Scholarly article on (1S,2R)-2-chlorocyclopropanecarboxylic acid (1S,2R,5S)-5-isopropyl-2-methylcyclohexyl ester 440103-62-8 from Journal of the American Chemical Society p. 10396

Published on Web 08/07/2002

Callipeltoside A: Total Synthesis, Assignment of the Absolute

and Relative Configuration, and Evaluation of Synthetic

Analogues

Barry M. Trost,* Janet L. Gunzner, Olivier Dirat, and Young H. Rhee

Contribution from the Department of Chemistry, Stanford UniVersity,

Stanford, California 94305-5080

Received April 11, 2002

Abstract: The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues,

is accomplished and allows assignment of the stereochemistry not previously established. A convergent

strategy is employed wherein the target is dissected into three unitssthe core macrolactone, the sugar

callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives

from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The

stereochemistry of the latter derives from the chiral pool and two asymmetric reactionssa ketone reduction

using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the

latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is

generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of

geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium

catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the

thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chainsone based upon

olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of

choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is

developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route

provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction.

It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20

and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis

in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for

the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance

of the chloro substituent and the necessity of the sugar.

Introduction and Retrosynthetic Analysis

figuration of the trans-chlorocyclopropane with regard to the

macrolactone is not known, and (3) the absolute configuration

remains to be assigned. Despite these structural ambiguities,

many groups have embarked on the total synthesis of this

compound, with different stereoisomers as targets.²In previous

communications, we reported the total synthesis of deschloro-

callipeltoside A (2),³as well as the first total synthesis of

callipeltoside A (1).⁴In this article, we report a full account of

Callipeltoside A (1) was isolated in 1996 by Minale and co-

workers from the shallow-water lithistid sponge callipelta sp.,

collected off the east coast of New Caledonia.¹It was found to

inhibit the proliferation of NSCLC-L6 human bronchopulmo-

nary nonsmall-cell lung carcinoma (11.26 µg mL^-1) and P388

(15.26 µg mL^-1) cells in vitro.^1aResults indicate this activity

to be cell-cycle dependent, blocking proliferation in the G1

phase, highlighting callipeltoside A as a putative, mechanism-

based lead. Unfortunately, the isolation process is extremely

low yielding, and only 3.5 mg of callipeltoside A was obtained

and consumed since. This initial isolation led to the determi-

nation of its structure by extensive NMR spectroscopy studies

and to the initial report of its biological activity. To study this

fascinating new macrolide and its biological properties, an

efficient synthesis is required. Furthermore, there are several

unresolved stereochemical issues: (1) the relative stereochemical

relationship of callipeltose to the macrolactone rests only on

two nuclear Overhauser effects (nOe’s), (2) the relative con-

(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis, C.

J. Am. Chem. Soc. 1996, 118, 11085. (b) Zampella, A.; D’Auria, M. V.;

Minale, L. Tetrahedron 1997, 53, 3243.

(2) For synthetic work towards callipeltoside aglycon, see: (a) Hoye, T. R.;

Zhao, H. Org. Lett. 1999, 1, 169. (b) Velazquez, F.; Olivo, H. V. Org.

Lett. 2000, 2, 1931. (c) Paterson, I.; Davies, R. D. M.; Marquez, M. Angew.

Chem., Int. Ed. 2001, 40, 603. For synthetic work toward the side chain,

see: (d) Olivo, H. F.; Velazquez, F.; Trevisan, H. C. Org. Lett. 2000, 2,

4055. (e) Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503. For synthetic

work toward callipeltose, see: (f) Smith, G. R.; Finley, J. J., IV; Giuliano,

R. M. Carbohydr. Res. 1998, 308, 223. (g) Gurjar, M. K.; Reddy, R.

Carbohydr. Lett. 1998, 3, 169. (h) Pihko, A. J.; Nicolaou, K. C.; Koskinen,

A. M. P. Tetrahedron: Asymmetry 2001, 12, 937. (i) Evans, D. A.; Hu, E.;

Tedrow, J. S. Org. Lett. 2001, 3, 3133. After submission of this paper, an

elegant total synthesis of callipeltoside A appeared: Evans, D. A.; Hu, E.;

Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654.

(3) Trost, B. M.; Gunzner, J. L. J. Am. Chem. Soc. 2001, 123, 9449.

(4) Trost, B. M.; Dirat, O.; Gunzner, J. L. Angew. Chem., Int. Ed. 2002, 41,

841.

* To whom correspondence should be addressed. E-mail: bmtrost@

stanford.edu.

9

10396

J. AM. CHEM. SOC. 2002, 124, 10396-10415

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Figure 1. Retrosynthetic analysis of callipeltoside A (1).

Therefore we chose L-rhamnose as starting material for the sugar

synthesis. We also evolved a strategy that could provide either

enantiomer with equal facility. To the extent that the nOe

correlation between the carbohydrate and the macrolactone in

the original structural determination is valid, the absolute

configuration of the macrolactone then is also indicated.

Synthesis of the C-7 to C-11 Fragment

Scheme 1 begins the journey with the synthesis of the C-7

to C-11 fragment starting with the commercially available

methyl (S)-3-hydroxy-2-methyl propionate (7), which is pro-

tected as its tert-butyldimethylsilyl ether 8. Various conditions

were screened for the formation of the Weinreb amide 9.

Aluminum reagents gave moderate yields on the tert-butyl-

diphenylsilyl ether analogue of 8 (Me₃Al, PhMe, 80 °C, or

Me₂AlCl, PhMe, room temperature, 65% yield), and poor yields

on 8 itself. A solution was found by using the method developed

by Merck (iPrMgCl, tetrahydrofuran (THF), -20 °C) which

gave the desired amide 9 in 99% yield after 15 min.⁶Formation

of the propynyl ketone 10 occurred smoothly by treatment of

the Weinreb amide 9 with 1-propynylmagnesium bromide at 0

°C. The resulting ketone needs to be selectively reduced to

afford the desired threo alcohol 11. Unfortunately, diastereo-

selective reduction of 10 with the achiral reducing agent

DIBAL-H proved disappointing with threo/erythro ratios rang-

ing from 0.7/1.0 (butylated hydroxytoluene (BHT), THF, -78

°C) to 1.4/1.0 (PhMe, -78 °C).⁷Using 2-methyl-(S)-CBS-

Figure 2. Structure of auriside B.

these syntheses as well as a second generation total synthesis

of these molecules.

Figure 1 illustrates a simplification of the synthetic target to

three building blocks: the macrolactone 3, the side chain 4,

and the sugar 5. The two bond disconnections depicted facilitate

the synthesis of the core 3. The stereocenter at C-13 is

envisioned to derive from a palladium catalyzed asymmetric

allylic alkylation and that at C-9 by a diastereoselective

reduction. The stereocenters at C-5, C-6, and C-7 were

conceived to derive from diastereoselective aldol type processes.

The coupling of the core with the side chain is thought to be

made either by a Wittig type reaction or by an olefin cross-

metathesis. The macrolactonization is envisioned to derive from

a thermal conversion of a dioxolenone to an acylketene as the

reactive acylating agent. The stereocenters at C-20 and C-21

are envisioned to derive from 6 by conversion of one of the

carboxylic acids to a chloride.

(5) Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1996, 61, 8956.

(6) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-

H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.

(7) The stereochemistry was assigned on the basis of ¹H NMR coupling

constants in correlation with those reported in: Williams, D. R.; Kissel,

W. S. Total Synthesis of (+)-Amphidinolide J. J. Am. Chem. Soc. 1998,

120, 11198. These are reported for

Our choice for the absolute configuration of the macrolactone

that we synthesized has been dictated by analogy with a struc-

turally similar molecule, auriside B (Figure 2). The absolute

configuration of this marine macrolide has been determined by

degradation studies, and its sugar moiety matches L-rhamnose.⁵

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J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10397

A R T I C L E S

Trost et al.

Scheme 1. ^aSynthesis of C-7 Alkyne

^aReagents and conditions: (i) TBDMSCl, imidazole, CH₂Cl₂, room temperature, 2 h, 99%; (ii) MeNHOMe‚HCl, i-PrMgCl, THF, -20 °C, 15 min, 99%;

(iii) 1-propynylmagnesium bromide, THF, 0 °C, 2 h, 89%; (iv) 2-methyl (S)-CBS-oxazaborolidine, BH₃‚SMe₂, THF, -30 °C, 1 h, 10/1 dr, 99%; (v) MeI,

Ag₂O, Et₂O, room temperature, 4 h, 92%.

Scheme 2. Ruthenium-catalyzed Alder-ene Reaction

plained by the coordination of the propargylic methyl ether in

ruthenacycle B (Scheme 3), and/or the inductive effect of the

homoallylic oxygen which might speed up the â-hydride

elimination step, thereby decreasing the equilibration of the

oxidative addition step.

With allyl carbonate 17 in hand, the palladium catalyzed

asymmetric allylic alkylation was explored using p-methoxy-

phenol as the nucleophile (eq 1). The use of a chiral ligand

was anticipated to control the regio- and the diastereoselectivity

to set the C-13 stereocenter.¹⁰To this end, ligands 18-23

(Figure 3) have been screened (Table 1).¹¹The best result was

obtained using the (R,R)-diphenyl ligand 19 with 100% conver-

sion, 3/1 branched to linear regioselectivity and 19/1 diastere-

omeric ratio (dr). THF and acetonitrile were unsuccessfully tried

as solvents, and lowering the temperature to 0 °C stopped the

reaction. Previous examples which used (R,R) ligands with a

substrate similar to 17 gave (R)-stereochemistry at the newly

generated stereocenter. However, when we checked the absolute

configuration of C-13 using the O-methylmandelate method at

a later stage molecule of the synthesis, we found that the (S)-

diastereomer was formed, opposite to what was expected

(Scheme 4).¹²

The mechanism of this reaction is depicted in Scheme 5.

Coordination of the olefin leads to ionization of the carbonate

and formation of a π-allylpalladium intermediate which under-

goes diastereofacial exchange. The addition of chloride ion

(nBu₄NCl) speeds up the equilibration by coordination to the

palladium, thereby allowing the coordination of the allyl

substrate to switch from η³to η¹. The σ-bond formation at the

oxazaborolidine, the reduction was nearly quantitative along with

a 10/1 ratio using 2 equiv of the chiral reagent, but the selectivity

eroded to 5/1 when a substoichiometric amount (35 mol %)

was used.⁸A methylation using silver oxide and methyl iodide

completes the C-7 to C-11 fragment synthesis. This synthesis

is very efficient and has been carried out on multigram

quantities.

Synthesis of the Callipeltoside Core

The extension of the C-7 to C-11 fragment requires the

stereoselective formation of the trisubstituted double bond,

which is sought to be achieved by a regioselective ruthenium

catalyzed Alder-ene reaction.⁹To our delight, all the reactions

carried out were completely regioselective, affording only the

linear product (Scheme 2). When the reactions were carried out

using the free homoallylic alcohol 15, better results were

obtained with the substrate bearing the more robust protecting

group (compare entries A and B). However, we were gratified

to find that using lower catalyst loading (5 mol % instead of

10) and shorter reaction times (30 min instead of 2 h), 14 could

react with the homoallylic carbonate 16 to give exclusively the

linear product in 85% yield. This reaction is one of few

examples of a ruthenium catalyzed Alder-ene with exclusive

linear selectivity.^9aThis exceptional selectivity could be ex-

(10) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.

(11) For recent reviews on the palladium catalyzed asymmetric allylic alkylation

(AAA) reactions using the Trost ligands, see: (a) Trost, B. M. Bull. Chem.

Pharm. 2002, 50, 1. (b) Trost, B. M.; Lee. C. B. In Catalytic Asymmetric

Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 593-

651.

(8) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.

(9) (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101,

2067. (b) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739.

(12) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J.

M. J. Org. Chem. 1986, 51, 2370.

9

10398 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Scheme 3. Proposed Mechanism of the Ruthenium-Catalyzed Alder-ene Reaction

secondary π-allyl position permits syn to anti-π-allyl intercon-

version. Only once the palladium is bound to the substrate with

a σ-bond at the primary position can it readily undergo

diastereofacial exchange.¹³Due to the chirality of the ligand,

one of these two intermediates is more stable and has an open

space for the nucleophile to enter for attack upon the π-allyl

moiety. One possible explanation for this reverse selectivity is

that the substituted end of the π-allyl is much larger than the

previously reported substrates. This additional steric bulk in the

substrate might cause the reactive π-allyl to switch from the

syn to the anti form. If the anti-π-allyl is the one being attacked,

the opposite configuration at C-13 will be obtained. Alterna-

tively, the trisubstituted olefin could also be coordinating to the

palladium causing the unexpected reversal in selectivity. After

the nucleophilic attack, decomplexation of the palladium occurs

to release the product and regenerate the catalyst.

This reverse selectivity is, however, inconsequential for our

synthesis since a simple switch of the configuration of the ligand

(ent-19) allows us to obtain the desired diastereoisomer 28 with

20/1 dr and a somewhat reduced branched to linear 2/1

regioselectivity from which the desired diastereomer was

isolated in 51% yield (see Scheme 6).¹⁴The synthesis of the

core was then completed. The silyl ether in 28 was cleanly

removed by treatment with tetrabutylammonium flouride (TBAF)

(96% yield), and the resulting alcohol 29 was oxidized to

aldehyde 30 with the use of Dess-Martin periodinane (84%

yield). The kinetically formed E lithium enolate of tert-butyl

thiopropionate adds to aldehyde 30 to provide the Cram type

addition product 31 with 5/1 diastereoselectivity in 82%

yield.^15,16Aldol product 31 was protected as the tert-butyldi-

methylsilyl ether 33 and the thioester was selectively reduced

to aldehyde 34 through the use of DIBAL-H. Felkin-Ahn type

addition to aldehyde 34 of the dienyl silyl ether 35¹⁷produced

a single diastereoisomer 36 in 94% yield. To suppress any

dehydration, a hindered base (2,6-di-tert-butylpyridine) had to

be used in the protection step. The silyl ether 37 formed was

then subjected to CAN to liberate the C-13 hydroxyl group for

the macrolactonization. The macrocyclization was performed

using Boeckman’s method which involves the thermolysis of

the dioxolenone functionality through a retro-hetero-Diels-

Alder reaction, thus generating a ketene intermediate which is

intramolecularly trapped by a hydroxyl group to form a 14-

membered macrolide 39.¹⁸This process proceeded smoothly

(14) Compound 17 and ligand 19 are a diastereomeric matched pair, whereas

17 and ent-19 are a mismatched pair giving rise to a lower regioselectivity.

(15) For similar aldol reactions with ethyl thiopropiolate, see: (a) Chamberlin,

A. R.; Dezube, M.; Reich, S. H.; Sall, D. J. J. Am. Chem. Soc. 1989, 111,

6247. (b) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29, 2219.

(c) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T. Tetrahedron

Lett. 1988, 29, 6449.

(16) To determine the stereochemistry of one of the newly formed stereocenters,

aldol product 31 was subjected to an ozonolysis cleavage to afford lactol

32 in 56% yield. After assigning each proton through a COSY spectrum

followed by acquisition of nOe data on lactol 32, it was clear that the newly

formed hydroxyl group (tied up as the ring oxygen on 32) had the desired

stereochemistry due to the 8.8% nOe across the ring.

(17) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.; Parlow, J.;

Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J. E. J. Org.

Chem. 1991, 56, 91.

(13) When the reaction is carried out, all conditions are equal, but with no

chloride ion source, the regioselectivity drops from 3/1 to 1.5/1.

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J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10399

A R T I C L E S

Trost et al.

we synthesized the other C-13 diastereoisomer 40 of the

callipeltoside core. The epimeric 24 (i.e. 28) derives from the

Pd AAA reaction using ligand 19 (cf. eq 1). Following the same

route as outlined for macrolactone 3 then provided the epimeric

one 40 (eq 2). The NMR data show clearly a better match

between the diastereoisomer 3 and the natural sample of

callipeltoside A than the other diastereoisomer 40.²⁰We also

checked the stereochemistry of the two aldol condensations by

NMR spectroscopy. For macrolactone 40, a 10.5 Hz coupling

constant was found for H-5 to H-6 and H-6 to H-7, which is

indicative of an axial-axial relationship between two protons

in a six membered ring. These data together with the 6% nOe

observed between H-5 and H-7 establish the diastereoselectivity

of the aldol reaction and the correctness of the relative and

absolute configuration of both 3 and 40.

Synthesis of the Callipeltoside Aglycon

Our first synthetic plan used a Wittig type olefination to attach

the side chain to the macrolactone. To test this strategy, we

first synthesized a deschloro side chain. Scheme 7 shows the

straightforward synthesis of phosphonate 45 in five steps from

propargyl alcohol and 1-alkynylcyclopropane. The timing for

installation of the side chain was dictated by the nature of the

two step oxidative cleavage of the terminal alkene and the

Emmons-Wadsworth-Horner reaction. Best results for the

oxidative cleavage were obtained by performing this transfor-

mation at the stage of the macrolide 39 using a sequential

dihydroxylation followed by a periodate cleavage of the diol to

form aldehyde 46.²¹Sodium and potassium 1,1,1,3,3,3-hexam-

ethyldisilylamide (HMDS) used as a base in the Emmons-

Wadsworth-Horner reaction between phosphonate 45 and

aldehyde 46 led to no E/Z selectivity and poor yields. Best

results were obtained with LiHMDS in THF with a temperature

gradient between -78 °C and room temperature over 3 h (40%

yield, 4/1 E/Z ratio). The deschlorocallipeltoside aglycon 48 is

obtained after deprotection using HF-pyridine in methanol,

followed by a transketalization with pyridinium p-toluene-

sulfonate (PPTS) in wet acetonitrile. The deschlorocallipeltoside

aglycon 48 is obtained in 60% yield over two steps (Scheme 8)

Figure 3. Chiral ligands screened for the palladium-catalyzed asymmetric

allylic alkylation reaction.

