, 75.8, 76.0, 76.2, 90.1,
95.3, 109.4, 110.1, 178.0, 179.5; IR (KBr) 3448, 1731 cm-1; [R]D
+67.4 (c ) 1.29, CH2Cl2). Anal. Calcd for C14H24O6: C, 58.32;
H, 8.39. Found: C, 58.50; H, 8.53.
3.80 (m, 2.6H), 4.04 (dt, 0.4H, J ) 4.9, 9.9), 4.32 (dd, 0.4H, J
) 4.9, 10.4), 4.39 (dd, 0.6H, J ) 4.6, 10.3), 5.10-5.14 (m, 1H),
5.37 (t, 0.6H, J ) 9.3), 5.51 (s, 0.6H), 5.52 (s, 0.4H), 5.59 (t,
0.4H, J ) 9.9), 5.79 (d, 0.6H, J ) 8.2), 6.31 (d, 0.4H, J ) 3.8),
7.35-7.45 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 20.4, 20.5,
20.7, 20.8, 64.9, 67.0, 68.2, 68.5, 68.7, 69.8, 71.2, 71.7, 78.0,
78.6, 89.6, 92.2, 101.6, 126.1, 126.1, 128.2, 129.1, 129.2, 136.6,
136.7, 168.8, 169.0, 169.5, 169.9; IR (KBr) 1750 cm-1; [R]D +4.3
(c ) 0.69, CH2Cl2). Anal. Calcd for C19H22O9: C, 57.87; H,
5.62. Found: C, 57.68; H, 5.80.
2,3-Di-O-acetyl-4,6-O-ben zyliden e-D-glu copyr an ose (28).
A solution of triacetate 27 (2.00 g, 5.07 mmol) and BnNH2 (831
µL, 7.61 mmol) in 10 mL of THF was stirred for 14 h. After
addition of 4 mL of 1 N HCl, the reaction mixture was stirred
for 1 h. The reaction mixture was diluted with 50 mL of 1 N
HCl and extracted with CH2Cl2 (3 × 50 mL). The combined
extracts were dried over Na2SO4, concentrated, and purified
by chromatography on silica gel with 30 f 50% EtOAc in
hexanes as eluent to give 1.57 g (88%) of a white amorphous
solid: R:â (CDCl3) ) 1:1; 1H NMR (CDCl3, 400 MHz) δ 2.06 (s,
1.5H), 2.06 (s, 1.5H), 2.09 (s, 3H), 3.55 (dt, 0.5H, J ) 5.0, 9.7),
3.61-3.86 (m, 2.5H), 4.17 (dt, 0.5H, J ) 4.9, 9.9), 4.29 (dd,
0.5H, J ) 4.9, 10.2), 4.36 (dd, 0.5H, J ) 4.9, 10.5), 4.79 (d,
0.5H, J ) 7.9), 4.88-4.92 (m, 1H), 5.34 (t, 0.5H, J ) 9.5), 5.41
(d, 0.5H, J ) 3.7), 5.49 (s, 0.5H), 5.50 (s, 0.5H), 5.62 (t, 0.5H,
J ) 9.8), 7.34-7.45 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ
20.7, 20.8, 62.3, 66.5, 68.4, 68.8, 68.8, 71.3, 71.9, 74.1, 78.4,
79.1, 90.9, 95.8, 101.4, 101.5, 126.1, 126.1, 128.2, 128.9, 129.0,
129.1, 129.7, 136.6, 136.8, 170.1, 170.5, 170.9; IR (KBr) 3461,
1745 cm-1; [R]D -8.4 (c ) 0.87, CH2Cl2). Anal. Calcd for
C17H20O8: C, 57.95; H, 5.72. Found: C, 57.72; H, 6.00.
2,3-Di-O-a cet yl-4,6-O-b en zylid en e-r-D-glu cop yr a n ose
1-Tr ich lor oa cetim id a te (29). A slurry of glucopyranose 28
(817 mg, 2.32 mmol), Cl3CCN (465 µL, 4.64 mmol), and Cs2-
CO3 (75 mg, 0.23 mmol) in 4 mL of CH2Cl2 was stirred for 12
h. The reaction mixture was filtered through a short pad of
silica gel, and the pad was washed with 250 mL of 40% EtOAc
in hexanes. The combined filtrate was concentrated to give
1.16 g of slightly yellowish oil. The product was immediately
used in the following step without further purification.
Meth yl (11S)-11-[[(2,3-Di-O-a cetyl-4,6-O-ben zylid en e-
â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu -
cop yr a n osyl]oxy]h exa d eca n oa te (30). The crude tricholo-
racetimidate 29 (1.16 g) and alcohol 25 (556 mg, 1.18 mmol)
were combined in a flask and concentrated from freshly
distilled benzene. To the resulting residue were added anhy-
drous AgOTf (596 mg, 2.32 mmol) and 3 mL of CH2Cl2. The
reaction flask was covered with aluminum foil, and the
reaction mixture was stirred for 40 h. The reaction mixture
was filtered though a pad of Celite, washing with EtOAc, and
the combined filtrate concentrated. Purification by chroma-
tography on silica gel with 20 f 30% EtOAc in hexanes as
eluent gave 795 mg (84%) of a clear, colorless oil that contained
a minor impurity: 1H NMR (C6D6, 400 MHz) δ 0.89 (t, 3H, J
) 7.1), 1.22-1.73 (m, 36H), 1.88 (s, 3H), 2.13 (t, 2H, J ) 7.5),
3.27 (dq, 1H, J ) 2.0, 6.6), 3.34 (s, 3H), 3.34-3.41 (m, 1H),
3.54 (dd, 1H, J ) 2.0, 5.2), 3.59 (t, 1H, J ) 10.2), 3.68 (t, 1H,
J ) 9.5), 3.72 (br m, 1H), 3.96-4.02 (m, 2H), 4.23 (dd, 1H, J
) 5.0, 10.3), 4.28 (d, 1H, J ) 7.6), 5.13 (d, 1H, J ) 7.5), 5.31
(s, 1H), 5.43 (dd, 1H, J ) 7.5, 8.7), 5.62 (dd, 1H, J ) 8.4, 9.5),
7.04-7.15 (m, 3H), 7.55 (d, 2H, J ) 7.0); 13C NMR (CDCl3,
100 MHz) δ 14.1, 16.6, 20.8, 20.8, 22.6, 24.7, 24.9, 25.1, 26.3,
27.9, 29.1, 29.3, 29.5, 29.7, 29.9, 31.9, 33.8, 34.1, 34.6, 51.4,
66.3, 68.5, 68.8, 72.0, 72.9, 76.4, 78.3, 79.2, 79.6, 80.5, 100.1,
100.7, 101.4, 109.6, 126.1, 128.2, 129.1, 136.9, 169.6, 170.1,
3,4-O-Isop r op ylid en e-2-O-p iva loyl-r-D-fu cop yr a n ose
1-Tr ich lor oa cetim id a te (23). A slurry of fucopyranose 22
(672 mg, 2.33 mmol), Cl3CCN (467 µL, 4.66 mmol), and Cs2-
CO3 (75 mg, 0.23 mmol) in 3 mL of CH2Cl2 was stirred for 12
h. The reaction mixture was filtered through a short pad of
silica gel, and the pad was washed with 250 mL of 30% EtOAc
in hexanes. The combined filtrate was concentrated to give
1.05 g of slightly yellowish oil. The product was immediately
used in the following step without further purification.
Meth yl (11S)-11-[(3,4-O-Isop r op ylid en e-2-O-p iva loyl-â-
D-fu cop yr a n osyl)oxy]h exa d eca n oa te (24). The crude tri-
choloracetimidate 23 (1.05 g) and alcohol 18 (500 mg, 1.75
mmol) were combined in a flask and concentrated from freshly
distilled benzene. The resulting residue was dissolved in 900
µL of CH2Cl2, and 940 µL of 0.05 M TMSOTf in CH2Cl2 was
added over 25 min. After the reaction mixture was stirred
for an additional 30 min, 10 mL of saturated NaHCO3 was
added with vigorous stirring. Following extraction with CH2-
Cl2, the combined organic layers were dried over Na2SO4 and
concentrated. The residue was purified by chromatography
on silica gel with 10% EtOAc in hexanes as eluent to give 768
mg (79%) of a clear, colorless oil: 1H NMR (C6D6, 400 MHz) δ
0.89 (t, 3H, J ) 7.0), 1.20-1.68 (m, 42H), 2.12 (t, 2H, J ) 7.4),
3.35 (s, 3H), 3.38 (m, 1H), 3.57 (dd, 1H, J ) 2.1, 5.3), 3.68 (m,
1H), 3.96 (m, 1H), 4.33 (d, 1H, J ) 8.3), 5.41 (t, 1H, J ) 8.0);
13C NMR (CDCl3, 100 MHz) δ 14.1, 16.6, 22.6, 24.6, 24.9, 25.3,
26.5, 27.2, 27.7, 29.1, 29.2, 29.4, 29.5, 29.9, 31.9, 33.9, 34.1,
34.5, 38.7, 51.4, 68.7, 73.2, 76.6, 76.7, 79.2, 99.4, 110.0, 174.3,
176.9; IR (thin film) 1740 cm-1; [R]D +9.0 (c ) 0.87, CH2Cl2).
Anal. Calcd for C31H56O8: C, 66.87; H, 10.14. Found: C,
66.75; H, 10.01.
Meth yl (11S)-11-[(3,4-O-Isop r op ylid en e-â-D-fu cop yr a -
n osyl)oxy]h exa d eca n oa te (25). To fucopyranoside 24 (704
mg, 1.27 mmol) were added 5 mL of MeOAc and 5 mL of 10%
NaOMe in MeOH sequentially. A white crystalline precipitate
was observed in the reaction mixture after stirring for 10 h.
