Syntheses of discodermolides useful for investigating microtubule binding and stabilization

11054

J. Am. Chem. Soc. 1996, 118, 11054-11080

Syntheses of Discodermolides Useful for Investigating

Microtubule Binding and Stabilization

Deborah T. Hung, Jennie B. Nerenberg, and Stuart L. Schreiber*

Contribution from the Howard Hughes Medical Institute, Department of Chemistry and Chemical

Biology, HarVard UniVersity, Cambridge, Massachusetts 02138

ReceiVed April 26, 1996^X

Abstract: Discodermolide is a marine natural product reported to inhibit the proliferation of T cells and exhibit

immunosuppresive activity. Total syntheses of the natural antipode of discodermolide and several variants are reported.

These studies provide reagents to investigate discodermolide’s recently discovered ability to bind and stabilize

microtubules in cells. Retrosynthetically, the polypropionate is divided into three fragments of approximately equal

complexity. This modular strategy provides convergency in the synthesis and facilitates the preparation of

discodermolide-based reagents.

Dissecting the regulatory pathways of the cell cycle is crucial

extension of a molecular handle without significant loss of

binding affinity. Our solutions to both of these challenges are

reported herein.

to understanding normal processes such as cell growth and

division, as well as abnormal ones such as cancer. Significant

progress has been made in identifying the choreographed

entrance and exit of specific kinases and phosphatases acting

to drive the cycle forward. Nevertheless, much of this regulation

remains a mystery.¹

Synthetic Plan. The design of the total synthesis was based

on a convergent approach to discodermolide, 1a. Retrosyn-

thetically, the polypropionate backbone was divided into three

fragments of roughly equal complexity (Figure 1). One of the

disconnections is between C7 and C8; in the synthetic direction,

this manipulation corresponds to a nucleophilic addition of the

appropriate synthon 3 to aldehyde 2. The other disconnection

is between C15 and C16; in the synthetic direction, this step

corresponds to an alkylation of a C17-ketone, 4a or 4b, with

an appropriate alkylating agent.

A common stereochemical triad appears in each of these three

fragments (2, 3, 4) that can be retrosynthetically reduced to the

homoallylic alcohols 5 and 6. With three stereocenters set in

each fragment by these homoallylic alcohols, nine of discoder-

molide’s 13 stereocenters are quickly established by methods

developed by Roush and co-workers for the addition of chiral

crotylboronates to a chiral aldehyde.⁶The two homoallylic

alcohols are readily prepared in high diastereomeric excess from

methyl (S)-(+)-3-hydroxy-2-methylpropionate.

Because the absolute stereochemistry of discodermolide was

not known at the outset of this work, both antipodes of starting

materials and chiral reagents were required.⁷This requirement

was fulfilled by the commercial availability of both enantiomers

of a 3-hydroxy-2-methylpropionate ester and access to both

enantiomers of Roush’s chiral boronates. All other stereocenters

of discodermolide are set by substrate-controlled reactions.

Synthesis of the Protected C1-C7 Lactone (2). The most

critical issue in the synthesis of the lactone fragment 2 was to

control the configuration of the C5 stereocenter. Starting from

5, we used the existing stereocenter and the conjugate addition

method of Evans and Gauchet-Prunet⁸(Scheme 1). The

homoallylic alcohol 5 was oxidatively cleaved and homologated

to the trans enoate 7 by a Wittig olefination. Treatment of 7

with benzaldehyde and catalytic KHMDS provided, after

The convergence of natural products chemistry with cell

biology has provided new tools to probe these processes.²

Natural products that inhibit proliferation by causing a specific

block in the cell cycle provide clues to cellular targets essential

to intracellular signaling pathways and provide a novel means

of studying their function. An affinity-based search for these

targets can aid in elucidating events in a natural product-sensitive

pathway, including events downstream of the direct block.

The marine natural product discodermolide (1a)³is a promis-

ing candidate for this approach. Originally isolated from the

sponge Discodermia dissoluta, discodermolide was shown to

possess immunosuppressive activity.⁴It inhibits purified murine

T cell proliferation with an IC₅₀of 9 nM, inhibits the mixed

leukocyte reaction, and suppresses graft-versus-host disease in

transplanted mice. Since only minute amounts (9 mg) of the

compound could be isolated from its natural source, a synthetic

process yielding larger quantities of discodermolide, including

a radiolabeled variant, was required.⁵Second, in order to use

affinity-based methods to study its cellular receptor, structural

variants of discodermolide are required that would allow the

^XAbstract published in AdVance ACS Abstracts, November 1, 1996.

(1) (a) Murray, A. W. Nature 1992, 359, 599. (b) Hunter, T. Cell 1993,

75, 839.

(2) (a) Schreiber, S. L. Chem. Eng. News 1992, 70 (43), 22. (b) Sigal,

N. H.; Dumont, F. J. Annu. ReV. Immunol. 1992, 10, 519. (c) Hung, D. T.;

Jamison, T. F.; Schreiber, S. L. Chem. Biol. 1996, 3, 623-639.

(3) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E. J. Org. Chem.

1990, 55, 4912 (correction: J. Org Chem. 1991, 56, 1346).

(4) (a) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;

Gunasekera, S. P. Transplantation 1991, 52, 650. In ViVo studies were also

performed: (b) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera,

M.; Gunasekera, S. P. Transplantation 1991, 52, 656.

(5) (a) Nerenberg, J. B.; Hung. D. T.; Somers, P. K.; Schreiber, S. L. J.

Am. Chem. Soc. 1993, 115, 12621. We have reported an initial communica-

tion of the total synthesis of (-)-discodermolide. Total synthesis of the

(-)-enantiomer has also been reported: (b) Smith, A. B.; Qiu, Y.; Jones,

D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. Other synthetic

efforts have been reported: (c) Golec, J. M. C.; Jones, S. D. Tetrahedron

Lett. 1993, 34 (50), 8259. (d) Golec, J. M. C.; Gillespie, R. J. Tetrahedron

Lett. 1993, 34 (50), 8167. (e) Evans, P. L.; Golec, J. M. C.; Gillespie, R.

J. Tetrahedron Lett. 1993, 34 (50), 8163. (f) Paterson, I.; Wren, S. P. J.

Chem. Soc., Chem. Commun. 1993, 24, 1790. (g) Yang, G.; Myles, D. C.

Tetrahedron Lett. 1994, 35 (16), 2503.

(6) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,

112, 6348.

(7) In fact, in our previously reported, initial synthesis of (-)-

discodermolide,^5awe arbitrarily chose to start with (R)-(-)-3-(hydroxy-

methyl)propionate, which resulted in the synthesis of the unnatural

enantiomer. While the stereochemistry drawn in Schemes 1-9 corresponds

to that of the natural enantiomer, the compounds depicted in Schemes 1, 2,

and 4-9 were initially characterized as the enantiomers of those drawn.

(8) Evans, D. A.; Gauche-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11055

Scheme 1

Scheme 2

thiophenyl group. The thiophenyl acetal can be hydrolyzed later

under mild conditions (Hg⁺²), with subsequent oxidation of the

lactol to the lactone. Conversion to the thiophenyl acetal was

accomplished by treatment with PhSSiMe₃, ZnI₂, and Bu₄NI,

to give 10 as a 2:1 mixture of anomers, â:R, separable by silica

gel flash chromatography.¹³

Synthesis of the C9-C15 Fragment (3). As the middle

fragment of the three-component disconnection, the elaboration

of the precise C9-C15 piece (3) would be determined by the

order of the couplings. Our initial approach involved forming

the C15-C16 bond first Via an alkylation of an enolate derived

from 4b with a C9-C15 allylic bromide, followed by elabora-

tion of C8 and C9 to the appropriate synthon for addition to

the C1-C7 lactone fragment.

The major challenge in the synthesis of the C9-C15 fragment

was the preparation of the trisubstituted olefin with stereochem-

ical control (Scheme 2). Homoallylic alcohol 6 was silylated

and oxidatively cleaved to provide an intermediate aldehyde.

The efficient construction of the cis-trisubstituted olefin was

accomplished by the method of Still and Gennari,¹⁴with the

potassium salt of (CF₃CH₂O)POCH(Me)CO₂Me. Reduction of

the resulting enoate by LiAlH₄provided allylic alcohol 11 in

good yield, without any 1,4-overreduction. Prior to coupling,

this alcohol could be converted to the allylic bromide for

alkylation of a C16-C24 ketone fragment.

Figure 1. Retrosynthetic analysis of discodermolide.

deprotection, acetal 8. The internal Michael addition of the

hemiacetal intermediate proceeded with complete stereoselec-

tivity.⁹Deprotection of the tert-butyldimethylsilyl (TBS) group

was difficult due to the lability of the benzylidene acetal, but

proceeded cleanly with anhydrous HF-pyridine to give 8.

Dess-Martin oxidation¹⁰of 8 to the corresponding aldehyde,

followed by immediate treatment with Amberlyst-15, an ion

exchange resin, in methanol provided the dimethyl acetal of

the the aldehyde. The Amberlyst-15 was removed by filtration,

and camphorsulfonic acid was added to cleave the benzylidene

acetal with concomitant cyclization to yield 9 as a 1.8 to 1

mixture of â to R anomers. The anomers could be separated

by silica gel flash chromatography or subjected as a mixture to

silylation and conversion to the Weinreb amide¹¹by lithium

hydroxide hydrolysis of the methyl ester and dicyclohexylcar-

bodiimide (DCC) coupling with N,O-dimethylhydroxylamine.¹²

Another important issue was the choice of functionality to

mask the lactone until late in the synthesis. The lactone was

protected in its lower oxidation state, as the lactol, by a

Synthesis of the C16-C24 Ketone (4a,b).¹⁵The major

considerations in the construction of the ketone fragment were

the choice of protecting group for the C19 alcohol and the

synthesis of the cis-diene. The protecting group on the C19

alcohol had to be orthogonal to the silicon-based protecting

groups of the other alcohols since it would have to be removed

selectively and carbamoylated late in the synthesis. In addition,

we needed to protect the alcohol while preserving the chelating

ability of the oxygen in the form of a protected ether since we

thought that chelation would play an important role in the

(13) (a) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K.

J. Am. Chem. Soc. 1988, 110, 4696. (b) Hanessian, S.; Guindon, Y.

Carbohydr. Res. 1980, 86, C3. For purposes of characterization, the anomers

were separated by silica gel flash chromatography and carried on indepen-

dently. However, they were equally efficacious in the remainder of the

synthesis of natural discodermolide.

(14) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.

Experimental modifications in: Wang, Z. Ph.D Thesis, Yale University,

1988.

(9) The relative stereochemistry was confirmed by NOE experiments.

(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.

(11) Levin, J. I.; Turos, E.; Weinreb S. M. Synth. Commun. 1982, 12,

989.

(12) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc. 1986,

108, 6016.

11056 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

Scheme 3

Figure 2. Predicted chelate model for C15-C16 alkylation reaction.

and the PMB ether oxygen would chelate a common lithium

counterion¹⁹(Figure 2). In this model, the transient six-

membered ring would allow the methyl group at C18 to confer

a facial bias to the approaching bromide approach, affording

the desired stereochemistry at C16.

Allylic alcohol 11 was converted to the bromide by treatment

with mesyl chloride, followed by lithium bromide in acetone²⁰

(Scheme 4). It was then treated with the (Z)-lithium enolate of

4b, formed with LiN(SiMe₂Ph)₂at -78 °C.²¹This provided a

10:1 ratio of diastereomers, 15, whose configurations at C16

were not rigorously assigned at the time.²²On the basis of the

model predicted by the chelated intermediate (Figure 2), the

major product was presumed to be the desired C16 epimer.

stereochemical outcome of the alkylation coupling. We chose

to protect homoallylic alcohol 6 as the p-methoxybenzyl (PMB)

ether by treating 6 with PMB bromide and sodium hydride

(Scheme 3).¹⁶Oxidative cleavage of the PMB-protected alcohol

provided an intermediate aldehyde that could be converted to

the diene by a two-step procedure. Conversion to the cis vinyl

iodide 12 was accomplished by a Wittig reaction with (iodom-

ethylene)triphenylphosphorane.¹⁷The vinyl iodide was con-

verted to the diene 13 by a palladium-catalyzed coupling with

vinylzinc bromide,¹⁸followed by TBS deprotection with trif-

luoroacetic acid. Dess-Martin oxidation with subsequent

Grignard addition of methyl- or ethylmagnesium bromide

provided a 4:1 mixture of epimeric alcohols. A subsequent

oxidation with Dess-Martin periodinane provided ketones 4a,b.

Initial Coupling Strategy. Our initial approach to couplings

involved performing the alkylation of ethyl ketone 4b with the

bromide derived from allylic alcohol 11. There is ample

precedent in the literature for facial selectivity in alkylation or

aldol reactions based on enolate geometry and chelation. We

anticipated that both the intermediate enolate derived from 4b

Reduction of the ketone at C17 with LiAlH₄at -78 °C

produced a 2:1 ratio of epimers at C17.²³Protection of the

secondary alcohol as a TBS silyl ether, followed by selective

deprotection of the primary TBS group wtih TFA:H₂O:THF,

completed the elaboration of a C9-C24 fragment. We then

turned our attention to formation of the C7-C8 bond.

Model studies on nucleophilic additions to the Weinreb amide

10 had shown that lithium acetylide could be added to give the

ynone in good yield. LiAlH₄reduction and catalytic hydroge-

nation using Lindlar catalyst poisoned with quinoline demon-

strated that a model cis-allylic alcohol could be synthesized by

the nucleophilic addition of a lithium acetylide to the Weinreb

amide.

On the basis of these studies, we proceeded to convert the

primary alcohol derived from 15 to the requisite acetylene by

Swern oxidation²⁴and one carbon homologation to the desired

acetylene 16 using Gilbert’s reagent.²⁵Deprotonation of 16 to

the lithium acetylide was best accomplished by lithium diiso-

propylamide (LDA) as judged by deuterium quenching experi-

(15) An alternative synthesis of the ketone fragment begins with a

different homoallylic diastereomer.

1

ments and H NMR. However, the lithium acetylide derived

from 16 failed to add to amide 10, even after many variations.²⁶

Attempted additions to aldehyde 2, derived from the LiAlH₄

reduction of 10, also were unsuccessful.²⁷

A new strategy for the formation of the C7-C8 bond involved

the NiCl₂/CrCl₂mediated coupling of aldehydes and iodoacety-

lenes or iodoolefins, developed by Nozaki and Kishi.²⁸These

reactions are performed under mild conditions with excellent

functional group compatibility. Attempted coupling with the

(20) Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. J. Am. Chem.

Soc. 1985, 107, 2730.

(21) Assignment of the Z-enolate geometry was based on correlation with

literature precedents for enolate geometry resulting from formation condi-

tions. Conditions examined included lithium hexamethyldisilazide (LiH-

MDS,) LiN(SiMe₂Ph)₂, dibutylboron triflate and Hunig’s base, and lithium

2,2,6,6-tetramethylpiperidide (LiTMP).

(22) Subsequent assignment of analogous substrates from this alkylation

reaction now suggest that the stereochemical outcome is opposite of that

predicted by the chelated transition state model.

(23) By analogy to other similar substrates that have now been rigorously

assigned, the major epimer corresponds to the desired 1,3-syn-alcohol.

(24) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.

(16) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.

Tetrahedron 1986, 42, 3021.

(17) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.

(18) Gardette, M.; Jabri, N.; Alexakis, A.; Normant, J. F. Tetrahedron

1984, 40, 2741.

(19) For a discussion of protecting groups and chelation in addition

reactions see: (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23,

556. (b) Masamune, S.; Ellingboe, J. W.; Choy, W. J. Am. Chem. Soc.

1982, 104, 5526. (c) Heathcock, C. H. In Asymmetric Synthesis; Morrison,

J. D., Ed. Academic Press: Orlando, FL, 1984; Volume 3, Chapter 2. (d)

Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc.

1981, 103, 3099. Use of a lithium enolate with an R-alkoxy chelating

protecting group in an aldol reaction has appeared: (e) Choudhury, A.;

Thornton, E. R. Tetrahedron Lett. 1993, 34, 2221.

(25) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973,

151; Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11057

Scheme 4

Scheme 5

cis vinyl iodide corresponding to 16 and aldehyde 2 resulted in

recovery of the protonated olefin, suggesting that metal insertion

into the C-I bond had occurred, but no addition had taken place.

Conversion of 16 to the iodoacetylene was achieved by

treatment with iodine and morpholine.²⁹A coupling of this

iodoacetylene and aldehyde 2, in the presence of catalytic

0.011% NiCl₂/CrCl₂, resulted in a 65% yield of two propargylic

alcohols in a ratio of 2:1, the major epimer being the desired

one.³⁰The full carbon backbone of discodermolide having been

assembled, only semihydrogenation of the fully coupled product

remained in order to attain 17.

Unfortunately, extensive investigation of reduction conditions

failed to identify conditions that would selectively reduce the

acetylene to the cis olefin, while leaving the terminal diene

31

intact. Hydrogenation over Lindlar catalyst or Pd/BaSO₄

resulted in only reduction of the terminal C23-C24 olefin. Other

reductions also failed to yield the desired product without

scrambling of the terminal diene.³²It became clear that the

reduction of the acetylene in the presence of the competing

terminal diene was problematic and that an alternative coupling

strategy was required.

Revised Coupling Strategy. Reversing the order of the

coupling reactions, namely performing the Nozaki-Kishi reac-

tion first between aldehyde 2 and a C8-C15 acetylene fragment

with subsequent reduction to the cis olefin, followed by

alkylation of ketone 4 circumvented the difficulties encountered

with the hydrogenation. This approach required a minor

revision in the elaboration of the C8-C15 fragment (Scheme

5).

The allylic alcohol 10 was protected as the pivaloate and

selectively deprotected with HF-pyridine buffered with excess

pyridine to provide the corresponding primary alcohol. This

alcohol was subjected to the same series of transformations that

was performed on 15 to afford acetylene 18 in excellent yield.

Conversion to the iodoacetylene and coupling of the iodoacety-

lene with aldehyde 2 under Nozaki-Kishi conditions yielded

(26) Changing counterions to cerium, magnesium, boron, and potassium,

or adding HMPA or TMEDA to the reaction medium did not have any

effect on the addition. The feasibility of a lithium vinyl anion addition to

the Weinreb amide or aldehyde was also investigated. The vinyl iodide

corresponding to 16 was synthesized by the addition of (iodomethylene)-

triphenylphosphorane to the common aldehyde leading to 16. Metallation

using tBuLi, however, resulted in decomposition of the substrate.

(27) Attempted addition of the acetylide to MeI also resulted in recovery

of starting material. It is now presumed that the terminal acetylene with its

branched substitution pattern on the other side behaves quite sterically large,

perhaps causing the difficulty in addition. Its sterically demanding behavior

is confirmed by the CBS reduction of ynone 23, in which the acetylene

functionality behaves as the larger group in the directed reduction.

(28) (a) Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463. (b)

Takai, K.; Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nozaki, H. Tetrahedron

Lett. 1985, 26, 5585. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am.

Chem. Soc. 1986, 108, 5644. (d) Takai, K.; Tagashira, M.; Kuroda, T.;

Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.

(29) Goekjian, P. G. Ph.D. Thesis, Harvard University, 1990. In our case,

this conversion was accompanied by some isomerization of the terminal

diene.

(31) For a review of semihydrogenation, see: Marvell, E. N.; Li, T.

Synthesis 1973, 457.

(30) The assignment of these alcohols is done by correlation to similar

substrates that have been rigorously assigned (Vide infra).

(32) Other reduction conditions tried were activated zinc with KCN, Cu/

Ag, copper hydride, trimethylstannylcopper, or tantalum/zinc.

11058 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

Scheme 6

molide in 22. At this time, the C16 stereochemistry was not

assigned, but the major component of the 7:1 mixture was

presumed to be the desired epimer based on our initial model.

Final elaboration of 22 was achieved by the LiAlH₄reduction

of the ketone. The reduction at -78 °C provided a 2:1 ratio of

alcohols, the major one being the desired epimer.³⁶Protection

of the C17 alcohol as the diethylisopropylsilyl (DEIPS) ether

afforded 24³⁷(Scheme 7). Conversion of the thiophenyl acetal

to the lactone was accomplished in two steps. Hydrolysis of

24 with mercuric chloride³⁸afforded a mixture of lactols that

was oxidized with Jones reagent³⁹to provide the corresponding

lactone.

Finally, DDQ deprotection of the PMB ether,¹⁶carbamoyl-

ation with trichloroacetyl isocyanate,⁴⁰and hydrolysis of the

trichloroacetyl group with potassium carbonate in methanol

afforded 25. Final deprotection of the silyl groups was

accomplished by treatment with excess p-toluenesulfonic acid

in THF and water to yield 1b.

19a as the major epimer in a 2:1 mixture.³³The minor epimer

19b could be efficiently recycled by Swern oxidation to ketone

23, followed by Corey’s asymmetric reduction with catecholbo-

rane and catalytic B-butyloxazaborolidine derived from D-

proline³⁴(Scheme 6). It is interesting to note that the acetylene

behaves as the larger substituent relative to the methylene group

in Corey’s model for stereoselectivity.³⁵

While high-resolution mass spectrometry revealed that the

molecular weight of 1b was identical to that of discodermolide,

1

the H NMR spectrum was not identical to that obtained for

Semihydrogenation of 19a with 10% palladium on carbon,

TBS protection, and removal of the pivaloyl group with

DIBAL-H afforded allylic alcohol 20. Conversion to the

bromide completed the synthesis of 21, which was then ready

to be coupled with ketone 4b.

The alkylation of 4b by 21 was peformed under the same

conditions that had been used in the initial coupling strategy,

forming the Z-enolate with LiN(SiMe₂Ph)₂at -78 °C. This

coupling thus afforded the full carbon backbone of discoder-

the natural product. Conversion to the tetraacetate also showed

discrepancies in the H NMR spectrum with that reported in

the literature. It became clear that we had synthesized an isomer

of discodermolide.

Correction of the C16 Stereochemistry. After a careful

re-examination of the assignment of each of the stereocenters,

and ruling out any epimerization that could have occurred during

the synthesis,⁴¹we suspected that the most likely difference

between the isomer that we had synthesized 1b and natural

discodermolide 1a was the C16 stereocenter set by the alkylation

reaction. COSY and NOESY studies on the tetraacetate of 1b

helped to confirm that we did not have a constitutional isomer

of discodermolide and to suggest a more extended conformation

1

(33) The C7 stereochemistry has been assigned by two methods.

Conversion to the mandelate esters by the method of Trost et al.: Trost, B.

M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;

Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J.

P. J. Org. Chem. 1986, 51, 2370. Also, the coupling products 18a and 18b

were converted to anti- and syn-1,3-diols, respectively, and assigned by

the formation of the 13C-acetonides by stereochemical analysis. The

acetonide of the major isomer had ¹³C resonances at 23.83 and 28.15 ppm,

whereas the acetonide of the minor isomer had ¹³C resonances at 19.78

and 30.03 ppm. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.

1993, 58, 3511.

(36) The C17 stereocenter in this and other related substrates was assigned

by treating the alcohol with anhydrous DDQ and performing NOE studies

on the resulting benzylidene acetal.

(37) DEIPSOTf was prepared from DEIPSCl in analogy to: (a) Corey,

E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455.

DEIPSCl was prepared according to: (b) Toshima, K.; Tatsuta, K.;

Kinoshita, T. Bull. Chem. Soc. Jpn. 1988, 61, 2369. This protecting group

was chosen after the TBS ether was shown to be stable to all deprotection

conditions and the TES ether was shown to be too labile to survive the

subsequent Jones oxidation conditions.

(38) Ikeda, T.; Hutchinson, C. R. J. Org. Chem. 1984, 49, 2837.

(39) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:

New York, 1967; Volume 1, p 142. We found that the ca. 1.2 M preparation

of this reagent was most effective for this oxidation.

(34) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem Soc. 1987,

109, 5551 and (b) Link, J. O. Ph.D. Thesis, Harvard University, 1992.

(35) Model studies on simple acetylene systems in the CBS reduction

have shown no appreciable stereoselectivity. Unpublished results of K. A.

Cimprich, D. T. Hung, S. L. Schreiber, and E. J. Corey. This is in contrast

to other published results that are consistent with Corey’s originally proposed

model, with the alkynyl substituent behaving as the smaller group. Parker,

K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61 (9), 3214.

(40) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.

(41) Epimerization during the alkylation reaction was ruled out by

resubjection of the alkylated product 27a to the reaction conditions without

any change in starting material ratios.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11059

Scheme 7

at C18, and yet, the minor product corresponds to approach from

the re face. An alternative model does not invoke a lithium

chelate; instead, the geometry of the enolate intermediate could

be determined by allylic (A^1,3) strain, and the conformation in

which the double bond of the enolate eclipses the C18-H18

bond may predominate (Figure 3).

Strategy for Final Elaboration to Discodermolide. The

final challenges in the synthesis of discodermolide were the

stereoselective reduction of the C17 ketone and selective

carbamoylation of the C19 alcohol. Several conditions were

examined for the reduction (Table 1).

In the reduction of the C16 methyl epimer 22, LiAlH₄

provided a 2:1 ratio of epimers, favoring the desired R

configuration at C17. Under these same conditions however,

reduction of 27a, with the corrected C16 methyl stereochemistry,

gave a 1:2 ratio, in favor of the undesired epimer. Other

reductions, including additives to promote â-chelation⁴⁴with

the C19 PMB ether, gave the same product ratios. In contrast,

reduction of the â-hydroxy ketone (resulting from deprotection

of the PMB ether by DDQ) by the Prasad-Narasaka method⁴⁵

using NaBH₄/Et₂BOMe yielded the syn-1,3-diol with selectivity

of 15:1. These results suggest that in general, the â-alkoxy

substituent in this substrate does not provide significant chelation

control, either in the syn-reduction of the ketone or in the

alkylation reaction. Instead, the LiAlH₄selectivity in this

substrate, for the two C16 methyl epimers, is more likely

controlled by a Cram-like model of addition.

Unfortunately, the good selectivity obtained in the Prasad-

Narasaka reduction could not be exploited because of the

inability to carbamoylate selectively the C19 alcohol over the

C17 alcohol. This problem was circumvented when it was

discovered that reduction of the C17 ketone with the carbamate

already installed at C19 gave excellent selectivity for the correct

R configuration. With the bulky lithium aluminum tri-tert-

butoxy hydride, a 30:1 preference for the desired epimer was

observed. It is presumed that the neighboring carbamate may

facilitate chelation-controlled reduction. This same selectivity

is observed for the carbamoylated substrate with the opposite

stereochemistry at C16.

Figure 3. Models for C15-C16 alkylation reaction.

to the isomer, relative to discodermolide. This conformation

could be consistent with a structure with the opposite stereo-

chemistry at C16. In a model derived from the originally

reported crystal structure,³inversion of the C16 stereochemistry

would result in two syn-pentane interactions between C30 (the

C16 methyl group) and both C29 and C31 (Scheme 7). These

interactions can be minimized by twisting the structure into a

more extended conformation, similar to that observed in NOESY

studies.

The most straightforward method to correct the C16 stereo-

chemistry was to perform the alkylation with the E-enolate rather

than the Z-enolate of 4b. The E-enolate derived from 4b was

obtained with lithium 2,2,6,6-tetramethylpiperidide (LiTMP) by

the method of Collum.⁴²Under these conditions, the reaction

with bromide 21 resulted in a 1:1 mixture of products. This

result suggests that the E-enolate geometry may be equilibrating

during the reaction prior to addition. (The corresponding Z-

and E-silyl enol ethers, formed by treatment of the enolates with

TMSCl, were determined to be stereochemically pure in a ratio

1

of greater than 10:1 by H (NOESY) and¹³C NMR.) Another

alternative to reversing the stereochemistry at C16 takes

advantage of the stereoselectivity observed with the Z-enolate.

Alkylation of a Z-enolate derived from 26a with methyl iodide

would probably proceed with the same facial bias as observed

with 4b, affording the correct desired stereochemistry in 27a

(Figure 3). Access to 26a is provided by a prior alkylation of

the methyl ketone 4a with bromide 21 (Scheme 8).

This alkylation reaction has now been studied by several other

groups with results that are consistent with those reported here.⁴³

We rationalize the unexpected stereochemical outcome by

revising our initial chelate model. Our original model (Figure

2) assumes that approach by the allylic bromide from the si

face of the chelate would be disfavored due to the methyl group

The final elaboration to discodermolide proceeded by trans-

formation of the thiophenyl acetal to the lactone, DDQ depro-

tection of the PMB ether, carbamoylation, and reduction of the

ketone to provide fully protected discodermolide (Scheme 9).

(43) (a) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35 (9), 1313.

(b) Clark D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58 (22) , 5878.

(44) For examples of the importance of the â-alkoxy group in the

stereochemical course of addition to aldehydes, see: (a) Keck, G. E.;

Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847. (b) Keck, G. E.;

Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51, 5480.

(45) (a) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,

M. J. Tetrahedron Lett. 1987, 28, 155. (b) Narasaka, K.; Pai, F. C.

Tetrahedron 1984, 40, 2233.

(42) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991,

113, 9571.

11060 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

Scheme 8

(+)-antipode ([R]²⁰_D) +14.0 (c ) 0.6, methanol), as described

herein, and characterization of the biological activities of both

enantiomers. This biological characterization allowed unequivo-

cal assignment of the absolute stereochemistry to be as drawn

in (+)-1a.

Table 1. Diastereoselectivities for C17-syn Reduction

Syntheses of Discodermolides Suitable for Studying In-

teractions with the Discodermolide Receptor. The most direct

approach to receptor isolation and purification exploits the high

affinity interaction between receptor and ligand. Indeed, a

tritiated variant of discodermolide (C17-[³H]-(+)-discoder-

molide), prepared by a modification of the route described

above,⁴⁶led to the discovery that discodermolide binds directly

to microtubules.⁴⁷Binding was shown to be stoichiometric with

tubulin dimer and mutually exclusive with and more potent than

taxol-binding to microtubules. Discodermolide-binding to mi-

crotubules was also shown to occur in vivo. These findings

are in agreement with the discovery that discodermolide

stabilizes microtubules and causes mitotic cell cycle arrest.⁴⁸

Concurrent with these cellular and biochemical studies, we

designed and synthesized several structural variants of (+)-

discodermolide that should be useful in further characterizing

the interaction of discodermolide with its receptor.

Several chemical criteria must be fulfilled in order to develop

a useful binding reagent. Most importantly, in order to attach

the ligand to another entity for immobilization or fluorescence-

based visualization, the molecule must permit extension of a

molecular “handle” off of it, without abolishing cellular activity

or binding affinity. Any alteration of the molecule must neither

sterically interfere with the ligand-receptor interface nor

indirectly affect recognition by significantly altering the con-

formation of the ligand. In many cases, such derivatization may

be done on the natural product itself, or some compound derived

therein.⁴⁹In other cases, the binding reagent may require

extensive chemical synthesis.

configuration diastereoselectivity

conditions

LiAlH₄

LiAlH₄, LiI

NaBH₄, LiI^a

NaBH₄,

MgBr₂(Et₂O)₂

DIBAL-H

R

at C16

of R:S at C17

PMB

R

S

2:1

1:2

a

H

S

R

S

R

1:1

a

NaBH₄

NaBH₄, Et₂BOMe^b

15:1^c

2.5:1

30:1^c

a

NaBH₄

CONH₂

a

b

LiAlH(OtBu)₃

b

^aReduction was performed on the lactone substrate. Treatment of

the thiophenyl acetal resulted in reduction of the pyran ring. ^bReduction

was performed on both the thiophenyl acetal and the lactone substrates.

Ratios were the same for both substrates. ^cRatios were determined by

HPLC. All other ratios were determined by proton NMR.

Deprotection of the silyl groups with 1% HCl in methanol

provided synthetic discodermolide 1a. This total synthesis

provided natural discodermolide in 36 steps, with an overall

yield of 4.3% over 24 steps (the longest linear sequence). The

synthetic material was identical to natural discodermolide as

judged by H and ¹³C NMR, IR, and high-resolution mass

1

Syntheses of Structural Variants of Discodermolide. An

insufficient supply of natural (+)-discodermolide exists to

provide material for derivatization of the natural product itself.^3,4

Thus, in order to develop probe reagents, synthetic variants

of the natural product were prepared to determine the least

intrusive modification that could be made without destroying

the antiproliferative activity and, more importantly, without

spectrometry.

The only issue that remained unresolved at the completion

of the total synthesis was the assignment of absolute stereo-

chemistry of the natural product. In contrast to the current study,

the initial synthesis of discodermolide that we reported⁵began

with (R)-(-)-3-hydroxy-2-methylpropionate and resulted in the

(-)-enantiomer ([R]²⁰) -13.0 (c ) 0.6, methanol)). The

D

(47) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996, 3 (4),

287.

