Halichondrin B: Synthesis of the C(37)-C(54) subunit

TETRAHEDRON

Pergamon

Tetrahedron 58 #2002) 2011±2026

Halichondrin B: synthesis of the Cꢀ37)±Cꢀ54) subunit

Brian C. Austad, Amy C. Hart and Steven D. Burke^p

Department of Chemistry, University of Wisconsin±Madison, 1101 University Avenue, Madison, WI 53706-1396, USA

Received 20 November 2001; accepted 10 December 2001

AbstractÐA synthesis of the C#37)±C#54) segment of the antimitotic polyether macrolide halichondrin B is described. b-Ketophosphonate

1, comprising rings L, M, and N of the natural product, contains the C#44) spiroketal, about which local C₂symmetry plays a key strategic

role. Based upon recognition of this local C₂symmetry, a Claisen self-condensation of 4 led to the dienone 3b. Asymmetric bis#dihydroxyl-

ation) set the C#40), C#41), C#47), and C#48) stereocenters, and the resulting bicyclic spiroketal 8a was oxidized to tetracyclic bis#lactone)

2a. Alcohol 13 was isolated from the mono-functionalization of bis#lactone) 2a via a carbonyl methylenation/hydroboration protocol.

Chelation-controlled allylation of the derived aldehyde, followed by diastereoselective iodocarbonate formation and hydrolysis established

the C#51)±C#54) sidechain in 17a. Protection of the side-chain hydroxyl groups, and conversion of the remaining lactone to the correspond-

ing b-ketophosphonate provided 1, a suitable coupling subunit #with a total of 10 asymmetric centers) for the total synthesis of halichondrin

B. Overall, a 22 step synthetic route from known epoxide 5 produced 1 #4% overall yield), in its natural con®guration. q 2002 Elsevier

Halichondrin B #Fig. 1) is the most potent component of a

class of polyether macrolides isolated in exceedingly low

yields #1.8£10²⁸to 4.0£10²⁵%) from a variety of sponge

genera.^1±5With a tubulin-based mechanism of action as an

antimitotic agent, halichondrin B displays an in vitro IC₅₀

value of 0.3 nM against L1210 leukemia and remarkable in

vivo activities against various chemoresistant human solid

tumor xenographs, including LOX melanoma, KM20L

colon, FEMX melanoma, and OVCAR-3 ovarian

tumors.^6±11In spite of its extremely limited supply from

natural sources, halichondrin B has been recommended by

the National Cancer Institute for stage A preclinical

development.^9,10Synthetic efforts have been described by

several groups,^12±34and one total synthesis of halichondrin

B by Kishi and co-workers has been reported.¹⁹Kishi has

also recently disclosed that a synthetic C#1)±C#38)

halichondrin B subunit exhibits an activity pro®le against

.60 cancer cell lines similar to that of halichondrin B, with

IC₅₀values within one order of magnitude of those

displayed by the natural product.¹²Munro has recently

reported on the aquacultural production of Lissodendoryx

n. sp. for the isolation of halichondrin B,³⁵estimating that

5000 tons/year of harvested sponge could generate 5 kg/year

of the natural product for clinical use. Our earlier synthetic

work towards halichondrin B focused on the C#1)±C#15)

and C#20)±C#36) segments of the natural product.^30±33In

this paper, we report the synthesis of the C#37)±C#54)

subunit 1 #Scheme 1) in its natural con®guration.³⁴

The synthetic plan for construction of the L, M, and N rings

of b-ketophosphonate 1, including 10 asymmetric centers,

was based upon the exploitation of local C₂symmetry about

the C#44)-spiroketal carbon, with late-stage symmetry

breaking by sequential extension at C#38) and C#50).

Proceeding through the tetracyclic bis#lactone) 2a #Scheme

1), the stereocenters at C#40), C#41), C#47), and C#48) were

to be established in a two-fold Sharpless asymmetric

dihydroxylation #SAD)³⁶of the C₂-symmetric dienone 3b.

Ketone 3b was presumed to be accessible through Claisen

self-condensation of ester 4, followed by decarboalkoxyl-

ation. As a g,d-unsaturated ester, 4 was expected to arise

from Claisen rearrangement of the appropriate allylic

alcohol 7, derivable from the chiral, enantiomerically pure

epoxide 5.

Figure 1.

The known #S)-epoxide 5 was available in high enantio-

meric excess #.95% ee) from #S)-malic acid using a slight

modi®cation of existing procedures,^37±39or by hydrolytic

kinetic resolution^40,41of racemic 5. In a two pot procedure,

Keywords: halichondrin B; spiroketal; desymmetrization.

Corresponding author. Tel.: 11-608-262-4941; fax: 11-608-265-4534;

e-mail: burke@chem.wisc.edu

p

PII: S0040-4020#02)00050-9

2012

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

Scheme 1.

enantiopure 5 was opened with the ethylene diamine

complex of lithium acetylide⁴²#Scheme 2), and the resulting

terminal alkyne was isomerized with KOt-Bu, affording the

thermodynamically favored internal alkyne 6 as the sole

product. Single pot conversions of epoxide 5 to propargyl

alcohol 6 with these reagents, similar to reactions reported

by Takano and co-workers,⁴²proceeded with signi®cantly

retarded rates and poor yields #50±60%). Reduction of 6

with LAH in THF afforded the E-allylic alcohol 7 as a

single geometrical isomer.⁴³Johnson ortho ester Claisen

rearrangement of allylic alcohol 7 proceeded smoothly in

re¯uxing triethylorthoacetate to provide ester 4 via the

bracketted chair transition structure shown.^44,45Claisen

self-condensation #Scheme 3) of ester 4 was effected by

the slow addition of LHMDS #2.5 equiv.) and TMEDA

#5.0 equiv.) to a solution of the ester in THF over 4.5 h at

Scheme 3. #e) LHMDS, TMEDA, THF, 08C 84%18% SM; #f) LiCl,

DMSO, H₂O, 1908C 96%; #g) AD-mix-a, 08C, t-BuOH/H₂O #1:1);

#h) CSA, #", MeOH/PhH #1:1) 85±92% two steps; #i) Pd#OH)₂on Carbon,

EtOH, H₂#g) 100%; and #j) TFA, MeOH, #" 98±100%.

08C, affording the b-ketoester 3a in good yield #8418%

SM). Decarboalkoxylation under Krapcho conditions^46,47

cleanly provided the C₂-symmetric ketone 3b as a viscous

oil #96%). SAD³⁶of 3b with 2.5 equiv. of AD-mix-a

furnished the C₂-symmetric tetraol as virtually a single

diastereomer, thus setting the C#40), C#41), C#47), and

C#48) stereocenters in a single step.

Partial spontaneous spiroketalization made determination of

the exact diastereoselectivity of the double SAD dif®cult.

Acid-catalyzed spiroketalization⁴⁸of the crude tetraol in

benzene/MeOH #1:1) yielded the thermodynamic ratio

#1.1:1.0) of the C₂-symmetric 1,7-dioxaspiro[5,5]undecane

8a, and the isomeric, unsymmetrical 1,6-dioxaspiro[4,5]-

decane 9. Ketal equilibration was slow in the absence of

methanol, and a kinetic ratio of products, favoring ®ve-

membered ring formation, could be isolated from reactions

run in straight benzene. All attempts to drive the formation

of 8a through selective crystallization from the equilibrating

conditions failed, as the reaction products oiled out as the

thermodynamic mixture. Isomers 8a and 9 were separable

by silica gel chromatography. Operationally however, the

mixture of ketals was carried forward to debenzylation via

hydrogenolysis and then the tetraols were equilibrated with

catalytic TFA in re¯uxing methanol to the more favorable

thermodynamic mixture of 10, plus 11 and 12 #5:2:1). After

chromatographic separation, ketals 11 and 12 were recycled

to 10 #62% after one recycle) by re-exposure to the

equilibrating conditions.

Scheme 2. #a) LiCCH´H₂NCH₂CH₂NH₂, DMSO, 158C!rt; #b) KOt-Bu,

DMSO, 158C 86% two steps; #c) LAH, THF, #" 96%; and #d) CH₃C#OEt)₃,

1408C, CH₃CH₂CO₂H #4 mol%) 92±96%.

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2013

vinyl ether 2b resulting from treatment of 2a with the

Tebbe^52a±c#Cp₂Ti-m-Cl-m-CH₂AlMe₂) or Petasis^52d

#Cp₂TiMe₂) reagents failed; facile isomerization to the

endocyclic enol ether occurred readily. Ultimately, a single

pot protocol was devised for the conversion of 2a #via 2b) to

alcohol 13, by reaction with 0.6±0.7 equiv. of the Tebbe

reagent followed by in situ hydroboration/oxidation of the

vinyl ether with 9-BBN/NaBO₃#aq). The unfavorable

statistical mixture of recovered starting material, mono-

functionalized, and di-functionalized products was avoided

by this partial conversion protocol, in that no signi®cant

amounts of bis#functionalized) products were isolated.

Alcohol 13 was isolated as a single stereoisomer, along

with recovered starting material 2a and a small amount of

the alkene 14. The fragmentation pathway leading to 14 was

greatly facilitated by excess 9-BBN, and apparently

involves Lewis acid activation and elimination of the

tetrahydrofuran ring oxygen in the trialkylborane to inter-

mediate. Similar decomposition pathways, facilitated by

Lewis acids, have been reported during the hydroboration

of vinyl ethers.^53±56Sodium perborate oxidation of the

borane intermediate afforded yields of alcohol 13 and

recovered 2a superior to those obtained with NaOH/H₂O₂

conditions, due to lactone saponi®cation problems under the

latter conditions.

Ê

Scheme 4. #k) TPAP, NMO, 4 A sieves, t-BuOH/CH₃CN, rt 75%; and

#l) Tebbe reagent, pyr, PhCH₃/THF, 2788C to rt; 9-BBN; NaBO₃´4H₂O,

H₂O 40% 13, 5% 14, 54% rec. 2a.

Selective oxidation of both primary alcohols in 10 was best

accomplished through the use of 5 mol% of tetrapropyl-

ammonium perruthenate#VII) #TPAP) with N-methyl-

morpholine-N-oxide #NMO) in t-BuOH and CH₃CN

#1:1).^49,50The C₂-symmetric bis#lactone) 2a #Scheme 4)

resulted, presumably via oxidation of the intermediate

®ve-membered hemiacetals. Con®rmation of the relative

and absolute stereochemistry of bis#lactone) 2a was secured

by X-ray crystal structure determination #Fig. 2), from

which a structural rationale for observed reactivity was

developed #vide infra).

Synthesis of the side-chain continued with the oxidation of

primary alcohol 13 with the Dess±Martin periodinane^57±59

to yield the corresponding aldehyde #Scheme 5). The crude

aldehyde was directly subjected to chelation-controlled

allylation⁶⁰with TiCl₄and allyltributylstannane^61±63to

afford the homoallylic alcohol 15a with excellent diastereo-

1

Symmetry breaking by reaction at one of the two identical

termini found in the C₂-symmetric bis#lactone) 2a was

required for introduction of the C#51)±C#54) side chain.

Such desymmetrization by mono-functionalization is

commonly a challenge, since communication between

such distal reaction centers is unlikely.⁵¹Carbonyl methyl-

enation with a reagent of easily controlled stoichiometry,

followed by an exo face-selective hydroboration, was seen

as an attractive possibility for installing a functionalized

C#51) and establishing the C#50) stereocenter in its natural

con®guration. However, all attempts to isolate the expected

control #.95% by H NMR) in good yield after 15 min at

2788C. Allyltrimethylsilane⁶¹failed to react with the

aldehyde under identical reaction conditions.

Facial selectivity in the SAD³⁶of homoallylic alcohol 15a

with #DHQD)₂AQN,⁶⁴#DHQD)₂PYR,^65,66or AD-mix-b

proved insuf®cient for the next step, yielding a 1:2 ratio of

17a #desired) to 17b. An identical ratio #1:2) favoring the

undesired C#53S) diastereomer was obtained when an

achiral amine ligand, pyridine, was employed. It was

apparent that the inherent facial selectivity of the ole®n in

Figure 2. X-Ray crystal structure of bis#lactone) 2a.

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B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

Scheme 5. #m) Dess±Martin, CH₂Cl₂, rt; #n) TiCl₄, #Allyl)SnBu₃, CH₂Cl₂, 2788C 77±96% #two steps); #o) #BOC)₂O, DMAP, pyr, CH₂Cl₂, rt 91±98%; #p) IBr,

PhCh₃, 2808C 96±99%; #q) 0.5 M LiOH#aq), DME, 60±708C; #r) CSA, PhH, D 80±94% #two steps); #s) TBDPSCI, DMAP, CH₂Cl₂, pyr, rt 90%; and

#t) TIPSOTf, pyr, DMAP, rt 99%.

15a was overpowering the directing affect of the Cinchona

alkaloid ligands in this case. Triisopropylsilyl #TIPS)

protection of the C#51) homoallylic alcohol, followed by

dihydroxylation with #DHQD)₂AQN afforded a slightly

improved 1:1 ratio of diastereomers. The stereoisomers

17a,b were assigned by application of Rychnovsky's ¹³C-

NMR analysis of the derived acetonides 19a,b #Fig. 3).⁶⁷

The acetonide 19a, derived from the syn 1,3-diol 17a,

shows distinctive axial and equatorial methyl resonances

that re¯ect the chair conformation of the 1,3-dioxane ring.

Acetonide, 19b, in contrast, has less distinctive acetonide

methyls because of a twist-boat 1,3-dioxane conformation,

adopted to avoid a 1,3-diaxial methyl±methyl interaction.

corresponding triols, such as with AMB-26-CO₃,

^{22 70}failed

to provide the desired triol 17a. The conversion of iodo-

carbonate 16 to the triol 17a was best accomplished with

0.5 M aqueous LiOH in DME. After 13 h at 608C, the

reaction contents were neutralized, concentrated, and the

resulting solids were treated with CSA in re¯uxing benzene,

which reclosed the g-lactone ring and provided 17a in

Alternatively #Scheme 5), the C#53) stereocenter was

successfully established #.18:1) in two steps via conversion

of homoallylic alcohol 15a to the corresponding BOC car-

bonate 15b with excess #BOC)₂O and DMAP, followed by

treatment with iodine monobromide at 2808C to afford the

iodocarbonate 16 in excellent yield #96%).^68,69Reported

procedures for converting iodocarbonates directly to the

Scheme 6. #u) LiCH₂P#O)#OMe)₂, #.100 equiv.), THF, 2788C, 20±

24%1SM; and #v) LiCH₂P#O)#OMe)₂#5 equiv.), THF, 5 min, 2788C,

D₂O.