Table 1. Palladium-Catalyzed Asymmetric Allylic Alkylation

Reaction

entry

ligand

conversion (%)

2°/1°

A

B

C

D

E

F

18

19

20

21

22

23

100

26

0

1.6/1

3/1

0.5/1

0/1

na

0

(82% yield) at high dilution in vigorously refluxing freshly

distilled toluene.¹⁹The macrolactone 39 was then transformed

into the callipeltoside core 3 by removal of the silyl protecting

groups by using HF-pyridine in methanol, followed by treat-

ment with PPTS in wet acetonitrile to remove the methyl ketal

(91% yield over two steps).

At this stage, we wanted to make sure that the stereochemistry

at the C-13 stereocenter was correctly assigned, and, to this end,

(18) (a) Boeckman, R. K., Jr.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111, 8286.

(b) Chen, C.; Quinn, E. K.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem.

1993, 58, 5011.

(19) When the reaction is carried out at 100 °C, no macrolide is obtained, but

instead a mixture of dimer and uncyclized methyl ketone.

(20) Please see Supporting Information for the ¹H NMR spectra of 3 and 40.

(21) If too much osmium tetroxide is used or the reaction is carried out for

more than 7 h, a significant amount of double dihydroxylation is observed.

9

10400 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Scheme 4^a

^aReagents and conditions: (i) TBAF, THF, room temperature, 12 h, 91%; (ii) Dess-Martin periodinane, NaHCO₃, CH₂Cl₂, 0 °C, 5 h, 86%; (iii) tert-

butylthiopropionate, LDA, THF, -108 °C, 3 h, 5/1 dr, 85%; (iv) TBDMSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 1 h, 85%; (v) CAN, MeCN, H₂O, 0 °C, 10 min,

69%; (vi) DCC, DMAP, CH₂Cl₂, room temperature, 12 h, 99%.

Scheme 5. Proposed Mechanism of the Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction

We then tried to improve the olefination step using the

deschlorocyclopropyl side chain and a simple model aldehyde

bearing a â-ketoester (see eq 3 and Table 2).²²The methyl

phosphonate 45 gives an excellent yield with this model

aldehyde 52 and about the same E/Z selectivity as with the real

aldehyde 46. The more bulky isopropyl phosphonate 49 is very

selective but not reactive enough. The arsonium ylide gave a

good selectivity but mediocre yield.²³The trimethyl phospho-

nium ylide gave excellent yields and very poor selectivity with

the four lithiated bases we tried.²⁴However, we thought that a

very reactive ylide could be beneficial in our system which

suffers from both poor yield and average selectivity. We there-

fore tried to favor the required equilibration at the transition

state to obtain the thermodynamically favored E isomer by em-

(22) Please see Experimental Section and Supporting Information for the

preparation of 49-51 and aldehyde 52.

(23) His, J. D.; Koreeda, M. J. Org. Chem. 1989, 54, 3229.

(24) Waterson, A. G.; Kruger, A. W. Meyers, A. I. Tetrahedron Lett. 2001, 42,

4305.

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A R T I C L E S

Trost et al.

Scheme 6. ^aSynthesis of the Macrolactone Core

^aReagents and conditions: (i) p-methoxyphenol, ent-19 (7.5 mol %), Pd₂dba₃‚CHCl₃(2.5 mol %), tetrabutylammonium chloride, CH₂Cl₂, room temperature,

20 h, 20/1 dr, 2/1 regioselectivity (2°/1°), 79%; (ii) TBAF, THF, room temperature, 12 h, 96%; (iii) Dess-Martin periodinane, NaHCO₃, CH₂Cl₂, 0 °C, 5

h, 84%; (iv) tert-butylthiopropionate, LDA, THF, -108 °C, 3 h, 5/1 dr, 82%; (v) TBDMSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 2 h, 86%; (vi) DIBAL-H, toluene,

-78 °C, 3 h, 79%; (vii) BF₃‚OEt₂, CH₂Cl₂, -78 °C, 45 min, 94%; (viii) TBDMSOTf, 2,6-di-tert-butylpyridine, CH₂Cl₂, 0 °C, 1 h, 95%; (ix) CAN, acetone/

H₂O (4/1), 0 °C, 5 min, 82%; (x) 0.5 mM in toluene, 110 °C, 1 h, 82%; (xi) HF‚pyridine, MeOH, 0 °C, 5 h; (xii) PPTS, MeCN, H₂O, room temperature,

3 h, 91% (2 steps).

Scheme 7. ^aSynthesis of Olefination Agent for Deschlorocallipeltoside A

^aReagents and conditions: (i) n-BuLi, I₂, THF, 0 °C, 2 h, 80%; (ii) CuI, pyrrolidine, THF, 0 °C to room temperature, 2 h, 38%; (iii) Red-Al, THF, 0 °C,

1 h, 96%; (iv) PPh₃, CBr₄, CH₂Cl₂, -40 °C, 1 h, 95%; (v) P(OMe)₃, 100 °C, 6 h, 97%.

ploying some additives. All the reactions carried out were nearly

quantitative. Alkoxides have no effect on the selectivity, but

addition of HMPA (optimum 6 equiv) gives rise to a satisfactory

10/1 E/Z ratio using n-butyllithium as the preferred base. This

ratio can be further improved by replacing THF by 1,2-dimeth-

oxyethane (DME), but this combination seemed too risky to

try on our sensitive aldehyde. With these new conditions in hand,

we carried out the synthesis of the optically active side chain.

To be able to assign unambiguously the relative configuration

of the trans-chlorocyclopropane with regard to the macrolactone,

both enantiomers of the side chain had to be synthesized and

attached to the macrolactone. Indeed, the isolation of the

chlorocyclopropane from the rest of the stereocenters provides

no detectable bias by NMR spectroscopy, as shown by the

synthesis of two diastereoisomers of the callipeltoside aglycon

by Paterson et al.^2cWe therefore performed the synthesis of

the side chain for both enantiomers, which starts from the

commercially available dimenthyl succinate 54²⁵to form known

cyclopropane 55 (see Scheme 9).²⁶The diastereomeric ratio is

greater than 99/1 when 0.5 equiv of electrophile are used;

(25) $3.1/mmol for both enantiomers (Aldrich), but easily accessible from the

inexpensive menthol and succinyl chloride.

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Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Scheme 8. ^aAttachment of Side Chain for Deschlorocallipeltoside A via Olefination Protocol

^aReagents and conditions: (i) OsO₄, NMO, THF/H₂O (4/1), 0 °C, 4 h; (ii) NaIO₄, THF/H₂O, room temperature, 3 h, 80% (2 steps); (iii) 45, LiHMDS,

THF, -78 °C, 3 h, 4/1 (E/Z), 40%; (iv) HF‚pyridine, MeOH, 0 °C, 2 h; (v) PPTS, MeCN, H₂O, room temperature, 3 h, 60% (2 steps).

Table 2. New E Selective Olefination Conditions for Unbiased

Substrates

embarked on a careful study of this reaction. To this end, we

prepared in a separate step the Barton ester 59 starting from

entry

X

base

additive

yield (%)

E/Z

the acid 56 using tributyl phosphine and 2,2′-dithiobis(pyridine-

N-oxide) (eq 4).³¹This esterification is essentially quantitative;

however, the Barton ester 59 is very sensitive to any purification

technique and was isolated pure in 48% yield. The direct radical

chain reaction of the pure Barton ester 59 yielded the chloro-

cyclopropane 58 in a disappointing 62% yield at c ) 0.02 M

after 6 h at reflux (eq 5). The reaction time can be reduced to

45 min with no loss in the yield by adding a radical initiator (5

mol % azobis(isobutyronitrile) (AIBN)), but the concentration

cannot be increased, as no product was detected at c ) 0.2 M.

To our surprise, when the crude esterification mixture was just

evaporated in vacuo and subjected to the radical reaction, no

product was detected. With those results in hand, we optimized

the two step, one pot process starting from acid chloride 57.

The best conditions were mixing the acid chloride 57, the

Barton salt, DMAP (20 mol %), and a phase-transfer catalyst

(nBu₄NI, 20 mol %) in carbon tetrachloride (0.02 M), and

stirring that mixture in the absence of light at room temperature

for 1 h. Thin-layer chromatography shows very clean formation

of the Barton ester 59. A radical initiator (AIBN, 5 mol %) is

then added, and the mixture is heated at reflux in the presence

of light for 5 h. This procedure allowed the obtention of desired

chlorocyclopropane 58 in a reproducible 60% yield on scales

up to 10 mmol with 33/1 diastereomeric ratio (eq 6). This

reaction can be performed in 10 min (instead of 6 h) under

microwave irradiation (150 °C) in 52% yield but needs to be

performed under the same dilute conditions (0.02 M), therefore

limiting the scale of each batch.³²

A

B

C

D

E

F

G

H

I

P(O)(OMe)₂LiHMDS

P(O)(OiPr)₂LiHMDS

100

15

31

4.7/1

19/1

6.5/1

2.5/1

2.2/1

2.7/1

2.5/1

2.8/1

5.3/1

10/1

9/1

BF₄AsPh₃

BrPMe₃

KHMDS

nBuLi

secBuLi

LiTMP

LiHMDS

LiHMDS H₂O

nBuLi

100

3 equiv of HMPA

6 equiv of HMPA

10 equiv of HMPA

J

K

however, this leads to a lot of unreacted starting material which

is difficult to remove from the product by column chromatog-

raphy. The dr is lowered to 12/1 if 1 equiv of electrophile is

used, but is easily amplified to 99/1 by a single recrystallization

in methanol.²⁷This stoichiometry reduces the amount of

unreacted starting material and therefore is preferred on large

scale. One of the menthyl esters was transformed into the known

acid chloride 57 in excellent yield using a literature procedure.²⁸

To place the chloride atom onto the cyclopropane, we first

envisioned a palladium mediated decarbonylation of 57. This

reaction would proceeded by insertion of the palladium into

the carbon-chloride bond, migration of CO, elimination of CO,

and reductive elimination. This process has some literature

precedents, but all our attempts using various palladium sources,

ligands, additives, and solvents remained unsuccessful.²⁹

Acid chloride 57 was successfully transformed into chloride

58 using the Barton-Crich-Motherwell decarboxylation in

carbon tetrachloride.³⁰We first applied the original conditions

for this reaction (2-mercaptopyridine-1-oxide sodium salt,

DMAP, in refluxing carbon tetrachloride), and obtained unre-

produceable yields ranging from 32 to 74%. We therefore

As shown in Scheme 10, chloride 58 was converted in three

steps into known dibromoolefin 62 via Weinreb amide 60 in

excellent yield.³³We used a Weinreb amide because it allowed

an easy separation of the menthol and has no volatility issue.³⁴

The dibromoolefin 62 has been synthesized in seven steps from

commercially available starting materials and reagents in 38%

overall yield. By using the enantiomeric starting succinate ester,

(26) Misumi, A.; Iwanaga, K.; Furuta, K. Yamamoto, H. J. Am. Chem. Soc.

1985, 107, 3343.

(27) Furuta, K.; Iwanga, K.; Yamamoto, H. Org. Synth. 1988, 67, 76.

(28) Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Kennedy, J. H.; Wright, R.

A.; Johnson, B. G.; Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp,

D. D.; Herin, M. J. Med. Chem. 1998, 41, 358.

(29) (a) Verbicky, J. W., Jr.; Dellacoletta, B. A.; Williams, L. Tetrahedron Lett.

1982, 23, 371. (b) Hori, K.; Ando, M.; Takaishi, N.; Inamoto, Y.

Tetrahedron Lett. 1986, 27, 4615.

(30) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983,

24, 4979.

(31) (a) Barton, D. H. R.; Chen, C.; Wall, G. M. Tetrahedron 1991, 47, 6127.

(b) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083.

(32) Microwave heating was carried out in a Smith Workstation US manufac-

tured by Personal Chemistry AB.

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10403

A R T I C L E S

Trost et al.

Scheme 9. ^aAsymmetric Synthesis of Chlorocyclopropane

^aReagents and conditions: (i) LiTMP, BrCH₂Cl, THF, -78 °C, 4 h, 99/1 dr, 87%; (ii) NaOH (5 M), iPrOH, 70 °C, 12 h, 92%; (iii) SOCl₂, room

temperature, 12 h, 97%.

ent-62 was obtained in similar yield. We then used the Stille

in 66% yield.³⁶Enyne 63 is easily transformed into phosphonate

65 via the corresponding bromide 64 in good yield. For

unknown reasons, we were not able to synthesize the corre-

sponding trimethyl phosphine salt from bromide 64.³⁷The side

chain 65 was synthesized over 10 linear steps from the

commercially available dimenthyl succinate 54 in an overall

yield of 20%.

As depicted in Scheme 11, the side chain 65 was coupled to

the aldehyde 46 using an Emmons-Wadsworth-Horner reac-

tion and proceeded in similar yield and selectivity as that with

the deschloro side chain 45 (52% yield, 4/1 E/Z). The callipel-

toside aglycon 67 was obtained in 96% yield after deprotection

with HF-pyridine in methanol.³⁸With the synthesis of one of

the diastereoisomers of the callipeltoside aglycon achieved, we

focused on finding a better reaction for the coupling of the side

chain to the macrolactone. Our route to the macrolactone 39

generates a terminal olefin. We therefore sought to use an olefin

cross-coupling metathesis reaction to shorten the synthesis.

Scheme 12 outlines our efforts toward this goal. No cross-

metathesis attempted between 39 and a terminal alkene pro-

ceeded using the first generation of Grubbs’ catalyst. While no

diene, dienyne, vinylborane, or vinyl silane worked, we were

delighted to achieve very clean cross-metathesis using styrene

(50% yield) or crotonaldehyde³⁹with the second generation of

Grubbs’ catalyst.⁴⁰R,â-Unsaturated aldehyde 68 obtained after

cross-metathesis has not been isolated, but in order to have an

estimate of the yield of the reaction, it was trapped by

(carbethoxymethylene)triphenylphosphorane to give a stable

R,â,γ,δ-unsaturated 69a ester in nearly quantitative yield. The

cross-metathesis reaction between 39 and crotonaldehyde is

therefore nearly quantitative. Surprisingly, this reaction does

not proceed in benzene at 60 °C. To couple the side chain, we

developed a one pot cross-metathesis-Takai olefination to

afford vinyl iodide 69b.⁴¹This one pot procedure yielded 69b

in 40% yield with a 7/1 E/Z ratio in straight THF as the Takai

conditions developed by Shen³⁵and used by Olivo^2dfor this

exact reaction to produce known enyne 63 and its enantiomer

(36) All the spectroscopic data with the exception of the rotation of 63/ent-63

are identical to the reported values.^2eRotation of 63, [R]_D) -222.7 (c

26

) 0.70, CH₂Cl₂); rotation of ent-63, [R]_D²⁶) + 225.5 (c ) 0.70, CH₂Cl₂);

lit. value,^2e[R]_D) -78.9 (c ) 0.705, CH₂Cl₂).

25

(33) All the spectroscopic data as well as the rotation of 62/ent-62 are iden-

tical to the reported values.^2eRotation of 62, [R]_D) -80.3 (c ) 0.77,

27

(37) To exclude any phosphine poisoning in that attempted transformation,

bromide 64 was also synthesized by displacing the mesylated analogue of

63 by lithium bromide.

CH₂Cl₂); rotation of ent-62, [R]_D²⁷) + 80.1 (c ) 1.40, CH₂Cl₂); lit. value,^2e

25

[R]_D) -80.5 (c ) 0.71, CH₂Cl₂).

(38) The transketalization (PPTS, MeCN, H₂O) used in the synthesis of 3, 40,

and 48 was not necessary upon modification of the workup conditions,

that is, adding a solution of sodium bicarbonate to the reaction mixture

instead of adding the reaction mixture to a solution of sodium carbonate.

This modification cannot be used for the synthesis 3 and 40 because the

C-5 hydroxyl is susceptible to deshydration in these substrates.

(39) Crotonaldehyde was preferred to acrolein for purity reasons.

(40) For the first report of the second generation catalyst, see: (a) Scholl, M.;

Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. For selected

reports of cross-metathesis, see: (b) Chatterjee, A. K.; Grubbs, R. H. Org.

Lett. 1999, 1, 1751. (c) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J.

Organomet. Chem. 2001, 624, 327.

(34) Menthyl bromide and dibromoolefin 62 are very difficult to separate.

(35) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. The mechanism of this

direct coupling of the dibromide to an enyne is quite intriguing. An

alternative mechanism from that proposed is illustrated as follows:

(41) The cross-metathesis reaction is performed in refluxing dichloromethane

for 3 h using 10 mol % of the Grubbs’ second generation catalyst. The

solvent as well as the excess of crotonaldehyde are then removed by

evaporation in vacuo. The Takai olefination is then carried out on the black

crude residue for 3 h at 0 °C.