(48) ter Harr, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R.

E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996,

35, 243.

(49) (a) Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L.

Nature 1989, 341, 758. (b) Fretz, H.; Albers, M. W.; Galat, A.; Standaert,

R. F.; Lane, W. S.; Burakoff, S. J.; Bierer, B. E.; Schreiber, S. L. J. Am.

Chem. Soc. 1991, 113, 1489. (c) Nadler, S. G.; Tepper, M. A.; Schacter,

B.; Mazzucio, C. E. Science 1992, 258, 484. (d) Crews,C. M.; Collins, J.

L.; Lane, W. S.; Snapper, M. L.; Schreiber, S. L. J. Bio. Chem. 1994, 269,

15411. (e) Crews, C. M.; Lane, W. S.; Schreiber, S. L. Proc. Nat. Acad.

Sci. U.S.A. 1996, 93, in press. (f) Taunton, J.; Hassig, C.; Schreiber, S. L.

Science 1996, 272, 408.

signs of the optical rotations of our synthetic discodermolide

and the natural product (reported:³([R]²⁰) +7.2 (c ) 0.72,

D

methanol))) were opposite; however, their small absolute values

diminished the confidence with which we could claim that the

two samples are enantiomeric. In addition, the assignment was

complicated by the observation that the synthetic (-)-antipode

was shown to be a potent inhibitor of cell proliferation.⁴⁶The

issue could only be clearly resolved by the synthesis of the other

(46) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. Chem. Biol. 1994,

1, 67.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11061

Scheme 9

oxidized to the lactone with Jones reagent. Silyl deprotection

with 1% HCl/methanol yielded a discodermolide variant without

C16-C24, 32. Similarly, a variant containing C8-C24 of

discodermolide 35, without C1-C7, was synthesized from

intermediate acetylene 18. Hydrogenation of 18 with palladium/

BaSO₄poisoned with quinoline³¹provided a terminal olefin

corresponding to the the cis C8-C9 olefin in natural discoder-

molide. Conversion of this olefin fragment to 35 was performed

analogously to the total synthesis. The observation that neither

of these two compounds was active in ViVo implied that the

full length of discodermolide is required for recognition by its

receptor.

Figure 4. Synthesis of stereoisomers of discodermolide.

At this point, analysis of the discodermolide structure and

our total synthesis allowed prioritization of potential targets that

would lead to binding reagents by the addition of an extension

(Figure 5). The obvious possibility is the acylation of one of

the four alcohol functionalities in discodermolide. Two con-

siderations warranted caution in this regard. Due to the

substitution pattern that creates the potential for development

of syn-pentane interactions following alteration of the natural

product, minor changes to the internal hydroxyls on C7 and

C11 may result in dramatic conformational changes, rendering

the variant inactive. Secondly, attempts to differentiate the

alcohols either by selective acylation of one hydroxyl in the

presence of the others, or by selective deprotection of a

tetrasilylated discodermolide, were not successful. The implica-

tion from these experiments was that any differentiation must

occur at some intermediate point along the total synthesis and

not at the end.

Binding Reagent Based on Site A. The C17-hydroxyl is

easily differentiable in intermediate 29 following reduction of

the ketone. This alcohol can be acylated with acetyl chloride/

pyridine and then deprotected with 1% HCl/MeOH to provide

the corresponding 17-acetyldiscodermolide 36 (Scheme 11). The

IC₅₀value of 70 nM for inhibition of proliferation was

promising. Unfortunately, all attempts failed to acylate this

hydroxyl with anything larger than acetyl chloride, including

acylation by N-Aloc-aminocaproic chloride with the bases

triethylamine, pyridine, and pyridine/DMAP, by N-Aloc-ami-

nocaproic acid using BOP or PyBroP,⁵⁰by N-Aloc-aminocaproic

isocyanate,⁵¹and finally, even acylation by propionyl chloride/

pyridine. Attempted acylations of 16-desmethyl discodermolide

also did not meet with success. The C17 hydroxyl may be either

too sterically hindered or too non-nucleophilic due to a hydrogen

bonding interaction with the neighboring carbamate to allow

addition of an extended linker that would be useful for synthesis

of a probe reagent.

altering binding to the cellular receptor. Thus, any synthesis

of potential probe reagents involves an active interplay between

synthetic efforts and cellular assays. Each compound that was

synthesized was tested for its ability to inhibit the replication

of cells by using a [³H]thymidine incorporation assay. Replicat-

ing cells incorporate thymidine into their DNA during the S

phase of the cell cycle.

The methodology we had previously established for synthesis

of the natural product^5ainfluenced our choice of synthetic

variants. The initial structural variants were simple stereoiso-

mers of discodermolide, resulting from elaboration of epimeric

side products to a final, fully deprotected product. Preparation

of these compounds is summarized in Figure 4.

Elaboration of the minor methyl epimer from the methyl

iodide alkylation (Scheme 8) resulted in 16-epi-discodermolide

1b. TBS deprotection of the minor epimeric alcohol produced

in the LiAlH(OtBu)₃reduction that yields 29 (Scheme 9)

afforded 17-epi-discodermolide 1c. Additionally, a 16-des-

methyl variant 31 was synthesized from the late intermediate

26b. The cell growth-inhibitory properties of these compounds

suggested that the conformation about C16 and C17 is critical

to discodermolide’s activity. Relative to discodermolide 1a,

which has an IC₅₀of 6 nM in the [³H]thymidine assay, 1b had

an IC₅₀value of 300 nM and 1c was completely inactive. In

contrast, the 16-normethyl compound 31 was as active in ViVo

as discodermolide itself. This finding became important in the

later development of binding reagents by obviating the second

alkylation step with methyl iodide and thus eliminating material

loss at that step.

The compounds that were next synthesized were truncated

versions of discodermolide, 32 and 35 (Scheme 10). An

examination of their activities was expected to give some

indication of whether the full length of the molecule is important

for receptor recognition. A C1-C15 fragment, 32, was made

by elaborating the allylic alcohol 20. The primary alcohol 20

was protected as the TBS ether, the thiophenyl acetal was

hydrolyzed with mercuric chloride, and the resulting lactols were

Binding Reagent Based on Site B. The C19 hydroxyl in

28 can likewise be easily differentiated and is selectively

(50) Coste, J.; Frereot, E.; Jouin, P. J. Org. Chem. 1994, 59, 2437.

(51) Satchell, D. P. N..; Satchell, R. S. Chem. Soc. ReV. 1975, 4, 231.

11062 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

Scheme 10

at C17) afforded variant 39. Deprotection of the Fmoc group

with piperdine yields a reagent that may help in characterizing

the binding properties of discodermolide.

Binding Reagent Based on Site C. Other variants that are

not directly accessible from a late intermediate could be accessed

fairly easily due to the convergent nature of our total synthesis.

One attractive target was a discodermolide variant 45 with an

extension off the terminal diene at C24. Such an addition should

not interfere with the conformation of the molecule significantly.

An extension was attained by a modified synthesis of the ketone

fragment 42, prior to the alkylation-based coupling (Scheme

13).

The major modification involved a palladium-catalyzed

coupling for synthesis of the cis-trans-diene in 42. Intermedi-

ate 14a was silylated and selectively deprotected with HF-

pyridine buffered with excess pyridine to give the primary

alcohol 40. Dess-Martin oxidation and Wittig olefination

afforded the corresponding cis-vinyl iodide. Only low conver-

sions were obtained in Stille couplings⁵²of the vinyl iodide and

various E-tributylstannanes with Pd(PPh₃)₄. However, Suzuki

coupling⁵³of the vinyl iodide and (E)-6-catecholboranoto-5-

hexen-1-ol pivalate,⁵⁴using Kishi’s modification with thallium

hydroxide,⁵⁵afforded the cis-trans-diene 41 in better yield. The

reaction was sluggish at room temperature, but proceeded

quickly upon heating to reflux in THF.

Figure 5. Potential sites for derivitization of discodermolide.

carbamoylated on route to the natural product. Treatment of

28 with acetyl chloride/pyridine yielded the corresponding

acetate of 28 (Scheme 12). Unfortunately, sodium borohydride

reduction of this compound resulted in acyl migration, giving

a 1:1 ratio of C17 and C19 acetates. Any attempt to separate

the acyl products failed due to migration that occurred during

silica gel flash chromatography.

Carbamoylation with a substituted isocyanate was envisioned

to afford a carbamate at C19 that would be less prone to

migration during reduction of the C17 ketone. Unfortunately,

all reactions of 28 with isocyanates or chloroformates failed,

with the exception of the highly reactive trichloroacetyl isocy-

anate⁴⁰used in the synthesis of the natural product. The

â-hydroxy ketone was not stable to the harsher conditions

needed to react the hindered secondary alcohol with an

isocyanate, affording only retroaldol products. Treatment of

28 with phosgene, followed by the addition of monoprotected

N-Aloc-1,6-hexanediamine returned only starting material.

Because of the inability to substitute selectively a linker for

the C19 carbamate without migration to C17, the â-acetyl

ketone, without reduction at C17, was deprotected to yield 37,

and tested for its ability to inhibit T cell proliferation. (Scheme

12). This compound was found to be completely inactive.

While thwarting efforts to produce a variant at C19 (site B),

these results did suggest a potential method to derivatize C17

(site A) (Scheme 12). Acylation of the C19 hydroxyl in 28 is

more facile than acylation of the C17 hydroxyl in 29, probably

due to less steric congestion â to an sp²rather than an sp³center.

Acylation of the desmethyl variant of 28 with N-Fmoc-

aminocaproic acid using EDC, DIPEA, and catalytic DMAP

afforded 38. Reduction of 38 with NaBH₄resulted in migration

of the aminocaproic group to a 1:1 mixture that was trapped

with Cl₃CONCO. The regio- and stereoisomers could be

separated by HPLC and silyl deprotection of the correct isomer

(carbamoylated at C19, acylated at C17, with the R-configuration

Tetrabutylammonium fluoride deprotection,⁵⁶followed by

Dess-Martin periodinane oxidation, afforded ketone 42, analo-

gous to ketone 4a with an additional trans-extension off the

diene. This ketone could be coupled to allylic bromide 21, and

elaborated to afford 45 in a manner analogous to that which

yielded natural discodermolide. The in ViVo activity of 45 was

encouraging, with an IC₅₀value of 70 nM, making this a prime

candidate for development as a binding reagent.

(52) (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813. (b)

Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c) Farina, V.;

Krishnana, B. J. Am. Chem. Soc. 1991, 113, 9585.

(53) (a) Miyaura, N.; Suginome, H.; Suzuki, A. Tetrahedron Lett. 1981,

22, 127. (b) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am.

Chem. Soc. 1985, 107, 972.

(54) This boronate was synthesized by heating 5-hexyn-1-ol pivalate with

1.5 equiv of catecholborane overnight at 80 °C. After removal in vacuo of

excess catecholborane, the product was sublimed at 160 °C, 0.5 mmHg.

Miyaura, N.; Suginome, H.; Suzuki, A Tetrahedron 1983, 39(20) 3271.

(55) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem.

Soc. 1987, 109, 4756.

(56) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11063

Scheme 11

Scheme 12

In the synthesis of an actual binding probe, the ideal extension

would contain a protected amine that could be easily deprotected

and coupled to an activated ester. We altered the synthesis of

45 to replace the pivaloyl group with an extension to a terminal

primary amine. In addition, the earlier observation that 16-

desmethyl discodermolide 31 was just as active as discoder-

molide 1a itself suggested that the absence of that methyl group

would not be detrimental to the probe reagent. Omitting the

methyl iodide alkylation step eliminated material loss obtained

as the undesired epimer. Coupled product 46 was reduced with

DIBAL-H at -78 °C to remove the pivaloyl group, with

concomitant reduction of the C17 ketone. The stereoselectivity

of the C17 reduction was inconsequential since it would be

reoxidized in the Jones oxidation and selectively reduced in later

steps. The diol was treated with N,N′-disuccinimidyl carbonate/

DMAP⁵⁷to provide selectively an intermediate mixed carbonate,

which reacted with N-Aloc-1,6-hexanediamine to provide a

carbamate.

The completion of the synthesis of this reagent mirrored that

of natural discodermolide. Mercuric chloride hydrolysis of the

thioacetal with subsequent Jones oxidation afforded lactone 47

in which the mixture of C17 alcohols had been reoxidized to

the ketone. DDQ deprotection, carbamoylation, LiAlH(OtBu)₃

reduction, and deprotection afforded discodermolide variant 49

that could be coupled to a matrix or other affinity compound.

When deprotected, the Aloc-carbamate would provide a terminal

primary amine for coupling.

the feasibility of acylation or extension at the C3 hydroxyl

demonstrated that a leaving group at C3 would be eliminated

during the final deprotection step, affording the enone. A variant

substituted at C1 in the lactol oxidation state, however, could

be accessed fairly easily since the lactone is masked as a

thiophenyl acetal until late in the total synthesis. Intermediate

27b could be easily elaborated to variant 50a in a manner

analogous to the final elaboration of discodermolide, without

the intervening thioacetal hydrolysis and Jones oxidation (Figure

6).

Both R and â thiophenyl anomers as well as the 16-desmethyl

version of the â anomer were synthesized, affording 50a, 50b,

and 51, respectively, to examine differences in activity due to

the stereochemistry at the anomeric center. The final depro-

tection of the R anomer was problematic, resulting in a 1:4 ratio

of the desired product to the methyl acetal from methanolysis.

In contrast, the â anomer resulted in a 9:1 ratio of desired to

side product. The anomers however, were equally active in

ViVo in inhibiting proliferation as natural discodermolide. While

these data were very encouraging, a concern is that this series

of compounds may be intracellularly bioactivated, perhaps

through enzyme-mediated hydrolysis of the thioacetal, and

possibly even oxidation to the lactone. Nevertheless, this series

of compounds was elaborated into binding reagents.

Exchange of the thiophenyl group to a different, amino-

functionalized thiol to form another S,O-acetal was preferable

to an O,O-acetal due to relative stability both to the deprotection

and, potentially, in ViVo conditions. On a model system

corresponding to 10 (Scheme 2), protected amino-substituted

thiophenols failed to react with the lactol or methyl acetal under

the same conditions in which the thiophenyl group was installed

(PhSTMS, ZnI₂, Bu₄NI).¹³Exchange to an alkanethiol, N-Aloc-

Binding Reagent Based on Site D. The lactone ring

presented another region of the molecule that might be altered

with minimal disturbance of conformation. Model studies on

(57) Ghosh, A. K.; Duong, T. T.; McKee, S. P. Tetahedron Lett. 1992,

33, 2781.

11064 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

Scheme 13

To circumvent this hydrolysis problem, exchange to a linker

could be done after the deprotection step. Studies in glycosy-

lation chemistry have resulted in several methods for making

O,O-acetals from thioacetals, including Nicoloau’s NBS/4 Å

sieves method⁵⁹and Kahne’s sulfoxide method.⁶⁰The most

reproducible method in our hands involved treating the thioacetal

38

51 with HgCl₂in a 1:1 solution of alcohol, N-Aloc-2-

aminoethanol, and THF⁶¹(Scheme 14). Deprotection of the

Aloc group in 52 with Pd(PPh₃)₄and dimedone⁶²yielded a

coupling reagent.

Binding Reagent Based on Site E. The last site for

modification that seemed both accessible by our synthetic route

and potentially suitable for binding was at C16. The late

installation of the C16 methyl group offered the possibility of

alkylating 26a with an alkyl halide other than methyl iodide.

Figure 6. Elaboration of thiophenyl derivatives.

2-aminoethanethiol, however, could be effected with

MgBr₂‚OEt₂,⁵⁸if the lactol had been previously converted to

the acetate by acetyl chloride/pyridine. While the alkyl thio-

acetal was stable to deprotection conditions (1% HCl/MeOH)

in the model system, it was completely hydrolyzed in the fully

elaborated discodermolide intermediate.

(59) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.

1983, 105 (8), 2430.

(60) Kahne, D.; Walker, S.; Chang, Y.; Van Engen, D. J. Am. Chem.

Soc. 1989, 111, 6881.

(61) The main side products recovered were lactols that were a mixture

of stereoisomers at C2. This was presumably a result of some elimination

to the pyran that was observed by mass spectrometry and nmr, to which

water added on silica gel.

(58) (a) Park, J. H.; Kim, S. Chem. Lett. 1989, 629. (b) Kim, S.; Park,

J. H.; Lee, S. Tetrahedron Lett. 1989, 30 (48), 6697.

(62) Hayakawa, Y.; Kato, H.; Uchiyama, M.; Kajino, H.; Noyori, R. J.

Org. Chem. 1986, 51, 2400.

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11065

Scheme 14

Scheme 15

In addition, the result that 16-desmethyldiscodermolide 31 is

no less active than natural discodermolide hinted at the

possibility that no significant loss of binding is associated with

the absence of this methyl group. If this is true, then the methyl

group might not sit in a hydrophobic pocket, contributing to

energy of binding, but instead, may be pointing out and away

from the binding pocket of its receptor. We therefore undertook

the synthesis of a substituted discodermolide at C16.

There were two possibilities for achieving this modification.

The first, as previously mentioned, would involve the alkylation

of 26a with a substituted alkyl halide. However, even with an

allylic bromide, alkylation at such a hindered site would be

difficult. A recent study on the alkylation of an ethyl ketone

analogous to 4b with allyl iodide suggested an alternative

method. Myles et al.⁴³showed that using LDA as a base for

formation of the enolate yielded a 2:1 ratio of desired to

undesired methyl epimers. On the basis of this result, alkylation

of ketone 53 with bromide 21 would probably afford 54 as the

major product. The synthesis of ketone 53 required the addition

of a terminally functionalized Grignard reagent to the primary

aldehyde rather than methyl or ethyl magnesium bromide. A

triethylsilyl (TES) protected alcohol was chosen as the func-

tionality to be elaborated into a linker. 6-(Triethylsiloxy)hexyl

magnesium bromide was the Grignard reagent of choice.

Alcohol 13 was oxidized with Dess-Martin periodinane,

treated with 6-(triethylsiloxy)hexyl magnesium bromide, and

reoxidized to afford ketone 53 (Scheme 15). Alkylation of this

ketone with allylic bromide 21, using LDA as the base, gave

fully coupled 54. Selective deprotection of the TES group with

HF/pyridine buffered with excess pyridine, followed by treat-

ment with N,N′-disuccinimidyl carbonate⁵⁶and N-Aloc-1,6-

hexanediamine, yielded 55. Final elaboration in the manner

analogous to discodermolide afforded compound 59, which

could be linked directly to a matrix or fluorescent reporter.

Unfortunately, this compound proved to be completely inactive,

11066 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Table 2. IC₅₀Values for Discodermolide Variants

Hung et al.

cm^-1; H NMR (500 MHz, CDCl₃) 7.01 (dd, J ) 15.8, 8.3 Hz, 1H),

5.83 (d, J ) 15.8 Hz, 1H), 3.67 (s, 3H), 3.75-3.62 (m, 3H), 2.42 (m,

1H), 1.75 (m, 1H), 0.96 (d, J ) 6.9 Hz, 3H), 0.85 (s, 9H), 0.02 (s,

6H); ¹³C NMR (125 MHz, CDCl₃) 167.0, 152.3, 120.9, 77.2, 68.4, 51.2,

40.3, 36.4, 25.8, 18.1, 16.2, 9.5, -5.6, -5.7; HRMS (FAB, NBA/NaI)

calcd for C₁₆H₃₂O₄SiNa 339.1968, found 339.1967. Anal. Calcd for

1

no.

IC₅₀^a(nM)

1

2

3

4

5

6

7

1a

31

1c

1b

32

35

36

6

10

300

8

9

10

11

12

13

37

45

50a

50b

51

70

6

4

C₁₆H₃₂O₄Si: C, 60.72; H, 10.19. Found: C, 60.67; H, 10.19. [R]²⁰

D

4

+22.8° (c 0.5, CHCl₃).

59

(2S,4S,5S,6R)-4-[(Carbomethoxy)methyl]-6-[(1S)-2-[[(1,1-di-

methylethyl)dimethylsilyl]oxy]-1-methylethyl]-5-methyl-2-phenyl-

1,3-dioxane. To a cooled (-20 °C) solution of 266 mg (0.84 mmol) of

enoate enant-7 in 8 mL of THF was added 86 µL (0.84 mmol) of freshly

distilled benzaldehyde and 168 µL of KHMDS solution (0.5 M in

toluene, 0.08 mmol). The yellow solution was stirred at -20 °C for 1

h when another aliquot of both reagents was added and again after

another 1 h period. After a total reaction time of 3.5 h, the solution

was quenched with 10 mL of saturated NH₄Cl solution and extracted

with 2 × 50 mL of EtOAc, dried over MgSO₄, filtered, and

concentrated. Flash chromatography (5-10% EtOAc/hexane) provided

251 mg (0.61 mmol, 73%) of benzylidene acetal: IR (thin film/NaCl)

1746 cm^-1; ¹H NMR (500 MHz, CDCl₃) 7.43-7.29 (m, 5H), 5.55 (s,

1H), 4.00 (td, J ) 9.6, 3.2 Hz, 1H), 3.70 (s, 3H), 3.74-3.66 (m, 3H),

3.48 (dd, J ) 9.5, 5.7 Hz, 1H), 2.72 (dd, J ) 15.4, 3.3 Hz, 1H), 2.56

(dd, J ) 15.4, 8.9 Hz, 1H), 1.99 (m, 1H), 1.73 (m, 1H), 0.89 (s, 9H),

0.88 (d, J ) 8.6 Hz, 3H), 0.81 (d, J ) 6.7 Hz, 3H), 0.03 (s, 6H); ¹³C

NMR (125 MHz, CDCl₃) 171.8, 138.9, 128.3, 127.9, 126.0, 100.0, 80.2,

79.1, 64.9, 51.6, 38.9, 36.6, 35.1, 25.9, 18.3, 11.7, 9.6, -5.3, -5.4;

HRMS (FAB, NBA/NaI) calcd for C₂₃H₃₈O₅SiNa 445.2386, found

70

^aIC₅₀values were measured by a [³H]thymidine incorporation assay

using MG63 cells (Error (5%).

suggesting that this site could not be altered without a deleterious

effect on binding.

In ViWo Biological Activities of the Structural Variants.

The synthetic discodermolides were next examined for their

potential as binding reagents. Three compounds have been

synthesized that could serve to explore interactions with

microtubules, namely compounds 39, 49, and 52. Compounds

39 (C17 variant), 49 (C24 variant), and 52 (C1 variant) appeared

promising on the basis of the in ViVo activities of related

compounds, 39 (70 nM), 45 (70 nM), and 51 (4 nM),

respectively (Table 2). This potential was confirmed by testing

the in ViVo activities of the variants themselves, using a

previously described binding assay,⁴⁶and their respective IC₅₀

values were 80, 200, and 20 nM. Some concern exists regarding

compound 52 due to the possibility that intracellular hydrolysis

may account for its activity. This possibility will be examined

by using the direct (in Vitro) microtubule-binding assay using

purified microtubules.⁴⁷Compounds 39 and 49 now appear to

be the best candidates for use as a binding reagent on the basis

of their antiproliferative and competition activity. They provide

an affinity-based approach for continued studies on the mech-

anism of discodermolide’s action and for investigations of its

ability to bind and stabilize microtubules.

445.2391; [R]²⁰-13.0° (c 0.5, CHCl₃).

D

(2S,4S,5S,6R)-4-[(Carbomethoxy)methyl]-6-[(1S)-2-hydroxy-1-

methylethyl]-5-methyl-2-phenyl-1,3-dioxane (enant-8). To an ambi-

ent temperature solution of 750 mg (1.78 mmol) of silyl ether in 10

mL of THF was added 1.8 mL of HF-pyridine, and the solution was

stirred for 15 min then quenched with 20 mL of saturated NaHCO₃

solution. This mixture was extracted with 3 × 75 mL of dichlo-

romethane, dried over MgSO₄, filtered, and concentrated. Chroma-

tography (33% EtOAc/hexane) provided 462 mg of alcohol enant-8

(1.50 mmol, 83%) as a white solid: mp 105-107 °C; IR (thin film/

NaCl) 3420 (br), 1740 cm^-1; ¹H NMR (500 MHz, CDCl₃) 7.40-7.28

(m, 5H), 5.58 (s, 1H), 3.99 (td, J ) 9.5, 3.3 Hz, 1H), 3.67 (s, 3H),

3.75-3.66 (m, 3H), 2.70 (dd, J ) 15.5, 3.3 Hz, 1H), 2.55 (dd, J )

15.5, 8.8 Hz, 1H), 2.29-2.19 (br s, 1H), 1.98 (m, 1H), 0.97 (d, J )

7.1 Hz, 3H), 0.80 (d, J ) 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

171.6, 138.4, 128.5, 128.0, 125.9, 100.1, 82.8, 79.0, 66.3, 51.6, 38.7,

35.7, 35.2, 11.5, 10.0; HRMS (FAB, NBA/NaI) calcd for C₁₇H₂₄O₅Na

331.1521, found 331.1530. Anal. Calcd for C₁₇H₂₄O₅: C, 66.21; H,

Experimental Section

General Experimental Methods. Optical rotations were recorded

1

using a sodium lamp (589 nm, D line) at 20 °C; H and ¹³C NMR

were recorded on a Bruker AM-500 (500 MHz) or AM-400 (400 MHz)

spectrometer. Chemical shifts are reported using the solvent resonance

internal standard (chloroform, 7.26 and 77.0 ppm). Low- and high-

resonance mass spectra were obtained using fast atom bombardment

(FAB) with NaI and m-nitrobenzyl alcohol (NBA) as a matrix. HPLC

purification was accomplished on a Waters Model 510 HPLC using a

Rainin Microsorb column, 10.0 × 250.0 mm.

7.84. Found: C, 65.98; H, 7.79. [R]²⁰+10.4° (c 0.5, CHCl₃).

D

Methyl [2S-(2r,3â,4â,5r)]-4-Hydroxytetrahydro-6-methoxy-3,5-

dimethyl-2H-pyran-2-ethanoate (enant-9). To an ambient temper-

ature solution of 2.60 g (6.13 mmol) of Dess-Martin periodinane in

25 mL of dichloromethane was added a solution of 1.46 g (4.74 mmol)

of alcohol 8 in 30 mL of dichloromethane (plus 2 × 5 mL rinses) Via

cannula over 5 min. After stirring 15 min, the mixture was diluted

with 100 mL of ether and poured into a well-stirred mixture of 35 mL

of 5% (w/w) Na₂S₂O₃solution and 75 mL of saturated NaHCO₃

solution. This biphasic mixture was stirred 20 min until all solids had

dissolved, then the layers were separated and the organic phase was

washed with 2 × 20 mL of saturated NaHCO₃, dried over MgSO₄,

filtered, and concentrated. The resulting white solid was immediately

dissolved in 40 mL of MeOH and treated with 1 g of Amberlyst 15

ion exchange resin at ambient temperature for 5 h. The reaction mixture

was concentrated to a volume of approximately 10 mL, diluted with

75 mL of dichloromethane (plus 2 × 25 mL rinses), and decanted into

a separatory funnel. The organic layers were washed with 2 × 25 mL

of saturated NaHCO₃solution, dried over MgSO₄, filtered, and

concentrated to provide a colorless oil.

Homoallylic alcohols 5 and 6 were the generous gifts of Hoffmann-

LaRoche Co. All other chemical reagents were purchased from Aldrich

Chemical Co., Fluka Chemical Corp., or Lancaster Chemical Co.

Compounds in Schemes 1, 2, and 4-9 were fully characterized as

the corresponding enantiomer of the structures depicted in the schemes

and are thus designated enant-# in the Experimental Section.

(E)-(4S,5S,6S)-Methyl 7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-

4,6-dimethyl-5-hydroxy-2-heptenoate (enant-7). A solution of 432

mg (1.67 mmol) of olefin 5 in 60 mL of 3:1 methanol:dichloromethane

containing 0.5 mL of pyridine was cooled to -78 °C and treated with

a stream of ozone and oxygen until the colorless solution had been

converted to a steel blue one. The solution was treated with 5 mL of

dimethyl sulfide, the cooling bath removed, and the solution allowed

to stir at ambient temperature for 3 h. The solution was concentrated

to a volume of approximately 2 mL, diluted with 50 mL if hexanes,

washed with 2 × 5 mL of water, and 1 × 5 mL of brine, dried over

MgSO₄, filtered, and concentrated to give a colorless oil. This oil was

dissolved in 10 mL of benzene, treated with 671 mg (2.01 mmol) of

methyl (triphenylphosphoranylidene)acetate and allowed to stir at

ambient temperature for 15 h. The pink solution was concentrated and

chromatographed (10-15% EtOAc/hexane) to provide 452 mg (1.43

mmol, 86%) of enoate enant-7: IR (thin film/NaCl) 3800 (br), 1727

The above crude reaction mixture was dissolved in 30 mL of MeOH,

treated with 1.65 g (7.11 mmol) of (1S)-(+)-10-camphorsulfonic acid,

and stirred at ambient temperature for 4.5 d. The reaction was quenched

by addition of 5 mL of triethylamine, concentrated, and chromato-

graphed (15-30% EtOAc/hexane) to provide 569 mg of enant-9a and

311 mg of enant-9b (3.79 mmol, 80% from alcohol 8). Data for enant-

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11067

1

9a: IR (thin film/NaCl) 3524 (br), 1744 cm^-1; H NMR (500 MHz,

CDCl₃) 4.49 (s, 1H), 4.07 (td, J ) 10.4, 2.7 Hz, 1H), 3.67 (s, 3H),

3.42 (s, 1H), 3.35 (s, 3H), 2.62 (dd, J ) 15.1, 2.7 Hz, 1H), 2.40 (dd,

J ) 15.1, 10.1 Hz, 1H), 2.08 (m, 1H), 1.71 (m, 1H), 0.99 (d, J ) 7.4

Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) 172.1,

103.1, 73.7, 66.5, 55.1, 51.6, 38.6, 38.3, 34.0, 14.9, 13.9; HRMS (FAB,

NBA/NaI) calcd for C₁₁H₂₀O₅Na 255.1208, found 255.1201. Anal.

Calcd for C₁₁H₂₀O₅: C, 56.88; H, 8.68. Found: C, 56.97; H, 8.64.

J ) 7.3 Hz, 3H), 0.87 (s, 9H), 0.84 (d, J ) 6.9 Hz, 3H), 0.02 (s, 3H),

-0.02 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) carbonyl too broad to

detect, 103.3, 73.3, 67.8, 61.2, 54.8, 38.8, 36.3, 36.0, 25.8, 18.1, 15.5,

13.5, -4.6, -4.8; HRMS (FAB, NBA/NaI) calcd for C₁₈H₃₇O₅NSiNa

398.2339, found 398.2350. Anal. Calcd for C₁₈H₃₇O₅NSi: C, 57.56;

H, 9.93; N, 3.73. Found: C, 57.55; H, 9.95; N, 3.68. [R]²⁰+23.1°

D

(c 0.7, CHCl₃).

[2S-(2r,3â,4â,5r,6â)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-

tetrahydro-N,6-dimethoxy-N,3,5-trimethyl-2H-pyran-2-ethan-

amide. Amide was prepared in a manner identical to that of its anomer,

providing it as a colorless oil (85% yield): IR (thin film/NaCl)1665

cm^-1; ¹H NMR (500 MHz, CDCl₃) 4.58 (d, J ) 2.3 Hz, 1H), 3.92 (td,

J ) 9.9, 3.2 Hz, 1H), 3.58 (s, 3H), 3.49 (t, J ) 2.7 Hz, 1H), 3.27 (s,

3H), 3.05 (s, 3H), 2.65 (br m, 1H), 2.35 (dd, J ) 14.9, 3.2 Hz, 1H),

1.75 (m, 1H), 1.59 (m, 1H), 0.77 (d, J ) 9.5 Hz, 3H), 0.77 (s, 9H),

0.70 (d, J ) 6.8 Hz, 3H), -0.08 (s, 3H), -0.10 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 172.1, 100.6, 76.4, 72.6, 60.9, 56.1, 40.7, 35.5,

35.0, 25.6, 17.8, 13.4, 9.5, -4.8, -5.1; HRMS (FAB, NBA/NaI) calcd

[R]²⁰+93.0° (c 1, CHCl₃). Data for enant-9b: IR (thin film/NaCl)

D

3501 (br), 1738 cm^-1; H NMR (500 MHz, CDCl₃) 4.62 (d, J ) 2.4

1

Hz, 1H), 3.88 (td, J ) 9.9, 3.4 Hz, 1H), 3.55 (overlapping s, 4H), 3.28

(s, 3H), 2.52 (d, J ) 2.5 Hz, 1H), 2.46 (dd, J ) 15.1, 3.5 Hz, 1H),

2.34 (dd, J ) 15.1, 9.7 Hz, 1H), 1.87 (m, 1H), 1.62 (m, 1H), 0.81 (d,

J ) 7.1 Hz, 3H), 0.78 (d, J ) 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

172.0, 100.8, 75.1, 72.5, 56.1, 51.3, 40.4, 38.5, 34.4, 12.6, 9.5; HRMS

(FAB, NBA/NaI) calcd for C₁₁H₂₀O₅Na 255.1208, found 255.1217;

[R]²⁰+16.8° (c 0.6, CHCl₃).

