Stereoselective construction of the tricyclic core of neoliacinic acid

Stereoselective Construction of the Tricyclic Core of Neoliacinic

Acid

J. Stephen Clark,*^,†Carl A. Baxter,^‡Alexander G. Dossetter,^‡Ste´phane Poigny,^‡

Jose´ L. Castro,^§,|and William G. Whittingham

WestCHEM, Department of Chemistry, Joseph Black Building, UniVersity of Glasgow, UniVersity AVenue,

Glasgow, G12 8QQ, United Kingdom, School of Chemistry, UniVersity of Nottingham, UniVersity Park,

Nottingham, NG7 2RD, United Kingdom, Merck Sharp and Dohme, Neuroscience Research Centre,

Terlings Park, Harlow, Essex, CM20 2QR, United Kingdom, and Crop Protection Research Chemistry,

Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom

stephenc@chem.gla.ac.uk

ReceiVed October 8, 2007

The tricyclic core of the plant-derived sesquiterpene natural product neoliacinic acid was synthesized

using a novel synthetic strategy. The pivotal synthetic transformations are construction of the key bicyclic

ether-bridged intermediate by sequential deployment of metal carbenoid C-H insertion and ylide-forming

reactions and installation of the lactone portion of neoliacinic acid by an acid-catalyzed intramolecular

ring-opening reaction of an epoxide with a carboxylic acid.

Introduction

that had been collected in Costa Rica,²and badgerin (3), isolated

from the Montana sagebrush Artemesia arbuscula.³The lactone

4 and tanargyrolide (5), which were isolated from Tanacetum

argyrophyllum and possess significant anti-bacterial activity, also

belong to this family of sesquiterpene natural products.⁴

Although little is known about the bioactivity of neoliacinic

acid (1), the workers who first isolated the compound suggested

that it might possess anti-tumor activity because neoliacine, a

very closely related sesquiterpene isolated from the same plant,

displays moderate cytotoxicity.⁵However, there have been no

further reports concerning the bioactivity of neoliacinic acid,

Neoliacinic acid (1) is a highly oxidized sesquiterpene natural

product, first isolated by acetone extraction of fresh leaves of

the plant Neolitsea acciculata Koidz by Takaoka and co-workers

in 1987.¹It is one of several structurally related ether-bridged

sesquiterpene lactones that have been isolated from a variety

of plant sources worldwide over the past 35 years. Other

members of this family of natural products include the epoxide

2, isolated from a sample of the plant Milleria quinqueflora

* Corresponding author. Fax: 44-141-330-4888.

^†University of Glasgow.

^‡University of Nottingham.

(2) Jakupovic, J.; Castro, V.; Bohlmann, F. Phytochemistry 1987, 26,

2011-2017.

(3) Shafizadeh, F.; Bhadane, N. R. J. Org. Chem. 1972, 37, 274-277.

(4) Go¨ren, N.; Jakupovic, J.; Topal, S. Phytochemistry 1990, 29, 1467-

1469.

^§Merck Sharp and Dohme.

^|Current address: GlaxoSmithKline, Neurology CEDD, New Frontiers

Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Syngenta.

(1) Takaoka, D.; Nozaki, H.; Nakayama, M. J. Chem. Soc., Chem.

Commun. 1987, 1861-1862.

(5) Nozaki, H.; Hiroi, M.; Takaoka, D.; Nakayama, M. J. Chem. Soc.,

Chem. Commun. 1983, 1107-1108.

Published on Web 01/03/2008

1040

J. Org. Chem. 2008, 73, 1040-1055

Construction of Tricyclic Core of Neoliacinic Acid

SCHEME 1. Retrosynthetic Analysis of Neoliacinic Acid

FIGURE 1. Various plant-derived sesquiterpene natural products

possessing an ether bridged core.

and so at present, there is no evidence to suggest that the

compound is a cytotoxic agent.

The complex ether-bridged tricyclic framework of neoliacinic

acid (1) makes it a highly attractive but challenging synthetic

target. The dense array of oxygen-containing functionalities at

different oxidation levels coupled with the contiguous nature

of the stereogenic centers that adorn the interlocking tricyclic

core of the natural product presents a formidable challenge to

current methods for ring construction and stereocontrol. In spite

of the obvious attraction of neoliacinic acid as a target, there

have been only two reports concerning synthetic endeavors

toward this compound: our own preliminary synthetic work⁶

and that of Paget and Paquette⁷concerning the construction of

a functionalized 3-methylenetetrahydropyran as a potential

building block for conversion into the natural product.

Over the past 15 years, we have explored the use of sequential

one-pot catalytic carbenoid formation, intramolecular oxonium

ylide generation, and ylide rearrangement to construct cyclic

ethers in a diastereoselective manner.⁸We wished to employ

this potentially powerful sequence as the key ring-forming

reaction to construct the bridged bicyclic ether core of neolia-

cinic acid and so performed our retrosynthetic analysis to

incorporate the corresponding disconnection. In studies per-

formed since the publication of our preliminary work on

neoliacinic acid,⁶we have used this key reaction sequence to

construct the bridged ether cores of marine diterpene natural

products of the cladiellin/eunicellin family; this work has

culminated in the total synthesis of (()-vigulariol and the core

ring system found in labiatin A.⁹

Retrosynthetic analysis of neoliacinic acid (1) incorporating

the key ylide rearrangement strategy is shown in Scheme 1. It

was anticipated that the natural product would be constructed

from a late-stage intermediate corresponding to the polyhy-

droxylated ether-bridged bicyclic system i obtained by retrosyn-

thetic opening of the lactone and various reductive functional

group interconversions (FGIs) such as replacement of the enone

with a 1,3-diol. The late-stage intermediate i possesses the six

stereogenic centers found in neoliacinic acid (1) and all of the

requisite oxygen functionality. This analysis requires introduc-

SCHEME 2. Synthesis of the Allylic Bromide 8

(6) (a) Clark, J. S.; Dossetter, A. G.; Blake, A. J.; Li, W. S.; Whittingham,

W. G. Chem. Commun. 1999, 749-750. (b) Clark, J. S.; Dossetter, A. G.;

Whittingham, W. G. Tetrahedron Lett. 1996, 37, 5605-5608.

(7) Paget, S. G.; Paquette, L. A. J. Indian Chem. Soc. 1999, 76, 515-

520.

(8) (a) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193-6196. (b) Clark, J.

S.; Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385-4388.

(c) Clark, J. S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381-6382.

(d) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N. Chem. Commun. 2003,

2578-2579. (e) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6,

1773-1776.

(9) (a) Clark, J. S.; Hayes, S. T.; Wilson, C.; Gobbi, L. Angew. Chem.,

Int. Ed. 2007, 46, 437-440. (b) Clark, J. S.; Baxter, C. A.; Castro, J. L.

Synthesis 2005, 3398-3404.

J. Org. Chem, Vol. 73, No. 3, 2008 1041

Clark et al.

SCHEME 3. Synthesis of the Diazo Ketone 15

tion of the enone and oxidation of the side chain late in the

synthesis. The compound i possesses four free hydroxyl groups

that correspond to two discrete 1,2-diol units. Recognition of

this functionality suggests further disconnection by retrosynthetic

double dihydroxylation, affording the diene ii. In a forward

sense, it seemed likely that a double dihydroxylation reaction

would lead to the required stereochemical outcome as a

consequence of the conformational preference of the diene ii.

Removal of the methylene group of the exocyclic alkene to

reveal a ketone and conversion of the allylic alcohol into a

transposed alkene then leads to the ketone iii, which would be

the product arising from [2,3] rearrangement of the oxonium

ylide generated by intramolecular trapping of a metal carbenoid

derived from the diazo ketone iv. Further simplification produces

the dihydro-3(2H)-furanone v, and a retrosynthetic carbenoid

C-H insertion reaction then reveals the diazo ketone vi. The

diazo ketone vi could be accessed from the relatively simple

allylic bromide vii and alcohol viii, both of which should be

readily available from simple chiral pool starting materials. Thus,

two of the stereogenic centers would be obtained from the

starting materials used to prepare intermediates vii and viii, and

the other four stereogenic centers would be introduced using

substrate control. In addition, the two key ring-forming reactions

would be accomplished by exploiting two contrasting facets of

metal carbenoid reactivity; two different catalysts would be used

to control chemoselectivity.

Peterson elimination and delivered the allylic silane 7 in

excellent yield.^11,12Reaction of the allylic silane 7 with

pyrrolidone hydrotribromide in THF, with careful control of

temperature, then delivered the required allylic bromide 8.¹³

The alcohol 11, required for coupling to the allylic bromide

8, was prepared from the commercially available D-mannitol-

derived bis-acetonide 10 in high yield (Scheme 3). Periodate

cleavage of the diol 10 afforded (R)-isopropylideneglyceralde-

hyde, which was then subjected to chelation-controlled addition

of the organocopper reagent prepared from copper(I) iodide and

3-[(4-methoxybenzyl)oxy]propylmagnesium bromide.¹⁴The al-

cohol 11 was then coupled to the allylic bromide 8 using

standard Williamson ether conditions to give the allylic ether

12. Acid-catalyzed removal of the acetonide protecting group

afforded the corresponding 1,2-diol, and treatment of this diol

with sodium periodate resulted in oxidative cleavage and

delivered the aldehyde 13 in excellent yield. A buffered chlorite

oxidation reaction¹⁵then provided the carboxylic acid 14, and

conversion of this compound into the diazo ketone 15 was

accomplished by treatment with isobutyl chloroformate and

reaction of the resulting mixed anhydride with a large excess

of ethereal diazomethane. The sequence of chlorite oxidation

and diazo ketone formation was highly efficient (94% over two

steps) and amenable to scale-up; multigram quantities of the

diazo ketone 15 could be obtained using this route.