9

10404 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Scheme 10. ^aSynthesis of Olefination Agent for Callipeltoside A

^aReagents and conditions: (i.) MeNHOMe‚HCl, iPrMgCl, THF, -20 °C, 1 h, 99%; (ii) DIBAL-H, CH₂Cl₂, -78 °C, 3 h; (iii) PPh₃, CBr₄, CH₂Cl₂, 0 °C,

4 h, 80% (2 steps); (iv) Pd₂dba₃‚CHCl₃, tris(4-methoxyphenyl)phosphine, DIPEA, DMF, 80 °C, 12 h, 66%; (v) PPh₃, CBr₄, CH₂Cl₂, -40 °C, 1 h, 90%; (vi)

P(OEt)₃, 100 °C, 4 h, 93%.

Scheme 11. ^aSynthesis of Callipeltoside A Aglycone via Olefination Protocol

^aReagents and conditions: (i) 65, LiHMDS, THF, -78 °C, 3 h, 4/1 (E/Z), 52%; (ii) HF‚pyridine, MeOH, 0 °C, 5 h, 96%.

Scheme 12. ^aAttachment of Side Chain A via Olefination Metathesis-Deschlorocallipeltoside A Aglycone

^aReagents and conditions: (i) crotonaldehyde, Grubb’s II catalyst, CH₂Cl₂, 40 °C, 4 h; then CrCl₂, CHI₃, dioxane/THF (4/1), 0 °C, 3 h, 10/1 (E/Z), 40%;

(ii) 1-alkynylcyclopropane, Cl₂Pd(PhCN)₂, PPh₃, CuI, DIPA, THF, -20 °C to room temperature, 1 h, 70%.

reaction solvent.⁴²This ratio can be improved to 10/1 by use

of a 4/1 mixture of dioxane/THF as the solvent.⁴³We achieved

a formal synthesis of the deschlorocallipeltoside aglycon 48 by

synthesizing its direct precursor 47 by a Sonogashira coupling

with 1-alkynylcyclopropane (70% yield).⁴⁴This three step, two

pot sequence shortens by five steps the previous synthesis of

the deschlorocallipeltoside aglycon 48 using the Emmons-

Wadsworth-Horner approach and is much more stereoselective

and efficient.

However, we were still not satisfied with the yield of the

one pot cross-metathesis-Takai olefination process. We an-

ticipated chemoselectivity issues associated with the â-ketoester

moiety induced by the chromium species present in the Takai

reaction. Accordingly, as illustrated in Scheme 13, this process

was performed on the bicyclic macrolide 3, and we were

rewarded with an excellent 84% yield along with 8/1 E/Z ratio.

Paterson et al. achieved a very efficient Sonogashira coupling

to form the callipeltoside aglycon on a protected version of 70.^2c

(42) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.

(43) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115, 11446.

(44) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119,

12159.

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10405

A R T I C L E S

Trost et al.

Scheme 13. ^aAttachment of Side Chain via Olefin Metathesis-20,21-Diepicallipeltoside A Aglycone

^aReagents and conditions: (i) crotonaldehyde, Grubb’s II catalyst, CH₂Cl₂, 40 °C, 5 h; then CrCl₂, CHI₃, dioxane/THF (4/1), 0 °C, 3 h, 8/1 (E/Z), 84%;

9ii) nBuLi, Me₃SnCl, Et₂O, -78 °C to room temperature, 1 h; then 70, Cl₂Pd(MeCN)₂, DMF, room temperature, 45 min, 70%.

Scheme 14. ^aSynthesis of Callipeltoside Glycosylating Agent

^aReagents and conditions: (i) ref 2f; (ii) TBDMSOTf, 2,6-lutidine, CH₂Cl₂, room temperature, 2 h, 55%; (iii) MeI, Ag₂O, DMF, room temperature, 12

h, 69%; (iv) H₂SO₄, PPTS, Ac₂O, room temperature, 2 h, 81%; (v) K₂CO₃, MeOH, room temperature, 5 min, 89%; (vi) Cl₃CCN, NaH, CH₂Cl₂, room

temperature, 10 min, 86%.

However, volatility and isolation problems for the alkynylchlo-

rocyclopropane used in this reaction are reported by Olivo and

Paterson.^2c,dSince we wanted to achieve a practical synthesis

of callipeltoside A, we decided to stay away from this compound

and developed a one pot procedure from the dibromoolefin ent-

62 to perform a Stille coupling with vinyl iodide 70. Indeed,

the byproducts of the elimination reaction used to form the

alkynyl stanane 71 from ent-62 are LiBr, LiCl, n-butyl bromide,

and butane, none of which in principle is harmful to the Stille

coupling reaction. After screening several palladium sources

(Pd₂dba₃‚CHCl₃, (PhCN)₂PdCl₂, and (MeCN)₂PdCl₂), ligands

(AsPh₃, PPh₃), and solvents (dimethylformamide (DMF), THF,

AcOEt, and NMP), we developed a one pot process using the

ligandless conditions for the Stille coupling ((MeCN)₂PdCl₂in

DMF) and the one pot sequence of formation of the stannane-

Stille coupling to afford a second diastereoisomer of the

callipeltoside aglycon 72 in 70% yield.^45,46Indeed, the ligandless

conditions gave exclusively the desired product; whereas, other

conditions gave significant amounts of reduced vinyl iodide.

As we obtained one diastereoisomer 67 of the callipeltoside A

aglycon using the Emmons-Wadsworth-Horner route, we

synthesized the other diastereoisomer 72 using this one pot

cross-metathesis-Takai olefination, one pot formation of the

alkynyl stanane-Stille coupling route. Comparison of the

analytical data of our synthetic aglycons with those of the

enantiomeric aglycons reported by Paterson et al. shows a

perfect match.^2c,47This new approach for the coupling of the

side chain is shorter, more stereoselective, and more efficient

than the Emmons-Wadsworth-Horner route.

Synthesis of Callipeltose

Scheme 14 outlines the synthesis of the trichloroacetimidate

of the N-silyl derivative of callipeltose 5. The intermediate 73

was synthesized from L-rhamnose as previously reported.^2fIn

our hands, the O-methylation was best accomplished on the

silylated oxazolidin-2-one 74 to give 75. The anomeric position

was freed using a mild two step protocol to yield lactol 76.

The sugar was then transformed into the trichloroacetimidate 5

in preparation for the Schmidt glycosidation conditions.⁴⁸

While this route proved productive and allowed generation

of sufficient amounts to complete the synthesis, we sought a

shorter route that might also provide easy access to either

enantiomer. All the other routes begin with the chiral pool,

typically a carbohydrate^2f-hexcept for the Evans²ⁱapproach

which utilizes threonine. Based upon the Du Bois reaction,⁴⁹

we envisaged the strategy depicted in Scheme 15. The ability

to form the target oxazolidin-2-one by the oxidative cyclization

of the carbamate 78 by the method of Du Bois potentially

simplifies the synthesis to the Danishefsky diene and acetalde-

hyde⁵⁰requiring a diastereoselective epoxidation of glycal 79⁵¹

and methyl anion addition to ketone 80. The diastereoselective

addition of methyllithium or methylmagnesium bromide to

5-methylcyclohexenone in an axial fashion⁵²bodes well for the

requisite diastereoselectivity in this addition to ketone 80.

Asymmetric versions of the hetero-Diels-Alder reaction have

(45) Dibromoolefin ent-62 in diethyl ether is treated with 2 equiv of nBuLi.

The resulting anion is trapped by trimethyltin chloride, and the solvents

are evaporated in vacuo (note: the alkynyl stanane 71 is not very volatile;

therefore no product is lost during this operation). To this residue is added

vinyl iodide 70, (MeCN)₂PdCl₂(three times 10 mol %), and DMF. The

callipeltoside aglycon 72 is obtained after 45 min of reaction at room

temperature.

(48) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731.

(49) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.

(50) For comprehensive reviews for this reaction, see: (a) Danishefsky, S. J.;

De Ninno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15. (b) Jo¨rgensen,

K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.

(46) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138.

(51) This reaction has been used on a different glycal in an expedient synthesis

of D-callipeltose; see ref 2h. Also see: (a) Rainier, J. D.; Allwein, S. P.;

Cox, J. J. Org. Chem. 2001, 66, 1380. (b) Saleh, T.; Rousseau, G. Synlett

1999, 617. (c) Belluci, G.; Catelani, G.; D’Andrea, F. Tetrahedron Lett.

1994, 35, 8433.

(47) See Supporting Information for ¹H and ¹³C NMR spectras of 67 and 72.

23

Rotation of 67, [R]_D) -39.4 (c ) 1.00, CHCl₃), to be compared with

the reported value for ent-67,^2c[R]_D²⁰) + 45.8 (c ) 0.28, CHCl₃). Rotation

of 72, [R]_D²⁵) +125.0 (c ) 1.00, CHCl₃), to be compared with the reported

2c

20

value for ent-72, [R]_D) -97.8 (c ) 0.19, CHCl₃).

(52) House, H. O.; Fischer, W. F., Jr. J. Org. Chem. 1968, 33, 949.

9

10406 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

Scheme 15. Retrosynthetic Analysis of Methyl Callipeltose 77

Scheme 16. ^aSynthesis of Racemic Methyl Callipeltose

^aReagents and conditions: (i.) BF_3;ether, -78 °C, 2h; (ii) CH₃Li, THF, -100 °C, 2 h; (iii) m-CPBA, NaHCO₃, CH₃OH, 0 °C, 2 h; (iv) NaH, CH₃I, THF,

0 °C, 6h; (v) CCl₃CONCO, CH₂Cl₂, room temperature, 1 h and then K₂CO₃, H₂O, CH₃OH, room temperature, 18 h; (vi) see text.

been developed.⁵³In fact, an asymmetric version for the exact

reaction required has already been reported.⁵⁴Thus, this strategy

may provide either enantiomer in a comparatively very short

sequence.

the assigned structure, and the molecule adopting a chair

conformation as depicted. For example, the signal for H-6 shows

a dqd, J ) 11.0, 6.4, 2.7 Hz, which is fully consistent with this

proton being axial and having typical ax-ax and ax-eq

coupling with the adjacent methylene group. The 1.6 Hz

coupling between H-2 and H-3 is consistent with eq-eq

coupling. A significant nOe between the methyl group at C-4

and H-6 confirms both of these groups being axial and supports

the diastereoselectivity assigned for formation of 81.

O-Methylation (to 83b) and carbamate formation (to 78)

proceeded uneventfully. Reaction of the carbamate with 10 mol

% rhodium acetate, 2.3 equiv of diacetoxyiodobenzene, and 1.4

equiv of base in refluxing methylene chloride gave 79-80%

conversion. Using MgO as base then led to a 57% yield of the

target 77 which increased to 63% using 2,6-di-tert-butylpyridine

as base. No significant improvement occurred by switching to

rhodium triphenylacetate as catalyst. In this case, a higher yield

(64%) was obtained with MgO as base compared to 2,6-di-

tert-butylpyridine (54%). Comparison of the spectral data with

those previously reported for methyl callipeltose^2hdemonstrated

their identity. Thus, racemic methyl callipeltose is available in

six steps and 17% overall yield. Since the asymmetric synthesis

of enone 80 is already known, this route is the shortest reported

synthesis to either enantiomer of this sugar moiety.

Scheme 16 summarizes our new route to racemic methyl

callipeltose. The known pyranone 80 was prepared as previously

described.⁵⁵Addition of methylithium at -100 °C gave an 11:1

1

diastereomeric ratio as determined by H NMR spectroscopy

using the signals for the vinyl proton at δ 6.28 (major) vs δ

6.38 (minor). The assignment of the relative stereochemistry

shown for 81 rests on the previously stated analogy and torsional

strain considerations at this point.⁵⁶Support for this assignment

also derives from an nOe study of a subsequent product. The

identity of our final target with that previously reported for

methyl callipeltose^2hultimately confirmed the correctness of this

assignment.

Epoxidation in methanol effected simultaneous solvolysis to

the desired product 83a as a single diastereomer presumably

via the epoxide 82. ¹H NMR spectroscopy is in full accord with

(53) (a) Keck, G. E.; Li, X. Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60,

5998. (b) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,

63, 403. (c) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue,

Y. J. Org. Chem. 1999, 64, 8660. (d) Roberson, M.; Jepsen, A. S.;

Jorgensen, K. A. Tetrahederon 2001, 57, 907. (e) Long, J.; Hu, J.; Shen,

X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002, 124, 10.

(54) Mituda, M.; Hasegawa, J. U.K. Pat. Appl. 1997, 33; Chem. Abstr. 1997,

127, 34124

(55) Danishefsky, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 1597.

(56) Wu, Y. D.; Houk, K. N.; Florez, J.; Trost, B. M. J. Org. Chem. 1991, 56,

3656.

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10407

A R T I C L E S

Trost et al.

Scheme 17. ^aSynthesis of Callipeltoside A, Its C-20, C-21 Epimers, and Deschloro Analogue

^aReagents and conditions: (i.) 5, TMSOTf, dichloroethane, 4 Å MS, -30 °C, 10 min, 73%; (ii) TBAF, AcOH, THF, room temperature, 5 min, 95%.

Table 6. Biological Data

Completion of the Synthesis

entry

compd

IC₅₀(µM)

The total synthesis of deschlorocallipeltoside A (2) and two

diastereoisomers of callipeltoside A 84 and 85 was then

completed after a Schmidt glycosidation using a catalytic amount

of TMSOTf in dichloroethane at -30 °C, followed by a buffered

TBAF deprotection of the only protecting group (see Scheme

17). These reactions proceeded excellently and gave single

A

B

C

D

67

1

78

2

>100

20.2

7.0

17.4

that the sugar is essential for the biological activity and that

the chloride atom is not essential to the biological activity.

1

diastereoisomers 2, 84, and 85 in high yield. The H and ¹³C

NMR spectroscopic data as summarized in Tables 3-5 (pro-

vided in the Supporting Information) show, as expected, no

difference between 84, 85, and the natural sample.⁵⁷The

unambiguous assignment of the absolute and relative configu-

ration comes from the rotation values. Indeed, 84 has a rotation

of [R]_D²²) -19.2 (c ) 1.0, CH₃OH), very close in the absolute

value and the same sign as the natural sample [R]_D) -17.6 (c

) 0.04, CH₃OH), whereas 85 has a rotation of [R]_D²²) +156.3

(c ) 0.55, CH₃OH). This significant difference allows us to

assign the absolute and relative configuration of callipeltoside

A (1) as 84.

Conclusion

The macrolactone part of callipeltoside A, 3, has been

synthesized in 16 linear steps from methyl-3-hydroxy-2-methyl

propionate. The C-13 epi analogue was also readily available

by the same route but just by employing a different catalyst in

the AAA reaction. This route highlights a new synthesis of

geometrically defined trisubstituted alkenes using ruthenium

catalysis and regio- as well as diastereoselective synthesis of

an allyl ether via palladium catalyzed AAA reaction that could

not be easily accomplished otherwise. This route also highlights

the utility of the Boeckman macrocyclization method since the

dioxolenone serves two purposessan efficient diastereoselective

aldol reaction of acetoacetate at the methyl group as the donor

and a convenient source of a reactive acylating agent.

Biological Activity

The cytotoxicity of 1, its diastereoisomer 78, 2, and callipel-

toside A aglycon 67 has been measured using a different cell

line (A2780 human ovarian carcinoma cells after a 48 h

incubation) than the one used by Minale et al. Table 6 shows

Overall, 84 (i.e. 1) was synthesized in 22 steps for the longest

linear sequence (3.8% overall yield) and 46 total steps in 0.05%

overall yield using the olefination protocol for attachment of

(57) See supporting material for ¹H and ¹³C NMR spectras of 77 and 78.

9

10408 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

δ 5.86-5.79 (m, 1 H), 5.68-5.60 (m, 1 H), 5.02 (ddd, J ) 9.5, 2.5,

1.0 Hz, 1 H), 4.74 (s, 2 H), 4.66 (dd, J ) 6.5, 1.0 Hz, 2 H), 3.85 (dd,

J ) 9.5, 2.5 Hz, 1 H), 3.55 (dd, J ) 10.0, 6.0 Hz, 1 H), 3.49 (dd, J )

10.0, 5.5 Hz, 1 H), 3.18 (s, 3 H), 2.79 (d, J ) 6.5 Hz, 2 H), 1.79-1.71

(m, 1 H), 1.64 (d, J ) 1.5 Hz, 3 H), 0.87 (s, 9 H) 0.79 (d, J ) 7.0 Hz,

3 H), 0.02 (s, 3 H), 0.00 (s, 3 H) ppm; ¹³C NMR (125 MHz, CDCl₃)

δ 153.8, 138.1, 135.6, 125.3, 124.3, 94.4, 77.9, 76.7, 69.4, 64.5, 55.9,

42.0, 40.5, 25.9, 18.3, 16.9, 12.5, -5.4, -5.5 ppm. Anal. Calcd for

C₂₁H₃₇O₅Si: C, 50.05; H, 7.40. Found: C, 50.17; H, 7.35.

the dienyne side chain from all commercially available starting

materials. The diepi 85 was also synthesized in 22 steps for the

longest linear sequence (5.1% overall yield) and 46 total steps

in 0.14% overall yield, all starting with commercially available

materials. In the case of the synthesis of callipeltoside A, its

synthesis would also be shortened by three to 43 total steps

using the olefin metathesis strategy for attaching the side chain.