The mixture was diluted with 50 mL of saturated NaHCO3
and extracted with CH2Cl2 (2 × 50 mL). The combined organic
extracts were dried over Na2SO4, concentrated, and purified
by chromatography on silica gel with 20 f 30% EtOAc in
hexanes as eluent to give 574 mg (96%) of a clear, colorless
oil: 1H NMR (C6D6, 400 MHz) δ 0.90 (t, 3H, J ) 7.0), 1.20-
1.72 (m, 33H), 2.12 (t, 2H, J ) 7.4), 2.36 (br s, 1H), 3.33 (dq,
1H, J ) 2.2, 6.6), 3.36 (s, 3H), 3.54 (dd, 1H, J ) 2.2, 5.5), 3.69
(m, 1H), 3.76 (tt, 1H, J ) 2.4, 7.9), 4.01 (dd, 1H, J ) 5.5, 7.3),
4.12 (d, 1H, J ) 8.2); 13C NMR (CDCl3, 100 MHz) δ 14.0, 16.6,
22.5, 24.7, 24.9, 25.1, 26.3, 28.2, 29.0, 29.1, 29.3, 29.4, 29.7,
31.8, 33.9, 34.0, 34.7, 51.4, 69.0, 73.7, 76.4, 78.8, 79.8, 101.3,
109.7, 174.2; IR (thin film) 3497, 1740 cm-1; [R]D +6.1 (c )
0.84, CH2Cl2). Anal. Calcd for C26H48O7: C, 66.07; H, 10.24.
Found: C, 65.93; H, 10.14.
Acet yl 1,2,3-Tr i-O-a cet yl-4,6-O-b en zylid en e-r-D-glu -
cop yr a n ose (27). A solution of glucopyranose 26 (3.25 g, 12.1
mmol) in 100 mL of CH2Cl2 was cooled in an ice bath and
treated with Et3N (15.2 mL, 109 mmol), Ac2O (7.32 mL, 72.6
mmol), and DMAP (148 mg, 1.21 mmol). The cooling bath was
removed, and the reaction solution was stirred overnight. The
reaction solution was diluted with 150 mL of CH2Cl2 and
washed with 1 N HCl, saturated NaHCO3, and H2O. The
organic layer was dried over Na2SO4, concentrated, and
purified by chromatography on silica gel with 40 f 60% EtOAc
in hexanes as eluent to give 4.61 g (96%) of a white amorphous
174.2; IR (thin film) 1755, 1740 cm-1
. Attempts to further
purify this compound for microanalysis were unsuccessful.
(11S)-11-[[(4,6-O-Ben zyliden e-â-D-glu copyr an osyl)-(1f2)-
3,4-O-isopr opyliden e-â-D-fu copyr an osyl]oxy]h exadecan o-
ic Acid (31). To a solution of triester 30 (400 mg, 0.496 mmol)
in 4.5 mL of THF was added 1.5 mL of 3.3 M LiOH. The
reaction solution was stirred for 15 h, acidified with 25 mL of
1 N HCl, and extracted with CH2Cl2. The combined extracts
were dried over Na2SO4, concentrated, and purified by chro-
matography on silica gel with 5 f 10% MeOH in CH2Cl2 as
eluent to give 258 mg (74%) of a clear, colorless, sticky solid:
1
solid: R:â ) 2:3; H NMR (CDCl3, 400 MHz) δ 2.04 (s, 1.2H),
2.05 (s, 1.8H), 2.06 (s, 1.8H), 2.08 (s, 1.2H), 2.11 (s, 1.8H), 3.64-

8414 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
1H NMR (C6D6, 400 MHz) δ 0.90 (t, 3H, J ) 6.9), 1.22-1.76
(m, 33H), 2.15 (t, 2H, J ) 6.4), 3.31 (dq, 1H, J ) 2.0, 6.5), 3.39
(dt, 1H, J ) 4.7, 9.6), 3.47-3.53 (m, 2H), 3.60 (t, 1H, J ) 10.1),
3.73-3.88 (m, 3H), 4.04 (t, 1H, J ) 7.5), 4.12 (dd, 1H, J ) 5.6,
7.0), 4.27 (dd, 1H, J ) 4.9, 10.3), 4.32 (d, 1H, J ) 7.9), 4.95 (d,
1H, J ) 7.5), 5.33 (s, 1H), 7.11-7.21 (m, 3H), 7.60 (d, 2H, J )
7.1); 13C NMR (CDCl3, 100 MHz) δ 14.0, 16.5, 22.6, 24.5, 24.6,
25.0, 26.1, 27.8, 28.9, 29.1, 29.3, 29.4, 29.9, 31.9, 33.6, 33.9,
34.4, 66.9, 68.5, 68.7, 72.6, 75.8, 76.5, 78.6, 79.8, 80.6, 80.8,
100.3, 101.9, 104.1, 110.2, 126.3, 128.2, 129.2, 137.0, 178.8;
IR (thin film) 3426, 1708 cm-1; [R]D -5.8 (c ) 1.70, CH2Cl2).
Anal. Calcd for C38H60O12: C, 64.39; H, 8.53. Found: C, 64.43;
H, 8.58.
MeOH sequentially. A white crystalline precipitate was
observed in the reaction mixture after stirring for 2 h. The
mixture was diluted with 50 mL of saturated NaHCO3 and
extracted with CH2Cl2. The combined organic extracts were
dried over Na2SO4, concentrated, and purified by chromatog-
raphy on silica gel with 40 f 50% EtOAc in hexanes as eluent
to give 558 mg (84%) of a clear, colorless oil: 1H NMR (C6D6,
500 MHz) δ 0.90 (t, 3H, J ) 7.0), 1.20-1.76 (m, 33H), 2.13 (t,
2H, J ) 7.4), 3.29 (dq, 1H, J ) 2.1, 6.5), 3.36 (s, 3H), 3.39 (dt,
1H, J ) 4.9, 9.6), 3.48-3.52 (m, 2H), 3.61 (t, 1H, J ) 10.2),
3.72-3.75 (m, 2H), 3.82 (t, 1H, J ) 8.9), 3.98 (t, 1H, J ) 7.6),
4.06 (dd, 1H, J ) 7.1, 5.6), 4.29-4.32 (m, 2H), 4.86 (d, 1H, J
) 7.6), 5.32 (s, 1H), 7.10-7.19 (m, 3H), 7.59 (d, 2H, J ) 7.1);
13C NMR (CDCl3, 100 MHz) δ 14.0, 16.4, 22.5, 24.4, 24.8, 24.9,
26.1, 27.7, 29.0, 29.1, 29.3, 29.5, 29.8, 31.8, 33.6, 34.0, 34.3,
51.3, 66.9, 68.4, 68.7, 72.5, 75.8, 76.4, 78.5, 79.7, 80.6, 80.9,
100.2, 101.8, 104.3, 110.2, 126.2, 128.2, 129.1, 137.0, 174.2;
IR (thin film) 3472, 1739 cm-1; [R]D -3.19 (c ) 5.01 CH2Cl2).
Anal. Calcd for C39H62O12: C, 64.80; H, 8.64. Found: C, 64.62;
H, 8.83.
(11S)-11-[[(4,6-O-Ben zyliden e-â-D-glu copyr an osyl)-(1f2)-
3,4-O-isopr opyliden e-â-D-fu copyr an osyl]oxy]h exadecan o-
ic Acid 3glu -La cton e (32). To a solution of acid 31 (50 mg,
0.0706 mmol) in 375 mL of benzene were added Et3N (591 µL,
4.24 mmol) and 2,4,6-trichlorobenzoyl chloride (440 µL, 2.82
mmol). DMAP (172 mg, 1.41 mmol) was added to the reaction
mixture in two portions, 1 h apart. After being stirred for 18
h, the milky white reaction mixture was washed with 100 mL
of H2O and separated. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over Na2-
SO4, concentrated, and purified by chromatography on silica
gel with 20 f 30% EtOAc in hexanes as eluent to give 35 mg
Met h yl (11S)-11-[[(3-O-Acet yl-4,6-O-b en zylid en e-â-D-
glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu cop y-
r a n osyl]oxy]h exa d eca n oa te (37). To a solution of diol 36
(265 mg, 0.367 mmol) in 10 mL of CH2Cl2 were added Et3N
(102 µL, 0.734 mmol), Ac2O (37 µL, 0.37 mmol), and DMAP (5
mg, 0.04 mmol). After being stirred for 50 min, the reaction
1
(71%) of a white solid: mp 186.5-188.5 °C; H NMR (C6D6,
400 MHz) δ 0.88 (t, 3H, J ) 7.0), 1.26-1.78 (m, 32H), 1.99 (m,
1H), 2.12 (m, 1H), 2.22 (m, 1H), 2.89 (d, 1H, J ) 4.2), 3.35-
3.43 (m, 3H), 3.53-3.55 (m, 2H), 3.62, (t, 1H, J ) 9.2), 3.83
(dt, 1H, J ) 3.5, 8.3), 4.01 (t, 1H, J ) 5.7), 4.11 (dd, 1H, J )
dd, 1H, J ) 3.9, 9.3), 4.19-4.26 (m, 2H), 5.12 (d, 1H, J ) 7.6),
5.22 (s, 1H), 5.44 (t, 1H, J ) 9.1), 7.04-7.15 (m, 3H), 7.51 (d,
2H, J ) 6.8); 13C NMR (CD2 Cl2, 100 MHz) δ 13.5, 16.1, 22.3,
24.9, 24.9, 25.5, 25.9, 26.7, 27.4, 28.1, 28.2, 29.2, 30.3, 31.6,
34.7, 35.5, 35.7, 65.8, 68.3, 68.4, 73.7, 74.5, 74.8, 76.5, 78.0,
79.0, 82.0, 98.4, 101.4, 101.7, 109.4, 126.0, 127.9, 128.8, 137.0,
173.7; IR (KBr) 3597, 1736 cm-1; [R]D -28.1 (c ) 0.48, CH2-
Cl2). Anal. Calcd for C38H58O11: C, 66.06; H, 8.46. Found:
C, 66.19; H, 8.59.
solution was diluted with 10 mL of CH2Cl2 and washed with
1 N HCl and saturated NaHCO3. The organic layer was dried
over Na2SO4, concentrated, and purified by chromatography
on silica gel with 20 f 40% EtOAc in hexanes as eluent to
give 224 mg (80%) of a clear oil: 1H NMR (C6D6, 400 MHz) δ
0.91 (t, 3H, J ) 7.0), 1.16-1.75 (m, 36H), 2.12 (t, 2H, J ) 7.4),
3.25 (br q, 1H), 3.35 (s, 3H), 3.35 (br m, 1H), 3.48 (dd, 1H, J )
5.2, 1.9), 3.54-3.61 (m, 2H), 3.71 (br m, 1H), 3.78 (d, 1H, J )
2.6), 3.88 (br t, 1H, J ) 9.6), 3.92-4.01 (m, 2H), 4.24-4.30
(m, 2H), 4.82 (d, 1H, J ) 7.6), 5.28 (s, 1H), 5.61 (t, 1H, J )
9.5), 7.04-7.45 (m, 3H), 7.58 (d, 2H, J ) 7.2); 13
C NMR (CDCl3,
100 MHz) δ 14.0, 16.4, 20.9, 22.5, 24.3, 24.8, 24.9, 26.1, 27.8,
29.0, 29.1, 29.3, 29.4, 29.8, 31.8, 33.5, 33.9, 34.3, 51.3, 66.8,
68.4, 68.6, 72.7, 74.1, 76.4, 78.5, 78.7, 79.3, 80.9, 99.9, 101.3,
104.3, 110.1, 126.0, 128.1, 128.9, 136.9, 170.2, 174.1; IR (CH2-
Cl2 solution) 3477, 1740 cm-1; [R]D -2.5 (c ) 2.59, CH2Cl2).