The first key ring-forming reaction in our synthetic routes

intramolecular diastereoselective C-H insertion to produce the

tetrahydrofuranswas now explored (Scheme 4).¹⁶The reaction

is complicated by the fact that there is more than one potential

site for C-H insertion of the intermediate carbenoid. In addition,

competing cyclopropanation of the alkene and anomalous C-H

Results and Discussion

The allylic bromide 8, required for introduction of the side

chain and corresponding to the fragment vii in the retrosynthetic

analysis, was prepared first (Scheme 2). This bromide was

synthesized in just two steps from a triisopropylsilyl-protected

Roche ester (6). Treatment of the ester 6 with 3 equiv of the

organocerium reagent generated by reaction of trimethylsilyl-

methylmagnesium chloride with anhydrous cerium(III) chlo-

ride¹⁰resulted in double Grignard addition.¹¹Workup and

exposure of the crude tertiary alcohol to silica gel facilitated

(12) Mickleson, T. J.; Koviach, J. L.; Forsyth, C. J. J. Org. Chem. 1996,

61, 9617-9620.

(13) (a) Grafstein, D. J. Am. Chem. Soc. 1955, 77, 6650-6651. (b)

Awang, D. V. C.; Wolfe, S. Can. J. Chem. 1969, 47, 706-709.

(14) (a) Jackson, D. Y. Synth. Commun. 1988, 18, 337-341. (b) Sato,

F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.; Kusakabe, M. J.

Chem. Soc., Chem. Commun. 1985, 1636-1638.

(15) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,

37, 2091-2096.

(16) (a) Adams, J.; Frenette, R. Tetrahedron Lett. 1987, 28, 4773-4774.

(b) Adams, J.; Poupart, M.-A.; Grenier, L.; Schaller, C.; Ouimet, N.;

Frenette, R. Tetrahedron Lett. 1989, 30, 1749-1752. (c) Adams, J.; Poupart,

M.-A.; Grenier, L. Tetrahedron Lett. 1989, 30, 1753-1756. (d) Spero, D.

M.; Adams, J. Tetrahedron Lett. 1992, 33, 1143-1146.

(10) Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37,

6787-6790.

(11) (a) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,

6261-6264. (b) Lee, T. V.; Channon, J. A.; Cregg, C.; Porter, J. R.; Roden,

F. S.; Yeoh, H. T.-L. Tetrahedron 1989, 45, 5877-5886.

1042 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

SCHEME 4. Synthesis of the Diazo Ketone 21

insertion of the carbenoid¹⁷are possible side reactions. The

success of the reaction also requires stereoselective insertion

of the carbenoid into one of the diastereotopic C-H bonds to

deliver the required cis substituted cyclic ether. To circumvent

these potential problems, we surveyed a wide range of rhodium-

(II) complexes. After extensive investigation of the reaction,

we found that rhodium(II) trifluoroacetamide was the optimum

complex for carbenoid generation;^17,18the carbenoid generated

from this complex in THF at reflux gave good levels of

diastereocontrol while producing minimal amounts of other

C-H insertion products and those arising from competing

cyclopropanation.

The highest yields of the tertiary alcohol 16 were obtained

when intramolecular C-H insertion and nucleophilic addition

of the methyl fragment were performed without isolation of the

intermediate ketone (cf. the ketone v in Scheme 1)sseparation

of the alcohol from minor byproducts arising during the C-H

insertion reaction was more straightforward than at the ketone

stage, and the alcohol 16 was more stable to purification.

Originally, the methyl group was introduced by treatment of

the intermediate ketone with trimethylaluminum,¹⁹but on scale-

up, this procedure afforded only modest yields of the alcohol

16 (34% over two steps). Fortunately, when methylmagnesium

chloride was used to install the methyl group, a substantially

improved yield of the alcohol 16 (56% over two steps) was

obtained on a >12 mmol scale. The Grignard addition reaction

was highly diastereoselective, but it was difficult to gauge the

exact level of diastereocontrol resulting from the addition of

methylmagnesium chloride to the major C-H insertion pro-

duct because several side products, including small amounts of

those arising from the addition of methylmagnesium chloride

to the minor trans disubstituted C-H insertion product, were

obtained, and complete separation of the minor products was

not possible.

Conversion of the alcohol 16 into the key cyclization pre-

cursor 21 was accomplished in five steps (Scheme 4). Acetyl-

ation of the tertiary alcohol 16 to give the acetate 17 followed

by removal of the p-methoxybenzyl protecting group using 2,3-

dichloro-5,6-dicyano-p-benzoquinone (DDQ) under aqueous

conditions afforded the primary alcohol 18. Oxidation of the

primary hydroxyl group to give the aldehyde 19 was performed

using the Dess-Martin periodinane,²⁰and subsequent chlorite

oxidation delivered the corresponding carboxylic acid 20.¹⁵The

diazo ketone 21 was then obtained by conversion of the sodium

salt of carboxylic acid 20 into the corresponding acid chloride

and subsequent treatment with an ethereal solution of diazome-

thane. The diazo ketone 21 required for the pivotal cyclization

reaction could be prepared in >6 mmol scale using this protocol.

In the course of model studies^6band those involving related

substrates,⁸we had established that copper(II) hexafluoroacety-

lacetonate was the catalyst of choice for the key oxonium ylide

formation and rearrangement sequence. However, we needed

to perform this reaction on a relatively large scale to obtain

sufficient amounts of material to complete the latter stages of

the synthesis. Using optimized reaction conditions (CH₂Cl₂at

reflux), the key cyclization reaction could be performed on a

reasonable scale (6 mmol), giving gram quantities of the ether-

(17) (a) Clark, J. S.; Dossetter, A. G.; Wong, Y.-S.; Townsend, R. J.;

Whittingham, W. G.; Russell, C. A. J. Org. Chem. 2004, 69, 3886-3898.

(b) Clark, J. S.; Dossetter, A. G.; Russell, C. A.; Whittingham, W. G. J.

Org. Chem. 1997, 62, 4910-4911.

(18) Dennis, A. M.; Korp, J. D.; Bernal, I.; Howard, R. A.; Bear, J. L.

Inorg. Chem. 1983, 22, 1522-1529.

(19) (a) Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75, 521-546.

(b) Nicoloau, K. C.; Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc. 1989,

111, 6666-6675.

(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-

7287.

J. Org. Chem, Vol. 73, No. 3, 2008 1043

Clark et al.

SCHEME 5. Ylide Formation and Rearrangement to Give

the Oxabicyclic Ketone 23

SCHEME 6. Synthesis of the Allylic Alcohol 27

bridged compounds 23 and 24 in a combined yield of 85%,

with the required [2,3] rearrangement product 23 (3:2, E/Z

isomer mixture) predominating.

Successful construction of the oxabicyclo[5.3.1]undecane core

of neoliacinic acid allowed introduction of the functionality

required for construction of the third ring to be explored. The

first issue to be addressed was isomerization of the mixture of

alkenes 23 (Scheme 6). The thermodynamically favored Z-

alkene was obtained in quantitative yield by exposure of the

alkene mixture to ethanethiol and azobisisobutyronitrile (AIBN)

in benzene at reflux.²¹Highly diastereoselective epoxidation of

alkene Z-23 was then accomplished using purified m-CPBA (to

avoid competing Baeyer-Villiger oxidation), and the structure

of the crystalline epoxide 25 was confirmed by X-ray

crystallography.^6a

The next objective was the regioselective ring opening of

the epoxide to deliver an allylic alcohol corresponding to the

intermediate ii in our retrosynthetic analysis (Scheme 1). In

principle, the epoxide could be converted into an allylic alcohol

either using a lithium amide base²²or under Lewis acidic

conditions.²³Although methylenation of the ketone carbonyl

group could be undertaken before or after conversion of the

epoxide into an allylic alcohol, many of the reagents required

to undertake the latter transformation are incompatible with the

ketone carbonyl group, and so we opted to perform methyl-

enation prior to introduction of the allylic alcohol. Methylenation

of the ketone 25 to give the alkene 26 was accomplished in

good yield using either dimethyltitanocene²⁴or by employing

the Nysted protocol.²⁵However, the Petasis protocol proved to

be the more reliable of the two methods, and so this method

was employed routinely.²⁴

Conversion of the epoxide 26 into the required allylic alcohol

was attempted using a wide range of Lewis acids and amide

bases, but only one set of conditions delivered viable yields of

the requisite allylic alcohol: treatment of the epoxide 26 with

aluminum triisopropoxide in toluene at reflux afforded the allylic

alcohol 27 (60% yield) with concomitant loss of the acetate

group.²⁶The unexpected tetrahydropyran diol 28 was also

formed (5.5:1 mixture of two diastereomers) under the reaction

conditions; this compound probably arises by Lewis acid

complexation of the epoxide and nucleophilic attack by the

bridging ether to give an oxonium ion, followed by sequential

ring scission, hydride migration, and in situ Meerwein-

Ponndorf-Verley reduction of the resulting complexed ketone

(Scheme 7).²⁷

The stage was now set for rapid introduction of much of the

oxygen functionality that adorns the core of the natural product.