Figure 3.

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2015

Scheme 7. #w) Me#Cl)Al±N#OMe)Me, PhH, 708C, 95%; #x) Ac₂O, CH₂Cl₂, DMAP 100%; #y) 1.0 M LiOH#aq), tBuOH/THF, rt; #z) TMSCHN₂, MeOH/PhH

#2:7), rt, two steps 95±100%; #aa) MPMOC#NH)CCl₃, BF₃´OEt₂, Et₂O, 2788C, 88%; #bb) H₂#g), Pd#OH)₂, EtOH, 100%; #cc) Ac₂O, DMAP, CH₂Cl₂, 99%;

and #dd) LiCH₂P#O)#OMe)₂, THF, 2788C, 54%.

excellent yield. Insuf®cient reaction times for the hydrolysis

of iodocarbonate 16 resulted in the isolation of the inter-

mediate C#53)±C#54) epoxide. Traces of undesired triol

17b, arising presumably from S_N2 attack at the secondary

position of the epoxide, were removed by silica gel

chromatography. Triol 17a isolated from the hydrolysis of

16 proved to be identical to the minor product previously

isolated from the SAD of homoallylic alcohol 15a. With the

global protecting group scheme in mind for the ultimate

total synthesis of halichondrin B, the primary alcohol in

17a was selectively protected as TBDPS ether 18a, and

the two secondary alcohols were then protected with

TIPSOTf, providing the desired lactone 18b in high yield.

At ambient temperature, lactone 18b proved unreactive with

the aluminum amide generated from trimethylaluminum

and MeNH#OMe)´HCl and required elevated temperatures

#re¯uxing benzene) to afford the corresponding Weinreb's

amide.^74±76Unfortunately, the strenuous conditions required

to open the lactone and form the Weinreb's amide facilitated

the clean rearrangement of the [5,5]-spiroketal to the

undesired [4,5]-spiroketal 22 #Scheme 7).⁴⁸The free

hydroxyl in amide 22 was converted to the corresponding

acetate 23, resulting in a signi®cant down®eld shift of what

was determined to be the C#40) hydrogen resonance. The

observed splitting pattern #td) and coupling constants

#J5.7, 1.2 Hz) strongly supported the assignment of 22

as the undesired [4,5]-spiroketal.

Attempts at nucleophilic addition to the lactone carbonyl of

18b with #lithiomethyl)dimethyl phosphonate^71±73resulted

in disappointingly low yields of the desired b-ketophospho-

nate hemiacetal 20 #Scheme 6). Only in the presence of a

large excess #.100 equiv.) of the nucleophile could

appreciable yields of phosphonate 20 be isolated #20±

24%). The reason for this was revealed by treatment of

19a with several equivalents of the lithiated phosphonate

at 2788C, followed by a D₂O quench, which produced

stereoselectively deuterated lactone 21 in good yield with

100% deuterium incorporation. Since deprotonated 18b is,

as the enolate, protected against nucleophilic attack, the

basis for the low conversion to 20 was apparent, and all

attempts to moderate the basicity of the metalated phos-

phonate failed to increase the yield of 20. The conforma-

tional constraints of the cis-fused lactones in 18b and 19a

evidently align the convex a-C±H bond with the carbonyl

p-system, signi®cantly increasing the acidity relative to

unconstrained esters. Examination of the analogous C±H

bond in the crystal structure of bis#lactone) 2a #Fig. 2)

supports this conjecture. Based upon this conclusion,

b-ketophosphonate formation from an acyclic ester derived

from 18b was pursued.

Ultimately, g-lactone 18b was saponi®ed with LiOH in

aqueous THF. The resulting seco acid was isolated by care-

ful concentration at ambient temperature under reduced

pressure and esteri®ed with TMSCHN₂at rt.⁷⁷Methyl

ester 24 was stable to silica gel chromatography and

isolated in a near-quantitative, two-step yield. Attempts to

protect the free hydroxyl in 24 as the silyl ether using

tertiary amine bases with or Ag₂O/MPMCl re-established

lactone 18b as the exclusive product. However, treatment

of hydroxy ester 24 with an excess of the MPM±trichloro-

acetimidate and stoichiometric BF₃´OEt₂at 2788C in Et₂O

provided the MPM ether 25 in good yield #88%).^78±80

While it was unlikely that the [5,5]-spiroketal had

rearranged prior to MPM protection in the presence of

BF₃´OEt₂at 2788C, a small portion of the MPM

protected methyl ester 25 was deprotected by hydro-

genolysis with Pd#OH)₂/H₂and converted to the corre-

sponding acetate 26. The down®eld methine resonance of

acetate 26 appeared as a very broad singlet with coupling

constants of ,1 Hz. This closely matched the data collected

for the diacetate 8b #Scheme 3) of the [5,5]-spiroketal diol

8a #bt, J1.2 Hz), supporting the assignment of 25 as the

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B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

desired methyl ester with the correct [5,5]-spiroketal

assembly intact.

provided on individual ¹³C NMR spectra are drawn at a

scale of 200 Hz/cm. High resolution mass spectra

#HRMS) using electron impact #EI, 70 eV) were recorded

using peak matching. High and low resolution fast atom

bombardment #FAB) mass spectra were obtained on a VG

Analytical ZAB-2F #Ion Tech FAB gun, 8 kV, Xe carrier

gas).

Fully protected methyl ester 25 was exposed to several

equivalents of lithiomethyl dimethylphosphonate at

2788C, affording the desired b-ketophosphonate 1 #54%,

unoptimized) with complete consumption of the starting

material. Problems with deprotonation to the unreactive

enolate, as described above for 18b, did not occur with

ester 25.

All moisture sensitive reactions were performed in ¯ame-

dried glassware under a stream of nitrogen unless otherwise

noted. External bath temperatures were used to record all

reaction temperatures. Concentrated in vacuo refers to the

removal of volatile solvents via distillation using a rotary

evaporator at water aspirator pressure, followed by residual

solvent removal at high vacuum #approximately 5 mTorr).

The acid free glassware utilized in the formation of vinyl

ethers was obtained by immersing all items in a 0.5 M solu-

tion of HCl in EtOH for 1 h, rinsing with de-ionized water,

immersing the items in a 0.5 M solution of KOH in EtOH

for at least 1 h, rinsing again with de-ionized water, and

oven drying.

1. Summary

To recapitulate, a 22 step synthesis of b-ketophosphonate 1

from the known epoxide 5 in 4% overall yield #based on

recovered starting materials) has been completed. Employ-

ment and desymmetrization of C₂-symmetric intermediates

formed the basis of the synthetic strategy. Introduction of

four asymmetric centers in a single step via asymmetric

dihydroxylation, followed immediately by formation of

the C#44) spiroketal linkage was the central event in the

synthesis. b-Ketophosphonate 1, with 10 asymmetric

centers set and rings N, M, L, and incipient ring K

established, is a substantial subunit for coupling to a

C#36)-terminated halichondrin B segment via an anticipated

Horner±Wadsworth Emmons reaction.⁸¹Studies toward

this end are underway.

Analytical thin-layer chromatography #TLC) was carried

out on E. Merck #Darmstadt) TLC plates pre-coated with

silica gel 60 F₂₅₄#250 mm layer thickness). Visualization

was accomplished using UV light, iodine vapors, a p-anisal-

dehyde #PAA) charring solution #18 mL p-anisaldehyde,

7.5 mL glacial acetic acid, 25 mL 12.0 M H₂SO₄, 675 mL

absolute EtOH) and/or phosphomolybdic acid solution

#10% PMA in EtOH). Flash column chromatography

#FCC) was performed on EM Science silica gel 60 #230±

400 mesh). Solvent mixtures for TLC and FCC are reported

in either v₁/v₂ratios or V₁/V_total£100.

2. Experimental

2.1. General procedures

Immediately prior to use, tetrahydrofuran #THF), diethyl

ether #Et₂O), and benzene were distilled from sodium/

benzophenone ketyl; toluene #PhCH₃) was distilled from

sodium metal/anthracene; methanol #MeOH) was distilled

from magnesium methoxide; dichloromethane #CH₂Cl₂),

hexanes #petroleum ether), diisopropylamine #i-Pr₂NH),

and triethylamine #Et₃N) were distilled from calcium

hydride. Acetonitrile #CH₃CN), ethylene glycol dimethyl-

ether #DME), collidine, pyridine #pyr), 1,1,1,3,3,3-hexa-

Optical rotations were measured on a digital polarimeter at

room temperature #21±228C). Concentrations #c) are

reported in g/100 mL. Infrared spectra #IR) are reported in

wavenumbers #cm²¹) with the designations #br), #s), and #w)

referring to broad, strong, and weak signals, respectively.

Melting points #mp) are uncorrected. Proton nuclear

magnetic resonance #¹H NMR) spectra were recorded in

deuterated solvents #CDCl₃, C₆D₆, CD₃OD) at 250, 300,

or 500 MHz, as indicated. Chemical shifts are reported in

parts per million #ppm, d) relative to tetramethylsilane

#TMS, d 0.00). Proton NMR splitting patterns are desig-

nated as singlet #s), doublet #d), triplet #t), quartet #q),

quintet #quin), sextet #sex), septet #sep), multiplet #m),

apparent #ap), and broad #br) with the coupling constants

reported in hertz #Hz). Signal expansions provided on indi-

vidual spectra are drawn at a scale of 20 Hz/cm. Carbon

nuclear magnetic resonance #¹³C NMR) spectra were

recorded in deuterated solvents #CDCl₃, C₆D₆, CD₃OD) at

75.4 MHz or 125 MHz, as indicated. Chemical shifts are

reported in parts per million #ppm, d) relative to tetra-

methylsilane #TMS, d 0.00). Carbon resonances were

assigned using distortionless enhancement by polarization

transfer #DEPT) spectra obtained with a phase angle of

1358: #C) not observed; #CH) positive; #CH₂) negative;

#CH₃) positive. Due to magnetically and chemically equiva-

lent carbons, the number of carbon resonances reported may

not match the actual number of carbons in the molecule.

Coincidental magnetically equivalent carbons were noted

when relative signal intensity allowed. Signal expansions

methyldisilazane

#DMSO) were distilled at reduced pressure from calcium

#HMDS),

and

dimethylsulfoxide

Ê

hydride and stored over 4 A molecular sieves. t-Butanol

utilized in the TPAP oxidation was distilled from sodium

Ê

metal and stored over 4 A molecular sieves. Mesyl chloride

#MsCl), titanium tetrachloride #TiCl₄), triethyl orthoacetate,

boron tri¯uoride diethyl etherate #BF₃´OEt₂), and propionic

acid were distilled prior to use. 4-Dimethylaminopyridine

#DMAP) was recrystallized from toluene. Lithium acetylide

ethylenediamine complex was purchased from Aldrich and

used without further puri®cation. Tebbe's reagent was

prepared and recrystallized from toluene/hexanes in

Schlenk glassware in a slight modi®cation of Grubb's pro-

cedure.^52cThe hydroborating agent, 9-BBN, was purchased

as a 0.5 M solution in THF and was used immediately.

Disiamylborane #Sia₂BH) was prepared immediately prior

to use from 2 equiv. of 2-methyl-2-butene and one equivalent

of borane THF complex in THF at 2788C followed by stir-

ring for 1 h at 08C. The Dess±Martin reagent was prepared in

bulk via Ireland's modi®ed procedure,⁵⁷and recrystallized

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2017

from Ac₂O/TsOH as necessary. The trichloroacetimidate of

p-methoxybenzyl alcohol was prepared according to litera-

ture precedent and Kugelrohr distilled immediately prior to

use.⁷⁸All other commercially obtained reagents and solvents

were used as received without further puri®cation unless

otherwise indicated.

82.2 mmol) was suspended in 200 mL of THF under an

argon atmosphere, and the slurry was cooled to 08C. A

solution of propargyl alcohol 6 #7.90 g, 38.7 mmol) in

100 mL of THF was added dropwise via cannula. After

H₂#g) evolution had ceased, the ice bath was removed and

the reaction was heated to re¯ux. After 4 h at re¯ux, the

reaction was cooled to 08C and quenched by a slow, drop-

wise addition of saturated aqueous potassium sodium

tartrate while maintaining an argon atmosphere. After gas

and heat evolution ceased, the reaction was transferred to a

larger vessel and diluted with 800 mL of Et₂O and 1 L of

saturated aqueous potassium sodium tartrate. This slurry

was vortexed with a magnetic stir plate for 12 h, until a

clean, biphasic solution was obtained. The phases were

separated, and the aqueous layer was extracted with Et₂O.

The combined organic layers were dried over MgSO₄,

®ltered through a silica gel plug with additional Et₂O, and

concentrated in vacuo. Silica gel chromatography with 25%

Et₂O/hexanes yielded the isomerically pure #3S, 4E)-1-

benzyloxy-4-hexyn-3-ol #7) #7.57 g, 96%) as a colorless

oil. Data for 7: R_f0.35 #1:1 Et₂O/hexanes, PAA);

2.1.1. Preparation of ꢀ3R)-1-benzyloxy-5-hexyn-3-ol. In a

dry ¯ask, 1.5 equiv. of lithium acetylide ethylenediamine

complex #6.42 g, 69.7 mmol) were suspended in DMSO

#100 mL), and the heterogeneous mixture was chilled to a

semi-frozen slurry with an ice bath. A solution of epoxide

5^37±39#8.01 g, 44.9 mmol) was cannula transferred to the

reaction ¯ask with 40 mL of DMSO, and the reaction was

allowed to warm to rt. After 12 h, the reaction was diluted

with 200 mL of Et₂O, cooled to 08C, quenched with 20 mL

of water, and then acidi®ed to pH 3 with 5% HCl#aq). The

layers were separated, and the aqueous phase was extracted

with Et₂O. The combined organic extracts were dried over

Na₂SO₄, ®ltered through a short plug of silica gel, and

concentrated in vacuo. The crude terminal alkyne was

used in the subsequent reaction without further puri®cation.