D

Methyl [2S-(2r,3â,4â,5r,6r)]-4-[[(1,1-Dimethylethyl)dimethyl-

silyl]oxy]tetrahydro-6-methoxy-3,5-dimethyl-2H-pyran-2-ethan-

oate. To a stirred solution of 311 mg (1.34 mmol) of alcohol enant-

9a in 10 mL of dichloromethane at ambient temperature was added

624 µL (574 mg, 5.36 mmol) of 2,6-lutidine followed by 616 µL (709

mg, 2.68 mmol) of TBSOTf. After stirring for 20 min, the solution

was concentrated and chromatographed to provide 460 mg (1.33 mmol,

for C₁₈H₃₇O₅NSiNa 398.2339, found 398.2360; [R]²⁰-9.6° (c 0.5,

D

CHCl₃).

[2S-(2r,3â,4â,5r)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-

tetrahydro-N-methoxy-6-thiophenyl-N,3,5-trimethyl-2H-pyran-2-

ethanamide (enant-10a and enant-10b). To a solution of 1.02 g (2.72

mmol) of a mixture of methyl anomers in 25 mL of dichloromethane

were successively added 2.60 g (8.14 mmol) of zinc iodide, 1.20 g

(3.24 mmol) of tetrabutylammonium iodide, and 2.58 mL (2.48 g, 13.60

mmol) of (phenylthio)trimethylsilane, and the solution was heated to

reflux for 2 h. The reaction was cooled to ambient temperature, poured

over 100 mL of hexanes plus 20 mL of saturated barium hydroxide

solution. The layers were separated, and the organic layer was washed

with 2 × 25 mL of saturated barium hydroxide solution. The combined

aqueous layers were extracted with 50 mL of hexanes and the organic

layers combined, dried over MgSO₄, filtered, and concentrated.

Chromatography (7-10-15% EtOAc/hexane) provided 370 mg of

enant-10b as a white solid and 712 mg of enant-10a (2.38 mmol

combined, 88%). Data for enant-10b: mp 90-92 °C; IR (thin film/

99%) of silyl ether: IR (thin film/NaCl) 1748 cm^-1; H NMR (500

1

MHz, CDCl₃) 4.32 (d, J ) 2.2 Hz, 1H), 4.18 (td, J ) 9.7, 3.4 Hz, 1H),

3.67 (s, 3H), 3.50 (t, J ) 4.0 Hz, 1H), 3.25 (s, 3H), 2.54 (dd, J ) 14.6,

3.4 Hz, 1H), 2.38 (dd, J ) 14.6, 10.1 Hz, 1H), 1.84 (m, 1H), 1.73 (m,

1H), 0.95 (d, J ) 7.4 Hz, 3H), 0.88 (s, 9H), 0.82 (d, J ) 6.9 Hz, 3H),

0.02 (s, 3H), -0.02 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) 172.2, 103.2,

73.3, 67.6, 54.7, 51.5, 39.0, 38.7, 35.9, 25.7, 18.1, 15.5, 13.6, -4.6,

-4.8; HRMS (FAB, NBA/NaI) calcd for C₁₇H₃₄O₅SiNa 369.2073,

found 369.2083; [R]²⁰+60.2° (c 0.5, CHCl₃).

D

Methyl [2S-(2r,3â,4â,5r,6â)]-4-[[(1,1-Dimethylethyl)dimethyl-

silyl]oxy]tetrahydro-6-methoxy-3,5-dimethyl-2H-pyran-2-ethan-

oate. The silyl ether of enant-9b was prepared in a manner identical

to that of enant-9a, providing it as a colorless oil (90% yield): IR (thin

1

NaCl) 1659 cm^-1; H NMR (500 MHz, CDCl₃) 7.36-7.11 (m, 5H),

film/NaCl) 1746 cm^-1; H NMR (500 MHz, CDCl₃) 4.69 (d, J ) 2.4

1

5.38 (d, J ) 2.1 Hz, 1H), 4.11 (td, J ) 10.1, 3.0 Hz, 1H), 3.62 (s, 1H),

3.61 (s, 3H), 3.09 (s, 3H), 2.79 (br m, 1H), 2.40 (dd, J ) 14.4, 3.0 Hz,

1H), 2.00 (m, 1H), 1.79 (m, 1H), 1.09 (d, J ) 7.1 Hz, 3H), 0.86 (s,

9H), 0.84 (d, J ) 7.0 Hz, 3H), 0.03 (s, 3H), 0.01 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 172.0, 136.2, 128.8, 128.6, 125.8, 83.3, 76.2, 75.7,

61.1, 41.7, 35.7, 34.8, 31.8, 25.8, 18.0, 14.0, 11.7, -4.6, -4.9; HRMS

(FAB, NBA/NaI) calcd for C₂₃H₃₉O₄NSiSNa 476.2267, found 476.2272;

[R]²⁰_D-25.8° (c 0.5, CHCl₃). Data for enant-10a: IR (thin film/NaCl)

1663 cm^-1; ¹H NMR (500 MHz, CDCl₃) 7.44-7.11 (m, 5H), 5.11 (s,

1H), 4.67 (td, J ) 9.5, 3.4 Hz, 1H), 3.60 (s, 3H), 3.58 (t, J ) 3.3 Hz,

1H), 3.08 (s, 3H), 2.66 (br m, 1H), 2.60 (br m, 1H), 2.14 (m, 1H),

1.90 (m, 1H), 1.12 (d, J ) 7.3 Hz, 3H), 0.97 (s, 9H), 0.89 (d, J ) 6.9

Hz, 3H), 0.11 (s, 3H), 0.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) 172.2,

138.7, 130.9, 128.4, 126.1, 89.0, 74.1, 68.2, 61.1, 41.5, 36.1, 35.7, 31.9,

26.1, 18.2, 17.6, 14.0, -4.1, -4.9; HRMS (FAB, NBA/NaI) calcd for

C₂₃H₃₉O₄NSiSNa 476.2267, found 476.2281. Anal. Calcd: C, 60.89;

H, 8.66; N, 3.09. Found: C, 60.79; H, 8.71; N, 3.02. [R]²⁰_D+145.5°

(c 0.4, CHCl₃).

Hz, 1H), 3.94 (td, J ) 9.9, 3.5 Hz, 1H), 3.67 (s, 3H), 3.60 (t, J ) 2.7

Hz, 1H), 3.40 (s, 3H), 2.55 (dd, J ) 15.0, 3.5 Hz, 1H), 2.43 (dd, J )

15.0, 9.6 Hz, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 0.90 (d, J ) 7.3 Hz,

3H), 0.90 (s, 9H), 0.79 (d, J ) 6.9 Hz, 3H), 0.04 (s, 3H), 0.02 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) 171.6, 100.8, 76.2, 72.6, 56.0, 51.1, 47.8,

38.4, 34.8, 25.6, 17.8, 13.3, 9.5, -4.8, -5.2; HRMS (FAB, NBA/NaI)

calcd for C₁₇H₃₄O₅SiNa 369.2073, found 369.2072; [R]²⁰-3.8° (c

D

0.5, CHCl₃).

[2S-(2r,3â,4â,5r,6r)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-

tetrahydro-N,6-dimethoxy-N,3,5-trimethyl-2H-pyran-2-ethana-

mide. N,O-Dimethylhydroxylamine was prepared as follows: 24.3 g

(250 mmol) of N,O-dimethylhydroxylamine hydrochloride was sus-

pended in 100 mL of ethylene glycol, and 41 mL (310 mmol) of

triethanolamine was added. A short-path distilling head was affixed

to the flask, the resulting thick slurry heated to reflux, and 11.6 g (190

mmol, 76%) of the free amine collected (bp 47-50 °C).

To a solution of 709 mg (2.05 mmol) of ester in 20 mL of 4:1:1

THF:MeOH:H₂O at ambient temperature was added 85 mg (3.54 mmol)

of LiOH, and the resulting yellow solution was stirred for 5 h when

the reaction was quenched with 1 N HCl until its yellow color was

returned to colorless (approximately 4 mL). The solution was diluted

with 100 mL of EtOAc, dried with MgSO₄, filtered, and concentrated.

The resulting viscous oil was dissolved in 4 mL of dichloromethane,

treated successively with 137 mg (2.25 mmol) of N,O-dimethylhy-

droxylamine, 314 mg (2.05 mmol) of 1-hydroxybenzotriazole hydrate,

and 285 µL (207 mg, 2.05 mmol) of triethylamine, then cooled to 0

°C, and finally treated with 422 mg (2.05 mmol) of 1,3-dicyclohexyl-

carbodiimide. The resulting white slurry was warmed to ambient

temperature and stirred for 10 h, then concentrated and chromatographed

(25% EtOAc/hexane) to provide 669 mg (1.78 mmol, 87% from ester)

of amide: IR (thin film/NaCl) 1669 cm^-1; ¹H NMR (125 MHz, CDCl₃)

4.30 (d, J ) 2.7 Hz, 1H), 4.24 (td, J ) 9.4, 3.4 Hz, 1H), 3.69 (s, 3H),

3.51 (t, J ) 4.4 Hz, 1H), 3.27 (s, 3H), 3.17 (s, 3H), 3.65 (br m, 1H),

2.52 (dd, J ) 14.5, 2.9 Hz, 1H), 1.82 (m, 1H), 1.78 (m, 1H), 0.95 (d,

[2S-(2r,3â,4â,5r,6r)]-4-[(tert-Butylsilyl)oxy]tetrahydro-N-meth-

oxy-6-(thiophenyl)-N,3,5-trimethyl-2H-pyran-2-ethanal (enant-2).

To a cooled (0 °C) solution of 297 mg (0.66 mmol) of amide in 5 mL

of THF was added 820 µL (0.82 mmol) of 1 M LiAlH₄solution in

THF, and the solution was stirred at 0 °C for 10 min when the reaction

was quenched with 2 mL of 0.28 M NaHSO₄solution. The mixture

was warmed to room temperature, diluted with 50 mL of EtOAc,

washed with 2 × 10 mL of 1 N HCl and 1 × 10 mL of brine, dried

over MgSO₄, filtered, concentrated, and chromatographed (5% EtOAc/

hexane) to provide 227 mg (0.58 mmol, 88%) of aldehyde enant-2 as

a colorless oil which solidified on standing in a -20 °C freezer to a

white powder: mp 36-38 °C; IR (thin film/NaCl) 1728, cm^-1; ¹H NMR

(500 MHz, CDCl₃) 9.64 (dd, J ) 4.0, 1.4 Hz, 1H), 7.38 (dd, J ) 8.5,

1.4 Hz, 2H), 7.22 (t, J ) 7.4 Hz, 2H), 7.15 (t, J ) 7.4 Hz, 1H), 5.21

(s, 1H), 4.76 (td, J ) 9.9, 3.3 Hz, 1H), 3.60 (t, J ) 2.7 Hz, 1H), 2.58

(ddd, J ) 15.6, 3.3, 1.4 Hz, 1H), 2.41 (ddd, J ) 15.6, 9.7, 4.0 Hz,

1H), 2.20 (m, 1H), 1.84 (m, 1H), 1.14 (d, J ) 7.3 Hz, 3H), 1.00 (s,

11068 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

9H), 0.86 (d, J ) 6.9 Hz, 3H), 0.13 (s, 3H), 0.07 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 202.1, 138.6, 129.7, 128.7, 126.2, 88.7, 73.8, 66.3,

46.5, 41.8, 35.3, 26.2, 18.3, 17.7, 14.0, -4.0, -4.9; HRMS (FAB, NBA/

CDCl₃) 133.4, 132.9, 78.4, 65.5, 61.8, 40.5, 35.7, 26.2, 26.0, 21.6, 18.4,

18.4, 17.4, 14.6, -3.9 (2), -5.3, -5.4; HRMS (FAB, NBA/NaI) calcd

for C₂₂H₄₈O₃Si₂Na 439.3040, found 439.3049. Anal. Calcd: C, 63.40;

H, 11.61. Found: C, 63.47; H, 11.54. [R]²⁰_D+14.6° (c 0.5, CHCl₃).

(2R,3S,4R)-2,4-Dimethyl-1-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3-[(4-methoxyphenyl)methoxy]hex-5-ene. To 25 g (180 mmol)

of 4-methoxybenzyl alcohol was added 20 mL of 48% HBr, and the

mixture was stirred at ambient temperature for 30 min. The reaction

mixture was diluted with 100 mL of diethyl ether, the layers were

separated, and the organic layer was washed with 3 × 30 mL of

saturated NaHCO₃solution. The organic layer was dried over K₂CO₃,

filtered, concentrated in Vacuo, and distilled under high vacuum to

afford a colorless oil that was used in the following reaction,

To a cooled (0 °C) suspension of 2.3 g (58 mmol, 60% suspension

in oil and washed in hexanes) of NaH in 10 mL of THF were added

10 mL of distilled DMF, a solution of 5.0 g (19 mmol) of 5 in 10 mL

of THF, and 8.68 mL (48 mmol) of PMBBr. After being stirred at

ambient temperature for 48 h, the reaction mixture was poured into

100 mL of 10xPBS buffer and diluted with 150 mL of diethyl ether.

The organic layer was washed 3 × 100 mL of 10xPBS buffer, dried

over K₂CO₃, filtered, concentrated in Vacuo, and chromatographed to

provide 6.4 g (18 mmol, 93%) of the PMB ether as a colorless oil: IR

(thin film/NaCl) 2957, 1614 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.28

(d, J ) 8.7 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 5.96 (ddd, J ) 7.9,

10.3, 17.4 Hz, 1H), 5.09 (ddd, J ) 1.1, 1.9, 17.2 Hz, 1H), 5.03 (ddd,

J ) 0.7, 1.9, 10.3 Hz, 1H), 4.55 (d, J ) 10.8 Hz, 1H), 4.47 (d, J )

10.7 Hz, 1H), 3.81 (s, 3H), 3.56 (dd, J ) 7.2, 9.8 Hz, 1H), 3.49 (dd,

J ) 6.0, 9.8 Hz, 1H), 3.39 (dd, J ) 3.9, 6.9 Hz, 1H), 2.49 (ddd, J )

6.8, 7.6, 13.8 Hz, 1H), 1.89 (m 1), 1.04 (d, J ) 6.9 Hz, 3H), 0.93 (s,

9H), 0.92 (d, J ) 6.9 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 159.0, 142.1, 141.9, 129.2, 114.0, 113.6, 82.8,

74.1, 65.7, 55.2, 41.0, 38.4, 26.1, 25.9, 18.2, 17.1, 11.3, -5.4; HRMS

(CI) m/z calcd for C₂₂H₃₈O₃Si 378.2588, found 378.2590; [R]²⁰_D+17.2°

(c 0.5, CHCl₃).

NaI) calcd for C₂₁H₃₄O₃SiSNa 417.1896, found 417.1919; [R]²⁰

D

+201.6° (c 0.5, CHCl₃).

(3S,4R,5S)-4,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,5-

dimethyl-1-hexene. To a cooled (0 °C) solution of 1.50 g (5.81 mmol)

of homoallylic alcohol enant-6 in 20 mL of dichloromethane was added

1.60 mL (1.16 g, 11.6 mmol) of triethylamine followed by 2.00 mL

(2.30 g, 8.70 mmol) of TBSOTf, and the solution was stirred for 30

min when 25 mL of brine was added. The mixture warmed to ambient

temperature and extracted with 3 × 50 mL of dichloromethane. The

combined organic layers were dried over MgSO₄, filtered, concentrated,

and chromatographed (1% EtOAc/hexane) to provide 2.01 g (5.40

mmol, 93%) of the silyl ether as a colorless oil: IR (thin film/NaCl)

1

2959, 2930 cm^-1; H NMR (500 MHz, CDCl₃) 5.80 (ddd, J ) 17.5,

10.3, 7.5 Hz, 1H), 4.94 (m, 2H), 3.68 (dd, J ) 9.8, 5.2 Hz, 1H), 3.50

(t, J ) 5.1 Hz, 1H), 3.36 (dd, J ) 9.8, 7.7 Hz, 1H), 2.35 (m, 1H), 1.80

(m, 1H), 0.96 (d, J ) 6.8 Hz, 3H), 0.89 (d, J ) 6.9 Hz, 3H), 0.88 (s,

9H), 0.87 (s, 9H), 0.02 (s, 3H), 0.01 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) 143.0, 113.5, 77.6, 65.3, 41.4, 40.6, 26.2, 26.0, 18.4, 18.3, 15.3,

14.3, -3.7, -4.0, -5.2, -5.3; HRMS (FAB, NBA/NaI) calcd for

C₂₀H₄₅O₂Si₂373.2958, found 373.2947. Anal. Calcd for C₂₀H₄₄O₂-

Si₂: C, 64.45; H, 11.90. Found: C, 64.40; H, 11.88. [R]²⁰+21.0°

D

(c 0.5, CHCl₃).

(Z)-(4S,5R,6S)-Methyl 5,7-Bis[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]2,4,6-trimethyl-2-heptenoate. A solution of 1.0 g (2.69 mmol)

of olefin in 50 mL of 3:1 methanol:dichloromethane containing 1 mL

of pyridine was cooled to -78 °C and treated with a stream of ozone

and oxygen until the colorless solution had been converted to a steel

blue one. The solution was treated with 10 mL of dimethyl sulfide,

the cooling bath removed, and the solution allowed to stir at ambient

temperature for 12 h. The solution was concentrated to a volume of

approximately 2 mL, diluted with 100 mL of EtOAc, washed with 2

× 25 mL of water and 1 × 25 mL of brine, dried over MgSO₄, filtered,

and concentrated to give a colorless oil.

(Z)-(3S,4S,5R)-3,5-Dimethyl-6-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-1-iodo-4-[(4-methoxyphenyl)methoxy]-hex-1-ene (12). To a

cooled (-78 °C) solution of 2.5 g (6.6 mmol) of olefin in 80 mL of

3:1 MeOH:CH₂Cl₂containing 1 mL of pyridine and one drop of Sudan

III solution was bubbled a stream of ozone until the pink solution

became colorless. The solution was treated wtih 15 mL of dimethyl

sulfide and then warmed to ambient temperature for 2 h. The solution

was concentrated in Vacuo, diluted with 50 mL of hexanes, washed

with 3 × 10 mL of H₂O and 1 × 10 mL of brine, dried over MgSO₄,

concentrated in Vacuo, and used crude in the following reaction.

To a suspension of 5.37 mg (10.1 mmol) of (iodomethyl)triph-

enylphosphonium iodide in 20 mL of THF was added 10.1 mL (10.1

mmol, 1 M in THF) of NaHMDS, and the slurry was stirred for 20

min at ambient temperature. After the dark red mixture was cooled to

-78 °C, 3.5 mL of HMPA was added, followed by the crude aldehyde

in 5 mL of THF. After the reaction mixture was warmed to ambient

temperature, the reaction was stirred for 1 h before being diluted with

hexanes, filtered through 100 g of silica gel, concentrated in Vacuo,

and chromatographed (3% EtOAc/hexanes) to provide 2.49 (5.0 mmol,

To a cooled (-78 °C) solution of 1.43 g (4.30 mmol) of (F₃-

CCH₂O)POCH(CH₃)CO₂Me and 1.42 g (5.37 mmol) of 18-crown-6

in 10 mL of THF was added 7.10 mL (4.30 mmol) of a 0.6 M KHMDS

solution in toluene. The resulting dark red solution was stirred for 10

min and then treated with the above prepared aldehyde in 5 mL of

THF (plus a 1 mL rinse) Via cannula, and the -78 °C bath was replaced

with a 0 °C bath and the reaction stirred for 5 h. The reaction was

quenched by addition of 15 mL of saturated NH₄Cl solution and

extracted into 2 × 50 mL of hexane. The combined organic layers

were dried over MgSO₄, filtered, concentrated, and chromatographed

(1% EtOAc/hexane) to provide 1.11 g (2.50 mmol, 93% from the olefin)

of ester: IR (thin film/NaCl) 1721 cm^-1; ¹H NMR (500 MHz, CDCl₃)

5.85 (dd, J ) 10.1, 1.1 Hz, 1H), 3.72 (s, 3H), 3.62 (dd, J ) 9.8, 5.2

Hz, 1H), 3.57 (dd, J ) 5.8, 4.9 Hz, 1H), 3.38 (dd, J ) 9.7, 7.5 Hz,

1H), 3.32 (m, 1H), 1.88 (d, J ) 0.8 Hz, 3H), 1.77 (m, 1H), 0.96 (d, J

) 6.7 Hz, 3H), 0.90 (d, J ) 10.0 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H),

0.04 (s, 3H), 0.02 (s, 6H), 0.00 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

168.3, 147.6, 125.0, 76.9, 65.3, 51.2, 41.1, 36.1, 26.1, 26.0, 20.8, 18.4,

18.3, 15.1, 13.5, -3.9, -4.0, -5.3, -5.4; HRMS (FAB, NBA/NaI)

calcd for C₂₃H₄₈O₄Si₂Na 467.2989, found 467.2975. Anal. Calcd for

75%) of 12 as a colorless oil: IR (thin film/NaCl) 3744, 1612 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J ) 8.7 Hz, 2H), 6.88 (d, J )

8.7 Hz, 2H), 6.27 (dd, J ) 7.4, 9.1 Hz, 1H), 6.17 (d, J ) 7.4 Hz, 1H),

4.54 (s, 2H), 3.81 (s, 3H), 3.53 (dd, J ) 1.7, 5.8 Hz, 2H), 3.48 (dd, J

) 4.6, 5.6 Hz, 1H), 2.81 (ddd, J ) 2.5, 4.7, 7.0 Hz, 1H), 1.79 (dd, J

) 5.8, 6.8 Hz, 1H), 1.06 (d, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.9 Hz,

3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 159.0, 143.8, 131.2, 129.2, 113.6, 82.7, 81.6, 74.4, 65.3, 55.2,

42.7, 39.3, 25.9, 18.2, 17.1, 12.7, -5.2, -5.3, -5.4; HRMS (FAB,

NBA/NaI) m/z calcd for C₂₂H₃₇IO₃SiNa 527.1454, found 527.1454;

C₂₃H₄₈O₄Si₂: C, 62.11; H, 10.88. Found: C, 62.17; H, 10.84. [R]²⁰

-22.0° (c 0.5, CHCl₃).

D

(Z)-(4S,5R,6S)-5,7-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-

2,4,6-trimethyl-2-hepten-1-ol (enant-11). To a cooled (0 °C) solution

of 2.15 g (4.84 mmol) of ester in 82 mL of THF is added 6.13 mL

(6.13 mmol) of 1 M LiAlH₄solution in THF, dropwise over 5 min.

After being stirred for 30 min, the solution was diluted with 100 mL

of ether, quenched with 3 mL of saturated NH₄Cl solution, warmed to

ambient temperature, and dried over Na₂SO₄. The mixture was filtered

over MgSO₄, concentrated and chromatographed (5% EtOAc/hexane)

to provide 1.86 g (4.47 mmol, 92%) of alcohol enant-11: IR (thin film/

NaCl) 3343 (br) cm^-1; ¹H NMR (500 MHz, CDCl₃) 5.12 (d, J ) 10.1

Hz, 1H), 4.15 (d, J ) 11.8 Hz, 1H), 3.96 (d, J ) 11.8 Hz, 1H), 3.70

(dd, J ) 10.0, 5.4 Hz, 1H), 3.40-3.33 (m, 2H), 2.66 (m, 1H), 1.85

(m, 1H), 1.77 (s, 3H), 0.91 (d, J ) 6.7 Hz, 3H), 0.89 (s, 9H), 0.87 (s,

9H), 0.85 (d, J ) 6.9 Hz, 3H), 0.02 (s, 12H); ¹³C NMR (125 MHz,

[R]²⁰+52.4° (c 0.5, CHCl₃).

D

(Z)-(2R,3S,4S)-2,4-Dimethyl-1-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3-[(4-methoxyphenyl)methoxy]-5,7-octadiene. To a suspension

of 5.28 g (23.5 mmol) of ZnBr₂in 10 mL of THF was added 23.5 mL

(23.5 mmol, 1 M in THF) of vinylmagnesium bromide, and the slurry

was stirred for 15 min at ambient temperature. After the reaction

mixture was cooled to 0 °C, a solution of 2.96 g (5.9 mmol) of 12 in

10 mL of THF was added, followed by 678 mg (590 µmol) of Pd-

(PPh₃)₄in 25 mL of THF. After being stirred at room temperature for

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11069

24 h, the reaction was quenched by the addition to 30 mL of saturated

NH₄Cl solution and extracted into 3 × 25 mL of hexanes. The organic

layers were combined, dried over MgSO₄, filtered, concentrated in

Vacuo, and chromatographed (2% EtOAc/hexanes) to provide 1.9 g

(4.7 mmol, 80%) of diene as a colorless oil: IR (thin film/NaCl) 1614,

3H), 3.61 (dd, J ) 7.8, 3.8 Hz, 1H), 2.80 (m, 1H), 2.71 (m, 1H), 2.09

(s, 3H), 1.16 (d, J ) 7.1 Hz, 3H), 1.06 (d, J ) 6.9 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) 212.1, 159.2, 134.1, 132.1, 130.7, 129.6, 129.3,

117.7, 113.7, 83.7, 75.0, 55.2, 50.7, 36.1, 29.6, 18.6, 13.4; HRMS (FAB,

NBA/NaI) m/z calcd for C₁₉H₂₆O₃Na 325.1780, found 325.1789; [R]²⁰

D

1

1514 cm^-1; H NMR (400 MHz, CDCl₃) δ 7.4 (d, J ) 8.6 Hz, 2H),

+53.2° (c 0.5, CHCl₃).

6.85 (d, J ) 8.6 Hz, 2H), 6.65 (ddd, J ) 10.3, 16.1, 20.5 Hz, 1H),

6.01 (apparent t, J ) 10.9 Hz, 1H), 5.51 (apparent t, J ) 10.4 Hz,

1H), 5.18 (dd, J ) 1.9, 16.9 Hz, 1H), 5.08 (d, J ) 10.1 Hz, 1H), 4.53

(d, J ) 10.6 Hz, 1H), 4.44 (d, J ) 10.7 Hz, 1H), 3.80 (s, 3H), 3.52

(dd, J ) 6.8, 9.8 Hz, 1H), 3.44 (dd, J ) 6.1, 9.9 Hz, 1H), 3.38 (dd, J

) 4.4, 6.1 Hz, 1H), 2.93 (ddd, J ) 6.7, 10.0, 13.3 Hz, 1H), 1.83 (ddd,

J ) 2.1, 6.5, 8.6 Hz, 1H), 1.00 (d, J ) 6.9 Hz, 3H), .092 (d, J ) 6.9

Hz, 3H), 0.91 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 158.9, 135.9, 132.7, 131.5, 129.3, 128.9, 117.0, 113.6, 83.0,

74.4, 65.6, 55.2, 38.7, 35.6, 25.9, 18.4, 18.3, 11.6, -5.3, -5.4; HRMS

(FAB, NBA/NaI) m/z calcd for C₂₄H₄₀O₃SiNa 427.2642, found

(Z)-(4R,5S,6R)-5-[(4-Methoxyphenyl)methoxy]-4,6-dimethyl-7,9-

decadien-3-one (4b). To a solution of 625 mg (2.16 mmol) of 13 in

5 mL of CH₂Cl₂was added 1.18 g (2.60 mmol) of Dess-Martin

periodinane. After being stirred at ambient temperature for 10 min,

the reaction was quenched by the addition of 20 mL of saturated

Na₂S₂O₃solution and 20 mL of saturated NaHCO₃solution and diluted

with 50 mL of diethyl ether. After 30 min of stirring, the layers were

separated and the organic layer was washed with 3 × 120 mL of

saturated NaHCO₃solution, dried over MgSO₄, filtered, concentrated

in Vacuo, and chromatographed (10% EtOAc/hexanes) to yield 560

mg of the aldehyde.

To a solution of 560 mg (1.94 mmol) of the aldehyde in 5 mL of

THF was added 2.59 mL (7.76 mmol, 3 M in Et₂O) of methylmagne-

sium bromide. After being stirred for 30 min at ambient temperature,

the reaction mixture was diluted with 30 mL of diethyl ether, washed

with 1 × 20 mL of 1 N HCl and 1 × 20 mL of saturated NaHCO₃

solution, dried over MgSO₄, filtered, concentrated in Vacuo, and

chromatographed (10% EtOAc/hexanes) to provide 553 mg of a 2:1

mixture of epimers.

427.2644; [R]²⁰+45.0° (c 0.5, CHCl₃).

D

(Z)-(2R,3S,4S)-2,4-Dimethyl-3-[(4-methoxyphenyl)methoxy]-5,7-

octadien-1-ol (13). To a solution of 1.5 g (3.7 mmol) of silyl ether in

8 mL of THF was added 1 mL of H₂O and then 1 mL of TFA. After

being stirred at ambient temperature for 8 h, the reaction was quenched

with 10 mL of saturated NaHCO₃solution and extracted into 3 × 20

mL of EtOAc. The organic layers were combined, dried over K₂CO₃,

filtered, concentrated in Vacuo, and chromatographed (35% EtOAc/

hexanes) to provide 870 mg (3.3 mmol, 88%) of 13 as a colorless oil:

The mixture of alcohols was dissolved in 5 mL of CH₂Cl₂, and 1.12

g (2.16 mmol) of Dess-Martin periodinane was added. After 30 min

of stirring at ambient temperature, the reaction was quenched by the

addition of 20 mL of saturated Na₂S₂O₃solution and 20 mL of saturated

NaHCO₃solution and diluted with 50 mL of diethyl ether. After 30

min of stirring, the layers were separated and the organic layer was

washed with 3 × 120 mL of saturated NaHCO₃solution, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed (5%

EtOAc/hexanes) to yield 550 mg (1.74 mmol, 80% for three steps) of

1

IR (thin film/NaCl) 3393, 1612 cm^-1; H NMR (400 MHz, CDCl₃) δ

7.26 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H), 6.69 (ddd, J )

10.8, 16.7, 18.4 Hz, 1H), 6.05 (apparent t, J ) 11.0 Hz, 1H), 5.55

(apparent t, J ) 10.4 Hz, 1H), 5.22 (dd, J ) 1.8, 16.8 Hz, 1H), 5.12

(d, J ) 10.2 Hz, 1H), 4.58 (d, J ) 10.7 Hz, 1H), 4.47 (d, J ) 10.7 Hz,

1H), 3.77 (s, 3H), 3.59 (m, 1H), 3.50 (dd, J ) 5.3, 10.7 Hz, 1H), 3.41

(dd, J ) 4.2, 6.1 Hz, 1H), 3.00 (ddd, J ) 6.7, 10.0, 13.3 Hz, 1H), 2.64

(br s, 1H), 1.94 (m, 1H), 1.03 (d, J ) 6.9 Hz, 3H), 0.97 (d, J ) 7.0

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.9, 135.3, 132.3, 130.7,

129.4, 129.3, 128.8, 117.2, 113.5, 113.4, 83.7, 73.8, 65.5, 55.0, 37.7,

35.0, 18.3, 11.3; HRMS (EI) m/z calcd for C₁₈H₂₆O₃290.1881, found

1

4b as a colorless oil: IR (thin film/NaCl)1709 cm^-1; H NMR (500

MHz, CDCl₃) 7.25 (d, J ) 4.7 Hz, 2H), 6.85 (d, J ) 8.5 Hz, 2H), 6.42

(ddd, J ) 16.8, 10.7, 10.6 Hz, 1H), 6.02 (t, J ) 11.0 Hz, 1H), 5.52 (t,

J ) 10.6 Hz, 1H), 5.17 (d, J ) 16.8 Hz, 1H), 5.07 (d, J ) 10.1 Hz,

1H), 4.55 (d, J ) 10.6 Hz, 1H), 4.48 (d, J ) 10.6 Hz, 1H), 3.78 (s,

3H), 3.62 (dd, J ) 8.2, 3.4 Hz, 1H), 2.75 (m, 2H), 2.40 (m, 2H), 1.16

(d, J ) 7.1 Hz, 3H), 1.07 (d, J ) 6.9 Hz, 3H), 0.98 (t, J ) 7.2 Hz,

3H); ¹³C NMR (125 MHz, CDCl₃) 214.6, 159.2, 133.9, 132.1, 130.8,

129.5, 129.2, 117.6, 113.7, 83.9, 75.2, 55.2, 50.1, 36.2, 35.5, 18.7, 14.0,

7.5; HRMS (FAB, NBA/NaI) m/z calcd for C₂₀H₂₈O₃Na 339.1936,

290.1882; [R]²⁰+46.6° (c 0.5, CHCl₃).