This sequence is also noteworthy for the development of a

convenient one pot olefin metathesis-Takai olefination protocol.

It highlights the efficiency of the Yamamoto protocol which

provides easy access to either enantiomeric chlorocyclopropane

using the Barton version of a Hunsdiecker reaction. The

deschloro analogue required only 36 total steps via the metath-

esis route. All of these syntheses will be reduced by four total

steps by employing the new synthesis of methyl callipeltose

described herein.

This strategy is highly convergent as the three main pieces

of the molecule, i.e., the macrolactone, the aglycone side chain,

and the sugar, are assembled within the last four steps of the

synthesis. This convergent approach is perfectly suited to pursue

structure-activity studies and enabled us to synthesize the C-13

epimeric macrolactone core and two isomers of 1 as well as

deschlorocallipeltoside A 2.

(E)-(2R,3R,7S)-tert-Butyl[3-methoxy-7-(4-methoxyphenoxy)-2,5-

dimethylnona-4,8-dienyloxy]dimethylsilane (24). To a degassed flask

containing Pd₂dba₃‚CHCl₃(40 mg, 0.039 mmol), (-)-(1R,2R)-bis(2′-

diphenylphosphinobenzamido)-1,2-diphenylethane (19) (92 mg, 0.12

mmol), 4-methoxylphenol (192 mg, 1.55 mmol), and tetrabutylammo-

nium chloride (108 mg, 0.39 mmol) was added degassed CH₂Cl₂(15

mL). After the purple reaction mixture was stirred for 15 min, the

solution became yellow, and allyl carbonate 17 (650 mg, 1.29 mmol)

was added as a solution in CH₂Cl₂(10 mL). The resulting reaction

mixture was stirred at ambient temperature for 12 h, concentrated, and

purified by flash column chromatography (SiO₂, 1/3 to 1/1, ether/PE)

to afford a 3.0/1.0 mixture of 2°/1° substitution (443 mg, 79%).

(a) 2° Substituted Aryl Ether 24. [R]_D) -2.3 (c ) 1.0, CH₂Cl₂);

IR (thin film, KBr) ν ) 2956, 2930, 2858, 1506, 1471, 1387, 1361,

1229, 1083, 1041, 925, 836, 776, 671 cm^-^{1 1}H NMR (500 MHz,

;

CDCl₃) δ 6.84-6.75 (m, 4 H), 5.83 (ddd, J ) 17.0, 10.5, 6.5 Hz, 1

H), 5.23 (d, J ) 17.0 Hz, 1 H), 5.17 (d, J ) 10.5 Hz, 1 H), 5.11 (d, J

) 9.5 Hz, 1 H), 4.63 (ddd, J ) 7.0, 6.5, 6.0 Hz, 1 H), 3.88 (dd, J )

9.5, 7.0 Hz, 1 H), 3.72 (s, 3 H), 3.55 (dd, J ) 9.5, 5.5 Hz, 1 H), 3.50

(dd, J ) 9.5, 5.0 Hz, 1 H), 3.19 (s, 3 H), 2.56 (dd, J ) 14.0, 7.0 Hz,

1 H), 2.39 (dd, J ) 14.0, 6.0 Hz, 1 H), 1.80-1.72 (m, 1 H), 1.74 (s,

3 H), 0.89 (s, 9 H) 0.80 (d, J ) 6.5 Hz, 3 H), 0.03 (s, 3 H), 0.02 (s, 3

H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 153.8, 152.1, 137.9, 136.2,

127.2, 117.1, 116.5, 114.4, 78.4, 77.7, 64.5, 55.8, 55.5, 46.0, 40.6, 25.8,

18.2, 17.4, 12.5, -5.5, -5.5 ppm. Anal. Calcd for C₂₅H₄₂O₄Si: C,

69.08; H, 9.74. Found: C, 68.88; H, 9.53.

Experimental Section

(2S,3S)-tert-Butyldimethylsilyloxy-2-methylhex-4-yn-3-ol (11). Ke-

tone 10 (0.05 g, 0.2 mmol) was dissolved in THF (1 mL, 0.2 M) and

cooled to -30 °C. To this solution was added 2-methyl (S)-CBS

oxazaborolidine (0.42 mL of 1 M in toluene, 0.42 mmol), and borane-

dimethyl sulfide (0.5 mL of a 2 M in THF, 1.0 mmol) was added

dropwise over 2 min. After the resulting reaction mixture was stirred

for 1 h at -30 °C, the reaction was quenched by addition of ethanol

(0.8 mL), warmed to room temperature, and diluted with water (10

mL) and diethyl ether (10 mL). The organic layer was dried (MgSO₄),

concentrated, and purified by flash column chromatography (SiO₂, 1/9

to 1/2 ether:PE) to afford a 10/1 dr of predominately 11 (48 mg, 99%):

[R]_D) +16.7 (c ) 1.0, CH₂Cl₂); IR (thin film, KBr) ν ) 3418, 2958,

2930, 2859, 2229, 1472, 1390, 1362, 1255, 1092, 1019, 838, 777, 668

cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 4.43-4.28 (m, 1 H), 3.86 (dd, J

) 10.0, 4.0 Hz, 1 H), 3.53 (dd, J ) 9.5, 7.0 Hz, 1 H), 3.49 (br s, 1 H),

1.90-1.82 (m, 1 H), 1.83 (d, J ) 2.0 Hz, 3 H), 0.96 (d, J ) 7.0 Hz,

3 H), 0.86 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm; ¹³C NMR (125

MHz, CDCl₃) δ 81.3, 79.2, 67.2, 67.0, 40.8, 25.8, 18.1, 13.0, 3.6, -5.6,

-5.7 ppm. Anal. Calcd for C₁₃H₂₆O₂Si: C, 64.41; H, 10.81. Found:

C, 64.60; H, 10.65.

(b) 1° Substituted Aryl Ether. [R]_D) +2.8 (c ) 1.0, CH₂Cl₂); IR

(thin film, KBr) ν ) 2956, 2930, 2858, 1667, 1592, 1464, 1386, 1230,

1181, 1107, 1082, 1040, 970, 836, 776, 669 cm^-1;¹H NMR (500 MHz,

CDCl₃) δ 6.85-6.76 (m, 4 H), 5.82-5.66 (m, 2 H), 5.03 (d, J ) 9.5

Hz, 1 H), 4.43 (d, J ) 5.5 Hz, 2 H), 3.85 (dd, J ) 10.0, 7.0 Hz, 1 H),

3.74 (s, 3 H), 3.55 (dd, J ) 9.5, 5.5 Hz, 1 H), 3.50 (dd, J ) 9.5, 5.0

Hz, 1 H), 3.19 (s, 3 H), 2.79 (d, J ) 6.5 Hz, 2 H), 1.79-1.71 (m, 1 H),

1.65 (s, 3 H), 0.88 (s, 9 H) 0.80 (d, J ) 7.0 Hz, 3 H), 0.02 (s, 3 H),

0.01 (s, 3 H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 153.8, 152.7, 138.7,

132.6, 126.9, 124.9, 115.7, 114.5, 77.9, 69.2, 64.5, 55.9, 55.7, 42.7,

40.5, 25.9, 18.3, 16.9, 12.6, -5.4, -5.5 ppm. Anal. Calcd for C₂₅H₄₂O₄-

Si: C, 69.08; H, 9.74. Found: C, 68.83; H, 9.90.

Undesired Diastereomer 12. [R]_D) +23.4 (c ) 1.0, CH₂Cl₂); IR

(thin film, KBr) ν ) 3436, 2958, 2930, 2859, 1472, 1256, 1090, 1022,

(E)-(2R,3R,7R)-tert-Butyl[3-methoxy-7-(4-methoxyphenoxy)-2,5-

dimethylnona-4,8-dienyloxy]dimethylsilane (28). Allyl carbonate 17

(10.5 g, 20.8 mmol) and 4-methoxyphenol (3.1 g, 25.0 mmol) were

dissolved in degassed CH₂Cl₂(350 mL) and treated with a solution of

tetrabutylammonium chloride (1.73 g, 6.24 mmol) in CH₂Cl₂(25 mL)

and a solution of Pd₂dba₃‚CHCl₃(0.538 g, 0.52 mmol) and (-)-(1S,2S)-

bis(2′-diphenylphosphinobenzamido)-1,2-diphenylethane (ent-19) (1.23

g, 1.56 mmol) in CH₂Cl₂(40 mL). The resulting reaction mixture was

stirred at room temperature for 20 h and concentrated, and the crude

¹H NMR showed a 2.0/1.0 mixture of 2°/1° substitution and a 20/1 dr.

The residue was purified by flash column chromatography (SiO₂, 1/3

to 1/1, ether/PE) to afford the 1° substitution product (2.4 g, 26%) and

desired 28 (4.6 g, 51%): [R]_D) 5.5 (c ) 1.0, CH₂Cl₂); IR (thin film,

KBr) ν ) 2929, 2857, 1850, 1729, 1667, 1644, 1592, 1506, 1464, 1443,

1387, 1361, 1228, 1182, 1082, 1040, 990, 925, 836, 776, 739, 670

1

837, 777 cm^-1; H NMR (500 MHz, CDCl₃) δ 4.40-4.35 (m, 1 H),

3.81 (d, J ) 7.5 Hz, 1 H), 3.80 (dd, J ) 9.5, 9.5 Hz, 1 H), 3.63 (dd,

J ) 10.0, 4.5 Hz, 1 H), 2.11-2.02 (m, 1 H), 1.83 (d, J ) 2.0 Hz, 3 H),

0.87 (s, 9 H), 0.84 (d, J ) 7.0 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 81.6, 78.3, 67.3, 66.8, 39.9, 25.8,

18.1, 12.4, 3.6, -5.6, -5.7 ppm. Anal. Calcd for C₁₃H₂₆O₂Si: C, 64.41;

H, 10.81. Found: C, 64.36; H, 10.78.

(2E,5E)(7S,8S)-9-(tert-Butyldimethylsilyloxy)-7-methoxy-5,8-di-

methylnona-2,5-dienoxycarbonyloxy-2,2,2-trichloroethyl (17). Alkyne

13 (900 mg, 3.5 mmol) and 3-butenyloxycarbonyloxy-2,2,2-trichloro-

ethane (16) (2.6 g, 10.5 mmol) were dissolved in acetone (7.0 mL, 0.5

M) and treated wtih CpRu(NCMe)₃PF₆(76 mg, 0.18 mmol) for 20

min at room temperature. The reaction mixture was concentrated and

purified by flash column chromatography (SiO₂, 1/9 to 1/3, ether:PE)

to afford 17 (1.49 g, 85%): [R]_D) +3.3 (c ) 1.0, CH₂Cl₂); IR (thin

film, KBr) ν ) 2930, 2858, 2818, 1761, 1667, 1463, 1389, 1237, 1082,

1029, 969, 914, 837, 778, 729, 670 cm^-1;¹H NMR (500 MHz, CDCl₃)

1

cm^-1; H NMR (500 MHz, CDCl₃) δ 6.84-6.74 (m, 4 H, ArH), 5.84

(ddd, J ) 17.5, 10.5, 6.5 Hz, 1 H, H-8), 5.22 (dt, J ) 17.5, 1.0 Hz, 1

H, H-9a), 5.17 (dt, J ) 10.5, 1.0 Hz, 1 H, H-9b), 5.11 (d, J ) 10.0, 1.0

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10409

A R T I C L E S

Trost et al.

Hz, 1 H, H-4), 4.62 (ddd, J ) 7.0, 6.5, 6.5 Hz, 1 H, H-7), 3.87 (dd, J

) 9.5, 7.5 Hz, 1 H, H-3), 3.73 (s, 3 H, MeOAr), 3.54 (dd, J ) 9.5, 6.0

Hz, 1 H, H-1a), 3.49 (dd, J ) 9.5, 5.5 Hz, 1 H, H-1b), 3.18 (s, 3 H,

MeO), 2.55 (dd, J ) 14.0, 7.5 Hz, 1 H, H-6a), 2.37 (dd, J ) 14.0, 6.0

Hz, 1 H, H-6b), 1.78-1.70 (m, 1 H, H-2), 1.72 (s, 3 H, MeS), 0.86 (s,

9 H, t-BuSi), 0.80 (d, J ) 7.0 Hz, 3 H, Me-2), 0.01 (s, 3 H, MeSi),

-0.02 (s, 3 H, MeSi) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 153.8,

152.2, 138.0, 136.2, 127.3, 117.1, 116.6, 114.4, 78.5, 77.8, 64.5, 55.9,

55.6, 46.1, 40.6, 25.9, 18.2, 17.3, 12.5, -5.5, -5.5 ppm. Anal. Calcd

for C₂₅H₄₂O₄Si: C, 69.08; H, 9.74. Found: C, 68.82; H, 9.86.

-4.4 ppm. Anal. Calcd for C₃₂H₅₄O₅SSi: C, 66.39; H, 9.40; S, 5.54.

Found: C, 66.37; H, 9.51; S, 5.31.

(E)-(2S,3R,4S,5R,6R,10R)-6-[4-(tert-Butyldimethylsilanyloxy)-2-

hydroxy-6-methoxy-10-(4-methoxyphenoxy)-3,5,8-trimethyldodeca-

7,11-dienyl]-2,2-dimethyl[1,3]dioxin-4-one (36). A solution of thioester

33 (900 mg, 1.55 mmol) in toluene (10 mL, 0.3 M) was cooled to -78

°C and treated with diisobutylaluminum hydride (6.22 mL of a 1 M

solution in toluene, 6.22 mmol). The resulting reaction was stirred at

-78 °C for 4 h and was quenched by addition of a solution of acetic

acid (886 µL, 15.5 mmol) in THF (5 mL), then warmed to 0 °C, and

diluted with water (50 mL) and ether (50 mL). The organic layer was

washed with a saturated aqueous solution of sodium bicarbonate (50

mL), dried (MgSO₄), and concentrated. The residue was purified by

flash column chromatography (SiO₂, 1/20 to 1/3, ether/PE) to afford

34 (600 mg, 79%): [R]_D) +16.0 (c ) 1.0, CH₂Cl₂); IR (thin film,

KBr) ν ) 2933, 2858, 2710, 2045, 1850, 1728, 1669, 1644, 1592, 1505,

1464, 1384, 1228, 1182, 1150, 1107, 1084, 1038, 927, 835, 775, 676

cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 9.69 (d, J ) 3.0 Hz, 1 H, CHO),

6.73-6.83 (m, 4 H, ArH), 5.83 (ddd, J ) 17.0, 10.5, 6.5 Hz, 1 H,

H-10), 5.23 (d, J ) 17.0 Hz, 1 H, H-11a), 5.17 (d, J ) 10.5 Hz, 1 H,

H-11b), 5.01 (dd, J ) 9.5, 1.0 Hz, 1 H, H-6), 4.62 (ddd, J ) 7.0, 6.5,

6.0 Hz, 1 H, H-9), 4.41 (dd, J ) 7.0, 1.5 Hz, 1 H, H-3), 3.75 (dd,

overlapped, 1 H, H-5), 3.73 (s, 3 H, MeOAr), 3.14 (s, 3 H, MeO),

2.55 (dd, J ) 13.5, 6.5 Hz, 1 H, H-8a), 2.49 (m, 1 H, H-2), 2.39 (dd,

J ) 13.5, 5.0 Hz, 1 H, H-8b), 1.71 (d, J ) 1.5 Hz, 3 H, Me-7), 1.58-

1.53 (m, 1 H, H-4), 1.01 (d, J ) 7.0 Hz, 3 H, Me-2), 0.86 (s, 9 H,

t-BuSi), 0.75 (d, J ) 7.0 Hz, 3 H, Me-4), 0.09 (s, 3 H, MeSi), 0.04 (s,

3 H, MeSi) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 205.2, 153.9, 152.1,

137.9, 136.9, 128.3, 117.1, 116.7, 114.4, 78.4, 77.1, 71.6, 55.6, 55.1,

51.8, 46.0, 41.7, 26.0, 18.4, 17.5, 11.5, 9.6, -4.0, -4.1 ppm.

(E)-(2R,3S,4R,5R,9R)-3-(tert-Butyldimethylsilanyloxy)-5-methoxy-

9-(4-methoxyphenoxy)-2,4,7-trimethylundeca-6,10-dienethioic Acid

S-tert-Butyl Ester (33). Diisopropylamine (5.7 mL, 41 mmol) was

placed in a flame-dried flask and dissolved in THF (45 mL), cooled to

-78 °C, and treated with n-butyllithium (23 mL, 36.7 mmol). The

reaction was stirred at -78 °C for 30 min, then warmed to 0 °C, and

then back to -78 °C before addition of tert-butyl thiopropionate (6.0

g, 40.8 mmol) as a solution in THF (50 mL). The resulting reaction

mixture was stirred at -78 °C for 30 min and then cooled to -107 °C

(liquid N₂in ether), and the aldehyde 30 (2.6 g, 8.2 mmol) was added

as a solution in THF (50 mL). The reaction was stirred at -107 °C for

3 h before quenching by addition of acetic acid (3.5 mL, 61.2 mmol)

as a solution in THF (20 mL). The reaction was then warmed to 0 °C,

diluted with ether (50 mL), and washed with a solution of saturated

aqueous sodium bicarbonate (50 mL). The organic layer was dried

(MgSO₄), concentrated, and purified by flash column chromatography

(SiO₂, 1:9 to 1/1, ether/PE) to afford the aldol product 31 (3.1 g,

82%): [R]_D) 0.4 (c ) 1.0, CH₂Cl₂); IR (thin film, KBr) ν ) 3514,

2967, 2936, 2055, 1853, 1682, 1505, 1455, 1364, 1289, 1228, 1182,

1

1084, 1039, 987, 958, 825, 751 cm^-1; H NMR (500 MHz, CDCl₃) δ

A solution of aldehyde 34 (600 mg, 1.22 mmol) in CH₂Cl₂(25 mL,

0.05 M) was cooled to -78 °C and treated with freshly prepared 2,2-

dimethyl-6-methylene-4-(trimethylsiloxy)-1,3-diox-4-ene (35) (1.3 g,

6.1 mmol) and boron trifluoride diethyl etherate (450 µL, 3.66 mmol).