The secondary and tertiary hydroxyl groups of the diol 27 were

first protected as triethylsilyl ethers to afford the diene 29

(21) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.; Raimondi, L.

J. Org. Chem. 1987, 52, 4674-4681.

(22) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345-443.

(23) Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.; Nozaki, H. J.

Am. Chem. Soc. 1974, 96, 6513-6514.

(25) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313-315.

(26) Matsui, J.; Yokota, T.; Bando, M.; Takeuchi, Y.; Mori, K. Eur. J.

Org. Chem. 1999, 2201-2210.

(24) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-

6394.

(27) Hach, V. J. Org. Chem. 1973, 38, 293-299.

1044 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

SCHEME 7. Proposed Reaction Mechanism for Formation

of the Diene 28

SCHEME 8. Synthesis of the Diol 30

SCHEME 9. Synthesis of the Hydroxy Ester 33

(Scheme 8). Initially, we had expected to perform simultaneous

dihydroxylation of both alkenes in the diene 29 using osmium

tetroxide. However, under standard conditions for catalytic

dihydroxylation, in which a sub-stoichiometric amount of

osmium tetroxide is used and N-methylmorpholine N-oxide is

employed as the stoichiometric reoxidant,²⁸the endocyclic

trisubstituted alkene proved to be remarkably resistant to

oxidation, and a clean and highly diastereoselective reaction of

the exocyclic alkene was accomplished, delivering the diol 30

in good yield.

The unexpected formation of the diol 30 rather than the

product arising from double dihydroxylation was a minor

problem that necessitated reordering of some of the synthetic

operations. We expected to be able to oxidize the primary

hydroxyl group of the diol 30 to give the corresponding

carboxylic acid and then perform dihydroxylation of the

trisubstituted alkene followed by lactonization with inversion

of configuration at the stereogenic center bearing the secondary

hydroxyl group of the 1,2-diol.

Various single (conditions D) and two-step oxidation proce-

dures (conditions A-C) were investigated to oxidize the diol

30 and thus generate the carboxylic acid 32 (Scheme 9).

However, this transformation proved to be extremely difficult

to effect in high yield, and substantial decomposition was

observed during isolation and storage of the carboxylic acid 32

or the intermediate aldehyde 31 (Scheme 9).²⁹To circumvent

this problem, it was necessary to convert the carboxylic acid

32 into the corresponding methyl ester 33 by immediate

treatment with either diazomethane or trimethylsilyl diaz-

omethane. The most consistent yields of the methyl ester 33

were obtained when diol 30 was oxidized sequentially using

the Parikh-Doering procedure (conditions B),³⁰followed by

chlorite oxidation,¹⁵and the resulting carboxylic acid was

immediately esterified using trimethylsilyl diazomethane.

The finding that modest yields are obtained when the diol

30 is oxidized to give the carboxylic acid 32 is consistent with

reports of fragmentation during oxidation reactions of related

vicinal diols.²⁹The fact that a substantial amount of the ketone

34 was obtained from the sequence in which a TEMPO-

mediated oxidation reaction (conditions C) was used to convert

the diol 30 into the aldehyde 31suggests that diol 30 undergoes

cleavage during oxidation or that the intermediate aldehyde 31

is unstable.

The synthesis of the methyl ester 33, albeit in modest yield,

meant that the second dihydroxylation reaction could be

performed (Scheme 10). In this case, stoichiometric quantities

of osmium tetroxide and a large excess of pyridine were required

to accomplish complete dihydroxylation of the sterically

hindered and unreactive trisubstituted alkene.^28,31The triol 35

was obtained as a single diastereoisomer in good yield from

1

the dihydroxylation reactionsthe H NMR spectrum of this

compound is diagnostic, showing an upfield shift for the methyl

group of the ester from δ 3.80 to δ 3.35 ppm, possibly as a

result of hydrogen bonding between the secondary hydroxyl

group and the ester carbonyl group. In addition, one of the

(28) For a review of alkene dihydroxylation using osmium tetroxide,

see: Schro¨der, M. Chem. ReV. 1980, 80, 187-213.

(29) Aladro, F. J.; Guerra, F. M.; Moreno-Dorado, F. J.; Bustamante, J.

M.; Jorge, Z. D.; Massanet, G. M. Tetrahedron Lett. 2000, 41, 3209-3213.

(30) Parikh, J. R.; Doering W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-

5507.

(31) Creigee, R. Justus Liebigs Ann. Chem. 1936, 522, 75-96.

J. Org. Chem, Vol. 73, No. 3, 2008 1045

Clark et al.

SCHEME 10. Attempted Closure of the Lactone with

Inversion of Configuration

SCHEME 11. Closure of the Third Ring

epoxide 38, the two possible modes of cyclizations5-exo-tet

and 6-endo-tetslead to two different products (39 and 40), and

the conditions under which the reaction is performed are likely

to have a considerable bearing on the outcome of the reaction.

Initially, base-mediated cyclization to give the cyclic ether via

a 5-exo-tet process was explored. However, treatment of the

epoxy diol 38 with anionic bases, such as potassium t-butoxide

and sodium hydride, or with the phosphazene bases developed

by Schwesinger et al.,³⁶failed to induce cyclization, and

substantial quantities of starting material were recovered from

these reactions.

triethylsilyl groups displays restricted rotation, possibly indicat-

ing that the system is rigidified by hydrogen bonding.

To construct the lactone 37 possessing the stereochemistry

found in neoliacinic acid (1), it was necessary to invert the

configuration at the stereogenic center bearing the secondary

hydroxyl group of the triol 35 (Scheme 10). Two approaches

were conceivable: inversion of configuration prior to lacton-

ization, or inversion during the lactonization reaction itself.

Initially, inversion of configuration was attempted using an

oxidation-reduction sequence, but the diol 35 was resistant to

oxidation, and even direct formation of R-hydroxy ketone 36

from the alkene 33 was not successful.³²Attempted activation

of the secondary hydroxyl group using Mitsunobu conditions³³

or by formation of the cyclic sulfate of the 1,2-diol,³⁴followed

by S_N2 displacement with a variety of external oxygen nucleo-

philes or intramolecularly with the free carboxylic acid, also

failed to deliver the lactone 37.

From the previous results, it was clear that the secondary

hydroxyl group of the triol 35 was extremely hindered and that

it would not be possible to invert the configuration of the

hydroxyl-bearing stereogenic center. This conclusion neces-

sitated substantial revision of our synthetic plan to avoid the

reaction sequence shown in Scheme 10. Reanalysis of the latter

part of our synthetic strategy led us to investigate formation of

the third ring by intramolecular nucleophilic opening of an

epoxide rather than esterification or displacement of an activated

alcohol.

Attention then turned to acid-mediated epoxide opening

reactions, in spite of obvious concerns that the epoxide 38 might

undergo competing 6-endo-tet cyclization at the more substituted

position instead of the required 5-exo-tet reaction. Treatment

of epoxide 38 with camphor sulfonic acid at 40 °C gave a single

compound in 75% yield (Scheme 11).^35,37Extensive NMR

analysis (¹H, ¹³C, DEPT, COSY, HMQC, and NOESY) of the

product failed to establish which of the two possible products

(39 and 40) had been produced. However, in an HMBC

experiment, a three-bond coupling was observed between the

carbon c and the protons a and b. This provides good evidence

for the formation of the required tricyclic compound 39 rather

than the 6-endo-tet product 40 because three-bond coupling

between carbon c and proton b is not possible in the latter

compound. The ¹H NMR spectrum of 39 has some other features

that are worthy of note. First, the protons a and b are coupled

with a J value of 4.7 Hz, whereas in the neoliacinic acid methyl

ester, the corresponding protons couple with a J value of 4.0

Hz. The signals corresponding to protons at carbon c have also

The epoxide required for further studies was prepared by

epoxidation of the alkene 30 (Scheme 11). Careful treatment

of this alkene with m-CPBA resulted in highly diastereoselective

epoxidation to give the epoxide 38 in 86% yield as a single

diastereomer. The next step was intramolecular opening of the

epoxide with the primary hydroxyl group, a reaction for which

there are abundant literature precedents.³⁵In the case of the

1

moved significantly in the H NMR spectrum when compared

to those in the starting epoxide 38 and now appear as two

separate doublets at δ 3.96 and 3.36 ppm with a geminal J value

(35) (a) Matsukura, H.; Morimoto, M.; Koshino, H.; Nakata, T.

Tetrahedron Lett. 1997, 38, 5545-5548. (b) Fujiwara, K.; Tokiwano, T.;

Murai, A. Tetrahedron Lett. 1995, 36, 8063-8066. (c) Gonza´lez, I. C.;

Forsyth, C. J. Tetrahedron Lett. 2000, 41, 3805-3807.

(36) (a) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. 1987,

26, 1167-1169. (b) Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz,

L.; Peters, E.-M.; Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.

1993, 32, 1361-1363.

(37) Lanthanide triflates were also investigated as catalysts, but only trace

amounts of the required cyclic ether 39 were obtained using LaOTf₃or

ScOTf₃. A 32% yield of 39 was obtained when the reaction was performed

using Cu(BF₄)₂in CH₂Cl₂at room temperature.