D

(Z)-(3R,4S,5R)-4-[(4-Methoxyphenyl)methoxy]-3,5-dimethyl-6,8-

nonadien-2-one (4a). To a solution of 500 mg (1.73 mmol) of 13 in

5 mL of CH₂Cl₂was added 950 mg (2.08 mmol) of Dess-Martin

periodinane. After being stirred at ambient temperature for 10 min,

the reaction was quenched by the addition of 20 mL of saturated

Na₂S₂O₃solution and 20 mL of saturated NaHCO₃solution, and diluted

with 50 mL of diethyl ether. After the mixture was stirred 30 min, the

layers were separated and the organic layer was washed with 3 × 120

mL of saturated NaHCO₃solution, dried over MgSO₄, filtered,

concentrated in Vacuo, and chromatographed (10% EtOAc/hexanes)

to yield 456 mg of the aldehyde.

To a solution of 456 mg (1.58 mmol) of the aldehyde in 5 mL of

THF was added 2.10 mL (6.32 mmol, 3 M in Et₂O) of methylmagne-

sium bromide. After being stirred for 30 min at ambient temperature,

the reaction mixture was diluted with 30 mL of diethyl ether, washed

with 1 × 20 mL of 1 N HCl and 1 × 20 mL of saturated NaHCO₃

solution, dried over MgSO₄, filtered, concentrated in Vacuo, and

chromatographed (10% EtOAc/hexanes) to provide 450 mg of a 2:1

mixture of epimers.

found 339.1933; [R]²⁰+40.2° (c 0.5, CHCl₃).

D

(Z)-(4S,5R,6S)-Methyl 5,7-Bis[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-2,4,6-trimethyl-1-[(2,2-dimethylpropanoyl)oxy]-2-heptene. To

a cooled (0 °C) solution of 393 mg (0.94 mmol) of alcohol enant-11 in

10 mL of dichloromethane was added 229 µL (224 mg, 2.83 mmol) of

pyridine followed by 233 µL (228 mg, 1.89 mmol) of pivaloyl chloride.

The cooling bath was removed and the reaction stirred at ambient

temperature for 4 h. The mixture was concentrated and chromato-

graphed (3% EtOAc/hexane) to provide 455 mg (0.91 mmol, 96%) of

pivaloate: IR (thin film/NaCl) 1732 cm^-1; ¹H NMR (500 MHz, CDCl₃)

5.28 (d, J ) 9.8 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.50 (d, J ) 12.0

Hz, 1H), 3.60 (dd, J ) 9.8, 5.8 Hz, 1H), 3.46 (t, J ) 5.4 Hz, 1H), 3.35

(dd, J ) 9.7, 7.5 Hz, 1H), 2.61 (m, 1H), 1.79 (m, 1H), 1.70 (s, 3H),

1.18 (s, 9H), 0.90 (d, J ) 6.7 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.86

(d, J ) 4.5 Hz, 3H), 0.02 (s, 3H), 0.00 (s, 6H), 0.00 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 178.3, 135.3, 128.4, 77.4, 65.4, 63.2, 41.2, 38.8,

35.3, 27.2, 26.1, 26.0, 21.4, 18.4, 18.3, 16.6, 13.4, -4.0, -4.0, -5.3,

-5.4; HRMS (FAB, NBA/NaI) calcd for C₂₇H₅₆O₄Si₂Na 523.3615,

found 523.3632. Anal. Calcd C₂₇H₅₆O₄Si₂: C, 64.74; H, 11.27.

The mixture of alcohols was dissolved in 5 mL of CH₂Cl₂, and 933

mg (2.16 mmol) of Dess-Martin periodinane was added. After 30

min of stirring at ambient temperature, the reaction was quenched by

the addition of 20 mL of saturated Na₂S₂O₃solution and 20 mL of

saturated NaHCO₃solution and diluted with 50 mL of diethyl ether.

After the mixture was stirred for 30 min, the layers were separated

and the organic layer was washed with 3 × 120 mL of saturated

NaHCO₃solution, dried over MgSO₄, filtered, concentrated in Vacuo,

and chromatographed (5% EtOAc/hexanes) to yield 388 mg (1.28

mmol, 74% for three steps) of 4a as a colorless oil: IR (thin film/

Found: C, 64.77; H, 11.23. [R]²⁰-0.8° (c 0.5, CHCl₃).

D

(Z)-(2S,3R,4S)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2,4,6-tri-

methyl-7-[(2,2-dimethylpropanoyl)oxy]-5-hepten1-ol. To a flask

charged with 455 mg (0.91 mmol) of pivaloate was added 10 mL of

HF-pyridine buffered with excess pyridine (prepared by the slow

addition of 5 mL of pyridine to 1.25 mL of HF-pyridine followed by

dilution with 12.5 mL of THF), and the resulting solution was stirred

at ambient temperature for 9 h. The reaction was quenched by slow

addition of 20 mL of saturated NaHCO₃solution and extracted with 2

1

NaCl)1711 cm^-1; H NMR (500 MHz, CDCl₃) 7.23 (d, J ) 8.6 Hz,

2H), 6.84 (d, J ) 8.7 Hz, 2H), 6.45 (dddd, J ) 16.1, 11.0, 10.2, 0.8

Hz, 1H), 6.02 (apparent t, J ) 11.0 Hz, 1H), 5.49 (apparent t, J )

10.6 Hz, 1H), 5.19 (dd, J ) 16.7, 1.0 Hz, 1H), 5.07 (d, J ) 10.2 Hz,

1H), 4.53 (d, J ) 10.6 Hz, 1H), 4.45 (d, J ) 10.6 Hz, 1H), 3.77 (s,

11070 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

× 50 mL of dichloromethane. The combined organic layers were

washed with 2 × 25 mL of saturated CuSO₄solution, dried over

MgSO₄, filtered, concentrated, and chromatographed (10% EtOAc/

hexane) to afford 317 mg (0.82 mmol, 90%) of alcohol: IR (thin film/

pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2-decen-7-ynyl Ester (enant-

19a and enant-19b). A mixture of 227 mg (0.58 mmol) of aldehyde

enant-2 and 650 mg (1.28 mmol) of iodide was azeotropically dried

with 3 × 10 mL portions of benzene, and the flask was evacuated and

filled with Ar three times. The mixture was transferred to an inert

atmosphere box, dissolved in 5 mL of THF, and treated with

approximately 100 mg of 0.011% NiCl₂/CrCl₂, and the resulting slurry

was stirred at room temperature for 23 h. The reaction was removed

from the inert atmosphere box, filtered over a Celite pad, and rinsed

with 100 mL of EtOAc. The filtrate was washed with 2 × 50 mL of

saturated NaHCO₃, the combined aqueous layers were extracted with

2 × 50 mL of EtOAc, and the organic layers were combined, dried

over MgSO₄, filtered, and chromatographed (2%-4%-6%-10%

EtOAc/hexanes) to provide 214 mg (0.28 mmol) of propargyl alcohol

enant-19a and 139 mg (0.18 mmol) of propargyl alcohol enant-19b

(79% combined). Data for enant-19a: IR (thin film/NaCl) 3513 (br),

1

NaCl) 3482 (br), 1730,cm^-1; H NMR (500 MHz, CDCl₃) 5.19 (d, J

) 10.0 Hz, 1H), 4.56 (d, J ) 12.0 Hz, 1H), 4.50 (d, J ) 12.0 Hz, 1H),

3.54 (m, 1H), 3.41 (dd, J ) 5.9, 4.4 Hz, 1H), 2.68 (m, 1H), 2.48 (br

s, 1H), 1.78 (m, 1H), 1.67 (s, 3H), 1.15 (s, 9H), 0.93 (d, J ) 7.3 Hz,

3H), 0.92 (d, J ) 6.9 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) 178.3, 134.1, 129.3, 80.5, 65.2, 63.2,

38.9, 38.8, 36.8, 27.1, 26.1, 21.3, 18.3, 17.1, 15.5, -3.8, -4.0; HRMS

(FAB, NBA/NaI) calcd for C₂₁H₄₂O₄SiNa 409.2750, found 409.2751.

Anal. Calcd for C₂₁H₄₂O₄Si: C, 65.24; H, 10.95. Found: C, 65.31;

H, 10.92. [R]²⁰+13.5° (c 0.4, CHCl₃).

D

(Z)-(4S,5R,6S)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2,4,6-tri-

methyl-1-[(2,2-dimethylpropanoyl)oxy]-2-octen-7-yne (enant-18). To

a solution of 290 µL (319 mg, 4.09 mmol) of DMSO in 5 mL of

dichloromethane at -78 °C was added 179 µL (260 mg, 2.05 mmol)

of oxalyl chloride. After 15 min, a solution of 316 mg (0.82 mmol) of

alcohol in 4 mL of dichloromethane (plus 1 mL rinse) was added Via

cannula. After 45 min at -78 °C, 1.14 mL (828 mg, 8.19 mmol) of

triethylamine was added, and after 5 min, the cooling bath was removed

and the reaction was stirred at ambient temperature for 15 min. The

resulting slurry was diluted with 50 mL of hexane and washed with 3

× 10 mL of H₂O, dried over MgSO₄, filtered, concentrated, taken up

in 50 mL of ether, refiltered through MgSO₄, reconcentrated, and used

immediately in the subsequent reaction.

1

1728 cm^-1; H NMR (500 MHz, CDCl₃) 7.50 (dd, J ) 8.4, 1.4 Hz,

2H), 7.26 (t, J ) 7.4 Hz, 2H), 7.17 (t, J ) 7.4 Hz, 1H), 5.24 (d, J )

10.1 Hz, 1H), 5.13 (d, J ) 1.3 Hz, 1H), 4.69 (d, J ) 12.1 Hz, 1H),

4.56 (d, J ) 12.1 Hz, 1H), 4.56-4.51 (m, 2H), 3.58 (t, J ) 3.1 Hz,

1H), 3.34 (dd, J ) 6.6, 3.4 Hz, 1H), 2.97 (d, J ) 6.3 Hz, 1H), 2.75 (m,

1H), 2.58 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H), 1.72 (d,

J ) 0.9 Hz, 3H), 1.18 (s, 9H), 1.12 (d, J ) 7.0 Hz, 3H), 1.11 (d, J )

6.9 Hz, 3H), 0.98 (s, 9H), 0.94 (d, J ) 6.6 Hz, 3H), 0.89 (s, 9H), 0.86

(d, J ) 6.8 Hz, 3H), 0.12 (s, 3H), 0.06 (s, 3H), 0.02 (s, 6H); ¹³C NMR

(125 MHz, CDCl₃) 178.6, 138.3, 134.4, 130.9, 129.1, 128.7, 126.5,

89.0, 86.5, 83.5, 78.5, 73.9, 68.1, 63.7, 59.4, 41.4, 40.6, 38.8, 36.6,

35.5, 31.9, 27.2, 26.1, 26.0, 21.4, 18.3, 18.2, 17.6, 17.5, 17.1, 13.9,

-3.9, -4.0, -4.1, -4.9; HRMS (FAB, NBA/NaI) calcd for C₄₃H₇₄O₆-

Si₂SNa 797.4642, found 797.4663; [R]²⁰_D+126.6° (c 0.5, CHCl₃). Data

To a cooled (-78 °C) solution of 101 mg (0.90 mmol) of potassium

tert-butoxide in 1 mL of THF was added 135 mg (0.90 mmol) of

dimethyl diazomethylphosphonate in 1 mL of THF Via cannula. After

stirring for 10 min, a solution of the above-prepared aldehyde (in 2

mL of THF plus 2 × 0.5 mL rinses) was added Via cannula and the

reaction removed to a constant temperature bath at -50 °C for 21 h.

The reaction was removed from the cooling bath and stirred at ambient

temperature for 1 h when the reaction volume was reduced to

approximately 1 mL and directly chromatographed (2% EtOAc/hexane)

to provide 310 mg (0.82 mmol, 99% from alcohol) of acetylene enant-

18: IR (thin film/NaCl) 1730 cm^-1; ¹H NMR (500 MHz, CDCl₃) 5.20

(d, J ) 10.3 Hz, 1H), 4.65 (d, J ) 12.1 Hz, 1H), 4.53 (d, J ) 12.0 Hz,

1H), 3.32 (dd, J ) 7.0, 3.3 Hz, 1H), 2.76 (m, 1H), 2.58 (m, 1H), 1.98

(d, J ) 2.4 Hz, 1H), 1.68 (d, J ) 0.6 Hz, 3H), 1.17 (s, 9H), 1.13 (d,

J ) 7.2 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 3H),

0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) 178.2, 133.9, 129.4, 86.1,

78.5, 70.0, 63.3, 38.7, 36.8, 31.5, 27.1, 25.9, 21.3, 18.3, 17.5, 17.3,

-3.9, -4.0; HRMS (FAB, NBA/NaI) calcd for C₂₂H₄₀O₃SiNa 403.2644,

found 403.2661. Anal. Calcd for C₂₂H₄₀O₃Si: C, 69.42; H, 10.59.

1

for enant-19b. IR (thin film/NaCl) 3517 (br), 1713 cm^-1; H NMR

(500 MHz, CDCl₃) 7.45 (d, J ) 7.5 Hz, 2H), 7.22 (t, J ) 8.1 Hz, 2H),

7.15 (dt, J ) 7.8, 1.0 Hz, 1H), 5.21 (d, J ) 10.2 Hz, 1H), 5.13 (s, 1H),

4.71 (d, J ) 12.1 Hz, 1H), 4.55 (d, J ) 12.1 Hz, 1H), 4.54 (m, 1H),

4.38 (td, J ) 10.1, 2.4 Hz, 1H), 3.57 (t, J ) 2.9 Hz, 1H), 3.32 (t, J )

3.3 Hz, 1H), 2.78 (m, 1H), 2.51 (m, 1H), 2.15 (m, 1H), 1.92 (m, 1H),

1.87 (m, 1H), 1.81 (m, 1H), 1.73 (s, 3H), 1.18 (s, 9H), 1.12 (d, J ) 7.3

Hz, 3H), 1.08 (d, J ) 7.2 Hz, 3H), 0.98 (s, 9H), 0.93 (d, J ) 6.6 Hz,

3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H), 0.00 (s, 6H); ¹³C NMR

(125 MHz, CDCl₃) 178.9, 138.5, 134.8, 130.6, 128.8, 128.6, 126.3,

88.9, 86.8, 83.2, 78.4, 73.9, 69.7, 63.9, 61.1, 41.4, 41.0, 38.8, 36.4,

35.8, 32.1, 27.2, 26.2, 26.2, 26.0, 21.4, 18.3, 18.2, 17.6, 17.4, 16.8,

14.0, -4.0 (2), -4.1, -4.9; HRMS (FAB, NBA/NaI) calcd for

C₄₃H₇₄O₆Si₂SNa 797.4642, found 797.4625; [R]²⁰+119.6° (c 0.5,

D

CHCl₃).

2,2-Dimethylpropanoic Acid, [2S-[2R(2Z,4S,5R,6S,9S),3â,4â,

5r,6r]]-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-10-[4-[[(1,1-di-

methylethyl)dimethylsilyl]]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-2,4,6-trimethyl-9-oxo-2-decen-7-ynyl Ester (enant-

23). To a solution of 44 µL (48 mg, 0.61 mmol) of DMSO in 4 mL

of dichloromethane at -78 °C was added 32 µL (47 mg, 0.37 mmol)

of oxalyl chloride. After 20 min, a solution of 95 mg (0.12 mmol) of

propargylic alcohol enant-19b in 3 mL of dichloromethane (plus 2 ×

1 mL rinses) was added Via cannula. After 2 h at -78 °C, 171 µL

(125 mg, 1.23 mmol) of triethylamine was added, and after 5 min, the

cooling bath removed and the reaction stirred at ambient temperature

30 min. The resulting slurry was diluted with 100 mL of hexane and

washed with 3 × 25 mL of H₂O and 1 × 25 mL of brine, dried over

MgSO₄, filtered, concentrated, and chromatographed (4% EtOAc/

hexane) to provide 93 mg (0.12 mmol, 98%) of ynone enant-23: IR

Found: C, 69.53; H, 10.60. [R]²⁰+7.4° (c 0.5, CHCl₃).

D

(Z)-(4S,5R,6S)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-8-iodo-

2,4,6-trimethyl-1-[(2,2-dimethylpropanoyl)oxy]-2-octen-7-yne (enant-

34). To a solution of 427 mg (4.90 mmol) of morpholine in 5 mL of

benzene was added 248 mg (0.98 mmol) of iodine, and the suspension

was heated, shielded from light, to 45-50 °C for 1 h. The resulting

red suspension was treated with 310 mg (0.82 mmol) of acetylene enant-

18 in 3 mL of benzene (plus 2 × 1 mL rinses) and stirred at 45-50

°C, shielded from light, for 22 h. The suspension was poured over 50

mL of hexanes plus 10 mL of saturated Na₂SO₃solution and shaken

vigourously until the organic layer was colorless. The layers were

separated, and the organic layer was washed with 1 × 10 mL of Na₂-

SO₃, dried over MgSO₄, filtered, concentrated, and chromatographed

(2% EtOAc/hexane) to afford 377 mg (0.75 mmol, 91%) of iodide:

1

IR (thin film/NaCl) 1730 cm^-1; H NMR (500 MHz, CDCl₃) 5.24 (d,

1

(thin film/NaCl) 1728, 1676 cm^-1; H NMR (500 MHz, CDCl₃) 7.40

J ) 10.2 Hz, 1H), 4.63 (d, J ) 12.0 Hz, 1H), 4.51 (d, J ) 12.0 Hz,

1H), 3.34 (dd, J ) 6.7, 3.8 Hz, 1H), 2.74 (m, 1H), 2.69 (m, 1H), 1.72

(s, 3H), 1.19 (s, 9H), 1.12 (d, J ) 7.1 Hz, 3H), 0.93 (d, J ) 6.6 Hz,

3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) 178.3, 133.9, 129.6, 96.8, 78.7, 63.4, 38.8, 36.7, 34.0, 27.2,

26.0, 21.6, 18.3, 17.4, 17.0, -3.8, -4.0; HRMS (FAB, NBA/NaI) calcd

(dd, J ) 7.5, 1.2 Hz, 2H), 7.21 (t, J ) 7.5 Hz, 2H), 7.10 (m, 1H), 5.19

(d, J ) 10.1 Hz, 1H), 5.11 (s, 1H), 4.81 (td, J ) 9.8, 3.3 Hz, 1H), 4.64

(d, J ) 12.2 Hz, 1H), 4.45 (d, J ) 12.1 Hz, 1H), 3.58 (t, J ) 2.6 Hz,

1H), 3.32 (dd, J ) 6.6, 3.8 Hz, 1H), 2.74 (dd, J ) 14.8, 3.5 Hz, 1H),

2.60 (m, 2H), 2.46 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.67 (d, J )

1.2 Hz, 3H), 1.17 (s, 9H), 1.11 (d, J ) 7.3 Hz, 3H), 1.08 (d, J ) 7.1

Hz, 3H), 0.99 (s, 9H), 0.86 (s, 9H), 0.89-0.82 (overlapping d, 6H),

0.12 (s, 3H), 0.06 (s, 3H), -0.02 (s, 3H), -0.03 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 185.7, 178.2, 139.4, 133.4, 129.7, 129.6, 128.5,

125.9, 96.5, 89.0, 82.7, 78.0, 74.0, 67.8, 63.2, 49.4, 42.0, 38.8, 36.7,

35.3, 32.2, 27.2, 26.2, 26.0, 21.3, 18.3, 18.2, 17.6, 17.3, 15.6, 14.1,

for C₂₂H₃₉O₃SiINa 529.1613, found 529.1622; [R]²⁰-12.2° (c 0.5,

D

CHCl₃).

2,2-Dimethylpropanoic Acid, [2S-[2r(2Z,4S,5R,6S,9S]),3â,4â,5r,

6r]]5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-10-[4-[[(1,1-dimethyl-

ethyl)dimethylsilyl]]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-2H-

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11071

-3.9, -4.0, -4.1, -4.9; HRMS (FAB, NBA/NaI) calcd for C₄₃H₇₂O₆-

9H), 0.85 (d, J ) 7.0 Hz, 3H), 0.79 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H),

0.04 (s, 3H), 0.02 (s, 3H), -0.14 (s, 3H), -0.27 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) 178.3, 140.6, 135.3, 134.6, 131.2, 128.5, 128.4,

128.1, 125.1, 87.5, 80.4, 74.2, 68.0, 66.1, 63.3, 42.9, 41.7, 38.8, 36.9,

36.0, 35.4, 27.2, 26.3, 26.2, 25.9, 21.5, 18.5, 18.3, 18.1, 18.0, 17.6,

16.0, 14.2, -3.0, -3.6, -4.0, -4.1, -4.9, -5.1; HRMS (FAB, NBA/

Si₂SNa 795.4485, found 795.4499; [R]²⁰+63.0° (c 0.5, CHCl₃).

D

CBS Reduction of Ynone 23. A 0.2 M solution of the B-

butyloxazaborolidine catalyst in toluene was generated as follows: To

a flask fitted with a three-way stopcock containing 460 mg (1.8 mmol,

azeotropically dried with toluene) of (S)-2-(diphenylhydroxymethyl)-

pyrrolidine was added 5 mL of toluene and 360 µL (1.5 mmol) of

bis(trifluoroethyl) ethylboronate with stirring. After 15 min at ambient

temperature, the toluene was removed in Vacuo and the resulting

colorless oil heated at 110 °C at 1.0 Torr for 30 min. After the mixture

was cooled to room temperature and returned to 1 atm, 7.2 mL of

toluene was added to afford a 0.2 M catalyst solution. A solution of

423 mg (0.55 mmol) of ynone 23 in 5 mL of toluene was treated with

1.4 mL (0.28 mmol) of the above freshly prepared 0.2 M catalyst

solution at room temperature. After cooling to -78 °C, freshly distilled

catecholborane (430 µL, 0.85 mmol, 2 M in toluene) was added over

10 min and the reaction removed to a -20 °C freezer for 7.5 h. The

reaction was quenched by addition of 5 mL of 1 N HCl and diluted

with 50 mL of ether and the layers were separated. The organic layer

was washed with 1 N NaOH until the aqueous layer was colorless (6

× 5 mL 1 N NaOH), the organic layer dried over MgSO₄, filtered,

concentrated, and chromatographed (4% EtOAc/hexane) to afford 343

mg (0.44 mmol, 81%) of propargylic alcohol 19a, identical in all

respects to that prepared earlier.

NaI) calcd for C₄₉H₉₀O₆Si₃SNa 913.5663, found 913.5674; [R]²⁰

D

+31.8° (c 0.5, CHCl₃).

[2S-[2r(2Z,4S,5R,6S,9S),3â,4â,5r,6r]]-5,9-Bis[[(1,1-dimethyleth-

yl)dimethylsilyl]oxy]-10-[4-[[(1,1-dimethylethyl)dimethylsilyl]]oxy]-

tetrahydro-3,5-dimethyl-6-(phenylthio)-2H-pyran-2-yl]-2,4,6-trimethyl-

2,7-decadien-1-ol (enant-20). To a cooled (-78 °C) solution of 764

mg (0.86 mmol) of pivaloyl ester in 10 mL of dichloromethane was

added 1.7 mL of DIBAL-H (1.5 M in toluene, 2.57 mmol), and the

solution was stirred for 25 min when it was quenched with 25 mL of

0.5 M NaK tartrate solution saturated with NaCl and 25 mL of brine,

warmed to room temperature, and stirred until the layers separated.

The layers were separated, the aqueous layer was extracted with 3 ×

50 mL of dichloromethane, and the organic layers were combined, dried

over MgSO₄, filtered, concentrated, and chromatographed (3% EtOAc/

hexanes) to provide 680 mg (0.84 mmol, 98%) of primary alcohol enant-

1

20 as a white foam: IR (thin film/NaCl) 3452 (br) cm^-1; H NMR

(500 MHz, CDCl₃) 7.46 (dd, J ) 8.5, 1.1 Hz, 2H), 7.21 (t, J ) 7.4 Hz,

2H), 7.13 (t, J ) 7.4 Hz, 1H), 5.43-5.34 (m, 2H), 5.22 (s, 1H), 5.12

(d, J ) 9.5 Hz, 1H), 4.49 (t, J ) 9.2 Hz, 1H), 4.36 (t, J ) 10.2 Hz,

1H), 4.15 (dd, J ) 12.3, 3.8 Hz, 1H), 3.95 (dd, J ) 12.2, 7.3 Hz, 1H),

3.58 (t, J ) 2.9 Hz, 1H), 3.32 (dd, J ) 6.0, 3.5 Hz, 1H), 2.63 (m, 1H),

2.50 (m, 1H), 2.15 (m, 1H), 1.99 (m, 1H), 1.78-1.69 (m, 2H), 1.67

(d, J ) 0.8 Hz, 3H), 1.38 (m, 1H), 1.14 (d, J ) 7.3 Hz, 3H), 1.00 (d,

J ) 7.0 Hz, 3H), 0.98 (s, 9H), 0.92 (s, 9H), 0.91 (d, J ) 7.0 Hz, 3H),

0.85 (d, J ) 6.8 Hz, 3H), 0.81 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06

(s, 3H), 0.05 (s, 3H), -0.10 (s, 3H), -0.23 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) 140.0, 134.3, 133.6, 132.4, 130.8, 128.8, 128.4, 125.4,

87.9, 80.9, 74.2, 68.0, 65.9, 61.7, 42.7, 41.7, 36.7, 36.6, 35.4, 26.3,

26.2, 26.0, 21.2, 19.2, 18.5, 18.3, 18.0, 17.7, 17.5, 14.2, -3.2, -3.3,

-3.7, -4.0, -4.7, -4.8; HRMS (FAB, NBA/NaI) calcd for C₄₄H₈₂O₅-

2,2-Dimethylpropanoic Acid, [2S-[2r(2Z,4S,5R,6S,9S),3â,4â,5r,

6r]]-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-10-[4-[[(1,1-dimeth-

ylethyl)dimethylsilyl]]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2,7-decadienyl Ester.

Through a suspension of 200 mg of 10% Pd/C in 4 mL of EtOAc was

bubbled H₂for 15 min (from a balloon through a needle and exiting

Via a capillary pipet inserted through the rubber septum) when 200 mg

(0.26 mmol) of acetylene enant-19a was added by syringe in 2 mL of

EtOAc (plus 2 × 1 mL rinses) and the H₂bubbled through the resulting

suspension for 30 min. The mixture was filtered through Celite, washed

with 150 mL of EtOAc, concentrated, and chromatographed (3%

EtOAc/hexanes) to provide 170 mg (0.22 mmol, 85%) of cis-olefin as

1

a viscous oil: IR (thin film/NaCl) 3522 (br), 1729 cm^-1; H NMR

Si₃SNa 829.5088, found 829.5072; [R]²⁰+51.6° (c 0.5, CHCl₃).

D

(500 MHz, CDCl₃) 7.44 (dd, J ) 8.4, 1.3 Hz, 2H), 7.23 (t, J ) 7.4 Hz,

2H), 7.15 (t, J ) 6.5 Hz, 1H), 5.45 (apparent t, J ) 10.7 Hz, 1H), 5.36

(dd, J ) 11.0, 8.5 Hz, 1H), 5.25 (s, 1H), 5.20 (d, J ) 9.1 Hz, 1H),

4.58 (d, J ) 12.0 Hz, 1H), 4.52 (m, 1H), 4.42 (d, J ) 11.8 Hz, 1H),

4.41 (m, 1H), 3.59 (t, J ) 2.9 Hz, 1H), 3.30 (dd, J ) 5.9, 4.2 Hz, 1H),

2.60 (m, 1H), 2.53 (m, 1H), 2.26 (d, J ) 3.8 Hz, 1H), 2.16 (m, 1H),

1.85 (m, 1H), 1.75 (m, 1H), 1.69 (m, 1H), 1.67 (d, J ) 1.2 Hz, 3H),

1.55 (m, 1H), 1.17 (s, 9H), 1.14 (d, J ) 7.3 Hz, 3H), 0.98 (s, 9H),

0.96 (d, J ) 6.9 Hz, 3H), 0.91 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H), 0.85

(d, J ) 6.8 Hz, 3H), 0.11 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) 178.3, 138.6, 134.7, 134.0, 131.6,

129.8, 128.7 (2), 126.2, 88.5, 80.3, 74.0, 67.5, 64.2, 63.3, 41.5, 39.8,

38.8, 37.1, 36.7, 35.4, 27.2, 26.2, 26.1, 21.4, 18.7, 18.4, 18.3, 17.7,

17.2, 14.0, -3.4, -3.9, -4.0, -4.8; HRMS (FAB, NBA/NaI) calcd

[2S-[2r(2Z,4S,5R,6S,9S),3â,4â,5r,6r]]-5,9-Bis[[(1,1-dimethyleth-

yl)dimethylsilyl]oxy]-1-bromo-10-[4-[[(1,1-dimethylethyl)dimethyl-

silyl]]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-2H-pyran-2-yl]-

2,4,6-trimethyl-2,7-decadiene (enant-21). To a cooled (0 °C) solution

of 113 mg (140 µmol) of alcohol enant-20 in 2 mL of CH₂Cl₂were

added Et₃N (78 µL, 560 µmol) in one portion and MsCl (22 µL, 280

µmol) dropwise over 10 min. After stirring for 1 h at 0 °C, during

which time a white precipitate formed, a solution of LiBr (122 mg,

1.4 mmol) in 3 mL of acetone was added and the resulting suspension

warmed to room temperature and stirred for an additional 15 min.

Dilution with 50 mL of hexanes and filtration over MgSO₄provided

113 mg (130 µmol, 93%) of bromide enant-21 as a colorless oil used

without further purification: ¹H NMR (500 MHz, CDCl₃) 7.43 (d, J )

6.7 Hz, 2H), 7.20 (dt, J ) 8.6, 1.4 Hz, 2H), 7.09 (t, J ) 7.1 Hz, 1H),

5.35-5.25 (m, 3H), 5.23 (s, 1H), 4.52 (apparent t, J ) 8.9 Hz, 1H),

4.25 (apparent t, J ) 10.1 Hz, 1H), 4.00 (dd, J ) 9.6, 1.4 Hz, 1H),

3.91 (dd, J ) 9.6, 1.4 Hz, 1H), 3.58 (apparent s, 1H), 3.42 (apparent

t, J ) 4.4 Hz, 1H), 2.64 (m, 1H), 2.56 (m, 1H), 2.14 (m, 1H), 1.78 (s,

3H), 1.81-1.65 (m, 2H), 1.40 (dd, J ) 13.8, 10.3 Hz, 1H), 1.25 (m,

1H), 1.11 (dd, J ) 7.3, 1.4 Hz, 3H), 1.00 (dd, J ) 6.9, 1.3 Hz, 3H),

0.97 (s, 9H), 0.91 (s, 9H), 0.87-0.83 (2 overlapping d, 6H), 0.78 (s,

9H), 0.11 (s, 3H), 0.05 (s, 6H), 0.02 (s, 3H), -0.13 (s, 3H), -0.27 (s,

3H).

for C₄₃H₇₆O₆Si₂SNa 799.4799, found 799.4818; [R]²⁰+59.0° (c 0.5,

D

CHCl₃).