Anal. Calcd for C41H64O13: C, 64.38; H, 8.43. Found: C, 64.51;
H, 8.63.
Equ ilibr a tion of Meth yl 2-O-Acetyl-4,6-O-ben zylid en e-
â-D-glu cop yr a n osid e (34). A solution of 2-acetyl compound
34 (25 mg, 0.77 mmol) and 1 mg of 60% NaH in mineral oil in
3 mL of THF was stirred for 15 min. The reaction was
quenched with 5 mL of H2O and extracted with CH2Cl2 (2 ×
10 mL). The combined organic extracts were dried over Na2-
SO4 and concentrated. 1H NMR of the crude reaction mixture
shows a 1.3:1 ratio of the 3-acetyl compound to the 2-acetyl
compound.
Meth yl 2-O-Acetyl-4,6-O-ben zylid en e-â-D-glu cop yr a n o-
sid e (34) a n d Meth yl 3-O-Acetyl-4,6-O-ben zylid en e-â-D-
glu cop yr a n osid e (35). To a solution of methyl 4,6-O-
benzylidene-â-D-glucopyranoside (400 mg, 1.42 mmol) in 15 mL
of CH2Cl2 was added Et3N (396 µL, 2.84 mmol), Ac2O (143 µL,
1.42 mmol), and DMAP (17 mg, 0.14 mmol). After being
stirred for 2 days, the reaction solution was diluted with 50
mL of CH2Cl2 and washed with 1 N HCl and saturated
NaHCO3. The organic layer was dried over Na2SO4, concen-
trated, and purified by chromatography on silica gel with 30
f 50% EtOAc in hexanes as eluent to give 137 mg (30%) of a
less polar compound and 152 mg (33%) of a more polar
compound. Less polar compound: white solid; mp 162-164
1
°C; H NMR (C6D6, 400 MHz) δ 1.73 (s, 3H), 2.15 (d, 1H, J )
4.3), 3.05 (dt, 1H, J ) 4.8, 9.5), 3.12 (t, 1H, J ) 9.2), 3.20 (s,
3H), 3.42 (t, 1H, J ) 10.1), 3.69 (dt, 1H, J ) 4.2, 9.2), 4.09
(dd, 1H, J ) 10.3, 4.9), 4.11 (d, 1H, J ) 7.9), 5.15 (s, 1H), 5.25
(dd, 1H, J ) 9.3, 8.0), 7.10-7.35 (m, 3H), 7.57 (d, 2H, J )
6.9); 13C NMR (CDCl3, 100 MHz) δ 20.9, 57.0, 66.1, 68.5, 72.1,
73.9, 80.8, 101.7, 102.1, 126.2, 128.3, 129.2, 136.9, 170.3; IR
(CH2Cl2 solution) 3584, 3048, 2988, 1749 cm-1; [R]D -77.7 (c
) 1.72, CH2Cl2). Anal. Calcd for C16H20O7: C, 59.25; H, 6.22.
Found: C, 59.55; H, 6.57. More polar compound: white solid;
mp 146-147 °C; 1H NMR (C6D6, 400 MHz) δ 1.70 (s, 3H), 2.37
(d, 1H, J ) 3.6), 3.17 (m, 1H), 3.18 (s, 3H), 3.41 (t, 1H, J )
9.6), 3.42 (t, 1H, J ) 10.2), 3.59 (ddd, 1H, J ) 9.3, 7.6, 3.5),
3.93 (d, 1H, J ) 7.6), 4.08 (dd, 1H, J ) 10.3, 5.0), 5.18 (s, 1H),
5.49 (t, 1H, J ) 9.5), 7.04-7.15 (m, 3H), 7.58-7.60 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 20.9, 57.6, 66.4, 68.6, 73.4, 73.6,
78.5, 101.4, 104.5, 126.1, 128.2, 129.0, 136.9, 171.0; IR (CH2-
Cl2 solution) 3588, 3057, 1742 cm-1; [R]D -42.0 (c ) 3.86, CH2-
Cl2). Anal. Calcd for C16H20O7: C, 59.25; H, 6.22. Found: C,
59.13; H, 6.34.
Equ ilibr a tion of Meth yl 3-O-Acetyl-4,6-O-ben zylid en e-
â-D-glu cop yr a n osid e (35). A solution of 3-acetyl compound
35 (25 mg, 0.77 mmol) and 1 mg of 60% NaH in mineral oil in
3 mL of THF was stirred for 15 min. The reaction was
quenched with 5 mL of H2O and extracted with CH2Cl2 (2 ×
10 mL). The combined organic extracts were dried over Na2-
SO4 and concentrated. 1H NMR of the crude reaction mixture
shows a 1.2:1 ratio of the 3-acetyl compound to the 2-acetyl
compound.
Equ ilibr a tion of Meth yl (11S)-11-[[(3-O-Acetyl-4,6-O-
ben zylid en e-â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op y-
lid en e-â-D-fu cop yr a n osyl]oxy]h exa d eca n oa te (37). A so-
lution of 3-acetyl compound 37 (10 mg, 0.013 mmol) and 1 mg
of 60% NaH in mineral oil in 2 mL of THF was stirred for
15-120 min. The reaction was quenched with 5 mL of H2O
and extracted with CH2Cl2. The combined organic extracts
were dried over Na2SO4 and concentrated. 1H NMR of the
crude reaction mixture shows a 1.3:1 ratio of the 3-acetyl
compound 37 to a new compound: 1H NMR (C6D6, 500 MHz)
δ 0.88-0.92 (3.00H), 1.16-1.73 (m, 33.00H), 1.73 (s, 1.68H),
1.88 (s, 1.32H), 2.11-2.15 (m, 2.00H), 2.45 (d, 0.44H, J ) 4.0),
3.25-3.40 (m, 4.56H), 3.45-3.49 (m, 1.00H), 3.54-3.65 (m,
2.00H), 3.71-3.74 (m, 1.56H), 3.80 (dt, 0.44H, J ) 3.6, 8.9),
Meth yl (11S)-11-[[(4,6-O-Ben zylid en e-â-D-glu cop yr a n o-
syl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu cop yr a n osyl]oxy]-
h exa d eca n oa te (36). To diacetate 30 (740 mg, 0.918 mmol)
were added, 5 mL of MeOAc and 15 drops of 25% NaOMe in

Total Synthesis of Tricolorin A
J . Org. Chem., Vol. 62, No. 24, 1997 8415
3.87 (m, 0.56H), 3.93 (t, 0.56H, J ) 7.6), 3.97-4.03 (m, 1.32H),
4.24-4.29 (m, 2.00H), 4.81 (d, 0.56H, J ) 7.6), 5.07 (d, 0.44H,
J ) 7.5), 5.28 (s, 0.56H), 5.32-5.36 (m, 0.88H), 5.61 (t, 0.56H,
J ) 9.5), 7.05-7.19 (m, 3.00H), 7.57-7.59 (m, 2.00H). The
compounds were chromatographically inseparable.
0.20 mmol) were added. The reaction solution was stirred for
1 h. The reaction solution was then diluted with 50 mL of
CH2Cl2 and washed with saturated NaHCO3 and H2O. The
organic layer was dried over Na2SO4 and concentrated to give
a slightly yellowish oil.
Equ ilibr a tion of (11S)-11-[[(4,6-O-Ben zylid en e-â-D-glu -
cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu cop yr a -
n osyl]oxy]h exa d eca n oic Acid 3glu -La cton e (32). A solu-
tion of lactone 32 (5 mg, 7 mmol) and 1 mg of 60% NaH in
mineral oil in 1 mL of THF was stirred for 7-30 min. The
reaction was quenched with 5 mL of H2O and extracted with
CH2Cl2 (2 × 10 mL). The combined organic extracts were dried
over Na2SO4 and concentrated. 1H NMR of the crude reaction
mixture shows a 5.8:1 ratio of the lactone 32 to a new
compound. An attempt to isolate the new compound by
purification of the crude reaction mixture with 10% EtOAc in
toluene as eluent gave ∼0.5 mg of an impure, colorless oil.
Major component: 1H NMR (C6D6, 500 MHz) δ 0.86 (t, 3H, J
) 7.1), 1.24-1.83 (m, 33H), 2.17-2.29 (m, 3H), 3.18 (t, 1H, J
) 9.2), 3.36-3.40 (m, 2H), 3.46 (t, 1H, J ) 10.1), 3.53 (dd, 1H,
J ) 5.4, 2.1), 3.72 (br m, 1H), 3.79 (br t, 1H), 4.02 (dd, 1H, J
) 6.9, 5.5), 4.14 (dd, 1H, J ) 10.2, 4.7), 4.27 (dd, 1H, J ) 8.2,
7.1), 4.33 (d, 1H, J ) 8.3), 5.18 (s, 1H), 5.34-5.38 (m, 2H),
7.08-7.19 (m, 3H), 7.51 (d, 2H, J ) 7.0).
Allyl 2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osid e (41). A
solution of 2.77 g of allyl rhanmopyranoside 40 in 50 mL of
DMF was cooled in an ice bath. To the solution were added
NaH (3.26 g of 60% oil dispersion, 81.6 mmol), Bu4NI (1.51 g,
4.1 mmol), and BnBr (9.71 mL, 81.6 mmol). The cooling bath
was removed, and the reaction solution was stirred overnight.