The reaction was stirred at -78 °C for 45 min before quenching with

aqueous phosphate buffer (pH 7.0, 25 mL). The product was extracted

into ether (3 × 20 mL), dried (MgSO₄), and concentrated. The residue

was purified by flash column chromatography (SiO₂, 1/2 to 3/1, ether/

PE) to afford 36 (725 mg, 94%): [R]_D) +1.5 (c ) 1.0, CH₂Cl₂); IR

(thin film, KBr) ν ) 3479, 2933, 2857, 2248, 1732, 1634, 1505, 1464,

1392, 1228, 1080, 1015, 905, 834, 774, 735, 674 cm^-1; ¹H NMR (500

MHz, CDCl₃) δ 6.82-6.72 (m, 4 H, ArH), 5.82 (ddd, J ) 17.5, 10.5,

6.5 Hz, 1 H, H-14), 5.32 (s, 1 H, H-2), 5.21 (d, J ) 17.5 Hz, 1 H,

H-15a), 5.16 (d, J ) 10.5 Hz, 1 H, H-15b), 4.99 (d, J ) 9.5 Hz, 1 H,

H-10), 4.61 (ddd, J ) 7.0, 6.5, 6.5 Hz, 1 H, H-5), 4.30-4.25 (m, 1 H,

H-13), 4.09 (dd, J ) 4.0, 2.0 Hz, 1 H, H-7), 3.72 (s, 3 H, MeOAr),

3.67 (dd, J ) 9.5, 9.5 Hz, 1 H, H-9), 3.15 (s, 3 H, MeO), 3.02 (d, J )

2.5 Hz, 1 H, OH), 2.54 (dd, J ) 14.0, 7.5 Hz, 1 H, H-4a), 2.42 (dd, J

) 14.5, 9.5 Hz, 1 H, H-12a), 2.38 (dd, J ) 14.0, 5.5 Hz, 1 H, H-4b),

2.20 (dd, J ) 14.5, 4.5 Hz, 1 H, H-12b), 1.74-1.66 (m, 1 H, H-8),

1.71 (d, J ) 1.0 Hz, 3 H, Me-11), 1.66 (2s, 6 H), 1.50-1.44 (m, 1 H,

H-6), 0.94 (d, J ) 7.0 Hz, 3 H, Me-6), 0.88 (s, 9 H, t-BuSi), 0.78 (d,

J ) 7.5 Hz, 3 H, Me-8), 0.09 (s, 3 H, MeSi), 0.09 (s, 3 H, MeSi) ppm;

¹³C NMR (125 MHz, CDCl₃) δ 169.6, 161.1, 153.8, 152.0, 137.9, 136.9,

127.8, 117.1, 116.7, 114.3, 106.4, 94.7, 79.0, 78.3, 75.3, 68.1, 55.5,

55.4, 46.0, 43.2, 41.6, 39.6, 26.1, 25.3, 24.7, 18.3, 17.4, 11.1, 10.2,

-3.9, -4.3 ppm. Anal. Calcd for C₃₅H₅₆O₈Si: C, 66.42; H, 8.92.

Found: C, 66.23; H, 8.85.

6.83-6.73 (m, 4 H, ArH), 5.81 (ddd, J ) 17.0, 9.5, 6.5 Hz, 1 H, H-10),

5.24 (d, J ) 9.5 Hz, 1 H, H-6), 5.21 (dd, J ) 17.0, 1.0 Hz, 1 H, H-11),

5.16 (dd, J ) 10.5, 1.0 Hz, 1 H, H-11′), 4.61 (ddd, J ) 6.5, 6.5, 6.5

Hz, 1 H, H-9), 4.20-4.15 (m, 1 H, H-3), 3.90 (dd, J ) 9.5, 6.0 Hz, 1

H, H-5), 3.72 (s, 3 H, MeOAr), 3.15 (s, 3 H, MeO), 2.90 (d, J ) 4.0

Hz, 1 H, OH), 2.65-2.58 (m, 1 H, H-2), 2.52 (dd, J ) 14.0, 7.5 Hz,

1 H, H-8), 2.37 (dd, J ) 14.0, 6.0 Hz, 1 H, H-8′), 1.71 (s, 3 H, Me-6),

1.62-1.55 (m, 1 H, H-4), 1.44 (s, 9 H, t-BuS), 1.00 (d, J ) 7.0 Hz, 3

H, Me-2), 0.84 (d, J ) 7.0 Hz, 3 H, Me-4) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 204.4, 153.8, 152.0, 137.8, 136.6, 127.7, 117.1, 116.7, 114.3,

80.1, 78.3, 72.3, 56.1, 55.6, 52.1, 47.9, 45.9, 39.4, 29.7, 17.3, 14.8,

9.3 ppm. HRMS. Calcd for C₂₆H₄₀O₅S: 464.2596. Found: 464.2598.

The alcohol (1.5 g, 3.23 mmol) was dissolved in CH₂Cl₂(32 mL,

0.1 M), cooled to 0 °C, and treated with 2,6-lutidine (1.13 mL, 9.7

mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.48 mL,

6.46 mmol). The reaction was stirred at 0 °C for 1 h and quenched by

addition of a solution of saturated aqueous sodium bicarbonate (50 mL),

and the product was extracted into ether (2 × 50 mL). The combined

organic layers were dried (MgSO₄), concentrated, and purified by flash

column chromatography (SiO₂, 1/19 to 1/3, ether/PE) to afford 33 (1.6

g, 86%): [R]_D) +31.3 (c ) 1.0, CH₂Cl₂); IR (thin film, KBr) ν )

2929, 2857, 1851, 1682, 1592, 1506, 1463, 1364, 1228, 1152, 1082,

1

1041, 955, 834, 776, 738, 672 cm^-1; H NMR (500 MHz, CDCl₃) δ

6.84-6.74 (m, 4 H, ArH), 5.83 (ddd, J ) 17.5, 10.5, 6.5 Hz, 1 H,

H-10), 5.21 (d, J ) 17.5 Hz, 1 H, H-11a), 5.16 (d, J ) 10.5 Hz, 1 H,

H-11b), 4.99 (d, J ) 10.0 Hz, 1 H, H-6), 4.61 (ddd, J ) 7.0, 6.5, 6.5

Hz, 1 H, H-9), 4.51 (d, J ) 8.0 Hz, 1 H, H-3), 3.74 (dd, overlapped,

1 H, H-5), 3.73 (s, 3 H, MeOAr), 3.13 (s, 3 H, MeO), 2.69-2.62 (m,

1 H, H-2), 2.54 (dd, J ) 14.0, 7.5 Hz, 1 H, H-8a), 2.37 (dd, J ) 14.0,

6.0 Hz, 1 H, H-8b), 1.70 (d, J ) 1.5 Hz, 3 H, Me-7), 1.56-1.50 (m,

1 H, H-4), 1.43 (s, 9 H, t-BuSi), 1.05 (d, J ) 7.0 Hz, 3 H, Me-2), 0.86

(s, 9 H, t-BuSi), 0.68 (d, J ) 6.5 Hz, 3 H, Me-4), 0.08 (s, 3 H, MeSi),

0.04 (s, 3 H, MeSi) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 203.3, 153.8,

152.1, 138.0, 136.5, 128.8, 117.1, 116.7, 114.4, 78.5, 76.9, 70.5, 55.6,

55.0, 54.6, 47.8, 46.1, 40.2, 29.9, 26.3, 18.5, 17.5, 15.5, 8.9, -4.0,

(E)-(2S,3R,4S,5R,6R,10R)-6-[2,4-Bis(tert-butyldimethylsilanyloxy)-

10-hydroxy-6-methoxy-3,5,8-trimethyldodeca-7,11-dienyl]-2,2-

dimethyl[1,3]dioxin-4-one (38). Aryl ether 37 (530 mg, 0.71 mmol)

was dissolved in acetone (12 mL) and treated with a solution of ceric

ammonium nitrate (973 mg, 1.78 mmol) in water (2.8 mL) at 0 °C

over 5 min. The product was extracted into ether (2 × 15 mL), and the

combined organic layers were washed with brine (15 mL), dried

(MgSO₄), and concentrated. The residue was purified by flash column

9

10410 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

chromatography (SiO₂, 1/2 to 2/1, ether/PE) to afford 38 (374 mg,

82%): [R]_D) +3.84 (c ) 1.0, CH₂Cl₂); IR (thin film, KBr) ν ) 3454,

2930, 2895, 2857, 1732, 1634, 1476, 1391, 1273, 1254, 1205, 1082,

Hz, 6.0, 1 H), 5.76 (m, 1 H), 5.29 (d, J ) 9.0 Hz, 1 H), 5.28 (dt, J )

17.0, 1.5 Hz, 1 H), 5.17 (dt, J ) 10.5, 1.0 Hz, 1 H), 5.07 (d, J ) 2.5

Hz, 1 H), 3.79 (dd, J ) 9.5, 2.5 Hz, 1 H), 3.77 (ddd, J ) 12.0, 12.0,

4.5 Hz, 1 H), 3.60 (dd, J ) 10.0, 2.5 Hz, 1 H), 3.22 (s, 3 H), 2.53 (d,

J ) 13.0 Hz, 1 H), 2.43 (d, J ) 13.0 Hz, 1 H), 2.26 (m, 2 H), 2.19 (m,

1 H), 2.09 (dd, J ) 4.5, 12.0 Hz, 1 H), 1.73 (d, J ) 1.0 Hz, 3 H), 1.56

(s, 1 H), 1.38 (m, 1 H), 1.29 (ddd, J ) 2.5, 12.0, 12.0 Hz, 1 H), 0.97

(d, J ) 7.0 Hz, 3 H), 0.95 (d, J ) 6.5 Hz, 3 H) ppm; ¹³C NMR (125

MHz, CDCl₃) δ 172.0, 136.1, 132.6, 127.6, 116.5, 95.3, 79.8, 74.9,

72.2, 69.5, 55.2, 46.8, 44.7, 43.8, 40.1, 36.8, 16.1, 12.0, 6.5 ppm. HRMS

(ESI). Calcd for C₁₉H₃₀O₆Na: 377.1940. Found: 377.1927.

1

1016, 920, 903, 836, 810, 774, 734, 679 cm^-1; H NMR (500 MHz,

CDCl₃) δ 5.86 (ddd, J ) 16.5, 10.5, 6.0 Hz, 1 H, H-14), 5.33 (s, 1 H,

H-2), 5.25 (dt, J ) 16.0, 1.5 Hz, 1 H, H-15a), 5.10 (dt, J ) 10.5, 1.5

Hz, 1 H, H-15b), 4.95 (dd, J ) 10.0, 1.0 Hz, 1 H, H-10), 4.26-4.20

(m, 1 H, H-13), 4.21 (d, J ) 6.5 Hz, 1 H, H-7), 3.92 (dd, J ) 11.0, 6.0

Hz, 1 H, H-5), 3.66 (dd, J ) 10.0, 10.0 Hz, 1 H, H-9), 3.16 (s, 3 H,

MeO), 2.55 (dd, J ) 15.0, 5.0 Hz, 1 H, H-4a), 2.41 (dd, J ) 15.0, 6.0

Hz, 1 H, H-4b), 2.29 (dd, J ) 13.0, 5.5 Hz, 1 H, H-12a), 2.25 (dd, J

) 13.0, 8.0 Hz, 1 H, H-12b), 1.80-1.72 (m, 1 H, H-6), 1.69 (d, J )

1.5 Hz, 3 H, Me-11), 1.67 (s, 3 H, Me), 1.66 (s, 3 H, Me), 1.55-1.47

(m, 1 H, H-8), 0.88 (s, 9 H, t-BuSi), 0.87 (d, overlapped, 3 H, Me-6),

0.86 (s, 9 H, t-BuSi), 0.70 (d, J ) 7.0 Hz, 3 H, Me-8), 0.08 (s, 3 H,

MeSi), 0.06 (s, 3 H, MeSi), 0.06 (s, 3 H, MeSi), 0.05 (s, 3 H, MeSi)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 169.5, 161.1, 140.4, 136.9, 128.8,

114.9, 106.3, 95.6, 78.2, 70.9, 70.7, 70.5, 55.3, 47.9, 44.0, 39.8, 39.7,

26.1, 25.9, 25.3, 24.9, 18.4, 18.2, 17.2, 11.0, 10.5, -3.4, -3.7, -4.1,

-4.5 ppm. Anal. Calcd for C₃₄H₆₂O₇Si₂: C, 63.91; H, 9.78. Found:

C, 63.76; H, 9.70.

(E)-(1S,5S,9R,10R,11R,12R,13S)-1,13-Dihydroxy-9-methoxy-

7,10,12-trimethyl-5-vinyl-4,15-dioxabicyclo[9.3.1]pentadec-7-en-3-

one (40). [R]_D) -29.3 (c ) 1.0, CH₂Cl₂); IR (thin film, KBr) ν )

3460, 2920, 1706, 1435, 1383, 1297, 1232, 1165, 1087, 1050, 1025,

1

986, 931, 901, 866, 724 cm^-1; H NMR (500 MHz, pyridine-d₅) δ

5.97 (ddd, J ) 17.0, 10.5, 5.0 Hz, 1 H, H-14), 5.82-5.76 (m, 1 H,

H-13), 5.50 (d, J ) 10.0 Hz, 1 H, H-10), 5.35 (dd, J ) 17.0, 1.5 Hz,

1 H, H-15a), 5.15 (d, J ) 10.5 Hz, 1 H, H-15b), 4.57 (d, J ) 2.0 Hz,

1 H, OH), 4.18 (dd, J ) 10.0, 4.5 Hz, 1 H, H-9), 4.10 (ddd, J ) 10.5,

10.5, 4.5 Hz, 1 H, H-5), 3.72 (d, J ) 10.5 Hz, 1 H, H-7), 3.25 (s, 3 H,

OMe), 2.97 (d, J ) 13.5 Hz, 1 H, H-2a), 2.88 (d, J ) 13.5 Hz, 1 H,

H-2b), 2.72 (dd, J ) 16.0, 4.0 Hz, 1 H, H-12), 2.61-2.55 (m, 1 H,

H-8), 2.53 (dd, J ) 12.5, 5.0 Hz, 1 H, H-4a), 2.27 (dd, J ) 16.0, 8.0

Hz, 1 H, H-2b), 1.80-1.78 (m, 1 H, H-6), 1.78 (s, 3 H, Me-11), 1.75

(dd, J ) 11.0, 11.0 Hz, 1 H, H-4b), 1.21 (d, J ) 6.5 Hz, 3 H), 1.20 (d,

J ) 7.0 Hz, 3 H) ppm; ¹³C NMR (125 MHz, pyridine-d₅) δ 168.8,

137.7, 132.9, 124.4, 115.7, 96.0, 79.8, 74.3, 72.9, 69.6, 55.1, 48.5, 45.3,

42.2, 41.2, 37.4, 18.9, 13.1, 6.4 ppm; ¹H NMR (500 MHz, CD₃OD) δ

5.99 (ddd, J ) 17.0, 10.5, 5.0 Hz, 1 H, H-14), 5.63-5.57 (m, 1 H,

H-13), 5.30 (d, J ) 17.0 Hz, 1 H, H-15a), 5.19 (d, overlapped, 1 H,

H-10), 5.19 (d, J ) 10.5 Hz, 1 H, H-15a), 4.60 (br s, 1 H, OH), 4.03

(dd, J ) 10.0, 5.0 Hz, 1 H, H-9), 3.52 (ddd, J ) 11.0, 11.0, 4.5 Hz, 1

H, H-5), 3.35 (d, J ) 10.5 Hz, 1 H, H-7), 3.21 (s, 3 H, OMe), 2.80 (d,

J ) 14.0 Hz, 1 H, H-2a), 2.73 (dd, J ) 16.0, 4.5 Hz, 1 H, H-12a), 2.56

(d, J ) 14.5 Hz, 1 H, H-2b), 2.38-2.30 (m, 2 H, H-8 & H-4a), 2.09

(dd, J ) 12.5, 5.0 Hz, 1 H, H-12b), 1.77 (s, 3 H, Me-11), 1.40-1.32

(m, 1 H, H-6), 1.31 (dd, J ) 12.0, 12.0 Hz, 1 H, H-4b), 0.96 (d, J )

6.5 Hz, 3 H), 0.87 (d, J ) 7.0 Hz, 3 H) ppm. HRMS. Calcd for

C₁₉H₃₀H₃₀O₆Na (M⁺+ Na): 377.1940. Found: 377.1927.