2,2-Dimethylpropanoic Acid, [2S-[2r(2Z,4S,5R,6S,9S),3â,4â,

5r,6r]]-5,9-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-10-[4-[[(1,1-

dimethylethyl)dimethylsilyl]]oxy]tetrahydro-3,5-dimethyl-6-

(phenylthio)-2H-pyran-2-yl]-2,4,6-trimethyl-2,7-decadienyl Ester. To

a solution of 87 mg (0.11 mmol) of alcohol in 2 mL of dichloromethane

at ambient temperature was added 52 µL (48 mg, 0.45 mmol) of 2,6-

lutidine followed by 51 µL (59 mg, 0.22 mmol) of TBSOTf. After

standing for 30 min, the solution was quenched with 0.5 mL of MeOH,

concentrated, and chromatographed (1% EtOAc/hexanes) to provide

[2S-[2â(3Z,5S,6S,7R,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-

14,18-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-19-[4-[[(1,1-dimeth-

ylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-6-[(4-methoxyphenyl)methoxy]-5,7,11,13,15-

pentamethyl-1,3,11,16-nonadecatetraen-8-one (26b). To a cooled

solution (0 °C) of 100 mg (124 µmol) of 20 in 1 mL of CH₂Cl₂was

added 69 µL (50 mg, 496 µmol) of Et₃N, followed by 19 µL (28 mg,

248 µmol) of MsCl. After stirring for 1 h, a solution of 108 mg (1.24

mmol) of LiBr in 3 mL of acetone was added. After the mixture was

warmed to ambient temperature and stirred for an additional 15 min,

the suspension was diluted with 20 mL of hexanes, filtered through

99 mg (0.11 mmol, 99%) of silyl ether: IR (thin film/NaCl) 1731 cm^-1

;

¹H NMR (500 MHz, CDCl₃) 7.43 (dd, J ) 8.4, 1.3 Hz, 2H), 7.20 (t,

J ) 7.5 Hz, 2H), 7.09 (t, J ) 7.4 Hz, 1H), 5.33 (d, J ) 10.7 Hz, 1H),

5.32 (d, J ) 11.0 Hz, 1H), 5.25 (d, J ) 10.2 Hz, 1H), 5.23 (d, J ) 1.2

Hz, 1H), 4.60 (d, J ) 12.2 Hz, 1H), 4.51 (m, 1H), 4.51 (d, J ) 12.1

Hz, 1H), 4.24 (t, J ) 10.1 Hz, 1H), 3.58 (t, J ) 3.0 Hz, 1H), 3.35

(apparent t, J ) 4.9 Hz, 1H), 2.63 (m, 1H), 2.61 (m, 1H), 2.14 (m,

1H), 1.72 (m, 1H), 1.70 (d, J ) 1.1 Hz, 3H), 1.69 (m, 1H), 1.46 (dd,

J ) 13.4, 10.5 Hz, 1H), 1.19 (s, 9H), 1.10 (d, J ) 7.3 Hz, 3H), 0.99

(d, J ) 6.3 Hz, 3H), 0.98 (s, 9H), 0.96 (d, J ) 6.8 Hz, 3H), 0.91 (s,

11072 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

MgSO₄and 5 g of silica gel, eluting from the silica gel with 20 mL of

10% EtOAc/hexanes, and concentrated in Vacuo to provide crude

bromide 21.

NaI) m/z calcd for C₆₄H₁₀₈O₇Si₃SNa 1127, found 1127; [R]²⁰_D+71.0°

(c 0.5, CHCl₃).

[2S-[2â(3Z,5S,6S,7R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-

14,18-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-19-[4-[[(1,1-dimeth-

ylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-6-[(4-methoxyphenyl)methoxy]-5,7,9,11,13,15-

hexamethyl-1,3,11,16-nonadecatetraen-8-one (30). To a cooled (-78

°C) solution of 60 mg (55 µmol) of 26b in 1 mL of THF was added

500 µL (275 µmol, 0.5 M in THF) of LiN(SiMe₂Ph)₂. After the reaction

was stirred at -78 °C for 1 h, 342 µL (781 µg, 5.5 mmol) of methyl

iodide was added. The reaction was warmed to 0 °C and stirred at

ambient temperature for 3 h. After quenching the reaction with 1.5

mL of saturated NH₄Cl solution, the mixture was extracted with 30

mL of EtOAc and the layers were separated. The organic layer was

dried over MgSO₄, filtered, concentrated in Vacuo, and chromatographed

(2% EtOAc‚hexanes). The resulting colorless oil was purified by HPLC

(2% EtOAc/hexanes) to provide 16 mg (13 µmol, 24%) of 30 as a

To a cooled (-78 °C) solution of the crude bromide 21 and 115 mg

(381 µmol) of ketone 4a in 1 mL of THF was added 846 mL (423

µmol, 0.5 M solution in THF) of LDA. The mixture was stirred for 3

h at 0 °C, and then the reaction was quenched by the addition of 1.5

mL of saturated NH₄Cl solution. The mixture was extracted into 30

mL of EtOAc, dried over MgSO₄, filtered, concentrated in Vacuo, and

chromatographed (0.5%-1%-2% EtOAc/hexanes) to provide 110 mg

(101 µmol, 81% for two steps) of 26b as a colorless oil: IR (thin film/

NaCl) 1710 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, J ) 7.0 Hz,

2H), 7.27-7.23 (m, 5H), 6.85 (d, J ) 8.6 Hz, 2H), 6.45 (ddd, J )

10.6, 16.9, 21.1 Hz, 1H), 6.03 (apparent t, J ) 10.9 Hz, 1H), 5.52

(apparent t, J ) 10.5 Hz, 1H), 5.31 (d, J ) 1.9 Hz, 1H), 5.29 (obscured

dd, J ) 7.5, 11.1 Hz, 1H), 5.23 (d, J ) 10.3 Hz, 1H), 5.19 (d, J )

16.2 Hz, 1H), 5.09 (overlapping d, J ) 9.0 Hz, 1H), 5.08 (overlapping,

J ) d, 9.9 Hz, 1H), 4.56 (overlapping m, 1H), 4.55 (overlapping d, J

) 10.6 Hz, 1H), 4.49 (d, J ) 10.6 Hz, 1H), 3.79 (s, 3H), 3.66-3.60

(obscured m, 3H), 3.29 (apparent t, J ) 4.9 Hz, 1H), 2.79 (m, 1H),

2.73 (m, 1H), 2.65 (m, 1H), 2.45 (m, 3H), 2.36 (m, 1H), 2.08 (m, 1H),

2.00 (m, 1H), 1.62 (s, 3H), 1.58 (obscured m, 2H), 1.48 (dd, J ) 13.1,

23.8 Hz, 1H), 1.17 (s, J ) 7.1 Hz, 3H), 1.08 (d, J ) 6.9 Hz, 3H), 1.06

(d, J ) 7.2 Hz, 3H), 0.97 (d, J ) 7.0 Hz, 3H), 0.96 (d, J ) 7.0 Hz,

3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.78 (s, 9H), 0.77 (overlapping d, 3H),

0.05 (s, 3H), 0.03 (overlapping s, 6H), 0.02 (s, 3H), -0.12 (s, 3H),

-0.26 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 213.5, 159.1, 135.5,

134.4, 133.9, 132.6, 132.0, 131.7, 131.6, 131.4, 130.7, 129.6, 129.3,

128.7, 127.1, 117.9, 113.7, 84.6, 83.7, 80.5, 76.5, 75.1, 74.7, 65.6, 55.2,

50.3, 42.6, 41.9, 41.0, 36.6, 36.1, 35.6, 34.1, 26.3, 25.9, 25.8, 23.2,

18.7, 18.5, 18.0, 17.9, 16.4, 14.3, 13.9, 11.4, -2.8, -4.1, -4.2, -4.6,

-5.0, -5.1; LRMS (FAB, NBA/NaI) m/z calcd for C₆₃H₁₀₆O₇Si₃SNa

1

colorless oil: IR (thin film/NaCl) 1710 cm^-1; H NMR (500 MHz,

CDCl₃) δ 7.49 (d, J ) 6.5 Hz, 2H), 7.29-7.23 (m, 5H), 6.86 (d, J )

8.7 Hz, 2H), 6.43 (ddd, J ) 10.8, 16.6, 21.1 Hz, 1H), 6.03 (apparent

t, J ) 11.0 Hz, 1H), 5.62 (apparent t, J ) 10.3 Hz, 1H), 5.30

(overlapping d, J ) 2.1 Hz, 1H), 5.29 (overlapping dd, J ) 7.6, 10.9

Hz, 1H), 5.23 (d, J ) 9.8 Hz, 1H), 5.18 (dd, J ) 1.7, 5.7 Hz, 1H),

5.15 (s, 1H), 5.12 (obscured m, 1H), 5.06 (d, J ) 10.1 Hz, 1H), 4.56

(obscured m, 1H), 5.54 (overlapping d, J ) 2.2 Hz, 2H), 3.80 (s, 3H),

3.61 (obscured t, J ) 10.5 Hz, 1H), 3.59 (br s, 2H), 3.27 (dd, J ) 3.1,

6.7 Hz, 1H), 2.84 (m, 1H), 2.75 (m, 1H), 2.68 (m, 2H), 2.52 (m, 1H),

2.32 (dd, J ) 5.6, 13.5 Hz, 1H), 1.99 (ddd, J ) 2.6, 5.3, 7.1 Hz, 1H),

1.92 (dd, J ) 8.6, 13.5 Hz, 1H), 1.63 (d, J ) 0.9 Hz, 3H), 1.59 (m,

1H), 1.53 (m, 1H), 1.16 (d, J ) 7.1 Hz, 3H), 1.08 (d, J ) 6.9 Hz, 3H),

1.05 (d, J ) 7.1 Hz, 3H), 0.97 (overlapping d, J ) 7.4 Hz, 3H), 0.96

(overlapping d, J ) 7.4 Hz, 3H), 0.94 (overlapping d, J ) 7.1 Hz,

3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.78 (s, 9H), 0.75 (d, J ) 6.8 Hz, 3H),

0.03 (overlapping s, 9H), 0.01 (s, 3H), -0.14 (s, 3H), -0.27 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 216.7, 159.1, 135.3, 134.5, 133.6, 133.4,

132.7, 132.3, 132.1, 130.8, 129.7, 129.3, 128.8, 127.2, 117.7, 113.7,

84.7, 83.7, 80.3, 77.2, 76.5, 75.4, 74.7, 65.6, 55.3, 49.6, 44.3, 42.841.9,

36.8, 36.5, 34.9, 34.1, 26.4, 25.8, 23.5, 19.3, 18.5, 18.0, 17.9, 17.7,

16.1, 15.2, 14.3, 13.9, 11.4, -2.5, -4.2, -4.5, -4.9, -5.2; LRMS

(FAB, NBA/NaI) m/z calcd for C₆₄H₁₀₈O₇Si₃SNa 1127, found 1127;

1113, found 1113; [R]²⁰+64.8° (c 0.5, CHCl₃).

D

[2S-[2â(3Z,5S,6S,7R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-

14,18-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-19-[4-[[(1,1-dimeth-

ylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-6-[(4-methoxyphenyl)methoxy]-5,7,9,11,13,15-

hexamethyl-1,3,11,16-nonadecatetraen-8-one (27b). To a cooled

(-78 °C) solution of 60 mg (55 µmol) of 26b in 1 mL of THF was

added 500 µL (275 µmol, 0.5 M in THF) of LiN(SiMe₂Ph)₂. After

the reaction was stirred at -78 °C for 1 h, 342 µL (781 µg, 5.5 mmol)

of methyl iodide was added. The reaction was warmed to 0 °C and

stirred at ambient temperature for 3 h. After quenching the reaction

with 1.5 mL of saturated NH₄Cl solution, the mixture was extracted

with 30 mL of EtOAc and the layers were separated. The organic

layer was dried over MgSO₄, filtered, concentrated in Vacuo, and

chromatographed (2% EtOAc‚hexanes). The resulting colorless oil was

purified by HPLC (2% EtOAc/hexanes) to provide 32 mg (26 µmol,

[R]²⁰+64.3° (c 0.5, CHCl₃).

D

[3S-[3r,4â,5â,6r (2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)]]-6-

[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-[(4-methoxy-

phenyl)methoxy]-5,7,9,11,13,15-hexamethyl-12-oxo-3,8,16,18-nona-

decatetraenyl]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]tetrahydro-

3,5-dimethyl-2H-pyran-2-one. To a solution of 75 mg (68 µmol) of

27b in 1 mL of THF were added 1 mL of MeCN, 1 mL of pH 7 buffer

solution concentrate, and 184 mg (679 µmol) of HgCl₂. The suspension

was stirred for 20 min, when TLC analysis indicated no starting material

remained, and then was treated with 10 mL of brine and extracted into

3 × 25 mL of CH₂Cl₂. The organic layers were combined, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed (1%

EtOAc/hexanes) to provide 60 mg of a mixture of lactols.

1

48%) of 27b as a colorless oil: IR (thin film/NaCl) 1705 cm^-1; H

NMR (500 MHz, CDCl₃) δ 7.48 (d, J ) 8.7 Hz, 2H), 7.27-7.22 (m,

5H), 6.86 (d, J ) 8.7 Hz, 2H), 6.44 (ddd, J ) 10.3, 16.9, 20.6 Hz,

1H), 6.02 (apparent t, J ) 11.0 Hz, 1H), 5.60 (apparent t, J ) 10.3

Hz, 1H), 5.30 (d, J ) 2.2 Hz, 1H), 5.26 (obscured dd, J ) 7.6, 11.0

Hz, 1H), 5.21-5.16 (overlapping d, 3H), 5.05 (d, J ) 10.2 Hz, 1H),

4.56 (obscured dd, J ) 5.1, 9.2 Hz, 1H), 4.55 (obscured d, J ) 6.5 Hz,

1H), 4.54 (d, J ) 8.7 Hz, 1H), 3.79 (s, 3H), 3.65 (overlapping dd, J )

3.0, 8.2 Hz, 1H), 3.62 (overlapping d, J ) 8.4 Hz, 1H), 3.59 (apparent

t, J ) 2.5 Hz, 1H), 3.25 (dd, J ) 3.8, 6.3 Hz, 1H), 2.88 (m, 1H), 2.70

(overlapping m, 1H), 2.67 (overlapping m, 1H), 2.50 (m, 1H), 2.17

(dd, J ) 11.1, 13.5 Hz, 1H), 2.00 (dd, J ) 3.9, 6.5 Hz, 3H), 1.60

obscured m (2), 1.58 (d, J ) 0., 6 Hz, 3H), 1.53 (dd, J ) 6.5, 7.8 Hz,

1H), 1.20 (d, J ) 7.1 Hz, 3H), 1.09 (d, J ) 6.9 Hz, 3H), 1.05 (d, J )

7.0 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 0.95 (overlapping d, J ) 6.3

Hz, 3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.82 (d, J ) 7.0 Hz, 3H), 0.77 (s,

9H), 0.75 (d, J ) 6.8 Hz, 3H), 0.02 (overlapping s, 9H), -0.01 (s,

3H), -0.14 (s, 3H), -0.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

217.0, 159.1, 135.4, 134.3, 133.7, 133.6, 132.7, 132.2, 130.9, 129.7,

129.6, 129.3, 129.2, 128.7, 127.1, 117.9, 113.8, 113.7, 84.7, 83.5, 80.5,

76.5, 75.3, 74.7, 65.6, 55.3, 49.3, 43.5, 42.7, 41.9, 36.8, 36.5, 35.1,

34.1, 26.4, 25.8, 23.2, 19.2, 18.5, 18.0, 17.9, 17.7, 15.5, 15.3, 14.3,

14.2, 11.4, -2.6, -4.2, -4.3, -4.5, -4.9, -5.1; LRMS (FAB, NBA/

The lactols were dissolved in 9 mL of acetone, cooled to 0 °C, and

treated with 500 µL (500 µmol) of 1 M Jones oxidant solution. The

reaction was stirred at 0 °C for 30 min, then warmed to ambient

temperature for 5 min. Excess oxidant was quenched by addition of

500 µL of iPrOH and stirred for 30 min, diluted with 30 mL of diethyl

ether, filtered through Celite, concentrated in Vacuo, and chromato-

graphed (2% EtOAc/hexanes) to provide 52 mg (52 µmol, 77% for

two steps) of lactone as a colorless oil: IR (thin film/NaCl) 1738 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 7.27 (d, J ) 8.5 Hz, 2H), 6.87 (d, J )

8.5 Hz, 2H), 6.44 (ddd, J ) 10.1, 16.2, 20.7 Hz, 1H), 6.03 (apparent

t, J ) 11.0 Hz, 1H), 5.61 (apparent t, J ) 10.4 Hz, 1H), 5.31 (dd, J )

7.9, 11.0 Hz, 1H), 5.18 (overlapping d, J ) 7.0 Hz, 1H), 5.16 (s, 1H),

5.14 (obscured dd, J ) 3.0, 9.9 Hz, 1H), 5.06 (d, J ) 10.1 Hz, 1H),

4.80 (apparent t, J ) 9.1 Hz, 1H), 4.57 (d, J ) 10.7 Hz, 1H), 4.55

(overlappign d, J ) 10.7 Hz, 1H), 4.52 (obscured m, 1H), 3.80 (s,

3H), 3.65 (obscured m, 1H), 3.64 (overlapping d, J ) 2.0 Hz, 1H),

3.24 (dd, J ) 4.0, 6.0 Hz, 1H), 2.58 (apparent t, J ) 7.4 Hz, 1H), 2.68

(overlapping m, 2H), 2.62 (m overlapping m, 2H), 2.49 (m, 1H), 2.17

(dd, J ) 9.1, 11.0 Hz, 1H), 1.97 (dd, J ) 2.8, 13.5 Hz, 1H), 1.82 (m,

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11073

1H), 1.74 (m, 1H), 1.59 (obscured m 1), 1.56 (s, 3H), 1.26 (obscured

m, 3H), 1.22 (d, J ) 7.8 Hz, 3H), 1.20 (d, J ) 7.4 Hz, 3H), 1.09 (d,

J ) 6.9 Hz, 3H), 0.96 (overlapping d, J ) 6.5 Hz, 3H), 0.94

(overlapping d, J ) 7.8 Hz, 3H), 0.90 (s, 9H), 0.87 (obscured d, 3H),

0.87 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H), 0.04

(s, 3H), -0.02 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 216.8, 173.3,

159.1, 133.6, 133.5, 133.4, 132.7, 132.1, 130.8, 129.7, 129.2, 117.8,

113.7, 83.5, 80.3, 75.3, 74.8, 64.6, 55.2, 49.2, 44.1, 43.5, 42.8, 37.4,

36.5, 34.9, 34.2, 34.1, 31.6, 26.3, 25.9, 25.7, 23.1, 22.6, 19.2, 18.4,

18.1, 17.9, 17.2, 16.4, 15.6, 15.3, 14.3, 14.1, 14.0, -3.0, -4.4, -4.5,

-4.6, -4.9; HRMS (FAB, NBA/NaI) m/z calcd for C₅₈H₁₀₂O₈Si₃Na

in 2 mL of THF was added 67 µL (67 µmol, 1 M in THF) of LiAl-

(OtBu)₃H. After 2 h of stirring at ambient temperature, the reaction

was quenched with 200 µL of saturated NH₄Cl solution, stirred for 2

h, dried over Na₂SO₄, filtered, concentrated in Vacuo, and chromato-

graphed (25% EtOAc/hexanes) to provide 19 mg (20.3 µmol, 90%) of

29 as a colorless oil: IR (thin film/NaCl) 3510 (br), 3364 (br), 1723,

1

cm^-1; H NMR (500 MHz, CDCl₃) δ 6.62 (ddd, J ) 10.3, 16.9, 21.4

Hz, 1H), 6.04 (apparent t, J ) 10.1 Hz, 1H), 5.37 (apparent t, J )

10.5 Hz, 1H), 5.31-5.21 (overlapping d, 3H), 5.14 (d, J ) 10.1 Hz,

1H), 5.10 (d, J ) 9.9 Hz, 1H), 4.80 (t, J ) 8.5 Hz, 1H), 4.75 (dd, J )

6.5, 5, 0 Hz, 1H), 4.51 (m, 3H), 3.64 (t. 2.3, 1H), 3.27 (m, 2H), 3.03

(ddd, J ) 6.7, 10.2, 6.7 Hz, 1H), 2.65-2.60 (m, 2H), 2.47 (m, 1H), 1

(94-1.70, J ) m Hz, 6H), 1.60 (overlapping s and t, 4H), 1.22

(overalpping d and m, 4H), 1.01 (d, J ) 6.8 Hz, 3H), 0.99 (d, J ) 6.9

Hz, 3H), 0.97-0.95 (overlapping d, J ) 6.9 Hz, 6H), 0.91 (s, 9H),

0.88-0.81 (overlapping s and d, 12H), 0.86 (s, 9H), 0.79 (d, J ) 6.3

Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 173.5, 157.0, 133.4, 133.1, 132.5,

132.1, 130.9, 129.9, 118.1, 80.6, 79.1, 76.6, 74.8, 64.6, 44.1, 42.7, 37.7,

37.2, 35.6, 64.7, 34.2, 26.3, 25.9, 25.7, 23.1, 18.5, 18.1, 18.0, 17.7,

17.5, 16.5, 15.8, 14.2, 14.1, 13.9, 8.6, -3.2, -4.2, -4.3, -4.5, -4.9;

HRMS (FAB, NBA/NaI) m/z calcd for C₅₁H₉₇O₈NSi₃Na 958.6414,

1033.6775, found 1033.6780; [R]²⁰-18.0° (c 0.5, CHCl₃).

D

[3S-[3r,4â,5â,6r(2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)]]-6-

[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-hydroxy-

5,7,9,11,13,15-hexamethyl-12-oxo-3,8,16,18-nonadecatetraenyl]-4-

[[(1,1-dimethylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-2H-

pyran-2-one (28). To a solution of 47 mg (46 µmol) of PMB ether in

2 mL if CH₂Cl₂was added 141 mg of NaHCO₃and then 712 µL (70

µmol, 90 mM in CH₂Cl₂) of DDQ. After being stirred for 1 h at

ambient temperature, the mixture was concentrated under a stream of

N₂and chromatographed (10% EtOAc/hexanes) to provide 30 mg (34

µmol, 91%) of 28 as a colorless oil: IR (thin film/NaCl) 3469 (br),

1711 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 6.59 (ddd, J ) 10.9, 16.7,

21.1 Hz, 1H), 6.11 (apparent t, J ) 11.0 Hz, 1H), 5.42 (apparent t, J

) 10.3 Hz, 1H), 5.31 (dd, J ) 11.0, 7.9 Hz, 1H), 5.33-5.12 (m, 4H),

4.79 (t, J ) 9.3 Hz, 1H), 4.52 (t, J ) 10.1 Hz, 1H), 3.70 (dd, J ) 8.1,

3.9 Hz, 1H), 3.64 (t, J ) 2.3, 3.25, dd, 6.1, 4.0 Hz, 1H), 2.82 (m, 2H),

2.75 (ddd, J ) 8.6, 7.0, 6.2 Hz, 1H), 2.64-2.60 (m, 2H), 2.49 (m,

1H), 2.20 (dd, J ) 9.4, 13.4 Hz, 1H), 2.06 (dd, J ) 5.2, 13.5 Hz, 1H),

1.83-1.79 (m, 1H), 1.74 (t, J ) 12.6 Hz, 1H), 1.61 (s, 3H), 1.25 (t, J

) 7.7 Hz, 1H), 1.22 (d, J ) 7.6 Hz, 3H), 1.17 (d, 7.1H, s), 1.01-0.87

(overlapping d, 15H), 0.89 (s, 9H), 0.86 (s, 9H), 0.07 (overlapping s,

6H), 0.05 (s, 3H), 0.04 (overlapping s, 6H), -0.01 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ 218.3, 173.3, 134.3, 133.6, 133.5, 132.5, 132.1,

130.4, 129.7, 118.2, 80.2, 74.8, 74.6, 64.7, 47.0, 44.1, 43.0, 42.8, 37.3,

35.4, 35.1, 35.0, 34.6, 34.2, 31.6, 26.3, 26.2, 26.1, 25.9, 25.7, 25.3,

23.4, 22.6, 20.7, 18.4, 18.1, 17.9, 17.6, 17.4, 16.4, 16.0, 15.6, 14.1,

14.1, 9.9, -3.0, -4.4, -4.5, -4.9; HRMS (FAB, NBA/NaI) m/z calcd

found 958.6411; [R]²⁰-26.6° (c 0.5, CHCl₃).

D

(+)-Discodermolide (1a). To 12 mg (13.1 µmol) of 29 was added

2 mL of 1% HCl in MeOH. (The HCl solution was made by the

addition of 500 µL of concentrated HCl to 50 mL of MeOH.) After

being stirred for 48 h at ambient temperature, the reaction was quenched

by the addition of 50 mg of NaHCO₃, concentrated under a stream of

N₂, and chromatographed (5% MeOH/CHCl₃) to provide 9 mg (10.1

µmol, 77%) of 1a as a white solid: IR (thin film/NaCl) 3409 (br),

1

1705 cm^-1; H NMR (500 MHz, 10% v/v D₃COD/CDCl₃) 6.53 (ddd,

J ) 16.9, 10.8, 10.4 Hz, 1H), 5.94 (apparent t, J ) 11.0 Hz, 1H),

5.39-5.32 (m, 2H), 5.27 (apparent t, J ) 10.5 Hz, 1H), 5.12 (d, J )

16.9 Hz, 1H), 5.03 (m, 2H), 4.64 (t, J ) 5.9 Hz, 1H), 4.58 (td, J )

7.5, 2.2 Hz, 1H), 4.48 (t, J ) 9.8 Hz, 1H), 3.56 (t, J ) 3.8 Hz, 1H),

3.15 (t, J ) 4.9 Hz, 1H), 3.08 (t, J ) 5.7 Hz, 1H), 2.94 (m, 1H), 2.62

(m, 1H), 2.58 (m, 1H), 2.43 (m, 1H), 1.81-1.70 (m, 6H), 1.53 (m,

1H), 1.53 (s, 3H), 1.20 (d, J ) 7.4 Hz, 3H), 0.96 (d, J ) 6.9 Hz, 3H),

0.93 (d, J ) 8.3 Hz, 3H), 0.91 (d, J ) 7.2 Hz, 3H), 0.86 (d, J ) 6.9

Hz, 3H), 0.84 (d, J ) 6.7 Hz, 3H), 0.72 (d, J ) 5.7 Hz, 3H); ¹³C NMR

(125 MHz, 10% v/v D₃COD/CDCl₃) 175.2, 157.8, 133.9, 133.3, 132.7,

132.4, 132.0, 130.0, 129.8, 117.8, 78.9, 77.5, 75.7, 72.5, 63.5, 43.0,

41.0, 37.2, 36.0, 35.7, 35.5, 35.1, 34.4, 33.1, 23.0, 18.0, 17.3, 15.5,

15.4, 13.8, 12.4, 8.6; HRMS (FAB, NBA/NaI) m/z calcd for C₃₃H₅₅O₈-

for C₅₀H₉₄O₇Si₃Na 913.6200, found 913.6202; [R]²⁰-26.6° (c 0.5,

D

CHCl₃).

[3S-[3r,4â,5â,6r(2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)]]-6-

[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-(carbamoyloxy)-

5,7,9,11,13,15-hexamethyl-12-oxo-3,8,16,18-nonadecatetraenyl]-4-

[[(1,1-dimethylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-2H-

pyran-2-one. To a solution of 25 mg (28 µmol) of 28 in 500 µL of

CH₂Cl₂was added 10 µL of Cl₃CONCO. After 10 min of stirring at

ambient temperature, 200 mg of neutral alumina (oven dried) was added.

The suspension was stirred for 4 h at ambient temperature, concentrated

under a stream of N₂, and chromatographed (10% EtOAc/hexanes) to

provide 24 mg (26 µmol, 92%) of carbamate as a colorless oil: IR

(thin film/NaCl) 1734, 1718 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 6.48

(ddd, J ) 10.7, 16.9, 21.3 Hz, 1H), 6.05 (apparent t, J ) 11.0 Hz,

1H), 5.42 (apparent t, J ) 10.4 Hz, 1H), 5.30 (dd, J ) 8.0, 11.0 Hz,

1H), 5.20 (d, J ) 17.1 Hz, 1H), 5.18-5.08 (overlapping d, 3H), 5.07

(d, J ) 5.3 Hz, 1H), 4.79 (apparent t, J ) 9.2 Hz, 1H), 4.63 (br s, 2H),

4.51 (t, J ) 10.3, 3.64, apparent s Hz, 1H), 3.24 (dd, J ) 4.0, 6.1 Hz,

1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.75 (m, 1H), 2.62 (ovlerapping m,

2H), 2.49 (m, 1H), 2.20 (dd, J ) 11.3, 13.2 Hz, 1H), 1.98 (dd, J )

2.0, 13.4 Hz, 1H), 1.82 (m, 1H), 1.74 (dd, J ) 11.2, 12.1 Hz, 1H),

1.62 (obscured m, 1H), 1.59 (s, 3H), 1.22 (d, J ) 7.6 Hz, 3H), 1.12 (d,

J ) 7.0 Hz, 3H), 1.02 (d, J ) 6.8 Hz, 3H), 0.97-0.92 (overlapping d,

9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.87 (obscured d, 3H), 0.86 (s, 9H),

0.06 (overlapping s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), -0.02

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 214.7, 173.4, 156.5, 156.5,

133.5, 133.4, 132.7, 132.5, 131.9, 130.5, 129.7, 118.4, 80.3, 74.8, 64.7,

46.7, 44.1, 42.8, 42.7, 37.4, 34.9, 34.7, 34.1, 33.9, 31.6, 26.3, 26.1,

25.9, 25.7, 23.1, 22.6, 18.4, 18.1, 18.0, 17.9, 17.3, 16.4, 15.5, 15.4,

14.1, 14.0, 14.0, 12.4, -3.0, -4.4, -4.4, -4.5, -4.9; HRMS (FAB,

NBA/NaI) m/z calcd for C₅₁H₉₅O₈Si₃NNa 956.6258, found 956.6263;

NNa 616.3826, found 616.3818; [R]²⁰+14.0° (c 0.6, MeOH).

D

16-Epidiscodermolide (1b): IR (thin film/NaCl) 3854 (br), 3422

1

(br), 1701 cm^-1; H NMR (500 MHz, CDCl₃) δ 6.53 (ddd, J ) 10.8,

16.8, 21.2 Hz, 1H), 5.95 (apparent t, J ) 11.0 Hz, 1H), 5.41 (apparent

t, J ) 10.8 Hz, 1H), 5.29 (overlapping m, 2H), 5.19 (d, J ) 9.6 Hz,

1H), 5.12 (d, J ) 16.8 Hz, 1H), 5.04 (4.69, J ) apparent t, 6.3 Hz,

1H), 4.61 (t, J ) 9.1 Hz, 1H), 4.49 (t, J ) 10.2 Hz, 1H), 3.56 (br s,

1H), 3.45-3.37 (obscured, 4H), 3.28 (t, J ) 1.3 Hz, 1H), 3.16 (dd, J

) 5.4, 7.4 Hz, 1H), 3.07 (dd, J ) 2.2, 5.2 Hz, 1H), 2.47 (m 1), 2.65-

2.57 (overlapping m, 2H), 2.48 (m, 1H), 2.24 (d, J ) 12.3 Hz, 1H),

1.82-1.70 (overlapping m, 4H), 1.62 (obscured m, 1H), 1.59 (s, 3H),

1.22 (d, J ) 7.4 Hz, 3H), 0.97 (d, J ) 6.8 Hz, 3H), 0.93 (d, J ) 6.7

Hz, 3H), 0.89 (d, J ) 6.7 Hz, 3H), 0.84 (d, J ) 6.8 Hz, 3H), 0.80 (d,

J ) 6.8 Hz, 3H), 0.59 (d, J ) 6.4 Hz, 3H), 0.; ¹³C NMR (125 MHz,

CDCl₃) δ 173.9, 157.4, 134.3, 134.0, 133.36, 133.1, 132.1, 130.3, 130.0,

118.0, 80.4, 78.6, 77.8, 77.2, 73.3, 64.5, 43.2, 41.0, 37.0, 36.4, 35.7,

35.6, 34.8, 34.6, 34.4, 24.1, 18.1, 17.7, 15.9, 15.6, 14.2, 12.6, 7.6;

HRMS (FAB, NBA/NaI) m/z calcd for C₃₃H₅₅O₈NNa 616.3822, found

616.3825; [R]²⁰+18.0° (c 0.4, CHCl₃).

D

17-Epidiscodermolide (1c): IR (thin film/NaCl) 3400 (br), 1707

1

cm^-1; H NMR (500 MHz, 10% CD₃OD-CDCl₃) δ 6.65 (ddd, J )

11.0, 16.9, 21.2 Hz, 1H), 6.04 (overlapping dd, J ) 11.1 Hz, 1H),

5.52 (dd, J ) 8.1, 11.3 Hz, 1H), 5.42 (overlapping dd, J ) 10.8 Hz,

1H), 5.29 (overlapping dd, J ) 10.4 Hz, 1H), 5.24 (obscured dd, 1H),

5.21 (obscured dd, 1H), 5.12 (d, J ) 10.0 Hz, 1H), 4.84 (dd, J ) 1.6,

7.6 Hz, 1H), 4.75 (m, 1H), 4.62 (ddd, J ) 2.4, 9.9, 12.2 Hz, 1H), 4.56

(br s, 2H), 3.74 (br s, 1H), 3.68 (d, J ) 4.6 Hz, 1H), 3.20 (dd, J ) 4.5,

6.9 Hz, 1H), 3.15 (m, 1H), 2.98 (ddd, J ) 2.7, 9.4, 16.2 Hz, 1H), 2.77

[R]²⁰-22.2° (c 0.5, CHCl₃).