Data for #3R)-1-benzyloxy-5-hexyn-3-ol: R_f0.20 #50% Et₂O

in hexanes, PAA); ¹H NMR #CDCl₃, 300 MHz) d 7.25±7.40

#m, 5H), 4.52 #s, 2H), 3.94±4.04 #m, 1H), 3.60±3.78 #m,

2H), 3.13 #d, 1H, J3.8 Hz), 2.40 #m, 2H), 2.03 #t, 1H,

J2.8 Hz), 1.77±1.97 #m, 2H).

22

[a]_D1.15 #c6.0, benzene); IR #thin ®lm) 3413, 3028,

2916, 2858, 1452, 1099 cm²¹; ¹H NMR #CDCl₃, 300 MHz)

d 7.25±7.40 #m, 5H), 5.68 #dqd, 1H, J15.3, 6.4, 1.1 Hz),

5.49 #ddq, 1H, J15.3, 6.4, 1.3 Hz), 4.51 #s, 2H), 4.23±4.31

#m, 1H), 3.69 #ddd, 1H, J9.4, 5.8, 5.1 Hz), 3.61 #ddd, 1H,

J9.4, 6.8, 5.5 Hz), 2.66 #d, 1H, J3.1 Hz), 1.75±1.90 #m,

2H), 1.69 #ddd, 3H, J6.4, 1.4, 0.9 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 138.0 #C), 133.6 #CH), 128.4 #CH), 127.7

#CH), 127.7 #CH), 126.4 #CH), 73.3 #CH₂), 71.7 #CH),

68.4 #CH₂), 36.7 #CH₂), 17.6 #CH₃); HRMS #EI) m/e

#relative intensity, assignment) 206 #0.6, M¹), 188 #4,

M¹2H₂O), 115 #61, M¹2CH₂Ph), 107 #100, PhCH₂O¹);

exact mass calcd for C₁₃H₁₈O₂requires 206.1307, found

206.1308.

2.1.2. Preparation of ꢀ3S)-1-benzyloxy-4-hexyn-3-ol ꢀ6).

The crude terminal alkyne from above was dissolved in dry

DMSO #150 mL) under a nitrogen atmosphere. The reaction

mixture was cooled to 158C and solid potassium t-butoxide

#21 g, 187 mmol) added. After stirring for 40 min, the

resulting dark brown solution was diluted with 200 mL of

Et₂O and cooled to 08C. The reaction was carefully

quenched by the dropwise addition of 3 M aqueous HCl.

The layers were transferred to a separatory funnel, rinsing

with Et₂O, and separated, and the aqueous layer was

extracted with Et₂O. The combined organic extracts were

washed with a 1:1 mixture of saturated NaHCO₃#aq) and

brine, dried over Na₂SO₄, ®ltered through a plug of silica

gel, and concentrated in vacuo. Silica gel chromatography

with a 25±50% Et₂O/hexanes gradient elution yielded the

internal alkyne 6 #7.91 g, 86% two-step yield) as a pale

yellow oil. Data for 6: R_f0.45 #1:1 Et₂O/hexanes, PAA);

2.1.4. Preparation of ꢀ3S,4E)-3-methyl-7-benzyloxy-4-

heptenoic acid ethyl ester ꢀ4). A solution of allylic alcohol

7 #11.1 g, 54.0 mmol) in 210 mL of triethyl orthoacetate

with catalytic propionic acid #0.15 mL, 2.0 mmol) was

heated at 1458C for 26 h. After cooling to rt, the contents

were diluted with 400 mL of EtOAc. The solution was

cooled with an ice bath, and the excess triethyl orthoacetate

quenched by the addition of 50 mL of 5% HCl#aq). After

10 min, the contents were transferred to a separatory funnel

and the layers were separated. The aqueous phase was

extracted with EtOAc, and the combined organics were

washed with 1:1 saturated NaHCO₃#aq)/brine. The resulting

solution was dried over MgSO₄, ®ltered through a small

plug of silica gel with additional EtOAc and concentrated

in vacuo. Silica gel chromatography with a gradient elution

of 10±25% Et₂O/hexanes yielded the pure ethyl ester 4

#13.7 g, 92%) as a pale yellow oil. Data for 4: R_f0.42 #1:3

22

[a]_D220.5 #c2.0, benzene); IR #thin ®lm) 3402 #br),

1

3030, 2920, 2856, 2243 #w), 1101, 1076 cm²¹; H NMR

#CDCl₃, 300 MHz) d 7.25±7.40 #m, 5H), 4.60 #tdq, 1H,

J6.1, 4.6, 2.2 Hz), 4.53 #s, 2H), 3.83 #ddd, 1H, J9.5,

7.2, 4.4 Hz), 3.66 #ddd, 1H, J9.5, 6.3, 4.8 Hz), 3.04 #d,

1H, J6.1 Hz), 2.04 #ddt, 1H, J14.3, 7.5, 4.6 Hz), 1.92

#dtd, 1H, J14.3, 6.2, 4.4 Hz), 1.82 #d, 3H, J2.2 Hz);

¹³C NMR #CDCl₃, 75.4 MHz) d 137.8 #C), 128.4 #CH),

127.5 #CH), 127.5 #CH), 81.0 #C), 79.7 #C), 73.2 #CH₂),

67.7 #CH₂), 61.5 #CH), 37.0 #CH₂), 3.5 #CH₃); HRMS #EI)

m/e #relative intensity, assignment) 204 #6, M¹), 203 #15,

M¹2H), 186 #48, M¹2H₂O), 159 #34, M¹2H₂O2C₂H₃),

147 #54, M¹2H₂O2C₃H₃), 107 #67, PhCH₂O¹), 91 #100,

PhCH₂¹); exact mass calcd for C₁₃H₁₆O₂requires 204.1150,

found 204.1145.

22

Et₂O/hexanes, PAA); [a]_D11.6 #c4.3, benzene); IR

1

#thin ®lm) 2850, 2769, 1734, 1172, 1101 cm²¹; H NMR

#C₆D₆, 300 MHz) d 7.05±7.35 #m, 5H), 5.29±5.51 #m, 2H),

4.31 #s, 2H), 3.95 #q, 2H J7.2 Hz), 3.30 #t, 2H, J7.2 Hz),

2.70 #hept, 1H, J6.7 Hz), 2.21±2.28 #m, 2H), 2.22 #dd, 1H,

J14.7, 7.2 Hz), 2.10 #dd, 1H, J14.7, 7.4 Hz), 0.95 #t, 3H,

J7.2 Hz), 0.95 #d, 3H, J6.8 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 172.5 #C), 138.5 #C), 136.1 #CH), 128.3

#CH), 128.3 #CH), 127.6 #CH), 127.5 #CH), 125.5 #CH),

72.8 #CH₂), 70.1 #CH₂), 60.1 #CH₂), 41.8 #CH₂), 33.6

2.1.3. Preparation of ꢀ3S,4E)-1-benzyloxy-4-hexen-3-ol

ꢀ7). Dry 95% lithium aluminum hydride #3.12 g,

2018

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

#CH), 32.9 #CH₂), 20.2 #CH₃), 14.2 #CH₃); MS #EI) m/e

#relative intensity, assignment) 276 #0.8, M¹), 258 #1,

M¹2H₂O), 230 #44, M¹2CH₃CH₂OH), 189 #40,

M¹2CH₂CO₂Et), 155 #44, M¹2CH₂OBn), 91 #100,

PhCH₂¹); exact mass calcd for C₁₇H₂₄O₃requires

276.1725, found 276.1729.

cooled to rt and transferred to a separatory funnel containing

50 mL of half-saturated brine with 100 mL of EtOAc. The

layers were separated, and the aqueous phase was extracted

with EtOAc. The combined organic layers were dried over

MgSO₄and ®ltered through a silica gel plug with Et₂O. The

C₂-symmetric ketone 3b #10.2 g, 96%) was isolated after

concentration in vacuo and silica gel chromatography with

3% EtOAc/benzene. Data for 3b: R_f0.31 #1:3 Et₂O/hexanes,

2.1.5. Preparation of ꢀ5S,6E)-5-methyl-2-[ꢀ1R,2E)-1-

methyl-5-ꢀbenzyloxy)-2-pentenyl]-3-oxo-9-ꢀbenzyloxy)-

6-nonenoic acid ethyl ester ꢀ3a). Ethyl ester 4 #3.82 g,

13.8 mmol) was dissolved in 10 mL of THF and cooled to

08C. In a separate, ¯ame-dried round bottom ¯ask, HMDS

#7.3 mL, 34.6 mmol) and TMEDA #10.4 mL, 79.2 mmol)

were combined in 10 mL of dry THF and cooled to 08C.

n-Butyl lithium #2.68 M in hexane, 12.9 mL, 34.6 mmol)

was added dropwise over 10 min, and the LHMDS solution

was stirred for an additional 30 min. The freshly generated

LHMDS/TMEDA solution was added dropwise to the solu-

tion of the ethyl ester over 4.5 h. #Shorter addition times led

to lower yields of the b-ketoester with greater amounts of

recovered starting material. Longer reaction times led to

more side product formation.) The reaction was diluted

with 300 mL of Et₂O and quenched by the addition of

400 mL of 5% HCl#aq) immediately following the

LHMDS addition. The layers were separated, and the

aqueous phase was extracted with Et₂O. The organic layers

were washed with 1:1 saturated NaHCO₃#aq)/brine, and

combined. The combined organics were dried over

MgSO₄, ®ltered through a small plug of silica gel with

additional Et₂O, and concentrated in vacuo. Silica gel

chromatography with 25% Et₂O/hexanes yielded the ethyl

b-ketoester 3a #2.95 g, 84%) as a mixture of diastereomers

in the form of a colorless oil plus a small amount of

recovered starting material #0.60 g, 8%). Data for 3a: R_f

22

PAA); [a]_D38.5 #c1.02, benzene); IR #thin ®lm) 3028,

2958, 2925, 2848, 1709, 1097 cm²^{1 1}H NMR #C₆D₆,

;

300 MHz) d 7.05±7.35 #m, 10H), 5.31±5.49 #m, 4H),

4.35 #s, 4H), 3.33 #t, 4H J6.6 Hz), 2.75 #hept, 2H, J

6.8 Hz), 2.28 #ap q, 4H), 2.06 #A of ABX, 2H, J_AB

16.0 Hz, J_AX6.5 Hz), 2.03 #B of ABX, 2H, J_AB16.0 Hz,

J_BX7.3 Hz), 0.94 #d, 6H, J6.8 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 209.3, #C), 138.5 #C), 128.3 #CH), 127.6

#CH), 127.5 #CH), 125.1 #CH), 72.8 #CH₂), 70.0 #CH₂),

50.5 #CH₂), 33.0 #CH₂), 32.4 #CH), 20.3 #CH₃); MS

#FAB) m/e #relative intensity, assignment) 435 #48,

M1H¹), 343 #31, M¹2C₇H₇), 221 #56, M1H¹22£

#C₇H₇O)), 147 #100, BnOC₃H₄¹); exact mass calcd for

C₂₉H₃₈O₃1H¹requires 435.290, found 435.2.

2.1.7. Preparation of ꢀ3S,4S,5S,9S,10S,11S)-1,13-bis-

ꢀbenzyloxy)-5,9-dimethyl-3,4,10,11-tetrahydroxytri-

decane-7-one. AD-mix-a #74 g, 2.3 equiv.) was dissolved

in 400 mL of water and 360 mL of t-butyl alcohol at rt. The

homogeneous solution was cooled to 08C with an ice bath,

initiating the precipitation of iron salts and the development

of distinct organic and aqueous phases. The C₂-symmetric

ketone 3b #10.1 g, 23.2 mmol) in 40 mL of t-butyl alcohol

was added dropwise over 10 min. The reaction was vortexed

with a magnetic stir bar at 08C for 24 h. #Reaction rates were

appreciably slower at higher concentrations.) The reaction

was diluted with 50 mL of water and excess oxidizing agent

was then quenched by the addition of solid Na₂S₂O₃#80 g,

500 mmol). After 10 min, the reaction was warmed to rt and

stirred for an additional 30 min. The reaction contents were

transferred to a separatory funnel with 300 mL of EtOAc

and 100 mL of water. The phases were separated and the

aqueous portion was further extracted with EtOAc. The

combined organics were dried over MgSO₄, ®ltered, and

concentrated in vacuo. The crude keto tetraol, prone to

spontaneous spiroketalization, was used in the subsequent

reaction without further puri®cation. Data for tetraol: R_f

0.20 #1:19 MeOH/CH₂Cl₂, PAA).