(E)-(6S,7R,8S,9R,10R,14R)-6,8-Bis(tert-butyldimethylsilanyloxy)-

10-methoxy-7,9,12-trimethyl-14-vinyloxacyclotetradec-11-ene-2,4-

dione (39). A solution of alcohol 38 (200 mg, 0.313 mmol) in freshly

distilled toluene (100 mL) was added via cannula to toluene (500 mL,

0.5 mM) at reflux over 45 min. The reaction was stirred at reflux for

1.5 h, cooled, and concentrated. The residue was purified by flash

column chromatography (SiO₂, 1/19 to 1/4, ether/PE) to afford cyclized

product 39 (150 mg, 82%): [R]_D) -28.6 (c ) 1.0, CH₂Cl₂); IR (thin

film, KBr) ν ) 2957, 2888, 2857, 1748, 1722, 1472, 1387, 1360, 1256,

1186, 1105, 1005, 939, 838, 776, 676 cm^-1; ¹H NMR (500 MHz, C₆D₆,

50 °C) δ 5.66-5.60 (m, 2 H, H-13 & H-14), 5.57 (br d, J ) 9.5 Hz,

1 H, H-10), 5.14 (dd, J ) 16.0, 1.0 Hz, 1 H, H-15a), 4.96 (dd, J ) 9.0,

1.0 Hz, 1 H, H-15b), 4.49 (dd, J ) 3.0, 1.5 Hz, 1 H, H-7), 4.23 (ddd,

J ) 9.0, 6.5, 2.5 Hz, 1 H, H-5), 3.72 (dd, J ) 9.5, 2.0 Hz, 1 H, H-9),

3.21 (d, J ) 16.0 Hz, 1 H, H-2a), 3.05 (dd, J ) 17.0, 9.0 Hz, 1 H,

H-4a), 3.04 (s, 3 H, MeO), 2.99 (d, J ) 16.0 Hz, 1 H, H-2b), 2.43 (dd,

J ) 14.0, 11.5 Hz, 1 H, H-12a), 2.26 (dd, J ) 17.0, 2.0 Hz, 1 H,

H-4b), 2.19-2.12 (m, 1 H, H-6), 2.09 (d, J ) 14.0 Hz, 1 H, H-12b),

1.69-1.60 (m, 1 H, H-8), 1.57 (s, 3 H, Me-11), 1.19 (d, J ) 7.0 Hz,

3 H, Me-8), 1.08 (s, 9 H, t-BuSi), 1.00 (s, 9 H, t-BuSi), 0.93 (d, J )

7.0 Hz, 3 H, Me-6), 0.29 (s, 3 H, MeSi), 0.24 (s, 3 H, MeSi), 0.22 (s,

3 H, MeSi), 0.18 (s, 3 H, MeSi) ppm; ¹³C NMR (125 MHz, C₆D₆) δ

191.4, 157.5, 128.0, 126.3, 121.1, 107.8, 73.8, 63.7, 63.0, 60.2, 47.0,

41.9, 39.2, 37.5, 37.0, 31.3, 17.8, 17.8, 10.2, 9.8, 7.0, 6.7, 3.5, -12.3,

-12.7, -12.8 ppm. Anal. Calcd for C₃₁H₅₈O₆Si₂: C, 63.87; H, 10.03.

Found: C, 64.01; H, 9.86.

(1S,2R)-2-Chlorocyclopropanecarboxylic Acid (1S,2R,5S)-5-Iso-

propyl-2-methylcyclohexyl Ester (58). To a solution of acid chloride

57 (2.5 g, 8.75 mmol) in carbon tetrachloride (430 mL, 0.02 M) is

added, at room temperature and in the dark, 2-mercaptopyridine-1-

oxide sodium salt (1.57 g, 10.5 mmol), DMAP (0.214 g, 1.75 mmol),

and tetrabutylammonium iodide (0.650 g, 1.75 mmol). This mixture is

stirred in the dark at room temperature for 1 h. At this time, thin layer

chromatography (TLC) shows clean formation of the Barton ester 59

[R_f) 0.66 (ether)]. 2,2′-Azobis(isobutyronitrile) (0.072 g, 0.44 mmol)

is then added, and the mixture is placed under reflux in the presence

of light for 5 h. At this time, TLC shows disappearance of the Barton

ester. The mixture is then evaporated in vacuo and the trans chloride

58 (1.328 g, 5.25 mmol, 60% yield) is isolated as pure white crystals

after column chromatography (petroleum ether/ether 100/3). The cis

isomer of the chloride 58 (0.04 g, 0.16 mmol) is isolated as well as a

white solid. The diastereomeric ratio is 33/1 in favor of the trans 58:

(E)-(1S,5R,9R,10R,11R,12R,13S)-1,13-Dihydroxy-9-methoxy-

7,10,12-trimethyl-5-vinyl-4,15-dioxabicyclo[9.3.1]pentadec-7-en-3-

one (3). To a solution of 39 (20 mg, 34.3 µmol) in methanol (1.5 mL)

at 0 °C, is added in 4 portions over 4 h a premixed solution of HF-

pyridine (3 mL) in methanol (4 mL). After 5 h, the mixture is added

to a saturated solution of sodium bicarbonate (200 mL). This solution

is extracted 5 times by ethyl acetate, and the combined organic fractions

are washed with brine, dried over magnesium sulfate, filtrated, and

evaporated in vacuo. The residue was redissolved in benzene (5 mL)

and evaporated in vacuo. This residue is dissolved in a 3/1 mixture of

acetonitrile and water (2 mL), and PPTS (10 mg) is added. After 3 h

at room temperature, a saturated solution of sodium bicarbonate is added

and the mixture is extracted 3 times by dichloromethane. The organic

phases are washed with brine, dried over magnesium sulfate, filtrated,

and evaporated in vacuo. The tetrahydropyran 3 (11 mg, 31.1 µmol) is

obtained pure after column chromatography (PE/ether 1/1) with 91%

yield: R_f) 0.46 (PE/EtOAc 1/1); [R]_D²⁵) - 40.2 (c ) 0.5, CH₂Cl₂);

IR (neat) 3450, 2969, 2927, 1704, 1416, 1352, 1319, 1229, 1178, 1081,

24

R_f) 0.75 (PE/ether 9/1); mp 60 °C; [R]_D) -29.8 (c ) 1.1, CH₂-

1

Cl₂); IR (neat) 2954, 2920, 2860, 1720, 1430, 1390, 1180 cm^-1; H

NMR (500 MHz, CDCl₃) δ 4.64 (dt, J ) 4.4, 11.0 Hz, 1 H), 3.34

(ddd, J ) 2.7, 4.6, 7.0 Hz, 1 H), 1.95 (ddd, J ) 2.7, 5.9, 9.3 Hz, 2 H),

1.82 (dquintuplet, J ) 2.4, 6.8 Hz, 1 H), 1.66 (m, 2 H), 1.52 (m, 2 H),

1.34 (m, 2 H), 1.04 (m, 3 H), 0.88 (d, J ) 6.6, 3 H), 0.87 (d, J ) 6.8,

3 H), 0.72 (d, J ) 6.8, 3 H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ (in

italics are the carbons belonging to the cyclopropane ring) 171.0, 75.0,

47.0, 40.8, 34.2, 33.2, 31.4, 26.2, 24.0, 23.4, 22.0, 20.7, 18.3, 16.3.

1

1024 cm^-1; H NMR (500 MHz, CDCl₃) δ 5.86 (ddd, J ) 17.0, 10.5

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10411

A R T I C L E S

Trost et al.

Anal. Calcd for C₁₄H₂₃O₂Cl: C, 64.98 H, 8.96; Cl, 13.70. Found: C,

65.12; H, 8.99; Cl, 13.99.

(E)-(6S,7R,8S,9R,10R,14R)-6,8-Bis(tert-butyldimethylsilanyl-

oxy)-14-[(1E,3E)-4-iodobuta-1,3-dienyl]-10-methoxy-7,9,12-trimethyl-

oxacyclotetradec-11-ene-2,4-dione (69b). To a solution of macrolac-

tone 39 (18 mg, 30.9 µmol) and freshly distilled crotonaldehyde (26

µL, 0.3 mmol) in dry degassed dichloromethane (1 mL) at room

temperature is added Grubb’s II catalyst (2.7 mg, 3 µmol), and the

mixture is heated to 40 °C for 4 h. The mixture is then cooled to room

temperature, evaporated in vacuo, and dried under high vacuum. Crude

NMR (benzene-d₆) shows total conversion. The crude aldehyde 68 is

used with no purification in the next step.

(1R,2S)-2-Chlorocyclopropanecarboxylic Acid (1R,2S,5R)-5-Iso-

propyl-2-methylcyclohexyl Ester (ent-58). [R]_D²⁴) +27.0 (c ) 1.00,

CH₂Cl₂). (E)-(6S,7R,8S,9R,10R,14R)-6,8-Bis(tert-butyldimethylsila-

nyloxy)-14-[(1E,3E)-6-((1S,2R)-2-chlorocyclopropyl)hexa-1,3-dien-

5-ynyl]-10-methoxy-7,9,12-trimethyloxacyclotetradec-11-ene-2,4-

dione (66). To a solution of phosphonate 65 (29 mg, 0.10 mmol) in

THF (1 mL) at -78 °C is added dropwise lithium bis(trimethylsilyl)

amide (1 M in THF) (100 µL, 0.10 mmol). The mixture is stirred 2

ï

min at -78 °C, warmed to 0 C over 5 min and recooled to -78 °C.

Chromium chloride (33 mg, 0.27 mmol) is placed in a flask in a

drybox under nitrogen atmosphere. In a separate flask is placed the

aldehyde 68 as well as iodoform (53 mg, 0.13 mmol), and the flask is

purged with argon. Dry degassed THF (0.3 mL) is added to the

chromium chloride flask, and this suspension is cooled to 0 °C. Dry

degassed dioxane (1 mL) is added to the other flask, and its content is

transferred into the chromium chloride flask. This dark mixture is

scealed and stirred at 0 °C for 3 h. Water and ether are then added,

and the mixture is extracted with ether. The organic layer is washed

with brine, dried over magnesium sulfate, filtered, and evaporated in

vacuo. The vinyl iodide 69b (9.2 mg, 12.5 µmol, 40% yield) is obtained

pure as a clear oil after column chromatography (PE/ether 95/5, then

93/7, and then 90/10) as a 10/1 mixture of E/Z isomers (determined

A solution of the aldehyde 46 (23 mg, 39 µmol) in THF (1 mL) is

then added dropwise, and the mixture is stirred for 2 h at -78 °C, 30

min at -40 °C, and 15 min at room temperature. Water and ether are

then added, and the mixture is extracted by ether. The organic layer is

washed with brine, dried over magnesium sulfate, filtered, and

evaporated in vacuo. The cis diene (2.5 mg, 3.5 µmol, 9% yield)

[R_f) 0.34 (PE/ether 9/1)] and then the trans diene 66 (12 mg, 17

µmol, 43% yield) (52% yield with 4/1 E/Z ratio) are obtained pure

as clear oils after column chromatography (PE/ether 95/5, then

25

93/7, then 90/10, and then 85/15): R_f) 0.22 (PE/ether 9/1); [R]_D

)

-67.3 (c ) 1.0, CH₂Cl₂); IR (neat) 2930, 2855, 2282, 2215, 1746,

1716, 1470, 1390, 1360, 1250, 1184, 1103 cm^-1; ¹H NMR (500 MHz,

C₆D₆50 °C) δ 6.43 (dd, J ) 15.4, 10.7 Hz, 1 H), 6.13 (dd, J ) 15.2,

10.7 Hz, 1 H), 5.63 (m, 1 H), 5.57 (d, J ) 9.5 Hz, 1 H), 5.52 (dd, J )

15.6, 1.7 Hz, 1 H), 5.45 (dd, J ) 15.1, 6.6 Hz, 1 H), 4.48 (s, 1 H),

4.23 (ddd, J ) 8.5, 2.0, 2.0 Hz, 1 H), 3.73 (d, J ) 9.5 Hz, 1 H), 3.20

(d, J ) 15.6 Hz, 1 H), 3.06 (s, 3 H), 3.04 (m, 1 H), 2.97 (d, J ) 15.6

Hz, 1 H), 2.88 (ddd, J ) 8.8, 5.6, 3.2 Hz, 1 H), 2.40 (dd, J ) 12.0,

14.4 Hz, 1 H), 2.26 (dd, J ) 15.1, 1.7 Hz, 1 H), 2.15 (dquint, J ) 3.2,

6.8 Hz, 1 H), 2.03 (d, J ) 14.2 Hz, 1 H), 1.68 (m, 1 H), 1.59 (s, 3 H),

1.38 (m, 1 H), 1.20 (d, J ) 7.1 Hz, 3 H), 1.08 (s, 9 H), 1.00 (s, 9 H),

0.94 (d, J ) 7.3 Hz, 3 H), 0.84 (m, 2 H), 0.30 (s, 3 H), 0.25 (s, 3 H),

0.22 (s, 3 H), 0.18 (s, 3 H) ppm; ¹³C NMR (125 MHz, C₆D₆50 °C) δ

200.0, 166.2, 140.4, 134.6, 133.1, 131.7, 130.0, 127.5, 125.8, 113.3,

92.8, 82.5, 78.1, 71.7, 71.6, 55.7, 50.5, 47.7, 46.2, 45.8, 40.0, 34.3,

30.5, 30.1, 26.5, 19.2, 18.8, 18.5, 15.6, 15.3, 12.3, -3.6, -4.0, -4.05,

-4.1 ppm. HRMS (ESI). Calcd for C₃₈H₆₃ClO₆Si₂Na: 729.3749.

Found: 729.3762.

1

27

by H NMR): R_f) 0.24 (PE/ether 9/1); [R]_D) -7.9 (c ) 0.70,

CH₂Cl₂); IR (neat) 3446, 2930, 2855, 1746, 1717, 1472, 1387, 1360,

1250, 1185, 1103 cm^-1; ¹H NMR (500 MHz, C₆D₆50 °C) δ 6.73 (dd,

J ) 14.4, 10.7 Hz, 1 H), 5.99 (d, J ) 14.4 Hz, 1 H), 5.87 (dd, J )

15.4, 10.7 Hz, 1 H), 5.56 (m, 2 H), 5.27 (dd, J ) 15.2, 6.6 Hz, 1 H),

4.48 (s, 1 H), 4.23 (apparent t, J ) 6.6 Hz, 1 H), 3.72 (d, J ) 9.8 Hz,

1 H), 3.23 (d, J ) 15.9 Hz, 1 H), 3.06 (s, 3 H), 3.00 (m, 2 H), 2.39

(dd, J ) 14.4, 11.7 Hz, 1 H), 2.27 (dd, J ) 1.7, 16.6 Hz, 1 H), 2.16

(dt, J ) 2.9, 6.8 Hz, 1 H), 2.02 (d, J ) 15.6 Hz, 1 H), 1.67 (m, 1 H),

1.58 (s, 3 H), 1.21 (d, J ) 6.6 Hz, 3 H), 1.08 (s, 9 H), 1.00 (s, 9 H),

0.95 (d, J ) 7.1 Hz, 3 H), 0.30 (s, 3 H), 0.25 (s, 3 H), 0.22 (s, 3 H),

0.17 (s, 3 H) ppm; ¹³C NMR (125 MHz, C₆D₆50 °C) δ 200.0, 166.2,

144.2, 134.5, 132.2, 131.7, 130.1, 125.8, 82.5, 81.3, 71.5, 55.7, 50.5,

47.7, 46.1, 45.9, 40.0, 30.5, 26.5, 18.8, 18.5, 15.7, 15.3, 12.3, -3.7,

-4.0, -4.1, -4.1 ppm. HRMS (ESI). Calcd for C₃₃H₅₉IO₆Si₂Na:

757.2793. Found: 757.2773.

(E)-(1S,5R,9R,11R,12R,13S)-5-[(1E,3E)-6-((1S,2R)-2-Chlorocyclo-

propyl)hexa-1,3-dien-5-ynyl]-1,13-dihydroxy-9-methoxy-7,10,12-tri-

methyl-4,15-dioxabicyclo[9.3.1]pentadec-7-en-3-one (67). To a so-

lution of 66 (20 mg, 28.3 µmol) in methanol (1.5 mL) at 0 °C is added

in 4 portions over 4 h a premixed solution of HF-pyridine (3 mL) in

methanol (4 mL). After 5 h, a saturated solution of sodium bicarbonate

(5 mL) is slowly and carefully added to the reaction mixture. The

resulting mixture is then carefully added to a saturated solution of

sodium bicarbonate (200 mL). This solution is extracted 5 times with

ethyl acetate, and the combined organic fractions are washed with brine,

dried over magnesium sulfate, filtered, and evaporated in vacuo. The

tetrahydropyran 67 (13 mg, 27 µmol, 96% yield) is obtained pure after

column chromatography (petroleum ether/ether 1/1): R_f) 0.46 (PE/

(E)-(6S,7R,8S,9R,10R,14R)-6,8-Bis(tert-butyldimethylsilanyloxy)-

14-[(1E,3E)-6-cyclopropyl)hexa-1,3-dien-5-ynyl]-10-methoxy-7,9,12-

trimethyloxacyclotetradec-11-ene-2,4-dione (47). A solution of vinyl

iodide 69b (4 mg, 5.4 µmol), 1-alkynylcyclopropane (4 mg, 54 µmol),

triphenylphosphine (0.3 mg, 1.1 µmol), freshly purified copper iodide-

(I) (0.3 mg, 1.6 µmol) and (di(benzonitrile))palladium dichloride (0.2

mg, 0.54 µmol) is diluted by a 1/1 mixture of THF and diisopropylamine

(1 mL) at -20 °C. After 30 min at this temperature, the mixture is

warmed to room temperature. After 30 min, the mixture is evaporated

in vacuo and dried with high vacuum. The enyne 47 (2.6 mg, 3.8 µmol,

70% yield) is isolated pure as a clear oil after preparative thin layer

25

chromatography (PE/ether 85/15): R_f) 0.22 (PE/ether 9/1); [R]_D

)