(32) (a) Lablanc, Y.; Black, W. C.; Chan, C. C.; Charleson, S.; Delorme,

D.; Denis, D.; Gauthier, J. Y.; Grimm, E. L.; Gordon, R.; Guay, D.; Hamel,

P.; Kargman, S.; Lau, C. K.; Mancini, J.; Ouellet, M.; Percival, D.; Roy,

P.; Skorey, K.; Tagari, P.; Vickers, P.; Wong, E.; Xu, L.; Prasit, P. Bioorg.

Med. Chem. Lett. 1996, 6, 731-736. (b) David, K.; Greiner, A.; Gore´, J.;

Gazes, B. Tetrahedron Lett. 1996, 37, 3333-3334.

(33) Mitsunobu, O. Synthesis 1981, 1-28.

(34) Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-

7091.

1046 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

SCHEME 12. Attempted Oxidation of the Tricyclic Diol 39

to Form the Lactone 37

SCHEME 13. Closure of the Lactone 37

of 9.4 Hz, rather than as a single peak at 3.65 ppm. Only one

of the hydroxyl group protons (that next to the side chain) can

1

be detected in the H NMR spectrum when it is obtained in

either CDCl₃(singlet δ 4.70 ppm) or C₆D₆, and the signal

disappears when D₂O is added to the NMR sample.

SCHEME 14. Possible Acid-Catalyzed 6-endo-tet

Cyclization with Acyl Group Migration

The successful outcome of the cyclization reaction was

significant because for the first time, we had constructed the

complete tricyclic ring system of neoliacinic acid with all six

of the stereogenic centers in place and with a high degree of

stereocontrol. The next objective was the introduction of the

lactone carbonyl group by oxidation of the methylene group

present in the tetrahydrofuran portion of the tricyclic compound

39. One particularly attractive method for performing this

oxidation reaction involves the use of ruthenium tetroxide.³⁸

Paquette and co-workers successfully exploited this reaction to

oxidize a structurally complex polycyclic substrate that was

similar to our own, as the final step in their total synthesis of

(+)-asteriscanolide,³⁹and so we were reasonably confident that

we could perform the same transformation on our compound.

Various oxidative conditions to effect this transformation were

investigated (Scheme 12). However, the lactone 37 was not ob-

tained from any of these oxidation reactions, and instead, oxida-

tion and subsequent elimination occurred at one of the bridge-

head methine positions. Ruthenium tetroxide, prepared in situ

from ruthenium(III) chloride and sodium periodate,⁴⁰afforded

the unexpected alkene 41 in 75% yield (based on recovered

starting material). More esoteric reagents such as dimanganese

heptoxide⁴¹delivered the same product (41), but in lower yield,

whereas treatment of 39 with PCC⁴²resulted in no reaction.

These results were disappointing, but most literature examples

of the direct oxidation of cyclic ethers to give lactones involve

simple substrates, and few methods are available for the efficient

oxidation of more complex furan-containing systems.³⁸

It was not possible to oxidize a cyclic ether intermediate to

produce the required lactone, and so clearly it was necessary to

undertake the cyclization reaction using a substrate in which

the correct oxidation level had already been achieved. In

practice, this would mean effecting ring closure by opening the

epoxide with a carboxylic acid or ester under acidic conditions

(Scheme 13).⁴³On the basis of the protocol employed to prepare

(38) Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980,

10, 205-211.

(39) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am.

Chem. Soc. 2000, 122, 2742-2748.

(40) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.

Org. Chem. 1981, 46, 3936-3938.

(41) (a) Ito, K.; Fukuda, T.; Katsuki, T. Heterocycles 1997, 46, 401-

411. (b) Tro¨mel, M.; Russ, M. Angew. Chem., Int. Ed. 1987, 26, 1007-

1009.

(42) (a) Bonini, C.; Iavarone, C.; Trogolo, C.; Di Fabio, R. J. Org. Chem.

1985, 50, 958-961. (b) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975,

31, 2647-2650.

J. Org. Chem, Vol. 73, No. 3, 2008 1047

Clark et al.

SCHEME 15. Formation of the Lactone 47 with Retention of Configuration

the methyl ester 33 (Scheme 9), a two-step TEMPO and chlorite

oxidation sequence was used to give the acid 42. Concerns

regarding the instability of the intermediate carboxylic acid

proved to be well-founded and prompted us to treat the crude

product immediately with camphor sulfonic acid to give two

products that were tentatively assigned as the lactone 37 and

the bicyclic ketone 43. The lactone 37 was formed in a 38%

yield over three steps, with the fragmentation product 43 making

up a significant proportion of the mass balance (44% yield).

Several other oxidation procedures were investigated, but there

was no improvement in yield of lactone 37 and an increased

amount of the fragmentation product 43 was obtained in some

cases.

In principle, both the 5-exo and the 6-endo modes of

cyclization were possible, and so proving that constructing the

lactone 37 was more difficult than expected. A peak at 1777

cm^-1was observed in the IR spectrum of the cyclization

product, which is indicative of a five-membered lactone, but it

is conceivable that two different five-membered lactones could

be isolated from the acid-mediated cyclization reaction (Scheme

14). The lactone 37 arises from direct 5-exo cyclization of the

acid onto the epoxide, giving the stereochemistry corresponding

to that found in the natural product. The lactone 45 would arise

from a 6-endo-tet cyclization to give the intermediate lactone

44 followed by acyl group migration to the less hindered

secondary hydroxyl group. Unfortunately, ¹H NMR NOE

experiments did not provide firm evidence on which to make

an unambiguous structural assignment. However, the NMR data

strongly suggest that the lactone 37 was formed because the

magnitude of the coupling constant between the bridgehead

proton H_aand the lactone ring junction proton H_bis comparable

to that in the target compound (vide infra).

to give the lactone 47. The successful preparation of this new

lactone along with the availability of the two tricyclic systems

synthesized previously allowed ¹H NMR data for this series of

compounds to be compared with that of methyl ester of the

natural product (Figure 2). This comparison is very informative

and reveals that the protons H_aand H_bin the cyclic ether 39

and the lactone 37 have similar coupling constants and that these

correlate well with the corresponding coupling constant in the

¹H NMR spectrum of neoliacinic acid methyl ester (48). The

lactone 47 shows a considerably larger coupling constant

between the protons H_aand H_b, as expected. On the basis of

this analysis, the lactone generated in Scheme 13 can be assigned

as compound 37. We are now confident that we have success-

fully prepared an advanced intermediate for the synthesis of

neoliacinic acid. This key intermediate contains the entire

tricyclic core of neoliacinic acid and possesses all six stereogenic

centers with the correct configuration.

Conclusion

The fully functionalized tricyclic lactone core of the sesquit-

erpene natural product neoliacinic acid has been synthesized in

a concise manner. Two metal carbenoid reactionssC-H

insertion and oxonium ylide formation and rearrangementswere

utilized to construct an oxabicyclic intermediate in an efficient

manner. Formation of the lactone by ring closure onto the

secondary hydroxyl of a 1,2-diol with inversion of configuration

before or during cyclization was not possible. However, acid-

catalyzed cyclization of a carboxylic acid onto an epoxide did

deliver the required lactone along with a significant amount of

the product resulting from cleavage of the sensitive R-hydroxy

aldehyde/carboxylic acid unit. The lactone diol 37 was con-

structed in a total of 24 steps from (R)-(+)-2,3-isopropylidene

glyceraldehyde and is the most advanced precursor to neoliacinic

acid yet prepared, possessing all three rings and all six of the

stereogenic centers present in the natural product.

To obtain further evidence confirming the synthesis of the

lactone 37, the methyl ester 35 was treated with an excess of

potassium trimethylsilanolate to afford the potassium carboxylate

salt 46 (Scheme 15).⁴⁴Acidic workup then resulted in cyclization

Experimental Section

Methyl (R)-3-[(Triisopropysilyl)oxy]-2-methylpropionate (6).

Triisopropylsilylchloride (36.5 mL, 171 mmol) was added over 10

min to a solution of methyl-(R)-(-)-3-hydroxy-2-methylpropionate

(20.17 g, 170.7 mmol) and imidazole (23.25 g, 341.5 mmol) in

dry DMF (60 mL) at room temperature under Ar. The mixture was

stirred at room temperature for 5 days and then poured into a two

phase mixture of water (70 mL) and ether (200 mL). The organic

layer was separated, and the aqueous layer was extracted with ether

(2 × 200 mL). The ether extracts were combined and washed with

water (150 mL) and brine (100 mL), then dried (MgSO₄), and

concentrated in vacuo to yield a clear oil. Vacuum distillation

(86 °C at 0.5 mmHg) gave the silyl ether 6 (45.84 g, 98%) as a

24

clear oil: R_f) 0.56 (petroleum ether-ethyl acetate, 19:1): [R]_D

(43) For related examples of lactone formation by epoxide opening,

see: (a) Paquette, L. A.; Sturino, C. F.; Wang, X.; Prodger, J. C.; Koh, D.

J. Am. Chem. Soc. 1996, 118, 5620-5633. (b) Paquette, L. A.; Koh, D.;

Wang, X.; Prodger, J. C. Tetrahedron Lett. 1995, 36, 673-676.