22

0.42 #1:3 Et₂O/hexanes, PAA); [a]_D19.9 #c4.39,

benzene); IR #thin ®lm) 3026, 2956, 1741, 1714, 1454,

1

1101 cm²¹; H NMR #CDCl₃, 300 MHz) d 7.24±7.40 #m,

20H), 5.28±58 #m, 8H), 4.50 #s, 4H), 4.49 #s, 2H), 4.48 #s,

2H), 4.15 #q, 2H, J7.2 Hz), 4.08 #q, 2H, J7.0 Hz), 3.40±

3.50 #m, 8H), 3.33 #d, 1H, J6.8 Hz), 3.28 #d, 1H,

J6.8 Hz), 2.85±3.05 #m, 2H), 2.60±2.77 #m, 2H), 2.22±

2.55 #m, 12H), 1.24 #t, 3H, J7.2 Hz), 1.19 #t, 3H, J

7.0 Hz), 1.02 #d, 3H, J6.6 Hz), 0.96 #d, 3H, J6.6 Hz),

0.95 #d, 3H, J6.6 Hz), 0.91 #d, 3H, J6.6 Hz); ¹³C NMR

#CDCl₃, 75.4 MHz) d 203.3 #C), 203.2 #C), 168.4 #C), 168.3

#C), 138.5 #C), 138.4 #C), 136.4 #CH), 136.2 #CH), 133.5

#CH), 133.4 #CH), 128.3 #CH), 127.8 #CH), 127.6 #CH),

127.5 #CH), 125.4 #CH), 125.0 #CH), 72.8 #CH₂), 70.0

#CH₂), 69.8 #CH₂), 66.0 #CH), 65.6 #CH), 61.1 #CH₂),

61.0 #CH₂), 49.9 #CH₂), 49.7 #CH₂), 37.0 #CH), 36.8

#CH), 32.9 #CH₂), 31.9 #CH), 31.5 #CH), 20.0 #CH₃), 19.9

#CH₃), 18.6 #CH₃), 14.1 #CH₃); MS #FAB) m/e #relative

intensity, assignment) 507 #50, M1H¹), 461 #26,

M¹2OCH₃), 189 #60, BnO#CH₂)₂#CH)₃CH₃¹); exact mass

calcd for C₃₂H₄₂O₅1H¹requires 507.300, found 507.3.

2.1.8. Preparation of ꢀ2S,3S,4S,8S,9S,10S)-2,8-diꢀ2-

benzyloxyethyl)-3,9-dihydroxy-4,10-dimethyl-1,7-dioxa-

spiro[5,5]undecane ꢀ8a). The crude tetraol from above was

dissolved in 300 mL of benzene/methanol #2:1) in a round

bottom ¯ask equipped with a Dean/Stark trap. Catalytic

CSA #158 mg, 0.68 mmol) was added to the reaction vessel,

and the reaction was heated to re¯ux. The reaction volume

was then reduced by two-thirds via the Dean/Stark trap.

After cooling to rt, the resulting solution was transferred

to a separatory funnel with EtOAc and washed with

saturated NaHCO₃#aq)/brine #1:1). The aqueous layer was

extracted with EtOAc, and the combined organic layers

were dried over MgSO₄, ®ltered, and concentrated in

vacuo. Silica gel chromatography with gradient elution

#10±30% EtOAc/CH₂Cl₂) yielded a 1.1:1 mixture #9.84 g,

88%) of the desired spiroketal 8a and the unsymmetrical

2.1.6. Preparation of ꢀ3E,5S,9S,10E)-5,9-dimethyl-1,13-

bisꢀbenzyloxy)-3,10-tridecadien-7-one ꢀ3b). b-Ketoester

3a #12.4 g, 24.5 mmol) was dissolved in 100 mL of

DMSO containing water #1.4 mL, 77.8 mmol) and lithium

chloride #3.9 g, 92.0 mmol). The reaction vessel was ®tted

with a re¯ux condenser, thoroughly ¯ushed with nitrogen,

and heated to 1908C. After 40 min the reaction mixture was

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2019

spiroketal 9. Trace amounts of the 1,5-dioxaspiro[4,4]-

nonane were also observed. Data for symmetrical spiroketal

NMR #CDCl₃, 75.4 MHz) d 171.0 #C), 138.3 #C), 128.3

#CH), 127.9 #CH), 127.6 #CH), 96.6 #C), 73.1 #CH₂), 71.9

#CH), 68.0 #CH), 66.7 #CH₂), 37.5 #CH₂), 31.7 #CH₂), 28.7

#CH), 20.8 #CH₃), 17.0 #CH₃).

22

8a: R_f0.65 #1:1 EtOAc/CH₂Cl₂, PAA); [a]_D259.7

#c1.52, benzene); mp 108±1098C; IR #thin ®lm) 3427

#br), 3032, 2954, 1454, 1205, 1103, 987, 743, 698 cm²¹

;

¹H NMR #C₆D₆, 300 MHz) d 7.05±7.30 #m, 10H), 4.25 #s,

4H), 3.81 #ddd, 2H, J8.8, 4.9, 0.9 Hz), 3.49 #ap dd, 4H,

J6.4, 5.5 Hz), 3.17 #br d, 2H, J5.6 Hz), 1.96±2.15 #m,

4H), 1.79±1.92 #m, 2H), 1.75 #br d, 2H J6.5 Hz), 1.28±

1.42 #ap d, 4H), 0.99 #D, 6H, J5.0 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 138.1 #C), 128.2 #CH), 127.6 #CH), 127.5

#CH), 96.5 #C), 72.9 #CH₂), 70.3 #CH), 69.4 #CH), 66.7

#CH₂), 36.9 #CH₂), 31.6 #CH₂), 30.0 #CH), 17.4 #CH₃);

MS #FAB) m/e #relative intensity, assignment) 485 #100,

M1H¹); exact mass calcd for C₂₉H₄₀O₆1H¹requires

485.286, found 485.3. Data for spiroketal 9: R_f0.68 #1:1

EtOAc/CH₂Cl₂, PAA); IR #thin ®lm) 3450 #br), 3030,

2.1.10. Preparation of ꢀ2S,3S,4S,8S,9S,10S)-3,9-di-

hydroxy-2,8-diꢀ2-hydroxyethyl)-4,10-dimethyl-1,7-dioxa-

spiro[5,5]undecane ꢀ10). The thermodynamic mixture of

spiroketals 8a and 9 #8.5 g, 17.5 mmol) was dissolved in

200 mL of absolute ethanol. Catalytic palladium#II)

hydroxide #20 w/w% on carbon, 369 mg, 0.529 mmol)

was suspended in the ethanol solution, and the system was

placed under 1 atm of hydrogen. The reaction was vortexed

with rapid stirring at rt for 12 h, with periodic regeneration

of the hydrogen atmosphere. The resulting mixture was

diluted with 400 mL of CH₂Cl₂and ®ltered through a plug

of silica gel. The plug was ¯ushed with 10% MeOH/CH₂Cl₂,

and the solution was concentrated in vacuo. Residual

hydroxylic solvents were removed azeotropically with

benzene, and the residue was placed under vacuum over-

night to afford a 5:2:1 mixture of tetraol spiroketals 10±12

#5.33 g, 100%). Silica gel chromatography with 3% MeOH/

EtOAc cleanly separated 1,7-dioxaspiro[5,5]undecane ketal

10 from the undesired spiroketals 11 and 12. Data for 1,7-

dioxyspiro[5,5]undecane 10: R_f0.23 #1:9 MeOH/EtOAc,

1

2954, 2925, 1454, 1097, 981 cm²¹; H NMR #CDCl₃,

300 MHz) d 7.20±7.35 #m, 10H), 4.47 #AB_q, 2H,

J_AB11.9 Hz, Dn_AB19.8 Hz), 4.04 #br t, 1H, J6.2 Hz),

3.58±3.68 #m, 2H), 3.45±3.55 #m, 4H), 3.33 #br d, 1H,

J5.3 Hz), 2.61 #d, 1H, J8.3 Hz), 2.49±2.62 #m, 1H),

2.17 #dd, 1H, J12.5, 7.0 Hz), 1.98±2.11 #m, 1H), 1.40±

1.95 #m, 8H), 1.02 #d, 3H, J6.6 Hz), 0.97 #d, 3H,

J6.8 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 138.5 #C),

138.1 #C), 128.3 #CH), 127.7 #CH), 127.6 #CH), 127.5

#CH), 105.7 #C), 90.7 #CH), 73.2 #CH₂), 72.7 #CH₂), 70.3

#CH), 69.9 #CH), 68.7 #CH), 67.3 #CH₂), 65.9 #CH₂), 47.2

#CH₂), 36.2 #CH₂), 35.0 #CH₂), 32.5 #CH), 31.8 #CH₂), 31.5

#CH), 17.7 #CH₃), 17.3 #CH₃); MS #FAB) m/e #relative

intensity, assignment) 485 #100, M1H¹); exact mass

calcd for C₂₉H₄₀O₆1H¹requires 485.286, found 485.2.

Data for the 1,5-dioxaspiro[4,4]nonane: R_f0.68 #1:1

EtOAc/CH₂Cl₂, PAA); IR #thin ®lm) 3450 #br), 3030,

22

PAA); [a]_D2110 #c0.200, MeOH); mp 123±1248C;

IR #thin ®lm) 3363 #br), 2922, 2872 cm²^{1 1}H NMR

;

#CD₃OD, 300 MHz) d 3.72 #dd, 2H, J10.1, 2.9 Hz),

3.65±3.70 #m, 4H), 3.20 #br d, 2H, J1.5 Hz), 1.96±2.04

#m, 2H), 1.80 #ddt, 2H, J14.5, 10.1, 5.0 Hz), 1.55 #dddd,

2H, J14.5, 7.8, 6.6, 3.3 Hz), 1.35 #AB of ABX, 4H), 0.85

#d, 6H, J6.8 Hz); ¹³C NMR #CD₃OD, 75.4 MHz) d 97.9

#C), 71.7 #CH), 70.2 #CH), 59.8 #CH₂), 38.0 #CH₂), 35.9

#CH₂), 31.6 #CH), 18.1 #CH₃); MS #FAB) m/e #relative

intensity, assignment) 305 #100, M1H¹), 289 #65,

M1H¹2H₂O); exact mass calcd for C₁₅H₂₈O₆1H¹

requires 305.1523, found 305.1. Data for spiroketal 11: R_f

0.19 #1:9 MeOH/EtOAc, PAA); ¹H NMR #CD₃OD,

300 MHz) d 3.98 #ddd, 1H, J9.8, 3.6, 0.2 Hz), 3.44±65

#m, 6H), 3.35 #dd, 1H, J8.6, 4.6 Hz), 3.15±3.22 #m, 2H),

2.29±2.46 #m, 1H), 1.90±2.12 #m, 2H), 1.44±1.78 #m, 6H),

1.13±1.42 #m, 3H), 0.94 #d, 3H, J6.6 Hz), 0.85 #d, 3H,

J6.6 Hz); ¹³C NMR #CD₃OD, 75.4 MHz) d 106.7 #C),

94.6 #CH), 71.4 #CH), 70.4 #CH), 70.1 #CH), 60.0 #CH₂),

59.1 #CH₂), 48.4 #CH₂), 37.6 #CH₂), 37.2 #CH₂), 35.6 #CH₂),

33.9 #CH), 32.9 #CH), 18.2 #CH₃), 17.6 #CH₃). Data for

1

2954, 2925, 1454, 1097, 981 cm²¹; H NMR #CDCl₃,

300 MHz) d 7.20±7.35 #m, 10H), 4.48 #AB_q, 4H,

J_AB12.0 Hz, Dn_AB22.7 Hz), 3.57±3.75 #m, 6H), 3.45

#dd, 2H, J8.4, 2.8 Hz), 3.32 #br s, 1.5 H), 2.46±2.63 #m,

2H), 2.12 #dd, 2H, J12.3, 6.8 Hz), 1.67±1.92 #m, 4H), 1.66

#dd, 2H, J12.3, 12.1 Hz), 1.03 #d, 6H, J6.6 Hz); ¹³C

NMR #CDCl₃, 75.4 MHz) d 138.4 #C), 128.4 #CH), 127.6

#CH), 127.5 #CH), 113.7 #C), 89.4 #CH), 73.1 #CH₂), 68.8

#CH), 68.0 #CH₂), 44.0 #CH₂), 35.0 #CH₂), 33.5 #CH), 17.5

#CH₃).

2.1.9. Preparation of ꢀ2S,3S,4S,8S,9S,10S)-2,8-diꢀ2-

benzyloxyethyl)-3,9-diacetoxy-4,10-dimethyl-1,7-dioxa-

spiro[5,5]undecane ꢀ8b). The spiroketal 8a #10.1 mg,

0.021 mmol) was combined with Ac₂O #0.2 mL) in

2.0 mL of pyridine at rt. After 14 h, the products were

diluted with 30 mL of Et₂O and washed ®rst with a saturated

CuSO₄#aq) and then brine. The organic layer was dried over

MgSO₄, ®ltered through a short silica gel plug with addi-

tional Et₂O and concentrated in vacuo. Silica gel chromato-

graphy using a 25±50% Et₂O/hexanes gradient elution

provided the diacetate as a white solid #9.1 mg, 77%).

Data for 8b: R_f0.9 #1:9 MeOH/CH₂Cl₂, PAA); mp 96±

1

spiroketal 12: R_f0.16 #1:9 MeOH/EtOAc, PAA); H NMR

#CD₃OD, 300 MHz) d 4.57 #br s, 4H), 3.52±3.63 #m, 6H),

3.30 #dd, 2H, J8.4, 2.7 Hz), 2.32±2.51 #m, 2H), 2.02 #dd,

2H, J12.3, 6.7 Hz), 1.50±1.73 #m, 6H), 0.96 #d, 6H,

J6.6 Hz); ¹³C NMR #CD₃OD, 75.4 MHz) d 114.8 #C),

90.6 #CH), 68.7 #CH), 60.1 #CH₂), 45.1 #CH₂), 38.6

#CH₂), 34.8 #CH), 17.6 #CH₃).

2.1.11. Equilibration to ꢀ2S,3S,4S,8S,9S,10S)-3,9-di-

hydroxy-2,8-diꢀ2-hydroxyethyl)-4,10-dimethyl-1,7-dioxa-

spiro[5,5]undecane ꢀ10). The undesired spiroketal 11

#2.1 g, 6.9 mmol) was dissolved with 50 mL of MeOH in

a round bottom ¯ask equipped with a re¯ux condenser.