D

3,7,11-Tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-

discodermolide (29). To a solution of 21 mg (22.5 mol) of carbamate

11074 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

(ddd, J ) 6.8, 9.7, 13.6 Hz, 1H), 2.68 (m, 1H), 2.63 (m, 1H), 2.21 (dd,

J ) 11.4, 12.9 Hz, 1H), 2.04 (br s, 1H), 2.00-1.80 (overlapping m,

4H), 1.73 (m, 1H), 1.68 (d, J ) 0.8 Hz, 3H), 1.32 (d, J ) 7.3 Hz, 3H),

1.07 (d, J ) 7.0 Hz, 3H), 1.02 (d, J ) 6.8 Hz, 3H), 0.98 (d, J ) 6.8

Hz, 3H), 0.96 (d, J ) 6.7 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H), 0.89 (d,

J ) 7.0 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for C₃₃H₅₅O₈-

NNa 616.3822, found 616.3825.

iodide was added. The reaction was warmed to 0 °C and stirred at

ambient temperature for 3 h. After quenching the reaction with 1.5

mL of saturated NH₄Cl solution, the mixture was extracted with 30

mL of EtOAc and the layers were separated. The organic layer was

dried over MgSO4, filtered, concentrated in Vacuo, and chromato-

graphed (2% EtOAc.hexanes). The resulting colorless oil was purified

by HPLC (2% EtOAc/hexanes) to provide 38 mg (64 µmol, 44%) of

1

33 as a colorless oil: IR (thin film/NaCl) 1705 cm^-1; H NMR (500

16-Desmethyldiscodermolide (31): IR (thin film/NaCl) 3854 (br),

1

3744 (br), 1701 cm^-1; H NMR (500 MHz, 10% CD₃OD-CDCl₃) δ

MHz, CDCl₃) δ 7.28 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H),

6.45 (ddd, J ) 10.5, 16.8, 20.8 Hz, 1H), 6.04 (apparent t, J ) 11.0 Hz,

1H), 5.83 (ddd, J ) 8.0, 10.5, 17.8 Hz, 1H), 5.61 (apparent t, J ) 10.4

Hz, 1H), 5.18 (dd, J ) 1.0, 16.7 Hz, 1H), 5.06 (apparent t, J ) 10.0

Hz, 2H), 4.96 (dd, J ) 1.9, 10.4 Hz, 1H), 4.92 (dd, J ) 0.7, 18.0 Hz,

1H), 4.57 (d, J ) 10.7 Hz, 1H), 4.54 (d, J ) 10.7 Hz, 1H), 3.80 (s,

3H), 3.66 (dd, J ) 3.0, 8.0 Hz, 1H), 3.28 (dd, J ) 3.7, 6.5 Hz, 1H),

2.90 (m, 1H), 2.71 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 2.22 (dd, J )

11.3, 13.5 Hz, 1H), 1.96 (dd, J ) 2.9, 13.6 Hz, 1H), 1.57 (s, 3H), 1.21

(d, J ) 7.1 Hz, 3H), 1.10 (d, J ) 6.9 Hz, 3H), 0.99 (d, J ) 7.0 Hz,

3H), 0.96 (d, J ) 6.9 Hz, 3H), 0.92 (s, 9H), 0.89 (d, J ) 6.8 Hz, 3H),

0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 217.0, 159.2,

141.4, 133.6, 132.8, 132.1, 130.8, 130.2, 129.7, 129.3, 117.8, 114.0,

113.7, 83.5, 80.7, 75.3, 55.3, 49.2, 43.4, 42.8, 36.5, 36.3, 34.4, 26.2,

23.1, 19.2, 18.4, 17.6, 17.4, 15.3, 14.3, -3.6, -3.7; HRMS (FAB, NBA/

6.54 (ddd, J ) 10.9, 17.4, 21.9 Hz, 1H), 5.97 (overlapping dd, J )

11.0 Hz, 1H), 5.42 (dd, J ) 7.8, 11.1 Hz, 1H), 5.36 (apparent t, J )

9.4 Hz, 1H), 5.29 (apparent t, J ) 10.6 Hz, 1H), 5.16 (dd, J ) 1.7,

16.7 Hz, 1H), 5.06 (d, J ) 10.1 Hz, 1H), 5.03 (d, J ) 9.9 Hz, 1H),

4.67 (t, J ) 5.6 Hz, 1H), 4.62 (overlapping ddd, J ) 2.8, 10.3 Hz,

1H), 4.52 (ddd, J ) 2.0, 10.4, 12.1 Hz, 1H), 3.59 (t, J ) 3.6 Hz, 1H),

3.48 (m, 1H), 3.32 (t, J ) 1.6 Hz, 2H), 3.12 (t, J ) 5.0 Hz, 1H), 2.95

(ddd, J ) 6.6, 10.2, 13.2 Hz, 1H), 2.66 (ddd, J ) 6.6, 9.3, 13.3 Hz,

1H), 2.60 (ddd, J ) 3.3, 7.4, 10.7 Hz, 1H), 2.46 (ddd, J ) 6.7, 9.6,

12.2 Hz, 1H), 2.07 (m, 1H), 1.89 (m, 1H), 1.82 (ddd, J ) 3.4, 6.8,

10.1 Hz, 1H), 1.75 (ddd, J ) 2.2, 10.0, 12.2 Hz, 1H), 1.68 (ddd, J )

3.8, 5.2, 7.0 Hz, 1H), 1.60 (d, J ) 1.1 Hz, 1H), 1.58 (obscured m,

1H), 1.43 (m, 1H), 1.23 (d, J ) 7.4 Hz, 3H), 0.99 (d, J ) 6.9 Hz, 3H),

0.96 (d, J ) 6.6 Hz, 3H), 0.94 (d, J ) 6.8 Hz, 3H), 0.88 (d, J ) 0.7

Hz, 3H), 0.86 (d, J ) 7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ

174.0, 157.4, 134.4, 134.2, 133.5, 133.0, 132.1, 130.0, 129.1, 118.0,

79.7, 79.0, 73.2, 73.1, 64.2, 43.2, 41.1, 40.0, 36.4, 35.7, 35.4, 34.9,

33.1, 28.7, 23.4, 18.4, 17.6, 15.6, 15.5, 12.6, 8.0; HRMS (FAB, NBA/

NaI) m/z calcd for C₃₇H₆₀O₄SiNa 619.4155, found 619.4158; [R]²⁰

+24.6° (c 0.5, CHCl₃).

D

(3S,4S,5S,6Z,11R,12S,13S,14Z)-12-(Carbamoyloxy)-4-[[(1,1-di-

methylethyl)dimethylsilyl]oxy]-3,5,7,9,11,13-hexamethyl-1,6,14,16-

heptadecatetraen-10-ol (34). To a solution of 7 mg (13 µmol) of

carbamate in 500 µL of THF was added 15 mg (390 µmol) of NaBH₄

in 500 µL of EtOH. After the reaction was stirred at ambient

temperature for 1.5 h, it was quenched with 1 mL of MeOH, stirred

for 1 h, concentrated under a stream of N₂, and chromatographed (25%

EtOAc/hexanes) to provide 4 mg (7 µmol, 57%) of 34 as a colorless

NaI) m/z calcd for C₃₂H₅₃O₈NH 580.3846, found 580.3849; [R]²⁰

+23.2° (c 0.5, CHCl₃).

D

[3R[3â,4â,5â,6r(2R,3Z,5R,6R,7R,8Z)]]-4-Hydroxy-6-[2,6,10-tri-

hydroxy-5,7,9-trimethyl-3,8-decadienyl]tetrahydro-3,5-dimethyl-2H-

pyran-2-one (32). To 5 mg (6 mol) of silyl ether was added 100 µL

of 0.5% HCl in MeOH. (The HCl solution was made by the addition

of 500 µL of concentrated HCl to 100 mL of MeOH.) After 3 days of

stirring at ambient temperature, the reaction was quenched by the

addition of 50 mg of NaHCO₃, concentrated under a stream of N₂, and

chromatographed (5% MeOH/CHCl₃) to provide 1.2 mg (3 µmol, 54%)

of 32 as a colorless oil: IR (thin film/NaCl) 3366, 1711 cm^-1; ¹H NMR

(500 MHz, 10% CD₃OD-CDCl₃) δ 5.54 (dd, J ) 8, 11.1 Hz, 1H),

5.49 (dd, J ) 13.7, 24.7 Hz, 1H), 5.22 (d, J ) 9.9 Hz, 1H), 4.71 (td,

J ) 3.5, 8.7 Hz, 1H), 4.59 (td, J ) 1.9, 10.3 Hz, 1H), 4.18 (d, J )

11.8 Hz, 1H), 3.96 (d, J ) 11.9 Hz, 1H), 3.73 (br s, 1H), 3.23 (t, J )

5.6 Hz, 1H), 2.80 (ddd, J ) 6.6, 9.8, 13.3 Hz, 1H), 2.69 (m, 1H), 2.64

(m, 1H), 1.92 (m, 1H), 1.86 (m, 1H), 1.82 (s, 3H), 1.70 (m, 3H), 1.33

(d, J ) 7.4 Hz, 3H), 1.07 (d, J ) 7.0 Hz, 3H), 1.05 (d, J ) 6.8 Hz,

3H), 1.02 (d, J ) 6.9 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for

C₂₀H₃₄O₆Na 393.2251, found 393.2253.

1

oil: IR (thin film/NaCl) 3358 (br), 3354 (br), 1713 cm^-1; H NMR

(500 MHz, CDCl₃) δ 6.62 (ddd, J ) 10.1, 16.0, 20.4 Hz, 1H), 6.05

(apparent t, J ) 11.0 Hz, 1H), 6.85 (ddd, J ) 8.1, 10.4, 17.4 Hz, 1H),

5.36 (t, J ) 10.5 Hz, 1H), 5.24 (d, J ) 16.8 Hz, 1H), 5.13 (d, J ) 10.1

Hz, 1H), 4.97 (d, 10.1H, a), 4.94 (dd, J ) 2.1, 10.1 Hz, 1H), 4.89 (dd,

J ) 3.1, 17.3 Hz, 1H), 4.76 (dd, J ) 5.2, 6.4 Hz, 1H), 4.52 (br s, 2H),

3.28 (m 2), 3.02 (ddd, J ) 6.7, 10.3, 13.2 Hz, 1H), 2.43 (ddd, J ) 6.8,

10.0, 13.7 Hz, 1H), 2.33 (ddd, J ) 3.3, 7.7, 10.3 Hz, 1H), 1.98-1.91

(m 2), 1.87 (m, 1H), 1.73 (d, J ) 5.6 Hz, 1H), 1.60 (d, J ) 1.0 Hz,

3H), 1.02 (d, J ) 6.8 Hz, 3H), 0.98 (d, J ) 7.0 Hz, 3H), 0.96 (d, J )

7.0 Hz, 3H), 0.92 (s, 9H), 0.89 (d, J ) 6.7 Hz, 3H), 0.81 (d, J ) 6.4

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.0, 141.5, 133.3, 132.0,

131.6, 131.4, 130.0, 118.1, 113.9, 80.9, 79.5, 77.2, 42.7, 37.0, 36.5,

35.8, 34.7, 33.2, 26.2, 22.9, 18.5, 18.0, 17.5, 14.3, 8.3, -3.5, -3.6;

HRMS (FAB, NBA/NaI) m/z calcd for C₃₀H₅₅NO₄SiNa 544.3795, found

2,2-Dimethylpropanoic Acid, (2Z,4S,5S,6S)-5-[[(1,1-Dimethyl-

ethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-2,7-octadienyl Ester. Through

a suspension of 75 mg of 10% Pd‚BaSO₄and 50 µL of quinoline in 4

mL of MeOH was bubbled a stream of H₂for 30 min. To this

suspension was added 150 mg (395 µmol) of 10 in 2 mL of MeOH

and stirred for 10 min under a constant stream of H₂. The mixture

was filtered through Celite, concentrated in Vacuo, and chromatographed

(1% EtOAc/hexanes) to provide 133 mg (348 µmol, 88%) of olefin as

544.3798; [R]²⁰+26.0° (c 0.5, CHCl₃).

D

(3S,4S,5S,6Z,11R,12S,13S,14Z)-12-(Carbamoyloxy)-3,5,7,9,11,13-

hexamethyl-1,6,14,16-heptadecatetraen-4,10-diol (35). To 1.6 mg

(3 mol) of 34 was added 250 µL of 1% HCl in MeOH. (The HCl

solution was made by the addition of 500 µL of concentrated HCl to

50 mL of MeOH.) After 6.5 h of stirring at ambient temperature, the

reaction was quenched by the addition of 50 mg of NaHCO₃,

concentrated under a stream of N₂, and chromatographed (30% EtOAc/

hexanes) to provide 1.0 mg (2.5 µmol, 83%) of 35 as a colorless oil:

1

a colorless oil: IR (thin film/NaCl) 1732, cm^-1; H NMR (500 MHz,

CDCl₃) δ 5.80 (ddd, J ) 8.2, 10.3, 17.5 Hz, 1H), 5.17 (d, J ) 10.1

Hz, 1H), 4.92 (dd, J ) 1.9, 33.7 Hz, 1H), 4.92 (dt, J ) 1.0, 1.6, 6.4

Hz, 1H), 4.58 (d, J ) 12.0 Hz, 1H), 4.47 (d, J ) 12.1 Hz, 1H), 3.31

(dd, J ) 3.3, 7.0 Hz, 1H), 2.56 (ddd, J ) 6.8, 11.1, 14.7 Hz, 1H), 2.31

(m, 1H), 1.70 (s, 3H), 1.26 (m, 1H), 1.19 (s, 9H), 0.99 (d, J ) 7.1 Hz,

3H), 0.92 (d, J ) 6.7 Hz, 3H), 0.90 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 178.4, 141.0, 134.5, 128.6, 114.3, 80.3,

63.4, 42.9, 38.8, 36.7, 27.2, 26.1, 21.3, 18.4, 17.8, 17.7, -3.6, -3.7;

HRMS (FAB, NBA/NaI) m/z calcd for C₂₂H₄₂O₃Si 383.2979, found

1

IR (thin film/NaCl) 3452 (br), 3358 (br), 1716 cm^-1; H NMR (500

MHz, CDCl₃) δ 6.63 (ddd, J ) 6.5, 11.2, 17.2 Hz, 1H), 6.04 (apparent

t, J ) 9.0 Hz, 1H), 5.80 (ddd, J ) 8.0, 10.4, 17.4 Hz, 1H), 5.37

(apparent t, J ) 10.5 Hz, 1H), 5.22 (dd, J ) 1.5, 16.8 Hz, 1H), 5.12

(br s, 1H), 5.14-5.10 (obscured dd, 2H), 5.06 (dd, J ) 0.9, 17.4 Hz,

1H), 4.75 (dd, J ) 4.6, 6.9 Hz, 1H), 4.50 (br s, 2H), 3.29 (br s, 1H),

3.17 (br s, 1H), 3.02 (ddd, J ) 6.8, 11.2, 14.6 Hz, 1H), 2.51 (ddd, J )

6.7, 10.0, 13.3 Hz, 1H), 2.37 (dd, J ) 6.9, 12.3 Hz, 1H), 1.96-1.86

(m, 5H), 1.65 (d, J ) 1.1 Hz, 3H), 1.06 (d, J ) 6.9 Hz, 3H), 1.02 (d,

J ) 6.7 Hz, 3H), 0.99 (d, J ) 6.9 Hz, 3H), 0.97 (d, J ) 6.9 Hz, 3H),

0.84 (d, J ) 6.0 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for

C₂₄H₄₁O₄NNa 430.2931, found 490.2934.

383.2981; [R]²⁰+4.8° (c 0.5, CHCl₃).

D

(3S,4S,5S,6Z,11R,12S,13S,14Z)-4-[[(1,1-Dimethylethyl)dimethyl-

silyl]oxy]-3,5,7,9,11,13-hexamethyl-12-[(4-methoxyphenyl)methoxy]-

1,6,14,16-heptadecatetraen-10-one (33). To a cooled (-78 °C)

solution of 85 mg (146 µmol) of ketone in 1 mL of THF was added

1.46 mL (730 µmol, 0.5 M in THF) of LiN(SiMe₂Ph)₂. After the

reaction was stirred at -78 °C for 1 h, 934 µL (15 mmol) of methyl

17-Acetoxydiscodermolide (36). To 1.8 mg (1.8 µmol) of acetate

was added 200 µL of 1% HCl in MeOH. (The HCl solution was made

by the addition of 500 µL of concentrated HCl to 50 mL of MeOH.)

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11075

After 48 h of stirring at ambient temperature, the reaction was quenched

by the addition of 50 mg of NaHCO₃, concentrated under a stream of

N₂, and chromatographed (5% MeOH/CHCl₃) to provide 0.5 mg (0.8

µmol, 42%) of 36 as a colorless oil: IR (thin film/NaCl) 3377 (br),

(s, 3H), -0.01 (s, 3H); LRMS (FAB, NBA/NaI) m/z calcd for C₇₀H₁₁₃

-

NO₁₀Si₃Na 1234, found 1234.

17-[[[5-[[(9′-Fluorenylmethoxy)carbonyl]amino]pentyl]carbonyl]-

oxy]discodermolide (39). To 5 mg (5 µmol) of silyl ether was added

500 µL of 1% HCl in MeOH. (The HCl solution was made by the

addition of 500 µL of concentrated HCl to 50 mL of MeOH.) After 72

h of stirring at ambient temperature, the reaction was quenched by with

50 mg of NaHCO₃, concentrated, and chromatographed (5% MeOH/

CHCl₃) to provide 1.6 mg (5 µmol, 56%) of 39 as a colorless oil: IR

(thin film/NaCl) 3354 (br), 1711 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ

7.70 (d, J ) 7.5 Hz, 2H), 7.53 (d, J ) 7.4 Hz, 2H), 7.34 (t, J ) 7.4

Hz, 2H), 7.25 (t, J ) 7.4 Hz, 2H), 6.67 (ddd, J ) 10.6, 16.8, 21.3 Hz,

1H), 6.05 (apparent t, J ) 10.9 Hz, 1H), 5.43 (apparent t, J ) 10.2

Hz, 1H), 5.34 (ap t, J ) 10.6 Hz, 1H), 5.24 (s, 1H), 5.20 (obscured d,

1H), 5.14 (d, J ) 10.1 Hz, 1H), 5.06 (d, J ) 9.4 Hz, 1H), 4.92 (dd, J

) 4.1, 7.9. Hz, 2H), 4.71 (t, J ) 7.3 Hz, 1H), 4.66 (apparent t, J )

5.9 Hz, 1H), 4.61 (apparent t, J ) 8.9 Hz, 1H), 4.53 (br s, 2H), 4.40

(d, J ) 7.0 Hz, 2H), 4.21 (d, J ) 6.5 Hz, 1H), 3.73 (br s, 1H), 3.19

(m, 4H), 3.15 (m, 1H), 3.09 (m, 1H), 2.74 (m, 1H), 2.67 (m, 1H), 2.40

(m, 2H), 2.35 (m, 2H), 2.08 (br s, 1H), 1.99-1.67 (overlapping m, 10H),

1.66 (apparent s, 3H), 1.64-1.38 (overlapping m, 3H), 1.31 (d, J )

7.3 Hz, 3H), 1.06 (d, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.8 Hz, 3H), 0.97

(d, J ) 6.7 Hz, 3H), 0.95 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.9 Hz),

3H); HRMS (FAB, NBA/NaI) m/z calcd for C₅₃H₇₆N₂O₁₁Na 939.5343

found 939.5345.

1

1716 cm^-1; H NMR (500 MHz, 10% CD₃OD-CDCl₃) δ 6.71 (ddd, J

) 11.0, 16.8, 21.2 Hz, 1H), 6.05 (overlapping dd, J ) 11.0 Hz, 1H),

5.53-5.43 (obscured dd, 2H), 5.34 (apparent t, J ) 10.5 Hz, 1H), 5.23

(dd, J ) 2.0, 16.8 Hz, 1H), 5.16 (d, J ) 10.1 Hz, 1H), 5.12 (d, J ) 9.8

Hz, 1H), 4.81 (t, J ) 5.9 Hz, 1H), 4.71 (br t, J ) 7.2 Hz, 1H), 4.64-

4.59 (partially obscured d, 2H), 4.58 (br s, 2H), 3.76 (dd, J ) 4.1, 8.2

Hz, 1H), 3.15 (br t, J ) 5.6 Hz, 1H), 3.12 (partially obscured ddd, J

) 6.1, 10.8, 17.2 Hz, 1H), 2.74 (ddd, J ) 6.6, 9.3, 13.1 Hz, 1H), 2.68

(m, 1H), 2.43 (m, 1H), 2.10 (s, 3H), 2.06 (partially obscured m, 1H),

1.97 (m, 1H), 1.82 (ddd, J ) 2.3, 7.6, 14.3 Hz, 1H), 1.71 (dd, J ) 2.9,

10.3 Hz, 1H), 1.68 (t, J ) 2.7 Hz, 1H), 1.65 (d, J ) 0.9 Hz, 3H), 1.32

(d, J ) 7.3 Hz, 3H), 1.08 (d, J ) 7.0 Hz, 3H), 1.01 (d, J ) 6.8 Hz,

3H), 0.98 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H), 0.93 (d, J )

6.7 Hz, 3H), 0.73 (d, J ) 6.7 Hz, 3H); HRMS (FAB, NBA/NaI) m/z

calcd for C₃₅H₅₇O₉NNa 658.3928, found 658.3931.

[3S-[3â,4r,5r,6r(2R,3Z,5R,6R,7R,8Z,11S,13R,14S,15S,16Z)]]-6-

[14-Acetoxy-2,6-dihydroxy-5,7,9,11,13,15-hexamethyl-12-oxo-3,8,

16,18-nonadecatetraenyl]-4-[[(1,1-dimethylethyl)dimethylsilyl]ox-

y]tetrahydro-3,5-dimethyl-2H-pyran-2-one (37). To 9 mg (9 µmol)

of silyl ether was added 1 mL of 1% HCl in MeOH. (The HCl solution

was made by the addition of 500 µL of concentrated HCl to 50 mL of

MeOH.) After for 48 h of stirring at ambient temperature, the reaction

was quenched by the addition of 50 mg of NaHCO₃, concentrated under

a stream of N₂, and chromatographed (5% MeOH/CHCl₃) to provide 3

mg (5 µmol, 56%) of 37 as a colorless oil: IR (thin film/NaCl) 3441

(br), 1713 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 6.48 (dddd, J ) 10.3,

16.0, 16.9, 20.5 Hz, 1H), 6.04 (apparent t, J ) 10.9 Hz, 1H), 5.56 (dd,

J ) 8.0, 11.0 Hz, 1H), 5.40-5.35 (obscured, 2H), 5.27 (d, J ) 9.7 Hz,

1H), 5.22 (m, 1H), 5.18 (dd, J ) 5.8, 6.8 Hz, 1H), 5.11 (d, J ) 10.1

Hz, 1H), 4.75 (t, J ) 7.9 Hz, 1H), 4.62 (ddd, J ) 2.3, 10.1, 12.2 Hz,

1H), 3.75 (d, J ) 3.6 Hz, 1H), 3.14 (dd, J ) 3.2, 7.6 Hz, 1H), 2.90-

2.84 (overlapping m, 3H), 2.75 (ddd, J ) 7.1, 9.5, 14.4 Hz, 1H), 2.69

(m, 1H), 2.54 (ddd, J ) 3.6, 6.7, 10.1 Hz, 1H), 2.30 (dd, J ) 6.3, 13.5

Hz, 1H), 2.17 (br s, 1H), 2.01 (s, 3H), 1.97-1.92 (overlapping m, 2H),

1.88 (ddd, J ) 2.4, 6.6, 11.4 Hz, 1H), 1.73 (dd, J ) 3.0, 10.2 Hz, 1H),

1.69 (d, J ) 1.2 Hz, 3H), 1.32 (d, J ) 7.4 Hz, 3H), 1.07 (overlapping

d, J ) 7.2 Hz, 3H), 1.06 (overlapping d, J ) 7.2 Hz, 3H), 0.99

(overlapping d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 6.8 Hz, 3H), 0.91 (d, J

) 6.7 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for C₃₄H₅₄O₈Na

613.3713, found 613.3716.

(2R,3S,4R)-2,4-Dimethyl-5-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3-[(4-methoxyphenyl)methoxy]hexan-1-ol (40). To 2.41 g (4.9

mmol) of silyl ether was added 37.5 mL of a HF-pyridine buffered

with excess pyridine solution (prepared by adding 2.5 mL of HF-

pyridine and then 25 mL of THF to 10 mL of pyridine). After 6 h of

stirring at ambient temperature, the reaction was quenched by the slow

addition of a saturated NaHCO₃solution and extracted 3 × 50 mL of

CH₂Cl₂. The combined organic layers were washed with 2 × 50 mL

of saturated CuSO₄, dried over MgSO₄, filtered, concentrated in Vacuo,

and chromatographed (2% EtOAc/hexanes) to provide 1.6 g (4.0 mmol,

83%) of 40 as a colorless oil: IR (thin film/NaCl) 3450 (br), 1614

1

cm^-1; H NMR (500 MHz, CDCl₃) δ (assigned resonances of major

epimer (5:1)), 7.26 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 4.60

(d, J ) 10.5 Hz, 1H), 4.50 (d, J ) 10.5 Hz, 1H), 3.82 (dd, J ) 6.3, 7.2

Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J ) 2.8, 7.5 Hz, 1H), 3.65 (dd, J )

2.0, 4.1 Hz, 1H), 1.85 (ddd, J ) 4.3, 6.7, 11.2 Hz, 1H), 1.69 (apparent

ddd, J ) 2.7, 7.1, 9.9 Hz, 1H), 1.18 (d, J ) 6.2 Hz, 3H), 0.97 (d, J )

7.0 Hz, 3H), 0.96 (d, J ) 7.0 Hz, 3H), 0.94 (s, 9H), 0.12 (s, 3H), 0.11

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ (mixture of epimers), 159.3,

130.8, 129.2, 129.1, 113.9, 113.8, 84.2, 74.5, 71.0, 66.6, 55.2, 44.6,

38.8, 26.0, 26.0, 21.4, 18.1, 15.0, 10.5, -3.6, -4.4; HRMS (FAB, NBA/

NaI) m/z calcd for C₂₂H₄₀O₄SiNa 419.2591, found 419.2594.

[3S-[3â,4r,5r,6r(2R,3Z,5R,6R,7R,8Z,11S,13R,14S,15S,16Z)]]-6-

[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-[[[5-[[(9′-fluo-

renylmethoxy)carbonyl]amino]pentyl]carbonyl]oxy]-5,7,9,11,13,15-

hexamethyl-12-oxo-3,8,16,18-nonadecatetraenyl]-4-[[(1,1-dimethyl-

ethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-2H-pyran-2-one (38).

To as solution of 26 mg (29 µmol) of hydroxy ketone and 50 mg (143

µmol) of Fmoc-N-aminocaproic acid in 500 µL of CH₂Cl₂was added

27.4 mg (143 µmol) of EDC, 48 µL (286 µmol) of DIEA, and 2 mg of

DMAP. After stirring at ambient temperature for 5 h, the reaction

mixture was concentrated under a stream of N₂and chromatographed

(5% EtOAc/hexanes) to provide 24 mg (19.8 µmol, 68%) of 38 as a

(Z)-(3R,4S,5R)-3,5-Dimethyl-6-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-1-iodo-4-[(4-methoxyphenyl)methoxy]hex-1-ene. To a solution

of 159 mg (400 µmol) of 40 in 3 mL of CH₂Cl₂was added 215 mg

(480 µmol) of Dess-Martin periodinane. After being stirred at ambient

temperature for 10 min, the reaction was quenched by the addition of

10 mL of saturated Na₂S₂O₃solution and 10 mL of saturated NaHCO₃

solution and diluted with 30 mL of diethyl ether. After 30 min of

stirring, the layers were separated and the organic layer was washed

with 3 × 120 mL of saturated NaHCO₃solution, dried over MgSO₄,

filtered, concentrated in Vacuo, and used crude in the next reaction.

To a suspension of 473 mg (890 µmol) of (iodomethyl)triph-

enylphosphonium iodide in 2 mL of THF was added 890 µL (890 µmol,

1 M in THF) of NaHMDS, and the slurry was stirred for 20 min at

ambient temperature. After the dark red mixture was cooled to -78

°C, 550 µL of HMPA was added, followed by the crude aldehyde in

2 mL of THF. After being warmed to ambient temperature, the reaction

mixture was stirred for 1 h before being diluted with hexanes, filtered

through 50 g of silica gel, concentrated in Vacuo, and chromatographed

(3% EtOAc/hexanes) to provide 182 mg (352 mol, 88%) of vinyl iodide

as a colorless oil: IR (thin film/NaCl) 1612 cm^-1; ¹H NMR (500 MHz,

CDCl₃) δ 7.30 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 6.30 (dd,

J ) 7.3, 9.1 Hz, 1H), 6.18 (d, J ) 7.4 Hz, 1H), 4.55 (obscured d, J )

7.8 Hz, 1H), 4.55 (obscured d, J ) 8.5 Hz, 1H), 3.98 (ddd, J ) 3.1,

6.2, 9.3 Hz, 1H), 3.81 (s, 3H), 3.39 (dd, J ) 2.7, 8.1 Hz, 1H), 2.89

(apparent ddd, J ) 2.6, 6.8, 9.4 Hz, 1H), 1.48 (apparent ddd, J ) 3.0,

1

colorless oil: IR (thin film/NaCl) 1734, 1718 cm^-1; H NMR (500

MHz, CDCl₃) δ 7.76 (d, J ) 7.6 Hz, 2H), 7.59 (d, J ) 7.6 Hz, 2H),

7.40 (t, J ) 7.3 Hz, 2H), 7.31 (t, J ) 1.0, 7.5 Hz, 2H), 6.48 (ddd, J )

10.7, 16.4, 21.1 Hz, 1H), 6.04 (apparent t, J ) 10.8 Hz, 1H), 5.28-

5.33 (overlapping m, 2H), 5.19-5.26 (overlapping m, 3H), 5.11 (d, J

) 10.1 Hz, 1H), 5.04 (d, J ) 9.2 Hz, 1H), 4.87 (br s, 1H), 4.78 (br t,

J ) 9.2 Hz, 1H), 4.52 (t, J ) 10.1 Hz, 1H), 4.39 (d, J ) 6.8 Hz, 2H),

4.21 (t, J ) 6.5 Hz, 1H), 3.64 (t, J ) 2.5 Hz, 1H), 3.26 (t, J ) 5.1 Hz,

1H), 3.19 (dd, J ) 6.6, 15.6 Hz, 1H), 2.90 (m, 1H), 2.79 (m, 1H), 2.62

(overlapping dd, J ) 2.7, 7.6 Hz, 1H), 2.60 (obscured m, 1H), 2.50

(dd, J ) 5.4, 11.0 Hz, 1H), 2.45 (obscured m, 1H), 2.35 (m, 1H), 2.28

(t, J ) 7.3 Hz, 2H), 2.02 (dd, J ) 4.8, 10.2 Hz, 1H), 1.83 (m, 1H),

1.73 (m, 1H), 1.60 (d, J ) 1.0 Hz, 3H), 1.50 (obscured m, 3H), 1.33

(overlapping m, 6H), 1.22 (d, J ) 7.6 Hz, 3H), 1.07 (d, J ) 7.0 Hz,

3H), 0.98 (d, J ) 6.7 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 3H), 0.95 (d, J )

7.0 Hz, 3H), 0.87 (obscured d, 3H), 090 (s, 9H), 0.88 (s, 9H), 0.86 (s,

9H), 0.07 (overlapping s, 6H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04

11076 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

1

6.8, 10.0 Hz, 1H), 1.13 (d, J ) 6.2 Hz, 3H), 1.12 (d, J ) 7.0 Hz, 3H),

1.01 (d, J ) 6.8 Hz, 3H), 0.95 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 158.9, 131.1, 129.1, 113.7, 83.8, 81.8, 74.9,

68.2, 55.2, 44.3, 42.5, 25.9, 17.1, 9.4, -3.8, -4.6; HRMS (FAB, NBA/

NaI) m/z calcd for C₂₃H₃₉IO₃SiNa 541.1611, found 541.1611.

colorless oil: IR (thin film/NaCl) 1730 cm^-1; H NMR (500 MHz,

CDCl₃) δ 7.49 (dd, J ) 1.4, 8.3 Hz, 2H), 7.28-7.21 (overlapping m,

5H), 6.86 (dd, J ) 2.8, 9.5 Hz, 2H), 6.15 (dd, J ) 11.0, 14.2 Hz, 1H),

5.98 (apparent t, J ) 11.0 Hz, 1H), 5.63 (overlapping ddd, J ) 7.1,

14.4 Hz, 1H), 5.44 (apparent t, J ) 10.2 Hz, 1H), 5.31 (d, J ) 1.8 Hz,

1H), 5.29 (partially obscured dd, J ) 7.5, 11.0 Hz, 1H), 5.20 (br d, J

) 9.8 Hz, 1H), 5.15 (t, J ) 10.2 Hz, 1H), 4.56 (partially obscured t,

J ) 11.0 Hz, 1H), 4.54 (partially obscured d, 1H), 4.52 (d, J ) 10.7

Hz, 1H), 4.04 (obscured m, 1H), 3.80 (s, 3H), 3.64-3.59 (overlapping

m, 3H), 3.27 (dd, J ) 3.7, 6.2 Hz, 1H), 2.90 (apparent t, J ) 7.2 Hz,

1H), 2.72-2.64 (overlapping m, 3H), 2.51 (m, 1H), 2.18 (dd, J ) 11.1,

13.4 Hz, 1H), 2.12-1.98 (overlapping m, 4H), 1.64-1.59 (obscured

m, 4H), 1.59 (s, 3H), 1.50 (m, 1H), 1.46-1.39 (overlapping m, 2H),

1.19 (s, 9H), 1.07 (d, J ) 7.7 Hz, 3H), 1.06 (d, J ) 7.3 Hz, 3H), 0.98

(d, J ) 7.0 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 0.91 (s, 9H), 0.90

(obscured d, 3H), 0.88 (s, 9H), 0.80 (obscured d, 3H), 0.78 (s, 9H),

0.75 (d, J ) 6.8 Hz, 3H), 0.03 (overlapping s, 9H), 0.01 (s, 3H), -0.13

(s, 3H), -0.26 (s, 3H); LRMS (FAB, NBA/NaI) m/z calcd for

C₇₃H₁₂₄O₉Si₃SNa 1283, found 1283.