(44) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-

5834.

FIGURE 2. Comparison of key ring junction ¹H NMR coupling

constants for the tricyclic compounds 37, 39, and 47 with that of methyl

neoliacinate (48).

1048 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

-19.7 (c ) 1.17, CHCl₃); ν_max(CHCl₃) 2944, 2891, 2866, 1732

(100 MHz, CDCl₃) δ 148.7, 114.9, 68.4, 39.6, 37.5, 18.1, 16.8,

12.0. Anal. calcd for C₁₅H₃₁OSiBr: C, 53.72; H, 9.32. Found: C,

53.98; H, 9.08.

1

cm^-1; H NMR (400 MHz, CDCl₃) δ 3.86 (1H, dd, J ) 9.5, 6.7

Hz), 3.76 (1H, dd, J ) 9.5, 6.0 Hz), 3.67 (3H, s), 2.66 (1H, qdd,

J ) 7.0, 6.7, 6.0 Hz), 1.15 (3H, d, J ) 7.0 Hz), 1.10-0.98 (21H,

m); ¹³C NMR (100 MHz, CDCl₃) δ 175.6, 65.8, 51.5, 42.8, 18.0,

13.5, 12.2; HRMS (CI, CH₄) m/z calcd for C₁₄H₃₁O₃Si [M + H]⁺

275.2042, found 275.2045 (∆ 0.8 ppm). Anal. calcd for C₁₄H₃₀O₃-

Si: C, 61.26; H, 11.02. Found: C, 61.32; H, 10.82.

(S)-2-Methyl-1-[(triisopropylsilyl)oxy]-3-[(trimethylsilyl)meth-

yl]but-3-ene (7). Cerium(III) chloride heptahydrate (61.46 g, 165.0

mmol) was added to a 1 L three-necked round-bottomed flask and

dried under vacuum at 120 °C for 2 h and then at 160 °C for 2 h.

The flask was allowed to cool and was purged with N₂for 10 min,

and dry THF (250 mL) was added. The mixture was stirred for 20

h at room temperature under N₂, and sonication (2 × 50 min) of

the mixture then gave the cerium(III) chloride-THF complex as a

white precipitate.

A solution of (chloromethyl)trimethylsilane (20.77 mL, 163.7

mmol) in dry THF (130 mL) was added dropwise to a stirred

suspension of magnesium turnings (3.65 g, 150 mmol) and 1,2-

dibromoethane (4 drops) in dry THF (30 mL) under N₂. Formation

of the Grignard reagent was accomplished by heating the mixture

to reflux, followed by slow addition of the halide to maintain reflux.

The Grignard reagent was stirred at room temperature for 2 h and

then added by cannula to the cerium(III) chloride-THF complex at

-78 °C under N₂. The gray solution was stirred for 30 min, and

then the ester 6 (13.72 g, 49.99 mmol) in dry THF (30 mL) was

added (cannula) at -78 °C. The reaction was stirred at -78 °C for

2 h, the flask was then removed from the cold bath, and the mixture

was stirred at room temperature for 15 h. The reaction mixture

was cooled to 0 °C, a saturated solution of ammonium chloride

(150 mL) was added at 0 °C, and the mixture was stirred for 20

min. Water (500 mL) was added, and the mixture was extracted

with ether (3 × 300 mL). The combined ether extracts were washed

with water (200 mL) and brine (100 mL), then dried (MgSO₄) and

concentrated in vacuo to give a yellow oil. The oil was loaded onto

a silica column and left on the column for 1 h before elution

(petroleum ether then petroluem ether-ethyl acetate, 9:1) to give

the allylic silane 7 (14.8 g, 90%) as a clear oil: R_f) 0.67 (100%

hexane). [R]_D²⁵-22 (c ) 0.50, CHCl₃); ν_max(CHCl₃) 2944, 2892,

2866, 1630, 882 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.62 (1H, t,

J ) 0.8 Hz), 4.58 (1H, t, J ) 0.8 Hz), 3.75 (1H, dd, J ) 9.4, 4.9

Hz), 3.42 (1H, dd, J ) 9.4, 8.1 Hz), 2.13 (1H, dqd, J ) 8.1, 7.0,

4.9 Hz), 1.58 (1H, dd, J ) 13.6, 0.8 Hz), 1.56 (1H, dd, J ) 13.6,

0.8 Hz), 1.12-1.01 (24H, m), 0.03 (9H, s); ¹³C NMR (100 MHz,

CDCl₃) δ 150.0, 106.3, 68.2, 43.8, 27.2, 18.2, 16.8, 12.1, -1.2;

HRMS (EI) m/z calcd for C₁₈H₄₀OSi₂[M]⁺: 328.2618, found

328.2613 (∆ 1.3 ppm). Anal. calcd for C₁₈H₄₀OSi₂: C, 65.78; H,

12.27. Found: C, 65.71; H, 12.11.

(2R,3R)-1,2-O-Isopropylidene-6-[(4-methoxybenzyl)oxy]hex-

ane-1,2,3-triol (11). A solution of 4-methoxybenzyl-3-bromopropyl

ether (53.76 g, 207.5 mmol) in dry THF (200 mL) was added

dropwise to a suspension of magnesium turnings (6.05 g, 249 mmol)

and 1,2-dibromoethane (4 drops) in dry THF (30 mL) under N₂.

Formation of the Grignard reagent was accomplished by heating

the mixture to reflux followed by slow addition of the halide to

maintain the reflux. The solution of the Grignard reagent was stirred

at room temperature for 2 h and then was added (cannula) to a

solution of copper(I) iodide (43.37 g, 227.7 mmol), dry dimethyl-

sulfide (130 mL), and dry THF (600 mL) at -78 °C under N₂.

The solution changed from a clear yellow to bright orange upon

addition of the Grignard reagent. The mixture was stirred at -78

°C for 15 min, and then a solution of (R)-2,3-isopropylidene

glyceraldehyde (18.0 g, 138 mmol) in dry THF (50 mL) was added

over 5 min at -78 °C under N₂.⁴⁵The mixture was allowed to

warm to room temperature and was stirred for 15 h. The reaction

was quenched by the addition of ice (ca. 2 g) followed by a saturated

solution of ammonium chloride (500 mL) and ether (300 mL). The

organic layer was removed, and the aqueous layer was extracted

with further ether (2 × 200 mL). The ether extracts were combined

and washed with water (300 mL) and brine (300 mL), then dried

(MgSO₄) and concentrated in vacuo to give a yellow oil. Purification

by column chromatography on silica gel (petroleum ether-ethyl

acetate, 4:1 to 1:1) gave the alcohol 11 (39.78 g, 93%) as a clear

24

oil: R_f) 0.07 (hexane-ethyl acetate, 4:1); [R]_D+15 (c ) 1.0,

CHCl₃); ν_max(CHCl₃) 3580, 2987, 2936, 2885, 1612, 861 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.24 (2H, d, J ) 8.7 Hz), 6.87 (2H,

d, J ) 8.7 Hz), 4.43 (2H, s), 4.01-3.96 (2H, m), 3.79 (3H, s),

3.74-3.69 (1H, m), 3.53-3.48 (1H, m), 3.50-3.46 (2H, m), 2.67

(1H, s), 1.85-1.66 (2H, m), 1.57-1.44 (2H, m) 1.42 (3H, s), 1.36

(3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 159.2, 130.4, 129.3, 113.8,

109.4, 79.2, 72.6, 72.0, 69.8, 66.1, 55.3, 30.6, 26.7, 26.0, 25.4;

HRMS (APCI) m/z calcd for C₁₇H₂₆O₅Na [M + Na]⁺: 333.1678,

found: 333.1681 (∆ 0.9 ppm). Anal. calcd for C₁₇H₂₆O₅: C, 65.78;

H, 8.44. Found: C, 65.43; H, 8.42.

(2R,3R)-1,2-O-Isopropylidene-6-[(4-methoxybenzyl)oxy]-3-

{(3S)-3-methyl-2-methylene-4-[(triisopropylsilyl)oxy]butoxy}-

hexane-1,2-diol (12). A solution of the alcohol 11 (6.13 g, 19.7

mmol) in dry THF (32 mL) was added to a stirred suspension of

NaH (569 mg, 23.7 mmol) in dry THF (208 mL) at room

temperature under N₂. The mixture was heated at reflux for 1 h

under N₂, and then the bromide 8 (8.62 g, 25.7 mmol) in dry THF

(81 mL) was added (cannula) under N₂. The reaction was heated

at reflux for 24 h and then cooled to room temperature. The reaction

was quenched by the addition of a saturated solution of ammonium

chloride (20 mL) and water (100 mL). The reaction mixture was

extracted with ether (3 × 200 mL), and the ether extracts were

combined and washed with water (200 mL) and brine (200 mL),

then dried (MgSO₄) and concentrated in vacuo to give a brown

oil. Purification by column chromatography on silica gel (petroleum

ether-ethyl acetate, 19:1 to 5:1) gave the acetonide 12 (8.39 g, 75%)