Catalytic tri¯ic acid #0.06 mL, 0.78 mmol) was added, and

the system was heated to re¯ux for 50 min. After cooling,

the contents were diluted with 100 mL of benzene and

concentrated in vacuo. The resulting mixture of ketals

1

978C; H NMR #CDCl₃, 300 MHz) d 7.21±7.36 #m, 10H),

4.83 #br t, 2H, J1.3 Hz), 4.35 #s, 4H), 3.78 #ddd, 2H,

J9.2, 4.2, 0.9 Hz), 3.48 #t, 4H, J6.9 Hz), 2.12±2.28 #m,

2H), 2.10 #s, 6H), 1.60±1.78 #m, 4H), 1.52 #A of ABX, 2H,

J_AB13.4 Hz, J_AX4.3 Hz), 1.43 #B of ABX, 2H,

J_AB13.4 Hz, J_BX10.5 Hz), 1.61 #d, 6H, J7.0 Hz); ¹³C

2020

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

#2.06 g, 98%) was further azeotroped with two 100 mL

portions of benzene, and then subjected to silica gel FCC

with 3% MeOH/EtOAc. Any mixed fractions favoring the

desired 1,7-dioxaspiro-[5,5]-undecane ketal 10 were

recrystallized from EtOAc. All spectroscopic data for the

recrystallized product 10 were consistent with those above.

for 30 min. The reaction was quenched with 2 mL of

water, diluted with 10 mL of THF, and oxidized by adding

excess sodium perborate tetrahydrate #75 mg, 0.69 mmol)

and stirring for 2 h. The reaction contents were poured

onto 10 mL of saturated NaHSO₃#aq), and after 15 min,

30 mL of saturated Rochelle's salt#aq) was added. After

10 additional min, the biphasic system was transferred to

a separatory funnel containing 10 mL of 1.25 M NaOH#aq).

The layers were separated, and the aqueous phase was

extracted with EtOAc. The combined organic layers were

washed with brine, dried over MgSO₄, ®ltered, and concen-

trated in vacuo. The resulting mixture of recovered starting

material 2a, mono-functionalized alcohol 13, and side

products was loaded onto a silica gel column with

CH₂Cl₂/hexanes #1:1). One column volume of hexanes

followed by 10 column volumes of Et₂O were used to

elute higher R_fside products. Recovered starting material

2a and the desired primary alcohol 13 were then co-eluted

with 1:1 Et₂O/CH₂Cl₂. The starting material 2a #37 mg,

54%) and primary alcohol 13 #29 mg, 40%) were then sepa-

rated by FCC using a 10±25% Et₂O/CH₂Cl₂gradient. Data

for primary alcohol 13: R_f0.2 #2% MeOH/Et₂O, PAA); IR

2.1.12. Preparation of ꢀ2S,3S,4S,8S,9S,10S)-2,8-bisꢀ2-

ethanoic acid-g-lactone)-3,9-dihydroxy-4,10-dimethyl-

1,7-dioxaspiro[5,5]undecane ꢀ2a). The C₂-symmetric 1,7-

dioxaspiro[5,5]undecane 10 #1.85 g, 6.08 mmol) was

Ê

combined with powdered 4 A molecular sieves and NMO

#4.5 g, 38.4 mmol) in 100 mL of t-butyl alcohol/acetonitrile

#1:1). After the heterogeneous solution was stirred at rt for

20 min, TPAP #107 mg, 5 mol%) was added, and the reac-

tion was stirred for 60 min. An additional 5 mol% of TPAP

was added, and the reaction stirred for 12 h, after which the

starting tetraol was no longer present. The solution was

diluted with 30 mL of CH₂Cl₂, and 1 mol% portions of

TPAP were added every 20 min until partially oxidized

intermediates were no longer observed by TLC. The reac-

tion was diluted again with CH₂Cl₂#500 mL) and ®ltered

1

through a plug of silica gel, removing the 4 A molecular

#thin ®lm) 3462 #br), 2928, 2828, 1780, 1117 cm²¹; H

Ê

sieves, TPAP, and excess NMO. The silica gel plug was

rinsed with 25% Et₂O/CH₂Cl₂, and the pale yellow solution

was concentrated in vacuo. Complete removal of the oxidiz-

ing agents prior to concentration was necessary for optimum

yields. The resulting bis#lactone) was immediately puri®ed

by silica gel chromatography #1:9 Et₂O/CH₂Cl₂). Any

mixed fractions were further puri®ed by dissolving the

impure bis#lactone) 2a in a minimal amount of hot benzene,

adding an equivalent volume of hot hexanes, and allowing

overnight crystal growth at room temperature. Careful and

rapid puri®cation resulted in reproducibly high yields of the

C₂-symmetric bis#lactone) 2a #1.35 g, 75%) as a white crys-

talline solid. Data for 2a: R_f0.55 #1:3 Et₂O/CH₂Cl_2,PAA);

NMR #C₆D₆, 300 MHz) d 3.87±3.95 #m, 1H), 3.76 #ddd,

1H, J11.2, 3.7, 3.3 Hz), 3.48 #dt, 1H, J11.2, 4.6 Hz),

3.40±3.42 #m, 1H), 3.38 #dd, 1H, J4.1, 2.4 Hz), 3.34

#dd, 1H, J3.2, 2.4 Hz), 3.16 #br t, 1H, J2.4 Hz), 2.24

#br t, 1H, J4.0 Hz), 2.22 #A of ABX, 1H, J_AB16.9 Hz,

J_AX0.1 Hz), 1.91±2.10 #m, 2H), 1.92 #B of ABX, 1H,

J_AB16.9 Hz, J_BX4.3 Hz), 1.600±1.74 #m, 2H), 1.31 #A

of ABX, 1H, J_AB13.3 Hz, J_AX12.7 Hz), 1.17 #ap d, 1H),

1.09 #B of ABX, 1H, J_AB16.9 Hz, J_BX4.4 Hz), 1.02 #d,

3H, J7.2 Hz), 0.86 #d, 3H, J7.2 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 175.8 #C), 96.9 #C), 80.4 #CH), 79.6 #CH),

72.4 #CH), 68.9 #CH), 65.0 #CH), 38.4 #CH₂), 36.4 #CH₂),

36.2 #CH₂), 34.6 #CH₂), 29.6 #CH₂), 25.5 #CH), 25.5 #CH),

17.7 #CH₃), 17.2 #CH₃); HRMS #EI) m/e #relative intensity,

assignment) 313 #0.3, M1H¹), 281 #17, M¹2CH₂OH), 144

#58, C₇H₁₂O₃¹); exact mass calcd for C₁₆H₂₄O₆1H¹

requires 313.1651, found 313.1645. Data for terminal

alkene 14: R_f0.7 #2% MeOH/Et₂O, PAA); IR #thin ®lm)

22

R_f0.1 #2% MeOH/Et₂O, PAA); [a]_D2188 #c0.365,

CH₂Cl₂); mp #dec.) 2318C; IR #thin ®lm) 2933, 1776,

1186, 1159, 1014 cm²^{1 1}H NMR #C₆D₆, 300 MHz) d

;

3.32 #t, 2H, J2.6 Hz), 3.21 #dd, 2H, J4.4, 2.2 Hz), 2.16

#A of ABX, 2H, J_AB16.9 Hz, J_AX0.1 Hz), 1.90 #B of

ABX, 2H, J_AB16.9 Hz, J_BX4.3 Hz), 1.71±1.85 #m, 2H),

1.03 #A of ABX, 2H, J_AB13.6 Hz, J_AX14.7 Hz), 0.94 #B

of ABX, 2H, J_AB13.6 Hz, J_BX6.1 Hz), 0.88 #d, 6H,

J7.0 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 175.6 #C),

96.5 #C), 80.3 #CH), 69.2 #CH), 38.4 #CH₂), 35.7 #CH₂),

25.4 #CH), 17.1 #CH₃); HRMS #EI) m/e #relative intensity,

assignment) 297 #0.9, M1H¹), 296 #3.6, M¹), 208 #23,

M¹22£CO₂), 169 #22, C₁₀H₁₇O₂¹), 168 #100, C₁₀H₁₆O₂¹);

exact mass calcd for C₁₅H₂₀O₆requires 296.1260, found

296.1256.

1

3394 #br), 2917, 2848, 1780, 1191, 1016 cm²¹; H NMR

#CDCl₃, 300 MHz) d 5.84 #dddd, 1H, J17.1, 10.2, 7.7,

6.8 Hz), 5.15 #ddt, 1H, J17.1, 2.0, 1.4 Hz), 5.07 #ddt,

1H, J10.2, 2.0, 0.9 Hz), 4.24 #t, 1H, J2.6 Hz), 4.21

#dd, 1H, J4.0, 2.2 Hz), 3.63 #ddd, 1H, J8.5, 5.5,

0.9 Hz), 3.42 #dd, 1H, J7.8, 0.9 Hz), 2.68 #A of ABX,

1H, J_AB17.1, J_AX4.1 Hz), 2.51 #B of ABX, 1H,

J_AB17.1, J_BX0.1 Hz), 2.23±2.48 #m, 3H), 1.98±2.15

#m, 1H), 1.35±1.60 #m, 5H), 1.11 #d, 3H, J7.2 Hz), 0.97

#d, 3H, J6.8 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 176.1

#C), 134.7 #CH), 117.5 #CH₂), 96.6 #C), 80.6 #CH), 72.9

#CH), 69.8 #CH), 68.3 #CH), 38.4 #CH₂), 36.4 #CH₂), 36.1

#CH₂), 36.0 #CH₂), 30.0 #CH), 25.8 #CH), 17.4 #CH₃), 17.2

#CH₃); MS #FAB) m/e #relative intensity, assignment) 297

#10, M1H¹); exact mass calcd for C₁₆H₂₄O₅1H¹requires

297.1702, found 297.2.

2.1.13. Preparation of primary alcohol ꢀ13). C₂-

Symmetric bis#lactone) 2a #67.8 mg, 0.229 mmol) was

dissolved in 2.0 mL of THF and 2.0 mL of toluene with a

catalytic amount of pyridine #1.1 mg, 0.015 mmol) under an

argon atmosphere, and the solution was cooled to 2788C. A

0.7 M solution of the Tebbe reagent^52cin toluene #0.24 ml,

0.168 mmol) was added dropwise, and after 5 min at

2788C, the dry ice bath was removed and the reaction

was warmed to rt. After 40 min, a 0.5 M solution of 9-bora-

bicyclononane #9-BBN) in THF was added via syringe

#0.46 mL, 0.23 mmol), and the reaction was stirred at rt

2.1.14. Preparation of the Cꢀ51) aldehyde. Primary

alcohol 13 #125 mg, 0.40 mmol) was combined with the

Dess±Martin periodinane reagent⁵⁷#281 mg, 0.67 mmol)

in 10 mL of CH₂Cl₂. The reaction was stirred for 2.5 h at

rt, at which time only traces of starting material remained.

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2021

The resulting heterogeneous mixture was diluted with

10 mL of EtOAc and quenched with 20 mL of a saturated

aqueous solution of sodium bicarbonate doped with sodium

thiosulfate #25 g/100 mL). After 10 min, the contents were

transferred to a separatory funnel with an additional 30 mL

of EtOAc, separated, and the organic layer was washed with

brine. The aqueous layers were extracted one additional

time with EtOAc, and the combined organics were dried

over Na₂SO₄, ®ltered, and concentrated at 258C in vacuo.

The crude aldehyde was used without further puri®cation.

Data for the aldehyde: R_f0.32 #1:3 Et₂O/CH₂Cl₂, PAA); ¹H

NMR #C₆D₆, 300 MHz) d 9.57 #br d, 1H, J0.7 Hz), 3.95

#br d, 1H, J9.9 Hz), 3.31±3.33 #m, 2H), 3.26±3.28 #m,

2H), 2.20 #A of ABX, 1H, J_AB16.7 Hz, J_AX0.1 Hz),

1.90 #m, 2H), 1.93 #B of ABX, 1H, J_AB16.7 Hz,

J_BX0.1 Hz), 1.76±1.88 #m, 1H), 1.58±1.70 #m, 1H),

1.06±1.27 #m, 4H), 1.02 #d, 3H, J7.2 Hz), 0.85 #d, 3H,

J7.0 Hz).

in 1 mL of t-butanol with 2 mL of water and stirred at rt

until a homogeneous solution was achieved. The mixture

was then cooled to 08C, and distinct organic and aqueous

phases developed. A solution of homoallylic alcohol 15a

#4.0 mg, 0.011 mmol) in 1 mL of t-butanol was added.

After 2 h at 08C, the reaction was quenched by the addition

of NaHSO₃and warmed to rt. The system was diluted with

10 mL of water and 30 mL of EtOAc, and the layers were

separated. The aqueous phase was extracted with EtOAc.

The combined organic layers were dried over MgSO₄,

®ltered through a short plug of silica gel with 10% MeOH

in CH₂Cl₂, and concentrated in vacuo. Azeotropic removal

of trace MeOH with benzene was followed by silica gel

chromatography #3% MeOH/CH₂Cl₂) cleanly provided a

1:2 mixture of diastereomeric triols 17a and b #4.2 mg,

96%) as a viscous oil. The diastereomers could be separated

via silica gel FCC #3% MeOH/EtOAc). Data for #53R)-triol

22

17a: R_f0.29 #1:9 MeOH/EtOAc, PAA); [a]_D286.4

#c0.550, EtOAc); IR #thin ®lm) 3431 #br), 2929, 2875,

1

2.1.15. Preparation of Cꢀ51)-ꢀS)-homoallylic alcohol

ꢀ15a). The crude C#51) aldehyde from above #0.40 mmol)

was dissolved in 10 mL of dry CH₂Cl₂under an argon

atmosphere and cooled to 2788C. Freshly distilled TiCl₄

#60 mL, 0.547 mmol) was added dropwise, and the reaction

mixture was aged for 10 min. Allyltri#n-butyl)stannane

#0.19 mL, 0.612 mmol) was added dropwise via syringe,

and the reaction was stirred for 20 min. One milliliter of

water was added to quench the reaction, and the dry ice/

acetone bath was removed. After the slurry had reached rt, it

was acidi®ed with 3% HCl#aq) and transferred to a

separatory funnel with 30 mL of EtOAc. The layers were

separated, and the organic phase was washed once with a

1:1 mixture of saturated NaHCO₃#aq) and brine. The

aqueous layers were extracted with EtOAc, and the

combined organics were dried over MgSO₄, ®ltered, and

concentrated in vacuo. Silica gel chromatography with

EtOAc/CH₂Cl₂/hexanes #1:1:1) yielded the desired homo-

allylic alcohol 15a #109 mg, 77%) as a pale yellow oil.