2,2-Dimethylpropanoic Acid, (5E,7Z,9S,10S,11R)-9,11-Dimethyl-

12-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-10-[(4-methoxyphenyl)-

methoxy]-5,7-tridecadienyl Ester (41). To a solution of 1.64 g (3.2

mmol) of vinyl iodide and 1.43 g (4.7 mmol) of (E)-6-catecholboranoto-

5-hexen-1-ol pivalate in 100 mL of degassed THF was added 9.5 mL

(10% in H₂O) of thallium hydroxide. To this solution was added a

solution of 915 mg (790 µmol) of Pd(PPh₃)₄in 40 mL of degassed

THF. After heating to reflux for 30 min under an argon atmosphere,

the reaction was diluted with 250 mL of diethyl ether and the layers

were separated. The organic layer was dried over MgSO₄, filtered

through 100 g of silica gel, concentrated in Vacuo, and chromatographed

to provide 680 mg (1.2 mmol, 38%) of 41 as a colorless oil: IR (thin

1

film/NaCl) 1730 cm^-1; H NMR (500 MHz, CDCl₃) δ 7.28 (d, J )

8.6 Hz, 2H), 6.86 (d, J ) 8.2 Hz, 2H), 6.29 (dd, J ) 10.7, 15.1 Hz,

1H), 5.97 (ddd, J ) 2.6, 11.0, 13.6 Hz, 1H), 5.64 (overlapping ddd, J

) 7.0, 14.5, 22.0 Hz, 1H), 5.42 (dd, J ) 10.6, 21.2 Hz, 1H), 4.55 (d,

J ) 10.7 Hz, 1H), 4.47 (d, J ) 10.8 Hz, 1H), 4.06 (t, J ) 6.6 Hz, 2H),

3.83 (dd, J ) 4.3, 6.1 Hz, 1H), 3.79 (s, 3H), 3.33 (m, 1H), 2.97 (m,

1H), 2.14 (dd, J ) 7.3, 14.6 Hz, 2H), 1.64 (m, 2H), 1.58 (ddd, J )

4.3, 6.8, 11.0 Hz, 1H), 1.47 (m, 2H), 1.21 (s, 9H), 1.08 (apparent t, J

) 7.3 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 0.93 (partially obscured d,

3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 178.4, 158.9, 158.9, 134.1, 134.0, 132.5, 131.5, 131.4, 129.0,

128.9, 128.3, 128.2, 126.2, 113.5, 83.9, 83.7, 74.4, 74.3, 69.6, 69.0,

64.1, 55.1, 43.9, 43.7, 38.6, 36.1, 35.4, 32.4, 32.3, 28.1, 27.1, 26.0,

25.9, 25.8, 25.7, 21.6, 19.8, 18.6, 18.5, 18.0, 18.0, 10.1, 9.7, -4.0,

-4.1, -4.7, -4.8; HRMS (FAB, NBA/NaI) m/z calcd for C₃₄H₅₈O₅-

SiNa 597.3948, found 597.3951.

[3R-[3r,4â,5â,6r(2R,3Z,5R,6R,7R,8Z,11S,12R,13R,14S,15S,

16Z,17E)]]-6-[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-(car-

bamoyloxy)-23-[(2,2-dimethylpropanoyl)oxy]-5,7,9,11,13,15-hexa-

methyl-12-hydroxy-3,8,16,18-trieicosatetraenyl]-4-[[(1,1-di-

methylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-2H-pyran-

2-one (44). To a solution of 4 mg (3.5 µmol) of ketone in 500 µL of

THF was added 14 µL (14 µmol, 1 M in THF) of LiAl(OtBu)₃H. After

being stirred for 2 h at ambient temperature, the reaction was quenched

with 200 µL of saturated NH₄Cl solution, stirred for 1 h, dried over

Na₂SO₄, filtered, concentrated in Vacuo, and chromatographed (25%

EtOAc/hexanes) to provide 2 mg (1.8 µmol, 51%) of 44 as a colorless

oil: IR (thin film/NaCl) 1726 cm^-1; H NMR (500 MHz, CDCl₃) δ

1

6.29 (dd, J ) 9.2, 14.4 Hz, 1H), 5.98 (apparent t, J ) 11.0 Hz, 1H),

5.68 (overlapping ddd, J ) 6.9, 14.3 Hz, 1H), 5.29 (dd, J ) 7.8, 11.2

Hz, 1H), 5.26-5.20 (overlapping dd, 2H), 5.19 (d, J ) 9.8 Hz, 1H),

4.80 (t, J ) 8.8 Hz, 1H), 4.75 (dd, J ) 5.0, 6.5 Hz, 1H), 4.53 (obscured

t, J ) 10.2 Hz, 1H), 4.51 (br s, 2H), 4.06 (t, J ) 6.6 Hz, 2H), 3.64 (t,

J ) 2.4 Hz, 1H), 3.28 (ddd, J ) 3.7, 5.8, 8.1 Hz, 2H), 3.00 (ddd, J )

6.6, 9.8, 13.3 Hz, 1H), 2.63 (obscured m, 1H), 2.63 (dd, J ) 2.7, 7.5

Hz, 1H), 2.46 (m, 1H), 2.15 (m, 2H), 1.96-1.87 (overlapping m, 3H),

1.82 (m, 3H), 1.72 (m, 1H), 1.64 (m, 2H), 1.60 (s, 3H), 1.47 (t, J )

7.5 Hz, 2H), 1.23 (d, J ) 7.7 Hz, 3H), 1.20 (s, 9H), 1.00 (d, J ) 6.7

Hz, 3H), 0.99 (d, J ) 6.8 Hz, 3H), 0.97 (d, J ) 6.8 Hz, 3H), 0.96 (d,

J ) 7.0 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.88 (obscured d, 3H),

0.87 (s, 9H), 0.80 (d, J ) 6.2 Hz, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.06

(s, 3H), 0.05 (s, 3H), 0.05 (s, 3H), 0.01 (s, 3H); LRMS (FAB, NBA/

NaI) m/z calcd for C₆₀H₁₁₃O₁₀Si₃NNa 1114, found 1114.

2,2-Dimethylpropanoic Acid, 24-(Hydroxybutyl)discodermolide

Ester (45). To 2 mg (1.8 µmol) of 44 was added 200 µL of 1% HCl

in MeOH. (The HCl solution was made by the addition of 500 µL of

concentrated HCl to 50 mL of MeOH.) After stirring for 48 h at ambient

temperature, the reaction was quenched by the addition of 50 mg of

NaHCO₃, concentrated under a stream of N₂, and chromatographed

(5% MeOH/CHCl₃) to provide 0.8 mg (1.1 µmol, 61%) of 45 as a

colorless oil: IR (thin film/NaCl) 3427 (br), 1713 cm^-1; ¹H NMR (500

MHz, CDCl₃) δ 6.27 (dd, J ) 9.8, 13.8 Hz, 1H), 5.98 (apparent t, J )

11.2 Hz, 1H), 5.67 (m, 1H), 5.53 (dd, J ) 7.9, 11.2 Hz, 1H), 5.44

(apparent t, J ) 10.5 Hz, 1H), 5.23 (t, J ) 10.7 Hz, 1H), 5.16 (d, J )

9.9 Hz, 1H), 4.71 (overlapping m, 2H), 4.63 (overlapping m, 2H), 4.06

(t, J ) 6.6 Hz, 2H), 3.73 (m, 1H), 3.29 (m, 1H), 3.20 (m, 1H), 2.97

(m, 1H), 2.80 (m, 1H), 2.69 (m, 1H), 2.59 (m, 1H), 2.14 (overlapping

m, 2H), 2.09 (br s, 1H), 1.97-1.88 (overlapping m, 4H), 1.67 (m, 1H),

1.66 (s, 3H), 1.49 (overlapping m, 4H), 1.32 (d, J ) 7.3 Hz, 3H), 1.20

(s, 9H), 1.08 (d, J ) 7.0 Hz, 3H), 1.02 (d, J ) 6.7 Hz, 3H), 0.99 (d,

J ) 6.6 Hz, 3H), 0.98 (d, J ) 6.7 Hz, 3H), 0.95 (d, J ) 6.7 Hz, 3H),

0.83 (d, J ) 5.6 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for

C₄₂H₇₁O₁₀N 772.4972, found 772.4976.

2,2-Dimethylpropanoic Acid, (5E,7Z,9S,10S,11R)-9,11-Dimethyl-

10-[(4-methoxyphenyl)methoxy]-12-oxo-5,7-tridecadienyl Ester (42).

To a solution of 323 mg (650 µmol) of alcohol in 5 mL of CH₂Cl₂was

added 413 mg (970 µmol) of Dess-Martin periodinane. After stirring

at ambient temperature for 10 min, the reaction was quenched by the

addition of 10 mL of saturated Na₂S₂O₃solution, 10 mL of saturated

NaHCO₃solution, and diluted with 30 mL of diethyl ether. After 30

min of stirring, the layers were separated and the organic layer was

washed with 3 × 120 mL of saturated NaHCO₃solution, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed to provide

277 mg (560 µmol, 86%) of 42 as a colorless oil: IR (thin film/NaCl)

1

1726, 1711cm^-1; H NMR (500 MHz, CDCl₃) δ 7.24 (d, J ) 8.6 Hz,

2H), 6.85 (d, J ) 8.7 Hz, 2H), 6.15 (ddd, J ) 0.9, 11.0, 15.0 Hz, 1H),

5.98 (overlapping dd, J ) 11.0 Hz, 1H), 5.64 (overlapping ddd, J )

7.0, 14.4, 21.9 Hz, 1H), 5.35 (apparent t, J ) 10.6 Hz, 1H), 4.54 (d, J

) 10.6 Hz, 1H), 4.46 (d, J ) 10.7 Hz, 1H), 4.04 (apparent t, J ) 6.5

Hz, 2H), 3.78 (s, 3H), 3.62 (dd, J ) 3.9, 7.7 Hz, 1H), 2.78 (m, 1H),

2.74 (m, 1H), 2.09 (s, 3H), 1.62 (m, 2H), 1.43 (m, 2H), 1.18 (s, 9H),

1.17 (d, J ) 6.7 Hz, 3H), 1.06 (d, J ) 6.9 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 212.2, 178.5, 159.1, 134.7, 131.4, 130.7, 129.2, 129.0,

125.9, 113.6, 83.7, 74.9, 64.1, 55.1, 50.6, 38.6, 36.0, 32.3, 29.6, 28.1,

27.1, 25.7, 18.6, 13.3; HRMS (FAB, NBA/NaI) m/z calcd for C₂₈H₄₂O₅-

Na 481.2928, found 481.2930; [R]²⁰+53.4° (c 0.5, CHCl₃).

D

2,2-Dimethylpropanoic Acid, [2S-[2r(5E, 7Z,9S,10S,11R,13R,

15Z,17R,18R,19R,20Z,22R),3â,4â,5r,6â]]-18,22-Bis[[(1,1-dimethyl-

ethyl)dimethylsilyl]oxy]-23-[4-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-2H-pyran-2-yl]-9,11,

13,15,17,19-hexamethyl-10-[(4-methoxyphenyl)methoxy]-12-oxo-

5,7,15,20-trieicosatetraenyl ester (43). To a cooled (-78 °C) solution

of 141 mg (11 µmol) of ketone in 1 mL of THF was added 1.13 mL

(565 µmol, 0.5 M in THF) of LiN(SiMe₂Ph)₂. After the reaction was

stirred at -78 °C for 1 h, 704 µL (1.6 g, 11 mmol) of methyl iodide

was added. The reaction was warmed to 0 °C and stirred at ambient

temperature for 3 h. After the reaction was quenched with 1.5 mL of

saturated NH₄Cl solution, the mixture was extracted with 30 mL of

EtOAc and the layers were separated. The organic layer was dried

over MgSO4, filtered, concentrated in Vacuo, and chromatographed

(2% EtOAc.hexanes). The resulting colorless oil was purified by HPLC

(4% EtOAc/hexanes) to provide 51 mg (41 µmol, 36%) of 43 as a

[3R-[3a,4b,5b,6a(2R,3Z,5R,6R,7R,8Z,11S,13R,14S,15S,16Z,17E)]]-

6-[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hex-

amethyl-14-[(4-methoxyphenyl)methoxy]-12-oxo-20-[[[[[[(2-propenyl-

oxy)carbonyl]amino]hexyl]amino]carbonyl]oxy]3,8,16,18-

trieicosatetraenyl]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-

tetrahydro-3,5-dimethyl-2H-pyran-2-one (47). To a cooled (-78 °C)

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11077

solution of 68 mg (54 µmol) of 46 in 200 µL of CH₂Cl₂was added

800 µL (800 µmol, 1 M in CH₂Cl₂) of DIBAL-H. After being stirred

at -78 °C for 2 h, the reaction was quenched by the addition of 10

mL of 0.5 M NaK tartrate saturated with NaCl and diluted with 25 mL

of CH₂Cl₂. After 12 h of stirring at ambient temperature, the layers

were separated and the aqueous layer was extracted with 3 × 20 mL

of CH₂Cl₂. The organic layers were combined, dried over MgSO₄,

filtered, concentrated in Vacuo, and chromatographed to provide 60

mg (50 µmol, 93%) of a mixture of epimeric diols that was used directly

in the following reaction.

To a solution of 60 mg (50 µmol) of diols in 1 mL of MeCN was

added 42 µL (40 mg, 510 µmol) of pyridine, 132 mg (510 µmol) of

N,N′-disuccinimidyl carbonate, and 5 mg of DMAP. After being stirred

at ambient temperature for 30 min, the reaction mixture was concen-

trated under a stream of N₂and chromatographed (25% EtOAc/hexanes)

to provide 45 mg of the mixed carbonate that was used directly in the

following reaction.

To a solution of the mixed carbonate in 2 mL of CH₂Cl₂was added

76 mg (750 µmol) of N-Aloc-1,6-hexanediamine and 42 mg (340 µmol)

of DMAP. After 10 min of stirring at ambient temperature, the reaction

mixture was concentrated under a stream of N₂and chromatographed

(20% EtOAc/hexanes) to provide 56 mg (40 µmol, 80% for two steps)

of carbamate that was used directly in the following reaction.

To a solution of 56 mg (40 µmol) of carbamate in 500 µL of THF

were added 500 µL of MeCN, 500 µL of pH 7 buffer solution

concentrate, and 108 mg (400 µmol) of HgCl₂. The suspension was

stirred for 20 min, when TLC analysis indicated no starting material

remained, and then was treated with 10 mL of brine and extracted into

3 × 25 mL of CH₂Cl₂. The organic layers were combined, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed (25%

EtOAc/hexanes) to provide 44 mg of a mixture of lactols.

The lactols were dissolved in 6 mL of acetone, cooled to 0 °C, and

treated with 500 µL (500 µmol) of 1 M Jones oxidant solution. The

reaction was stirred at 0 °C for 30 min, then warmed to ambient

temperature for 5 min. Excess oxidant was quenched by addition of

500 µL of iPrOH and stirred for 30 min, diluted with 30 mL diethyl

ether, filtered through Celite, concentrated in Vacuo, and chromato-

graphed (20% EtOAc/hexanes) to provide 28 mg (22 µmol, 55% for

two steps) of 47 as a colorless oil: IR (thin film/NaCl) 1709 cm^-1; ¹H

NMR (500 MHz, CDCl₃) δ 7.23 (d, J ) 8.6 Hz, 2H), 6.84 (d, J ) 8.6,

6.12, m Hz, 1H), 5.96 (apparent t, J ) 11.0 Hz, 1H), 5.90 (m, 1H),

5.63 (m, 1H), 5.35 (t, J ) 10.5 Hz, 1H), 5.31 (obscured m, 2H), 5.30

(obscured d, J ) 1.6 Hz, 1H), 5.27 (obscured d, J ) 1.3 Hz, 1H), 5.19

(dd, J ) 6.3, 10.4 Hz, 1H), 5.02 (d, J ) 9.2 Hz, 1H), 4.75 (overlapping

m, 3H), 4.53 (dd, J ) 6.8, 9.7 Hz, 2H), 4.47 (apparent t, J ) 10.6 Hz,

1H), 4.02 (br s, 2H), 3.78 (s, 3H), 3.63 (overlapping m, 2H), 3.34 (m,

1H), 3.25 (m, 1H), 3.15 (br t, J ) 6.4 Hz, 4H), 2.72 (overlapping m,

2H), 2.60 (overlapping m, 2H), 2.43 (overlapping m, 2H), 2.35 (m,

1H), 2.07 (m, 2H), 2.01 (m, 2H), 1.73 (m, 1H), 1.70 (m, 1H), 1.67 (s,

3H), 1.58 (m, 3H), 1.49 (m, 4H), 1.42 (m, 2H), 1.32 (m, 5H), 1.25 (m,

1H), 1.25 (m, 1H), 1.21 (d, J ) 7.6 Hz, 3H), 1.16 (d, J ) 7.0 Hz, 3H),

1.04 (d, J ) 6.7 Hz, 3H), 0.96 (d, J ) 6.2 Hz, 3H), 0.95 (d, J ) 8.1

Hz, 3H), 0.90 (obscured d, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.865 (s,

9H), 0.06 (overlapping s 6), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H),

0.03 (s, 3H), -0 (02, J ) s Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

213.3, 173.3, 159.1, 156.7, 156.3, 134.9, 134.2, 133.6, 133.0, 132.3,

131.6, 131.4, 131.3, 130.9, 130.8, 129.3, 129.1, 125.9, 117.5, 113.7,

96.2, 83.6, 80.4, 79.8, 76.8, 74.9, 74.8, 65.4, 64.7, 64.6, 64.4, 55.2,

50.1, 44.1, 42.7, 40.8, 40.7, 37.3, 36.1, 35.3, 34.2, 32.4, 2/9.9, 29.8,

28.7, 28.6, 28.0, 26.3, 26.2, 26.1, 26.0, 25.9, 25.9, 25.8, 25.7, 23.1,

23.0, 19.0, 18.7, 18.4, 18.3, 1831, 18.0, 17.9, 17.4, 17.3, 16.4, 16.3,

14.0, 13.5, -3.1, -4.3, -4.5, -4.9; LRMS (FAB, NBA/NaI) m/z calcd

for C₇₂H₁₂₆N₂O₁₂Si₃Na 1317 found 1317; [R]²⁰_D+32.0° (c 0.5, CHCl₃).

[3R-[3a,4b,5b,6a (2R,3Z,5R,6R,7R,8Z,11S,12R,13R,14S,15S,16Z,

17E)]]-6-[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-(car-

bamoyloxy)-5,7,9,11,13,15-hexamethyl-12-hydroxy-20-[[[[[[(2-pro-

penyloxy)carbonyl]amino]hexyl]amino]carbonyl]oxy]-3,8,16,18-

trieicosatetraenyl]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]tetrahydro-

3,5-dimethyl-2H-pyran-2-one (48). To a solution of 12 mg (9.7 mol)

of ketone in 2 mL of THF was added 50 µL (50 µmol, 1 M in THF)

of LiAl(OtBu)₃H. After 2 h of stirring at ambient temperature, the

reaction was quenched with 200 µL of saturated NH₄Cl solution, stirred

for 1 h, dried over Na₂SO₄, filtered, concentrated in Vacuo, and

chromatographed (30% EtOAc/hexanes) to provide 8 mg (6.5 µmol,

67%) of 48 as a colorless oil: IR (thin film/NaCl) 1717, 1701 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 6.29 (overlapping dd, J ) 11.5 Hz,

1H), 5.97 (apparent t, J ) 10.9 Hz, 1H), 5.90 (m, 1H), 5.67 (m, 1H),

5.29 (obscured d, J ) 17.9 Hz, 1H), 5.29 (obscured m, 1H), 5.23

(obscured d, J ) 10.7 Hz, 1H), 5.20 (obscured m, 2H), 5.05 (d, J )

9.5 Hz, 1H), 4.80 (overlapping m, 4H), 4.75 (br s, 1H), 4.59 (br s,

1H), 4.55 (d, J ) 5.2 Hz, 2H), 4.50 (obscured t, J ) 10.2 Hz, 1H),

4.06 (br t, J ) 10.3 Hz, 2H), 3.64 (t, J ) 2.3 Hz, 1H), 3.58 (m, 1H),

3.28 (dd, J ) 4.4, 9.8 Hz, 1H), 3.16 (overlapping m, 3H), 2.96 (ddd,

J ) 7.0, 9.8, 13.6 Hz, 1H), 2.61 (m, 2H), 2.49 (m, 1H), 2.29 (m, 1H),

2.14 (m, 5H), 1.91 (m, 1H), 1.78 (m, 3H), 1.71 (m, 3H), 1.64 (2, 3H),

1.62 (obscured m, 2H), 1.49 (m, 5H), 1.33 (m, 4H), 1.22 (d, J ) 7.0

Hz, 3H), 0.99 (d, J ) 6.8 Hz, 3H), 0.96 (overlapping d, J ) 6.7 Hz,

3H), 0.95 (overlapping d, J ) 6.4 Hz, 3H), 0.94 (d, J ) 7.1 Hz, 3H),

0.90 (obscured d, J ) 7.1 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.80 (s,

9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 173.6, 157.2, 156.8, 135.0, 133.3, 132.7,

131.0, 130.9, 129.4, 125.9, 80.6, 79.8, 74.8, 73.3, 65.4, 64.7, 44.1, 42.8,

40.8, 39.8, 37.5, 35.5, 34.8, 34.2, 33.2, 32.3, 29.9, 28.8, 26.3, 26.2,

25.9, 25.7, 25.5, 23.4, 18.5, 18.1, 17.9, 17.7, 16.4, 15.9, 14.1, 8.1, -3.1,

-4.1, -4.3, -4.5, -4.9; LRMS (FAB, NBA/NaI) m/z calcd for

C₆₅H₁₂₁N₃O₁₂Si₃Na 1242, found 1242; [R]²⁰+38.0° (c 0.2, CHCl₃).

D

[[[[(2-Propenyloxy)carbonyl]amino]hexyl]amino]carbonyl]oxy]-

24-(hydroxybutyl)discodermolide carbamate (49). To 3.3 mg (1.8

µmol) of 48 was added 200 µL of 1% HCl in MeOH. (The HCl

solution was made by the addition of 500 µL of concentrated HCl to

50 mL of MeOH.) After stirring for 48 h at ambient temperature, the

reaction was quenched by the addition of 50 mg of NaHCO₃,

concentrated under a stream of N₂, and chromatographed (5% MeOH/

CHCl₃) to provide 1.0 mg (0.8 µmol, 42%) of 49 as a colorless oil: IR

(thin film/NaCl) 3746 (br), 3345 (br), 1701 cm^-1; ¹H NMR (500 MHz,

CDCl₃) δ 6.27 (dd, J ) 11.3, 14.4 Hz, 1H), 5.97 (apparent t, J ) 11.0

Hz, 1H), 5.90 (m, 1H), 5.66 (m, 1H), 5.53 (dd, J ) 8.1, 11.2 Hz, 1H),

5.43 (t, J ) 10.6 Hz, 1H), 5.30 (dd, J ) 1.4, 17.2 Hz, 1H), 5.20 (dd,

J ) 7.6, 9.4 Hz, 2H), 5.12 (d, J ) 9.5 Hz, 1H), 4.76-4.61 (overlapping

m, 6H), 4.55 (d, J ) 5.0 Hz, 2H), 4.03 (br t, J ) 6.0 Hz, 2H), 3.72 (m,

2H), 3.71-3.46 (overlapping m, 5H), 3.18 (obscured m, 1H), 3.16 (m,

J ) obscured m Hz, 2H), 2.96 (ddd, J ) 6.8, 9.9, 13.6 Hz, 1H), 2.77

(ddd, J ) 6.8, 9.7, 13.5 Hz, 1H), 2.68 (m, 1H), 2.56 (m m, 1H), 2.34

(m, 1H), 2.13 (overlapping m, 4H), 2.05 (m, 3H), 1.94 (m, 2H), 1.86

(dd, J ) 2.3, 9.6 Hz, 1H), 1.83 (dd, J ) 2.3, 7.6 Hz, 1H), 1.70 (m,

4H), 1.67 (d, J ) 1.0 Hz, 3H), 1.60 (m, 4H), 1.49 (m, 4H), 1.34 (m,

2H), 1.32 (obscured d 3), 1.07 (d, J ) 7.0 Hz, 3H), 1.01 (d, J ) 6.7

Hz, 3H), 0.99 (d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.8 Hz, 3H), 0.93 (d,

J ) 7.0 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for C₄₇H₇₉N₃O₁₂-

Na 900.5557, found 900.5554.

[2S-[2r(3Z,5S,6R,7R,8R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6â]]-

6-(Carbamoyloxy)-19-[4-hydroxytetrahydro-3,5-dimethyl-6-

(phenylthio)-2H-pyran-2-yl]-5,7,9,11,13,15-hexamethyl-1,3,11,16-

nonadecatetraen-8,14,18-triol (50b). To 2 mg (2 µmol) of silyl ether

was added 200 µL of 1% HCl in MeOH. (The HCl solution was made

by the addition of 500 µL of concentrated HCl to 50 mL of MeOH.)

After stirring for 3 days at ambient temperature, the reaction was

quenched by the addition of 50 mg of NaHCO₃, concentrated under a

stream of N₂, and chromatographed (5% MeOH/CHCl₃) to provide 1.0

mg (1.5 µmol, 78%) of 50b as a colorless oil: IR (thin film/NaCl) 3752

(br), 3443 (br), 1711 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.49 (dd, J

) 1.4, 8.5 Hz, 2H), 7.32-7.25 (m, 3H), 6.62 (ddd, J ) 10.9, 16.8,

21.2 Hz, 1H), 6.04 (apparent t, J ) 11.1 Hz, 1H), 5.47 (dd, J ) 8.3,

11.1 Hz, 1H), 5.38-5.31 (overlapping m, 3H), 5.20 (dd, J ) 1.7, 6.8

Hz, 1H), 5.15 (dd, J ) 11.6 Hz, 1H), 4.74 (dd, J ) 4.4, 7.1 Hz, 1H),

4.45 (dd, J ) 8.1 Hz, 1H), 4.35 (ddd, J ) 2.4, 10.5, 18.9 Hz, 1H),

3.65 (t, J ) 3.5 Hz, 1H), 3.27 (br s, 1H), 3.17 (dd, J ) 4.8, 6.5 Hz,

1H), 3.01 (ddd, J ) 6.9, 10.2, 14.0 Hz, 1H), 2.61-2.51 (overlapping

m, 2H), 2.27 (m, 2H), 2.23 (d, J ) 7.0 Hz, 1H), 1.97-1.83 (overlapping

m, 4H), 1.72 (m, 1H), 1.62 (d, J ) 1.2 Hz, 3H), 1.20 (d, J ) 7.2 Hz,

3H), 1.00 (d, J ) 6.7 Hz, 3H), 0.99 (obscured d, 3H), 0.99 (d, J ) 7.0

Hz, 3H), 0.98 (d, J ) 7.2 Hz, 3H), 0.93 (d, J ) 6.9 Hz, 3H), 0.84 (d,

J ) 6.2 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for C₃₉H₆₁O₇-

NSNa 710.4063, found 710.4066.

11078 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

[2S-[2r(3Z,5S,6R,7R,8R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-

6-(Carbamoyloxy)-19-[4-hydroxytetrahydro-3,5-dimethyl-6-

(phenylthio)-2H-pyran-2-yl]-5,7,9,11,13,15-hexamethyl-1,3,11,16-

nonadecatetraen-8,14,18-triol (50a). To 20 mg (19 µmol) of silyl

ether was added 2 mL of 1% HCl in MeOH. (The HCl solution was

made by the addition of 500 µL of concentrated HCl to 50 mL of

MeOH.) After stirring for 48 h at ambient temperature, the reaction

was quenched by the addition of 50 mg of NaHCO₃, concentrated under

a stream of N₂, and chromatographed (2% MeOH/CHCl₃). The residue

was purified by HPLC (2.5% MeOH/CH₂Cl₂) to provide 1.8 mg (2.6

µmol, 14%) of 50a as a colorless oil: IR (thin film/NaCl) 1734, 1717

cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.50 (ddd, J ) 1.4, 3.5, 7.4 Hz,

2H), 7.31-7.22 (overlapping m, 3H), 6.61 (ddd, J ) 0.7, 10.9, 16.7

Hz, 1H), 6.03 (apparent t, J ) 11.0 Hz, 1H), 5.42 (dd, J ) 6.0, 9.2 Hz,

1H), 5.38-5.30 (overlapping m, 3H), 5.23 (dd, J ) 0.7, 5.7 Hz, 1H),

5.16 (d, J ) 9.9 Hz, 1H), 5.11 (d, J ) 10.0 Hz, 1H), 4.73 (dd, J ) 4.5,

7.1 Hz, 1H), 4.62 (t, J ) 7.8 Hz, 1H), 4.57 (br s, 2H), 3.83 (ddd, J )

2.9, 8.8, 11.1 Hz, 1H), 3.71 (d, J ) 2.1 Hz, 1H), 3.28 (overlapping dd,

J ) 5.0 Hz, 1H), 3.16 (dd, J ) 4.5, 6.9 Hz, 1H), 3.00 (ddd, J ) 6.8,

10.2, 13.7 Hz, 1H), 2.80 (br s, 1H), 2.67 (ddd, J ) 6.8, 9.6, 13.6 Hz,

1H), 2.57 (m, 1H), 2.17 (ddd, J ) 2.5, 5.0, 7.1 Hz, 1H), 2.04-1.85

(overlapping m, 5H), 1.78 (ddd, J ) 3.1, 9.0, 12.2 Hz, 1H), 1.74 (br d,

J ) 2.5 Hz, 2H), 1.66 (ddd, J ) 2.6, 8.7, 11.3 Hz, 1H), 1.63 (d, J )

1.1 Hz, 3H), 1.60 (br s, 1H), 1.15 (d, J ) 7.2 Hz, 3H), 1.00 (d, J ) 6.8

Hz, 3H), 0.99 (d, J ) 6.5 Hz, 3H), 0.98 (d, J ) 6.7 Hz, 3H), 0.92 (d,

J ) 6.8 Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H), 0.83 (d, J ) 6.0 Hz, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 157.0, 134.5, 133.6, 133.5, 133.3, 133.2,

132.1, 131.1, 130.0, 129.7, 128.7, 127.1, 117.9, 84.8, 78.9, 77.2, 75.8,

75.7, 75.4, 65.0, 41.4, 39.4, 37.2, 36.0, 35.8, 34.9, 34.7, 33.8, 33.0,

26.6, 18.1, 17.4, 15.4, 13.9, 13.2, 11.7, 8.8; HRMS (FAB, NBA/NaI)

m/z calcd for C₃₉H₆₁O₇NSNa 710.4063, found 710.4066; [R]²⁰_D+87.6°

(c 0.5, CHCl₃).