as a clear oil: R_f) 0.28 (hexane-ethyl acetate, 9:1); [R]_D²⁵+14 (c

(S)-3-Bromomethyl-2-methyl-1-[(triisopropylsilyl)oxy]but-3-

ene (8). Pyrrolidone hydrotribromide (8.57 g, 17.3 mmol) was added

to a stirred solution of the allylic silane 7 (5.68 g, 17.3 mmol) and

pyridine (9 mL) in dry THF (732 mL) at -10 °C under Ar. The

mixture was stirred for 2 h and allowed to warm to room

temperature during this period. A saturated solution of sodium

thiosulfate (100 mL) was added, and the mixture reduced in volume

(ca. 100 mL) in vacuo. The mixture was diluted with ether (200

mL), and the aqueous layer was removed and extracted with further

ether (200 mL). The ether extracts were combined and washed with

water (100 mL) and brine (75 mL), then dried (MgSO₄) and

concentrated in vacuo to deliver a yellow oil. Purification by column

chromatography on silica gel (petroleum ether) gave the bromide

1

) 0.90, CHCl₃); ν_max(CHCl₃) 2942, 2866, 1612, 883 cm^-1; H

NMR (400 MHz, CDCl₃) δ 7.24 (2H, d, J ) 8.7 Hz), 6.86 (2H, d,

J ) 8.7 Hz), 5.09 (1H, s), 4.90 (1H, s), 4.42 (2H, s), 4.19 (1H, d,

J ) 12.6 Hz), 4.16 (1H, app. q, J ) 6.5 Hz), 4.03 (1H, d, J ) 12.6

Hz), 3.96 (1H, dd, J ) 8.2, 6.5 Hz), 3.79 (3H, s), 3.72-3.66 (2H,

m), 3.54 (1H, dd, J ) 9.4, 7.3 Hz), 3.47-3.42 (2H, m), 3.35 (1H,

ddd, J ) 8.4, 6.3, 3.8 Hz), 2.37 (1H, dqd, J ) 7.3, 6.9, 5.4 Hz),

1.85-1.74 (1H, m), 1.72-1.60 (1H, m), 1.58-1.40 (2H, m), 1.41

(3H, s), 1.34 (3H, s), 1.10 (3H, d, J ) 6.9 Hz), 1.07-1.03 (21H,

25

8 (4.91 g, 85%) as a clear oil: R_f) 0.22 (hexane); [R]_D-31.5

(c ) 2.67, CHCl₃); ν_max(CHCl₃) 2941, 2891, 2866, 2725, 1829,

1

1638, 911, 883, 642 cm^-1; H NMR (400 MHz, CDCl₃) δ 5.26

(1H, d, J ) 0.7 Hz), 5.03 (1H, s), 4.10 (1H, dd, J ) 10.0, 0.7 Hz),

4.04 (1H, d, J ) 10.0, 0.5 Hz), 3.71 (1H, dd, J ) 9.5, 6.1 Hz),

3.65 (1H, dd, J ) 9.5, 6.5 Hz), 2.60 (1H, qdd, J ) 7.0, 6.5, 6.1

Hz), 1.14 (3H, d, J ) 7.0 Hz), 1.11-1.04 (21H, m); ¹³C NMR

(45) (R)-(+)-2,3-Isopropylidene glyceraldehyde was prepared according

20

to the procedure of Jackson (ref 14a): [R]_D+79 (c ) 1.0, CHCl₃), lit.

[R]_D+63.3 (c ) 1.25, C₆H₆).

J. Org. Chem, Vol. 73, No. 3, 2008 1049

Clark et al.

m); ¹³C NMR (100 MHz, CDCl₃) δ 159.2, 149.2, 130.7, 129.3,

113.8, 110.8, 109.3, 79.8, 78.3, 73.6, 72.6, 70.0, 68.0, 66.0, 55.3,

39.5, 27.4, 26.6, 26.0, 25.5, 18.1, 16.5, 12.0; HRMS (FAB) m/z

calcd for C₃₂H₅₆O₆Si [M]⁺: 564.3846, found: 564.3888 (∆ 7.3

ppm). Anal. calcd for C₃₂H₅₆O₆Si: C, 68.04; H, 9.99. Found: C,

67.93; H,10.02.

s), 3.81-3.76 (1H, m), 3.67 (1H, dd, J ) 9.5, 5.9 Hz), 3.55 (1H,

dd, J ) 9.5, 6.8 Hz), 3.47-3.42 (2H, m), 2.36 (1H, qdd, J ) 6.8,

6.8, 5.9 Hz), 1.81-1.67 (4H, m), 1.09 (3H, d, J ) 6.8 Hz), 1.07-

1.02 (21H, m); ¹³C NMR (100 MHz, CDCl₃) δ 197.5, 159.2, 148.1,

130.7, 129.3, 113.8, 111.5, 83.6, 73.0, 72.6, 69.7, 68.1, 55.3, 52.3,

39.6, 30.1, 25.4, 18.1, 16.5, 12.0; HRMS (FAB) m/z calcd for

C₂₉H₄₉O₅N₂Si [M + H]⁺: 533.3411, found: 533.3394 (∆ 3.1 ppm).

Anal. calcd for C₂₉H₄₈O₅N₂Si: C, 65.38; H, 9.08; N, 5.26. Found:

C, 65.22; H, 8.98; N, 5.11.

(2R)-5-[(4-Methoxybenzyl)oxy]-2-{(3S)-3-methyl-2-methylene-

4-[(triisopropylsilyl)oxy]butoxy}pentanal (13). PPTS (1.36 g, 5.39

mmol) was added to a solution of the acetonide 12 (15.2 g, 26.9

mmol) in ethylene glycol (375 mL), THF (180 mL), and CH₂Cl₂

(180 mL), and the mixture was heated to reflux for 20 h. The

reaction was allowed to cool to room temperature and was

neutralized with concd ammonia solution (ca. 8 mL). The mixture

was diluted with water (200 mL) and extracted with CH₂Cl₂(3 ×

200 mL). The organic extracts were combined and washed with

water (200 mL) and brine (200 mL), then dried (MgSO₄) and

concentrated in vacuo to give a yellow oil. The crude diol was

dissolved in THF (225 mL) and water (90 mL), and then NaIO₄

(23.08 g, 107.9 mmol) was added at room temperature over 10

min. The mixture was stirred for 90 min at room temperature, and

then water (700 mL) was added. The reaction mixture was extracted

with ether (3 × 200 mL), and the combined ether extracts were

washed with water (200 mL) and brine (200 mL), then dried

(MgSO₄) and concentrated in vacuo to give a yellow oil. Purification

by column chromatography on silica gel (petroleum ether-ethyl

acetate, 10:1) gave the aldehyde 13 (11.62 g, 88%) as a clear oil:

R_f) 0.32 (hexane-ethyl acetate, 9:1); [R]_D²¹+23 (c ) 0.84, CHCl₃);

(1R,6S)-1,4-Anhydro-3,5,6-trideoxy-1-{3-[(4-methoxybenzyl)-

oxy]propyl}-6-methyl -2-C-methyl-5-methylene-7-O-(triisopro-

pylsilyl)-D-xylo-heptitol (16). A solution of R-diazo ketone 15 (6.60

g, 12.4 mmol) in dry THF (450 mL) was added dropwise over 2 h

to a solution of rhodium(II) trifluoroacetamide dimer (30 mg, 0.046

mmol, 0.4 mol %) in dry THF (150 mL) at reflux under N₂. The

reaction was stirred at reflux for 10 min, allowed to cool to room

temperature, and concentrated in vacuo. The crude dihydrofuranone

was dissolved in dry THF (80 mL) and stirred under an atmosphere

of Ar. Methylmagnesium chloride (12.4 mL of a 3.0 M solution in

THF, 37.2 mmol) was added dropwise over 10 min at -78 °C,

and the reaction was stirred overnight under Ar, warming to room

temperature during that time. The reaction was cooled to 0 °C and

quenched carefully with a saturated solution of ammonium chloride

(10 mL). Water (100 mL) was added, and the mixture was extracted

with ether (3 × 150 mL). The ether extracts were combined and

washed with water (100 mL) and brine (80 mL), then dried (MgSO₄)

and concentrated in vacuo to deliver a yellow oil. Purification by

column chromatography on silica gel (petroleum ether-ethyl acetate,

19:1 to 3:1) gave the alcohol 16 (3.59 g, 56%) as a colorless oil:

1

ν_max(CHCl₃) 2942, 2865, 1731, 1612, 883 cm^-1; H NMR (400

MHz, CDCl₃) δ 9.64 (1H, d, J ) 2.1 Hz), 7.24 (2H, d, J ) 8.7

Hz), 6.87 (2H, d, J ) 8.7 Hz), 5.10 (1H, s), 4.98 (1H, s), 4.41 (2H,

s), 4.15 (1H, d, J ) 12.6 Hz), 3.96 (1H, d, J ) 12.6 Hz), 3.79 (3H,

s), 3.74-3.67 (1H, m), 3.69 (1H, dd, J ) 9.5, 5.7 Hz), 3.57 (1H,

dd, J ) 9.5, 7.0 Hz), 3.45 (2H, m), 2.39 (1H, qdd, J ) 7.0, 7.0, 5.7

Hz), 1.81-1.69 (4H, m), 1.09 (3H, d, J ) 7.0 Hz), 1.07-1.02 (21H,

m); ¹³C NMR (100 MHz, CDCl₃) δ 203.9, 159.2, 148.1, 130.6,

129.3, 113.8, 112.1, 83.2, 73.2, 72.6, 69.4, 68.0, 55.3, 39.4, 26.9,

25.1, 18.1, 16.4, 12.0; HRMS (CI, CH₄) m/z calcd for C₂₈H₄₈O₅Si

[M]⁺: 492.3271, found: 492.3250 (∆ 4.3 ppm). Anal. calcd for

C₂₈H₄₈O₅Si: C, 68.25; H, 9.82. Found: C, 67.98; H, 10.10.