After addition of 10 mL of MeOH, the solution was stirred for
2 h. The reaction solution was diluted with 100 mL of Et2O
and washed with H2O, 10% Na2S2O3, and brine. The organic
layer was dried over MgSO4, concentrated, and purified by
chromatography on silica gel with 5 f 10% EtOAc in hexanes
as eluent to give 5.90 g (92%) of a clear oil: 1H NMR (CDCl3,
400 MHz) δ 1.46 (d, 3H, J ) 6.1), 3.76 (t, 1H, J ) 9.3), 3.84
(dq, 1H, J ) 9.5, 6.1), 3.92 (dd, 1H, J ) 3.1, 1.9), 3.98-4.03
(m, 2H), 4.22 (ddt, 1H, J ) 13.0, 5.0, 1.6), 4.73 (br s, 2H), 4.75
(d, 1H, J ) 10.9), 4.83 (d, 1H, J ) 12.5), 4.87 (d, 1H, J ) 12.5),
4.92 (d, 1H, J ) 1.7), 5.07 (d, 1H, J ) 10.8), 5.24 (dd, 1H, J )
10.5, 1.6), 5.31 (dd, 1H, J ) 17.2, 1.6), 5.92 (m, 1H), 7.35-
7.49 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ 17.9, 67.5, 68.0,
72.0, 72.7, 74.8, 75.2, 80.1, 80.4, 97.0, 116.9, 127.4, 127.5, 127.5,
127.8, 127.9, 128.2, 133.7, 138.2, 138.5, 138.5; IR (thin film)
3030 cm-1; [R]D -15.1 (c ) 2.01, CH2Cl2). Anal. Calcd for
C30H34O5: C, 75.92; H, 7.22. Found: C, 75.67; H, 7.27.
2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n ose (42). A solution
of rhamnoside 41 (1.08 g, 2.28 mmol) and t-BuOK (256 mg,
2.28 mmol) in 5 mL of DMSO was heated at 100 °C for 15
min. After cooling, the reaction solution was diluted with 50
mL of Et2O, washed with H2O, and concentrated. The residue
was dissolved in a solution of 10 mL of reagent grade acetone
and 2 mL of 1 N HCl. The reaction solution was heated at
reflux for 30 min, cooled, neutralized with NaHCO3, and
concentrated to approximately 3 mL. After dilution with 25
mL of H2O, the reaction solution was extracted with CH2Cl2
(3 × 25 mL). The combined organic extracts were dried over
Na2SO4, concentrated, and purified by chromatography on
silica gel with 30% EtOAc in hexanes as eluent to give 825
mg (83%) of a white solid. A portion of this solid was
recrystallized from Et2O/hexanes to give white crystals: mp
88-89 °C (lit.23 mp 89-90 °C).
To the oil was added 7 mL of 20% H2O in HOAc while the
reaction flask was vigorously stirred. After 10 min, the
reaction solution was carefully poured into 100 mL of saturated
NaHCO3. The resulting mixture was extracted with CH2Cl2,
and the combined organic layers were dried over Na2SO4,
concentrated, and purified by chromatography on silica gel
with 35 f 40% EtOAc in hexanes as eluent to give 536 mg of
a white solid (by 1H NMR, a 7:1 ratio of 2,4:2,3 acetyl isomers.)
After two recrystallizations from 15% EtOAc in hexanes (7 mL/
g), 441 mg (77%) of a isomerically pure white solid was
isolated: mp 101-102 °C; 1H NMR (C6D6, 400 MHz) δ 1.18
(d, 3H, J ) 6.3), 1.62 (s, 3H), 1.70 (s, 3H), 2.48 (d, 1H, J )
8.1), 3.66 (ddt, 1H, J ) 13.0, 5.8, 1.4), 3.83 (dq, 1H, J ) 9.8,
6.3), 3.90 (ddt, 1H, J ) 13.1, 5.1, 1.5), 4.20 (ddd, 1H, J ) 9.8,
8.1, 3.6), 4.89 (d, 1H, J ) 1.4), 4.97 (dq, 1H, J ) 10.4, 1.5),
5.12 (dq, 1H, J ) 17.2, 1.6), 5.25 (t, 1H, J ) 9.8), 5.34 (dd, 1H,
J ) 3.6, 1.6), 5.61-5.71 (m, 1H); 13C NMR (CDCl3, 100 MHz)
δ 17.2, 20.8, 65.9, 68.1, 72.6, 74.5, 96.3, 117.5, 133.3, 170.5,
171.2; IR (thin film) 3436, 1737 cm-1; [R]D -46.7 (c ) 2.89,
CH2Cl2). Anal. Calcd for C13H20O7: C, 54.16; H, 6.99.
Found: C, 54.21; H, 7.04.
2,3,4-Tr i-O-b en zyl-r-L-r h a m n op yr a n ose 1-Tr ich lor o-
a cetim id a te (43). A slurry of rhamnopyranose 42 (2.22 g,
5.10 mmol), Cl3CCN (1.02 mL, 10.2 mmol), and Cs2CO3 (220
mg, 0.675 mmol) in 20 mL of CH2Cl2 was stirred for 3.5 h.
The reaction mixture was filtered through a short pad of silica
gel, and the pad was washed with 250 mL of 1:49:50 Et3N:
EtOAc:hexanes. The combined filtrate was concentrated to
give 2.93 g of slightly yellowish oil. The product was im-
mediately used in the following step without further purifica-
tion.
Allyl (2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-
2,4-d i-O-a cetyl-r-L-r h a m n op yr a n osid e (48). The crude
tricholoracetimidate 43 (2.93 g) and alcohol 46 (960 mg, 3.33
mmol) were each concentrated from freshly distilled benzene
in separate flasks. Alcohol 46 was dissolved in 1.0 mL of CH2-
Cl2, 4.0 mL of 17 mM BF3‚Et2O in CH2Cl2 was added, and the
reaction solution was stirred for 5 min. The tricholoracetimi-
date 43 in 7 mL of CH2Cl2 was added to the reaction solution
over 100 min. After the reaction mixture was stirred for an
additional 20 min, 10 mL of saturated NaHCO3 was added
with vigorous stirring. Following extraction with CH2Cl2, the
combined organic layers were dried over Na2SO4 and concen-
trated. The residue was purified by chromatography on silica
gel with 10 f 20% EtOAc in hexanes as eluent to give 2.18 g
(93%) of a clear oil: 1H NMR (C6D6, 500 MHz) δ 1.23 (d, 3H,
J ) 6.3), 1.43 (d, 3H, J ) 6.2), 1.62 (s, 3H), 1.65 (s, 3H), 3.70
(ddt, 1H, J ) 12.9, 5.9, 1.4), 3.81-3.85 (m, 2H), 3.88 (m, 1H),
3.93 (ddt, 1H, J ) 12.9, 5.3, 1.5), 4.05 (m, 1H), 4.07 (dd, 1H, J
) 8.8, 3.0), 4.32 (dd, 1H, J ) 9.9, 3.5), 4.48-4.55 (m, 3H), 4.60-
4.66 (m, 2H), 4.87 (d, 1H, J ) 11.4), 4.94 (d, 1H, J ) 1.7), 4.97
(dq, 1H, J ) 10.4, 1.4), 5.09 (d, 1H, J ) 2.1), 5.14 (dq, 1H, J )
17.2, 1.6), 5.50 (t, 1H, J ) 9.9), 5.63 (dd, 1H, J ) 3.4, 1.8),
5.67 (m, 1H), 7.04-7.18 (m, 9H), 7.25 (d, 2H, J ) 7.1), 7.30 (d,
2H, J ) 7.1), 7.34 (d, 2H, J ) 7.2); 13C NMR (CDCl3, 100 MHz)
δ 17.3, 17.8, 20.6, 20.9, 66.3, 68.3, 68.9, 71.9, 72.3, 72.6, 72.7,
74.7, 74.7, 75.2, 79.5, 80.2, 96.3, 100.5, 117.6, 127.4, 127.4,
127.5, 127.6, 127.6, 127.7, 127.7, 128.2, 128.3, 128.3, 133.3,
138.2, 138.5, 138.6, 169.6, 170.2; IR (thin film) 1746 cm-1; [R]D
-31.9 (c ) 3.27, CH2Cl2). Anal. Calcd for C40H48O11: C, 68.17;
H, 6.86. Found: C, 67.96; H, 6.84.
Allyl 2,4-Di-O-a cetyl-r-L-r h a m n op yr a n osid e (46). To a
solution of allyl rhanmopyranoside 40 (407 mg, 1.99 mmol) in
5 mL of CH2Cl2 were added triethyl orthoacetate (3.01 mL,
16.4 mmol) and p-TsOH‚H2O (38 mg, 0.20 mmol). The reaction
solution was stirred at room temperature overnight. After
addition of 0.5 mL of Et3N, the reaction solution was concen-
trated under high vacuum to give a slightly yellowish viscous
oil.
Allyl (2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-
r-L-r h a m n op yr a n osid e (49). A solution of rhamnopyrano-
side 48 (956 mg, 1.36 mmol), 10 mL of MeOH, and 1 mL of
25% NaOMe in MeOH was stirred overnight. The solution
was diluted with 50 mL of saturated NaHCO3 and extracted
with CH2Cl2. The combined organic extracts were dried over
Na2SO4, concentrated, and purified by chromatography on
silica gel with 30 f 40% EtOAc in hexanes as eluent to give
732 mg (87%) of a white solid: mp 105-106 °C; 1H NMR (C6D6,
400 MHz) δ 1.32 (d, 3H, J ) 6.2), 1.36 (d, 3H, J ) 6.2), 1.44
After the oil was dissolved in 4 mL of CH2Cl2, Ac2O (401
µL, 3.98 mmol), Et3N (832 µL, 5.97 mmol), and DMAP (24 mg,
(23) Rathore, H.; From, A.; Ahmed, K.; Fullerton, D. J . Med. Chem.
1986, 29, 1945.