Stannane impurities often contaminated the homoallylic

alcohol and necessitated repeated chromatography for

high levels of purity. Data for 15a: R_f0.26 #1:3 Et₂O/

CH₂Cl₂, PAA), R_f0.20 #1:1:1 EtOAc/CH₂Cl₂/hexanes,

1784, 1198, 1016, 976 cm²¹; H NMR #C₆D₆, 300 MHz)

d 4.05 #dt, 1H, J10.2, 3.0 Hz), 3.77±3.86 #m, 1H), 3.66

#dt, 1H, J9.6, 3.5 Hz), 3.47 #dd, 1H, J10.8, 3.9 Hz),

3.28±3.40 #m, 4H), 3.07 #t, 1H, J2.1 Hz), 2.22 #A of

ABX, 1H, J_AB16.7 Hz, J_AX0.1 Hz), 1.82±2.08 #m, 3H),

1.92 #B of ABX, 1H, J_AB16.7 Hz, J_BX4.3 Hz), 1.61 #ddd,

1H, J14.3, 9.7, 5.0 Hz), 1.05±1.53 #m, 6H), 1.01 #d, 3H,

J7.0 Hz), 0.83 #d, 3H, J7.0 Hz), 0.45 #br s, 3H); ¹³C

NMR #CDCl₃, 75.4 MHz) d 175.8 #C), 97.1 #C), 80.6

#CH), 80.3 #CH), 79.2 #CH), 72.5 #CH), 72.2 #CH), 71.8

#CH), 69.1 #CH), 66.2 #CH₂), 38.4 #CH₂), 36.5 #CH₂),

36.3 #CH₂), 36.1 #CH₂), 32.4 #CH₂), 25.5 #CH£2), 17.7

#CH₃), 17.2 #CH₃); HRMS #FAB1NaI) m/e #relative inten-

sity, assignment) 409 #100, M1Na¹); exact mass calcd for

C₁₉H₃₀O₈1Na¹requires 409.1838, found 409.1836. Data

for #53S)-triol 17b: R_f0.23 #1:9 MeOH/EtOAc, PAA); IR

#thin ®lm) 3430 #br), 2929, 2876, 1784, 1198, 1016 cm²¹

;

¹H NMR #C₆D₆, 300 MHz) d 4.13 #dt, 1H J9.0, 3.4 Hz),

3.87±3.94 #m, 1H), 3.78 #dt, 1H, J9.5, 3.6 Hz), 3.27±3.46

#m, 5H), 3.11 #t, 1H, J2.4 Hz), 2.23 #A of ABX, 1H,

J_AB16.9 Hz, J_AX0.1 Hz), 1.85±2.08 #m, 3H), 1.91 #B

of ABX, 1H, J_AB16.9 Hz, J_BX3.6 Hz), 1.50±1.73 #m,

2H), 1.05±1.47 #m, 8H), 1.01 #d, 3H, J7.2 Hz), 0.87 #d,

3H, J7.2 Hz); ¹H NMR #CDCl₃, 300 MHz) d 4.30 #dd, 1H,

J4.0, 3.4 Hz), 4.25 #dd, 1H, J3.3, 2.2 Hz), 3.93±4.12 #m,

4H), 3.66 #dd, 1H, J11.1, 3.6 Hz), 3.54±3.61 #m, 2H), 3.16

#br s, 1H), 3.04 #br s, 1H), 2.70 #A of ABX, 1H,

J_AB17.1 Hz, J_AX4.2 Hz), 2.53 #B of ABX, 1H,

J_AB17.1 Hz, J_BX0.1 Hz), 2.16 #ddd, 1H, J14.1, 9.4,

4.8 Hz), 2.02 #dd, 1H, J14.1, 3.6 Hz), 1.68 #br s, 1H),

1.42±1.65 #m, 5H), 1.11 #d, 3H, J7.0 Hz), 1.04 #d, 3H,

J7.1 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 175.8 #C), 97.1

#C), 80.7 #CH), 80.4 #CH), 79.2 #CH), 72.3 #CH), 69.9 #CH),

66.8 #CH₂), 38.5 #CH₂), 36.6 #CH₂), 36.5 #CH₂), 36.2 #CH₂),

32.6 #CH₂), 25.4 #CH£2), 17.7 #CH₃), 17.2 #CH₃).

22

PAA); [a]_D2109 #c0.210, CH₂Cl₂); IR #thin ®lm)

3465, 2927, 1786, 1200, 1016 cm²^{1 1}H NMR #C₆D₆,

;

300 MHz) d 5.82 #ddt, 1H, J17.1, 10.2, 7.0 Hz), 5.08

#dq, 1H, J17.1, 1.5 Hz), 5.04 #dm, 1H, J10.2 Hz), 4.28

#dd, 1H, J3.9, 2.3 Hz), 4.22 #dd, 1H, J3.2, 2.3 Hz),

4.01±4.06 #m, 2H), 3.85±3.92 #m, 1H), 3.65±3.80 #m,

1H), 3.52 #dd, 1H, J3.0, 1.8 Hz), 2.84 #d, 1H J2.4 Hz),

2.67 #A of ABX, 1H, J_AB17.1 Hz, J_AX4.3 Hz), 2.50 #B of

ABX, 1H, J_AB17.1 Hz, J_BX0.1 Hz), 1.97±2.41 #m, 5H),

1.37±1.52 #m, 4H), 1.06 #d, 3H, J7.0 Hz), 1.01 #d, 3H,

J7.2 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 175.8 #C),

134.6 #CH), 117.2 #CH₂), 97.0 #C), 80.4 #CH), 80.0 #CH),

79.1 #CH), 72.2 #CH), 71.6 #CH), 68.9 #CH), 38.6 #CH₂),

38.4 #CH₂), 36.5 #CH₂), 36.1 #CH₂), 32.1 #CH₂), 25.4

#CH£2), 17.7 #CH₃), 17.2 #CH₃).

2.1.17. Preparation of ꢀ51S)-BOC carbonate 15b. To

homoallylic alcohol 15a #20.1 mg, 0.057 mmol) and

DMAP #25 mg, 0.22 mmol) in pyridine #0.7 mL,

8.6 mmol), was added #BOC)₂O #185 mg, 0.85 mmol) at

rt. After 24 h, the reaction was diluted with 2 mL of

CH₂Cl₂and monitored by TLC for starting material. Addi-

tional #BOC)₂O #61 mg, 0.28 mmol) was added, and the

reaction stirred for 3 h. The reaction was quenched with

2.1.16. Preparation of Cꢀ51,53,54) triols 17a and b by

asymmetric dihydroxylation of alkene 15a. Potassium

ferricyanide #12.1 mg, 0.037 mmol), potassium carbonate

#9.0 mg, 0.065 mmol), #DHQD)₂AQN #,1 mg, ,0.001

mmol), and OsO₄#0.12 mg, 0.00048 mmol) were combined

2022

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

5% aqueous HCl and extracted with EtOAc. The organic

phase was washed with saturated NaHCO₃#aq)/brine #1:1).

The aqueous layers were extracted with EtOAc. The

combined organic layers were dried over MgSO₄and

®ltered through a short plug of silica gel with additional

EtOAc. After concentration in vacuo, silica gel chromato-

graphy with 50% Et₂O in hexanes yielded the BOC carbon-

ate 15b #23.3 mg, 91%) as an amorphous white solid. Data

for BOC carbonate 15b: R_f0.25 #3:1 Et₂O/hexanes, PAA);

36.8 #CH₂), 36.7 #CH₂), 35.5 #CH₂), 30.6 #CH₂), 25.8 #CH),

25.7 #CH), 17.9 #CH₃), 17.5 #CH₃), 5.9 #CH₂).

2.1.19. Preparation of Cꢀ51S,53R,54)-triol lactone 17a

from iodocarbonate 16. Iodocarbonate 16 #31.4 mg,

0.601 mmol) was combined with 1.0 M LiOH#aq)

#0.9 mL, 0.9 mmol) in 3.5 mL of DME and 0.9 mL of

water. The reaction was heated at 608C for 13 h, then cooled

to 08C and neutralized to pH 7.0 with HCl#aq). The reaction

mixture was concentrated in vacuo, azeotroped with

benzene #2£20 mL), and the resulting solids placed under

vacuum for several hours. The ¯ask was then ®tted with a

re¯ux condenser and charged with 10 mL of benzene and

one equivalent of CSA #140 mg, 0.602 mmol). The reaction

was heated at re¯ux for 1 h, cooled to rt, and transferred to a

separatory funnel with EtOAc. The solution was washed

once each with saturated aqueous NaHCO₃and brine. The

aqueous phases were extracted with EtOAc, and the

combined organic layers were dried over MgSO₄, ®ltered,

and concentrated in vacuo. Silica gel chromatography #3%

MeOH/CH₂Cl₂) cleanly provided the triol 17a #21.0 mg,

90%). Generally, the aqueous layers were saved until the

mass recovery of the lactone triol 17a was con®rmed. In

cases of low mass recovery, the saved aqueous phases

were combined, brought to neutral pH with HCl#aq), and

the extraction process repeated to recover additional 17a.

See data for 17a above.

22

[a]_D2107 #c0.510, CH₂Cl₂); IR #thin ®lm) 2962,

1

2929, 1785, 1741, 1277, 1250, 1163, 1016 cm²¹; H NMR

#C₆D₆, 300 MHz) d 5.82 #dddd, 1H, J17.3, 10.3, 7.7,

6.6 Hz), 5.12 #dq, 1H, J17.3, 1.3 Hz), 5.05 #ddt, 1H,

J10.3, 1.9, 1.0 Hz), 4.76 #td, 1H, J7.7, 4.0 Hz), 4.28

#dd, 1H, J4.0, 2.3 Hz), 4.22 #dd, J2.8, 2.6 Hz), 3.95±

4.02 #m, 2H), 3.59 #dd, 1H J2.9, 2.4 Hz), 2.68 #A of

ABX, 1H, J_AB17.1 Hz, J_AX0.4 Hz), 2.52±2.62 #m, 1H),

2.50 #B of ABX, 1H, J_AB17.1 Hz, J_BX4.1 Hz), 2.20±2.47

#m, 3H), 2.18 #ddd, 1H, J14.1, 9.2, 5.0 Hz), 1.88 #dd, 1H

J14.1, 3.8 Hz), 1.37±1.60 #m, 4H), 1.48 #s, 9H), 1.11 #d,

3H, J7.0 Hz), 1.02 #d, 3H, J7.0 Hz); ¹³C NMR #CDCl₃,

75.4 MHz) d 176.1 #C), 153.0 #C), 133.8 #CH), 117.5 #CH₂),

96.6 #C), 81.8 #C), 80.8 #CH), 79.9 #CH), 77.7 #CH), 77.6

#CH), 72.1 #CH), 68.8 #CH), 38.5 #CH₂), 36.6 #CH₂), 36.4

#CH₂), 35.7 #CH₂), 35.5 #CH₂), 27.8 #CH₃£3), 25.5 #CH),

17.7 #CH₃), 17.2 #CH₃); MS #FAB1NaI) m/e #relative

intensity, assignment) 475 #92, M1Na¹), 375 #100,

M1Na¹2BOC); exact mass calcd for C₂₄H₃₆O₈1Na¹

requires 475.2310, found 475.2.

2.1.20. Preparation of Cꢀ54)-t-butyldiphenylsilyloxy-

ꢀ51S,53R)-diol 18a. Triol 17a #10.9 mg, 0.028 mmol),

DMAP #3 mg, 0.027 mmol), and excess pyridine #0.5 mL,

6.2 mmol) were combined in 1 mL of CH₂Cl₂. A slight

excess of TBDPSCl #10 mL, 0.034 mmol) was added, and

the reaction was stirred for 16 h at rt. The excess TBDPSCl

was consumed by the addition of 0.2 mL of MeOH.

After 15 min, the reaction contents were transferred to a

separatory funnel with 30 mL of EtOAc and washed with

5% aqueous HCl and then saturated NaHCO₃#aq). The

aqueous layers were extracted with EtOAc, and the

combined organic layers were dried over MgSO₄. After

concentration in vacuo, the selectively protected diol 18a

was puri®ed by silica gel chromatography with a 50±100%

Et₂O/hexanes gradient elution #15.9 mg, 90%). Data for

2.1.18. Preparation of Cꢀ54)-iodo-ꢀ51S,53R) cyclic car-

bonate ꢀ16). Homoallylic carbonate 15b #23.1 mg,

0.051 mmol) was dissolved in dry toluene under an argon

atmosphere and cooled with a dry ice/Et₂O bath to 2808C.