(3R)-1-Diazo-6-[(4-methoxybenzyl)oxy]-2-{(3S)-3-methyl-2-

methylene-4-[(triisopropylsilyl)oxy]butoxy}hexan-2-one (15). A

solution of sodium chlorite (80%, 9.13 g, 80.8 mmol) and sodium

dihydrogenorthophosphate dihydrate (13.63 g, 87.37 mmol) in water

(135 mL) was added dropwise over 10 min at room temperature to

a solution of the aldehyde 13 (6.63 g, 13.5 mmol) in t-butanol (67.5

mL) and 2-methyl-2-butene (90%, 11.40 mL, 107.6 mmol). The

mixture was stirred for 90 min at room temperature, and the volatiles

were then removed in vacuo. The resulting solution was extracted

with ether (3 × 100 mL), and the extracts were combined and

washed with water (100 mL) and brine (100 mL), then dried

(MgSO₄) and concentrated in vacuo. The crude acid 14 was

dissolved in dry ether (140 mL) under Ar, and then triethylamine

(2.06 mL, 14.8 mmol) and i-butyl chloroformate (1.92 mL, 14.8

mmol) were added sequentially. The mixture was stirred for 3 h,

then filtered and added dropwise over 1 h to a solution of

diazomethane (∼150 mmol in 188 mL of ether) at 0 °C. The

resulting solution was stirred overnight, and then the excess

diazomethane was consumed by the addition acetic acid (10 mL).

After 30 min, the solution was diluted with ether (100 mL) and

washed with saturated sodium bicarbonate solution (100 mL) and

brine (100 mL). The yellow solution was dried (MgSO₄) and

concentrated in vacuo to afford a yellow oil. Purification by column

chromatography on silica gel (petroleum ether-ethyl acetate, 10:1

to 7:1) gave the R-diazo ketone 15 (6.73 g, 94%) as a yellow oil:

20

R_f) 0.38 (hexane-ethyl acetate, 4:1): [R]_D-6.7 (c ) 0.80,

CHCl₃); ν_max(CHCl₃) 3553, 2943, 2866, 1613, 883 cm^-1; ¹H NMR

(400 MHz, CDCl₃) δ 7.26 (2H, d, J ) 8.5 Hz), 6.87 (2H, d, J )

8.5 Hz), 5.33 (1H, s), 4.89 (1H, s), 4.44 (2H, s), 4.39 (1H, dd, J )

9.3, 4.9 Hz), 3.80 (3H, s), 3.66 (1H, dd, J ) 9.5, 5.6 Hz), 3.56-

3.46 (3H, m), 3.45 (1H, dd, J ) 9.5, 8.0 Hz), 2.21 (1H, dqd, J )

8.0, 6.9, 5.6 Hz), 2.21 (1H, dd, J ) 13.3, 9.3 Hz), 1.93 (1H, dd, J

) 13.3, 4.9 Hz), 1.93-1.81 (2H, m), 1.77-1.63 (3H, m), 1.25 (3H,

s), 1.13 (3H, d, J ) 6.9 Hz), 1.06-1.02 (21H, m); ¹³C NMR (100

MHz, CDCl₃) δ 159.2, 154.9, 130.8, 129.3, 113.8, 107.2, 86.7, 78.4,

78.0, 72.6, 70.2, 68.9, 55.3, 46.5, 39.2, 27.1, 25.3, 22.9, 18.1, 17.3,

12.0; HRMS (CI, CH₄) m/z calcd for C₃₀H₅₂O₅Si [M]⁺: 520.3584,

found: 520.3564 (∆ 3.8 ppm). Anal. calcd for C₃₀H₅₂O₅Si: C,

69.18; H, 10.06. Found: C, 68.99; H, 9.94.

(1R,6S)-2-O-Acetyl-1,4-anhydro-3,5,6-trideoxy-1-{3-[(4-meth-

oxybenzyl)oxy]propyl }-6-methyl-2-C-methyl-5-methylene-7-O-

(triisopropylsilyl)-D-xylo-heptitol (17). Acetic anhydride (2.95 mL,

31.2 mmol) was added to a solution of 16 (4.07 g, 7.81 mmol),

DMAP (2.86 g, 23.4 mmol), and Et₃N (8.79 mL, 63.1 mmol) in

dry ether (104 mL) at room temperature under Ar, and the resulting

solution was stirred for 20 h. Water (300 mL) was added, and the

mixture was extracted with ether (3 × 100 mL). The ether extracts

were combined and washed with water (100 mL) and brine (50

mL), then dried (MgSO₄) and concentrated in vacuo to give a yellow

oil. Purification by column chromatography on silica gel (petroleum

ether-ethyl acetate, 19:1 to 4:1) afforded the acetate 17 (3.94 g,

90%) as a clear oil: R_f) 0.40 (petroleum ether-ethyl acetate, 4:1);

23

[R]_D-6.8 (c ) 1.7, CHCl₃); ν_max(CHCl₃) 2942, 2865, 1728,

1

1612 cm^-1; H NMR (400 MHz, CDCl₃) δ 7.27 (2H, d, J ) 8.6

Hz), 6.87 (2H, d, J ) 8.6 Hz), 5.20 (1H, s), 4.86 (1H, s), 4.47 (1H,

d, J ) 11.6 Hz), 4.43 (1H, d, J ) 11.6 Hz), 4.31 (1H, dd, J ) 7.7,

7.5 Hz), 3.80 (3H, s), 3.67 (1H, dd, J ) 9.5, 5.5 Hz), 3.58-3.46

(3H, m), 3.44 (1H, dd, J ) 9.5, 7.9 Hz), 2.38 (1H, dd, J ) 14.0,

7.5 Hz), 2.33 (1H, dd, J ) 14.0, 7.7 Hz), 2.21-2.17 (1H, dqd, J )

7.9, 6.9, 5.5 Hz), 1.94 (3H, s), 1.91-1.88 (1H, m), 1.73-1.65 (3H,

m), 1.52 (3H, s), 1.09 (3H, d, J ) 6.9 Hz), 1.06-1.02 (21H, m);

¹³C NMR (100 MHz, CDCl₃) δ 170.5, 159.2, 152.4, 130.8, 129.3,

113.8, 108.4, 87.5, 86.1, 79.2, 72.5, 70.1, 68.8, 55.3, 43.7, 38.8,

27.0, 25.9, 22.1, 21.7, 18.1, 17.6, 12.0; HRMS (ES) m/z calcd for

C₃₂H₅₈O₆NSi [M + NH₄]⁺: 580.4033, found: 580.4044 (∆ 1.9

23

R_f) 0.27 (hexane-ethyl acetate, 5:1); [R]_D+28.6 (c ) 1.30,

CHCl₃); ν_max(CHCl₃) 3124, 2943, 2866, 2109, 1634, 883 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.24 (2H, d, J ) 8.7 Hz), 6.87 (2H,

d, J ) 8.7 Hz), 5.73 (1H, br), 5.10 (1H, s), 4.97 (1H, s), 4.42 (2H,

s), 4.06 (1H, d, J ) 12.8 Hz), 3.91 (1H, d, J ) 12.8 Hz), 3.80 (3H,

1050 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

ppm). Anal. calcd for C₃₂H₅₄O₆Si: C, 68.29; H, 9.67. Found: C,

67.93; H, 9.78.

The white solid was dissolved in dry benzene (89 mL), and oxalyl

chloride (3.52 mL, 40.4 mmol) was added dropwise over 10 min

at room temperature under Ar. The mixture was stirred for 2 h and

concentrated in vacuo, and the residue was dissolved in CH₂Cl₂

(75 mL). The solution was then added dropwise over 30 min to a

solution of diazomethane (∼40 mmol in 55 mL of ether) at 0 °C.

The resulting mixture was stirred for 2 h, and then the excess

diazomethane was consumed by the addition of acetic acid (5 mL).