8416 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
(d, 1H, J ) 4.6), 1.95 (d, 1H, J ) 4.0), 3.57 (dt, 1H, J ) 4.5,
9.4), 3.70-3.76 (m, 2H), 3.82-3.87 (m, 2H), 3.93-4.03 (m, 3H),
4.07-4.14 (m, 2H), 4.47-4.54 (m, 3H), 4.56-4.63 (m, 2H), 4.79
(d, 1H, J ) 1.4), 4.93 (d, 1H, J ) 11.3), 4.97 (dq, 1H, J ) 10.4,
1.6), 5.13 (dq, 1H, J ) 17.2, 1.7), 5.26 (d, 1H, J ) 2.0), 6.08
(m, 1H), 7.07-7.40 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ
17.5, 18.1, 67.8, 67.9, 69.1, 70.6, 72.1, 72.4, 72.7, 75.0, 75.1,
79.0, 79.7, 80.3, 98.5, 99.7, 117.4, 127.7, 127.7, 127.8, 128.0,
128.4, 128.4, 128.4, 133.7, 138.0, 138.3, 138.3; IR (thin film)
3465, 3031 cm-1; [R]D -50 (c ) 0.44, CH2Cl2). Anal. Calcd
for C36H44O9: C, 69.66; H, 7.14. Found: C, 69.49; H, 7.31.
Allyl (2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-
2,4-d i-O-[(2S)-2-m et h ylb u t yr yl]-r-L-r h a m n op yr a n osid e
(50). A solution of diol 49 (1.07 g, 1.72 mmol), (2S)-2-
methylbutyric acid (749 µL, 6.88 mmol), DCC (1.42 g, 6.88
mmol), and DMAP (86 mg, 0.70 mmol) in 10 mL of CH2Cl2
was stirred overnight. To the reaction solution was added 1
mL of MeOH, followed 10 min later by 50 mL of hexanes. The
mixture was filtered through a small plug of Celite, concen-
trated, and purified by chromatography on silica gel with 5 f
10% EtOAc in hexanes as eluent to give 1.25 g (92%) of a clear
oil: 1H NMR (C6D6, 400 MHz) δ 0.77 (t, 3H, J ) 7.4), 0.88 (t,
3H, J ) 7.4), 1.00 (d, 3H, J ) 7.0), 1.08 (d, 3H, J ) 7.0), 1.25
(m, 1H), 1.28 (d, 3H, J ) 6.3), 1.37 (m, 1H), 1.45 (d, 3H, J )
6.2), 1.65 (m, 1H), 1.79 (m, 1H), 2.16 (m, 1H), 2.31 (m, 1H),
3.71 (dd, 1H, J ) 12.8, 6.0), 3.85 (t, 1H, J ) 9.3), 3.83-3.93
(m, 3H), 4.03 (m, 1H), 4.11 (dd, 1H, J ) 9.2, 2.9), 4.42 (dd,
1H, J ) 9.9, 3.3), 4.48 (d, 1H, J ) 11.5), 4.58 (br m, 2H), 4.68
(d, 1H, J ) 12.3), 4.76 (d, 1H, J ) 12.3), 4.90 (d, 1H, J ) 11.4),
4.96 (dd, 1H, J ) 10.4, 1.4), 5.02 (d, 1H, J ) 1.5), 5.12-5.17
(m, 2H), 5.58 (t, 1H, J ) 9.9), 5.65-5.74 (m, 2H), 7.05-7.20
(m, 9H), 7.25 (d, 2H, J ) 7.0), 7.33 (d, 2H, J ) 7.2), 7.40 (d,
2H, J ) 7.1); 13C NMR (CDCl3, 100 MHz) δ 11.7, 11.8, 16.6,
16.7, 17.6, 17.8, 26.3, 26.5, 41.0, 41.1, 66.7, 68.4, 68.9, 71.8,
72.2, 72.3, 72.8, 74.6, 75.1, 75.6, 80.0, 80.1, 96.3, 100.8, 117.5,
127.2, 127.4, 127.4, 127.5, 128.1, 128.3, 128.3, 133.5, 138.4,
138.5, 138.9, 175.3, 175.9; IR (thin film) 1741 cm-1; [R]D -10.6
(c ) 1.27, CH2Cl2). Anal. Calcd for C46H60O11: C, 70.03; H,
7.66. Found: C, 70.33; H, 7.91.
Meth yl (2,3,4-Tr i-O-ben zyl-r-L-r h am n opyr an osyl)-(1f3)-
(2,4-d i-O-[(2S)-2-m eth ylbu tyr yl]-r-L-r h a m n op yr a n osyl)-
(1f2)-3-O-a ce t yl-4,6-O-b e n zylid e n e -â-D-glu cop yr a n o-
sid e (53). The crude tricholoracetimidate 52 (90 mg) and
alcohol 35 (20 mg, 0.062 mmol) were combined in a flask and
concentrated from freshly distilled benzene. The resulting
residue was dissolved in 400 µL of CH2Cl2, and 100 µL of 0.01
M TMSOTf in CH2Cl2 was added over 35 min. After the
reaction mixture was stirred for an additional 25 min, 5 mL
of saturated NaHCO3 was added with vigorous stirring.
Following extraction with CH2Cl2, the combined organic layers
were dried over Na2SO4 and concentrated. The residue was
purified by chromatography on silica gel with 20% EtOAc in
hexanes as eluent to give 48 mg (74%) of a clear, colorless oil:
1H NMR (C6D6, 500 MHz) δ 0.79 (t, 3H, J ) 7.4), 0.86 (t, 3H,
J ) 7.4), 1.04 (d, 3H, J ) 7.0), 1.06 (d, 3H, J ) 7.0), 1.27-1.39
(m, 2H), 1.42 (d, 3H, J ) 6.3), 1.56 (d, 3H, J ) 6.2), 1.65-1.77
(m, 2H), 2.19 (s, 3H), 2.21-2.19 (m, 2H), 3.12 (dt, 1H, J ) 4.8,
9.6), 3.23 (s, 3H), 3.29 (t, 1H, J ) 9.7), 3.40 (t, 1H, J ) 10.2),
3.70 (dd, 1H, J ) 9.3, 7.7), 3.85 (t, 1H, J ) 9.3), 3.94-4.01 (m,
3H), 4.06-4.10 (m, 2H), 4.37 (m, 1H), 4.48 (d, 1H, J ) 11.1),
4.50 (dd, 1H, J ) 10.0, 3.2), 4.56 (d, 1H, J ) 11.7), 4.70 (d,
1H, J ) 12.3), 4.78 (d, 1H, J ) 12.3), 4.88 (d, 1H, J ) 11.4),
5.17 (s, 1H), 5.27 (d, 1H, J ) 1.7), 5.30 (d, 1H, J ) 1.7), 5.50
(dd, 1H, J ) 3.1, 2.0), 5.61-5.68 (m, 2H), 7.05-7.19 (m, 12H),
7.24 (d, 2H, J ) 7.2), 7.33 (d, 2H, J ) 7.0), 7.40 (d, 2H, J )
7.1), 7.59 (d, 2H, J ) 7.2); 13C NMR (CDCl3, 100 MHz) δ 11.7,
11.8, 16.5, 16.7, 17.2, 17.6, 20.8, 26.4, 26.5, 41.0, 41.2, 57.1,
66.3, 67.0, 68.6, 68.9, 71.9, 72.0, 72.3, 72.8, 72.9, 74.7, 75.0,
75.7, 78.5, 78.9, 80.1, 80.1, 98.3, 100.8, 101.3, 103.2, 126.1,
127.2, 127.4, 127.4, 127.5, 128.1, 128.2, 128.3, 128.3, 129.0,
136.9, 138.5, 138.5, 138.9, 170.1, 175.3, 175.7; IR (thin film)
1738 cm-1; [R]D -17.7 (c ) 2.00, CH2Cl2). Anal. Calcd for
C59H74O17: C, 67.16; H, 7.07. Found: C, 66.82; H, 7.23.
2,3,4-Tr i-O-a cetyl-L-r h a m n op yr a n ose (54). A solution of
D-rhamnose‚H2O (500 mg, 2.74 mmol) in 25 mL of CH2Cl2 was
cooled in an ice bath. The solution was treated with Et3N (3.44
mL, 24.7 mmol), Ac2O (1.66 mL, 16.4 mmol), and DMAP (37
mg, 0.30 mmol). The cooling bath was removed, and the
reaction solution was stirred overnight. The reaction solution
was diluted with 25 mL of CH2Cl2 and washed with 1 N HCl,
saturated NaHCO3, and H2O. The organic layer was dried
over Na2SO4 and concentrated to yield a slightly yellow oil.
A solution of the oil and BnNH2 (449 µL, 4.11 mmol) in 15
mL of THF was stirred for 12 h. After addition of 5 mL of 1
N HCl, the reaction mixture was stirred for 30 min. The
reaction mixture was diluted with 50 mL of 1 N HCl and
extracted with CH2Cl2. The combined extracts were dried over
Na2SO4, concentrated, and purified by chromatography on
silica gel with 40% EtOAc in hexanes as eluent to give 629
mg (79%) of a white amorphous solid: 1H NMR (CDCl3, 400
MHz) δ 1.15 (d, 3H, J ) 6.1), 1.94 (s, 3H), 2.00 (s, 3H), 2.10 (s,
3H), 4.09 (m, 1H), 4.22 (d, 1H, J ) 3.8), 5.00 (t, 1H, J ) 10.0),
(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-2,4-d i-
O-[(2S)-2-m eth ylbu tyr yl]-r-L-r h a m n op yr a n ose (51).
A
solution of allyl rhamnoside 50 (1.25 g, 1.58 mmol) and (Ph3P)3-
RhCl (880 mg, 0.951 mmol) in 20 mL of 10% H2O in EtOH
was heated at reflux overnight. After cooling, the reaction
mixture was concentrated and dissolved in 50 mL of 10% H2O
in acetone, and HgCl2 (1.0 g, 3.7 mmol) and HgO (1.0 g,4.6
mmol) were added. The reaction mixture was stirred for 2 h,
filtered through a plug of Celite, and concentrated. The
residue was purified by chromatography on silica gel with 20
f 30% EtOAc in hexanes as eluent to give 994 mg (84%) of a
clear oil: 1H NMR (C6C6, 400 MHz) δ 0.76 (t, 3H, J ) 7.4),
0.87 (t, 3H, J ) 7.4), 0.99 (d, 3H, J ) 6.9), 1.08 (d, 3H, J )
7.0), 1.24 (m, 1H), 1.28 (d, 3H, J ) 6.2), 1.36 (m, 1H), 1.45 (d,
3H, J ) 6.1), 1.63 (m, 1H), 1.77 (m, 1H), 2.14 (m, 1H), 2.31
(m, 1H), 2.31 (d, 1H, J ) 4.3), 3.84 (t, 1H, J ) 9.3), 3.93-4.10
(m, 4H), 4.38 (dd, 1H, J ) 9.9, 3.0), 4.49 (d, 1H, J ) 11.5),
4.57 (br s, 2H), 4.67 (d, 1H, J ) 12.2), 4.76 (d, 1H, J ) 12.3),
4.90 (d, 1H, J ) 11.4), 5.08 (br d, 1H, J ) 3.9), 5.13 (br s, 1H),
5.52 (t, 1H, J ) 9.9), 5.54 (br s, 1H), 7.05-7.19 (m, 9H), 7.25
(d, 2H, J ) 7.5), 7.32 (d, 2H, J ) 7.6), 7.40 (d, 2H, J ) 7.6);
13C NMR (CDCl3, 100 MHz) δ 11.5, 11.6, 16.4, 16.5, 17.5, 17.6,
26.2, 26.4, 40.9, 41.0, 66.2, 68.7, 72.2, 72.3, 72.4, 72.6, 74.5,
74.7, 75.3, 79.8, 79.9, 91.2, 100.5, 127.1, 127.3, 127.3, 127.4,
127.9, 128.1, 138.0, 138.2, 138.6, 175.3, 176.1; IR (thin film)
3423, 1738 cm-1; [R]D +4.43 (c ) 12.29, CH2Cl2). Anal. Calcd
for C43H56O11: C, 68.96; H, 7.54. Found: C, 69.04; H, 7.68.