A 1.0 M solution of IBr in CH₂Cl₂#0.12 mL, 0.12 mmol)

was added dropwise over 2 min, and the reaction was held at

2808C for 3 h. After warming to 08C and stirring for

15 min, the reaction was quenched with 10 mL saturated

aqueous solution of sodium bicarbonate doped with sodium

thiosulfate #25 g/100 mL), diluted with 10 mL of EtOAc,

and stirred until colorless. The layers were transferred to a

separatory funnel, and the aqueous layer extracted with

EtOAc. The combined organic layers were dried over

MgSO₄, ®ltered through a short silica gel plug with addi-

tional EtOAc, and concentrated in vacuo. Silica gel chro-

matography with a 0±50% EtOAc/Et₂O solvent gradient

provided the iodocarbonate 16 in excellent yield #26.6 mg,

99%) as a single diastereomer within the detection limits of

¹H NMR. Data for 16: R_f0.58 #100% EtOAc, PAA);

22

18a: R_f0.70 #100% EtOAc, PAA); [a]_D262.7

#c0.415, benzene); IR #thin ®lm) 3417 #br), 2954, 2929,

1

2856, 1786, 1427, 1113, 1016 cm²¹; H NMR #CDCl₃,

300 MHz) d 7.59±7.70 #m, 4H), 7.30±7.45 #m, 6H), 4.30

#dd, 1H, J3.9, 2.3 Hz), 4.24 #br t, 1H, J2.7 Hz), 4.03 #dd,

1H, J4.4, 1.8 Hz), 3.90±4.00 #m, 3H), 3.62 #A of ABX,

1H, J_AB10.1 Hz, J_AX6.0 Hz), 3.60 #A of ABX, 1H,

J_AB10.1 Hz, J_BX4.8 Hz), 3.55 #dd, 1H, J2.9, 2.0 Hz),

3.42 #br s, 1H), 3.36 #br s, 1H), 2.69 #A of ABX, 1H,

J_AB17.1 Hz, J_AX4.1 Hz), 2.52 #B of ABX, 1H,

J_AB17.1 Hz, J_BX0.1 Hz), 2.20±2.45 #m, 2H), 2.14 #ddd,

1H, J14.1, 9.2, 5.0 Hz), 2.03 #dd, 1H, J14.1, 3.4 Hz),

1.74 #dt, 1H, J15.0, 2.1 Hz), 1.22±1.52 #m, 5H), 1.09 #d,

3H, J7.0 Hz), 1.06 #s, 9H), 1.02 #d, 3H, J7.0 Hz); ¹³C

NMR #CDCl₃, 75.4 MHz) d 175.8 #C), 135.6 #CH£4), 133.3

#C£2), 129.8 #CH£2), 127.8 #CH£4), 97.0 #C), 80.6 #CH),

80.5 #CH), 79.3 #CH), 72.8 #CH), 72.3 #CH), 72.1 #CH),

69.0 #CH), 67.7 #CH₂), 38.5 #CH₂), 36.5 #CH₂£2), 36.3

#CH₂), 33.0 #CH₂), 26.5 #CH₃£3), 25.5 #CH£2), 19.3 #C),

17.7 #CH₃), 17.2 #CH₃); MS #FAB1NaI) m/e #relative

22

[a]_D247.8 #c1.16, CH₂Cl₂); IR #thin ®lm) 2926,

1

1754, 1187, 1116, 1018 cm²¹; H NMR #C₆D₆, 300 MHz)

d 3.83 #ddd, 1H, J10.9, 7.0, 2.8 Hz), 3.54 #ddd, 1H,

J11.0, 9.0, 2.8 Hz), 3.41±3.45 #m, 2H), 3.29±3.38 #m,

1H), 3.37 #dd, 1H, J4.6, 1.8 Hz), 3.10 #dd, 1H, J2.6,

2.3 Hz), 2.53 #A of ABX, 1H, J_AB10.7 Hz, J_AX5.6 Hz),

2.44 #B of ABX, 1H, J_AB10.7 Hz, J_BX6.9 Hz), 2.26 #A of

ABX, 1H, J_AB16.7 Hz, J_AX0.1 Hz), 2.01 #B of ABX, 1H,

J_AB16.7 Hz, J_BX4.1 Hz), 1.90±2.08 #m, 3H), 1.84 #dd,

1H, J14.1, 3.4 Hz), 1.72 #ddd, 1H, J14.0, 9.8, 4.8 Hz),

1.09±1.36 #m, 5H), 1.01 #d, 3H, J7.1 Hz), 0.95 #d, 3H,

J6.9 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 174.6 #C),

147.1 #C), 96.6 #C), 80.0 #CH), 79.6 #CH), 79.5 #CH),

78.3 #CH), 76.5 #CH), 72.0 #CH), 69.1 #CH), 38.4 #CH₂),

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2023

intensity, assignment) 647.4 #100, M1Na¹); exact mass

calcd for C₃₅H₄₈O₈Si1Na¹requires 647.3016, found 647.4.

#2£CH), 127.6 #4£CH), 98.4 #C), 96.4 #C), 80.6 #CH),

80.2 #CH), 79.7 #CH), 72.5 #CH), 71.5 #CH), 70.1 #CH),

68.9 #CH), 67.5 #CH₂), 38.5 #CH₂), 37.0 #CH₂), 36.6

#CH₂), 35.2 #CH₂), 31.1 #CH₂), 30.0 #CH₂), 29.7 #CH₂),

26.8 #3£CH₃), 25.7 #CH), 25.6 #CH), 19.5 #CH₃), 19.3

#C), 17.7 #CH₃), 17.3 #CH₃); HRMS #FAB1Na¹) m/e

#relative intensity, assignment) 687.3 #100, M1Na¹);

exact mass calcd for C₃₈H₅₂O₈Si1Na¹requires 687.3329,

found 687.3328.

2.1.21. Preparation of Cꢀ54)-t-butyldiphenylsilyloxy-

ꢀ51S,53S)-diol 17c. Triol 17b #11.0 mg, 0.028 mmol),

DMAP #13 mg, 0.077 mmol), and excess pyridine

#0.5 mL, 6.2 mmol) were combined in 1 mL of CH₂Cl₂. A

slight excess of TBDPSCl #10 mL, 0.034 mmol) was added,

and the reaction was stirred for 16 h at rt. The excess

TBDPSCl was consumed by the addition of 0.2 mL of

MeOH. After 15 min, the reaction contents were transferred

to a separatory funnel with 30 mL of EtOAc and washed

with 5% aqueous HCl and then saturated NaHCO₃#aq). The

aqueous layers were extracted with EtOAc, and the

combined organic layers were dried over MgSO₄. After

concentration in vacuo, the selectively protected diol 17c

was puri®ed by silica gel chromatography with a 50±100%

Et₂O/hexanes gradient elution #16.6 mg, 93%). Data for

17c: R_f0.70 #100% EtOAc, PAA); IR #thin ®lm) 3458

2.1.23. Preparation of Cꢀ54)-t-butyldiphenylsilyloxy-

ꢀ51S,53S) acetonide 19b. To diol 17c #15.5 mg,

0.025 mmol) in excess 2,2-dimethoxypropane #1 mL), was

added catalytic CSA #1.0 mg, 0.0043 mmol) at rt. After

20 min, the reaction contents were rinsed into a separatory

funnel with 30 mL of Et₂O and washed with saturated

NaHCO₃#aq). The aqueous layer was extracted twice with

Et₂O, and the combined organic layers were dried over

MgSO₄. Filtration through a short plug of silica gel with

additional Et₂O and concentration in vacuo was followed

by silica gel FCC with 50% Et₂O in hexanes. The acetonide

19b #14.2 mg, 89%) was isolated as a colorless oil. Data for

19b: R_f0.55 #1:1 Et₂O/hexanes, PAA); IR #thin ®lm) 3070,

1

#br), 3070, 2929, 2856, 1786, 1427, 1112, 1016 cm²¹; H

NMR #C₆D₆, 300 MHz) d 7.60±7.70 #m, 4H), 7.35±7.49

#m, 6H), 4.29 #dd, 1H, J4.2, 2.8 Hz), 4.23 #dd, 1H,

J3.1, 2.4), 4.00±4.10 #m, 4H), 3.68 #dd, 1H, J10.1,

4.2 Hz), 3.53±3.68 #m, 2H), 3.03 #br d, 1H, J2.7 Hz),

2.86 #br d, 1H, J3.9 Hz), 2.68 #A of ABX, 1H,

J_AB17.0 Hz, J_AX4.2 Hz), 2.52 #B of ABX, 1H,

J_AB17.0 Hz, J_BX0.1 Hz), 2.32±2.42 #m, 1H), 2.22±2.31

#m, 1H), 2.12 #ddd, 1H, J14.0, 9.4, 5.0 Hz), 1.99 #dd, 1H,

J14.0, 3.7 Hz), 1.55 #ddd, 1H, J14.9, 7.0, 4.0 Hz), 1.39±

1.48 #m, 5H), 1.07 #d, 3H, J7.2 Hz), 1.06 #s, 9H), 1.02 #d,

3H, J7.2 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d 175.9 #C),

135.5 #CH£4), 133.2 #C£2), 129.8 #CH£2), 127.8 #CH£4),

97.0 #C), 80.6 #CH), 80.5 #CH), 79.2 #CH), 72.3 #CH), 69.7

#CH), 69.3 #CH), 69.0 #CH), 68.0 #CH₂), 38.5 #CH₂), 36.5

#CH₂), 36.2 #CH₂), 36.1 #CH₂), 32.7 #CH₂), 26.8 #CH₃£3),

25.5 #CH£2), 19.3 #C), 17.7 #CH₃), 17.2 #CH₃); MS

#FAB1NaI) m/e #relative intensity, assignment) 647.4

#100, M1Na¹); exact mass calcd for C₃₅H₄₈O₈Si1Na¹

requires 647.3016, found 647.4.

2929, 2856, 1788, 1379, 1113, 1016 cm²^{1 1}H NMR

;

#CDCl₃, 300 MHz) d 7.66 #m, 4H), 7.32±7.46 #m, 6H),

4.28 #dd, 1H, J3.9, 2.4 Hz), 4.22 #br t, 1H, J2.7 Hz),

4.00 #dd, 1H, J4.3, 2.0 Hz), 3.86±3.98 #m, 2H), 3.60±

3.82 #m, 4H), 2.67 #A of ABX, 1H, J_AB17.1 Hz,

J_AX4.2 Hz), 2.50 #B of ABX, 1H, J_AB17.1 Hz,

J_BX0.1 Hz), 2.29±2.43 #m, 1H), 2.18±2.27 #m, 1H), 2.13

#ddd, 1H, J13.6, 8.8, 4.6 Hz), 1.97 #dd, 1H, J4.6,

2.7 Hz), 1.65±1.87 #m, 2H), 1.23±1.45 #m, 4H), 1.35 #s,

3H), 1.31 #s, 3H), 1.07 #d, 3H, J7.0 Hz), 1.06 #s, 9H),

1.00 #d, 3H, J7.0 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d

176.1 #C), 135.7 #4£CH), 133.8 #C), 129.6 #2£CH), 127.6

#4£CH), 100.2 #C), 96.5 #C), 80.7 #CH), 80.1 #CH), 79.8

#CH), 72.5 #CH), 69.1 #CH), 68.9 #CH), 67.7 #CH), 66.7

#CH₂), 38.5 #CH₂), 36.7 #CH₂), 36.6 #CH₂), 35.7 #CH₂),

31.7 #CH₂), 26.9 #3£CH₃), 25.6 #2£CH), 24.8 #2£CH₃),

19.3 #C), 17.8 #CH₃), 17.3 #CH₃); MS #FAB1NaI) m/e

#relative intensity, assignment); exact mass calcd for

C₃₈H₅₂O₈Si1Na¹requires 687.3329, found 687.4.

2.1.22. Preparation of Cꢀ54)-t-butyldiphenylsilyloxy-

ꢀ51S,53R) acetonide 19a. To diol 18a #8.3 mg,

0.013 mmol) in excess 2,2-dimethoxypropane #1 mL), was

added catalytic CSA #0.5 mg, 0.0022 mmol) at rt. After

20 min, the reaction contents were rinsed into a separatory

funnel with 30 mL Et₂O and washed with saturated

NaHCO₃#aq). The aqueous layer was extracted with Et₂O,

and the combined organic layers were dried over MgSO₄.

Filtration through a short plug of silica gel with additional

Et₂O and concentration in vacuo was followed by silica gel

FCC with 50% Et₂O in hexanes. The acetonide 19a #7.1 mg,

80%) was isolated as a colorless oil. Data for 19a: R_f0.55

2.1.24. Preparation of Cꢀ54)-t-butyldiphenylsilyloxy-

ꢀ51S,53R)-bisꢀtriisopropylsilyloxy) lactone 18b. Diol

18a #125 mg, 0.200 mmol) was combined with DMAP

#44 mg, 0.39 mmol) under a nitrogen atmosphere and then

dissolved in 0.6 mL of dry pyridine. TIPSOTf #0.4 mL,

1.49 mmol) was added via syringe, and the reaction was

stirred for 15 h. Excess TIPSOTf was consumed by the

addition of 1.5 mL of dry MeOH. After 15 min, the reaction

was transferred to a separatory funnel with Et₂O and washed

®rst with 5% HCl and then with a 1:1 mixture of saturated

NaHCO₃#aq) and brine. The aqueous layers were extracted

with Et₂O, and the combined organic layers were dried over

MgSO₄. Filtration through a short silica gel plug with addi-

tional Et₂O and concentration in vacuo provided the crude

product, which was puri®ed by silica gel chromatography

#25% Et₂O in hexanes) to afford 187 mg #99%) of the

lactone 18b as a pale yellow oil. Data for 18b: R_f0.35

22

#1:1 Et₂O/hexanes, PAA); [a]_D237.9 #c0.34,

1

CH₂Cl₂); IR #thin ®lm) 2924, 2854, 1789, 1111 cm²¹; H

NMR #C₆D₆, 300 MHz) d 7.75±7.90 #m, 4H), 7.18±7.28

#m, 6H), 3.92±4.05 #m, 1H), 3.80±3.90 #m, 3H), 3.70 #dd,

1H, J10.4, 4.6 Hz), 3.45±3.52 #m, 2H), 3.42 #br t, 1H,

J2.9), 3.28 #br t, 1H, J2.4 Hz), 2.68 #A of ABX, 1H,

J_AB17.1, J_AX0.1 Hz), 2.53 #B of ABX, 1H, J_AB17.1,

J_BX4.1 Hz), 1.70±2.15 #m, 4H), 1.52 #s, 3H), 1.13±1.45

#m, 6H), 1.30 #s, 3H), 1.20 #s, 9H), 1.05 #d, 3H, J6.8 Hz),

0.95 #d, 3H, J6.8 Hz); ¹³C NMR #CDCl₃, 75.4 MHz) d

176.0 #C), 135.7 #4£CH), 133.9 #C), 133.8 #C), 129.6

22

#1:1 Et₂O/hexanes, PAA); [a]_D161.0 #c0.115, ben-

1

zene); IR #thin ®lm) cm²¹; H NMR #CDCl₃, 500 MHz) d

7.63±7.70 #m, 4H), 7.32±7.44 #m, 6H), 4.28 #dd, 1H, J3.9,

2024

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2.4 Hz), 4.21 #br t, 1H, J2.5 Hz), 4.07±4.15 #m, 2H), 3.98

#dd, 1H, J6.0, 2.2 Hz), 3.83 #ddd, 1H, J9.5, 6.6, 3.4 Hz),

3.66 #A of ABX, 1H, J_AB10.3 Hz, J_AX4.7 Hz), 3.61 #B of

ABX, 1H, J_AB10.3 Hz, J_BX5.5 Hz), 3.34 #br t, 1H,

2.6 Hz), 2.67 #A of ABX, 1H, J_AB17.3 Hz, J_AX4.5 Hz),

2.51 #B of ABX, 1H, J_AB17.3 Hz, J_BX0.1 Hz), 2.30±2.40

#m, 1H), 2.19±2.30 #m, 1H), 1.95±2.06 #m, 2H), 1.85±1.91

#m, 2H), 1.32±151 #m, 4H), 0.97±1.08 #m, 57H); ¹³C NMR

#CDCl₃, 75.4 MHz) d 174.6 #C), 136.1 #CH), 136.0 #CH),

134.1 #C), 133.7 #C), 130.0 #CH), 128.0 #CH), 96.8 #C), 81.2

#CH), 80.0 #CH), 79.8 #CH), 72.4 #CH), 71.8 #CH), 71.2

#CH), 69.0 #CH), 68.4 #CH₂), 38.7 #CH₂), 38.4 #CH₂),

37.0 #CH₂), 36.5 #CH₂), 34.9 #4£CH₃), 27.2 #CH₂), 25.8

#CH), 19.4 #C), 18.6 #2£CH₃), 18.0 #CH), 17.5 #CH), 13.5

#CH₃), 13.1 #CH₃); MS #FAB1NaI) m/e #relative intensity,

assignment) 959.6 #100, M1Na¹); exact mass calcd for

C₅₃H₈₈O₈Si₃1Na¹requires 959.5687, found 959.6.

diluted with Et₂O, and the phases were separated. The

organic phase was washed with a saturated solution of

NaHCO₃#aq)/brine #1:1), dried over MgSO₄, and ®ltered.