+3.0 (c ) 1.2, CH₂Cl₂); IR (neat) 2955, 2929, 2893, 2856, 2205, 1745,

1719, 1472, 1387, 1360, 1249, 1185, 1103, 1006 cm^-1; ¹H NMR (500

MHz, C₆D₆50 °C) δ 6.48 (dd, J ) 15.0, 11.0 Hz, 1 H), 6.12 (dd, J )

15.0, 11.0 Hz, 1 H), 5.65 (m, 1 H), 5.64 (dd, J ) 15.0, 1.5 Hz, 1 H),

5.58 (br d, J ) 10.0 Hz, 1 H), 5.39 (dd, J ) 15.0, 6.5 Hz, 1 H), 4.52

(s, 1 H), 4.23 (br ddd, J ) 9.5, 7.0, 2.5 Hz, 1 H), 3.71 (br d, J ) 9.0

Hz, 1 H), 3.15 (br d, J ) 16.0 Hz, 1 H), 3.07 (m, 1 H), 3.03 (s, 3 H),

2.91 (d, J ) 16.0 Hz, 1 H), 2.40 (dd, J ) 14.0, 12.0 Hz, 1 H), 2.16 (m,

1 H), 2.15 (br d, J ) 16.0 Hz, 1 H), 1.99 (d, J ) 14.5 Hz, 1 H), 1.64

(m, 1 H), 1.58 (s, 3 H), 1.20 (d, J ) 7.0 Hz, 3 H), 1.13 (m, 1 H), 1.09

(s, 9 H), 1.01 (s, 9 H), 0.90 (d, J ) 7.5 Hz, 3 H), 0.61 (m, 2 H), 0.39

(m, 2 H), 0.32 (s, 3 H), 0.26 (s, 3 H), 0.24 (s, 3 H), 0.20 (s, 3 H) ppm;

¹³C NMR (125 MHz, C₆D₆50 °C) δ 200.0, 166.2, 139.3, 134.8, 132.1,

132.1, 129.9, 127.6, 127.4, 114.4, 97.8, 82.5, 75.6, 71.9, 71.7, 55.7,

50.6, 47.7, 46.3, 45.8, 39.9, 26.5, 18.8, 18.5, 15.6, 15.3, 12.3, 8.8, 0.8,

23

EtOAc 1/1); [R]_D) -39.4 (c ) 1.0, CHCl₃); IR (neat) 3444, 2925,

1

1704, 1432, 1227, 1152 cm^-1; H NMR (500 MHz, CDCl₃) δ 6.46

(dd, J ) 15.4, 10.7 Hz, 1 H), 6.24 (dd, J ) 14.9, 10.7 Hz, 1 H), 5.80

(m, 1 H), 5.74 (dd, J ) 6.4, 15.1 Hz, 1 H), 5.55 (dd, J ) 15.6, 2.0 Hz,

1 H), 5.28 (d, J ) 9.5 Hz, 1 H), 5.01 (d, J ) 2.4 Hz, 1 H), 3.78 (dd,

J ) 9.5, 2.4 Hz, 1 H), 3.77 (m, 1 H), 3.59 (dd, J ) 10.3, 2.4 Hz, 1 H),

3.21 (s, 3 H), 3.16 (m, 1 H), 2.52 (d, J ) 12.9 Hz, 1 H), 2.42 (d, J )

13.0 Hz, 1 H), 2.26 (m, 2 H), 2.19 (m, 1 H), 2.08 (dd, J ) 4.6, 11.7

Hz, 1 H), 1.78 (m, 1 H), 1.71 (s, 3 H), 1.56 (s, 1 H), 1.38 (m, 1 H),

1.30 (m, 3 H), 0.95 (d, J ) 6.8 Hz, 6 H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 171.8, 140.1, 132.6, 132.3, 130.9, 127.8, 112.5, 95.3, 92.2,

79.7, 77.4, 74.9, 71.5, 69.5, 55.2, 46.9, 44.7, 43.7, 40.0, 36.8, 34.3,

19.3, 16.1, 12.03, 12.01, 6.5 ppm. HRMS (ESI). Calcd for C₂₆H₃₅-

ClO₆Na: 501.2020. Found: 501.2008.

9

10412 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

-3.6, -4.0, -4.1, -4.1 ppm. HRMS (ESI). Calcd for C₃₈H₆₄O₆Si₂Na:

695.4138. Found: 695.4138.

2 H), 2.19 (m, 1 H), 2.08 (dd, J ) 4.6, 11.7 Hz, 1 H), 1.78 (m, 1 H),

1.71 (s, 3 H), 1.56 (s, 1 H), 1.38 (m, 1 H), 1.30 (m, 3 H), 0.95 (d, J )

6.8 Hz, 6 H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 171.8, 140.1, 132.6,

132.3, 130.9, 127.8, 112.5, 95.3, 92.2, 79.7, 77.4, 74.9, 71.5, 69.5, 55.2,

46.9, 44.7, 43.7, 40.0, 36.8, 34.2, 19.3, 16.1, 12.03, 12.01, 6.5 ppm.

HRMS (ESI). Calcd for C₂₆H₃₅ClO₆Na: 501.2020. Found: 501.2006.

(E)-(1S,5R,9R,11R,12R,13S)-1,13-Dihydroxy-5-((1E,3E)-4-iodobuta-

1,3-dienyl)-9-methoxy-7,10,12-trimethyl-5-vinyl-4,15-dioxabicyclo-

[9.3.1]pentadec-7-en-3-one (70). To a solution of macrolactone 3 (10

mg, 28.2 µmol) and freshly distilled crotonaldehyde (23 µL, 0.28 mmol)

in dry degassed dichloromethane (1 mL) at room temperature is added

Grubb’s II catalyst (2.7 mg, 3 µmol), and the mixture is heated to 40

°C for 5 h. The mixture is then cooled to room temperature, evaporated

in vacuo, and dried under high vacuum. Crude NMR shows total

conversion. The crude aldehyde is used with no purification in the next

step.

Deschlorocallipeltoside A (2). A solution of core 48 (11 mg, 0.025

mmol) and sugar 5 (14 mg, 0.030 mmol) in dichloroethane (1.5 mL)

was transferred via cannula to a flask containing flame dried 4 Å MS

(200 mg). Trimethylsilyltriflate (24 µL of a solution of 50 µL in 1 mL

of dichloroethane, 0.006 mmol) was slowly added to the reaction

mixture, and it was stirred at room temperature for 30 min before

quenching by addition with triethylamine (0.1 mL) and a saturated

sodium bicarbonate solution (5 mL). The product was extracted into

dichloromethane (3 × 6 mL). The combined organic extracts were dried

(MgSO₄), concentrated, and purified by flash column chromatography

(SiO₂, 1/9 to 2/3, EtOAc/PE) to afford glycosylated product (14.5 mg,

80%): [R]_D) +2.8 (c ) 0.8, CH₂Cl₂); IR (thin film, KBr) ν ) 3453,

2933, 2204, 1738, 1732, 1713, 1463, 1416, 1366, 1325, 1250, 1228,

1201, 1182, 1155, 1138, 1103, 1065, 1025, 983, 893, 839, 806, 785,

737 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 6.43 (dd, J ) 15.0, 11.0 Hz,

1 H, H-16), 6.24 (dd, J ) 15.0, 11.0 Hz, 1 H, H-15), 5.82-5.75 (m,

1 H, H-13), 5.69 (dd, J ) 15.0, 6.5 Hz, 1 H, H-14), 5.57 (dd, J )

15.0, 1.5 Hz, 1 H, H-17), 5.27 (d, J ) 9.5 Hz, 1 H, H-10), 4.89 (d, J

) 2.0 Hz, 1 H, OH), 4.81 (d, J ) 6.0 Hz, 1 H, H-1′), 3.90-3.84 (m,

1 H, H-5′), 3.78 (dd, J ) 9.5, 2.5 Hz, 1 H, H-9), 3.75 (ddd, J ) 10.5,

10.5, 4.5 Hz, 1 H, H-5), 3.62 (dd, J ) 10.5, 2.5 Hz, 1 H, H-7), 3.56 (s,

3 H, OMe), 3.31 (d, J ) 2.5 Hz, 1 H, H-4′), 3.23-3.18 (m, 1 H, H-2′),

3.21 (s, 3 H, OMe), 2.48 (d, J ) 13.0 Hz, 1 H, H-2a), 2.39 (d, J )

13.0 Hz, 1 H, H-2b), 2.28-2.24 (m, 2 H, H-12), 2.21 (dd, J ) 12.0,

4.5 Hz, 1 H, H-4a), 2.24-2.17 (m, 1 H, H-8), 1.70 (s, 3 H, Me-11),

1.48 (s, 3 H, Me-3′), 1.50-1.42 (m, 1 H, H-6), 1.38-1.33 (m, 1 H,

H-20), 1.34-1.27 (m, 1 H, H-4b), 1.14 (d, J ) 6.5 Hz, 3 H, Me-6_),

1.00 (s, 9 H, t-BuSi), 0.95 (2d, J ) 7.0 Hz, 6 H, Me-6 & Me-8), 0.83-

0.79 (m, 2 H, H-21a), 0.73-0.68 (m, 2 H, H-21b) ppm; ¹³C NMR

(125 MHz, CDCl₃) δ 171.7, 161.0, 139.1, 132.4, 131.8, 131.3, 127.7,

113.4, 101.8, 97.3, 95.1, 82.2, 82.1, 79.8, 77.4, 74.9, 74.8, 71.5, 65.4,

65.3, 61.3, 55.3, 46.9, 44.8, 43.1, 38.5, 36.8, 27.7, 22.4, 20.1, 17.3,

16.1, 12.2, 8.7, 6.5, 0.4, -3.8, -4.0 ppm.

Chromium chloride (33 mg, 0.27 mmol) is placed in a flask in a

drybox under nitrogen atmosphere. In a separate flask is placed the

aldehyde as well as iodoform (53 mg, 0.13 mmol), and the flask is

purged with argon. Dry degassed THF (0.3 mL) is added to the

chromium chloride flask, and this suspension is cooled to 0 °C. Dry

degassed dioxane (1 mL) is added to the other flask, and its content is

transferred into the chromium chloride flask. This dark mixture is sealed

and stirred at 0 °C for 3 h. Water and ether are then added, and the

mixture is extracted with ether. The organic layer is washed with brine,

dried over magnesium sulfate, filtered, and evaporated in vacuo. The

vinyl iodide 70 (12 mg, 23.6 µmol, 84% yield) is obtained pure as a

clear oil after column chromatography (PE/ether 1/1) as a 8/1 mixture

1

of E/Z isomers (determined by H NMR): R_f) 0.40 (PE/ether 1/1);

[R]_D²²) +14.1 (c ) 1.10, CH₂Cl₂); IR (neat) 3451, 2925, 2360, 2055,

1

1704, 1462, 1226, 1152 cm^-1; H NMR (500 MHz, CDCl₃) δ 7.01

(dd, J ) 14.4, 11.0 Hz, 1 H), 6.40 (d, J ) 14.4 Hz, 1 H), 6.18 (dd, J

) 14.9, 10.7 Hz, 1 H), 5.74 (m, 2 H), 5.29 (d, J ) 9.7 Hz, 1 H), 5.00

(d, J ) 2.4 Hz, 1 H), 3.78 (dd, J ) 9.5, 2.4 Hz, 1 H), 3.75 (m, 1 H),

3.59 (dd, J ) 10.3, 2.4 Hz, 1 H), 3.21 (s, 3 H), 2.52 (d, J ) 12.9 Hz,

1 H), 2.42 (d, J ) 12.9 Hz, 1 H), 2.26 (m, 2 H), 2.20 (m, 1 H), 2.08

(dd, J ) 4.6, 11.9 Hz, 1 H), 1.71 (d, J ) 1.0 Hz, 3 H), 1.56 (s, 1 H),

1.38 (m, 1 H), 1.29 (ddd, J ) 2.4, 11.4, 11.5 Hz, 1 H), 0.96 (d, J )

7.1 Hz, 3 H), 0.95 (d, J ) 5.6 Hz, 3 H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 171.8, 144.0, 132.2, 131.4, 127.8, 125.5, 95.3, 81.0, 79.7,

74.9, 71.2, 69.5, 55.2, 46.8, 44.7, 43.7, 40.0, 36.8, 16.1, 12.0, 6.5 ppm.

HRMS. Calcd for C₂₁H₃₁O₆INa: 529.1063. Found: 529.1059.

(E)-(1S,5R,9R,11R,12R,13S)-5-[(1E,3E)-6-((1R,2S)-2-Chlorocyclo-

propyl)hexa-1,3-dien-5-ynyl]-1,13-dihydroxy-9-methoxy-7,10,12-tri-

methyl-4,15-dioxabicyclo[9.3.1]pentadec-7-en-3-one (72). To a so-

lution of ent-62 (23 mg, 88.4 µmol) in ether (1 mL) at -78 °C is added

nBuLi (1.4 M in hexanes) (64 µL, 88 µmol), and the mixture is allowed

to warm to room temperature over 15 min. The mixture is then recooled

to -78 °C and nBuLi (1.4 M in hexanes) (64 µL, 88 µmol) is added,

and the mixture is allowed to warm to 0 °C over 20 min. The mixture

is recooled to -78 °C, and a solution of trimethyltin chloride (18 mg,

88.4 µmol) in ether (0.5 mL) is added. After 30 min at room

temperature, the solvent is removed under vacuum. A solution of iodide

70 (9 mg, 17.7 µmol) in dry degassed DMF (1 mL) as well as

(MeCN)₂PdCl₂(0.4 mg, 1.8 µmol) is then added to the same flask at

0 °C. After 15 min at room temperature, the same quantity of palladium

catalyst is added. This operation is repeated after another 15 min. After

45 min of reaction, water and l ether are added, and the phases are

separated. The aqueous layer is back-extracted twice with ethyl acetate,

and the combined organic phases are washed with brine, dried over

magnesium sulfate, filtered, and evaporated in vacuo. The tetrahydro-

The glycosylated product (10 mg, 0.013 mmol) was dissolved in

THF (0.5 mL) and was treated with a solution (16 µL, 0.015 mmol) of

TBAF (1 mL of 1 M in THF) and acetic acid (50 µL) for 5 min at

room temperature. The reaction was quenched with a solution of

saturated sodium bicarbonate (1 mL), and the product was extracted

with dichloromethane (3 × 5 mL). The combined organic extracts were

dried (MgSO₄), concentrated, and purified by pipet column (SiO₂, 1/4

to 4/1, EtOAc/PE) to afford 2 (8 mg, 95%): [R]_D) +45.0 (c ) 0.5,

MeOH); IR (thin film, KBr): ν ) 3452, 3285, 2968, 2933, 2204, 1749,

1373, 1324, 1266, 1227, 1182, 1155, 1058, 1027, 980, 897, 822 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 6.43 (dd, J ) 15.0, 11.0 Hz, 1 H, H-16),

6.24 (dd, J ) 15.0, 11.0 Hz, 1 H, H-15), 5.82-5.76 (m, 1 H, H-13),

5.70 (dd, J ) 15.0, 6.5 Hz, 1 H, H-14), 5.67 (s, 1 H, NH), 5.58 (dd, J

) 15.0, 2.0 Hz, 1 H, H-17), 5.27 (d, J ) 8.5 Hz, 1 H, H-10), 4.93 (d,

J ) 2.5 Hz, 1 H, OH), 4.85 (d, J ) 6.0 Hz, 1 H, H-1′), 3.88 (ddd, J )

6.5, 6.5, 2.0 Hz, 1 H, H-5′), 3.78 (dd, J ) 9.5, 2.5 Hz, 1 H, H-9), 3.76

(ddd, J ) 10.5, 10.5, 5.0 Hz, 1 H, H-5), 3.63 (dd, J ) 10.5, 2.5 Hz, 1

H, H-7), 3.58 (s, 3 H, OMe), 3.32 (d, J ) 2.0 Hz, 1 H, H-4′), 3.23-

3.18 (m, 1 H, H-2′), 3.21 (s, 3 H, OMe), 2.49 (d, J ) 13.0 Hz, 1 H,

H-2a), 2.41 (d, J ) 13.0 Hz, 1 H, H-2b), 2.28-2.25 (m, 2 H, H-12),

2.21 (dd, J ) 12.0, 5.0 Hz, 1 H, H-4a), 2.23-2.17 (m, 1 H, H-8), 1.71

(d, J ) 1.0 Hz, 3 H, Me-11), 1.53 (s, 3 H, Me-3′), 1.50-1.43 (m, 1 H,

H-6), 1.38-1.33 (m, 1 H, H-20), 1.35-1.28 (m, 1 H, H-4b), 1.11 (d,

J ) 6.5 Hz, 3 H, Me-6′), 0.95 (d, J ) 7.0 Hz, 3 H, Me-6), 0.94 (d, J

) 6.5 Hz, Me-8), 0.83-0.79 (m, 2 H, H-21), 0.72-0.69 (m, 2 H, H-21′)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 171.7, 158.3, 139.1, 132.4, 131.8,

131.3, 127.6, 113.4, 101.6, 97.3, 95.1, 82.0, 81.8, 79.7, 77.7, 74.9, 74.8,

pyran 72 (6 mg, 12.5 µmol, 70% yield) is obtained pure after column

25

chromatography (PE/ether 1/1): R_f) 0.46 (PE /EtOAc 1/1); [R]_D

)

+125.0 (c ) 1.0, CHCl₃); IR (neat) 3444, 2925, 1704, 1432, 1227,

1

1152 cm^-1; H NMR (500 MHz, CDCl₃) δ 6.46 (dd, J ) 15.4, 10.7

Hz, 1 H), 6.24 (dd, J ) 14.9, 10.7 Hz, 1 H), 5.80 (m, 1 H), 5.74 (dd,

J ) 6.4, 15.1 Hz, 1 H), 5.55 (dd, J ) 15.6, 2.0 Hz, 1 H), 5.28 (d, J )

9.5 Hz, 1 H), 5.01 (d, J ) 2.4 Hz, 1 H), 3.78 (dd, J ) 9.5, 2.4 Hz, 1

H), 3.77 (m, 1 H), 3.59 (dd, J ) 10.3, 2.4 Hz, 1 H), 3.21 (s, 3 H), 3.16

(m, 1 H), 2.52 (d, J ) 12.9 Hz, 1 H), 2.42 (d, J ) 13.0, 1 H), 2.26 (m,

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10413

A R T I C L E S

Trost et al.