(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-2,4-d i-
O-[(2S)-2-m eth ylbu tyr yl]-r-L-r h a m n op yr a n ose 1-Tr ich lo-
r oa cetim id a te (52). A slurry of rhamnopyranose 51 (78 mg,
0.10 mmol), Cl3CCN (30 µL, 0.30 mmol), and Cs2CO3 (20 mg,
0.061 mmol) in 2 mL of CH2Cl2 was stirred for 9 h. The
reaction mixture was filtered through a short pad of silica gel,
and the pad was washed with 75 mL of 50% EtOAc in hexanes.
The combined filtrate was concentrated to give 90 mg of
slightly yellowish oil. The product was immediately used in
the following step without further purification.
5.09 (br s, 1H), 5.19 (br s, 1H), 5.30 (dd, 1H, J ) 10.0, 2.7); 13
C
NMR (CDCl3, 100 MHz) δ 17.3, 20.6, 20.7, 20.8, 66.1, 68.8,
70.4, 71.1, 91.8, 170.2, 170.2, 170.4. The preceding spectral
data was consistent with that prevously reported for this
compound.24
(2,3,4-Tr i-O-a cetyl-r-L-r h a m n op yr a n ose 1-Tr ich lor o-
a cetim id a te (55). A slurry of rhamnopyranose 54 (21 mg,
0.072 mmol), Cl3CCN (15 mL, 0.15 mmol), and Cs2CO3 (15
mg, 0.046 mmol) in 1 mL of CH2Cl2 was stirred for 2.5 h. The
reaction mixture was filtered through a short pad of silica gel,
and the pad was washed with 75 mL of 50% EtOAc in hexanes.
The combined filtrate was concentrated to give 30 mg of
slightly yellowish oil. The product was immediately used in
the following step without further purification.
(11S)-11-[[(2,3,4-Tr i-O-a cet yl-r-L-r h a m n op yr a n osyl)-
(1f2)-(4,6-O-ben zylid en e-â-D-glu cop yr a n osyl)-(1f2)-3,4-
O-isop r op ylid en e-â-D-fu cop yr a n osyl]oxy]h exa d eca n o-
ic Acid 3glu -La cton e (56). The crude tricholoracetimidate 55
(30 mg) and alcohol 32 (25 mg, 0.036 mmol) were combined in
a flask and concentrated from freshly distilled benzene. The
(24) Bashir, N.; Phythian, S., Reason, A., Roberts, S. J . Chem. Soc.,
Perkin Trans. 1 1995, 2203.

Total Synthesis of Tricolorin A
J . Org. Chem., Vol. 62, No. 24, 1997 8417
resulting residue was dissolved in 200 µL of CH2Cl2, and 220
µL of 0.01 M TMSOTf in CH2Cl2 was added over 30 min. After
the reaction mixture was stirred for an additional 30 min, 5
mL of saturated NaHCO3 was added with vigorous stirring.
Following extraction with CH2Cl2, the combined organic layers
were dried over Na2SO4 and concentrated. The residue was
purified by chromatography on silica gel with 10% EtOAc in
toluene as eluent. Isolation of two middle chromatography
fractions gave 10 mg of a clear, colorless oil that contained a
major component and minor impurities: 1H NMR (C6D6, 500
MHz) δ 0.87 (t, 3H, J ) 7.0), 1.12-1.88 (m, 45H), 2.34 (m,
1H), 2.79 (m, 1H), 3.19 (dq, 1H J ) 2.1, 6.6), 3.25 (dt, 1H, J )
5.0, 9.7), 3.43 (t, 1H, J ) 10.3), 3.56-3.57 (m, 2H), 3.80 (t,
1H, J ) 9.6), 4.06-4.09 (m, 2H), 4.19-4.25 (m, 2H), 4.44 (m,
1H), 4.51 (dd, 1H, J ) 7.0, 5.5), 5.27 (s, 1H), 5.29 (d, 1H, J )
6.9), 5.60 (d, 1H, J ) 1.7), 5.63 (t, 1H, J ) 9.9), 5.70-5.75 (m,
2H), 5.81 (dd, 1H, J ) 3.1, 2.0), 7.04-7.19 (m, 3H), 7.56 (d,
2H, J ) 7.1); 13C NMR (CDCl3, 125 MHz) δ 14.1, 16.7, 17.2,
20.7, 20.9, 20.9, 22.6, 24.1, 25.2, 25.2, 26.5, 26.9, 27.6, 27.7,
27.9, 29.1, 30.2, 31.9, 34.1, 34.6, 35.3, 65.0, 67.0, 68.8, 68.9,
69.0, 69.8, 70.9, 73.3, 75.0, 77.9, 79.5, 80.8, 81.2, 97.3, 97.9,
101.0, 101.3, 109.7, 126.2, 128.2, 128.6, 137.2, 169.6, 169.7,
1.75 (m, 45H), 2.13 (t, 1H, J ) 7.4), 2.16 (s, 3H), 3.32 (m, 1H),
3.34 (s, 3H), 3.45 (dq, 1H, J ) 1.9, 6.5), 3.53 (t, 1H, J ) 10.2),
3.59 (t, 1H, J ) 9.6), 3.70 (dd, 1H, J ) 5.7, 1.9), 3.73 (br m,
1H), 3.81-3.89 (m, 3H), 4.00 (m, 1H), 4.10 (dd, 1H, J ) 8.9,
2.9), 4.14 (dd, 1H, J ) 10.4, 4.9), 4.19 (t, 1H, J ) 7.1), 4.38-
4.58 (m, 7H), 4.69 (br s, 2H), 4.89 (d, 1H, J ) 11.3), 5.16 (d,
1H, J ) 7.4), 5.26 (d, 1H, J ) 1.8), 5.32 (s, 1H), 5.43 (d, 1H, J
) 1.7), 5.49 (dd, 1H, J ) 3.0, 2.1), 5.56 (t, 1H, J ) 9.9), 5.66 (t,
1H, J ) 9.2), 7.04-7.19 (m, 12H), 7.25 (d, 2H, J ) 7.1), 7.30
(d, 2H, J ) 7.2), 7.39 (d, 2H, J ) 7.3), 7.55 (d, 2H, J ) 7.2);
13C NMR (CDCl3, 100 MHz) δ 14.0, 16.6, 17.5, 17.8, 20.6, 20.9,
20.9, 22.6, 24.7, 24.9, 25.1, 26.3, 27.7, 29.1, 29.3, 29.5, 29.7,
29.9, 31.9, 34.0, 34.0, 34.7, 51.3, 65.8, 66.8, 68.4, 68.8, 68.9,
71.9, 72.3, 72.3, 72.5, 73.2, 74.8, 75.0, 75.1, 76.4, 76.7, 78.4,
79.2, 79.6, 80.2, 80.4, 98.1, 99.6, 100.3, 100.4, 101.3, 109.7,
126.1, 127.4, 127.6, 127.8, 128.1, 128.2, 128.3, 128.3, 128.9,
137.0, 138.2, 138.5, 138.6, 169.5, 170.0, 170.3, 174.1; IR (thin
film) 1745 cm-1; [R]D -25.6 (c ) 1.70, CH2Cl2). Anal. Calcd
for C78H106O23: C, 66.36; H, 7.57. Found: C, 66.00; H, 7.77.
(11S)-11-[[(2,3,4-Tr i-O-b en zyl-r-L-r h a m n op yr a n osyl)-
(1f3)-(r-L-r h a m n op yr a n osyl)-(1f2)-(4,6-O-ben zylid en e-
â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu -
cop yr a n osyl]oxy]h exa d eca n oic Acid (60). To a solution
of tetraester 59 (80 mg, 0.057 mmol) in 5 mL of THF was added
2 mL of 0.3 M LiOH. The reaction solution was stirred for 16
h, acidified with 25 mL of 1 N HCl, and extracted with CH2-
Cl2. The combined extracts were dried over Na2SO4, concen-
trated, and purified by chromatography on silica gel with 60%
EtOAc in hexanes as eluent to give 52 mg (72%) of a sticky
white solid: 1H NMR (C6D6, 400 MHz) δ 0.90 (t, 3H, J ) 7.0),
1.26-1.78 (m, 39H), 2.16 (t, 2H, J ) 7.0), 3.32 (dt, 1H, J )
4.7, 9.4), 3.45 (t, 1H, J ) 9.2), 3.49-3.51 (m, 2H), 3.75-3.80
(m, 3H), 3.84-3.92 (m, 3H), 4.07 (br s, 1H), 4.15-4.33 (m, 5H),
4.39 (dd, 1H, J ) 9.4, 6.3), 4.47-4.51 (m, 4H), 4.59-4.75 (m,
4H), 4.89 (d, 1H, J ) 11.2), 5.15 (d, 1H, J ) 7.4), 5.29 (s, 1H),
5.53 (br s, 1H), 5.70 (br s, 1H), 7.08 (m, 12H), 7.27 (d, 2H, J )
7.1), 7.40 (d, 2H, J ) 7.4), 7.43 (d, 2H, J ) 7.4), 7.56 (d, 2H, J
) 7.2); 13C NMR (CDCl3, 100 MHz) δ 14.1, 16.6, 17.6, 18.0,
22.6, 24.6, 24.8, 25.1, 26.2, 27.6, 28.8, 29.1, 29.3, 29.6, 29.8,
31.9, 33.8, 33.9, 34.8, 65.7, 68.1, 68.2, 68.7, 68.8, 70.4, 72.2,
72.4, 72.6, 74.4, 75.1, 75.3, 76.3, 77.9, 78.5, 78.7, 79.1, 79.9,
80.5, 80.8, 99.6, 100.4, 100.7, 101.7, 109.8, 126.2, 127.6, 127.7,
127.7, 127.8, 128.1, 128.2, 128.3, 129.1, 137.1, 138.1, 138.1,
138.4, 178.1; IR (thin film) 3458, 1712 cm-1; [R]D -37 (c ) 0.67,
170.1, 172.3; IR (thin film) 1752 cm-1
purify this compound were unsuccessful.