Concentration in vacuo was followed by silica gel FCC

with 2% Et₂O in benzene to yield the MPM protected

methyl ester 25 #3.1 mg, 91%) as a thin ®lm. Data for 25:

22

R_f0.60 #1:9 Et₂O/benzene, PAA); [a]_D275.9 #c0.145,

CH₂Cl₂); IR #thin ®lm) 2943, 2865, 1740, 1248, 1111, 1081,

1055, 1038, 998 cm²^{1 1}H NMR #CDCl₃, 500 MHz) d

;

7.64±7.71 #m, 4H), 7.32±7.42 #m, 6H), 7.23±7.29 #m,

2H), 6.84±6.90 #m, 2H), 4.50 #AB_q, 2H, J_AB11.1 Hz,

Dn/226.1 Hz), 4.12±4.17 #m, 1H), 4.08 #ddd, 1H,

J8.9, 5.0, 1.1 Hz), 4.03±4.07 #m, 2H), 3.80 #s, 3H), 3.78

#ddd, 1H, J9.1, 6.2, 5.0 Hz), 3.64 #s, 3H), 3.61±3.64 #m,

1H), 3.30 #br t, 1H, J2.8 Hz), 3.25 #br s, 1H), 2.64 #A of

ABX, 1H, J_AB15.4 Hz, J_AX9.1 Hz), 2.32 #B of ABX, 1H,

J_AB15.4 Hz, J_BX4.9 Hz), 2.12±2.23 #m, 2H), 1.93±2.05

#m, 2H), 1.80±1.91 #m, 2H), 1.31±1.52 #m, 4H), 0.99±1.05

#m, 51H), 0.95 #d, 3H, J7.1 Hz), 0.94 #d, 3H, F J7.0 Hz);

¹³C NMR #CDCl₃, 75.4 MHz) d 172.5 #C), 158.8 #C), 135.8

#CH), 135.7 #CH), 133.9 #C), 133.7 #C), 130.7 #C), 129.9

#CH), 129.5 #CH), 127.5 #CH), 113.6 #CH), 97.0 #C), 80.8

#CH), 79.8 #CH), 77.2 #CH), #74.8 #CH₂), 71.6 #CH), 70.7

#CH), 69.6 #CH), 67.9 #CH₂), 55.3 #CH₃), 51.5 #CH₃), 37.8

#CH₂), 36.9 #CH₂), 34.8 #CH₂), 30.2 #CH), 26.9 #3£CH₃),

25.8 #CH), 19.2 #C), 18.2 #n£CH₃), 18.1 #CH₃), 17.8 #CH),

13.1 #CH₃), 12.7 #CH₃); HRMS #FAB1NaI) m/e #relative

intensity, assignment) 1111.6574 #100, M1Na¹); exact

mass calcd for C₆₂H₁₀₀O₁₀Si₃1Na¹requires 1111.6522,

found 1111.6574.

2.1.25. Preparation of the Cꢀ38)-methyl ester 24. Fully

protected lactone 18b #34.8 mg, 0.037 mmol) in 2.5 mL of

THF and 2.0 mL of t-butanol was combined with excess

1.0 M LiOH#aq) #2.0 mL, 2.0 mmol) at rt. The hetero-

geneous system was stirred rapidly for 2 h and then diluted

with 20 mL of Et₂O and acidi®ed to pH 3 with 5% HCl#aq).

The layers were separated, and the aqueous phase was

extracted with Et₂O. The combined organic layers were

washed with brine, dried over Na₂SO₄, and concentrated

in vacuo at 228C. The crude hydroxy acid #0.037 mmol)

was dissolved in 1.3 mL of benzene/MeOH #7:2) at rt.

Several drops of a 2.0 M solution of trimethylsilyldiazo-

methane in hexanes was added, and the reaction stirred

until the seco acid was no longer visible by TLC #15 min).

The resulting solution was concentrated in vacuo at 228C

and the crude methyl ester was puri®ed by silica gel FCC

#1:3 Et₂O/hexanes). In vacuo concentration of the fractions

at 228C cleanly provided the methyl ester 24 #34.2 mg, 95%

two steps) as a pale yellow oil. Data for 24: R_f0.19 #1:1

Et₂O/hexanes, PAA); IR #thin ®lm) 3483 #br), 2942, 2864,

1742, 1462, 1111, 1003 cm²¹; ¹H NMR #C₆D₆, 300 MHz) d

7.80±7.89 #m, 4H), 7.20±7.32 #m, 6H), 4.39±4.49 #m, 2H),

4.27 #br q, 1H, J5.3 Hz), 4.16 #ddd, 1H, J10.1, 3.8,

1.1 Hz), 3.88±3.98 #m, 3H), 3.36 #s, 3H), 3.32 #br t, 1H,

J2.7 Hz), 3.04 #br d, 1H, J8.1 Hz), 2.80 #A of ABX, 1H,

J_AB15.8 Hz, J_AX9.7 Hz), 2.26 #B of ABX, 1H,

J_AB15.8 Hz, J_BX3.8 Hz), 1.95±2.43 #m, 6H), 1.08±1.65

#m, 43H), 1.12 #d, 3H, J7.2 Hz), 0.96 #d, 3H, J7.0 Hz);

¹³C NMR #CDCl₃, 75.4 MHz) d 171.9 #C), 136.2 #CH),

136.1 #CH), 134.2 #C), 133.9 #C), 129.9 #CH), 128.0

#CH), 97.1 #C), 81.3 #CH), 80.1 #CH), 72.3 #CH), 72.1

#CH), 71.5 #CH), 70.3 #CH), 69.7 #CH), 68.4 #CH₂), 51.0

#CH₃), 38.3 #CH₂), 37.6 #CH₂), 37.3 #CH₂), 37.0 #CH₂), 35.3

#CH₂), 30.2 CH), 27.2 #3£CH₃), 26.4 #2£CH), 19.5 #C), 18.6

#n£CH₃), 18.5 #n£CH), 18.3 #CH₃), 17.7 #CH), 13.5 #CH₃),

13.2 #CH₃).

2.1.27. Preparation of the b-ketophosphonate 1. In a

¯ame-dried ¯ask, dimethyl methylphosphonate #50 mL,

0.46 mmol) was combined with 4 mL of THF and cooled

to 2788C under an argon atmosphere. One equivalent of

n-butyllithium #0.46 mmol) was added via syringe, and

the mixture was allowed to stir for 15 min. In a separate

¯ask the methyl ester 25 #5.5 mg, 0.0051 mmol) was

dissolved in 1 mL of THF and cooled to 2788C. Approxi-

mately 0.2 mL of the lithiated dimethyl methylphosphonate

solution was cannula transferred to the reaction ¯ask. After

15 min, the reaction was quenched with 5% HCl#aq) and

allowed to warm to rt. The resulting mixture was diluted

with Et₂O. The organic phase was separated, washed with

saturated NaHCO₃#aq)/brine #1:1), and dried over MgSO₄.

Concentration in vacuo was followed by silica gel FCC

using a 0±2% MeOH/Et₂O gradient elution to provide the

b-ketophosphonate 1 #3.2 mg, 54%) as a thin ®lm. Data for

22

1: R_f0.09 #100% Et₂O, PAA); [a]_D221.6 #c0.25,

CH₂Cl₂); IR #thin ®lm) 2922, 2851, 1717, 1514, 1462,

1

1250, 1057, 1036, 997, 883, 819 cm²¹; H NMR #C₆D₆,

300 MHz) d 7.65±7.72 #m, 4H), 7.33±7.45 #m, 6H),

7.25±7.31 #m, 2H), 6.87±6.91 #m, 2H), 4.49 #AB_q, 2H,

J_AB11.3 Hz, Dn/236.4 Hz), 4.12 #m, 1H), 4.10 #ddd,

1H, J7.5, 4.4, 0.3 Hz), 4.01±4.07 #m, 1H), 4.00 #dd, 1H,

J5.8, 2.4 Hz), 3.83 #s, 3H), 3.75±3.81 #m, 1H), 3.77 #d,

3H, J_P±H11.8 Hz), 3.76 #d, 3H, J_P±H11.9 Hz), 3.60±3.69

#m, 2H), 3.31 #bt, 1H, J2.8 Hz), 3.23 #bs, 1H), 3.11 #A of

ABX, 1H, J_AB14.1 Hz, J_AXJ_H±P22.7 Hz), 3.03 #B of

ABX, 1H, J_AB14.1 Hz, J_BXJ_H±P22.1 Hz), 2.97 #dd,

1H, J16.1, 8.5 Hz), 2.45 #dd, 1H, J16.1, 4.3 Hz),

2.09±2.23 #m, 2H), 1.93±2.05 #m, 2H), 1.80±1.91 #m,

2H), 1.15±1.60 #m, 4H), 0.98±1.06 #m, 45H), 0.95 #d, 3H,

2.1.26. Preparation of the Cꢀ41)-ꢀmethoxybenzyloxy)

methyl ester 25. Alcohol 24 #3.0 mg, 0.0031 mmol) and

5 equiv. of the MPM±trichloroacetimidate^78±80in 1 mL of

Et₂O were cooled to 2788C. An aliquot from a 0.10 M

solution of BF₃´Et₂O in Et₂O #68 mL, 0.0068 mmol) was

added to the reaction. After 30 min, only traces of starting

material remained, and the reaction was quenched by the

addition of 5% HCl#aq) and warmed to rt. The mixture was

B. C. Austad et al. / Tetrahedron 58 .2002) 2011±2026

2025

J6.8 Hz), 0.94 #d, 3H, J6.9 Hz), 0.80±0.90 #m, 6H); ¹³

C

#c) Wang, Y.; Habgood, G. J.; Christ, W. J.; Kishi, Y.; Little-

®eld, B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2000, 10,

1029±1032. #d) Towle, M. J.; Salvato, K. A.; Budrow, J.;

Wels, B. F.; Kuznetsov, G.; Aalfs, K. K.; Welch, S.; Zheng,

W.; Seletsky, B. M.; Palme, M. H.; Habgood, G. J.; Singer,

L. A.; DiPietro, L. V.; Wang, Y.; Chen, J. J.; Quincy, D. A.;

Davis, A.; Yoshimatsu, K.; Kishi, Y.; Yu, M. J.; Little®eld,

B. A. Cancer Res. 2001, 61, 1013±1021.

NMR #CDCl₃, 75.4 MHz) d 201.2, 199.9, 159.3, 135.8,

135.7, 133.9, 133.6, 130.8, 129.8, 129.5, 127.5, 113.8,

96.9, 80.8, 79.6, 77.2, 74.8, 71.8, 71.6, 70.7, 69.4, 67.9,

55.3, 52.9, 46.0, 37.8, 37.0, 34.8, 31.9, 30.1, 29.7, 26.9,

25.8, 23.2, 22.7, 19.1, 18.2, 17.8, 14.1, 13.1, 12.7; ³¹P

NMR #CDCl₃, 75.4 MHz) d 23.4 #s); MS #FAB) m/e

#relative intensity, assignment); exact mass calcd for

C₆₄H₁₀₅O₁₂PSi₃1Na¹

requires

1203.6549,

found

13. Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463±

3466.

1203.6592.

14. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung,

S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33,

1549±1552.

Acknowledgements

15. Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi,

Y. Tetrahedron Lett. 1992, 33, 1553±1556.

Support of this research from the NIH #Grant CA 74394),

P®zer, and Merck is gratefully acknowledged, as is the

support of the departmental NMR facilities by grants from

the NIH #ISIO RRO 8389-01) and NSF #CHE-9208463).

We thank Drs Douglas R. Powell and Randy K. Hayashi

for X-ray crystallographic analysis.

16. Duan, J. J. W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 7541±

7544.

17. Fang, F. G.; Kishi, Y.; Matelich, M. C.; Scola, P. M.

Tetrahedron Lett. 1992, 33, 1557±1560.

18. Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8643±

8646.

19. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung,

S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.;

Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162±3164.

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3813±3816. #b) DiFranco, E.; Ravikumar, V. T.; Salomon,

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Article Doi

Halichondrin B: Synthesis of the C(37)-C(54) subunit

DOI: 10.1016/S0040-4020(02)00050-9

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