71.6, 63.4, 61.6, 61.3, 55.2, 46.9, 44.8, 43.0, 38.5, 36.8, 23.2, 16.1,

15.7, 12.2, 8.7, 6.5, 0.4 ppm; H NMR (500 MHz, CD₃OD) δ 6.43

methoxy-7,10,12-trimethyl-3-oxo-4,15-dioxabicyclo[9.3.1]pentadec-

7-en-13-yloxy]-7-methoxy-4,7a-dimethyltetrahydropyrano-

[3,4-d]oxazol-2-one (84 ) 1, Callipeltoside A). A mixture of alcohol

67 (10 mg, 20.9 µmol) and trichloroacetimidate 5 (13 mg, 27.4 µmol)

are dried by benzene azeotrope, diluted with dichloroethane (1 mL),

and transferred via cannula into a flask containing freshly flame dried

molecular sieves 4 Å (100 mg). This mixture is stirred for 10 min at

room temperature and then cooled to -30 °C. TMSOTf (10 µL of a

solution containing 50 µL of TMSOTf in 1 mL of dichloroethane, 2.8

µmol) is then added dropwise, and the mixture is stirred for 15 min.

Triethylamine (0.5 mL) is then added, and the mixture is warmed to

room temperature. A saturated solution of sodium bicarbonate is added,

and the mixture is extracted three times with dichloromethane. The

combined organic phases are washed with brine, dried over magnesium

sulfate, filtrated,and evaporated in vacuo. The glycosilated product (12

mg, 15.2 µmol) is obtained pure after two preparative TLC (PE/EtOAc

1/1 and then 7/3) with 73% yield.

This product (11 mg, 13.9 µmol) is diluted with THF (0.5 mL) and

buffered TBAF (17 µL of a solution containing 1 mL of a 1 M solution

of TBAF in THF, and 0.1 mL of acetic acid (17 µmol) is added at

room temperature. After 5 min, the reaction mixture is directly applied

on a preparative TLC (ethyl acetate pure) and then further purified by

preparative HPLC (C-18 Dynamax-60A) (methanol/water 60/40 5 mL/

min, room temperature ) 5.0 min) to yield callipeltoside A 1 (9 mg,

13.3 µmol) with 95% yield: R_f) 0.55 (EtOAc); [R]_D²²) -19.2 (c )

1.0, CH₃OH); IR (neat) 3445, 2926, 1748, 1538, 1417, 1373, 1262,

1150, 1097, 1058 cm^-1; ¹H NMR (500 MHz, CD₃OD) δ 6.39 (dd, J )

15.4, 10.7 Hz, 1 H), 6.22 (dd, J ) 14.4, 10.7 Hz, 1 H), 5.71 (m, 2 H),

5.54 (dd, J ) 1.7, 15.4 Hz, 1 H), 5.15 (bd, J ) 9.8 Hz, 1 H), 4.60 (d,

J ) 6.1 Hz, 1 H), 3.84 (dq, J ) 6.6, 1.7 Hz, 1 H), 3.77 (dd, J ) 9.5,

2.4 Hz, 1 H), 3.61 (dt, J ) 10.7, 4.6 Hz, 1 H), 3.54 (dd, J ) 10.5, 2.4

Hz, 1 H), 3.49 (s, 3 H), 3.34 (d, J ) 1.9 Hz, 1 H), 3.32 (d, J ) 6.1 Hz,

1 H), 3.14 (m, 1 H), 3.11 (s, 3 H), 2.42 (d, J ) 13.0 Hz, 1 H), 2.35 (d,

J ) 13.0 Hz, 1 H), 2.24 (m, 1 H), 2.16 (m, 1 H), 2.11 (m, 2 H), 1.70

(m, 1 H), 1.64 (s, 3 H), 1.42 (m, 1 H), 1.39 (s, 3 H), 1.29 (t, J ) 11.5

Hz, 1 H), 1.16 (m, 2 H), 0.98 (d, J ) 6.3 Hz, 3 H), 0.89 (d, J ) 6.6

Hz, 3 H), 0.85 (d, J ) 7.1 Hz, 3 H) ppm; ¹H NMR (500 MHz, pyridine-

d₅) δ 9.28 (s, 1 H), 6.66 (dd, J ) 15.4, 10.7 Hz, 1 H), 6.43 (dd, J )

15.4, 11.0 Hz, 1 H), 6.13 (s, 1 H), 5.99 (m, 1 H), 5.91 (dd, J ) 6.1,

15.1 Hz, 1 H), 5.83 (dd, J ) 1.7, 15.6 Hz, 1 H), 5.52 (d, J ) 9.8 Hz,

1 H), 5.13 (d, J ) 6.1 Hz, 1 H), 4.07 (m, 2 H), 4.00 (dd, J ) 2.4, 9.8

Hz, 1 H), 3.92 (dd, J ) 1.9, 10.3 Hz, 1 H), 3.63 (s, 3 H), 3.57 (d, J )

6.3 Hz, 1 H), 3.52 (d, J ) 1.2 Hz, 1 H), 3.41 (m, 1 H), 3.26 (s, 3 H),

2.78 (d, J ) 12.4 Hz, 1 H), 2.68 (d, J ) 12.7 Hz, 1 H), 2.55 (dd, J )

4.6, 12.0 Hz, 1 H), 2.43 (m, 2 H), 2.36 (m, 1 H), 1.98 (m, 1 H), 1.82

(s, 3 H), 1.76 (m, 1 H), 1.67 (dt, J ) 1.5, 11.0 Hz, 1 H), 1.59 (s, 3 H),

1.30 (m, 2 H), 1.26 (d, J ) 6.1 Hz, 3 H), 1.21 (d, 3 H), 1.05 (d, J )

6.3 Hz, 3 H) ppm; ¹³C NMR (125 MHz, CD₃OD) δ 172.9, 161.1, 141.6,

134.4, 134.3, 132.0, 128.3, 113.5, 103.7, 96.5, 92.8, 83.9, 83.0, 81.4,

78.7, 78.4, 76.4, 72.7, 65.3, 62.7, 62.0, 55.4, 47.8, 46.0, 44.5, 39.8,

38.2, 35.1, 23.0, 19.8, 16.3, 15.9, 12.8, 6.8 ppm. HRMS (ESI). Calcd

for C₃₅H₄₈ClNO₁₀Na: 700.2864. Found: 700.2862.

1

(dd, J ) 15.5, 11.0 Hz, 1 H, H-16), 6.31 (dd, J ) 14.0, 11.0 Hz, 1 H,

H-15), 5.82-5.75 (m, 1 H, H-13), 5.81-5.77 (m, 1 H, H-14), 5.63

(dd, J ) 15.5, 1.5 Hz, 1 H, H-17), 5.26 (d, J ) 9.5 Hz, 1 H, H-10),

4.70 (d, J ) 6.0 Hz, 1 H, H-1′), 3.95 (dq, J ) 6.5, 2.0 Hz, 1 H, H-5′),

3.88 (dd, J ) 9.5, 2.5 Hz, 1 H, H-9), 3.72 (ddd, J ) 10.5, 10.5, 4.5

Hz, 1 H, H-5), 3.65 (dd, J ) 10.5, 1.5 Hz, 1 H, H-7), 3.59 (s, 3 H,

OMe), 3.43 (d, J ) 2.0 Hz, 1 H, H-4′), 3.42 (d, J ) 6.5 Hz, 1 H,

H-2′), 3.21 (s, 3 H, OMe), 2.52 (d, J ) 12.5 Hz, 1 H, H-2a), 2.46 (d,

J ) 13.0 Hz, 1 H, H-2b), 2.35-2.27 (m, 2 H, H-12), 2.24-2.20 (m, 1

H, H-8), 2.23-2.18 (m, 1 H, H-4a), 1.74 (s, 3 H, Me-11), 1.52-1.46

(m, 1 H, H-6), 1.50 (s, 3 H, Me-3′), 1.42-1.36 (m, 1 H, H-4b), 1.40-

1.34 (m, 1 H, H-20), 1.08 (d, J ) 6.5 Hz, 3 H, Me-6′), 0.99 (d, J ) 6.5

Hz, 3 H, Me-6), 0.96 (d, J ) 7.0 Hz, 3 H, Me-8), 0.84-0.79 (m, 2 H,

H-21), 0.65-0.60 (m, 2 H, H-21) ppm; ¹³C NMR (125 MHz, CD₃OD)

δ 172.9, 161.1, 140.4, 134.5, 133.3, 132.4, 128.3, 114.5, 103.7, 97.9,

96.6, 83.9, 83.0, 81.4, 78.7, 76.4, 75.7, 72.8, 65.3, 62.7, 62.0, 55.4,

47.9, 46.0, 44.5, 39.9, 38.2, 23.0, 16.3, 15.9, 12.7, 9.0, 6.8, 0.9 ppm.

MALDI-FTMS. Calcd for C₃₅H₄₉NO₁₀(M + Na⁺): 666.3248.

Found: 666.3220.

(3aR,4S,7R,7aR)-6-[(1S,5R,9R,10R,11R,12R)-(E)-5-[(1E,3E)-6-

((1R,2S)-2-Chlorocyclopropyl)hexa-1,3-dien-5-ynyl]-1-hydroxy-9-

methoxy-7,10,12-trimethyl-3-oxo-4,15-dioxabicyclo[9.3.1]pentadec-

7-en-13-yloxy]-7-methoxy-4,7a-dimethyltetrahydropyrano-

[3,4-d]oxazol-2-one (85). A mixture of alcohol 72 (10 mg, 20.9 µmol)

and trichloroacetimidate 5 (13 mg, 27.4 µmol) are dried by benzene

azeotrope, diluted with dichloroethane (1 mL), and transferred via

cannula into a flask containing freshly flame dried molecular sieves 4

Å (100 mg). This mixture is stirred for 10 min at room temperature

and then cooled to -30 °C. TMSOTf (10 µL of a solution containing

50 µL of TMSOTf in 1 mL of dichloroethane, 2.8 µmol) is then added

dropwise, and the mixture is stirred for 15 min. Triethylamine (0.5

mL) is then added, and the mixture is warmed to room temperature. A

saturated solution of sodium bicarbonate is added, and the mixture is

extracted three times with dichloromethane. The combined organic

phases are washed with brine, dried over magnesium sulfate, filtrated,

and evaporated in vacuo. The glycosilated product (12 mg, 15.2 µmol)

is obtained pure after two preparative TLC (petroleum ether/ethyl

acetate 1/1 and then 7/3) with 73% yield.

This product (11 mg, 13.9 µmol) is diluted with THF (0.5 mL) and

buffered TBAF (17 µL of a solution containing 1 mL of a 1 M solution

of TBAF in THF, and 0.1 mL of acetic acid (17 µmol) is added at

room temperature. After 5 min, the reaction mixture is directly applied

on a preparative TLC (ethyl acetate pure) and then further purified by

preparative HPLC (C-18 Dynamax-60A) (methanol/water 60/40 5 mL/

min, room temperature ) 5.0 min) to yield 85 (9 mg, 13.3 µmol, 95%

22

yield): R_f) 0.55 (EtOAc); [R]_D) +156.3 (c ) 0.55, CH₃OH); IR

(neat) 3445, 2926, 1748, 1538, 1417, 1373, 1262, 1150, 1097, 1058

cm^-1; ¹H NMR (500 MHz, CD₃OD) δ 6.39 (dd, J ) 15.4, 10.7 Hz, 1

H), 6.22 (dd, J ) 14.4, 10.7 Hz, 1 H), 5.71 (m, 2 H), 5.54 (dd, J )

1.9, 15.6 Hz, 1 H), 5.16 (bd, J ) 9.5 Hz, 1 H), 4.60 (d, J ) 6.1 Hz, 1

H), 3.84 (dq, J ) 6.6, 1.7 Hz, 1 H), 3.77 (dd, J ) 9.7, 2.4 Hz, 1 H),

3.61 (dt, J ) 10.9, 4.8 Hz, 1 H), 3.54 (dd, J ) 10.5, 2.4 Hz, 1 H), 3.49

(s, 3 H), 3.34 (d, J ) 2.2 Hz, 1 H), 3.32 (d, J ) 6.3 Hz, 1 H), 3.14 (m,

1 H), 3.11 (s, 3 H), 2.42 (d, J ) 12.7 Hz, 1 H), 2.35 (d, J ) 12.9 Hz,

1 H), 2.24 (m, 1 H), 2.16 (m, 1 H), 2.11 (m, 2 H), 1.70 (m, 1 H), 1.64

(s, 3 H), 1.42 (m, 1 H), 1.39 (s, 3 H), 1.29 (t, J ) 11.5 Hz, 1 H), 1.16

(m, 2 H), 0.98 (d, J ) 6.3 Hz, 3 H), 0.89 (d, J ) 6.6 Hz, 3 H), 0.85

(d, J ) 7.1 Hz, 3 H) ppm; ¹³C NMR (125 MHz, CD₃OD) δ 172.9,

161.1, 141.6, 134.4, 134.3, 132.0, 128.3, 113.5, 103.7, 96.5, 92.8, 83.9,

83.0, 81.4, 78.7, 78.4, 76.4, 72.7, 65.3, 62.7, 62.0, 55.4, 47.8, 46.0,

44.5, 39.8, 38.2, 35.1, 23.0, 19.8, 16.3, 15.9, 12.8, 6.8 ppm. HRMS

(ESI). Calcd for C₃₅H₄₈ClNO₁₀Na: 700.2864. Found: 700.2852.

Acknowledgment. We thank Dr. Dean Toste for helpful

discussions. We thank the National Science Foundation and the

National Institutes of Health (Grant GM 33049) for their

generous support of our programs. O.D. was supported in part

by a fellowship from Association pour la Recherche contre le

Cancer (ARC). J.L.G. was supported in part by a NIH

postdoctoral fellowship from the National Cancer Institute. Mass

spectra were provided by the Mass Spectroscopy Facility at the

University of CaliforniasSan Francisco supported by the NIH

Division of Research Resources and the Mass Spectrometry

Facility at University of CaliforniasIrvine. We thank Dr. John

Greaves of the latter facility for his assistance. We are grateful

to Dr. Diane Harvey, Department of Cancer Research, Merck

(3aR,4S,7R,7aR)-6-[(1S,5R,9R,10R,11R,12R)-(E)-5-[(1E,3E)-6-

((1S,2R)-2-Chlorocyclopropyl)hexa-1,3-dien-5-ynyl]-1-hydroxy-9-

9

10414 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

Novel Antitumor Agent Callipeltoside A

A R T I C L E S

1

Research Laboratories, for performing the biological testing and

Dr. Samuel Graham for assistance in arranging for the testing.

60, 62-65, 74-76, Tables 3-5, and figures showing the H

and ¹³C NMR spectra of natural and synthetic callipeltoside A

(PDF). This material is available free of charge via the Internet

at http://pubs.acs.org.

Supporting Information Available: Text giving general

experimental conditions and preparations of 5, ent-6, 8-10, 13,

16, 25a,b, 27, 29, 30, 32, 37, 45, 47, 48, 51-53, 56, 57, 59,

JA0205232

9

J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10415

Article Doi

Callipeltoside A: Total synthesis, assignment of the absolute and relative configuration, and evaluation of synthetic analogues

DOI: 10.1021/ja0205232

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Article abstract of DOI:10.1021/ja0205232

Full text of DOI:10.1021/ja0205232

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