. Attempts to further
(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-2,4-d i-
O-a cetyl-r-L-r h a m n op yr a n ose (57). To a degassed solution
of (Ph3P)3RhCl (49 mg, 0.053 mmol) in 5 mL of THF was added
35 µL of 2.31 M n-BuLi in hexane. After stirring for 10 min,
the reaction solution was added to a degassed solution of allyl
rhamnoside 48 (372 mg, 0.528 mmol) in 10 mL of THF. The
reaction solution was heated at reflux for 15 min, cooled, and
concentrated. The residue was dissolved in 10 mL of 10% H2O
in acetone, and HgCl2 (300 mg, 1.10 mmol) and HgO (300 mg,
1.39 mmol) were added. The reaction mixture was stirred for
2 h, filtered through a plug of Celite, and concentrated. The
residue was purified by chromatography on silica gel with 30
f 40% EtOAc in hexanes as eluent to give 334 mg (95%) of a
clear oil: 1H NMR (C6C6, 400 MHz) δ 1.24 (d, 3H, J ) 6.2),
1.43 (d, 3H, J ) 6.2), 1.60 (s, 3H), 1.64 (s, 3H), 2.07 (d, 1H, J
) 4.2), 3.81-3.85 (m, 2H), 3.97-4.08 (m, 3H), 4.30 (dd, 1H, J
) 9.9, 3.4), 4.46-4.55 (m, 3H), 4.62 (br s, 2H), 4.87 (d, 1H, J
) 11.4), 5.01 (br m, 1H), 5.08 (br s, 1H), 5.46 (t, 1H, J ) 9.9),
5.51 (br m, 1H), 7.05-7.18 (m, 9H), 7.25 (d, 2H J ) 7.5), 7.30
(d, 2H, J ) 7.6), 7.34 (d, 2H, J ) 7.5); 13C NMR (CDCl3, 100
MHz) δ 17.4, 17.7, 20.6, 20.9, 66.1, 68.8, 72.3, 72.4, 72.6, 72.8,
74.3, 74.7, 75.0, 79.5, 80.1, 91.4, 100.3, 127.4, 127.6, 127.6,
127.7, 127.8, 128.2, 128.3, 128.3, 138.0, 138.3, 138.4, 169.8,
170.5; IR (thin film) 3416, 1746 cm-1; [R]D -9.74 (c ) 2.33,
CH2Cl2). Anal. Calcd for C71H98O20
Found: C, 66.69; H, 7.90.
: C, 67.07; H, 7.77.
DMAP ‚TF A. A solution of DMAP (1.00 g, 8.19 mmol) in
20 mL of THF was cooled in an ice bath. Trifluoroacetic acid
(631 µL, 8.19 mmol) was added to the solution. Without
replenishing the cooling bath, the reaction solution was stirred
overnight. The heterogeneous reaction solution was then
filtered, and the solid was washed with Et2O and dried under
vacuum to give 1.81 g of white crystals.
CH2Cl2). Anal. Calcd for C37H44O11
Found: C, 66.56; H, 6.74.
: C, 66.85; H, 6.67.
(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-(1f3)-2,4-d i-
O-a cet yl-r-L-r h a m n op yr a n ose 1-Tr ich lor oa cet im id a t e
(58). A slurry of rhamnopyranose 57 (153 mg, 0.230 mmol),
Cl3CCN (46 µL, 0.46 mmol), and Cs2CO3 (8 mg, 0.023 mmol)
in 1 mL of CH2Cl2 was stirred for 11 h. The reaction mixture
was filtered through a short pad of silica gel, and the pad was
washed with 100 mL of 50% EtOAc in hexanes. The combined
filtrate was concentrated to give 181 mg of slightly yellowish
oil. The product was immediately used in the following step
without further purification.
Meth yl (11S)-11-[[(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a -
n osyl)-(1f3)-(2,4-di-O-acetyl-r-L-r h am n opyr an osyl)-(1f2)-
(3-O-a cetyl-4,6-O-ben zyliden e-â-D-glu cop yr a n osyl)-(1f2)-
3 , 4 -O -i s o p r o p y l i d e n e -â-D -f u c o p y r a n o s y l ] o x y ] -
h exa d eca n oa te (59). The crude tricholoracetimidate 58 (181
mg) and alcohol 37 (117 mg, 0.153 mmol) were combined in a
flask and concentrated from freshly distilled benzene. The
resulting residue was dissolved in 400 µL of CH2Cl2, and 225
µL of 0.02 M TMSOTf in CH2Cl2 was added over 45 min. After
the reaction mixture was stirred for an additional 15 min, 10
mL of saturated NaHCO3 was added with vigorous stirring.
Following extraction with CH2Cl2, the combined organic layers
were dried over Na2SO4 and concentrated. The residue was
purified by chromatography on silica gel with 20 f 30% EtOAc
in hexanes as eluent to give 162 mg (75%) of a sticky white
solid: 1H NMR (C6D6, 500 MHz) δ 0.89 (t, 3H, J ) 7.0), 1.25-
(11S)-11-[[(2,3,4-Tr i-O-b en zyl-r-L-r h a m n op yr a n osyl)-
(1f3)-(r-L-r h a m n op yr a n osyl)-(1f2)-(4,6-O-ben zylid en e-
â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu -
cop yr a n osyl]oxy]h exa d eca n oic Acid 2r h a -La cton e (62)
a n d (11S)-11-[[(2,3,4-Tr i-O-ben zyl-r-L-r h a m n op yr a n osyl)-
(1f3)-(r-L-r h a m n op yr a n osyl)-(1f2)-(4,6-O-ben zylid en e-
â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu -
cop yr a n osyl]oxy]h exa d eca n oic Acid 3glu -La cton e (61).
DMAP (14 mg, 0.11 mmol) and DMAP‚TFA (23 mg, 0.097
mmol) were combined and azeotroped from benzene. To the
dried reagents was added DCC (20 mg, 0.097 mmol) and 25
mL of EtOH-free CHCl3. The reaction solution was then
heated to reflux. Triol 60 (25 mg, 0.020 mmol) was azeotroped
from benzene, dissolved in 7 mL of EtOH-free CHCl3, and
added to the reaction solution over 20 h. After addition was
complete, the reaction solution was heated at reflux for 1 h,
cooled, and concentrated to ∼2 mL. The solution was diluted
with 25 mL of Et2O, filtered, and concentrated. The residue
was purified by chromatography on silica gel with 5 f 20%
EtOAc in toluene as eluent to give 6 mg (24%) of a slightly
impure, less polar compound and 7 mg (28%) of a more polar
compound. Less polar compound: white solid; 1H NMR (C6D6,
500 MHz) δ 0.87 (t, 3H, J ) 7.1), 1.15-1.80 (m, 39H), 2.13 (br

8418 J . Org. Chem., Vol. 62, No. 24, 1997
Larson and Heathcock
s, 1H), 2.20 (m, 1H), 2.31 (m, 1H), 2.46 (br s, 1H), 3.18-2.26
(m, 2H), 3.34-3.40 (m, 2H), 3.43 (dd, 1H, J ) 5.1, 2.0), 3.62
(dt, 1H, J ) 3.2, 8.7), 3.68 (dd, 1H, J ) 8.6, 7.6), 3.77-3.78
(m, 2H), 3.85 (t, 1H, J ) 9.1), 3.92 (t, 1H, J ) 9.5), 4.05-4.13
(m, 3H), 4.22 (dd, 1H, J ) 9.5, 3.2), 4.25-4.36 (m, 3H), 4.41
(d, 1H, J ) 7.9), 4.48 (d, 1H, J ) 11.8), 4.52 (d, 1H, J ) 11.3),
4.56 (d, 1H, J ) 11.8), 4.57 (d, 1H, J ) 12.1), 4.67 (br s, 1H),
4.90 (d, 1H, J ) 11.3), 5.13 (s, 1H), 5.18 (d, 1H, J ) 2.0), 5.27
(d, 1H, J ) 7.5), 5.40 (br s, 1H), 5.85 (dd, 1H, J ) 3.9, 1.9),
7.08-7.20 (m, 12H), 7.30-7.31 (m, 4H), 7.41 (d, 2H, J ) 7.5),
7.51 (d, 2H, J ) 7.2); 13C NMR (CDCl3, 125 MHz) δ 14.1, 16.7,
18.0, 18.1, 22.6, 25.2, 25.5, 26.6, 27.8, 28.8, 29.2, 29.4, 29.7,
30.5, 31.9, 34.0, 34.6, 35.1, 65.8, 68.2, 68.4, 68.8, 69.1, 71.8,
72.0, 72.5, 72.6, 74.4, 74.5, 75.1, 75.5, 76.8, 78.4, 79.2, 80.2,
80.4, 80.4, 80.6, 84.4, 98.1, 99.7, 100.1, 100.8, 101.6, 109.7,
126.2, 127.7, 127.7, 127.8, 127.9, 128.0, 128.3, 128.3, 128.3,
128.4, 128.6, 129.0, 137.2, 138.1, 138.5, 138.5, 173.3; IR (CH2-
Cl2 solution) 3585, 1734 cm-1. Attempts to further purify this
compound were unsuccessful. More polar compound: clear oil;
1H NMR (C6D6, 500 MHz) δ 0.88 (t, 3H, J ) 7.1), 1.26-1.91
(m, 39H), 2.07 (br s, 1H), 2.21 (m, 1H), 2.28 (m, 1H), 3.28-
3.34 (m, 2H), 3.49 (t, 1H, J ) 10.2), 3.57 (br m, 1H), 3.61 (dd,
1H, J ) 5.3, 2.1), 3.69 (br t, 1H, J ) 9.1), 3.84-3.88 (m, 3H),
4.00-4.04 (m, 2H), 4.08-4.13 (m, 2H), 4.16 (dd, 1H, J ) 9.5,
3.0), 4.19-4.25 (m, 3H), 4.34 (br s, 1H), 4.50-4.53 (m, 4H),
4.70 (br s, 1H), 4.95 (d, 1H, J ) 11.4), 5.31 (s, 1H), 5.36 (d,
1H, J ) 6.5), 5.44 (d, 1H, J ) 2.0), 5.50 (br s, 1H), 5.61 (dd,
1H, J ) 9.5, 7.2), 7.05-7.23 (m, 12H), 7.30-7.33 (m, 4H), 7.47
(d, 2H, J ) 7.5), 7.54 (d, 2H, J ) 7.1); 13C NMR (CDCl3, 100
MHz) δ 14.1, 16.7, 17.4, 18.2, 22.6, 24.3, 25.2, 25.3, 26.5, 27.1,
27.7, 27.9, 27.9, 29.1, 30.2, 31.9, 34.5, 34.7, 35.4, 65.0, 68.7,
68.7, 68.9, 69.2, 70.6, 71.9, 72.3, 72.4, 74.1, 75.0, 75.1, 75.1,
77.2, 77.8, 78.9, 79.4, 79.8, 80.2, 80.8, 81.4, 98.2, 99.2, 99.2,
101.2, 101.2, 109.6, 126.1, 127.7, 127.7, 127.8, 127.9, 128.0,
128.2, 128.3, 128.4, 129.0, 137.2, 138.1, 138.4, 138.4, 172.3;
IR (CH2Cl2 solution) 3480, 1738 cm-1; [R]D -31 (c ) 0.74, CH2-
Cl2). Anal. Calcd for C71H96O19: C, 68.03; H, 7.72. Found:
C, 67.73; H, 7.70.