4.74 (dd, J ) 4.5, 6.8 Hz, 1H), 4.69 (obscured m, 1H), 4.64 (s, 1H),

4.57 (obscured m, 5H), 3.96 (br t, J ) 10.4 Hz, 1H), 3.88 (m, 1H),

3.58 (m, 2H), 3.51 (m, 2H), 3.47 (br d, J ) 1.9 Hz, 2H), 3.41 (s, 1H),

3.38 (m, 1H), 3.33 (m, 1H), 3.20 (dd, J ) 4.8, 6.9 Hz, 2H), 2.98 (ddd,

J ) 6.7, 9.9, 13.5, 12.75, m Hz, 1H), 2.59 (m, 1H), 2.25 (m, 1H), 2.12

(dd, J ) 1.7, 6.9 Hz, 2H), 2.03 (m, 1H), 2.00 (m, 1H), 1.77 (m, 3H),

1.68 (d, J ) 1.1 Hz, 3H), 1.54 (m, 3H), 1.04 (overlapping d, J ) 7.4

Hz, 3H), 1.03 (overlapping d, J ) 7.4 Hz, 3H), 1.00 (d, J ) 6.8 Hz,

3H), 0.95 (overlapping d, J ) 6.7 Hz, 3H), 0.94 (overlapping d, J )

6.7 Hz, 3H), 0.94 (overlapping d, J ) 7.0 Hz, 3H); HRMS (FAB, NBA/

NaI) m/z calcd for C₃₈H₆₄O₁₀N₂Na 731.4455, found 731.4459.

(8R,9S,10S,11Z)-8,10-Dimethyl-9-[(4-methoxyphenyl)methoxy]-

1-[(triethylsilyl)oxy]-11,13-tetradecadien-7-one (53). To a solution

of 400 mg (1.38 mmol) of 13 in 5 mL of CH₂Cl₂was added 760 mg

(1.66 mmol) of Dess-Martin periodinane. After being stirred at

ambient temperature for 10 min, the reaction was quenched by the

addition of 20 mL of saturated Na₂S₂O₃solution and 20 mL of saturated

NaHCO₃solution and diluted with 50 mL of diethyl ether. After 30

min of stirring, the layers were separated and the organic layer was

washed with 3 × 120 mL of saturated NaHCO₃solution, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed (10%

EtOAc/hexanes) to yield 312 mg of the aldehyde.

To make a 1 M solution of the Grignard reagent, 1.18 g (4 mmol)

of 1-bromo-6-[(triethylsilyl)oxy]hexane in 4 mL of THF was heated

with 117 mg (4.8 mmol) of magnesium turnings. To a solution of 312

mg (1.08 mmol) of the aldehyde in 2 mL of THF was added 3.25 mL

(3.25 mmol, 1 M in THF) of the Grignard reagent. After 30 min of

stirring at ambient temperature, the reaction mixture was diluted with

30 mL of diethyl ether, washed with 1 × 20 mL of 1 N HCl and 1 ×

20 mL of saturated NaHCO₃solution, dried over MgSO₄, filtered,

concentrated in Vacuo, and chromatographed (10% EtOAc/hexanes)

to provide 458 mg of a 2:1 mixture of epimers.

[2S-[2r(3Z,5S,6R,7R,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-6-

(Carbamoyloxy)-19-[4-hydroxytetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-5,7,11,13,15-pentamethyl-1,3,11,16-nonadecatet-

raene (51). To 20 mg (15 µmol) of silyl ether was added 200 µL of

1% HCl in MeOH. (The HCl solution was made by the addition of

500 µL of concentrated HCl to 50 mL of MeOH.) After 48 h of stirring

at ambient temperature, the reaction was quenched by the addition of

50 mg of NaHCO₃, concentrated under a stream of N₂, and chromato-

graphed (5% MeOH/CHCl₃) to provide 9 mg (12 µmol, 82%) of 51 as

The mixture of alcohols was dissolved in 5 mL of CH₂Cl₂, and 492

mg (1.16 mmol) of Dess-Martin periodinane was added. After being

stirred 30 min at ambient temperature, the reaction was quenched by

the addition of 20 mL of saturated Na₂S₂O₃solution and 20 mL of

saturated NaHCO₃solution and diluted with 50 mL of diethyl ether.

After 30 min of stirring, the layers were separated and the organic layer

was washed with 3 × 120 mL of saturated NaHCO₃solution, dried

over MgSO₄, filtered, concentrated in Vacuo, and chromatographed (5%

EtOAc/hexanes) to yield 368 mg (733 µmol, 53% for three steps) of

1

a colorless oil: IR (thin film/NaCl) 3428 (br), 1713 cm^-1; H NMR

1

53 as a colorless oil: IR (thin film/NaCl) 1709 cm^-1; H NMR (400

(500 MHz, CDCl₃) δ 7.49 (dd, J ) 1.3, 8.5 Hz, 2H), 7.31-7.22 (m 3),

6.60 (ddd, J ) 10.6, 17.1, 21.0 Hz, 1H), 6.04 (apparent t, J ) 11.0 Hz,

1H), 5.38 (dd, J ) 8.1, 11.1 Hz, 1H), 5.35 (d, J ) 2.2 Hz, 1H), 5.32

(obscured m, 1H), 5.22 (dd, J ) 1.3, 16.8, 5.14, overlapping d, 6.3

Hz, 1H), 5.12 (overlapping d, J ) 8.1 Hz, 1H), 4.74 (dd, J ) 4.5, 6.7

Hz, 1H), 4.61 (br s, 2H), 3.81 (m 1), 3.70 (br s, 1H), 3.58 (m, 1H),

3.15 (dd, J ) 4.4, 6.9 Hz, 1H), 2.98 (ddd, J ) 6.7, 10.0, 13.5 Hz, 1H),

2.87 (br s, 1H), 2.65 (ddd, J ) 6.8, 9.6, 13.8 Hz, 1H), 2.55 (m 1), 2.32

(br s, 1H), 2.19-2.15 (m 1), 2.14-2.09 (m 1), 1.98 (m 1), 1.89-1.79

(overlapping m, 2H), 1.78-1.73 (overlapping m, 2H), 1.67 (d, J ) 0.8

Hz, 3H), 1.55-1.47 (m 2), 1.14 (d, J ) 7.2 Hz, 3H), 0.99 (d, J ) 6.9

Hz, 3H), 0.98 (d, J ) 6.8 Hz, 3H), 0.93 (d, J ) 6.9 Hz, 3H), 0.92 (d,

J ) 6.8 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 157.3, 135.1, 134.5, 133.5, 133.4, 133.3, 132.1, 131.1, 130.0, 129.0,

128.9, 127.1, 118.0, 89.8, 79.7, 78.8, 77.2, 75.8, 75.4, 73.3, 65.1, 41.3,

39.9, 39.5, 36.0, 34.9, 34.6, 33.8, 33.1, 28.8, 23.5, 18.0, 17.6, 14.9,

13.2, 11.7, 7.9; HRMS (FAB, NBA/NaI) m/z calcd for C₃₉H₅₉NO₇SNa

MHz, CDCl₃) δ 7.27 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H),

6.46 (ddd, J ) 10.8, 16.8, 21.2 Hz, 1H), 6.04 (apparent t, J ) 11.0 Hz,

1H), 5.55 (apparent t, J ) 10.6 Hz, 1H), 5.19 (d, J ) 16.8 Hz, 1H),

5.08 (d, J ) 10.1 Hz, 1H), 4.57 (d, J ) 10.6 Hz, 1H), 4.50 (d, J )

10.6 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J ) 3.3, 8.2 Hz, 1H), 3.59 (t, J

) 6.6 Hz, 2H), 2.77 (obscured m, 1H), 2.74 (obscured m, 1H), 2.44

(m, 1H), 2.37 (m, 1H), 1.52 (overlapping m, 4H), 1.28 (overlapping

m, 4H), 1.17 (d, J ) 7.1 Hz, 3H), 1.09 (d, J ) 6.8 Hz, 3H), 0.97 (t, J

) 7.9 Hz, 9H), 0.60 (1, J ) 7.9 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃)

δ 272.4, 159.1, 133.9, 132.1, 130.7, 129.5, 129.2, 117.6, 113.6, 83.7,

75.2, 62.7, 55.1, 50.2, 42.4, 36.1, 32.7, 28.9, 25.6, 23.2, 18.7, 13.9,

6.7, 4.3; HRMS (FAB, NBA/NaI) m/z calcd for C₃₀H₅₀O₄SiNa

525.3373, found 525.3376; [R]²⁰+31.0° (c 0.5, CHCl₃).

D

[2S-[2â(3Z,5S,6S,7R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]]-

14,18-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-19-[4-[[(1,1-dimeth-

ylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-6-(phenylthio)-

2H-pyran-2-yl]-6-[(4-methoxyphenyl)methoxy]-5,7,11,13,15-

pentamethyl-9-[5-[(triethylsilyl)oxy]pentyl]-1,3,11,16-nonadecatetraen-

8-one (54). To a cooled solution (0 °C) of 120 mg (144 µmol) of 20

in 1 mL of CH₂Cl₂was added 83 µL (60 mg, 596 µmol) of Et₃N,

followed by 23 µL (44 mg, 298 µmol) of MsCl. After 1 h of stirring,

a solution of 130 mg (1.49 mmol) LiBr in 3 mL of acetone was added.

After the mixture was warmed to ambient temperature and stirred for

an additional 15 min, the suspension was diluted with 20 mL of hexanes,

filtered through MgSO₄and 5 g of silica gel, eluting from the silica

gel with 20 mL of 10% EtOAc/hexanes, and concentrated in Vacuo to

provide crude bromide 21.

708.2987, found 708.2984; [R]²⁰+82.4° (c 0.5, CHCl₃).

D

[(3Z,5S,6R,7R,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,6r]-6-(Car-

bamoyloxy)-19-[4-hydroxytetrahydro-3,5-dimethyl-6-[2-[[(2′-Pro-

penyl-oxy)carbonyl]amino]ethoxy]-2H-pyran-2-yl]-5,7,11,13,15-pen-

tamethyl-1,3,11,16-nonadecatetraene (52). To a solution of 7.5 mg

(10.7 µmol) of 51 and 50 µL of N-Aloc-ethanolamine in 50 µL of

THF was added 10 mg (110 µmol) of NaHCO₃and then 15 mg (55

µmol) of HgCl₂. After stirring for 10 min at ambient temperature, the

reaction was directly chromatographed (2%-4%-10% MeOH/CHCl₃)

to provide 2.5 mg (3.5 µmol, 33%) of 52 as a colorless oil: IR (thin

film/NaCl) 1701 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 6.60 (ddd, J )

10.9, 16.8, 21.2 Hz, 1H), 6.04 (apparent t, J ) 11.0 Hz, 1H), 5.92 (m,

1H), 5.56 (dd, J ) 8.1, 10.7 Hz, 1H), 5.42-5.12 (overlapping d, 8H),

To a cooled (-78 °C) solution of the crude bromide 21 and 300 mg

(596 µmol) of ketone 53 in 1 mL of THF was added 1.20 mL (596

µmol, 0.5 M solution in THF) of LDA. The reaction was stirred for

Syntheses of Discodermolides

J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11079

3 h at 0 °C and then quenched by the addition of 1.5 mL of saturated

NH₄Cl solution. The mixture was extracted into 30 mL of EtOAc,

dried over MgSO₄, filtered, concentrated in Vacuo, and chromatographed

(0.5%-1%-2% EtOAc/hexanes). The residue was purified by HPLC

(2% EtOAc/hexanes) to provide 51 mg (39 µmol, 27% for two steps)

of 54 as a colorless oil: IR (thin film/NaCl) 1707 cm^-1; ¹H NMR (400

MHz, CDCl₃) δ 7.44 (d, J ) 7.4 Hz, 2H), 7.24 (m, 4H), 7.12 (m, 1H),

6.85 (d, J ) 8.6 Hz, 2H), 6.47 (ddd, J ) 10.8, 16.9, 21.8 Hz, 1H),

6.03 (apparent t, J ) 11.1 Hz, 1H), 5.62 (apparent t, J ) 10.2 Hz,

1H), 5.33 (dd, J ) 7.8, 11.0 Hz, 1H), 5.23 (d, J ) 19.0 Hz, 1H), 5.22

(obscured m, 1H), 5.16 (obscured m, 1H), 5.07 (d, J ) 10.2 Hz, 1H),

4.56 (apparent t, J ) 8.9 Hz, 1H), 4.52 (s, 2H), 4.24 (apparent t, J )

10.1 Hz, 1H), 3.79 (apparent s, 3H), 3.64 (dd, J ) 3.2, 7.3 Hz, 1H),

3.57 (overlapping m, 3H), 3.30 (dd, J ) 3.2, 6.6 Hz, 1H), 2.73 (obscured

m, 2H), 2.70 (obscured m, 2H), 2.60 (m, 1H), 2.44 (dd, J ) 7.8, 15.8

Hz, 1H), 2.14 (m, 1H), 1.89 (dd, J ) 6.0, 13.6 Hz, 1H), 1.89 (dd, J )

10.3, 13.7 Hz, 1H), 1.67 (obscured m, 1H), 1.63 (d, J ) 0.7 Hz, 3H),

1.59 (obscured m, 1H), 1.50 (overlapping m, 4H), 1.26 (overlapping

m, 5H), 1.14 (d, J ) 7.1 Hz, 3H), 1.10 (d, J ) 7.2 Hz, 3H), 1.09 (d,

J ) 6.9 Hz, 3H), 1.01 (d, J ) 6.8 Hz, 3H), 0.99 (s, 9H), 0.96 (t, J )

8.0 Hz, 9H), 0.91 (s, 9H), 0.89 (obscured d, J ) 7.2 Hz, 3H), 0.84 (d,

J ) 6.8 Hz, 3H), 0.08 (s, 9H), 0.59 (q, J ) 7.8 Hz, 6H), 0.12 (s, 3H),

0.06 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H), -0.12 (s, 3H), -0.26 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 215.6, 159.1, 140.7, 134.6, 133.7, 133.2,

132.3, 132.1, 130.9, 130.1, 129.7, 129.1, 128.5, 127.8, 125.0, 117.7,

113.6, 87.2, 82.6, 80.4, 76.6, 74.9, 74.1, 67.9, 66.1, 62.8, 55.2, 50.1,

49.2, 42.8, 41.7, 36.8, 36.7, 35.2, 34.8, 33.3, 32.8, 31.2, 31.1, 27.7,

26.4, 26.2, 23.0, 25.9, 25.8, 23.4, 19.2, 18.5, 18.2, 17.9, 17.8, 17.5,

14.9, 14.3, 12.9, 6.8, 4.4, -2.7, -3.7, -4.0, -4.3, -5.0, -5.3; LRMS

(FAB, NBA/NaI) m/z calcd for C₇₅H₁₃₂O₈SSi₄Na 1313, found 1313;

50.1, 49.2, 42.8, 41.7, 40.8, 6.8, 36.7, 35.2, 34.9, 33.4, 31.0, 29.9, 28.8,

27.4, 26.4, 26.2, 26.1, 26.0, 25.9, 25.8, 23.5, 19.7, 18.5, 18.2, 17.9,

17.8, 17.5, 14.9, 14.3, 12.9, -2.7, -3.7, -4.0, -4.3, -4.5, -4.9, -5.0,

-5.3; LRMS (FAB, NBA/NaI) m/z calcd for C₇₉H₁₃₄N₂O₁₁SSi₃Na 1425,

found 1425; [R]²⁰-2.8° (c 0.5, CHCl₃).

D

[3S-[3r,4â,5â,6r(2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)]]-6-

[2,6-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-[(4-methoxyphen-

yl)methoxy]-9-[[[[5-[(2-propenyloxy)carbonyl]pentyl]amino]carbonyl]-

oxy]-5,7,11,13,15-pentamethyl-12-oxo-3,8,16,18-nonadecatetraenyl]-

4-[[(1,1-dimethylethyl) dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-

2H-pyran-2-one (56). To a solution of 43 mg (30 µmol) of 55 in 500

µL of THF were added 500 µL of MeCN, 500 µL of pH 7 buffer

solution concentrate, and 164 mg (600 µmol) of HgCl₂. The suspension

was stirred for 20 min, when TLC analysis indicated no starting material

remained, and then was treated with 10 mL of brine and extracted into

3 × 25 mL of CH₂Cl₂. The organic layers were combined, dried over

MgSO₄, filtered, concentrated in Vacuo, and chromatographed (4%

EtOAc/hexanes) to provide 33 mg of a mixture of lactols.

The lactols were dissolved in 4 mL of acetone, cooled to 0 °C, and

treated with 300 µL (300 µmol) of 1 M Jones oxidant solution. The

reaction was stirred at 0 °C for 30 min, then warmed to ambient

temperature for 5 min. Excess oxidant was quenched by addition of

300 µL of iPrOH and stirred for 30 min, diluted with 30 mL of diethyl

ether, filtered through Celite, concentrated in Vacuo, and chromato-

graphed (20% EtOAc/hexanes) to provide 24 mg (18 µmol, 60% for

two steps) of 56 as a colorless oil: IR (thin film/NaCl) 1716, 1707

1

cm^-1; H NMR (400 MHz, CDCl₃) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.85

(d, J ) 8.6 Hz, 2H), 6.46 (ddd, J ) 10.5, 17.2, 21.0 Hz, 1H), 6.01

(apparent t, J ) 11.2 Hz, 1H), 5.88 (m, 1H), 5.62 (apparent t, J ) 10.2

Hz, 1H), 5.31 (obscured m, 1H), 5.29 (obscured m, 1H), 5.21 (m, 2H),

5.19 (s, 1H), 5.15 (d, J ) 9.9 Hz, 2H), 5.11 (d, J ) 10.0 Hz, 1H), 5.06

(d, J ) 10.4 Hz, 1H), 4.80 (obscured t, J ) 8.9 Hz, 1H), 4.75 (br s,

1H), 4.68 (br s, 1H), 4.54 (apparent d, J ) 5.1 Hz, 2H), 4.52 (apparent

d, J ) 3.7 Hz, 2H), 3.99 (apparent t, J ) 6.1 Hz, 2H), 3.74 (s, 3H),

3.62 (m, 2H), 3.24 (dd, J ) 2.9, 6.6 Hz, 1H), 3.15 (m, 4H), 2.71 (m,

2H), 2.63 (m, 2H), 2.58 (m, 1H), 2.40 (m, 1H), 1.82 (obscured dd,

2H), 1.70 (obscured m, 3H), 1.61 (br s, 3H), 1.59-1.25 (overlapping

m 24), 1.20 (d, J ) 7.6 Hz, 3H), 1.11 (d, J ) 7.4 Hz, 3H), 1.09 (d, J

) 7.2 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 3H), 0.95 (d, J ) 6.7 Hz, 3H),

0.89 (s, 9H), 0.87 (s, 9H), 0.85 (d, J ) 7.2 Hz, 3H), 0.07 (s, 3H), 0.06

(s, 3H), 0.05 (overlapping s, 6H), 0.02 (s, 3H), -0.03 (s, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 215.3, 173.3, 159.1, 156.7, 156.3, 133.7,

133.5, 133.4, 133.0, 132.8, 132.3, 131.9, 130.8, 129.9, 129.3, 129.1,

117.7, 117.5, 113.7, 82.8, 82.7, 80.4, 77.2, 76.4, 75.0, 74.8, 65.4, 64.7,

55.2, 50.1, 49.3, 44.1, 42.7, 40.8, 67.4, 36.6, 34.8, 34.1, 33.2, 31.0,

29.9, 28.8, 27.4, 26.3, 26.2, 26.0, 25.9, 25.7, 23.5, 19.2, 18.9, 18.5,

18.1, 17.9, 17.5, 16.4, 15.0, 14.1, 13.0, 12.9, -2.8, -4.4, -4.5, -4.9;

LRMS (FAB, NBA/NaI) m/z calcd for C₇₂H₁₂₈N₂O₁₂SSi₃Na 1331, found

[R]²⁰-8.0° (c 0.5, CHCl₃).

D

[2S-[2â(3Z,5S,6S,7R,9S,11Z,13S,14S,15S,16Z,18S),3â,4â,5r,

6r]]-14,18-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-19-[4-[[(1,1-

dimethylethyl)dimethylsilyl]oxy]tetrahydro-3,5-dimethyl-6-(phen-

ylthio)-2H-pyran-2-yl]-5,7,11,13,15-pentamethyl-6-[(4-methoxy-

phenyl)methoxy]-9-[[[[5-[(2-propenyloxy)carbonyl]pentyl]amino]-

carbonyl]oxy]-1,3,11,16-nonadecatetraen-8-one (55). To a solution

of 48 mg (41 µmol) of alcohol in 1 mL of MeCN was added 35 µL

(34 mg, 430 µmol) of pyridine, 112 mg (430 µmol) of N,N′-

disuccinimidyl carbonate, and 5 mg of DMAP. After being stirred at

ambient temperature for 30 min, the reaction mixture was concentrated

under a stream of N₂and chromatographed (25% EtOAc/hexanes) to

provide 51 mg of the mixed carbonate that was used directly in the

following reaction.

To a solution of the mixed carbonate in 2 mL of CH₂Cl₂was added

34 mg (170 µmol) of N-Aloc-1,6-hexanediamine and 21 mg (170 µmol)

of DMAP. After being stirred for 10 min at ambient temperature, the

reaction mixture was concentrated under a stream of N₂and chromato-

graphed (20% EtOAc/hexanes) to provide 43 mg (30 µmol, 73%) of

1331; [R]²⁰+23.0° (c 0.5, CHCl₃).

D

1

55 as a colorless oil: IR (thin film/NaCl) 1707 cm^-1; H NMR (400

3,7,11-Tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-9-[[[[5-[(2-pro-

penyloxy)carbonyl]pentyl]amino]carbonyl]oxy]discodermolide (58).

To a solution of 14 mg (11 µmol) of ketone in 2 mL of THF was

added 55 µL (55 µmol, 1 M in THF) of LiAl(OtBu)₃H. After being

stirred for 2 h at ambient temperature, the reaction was quenched with

200 µL of saturated NH₄Cl solution, stirred for 1 h, dried over Na₂-

SO₄, filtered, concentrated in Vacuo, and chromatographed (40% EtOAc/

hexanes) to provide 12 mg (9.4 µmol, 86%) of 58 as a colorless oil:

IR (thin film/NaCl) 3339 (br), 1711 cm^-1; ¹H NMR (500 MHz, CDCl₃)

δ 6.61 (ddd, J ) 10.5, 16.8, 21.2 Hz, 1H), 6.01 (apaprent t, J ) 10.9

Hz, 1H), 5.91 (m, 1H), 5.37 (t, J ) 10.4 Hz, 1H), 5.31 (s, 1H), 5.29

(dd, J ) 5.2, 13.5 Hz, 1H), 5.21 (obscured d, J ) 11.4 Hz, 1H), 5.20

(obscured d, 1H), 5.19 (br s, 1H), 5.12 (d, J ) 10.4 Hz, 1H), 4.86 (br

s, 1H), 4.81 (br t, J ) 9.4 Hz, 1H), 4.76 (overlapping br s, 1H), 4.75

(dd, J ) 4.5, 7.0 Hz, 1H), 4.61 (br s, 2H), 4.54 (d, J ) 5.4 Hz, 1H),

4.51 (obscured t, J ) 10.2 Hz, 1H), 4.01 (overlapping m, 2H), 3.64 (t,

J ) 2.4 Hz, 1H), 3.46 (dd, J ) 5.4, 10.8 Hz, 1H), 3.32 (dd, J ) 3.1,

5.8 Hz, 1H), 3.15 (overlapping m, 3H), 3.02 (ddd, J ) 6.8, 10.0, 13.7

Hz, 1H), 2.60 (overlapping m, 2H), 2.56 (m, 1H), 2.06 (d, J ) 5.1 Hz,

1H), 2.02 (ovlerapping m, 2H), 1.92 (m, 1H), 1.88 (m, 1H), 1.80 (m,

1H), 1.74 (dd, J ) 12.3, 25.2 Hz, 1H), 1.69 (s, 3H), 1.57 (m, 2H),

1.48 (m, 4H), 1.32-1.24 (m, 17H), 1.01 (d, J ) 6.7 Hz, 3H), 0.98 (d,

J ) 6.7 Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H),

MHz, CDCl₃) δ 7.44 (d, J ) 7.4 Hz, 2H), 7.26 (m, 4H), 7.11 (m, 1H),

6.85 (d, J ) 8.6 Hz, 2H), 6.46 (ddd, J ) 10.5, 17.4, 21.7 Hz, 1H),

6.02 (apparent t, J ) 11.1 Hz, 1H), 5.91 (m, 1H), 5.62 (apparent t, J

) 10.2 Hz, 1H), 5.34 (obscured dd, J ) 7.8, 11.0 Hz, 1H), 5.31 (dd,

J ) 2.3, 3.7 Hz, 1H), 5.27 (d, J ) 1.5 Hz, 1H), 5.22 (d, J ) 19.7 Hz,

1H), 5.21 (obscured m, 1H), 5.16 (obscured m, 1H), 5.07 (d, J ) 10.3

Hz, 1H), 4.66 (br s, 1H), 4.57 (br s, 1H), 4.55 (d, J ) 4.8 Hz, 2H),

4.51 (apparent s, 2H), 4.23 (apparent t, J ) 10.1 Hz, 1H), 4.00 (apparent

t, J ) 6.3 Hz, 2H), 3.79 (s, 3H), 3.64 (dd, J ) 3.1, 7.4 Hz, 1H), 3.58

(obscured m, 1H), 3.29 (dd, J ) 3.1, 6.5 Hz, 1H), 3.16 (m, 4H), 2.73

(obscured m, 2H), 2.68 (obscured m, 2H), 2.58 (m, 1H), 2.45 (dd, J )

7.8, 13.4 Hz, 1H), 2.14 (m, 1H), 1.86 (dd, J ) 5.8, 13.5 Hz, 1H), 1.70

(dd, J ) 11.0, 14.2 Hz, 1H), 1.63 (br s, 3H), 1.54 (obscured dd, 3H),

1.49 (overlapping m, 6H), 1.33 (overlapping m, 5H), 1.31 (overlapping

m, 6H), 1.13 (d, J ) 7.1 Hz, 3H), 1.11 (d, J ) 7.3 Hz, 3H), 1.09 (d,

J ) 6.9 Hz, 3H), 1.01 (d, J ) 6.8 Hz, 3H), 0.99 (s, 9H), 0.91 (s, 9H),

0.88 (ovlerapping d, 3H), 0.84 (overlapping d, 3H), 0.79 (s, 9H), 0.12

(s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H), -0.13 (s, 3H), -0.27

(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 215.5, 159.1, 156.7, 156.3,

140.7, 134.6, 133.7, 133.3, 133.0, 132.9, 132.3, 132.1, 130.8, 130.0,

129.7, 129.3, 129.2, 129.1, 128.7, 127.8, 125.0, 117.7, 117.5, 113.7,

87.2, 82.6, 80.4, 77.2, 76.5, 74.9, 74.1, 67.9, 66.1, 65.4, 64.7, 55.2,

11080 J. Am. Chem. Soc., Vol. 118, No. 45, 1996

Hung et al.

0.90 (s, 9H), 0.88 (obscured d, 3H), 0.87 (s, 9H), 0.86 (s, 9H), 0.06 (s,

3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 173.5, 156.9, 156.8, 133.9, 133.3, 133.0,

132.7, 132.6, 132.4, 132.2, 129.8, 117.8, 117.6, 80.4, 78.3, 78.3, 77.3,

77.1, 74.7, 74.2, 65.4, 64.9, 64.7, 44.1, 42.8, 40.8, 37.9, 37.5, 37.0,

35.4, 34.5, 34.2, 31.9, 30.4, 29.9, 28.9, 26.4, 26.3, 26.2, 26.0, 25.9,

25.7, 23.7, 18.5, 18.1, 17.9, 17.5, 16.4, 15.2, 14.0, 9.4, -3.0, -4.1, -4.3,

-4.5, -4.9; LRMS (FAB, NBA/NaI) m/z calcd for C₆₆H₁₂₃N₃O₁₂Si₃-

7.4 Hz, 3H), 1.19 (overlapping m, 3H), 1.07 (d, J ) 6.9 Hz, 3H), 1.02

(d, J ) 6.8 Hz, 3H), 1.00 (d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 6.6 Hz,

3H), 0.94 (d, J ) 6.7 Hz, 3H); HRMS (FAB, NBA/NaI) m/z calcd for

C₄₈H₈₁N₃O₁₂Na 914.5713, found 914.5716.

Acknowledgment. These investigations have been supported

by grants from Hoffmann-La Roche and the New York Sea

Grant Institute and a fellowship to D.T.H. (NIH-MSTP Grant

No. 2-T32-GM07753-11 and the Life and Health Insurance

Medical Research Fund). We thank Dr. Jeff Tilley, Dr. Bob

Guthrie, and Mr. Frank Mennona of Hoffmann-La Roche for

providing homoallylic alcohols 5 and 6 as starting materials.

We thank Mr. Timothy F. Jamison for beneficial discussions.

Mass spectral data were obtained at the Harvard University Mass

Spectrometry Facility. We acknowledge the NIH BRS Shared

Instrumentation Grant Program (1 S10 RR01748-01A1) and

NSF (CHE88-14019) for providing NMR facilities. S.L.S. is

an Investigator at the Howard Hughes Medical Institute. We

dedicate this paper to Professor Yoshito Kishi for his pioneering

studies of acyclic stereocontrol and of its use to investigate

complex natural products.

Na 1256, found 1256; [R]²⁰+17.6° (c 0.5, CHCl₃).

D

9-[[[[5-[(2-Propenyloxy)carbonyl]pentyl]amino]carbonyl]oxy]-

discodermolide (59). To 12 mg (9.4 µmol) of 58 was added 1.2 mL

of 1% HCl in MeOH. (The HCl solution was made by the addition of

500 µL of concentrated HCl to 50 mL of MeOH.) After being stirred

for 48 h at ambient temperature, the reaction was quenched by the

addition of 50 mg of NaHCO₃, concentrated under a stream of N₂, and

chromatographed (5% MeOH/CHCl₃) to provide 5.0 mg (5.6 µmol,

60%) of 59 as a colorless oil: IR (thin film/NaCl) 3343 (br), 1699,

1

cm^-1; H NMR (500 MHz, CDCl₃) δ 6.61 (dd, J ) 10.5, 17.1, 20.9

Hz, 1H), 6.02 (apparent t, J ) 11.0 Hz, 1H), 5.92 (m, 1H), 5.54 (dd,

J ) 8.1, 11.0 Hz, 1H), 5.39 (d, J ) 11.1 Hz, 1H), 5.34 (d, J ) 10.8

Hz, 1H), 5.31 (d, J ) 1.4 Hz, 1H), 5.27 (apparent t, J ) 1.6 Hz, 1H),

5.25 (m, 1H), 5.19 (s, 1H), 5.11 (d, J ) 10.1 Hz, 1H), 4.95 (br s, 1H),

4.82 (br s, 1H), 4.76 (br t, J ) 7.6 Hz, 1H), 4.73 (dd, J ) 3.9, 7.5 Hz,

1H), 4.63 (br t, J ) 8.2 Hz, 1H), 4.58 (br s, 2H), 4.54 (m, 2H), 4.00

(overlapping m, 2H), 3.72 (m, 1H), 3.48 (m, 1H), 3.15 (overlapping

m, 5H), 3.01 (m, 1H), 2.75 (m, 1H), 2.68 (m, 1H), 2.61 (m, 1H), 2.54

(m, 1H), 2.46 (m, 1H), 2.20 (br s, 1H), 2.13 (dd, J ) 9.0, 19.0 Hz,

1H), 2.01 (dd, J ) 3.9, 13.7 Hz, 1H), 1.94 (overlapping m, 4H), 1.88

(overlapping m, 4H), 1.72 (d, J ) 0.8 Hz, 3H), 1.69 (obscured m, 1H),

1.53 (obscured m, 4H), 1.32 (obscured m, 6H), 1.30 (obscured d, J )

Supporting Information Available: Complete physical and

spectral data and experimental details for all compounds (16

pages). See any current masthead page for ordering and Internet

access information.

JA961374O

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Syntheses of discodermolides useful for investigating microtubule binding and stabilization

DOI: 10.1021/ja961374o

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