(11S)-11-[[(2,3,4-Tr i-O-b en zyl-r-L-r h a m n op yr a n osyl)-
(1f3)-(r-L-r h a m n op yr a n osyl)-(1f2)-(4,6-O-ben zylid en e-
â-D-glu cop yr a n osyl)-(1f2)-3,4-O-isop r op ylid en e-â-D-fu -
cop yr a n osyl]oxy]h exa d eca n oic Acid 3glu -La cton e (61). To
a solution of acid 60 (51 mg, 0.041 mmol) in 225 mL of benzene
were added Et3N (341 µL, 2.45 mmol) and 2,4,6-trichloroben-
zoyl chloride (256 µL, 1.64 mmol). DMAP (100 mg, 0.819
mmol) was added to the reaction mixture in two portions, 1 h
apart. After being stirred for 15 h, the milky white reaction
mixture was washed with 100 mL of H2O and separated. The
aqueous layer was extracted with CH2Cl2 (3 × 75 mL). The
combined organic layers were dried over Na2SO4, concentrated,
and purified by chromatography on silica gel with 20% EtOAc
in toluene as eluent to give 31 mg (61%) of a clear oil. The
isolated product was spectroscopically identical with the more
polar product obtained from the alternative macrolactoniza-
tion.
chromatography on silica gel with 3% EtOAc in toluene as
eluent to give 17 mg (61%) of a slightly impure, clear oil: 1H
NMR (C6D6, 500 MHz) δ 0.80 (t, 3H, J ) 7.4), 0.85-0.92 (m,
6H), 1.04-1.87 (m, 49H), 2.23-2.28 (m, 2H), 2.58 (m, 1H), 3.16
(dt, 1H, J ) 5.0, 9.8), 3.32 (dq, 1H, J ) 2.1, 6.6), 3.39 (t, 1H,
J ) 10.2), 3.58-3.60 (m, 2H), 3.77 (t, 1H, J ) 9.6), 3.91 (t, 1H,
J ) 9.4), 4.03-4.07 (m, 4H), 4.17 (dd, 1H, J ) 9.3, 3.0), 4.21-
4.26 (m, 2H), 4.45 (m, 1H), 4.54-4.61 (m, 4H), 4.66 (m, 1H),
4.86 (d, 1H, J ) 12.6), 4.89 (d, 1H, J ) 12.5), 4.97 (d, 1H, J )
11.4), 5.24 (s, 1H), 5.26 (d, 1H, J ) 7.0), 5.52 (d, 1H, J ) 1.7),
5.54 (d, 1H, J ) 1.9), 5.64-5.69 (m, 3H), 7.05-7.23 (m, 12H),
7.28 (d, 2H, J ) 7.9), 7.36 (d, 2H, J ) 7.1), 7.51-7.55 (m, 4H);
13C NMR (CDCl3, 125 MHz) δ 11.7, 11.8, 14.1, 16.7, 16.8, 16.8,
17.4, 17.8, 22.6, 24.0, 25.1, 25.2, 26.4, 26.5, 26.6, 26.9, 27.7,
27.8, 27.9, 29.2, 30.4, 31.9, 34.3, 34.8, 35.3, 41.2, 41.3, 65.2,
67.3, 68.7, 68.8, 68.9, 71.7, 72.0, 72.2, 72.3, 73.5, 74.7, 74.9,
75.0, 75.7, 76.7, 78.2, 79.2, 80.0, 80.2, 80.7, 82.1, 96.3, 98.0,
100.5, 101.3, 101.5, 109.7, 126.1, 127.2, 127.4, 127.5, 127.5,
127.6, 128.1, 128.2, 128.3, 128.3, 128.6, 129.0, 137.1, 138.3,
138.5, 139.0, 172.3, 175.2, 175.4; IR (thin film) 1741 cm-1
.
Attempts to further purify this compound were unsuccessful.
Tr icolor in A. To a solution of compound 63 (18 mg, 0.013
mmol) in 1 mL of MeOH was added 0.5 mL of 11% HCl in
MeOH and 10 mg of Pd(OH)2 on activated charcoal. The
reaction flask was evacuated and back-filled with H2 three
times. The reaction solution was stirred overnight under the
pressure of a balloon filled with H2. The reaction solution was
basified with 1 mL of Et3N and filtered through a small plug
of Celite. The Celite plug was washed with MeOH and the
combined filtrate and washes were concentrated and purified
by chromatography on silica gel with 10:10:1 acetone-CHCl3-
MeOH as eluent to give 10 mg (77%) of a white solid: mp 117-
119 °C. 1H NMR (C5D5N, 400 MHz) δ 0.79-0.84 (m, 6H), 0.90
(t, 3H, J ) 7.4), 1.08-1.89 (m, 43H), 2.27-2.47 (m, 3H), 2.99
(br dd, 1H), 3.45 (br dt, 1H), 3.80-3.82 (m, 2H), 3.88 (dd, 1H,
J ) 11.7, 2.7), 4.01 (br d, 1H, J ) 3.2), 4.08-4.14 (m, 2H),
4.20-4.23 (m, 3H), 4.34 (t, 1H, J ) 9.5), 4.40 (br m, 1H), 4.50
(dd, 1H, J ) 3.3, 1.5), 4.64 (d, 1H, J ) 7.8), 4.71 (dd, 1H, J )
9.3, 7.9), 4.77 (dd, 1H, J ) 9.9, 3.2), 4.92 (dq, 1H, J ) 9.9,
6.2), 5.49 (br s, 1H), 5.54 (br s, 1H), 5.69 (t, 1H, J ) 9.7), 5.75-
5.82 (m, 3H); 13C NMR (C5D5N, 100 MHz) δ 11.9, 14.3, 17.0,
17.1, 17.4, 18.4, 18.6, 22.9, 23.8, 24.9, 25.7, 26.7, 26.9, 27.1,
28.0, 28.4, 29.6, 31.8, 32.2, 34.5, 35.2, 41.5, 41.6, 61.3, 67.3,
69.6, 70.6, 71.4, 72.4, 72.6, 72.9, 73.3, 73.4, 73.5, 74.8, 76.0,
76.3, 79.1, 80.7, 80.9, 98.4, 99.9, 103.2, 104.7, 172.4, 173.4,
175.7, 175.8; IR (CH2Cl2 solution) 3444, 1735 cm-1; [R]D -24
(c ) 0.30, MeOH). Anal. Calcd for C50H86O21: C, 58.69; H,
8.47. Found: C, 58.84; H, 8.57. This compound was spectro-
scopically identical with a sample of authentic tricolorin A.
Ack n ow led gm en t. This work was supported by a
research grant from the United States Public Health
Service (GM 46057). An American Chemical Society
Division of Organic Chemistry Graduate Fellowship
(sponsored by Organic Syntheses, Inc.) to D.P.L. is
gratefully acknowledged. The authors wish to thank
Professor Rogelio Pereda-Miranda for providing a sample
of natural tricolorin A.
(11S)-11-[(2,3,4-Tr i-O-b en zyl-r-L-r h a m n op yr a n osyl)-
(1f3)-[2,4-d i-O-[(2S)-2-m eth ylbu tyr yl]-r-L-r h a m n op yr a -
n osyl]-(1f2)-[(4,6-O-b en zylid en e-â-D-glu cop yr a n osyl)-
(1 f2 )-3 ,4 -O -i s o p r o p y l i d e n e -â-D -fu c o p y r a n o s y l ]-
oxy]h exa d eca n oic Acid 3glu -La cton e (63). To a solution
of acid 60 (25 mg, 0.020 mmol) in 100 mL of benzene were
added Et3N (164 µL, 1.18 mmol) and 2,4,6-trichlorobenzoyl
chloride (123 µL, 0.788 mmol). DMAP (48 mg, 0.39 mmol) was
added to the reaction mixture in two portions, 1 h apart. After
the solution was stirred for 15 h, (2S)-2-methylbutyric acid
(43 µL, 0.39 mmol) was added and the reaction solution was
stirred for 2.5 h. The milky white reaction mixture was then
washed with 50 mL of H2O and separated. The aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried over Na2SO4, concentrated, and purified by
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 6-12 (Scheme 2),
1H NMR spectra of compounds 30, 32, 37, 39, 56, 61-63, and
1 (both synthetic and authentic natural product), and 13C NMR
spectra of 1 (15 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O971413U