After 30 min, the ethereal solution was diluted with ether (200 mL)

and washed with a saturated solution of sodium bicarbonate (150

mL). The aqueous layer was separated and extracted with ether (2

× 50 mL). The ether extracts were combined and washed with

water (100 mL) and brine (100 mL), then dried (MgSO₄) and

concentrated in vacuo to give a yellow oil. Purification by column

chromatography (petroleum ether-ethyl acetate, 9:1 to 4:1) gave

the R-diazo ketone 21 (2.91 g, 75%) as a yellow oil: R_f) 0.25

(1R,6S)-2-O-Acetyl-1,4-anhydro-3,5,6-trideoxy-1-(3-hydroxy-

propyl)-6-methyl-2-C-methyl-5-methylene-7-O-(triisopropylsi-

lyl)-D-XYLO-heptitol (18). DDQ (3.19 g, 14.1 mmol) was added in

one portion to a solution of 17 (5.28 g, 9.38 mmol) in CH₂Cl₂(162

mL) and water (16 mL), and the reaction was stirred at room

temperature for 3 h. The reaction was diluted with CH₂Cl₂(50 mL)

and washed successively with a saturated solution of sodium

bicarbonate (200 mL), water (150 mL), and brine (100 mL), then

dried (MgSO₄) and concentrated in vacuo to give a red-brown

oil. Purification by column chromatography (petroleum ether-ethyl

acetate, 10:1 to 3:1) gave the alcohol 18 (4.16 g, 100%) as a clear

21

oil: R_f) 0.08 (hexane-ethyl acetate, 4:1); [R]_D-11 (c ) 0.55,

CHCl₃); ν_max(CHCl₃) 3431, 2943, 2866, 1729, 1649, 883 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 5.19 (1H, s), 4.87 (1H, s), 4.37

(1H, dd, J ) 7.9, 7.1 Hz), 3.70 (2H, br), 3.64 (1H, dd, J ) 9.4, 5.8

Hz), 3.51 (1H, dd, J ) 7.0, 4.5 Hz), 3.45 (1H, dd, J ) 9.4, 8.0

Hz), 2.52 (1H, br), 2.45 (1H, dd, J ) 14.1, 7.1 Hz), 2.33 (1H, dd,

J ) 14.1, 7.9 Hz), 2.18 (1H, dqd, J ) 8.0, 7.0, 5.8 Hz), 1.94 (3H,

s), 1.80-1.76 (4H, m), 1.53 (3H, s), 1.08 (3H, d, J ) 7.0 Hz),

1.06-1.02 (21H, m); ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 152.2,

108.5, 87.9, 86.1, 79.4, 68.9, 63.0, 43.3, 38.7, 30.5, 26.1, 22.1, 21.5,

18.1, 17.5, 12.0; HRMS (ES) m/z calcd for C₂₄H₄₆O₅SiNa [M +

Na]⁺: 465.3012, found: 465.3017 (∆ 1.0 ppm). Anal. calcd for

C₂₄H₄₆O₅Si: C, 65.11; H, 10.47. Found: C, 65.14; H, 10.68.

(1R,6S)-2-O-Acetyl-1,4-anhydro-3,5,6-trideoxy-1-(3-oxopro-

pyl)-6-methyl-2-C-methyl-5-methylene-7-O-(triisopropylsilyl)-D-

xylo-heptitol (19). Dess-Martin periodinane (8.27 g, 19.5 mmol)

was added in three portions at 30 min intervals to a solution of the

alcohol 18 (5.77 g, 13.0 mmol) in dry CH₂Cl₂(63 mL) at 0 °C

under Ar. The mixture was stirred for a further 2 h at room

temperature, then quenched by the addition of a saturated solution

of sodium thiosulfate (150 mL) and extracted with ether (3 × 100

mL). The ether extracts were combined and washed successively

with a saturated solution of sodium bicarbonate (150 mL), water

(100 mL), and brine (100 mL), then dried (MgSO₄) and concen-

trated in vacuo to give a cloudy oil. Purification by column

chromatography on silica gel (petroleum ether-ethyl acetate, 19:1

to 3:1) gave the aldehyde 19 (5.34 g, 93%) as a clear oil: R_f)

23

(hexane-ethyl acetate, 4:1); [R]_D-0.98 (c ) 0.62, CHCl₃); ν_max

(CHCl₃) 2943, 2891, 2866, 2109, 1729, 1640, 883 cm^-1; ¹H NMR

(400 MHz, CDCl₃) δ 5.30 (1H, br) 5.18 (1H, s), 4.86 (1H, s), 4.33

(1H, dd, J ) 7.8, 7.5 Hz), 3.65 (1H, dd, J ) 9.5, 5.7 Hz), 3.51

(1H, dd, J ) 9.3, 3.5 Hz), 3.45 (1H, dd, J ) 9.5, 7.8 Hz), 2.61

(1H, br), 2.49 (1H, br), 2.40 (1H, dd, J ) 14.0, 7.5 Hz), 2.36 (1H,

dd, J ) 14.0, 7.8 Hz), 2.18 (1H, dqd, J ) 7.8, 6.9, 5.7 Hz), 2.02-

1.95 (2H, m), 1.96 (3H, s), 1.54 (3H, s), 1.09 (3H, d, J ) 6.9 Hz),

1.02-1.06 (21H, m); ¹³C NMR (100 MHz, CDCl₃) δ 194.8, 170.4,

152.4, 108.4, 86.5, 86.0, 79.4, 68.8, 54.6, 43.5, 38.8, 37.8, 24.4,

22.1. 21.6, 18.1, 17.6, 12.0; HRMS (FAB) m/z calcd for C₂₅H₄₅N₂O₅-

Si [M + H]⁺: 481.3098, found: 481.3132 (∆ 7.1 ppm). Anal. calcd

for C₂₅H₄₄N₂O₅Si: C, 62.46; H, 9.23; N, 5.83. Found: C, 62.82;

H, 9.36; N, 5.48.

(1R,2R,4Z,7R)-2-Methyl-5-{(1S)-1-methyl-2-[(triisopropylsi-

lyl)oxy]ethyl}-8-oxo-11-oxabicyclo[5.3.1]undec-4-en-2-yl Acetate

(23) and (1R,2R,4R,5R)-2-Methyl-4-{(2S)-2-methyl-1-methylene-

3-[(triisopropylsilyl)oxy]propyl}-6-oxo-9-oxabicyclo[3.3.1]non-

2-yl Acetate (24). A solution of the R-diazo ketone 21 (2.86 g,

5.95 mmol) in dry CH₂Cl₂(357 mL) was added dropwise over 1 h

to a solution of copper(II) hexafluoroacetylacetonate (65 mg, 0.13

mmol, 2.2 mol %) in dry CH₂Cl₂(89 mL) at reflux under N₂. The

reaction was stirred at reflux for 5 min, cooled to room temperature,

and concentrated in vacuo to a green oil. Purification by column

chromatography on silica gel (petroleum ether-ethyl acetate, 19:1

to 7:3) gave the [2,3] rearrangement product 23 (1.86 g, 69%, 2:3

mixture of E/Z isomers) as a white solid and the [1,2] shift product

23 (435 mg, 16%) as a colorless oil.

23

0.60 (hexane-ethyl acetate, 4:1); [R]_D-3.8 (c ) 0.90, CHCl₃);

ν_max(CHCl₃) 2943, 2892, 2866, 2728, 1727, 1649, 1602, 1649,

1

906, 883 cm^-1; H NMR (400 MHz, CDCl₃) δ 9.83 (1H, t, J )

1.3 Hz), 5.16 (1H, t, J ) 1.3 Hz), 4.86 (1H, s), 4.33 (1H, t, J ) 7.6

Hz), 3.64 (1H, dd, J ) 9.5, 5.7 Hz), 3.51 (1H, dd, J ) 9.2, 3.6

Hz), 3.45 (1H, dd, J ) 9.5, 7.7 Hz), 2.73 (1H, dddd, J ) 18.1, 8.0,

6.2, 1.3 Hz), 2.62 (1H, dddd, J ) 18.1, 8.0, 6.9, 1.3 Hz), 2.39-

2.36 (2H, m), 2.18 (1H, dqd, J ) 7.7, 6.9, 5.7 Hz), 2.01-1.94

(2H, m), 1.96 (3H, s), 1.55 (3H, s), 1.08 (3H, d, J ) 6.9 Hz), 1.06-

1.02 (21H, m); ¹³C NMR (100 MHz, CDCl₃) δ 202.3, 170.3, 152.2,

108.5, 86.5, 86.0, 79.4, 68.8, 43.6, 41.2, 38.7, 22.1, 21.8, 21.6, 18.1,

17.5, 12.0; HRMS (CI, NH₃) m/z calcd for C₂₄H₄₅O₅Si [M + H]⁺:

441.3036, found: 441.3028 (∆ 1.8 ppm).

AIBN (415 mg, 2.53 mmol) was added in four portions, over 4

h, to a solution of ketone 23 (2.29 g of a 3:2 Z/E isomer mixture,

5.06 mmol) and ethanethiol (18 mL) in dry benzene (226 mL) at

reflux under Ar. The solution was then cooled and concentrated in

vacuo to yield a yellow oil. Purification by column chromatography

on silica gel (petroleum ether-ethyl acetate, 19:1 to 9:1) afforded

the alkene Z-23 (2.28 g, >99%) as a white solid.

Z-23: mp 50-53 °C; R_f

) 0.38 (hexane-ethyl acetate, 4:1);

[R]_D²³+57 (c ) 1.3, CHCl₃); ν_max(CHCl₃) 2943, 2892, 2866, 1724,

1

883 cm^-1; H NMR (400 MHz, CDCl₃) δ 5.61 (1H, t, J ) 8.3

(1R,6S)-2-O-Acetyl-1,4-anhydro-3,5,6-trideoxy-1-(4-diazo-3-

oxobutyl)-6-methyl-2-C-methyl-5-methylene-7-O-(triisopropyl-

silyl)-D-xylo-heptitol (21). A solution of sodium chlorite (80%, 5.48

g, 48.5 mmol) and sodium dihydrogenorthophosphate dihydrate

(8.18 g, 52.5 mmol) in water (81 mL) was added dropwise over

10 min to a solution of the aldehyde 19 (3.56 g, 8.08 mmol) in

t-butanol (41 mL) and 2-methyl-2-butene (6.85 mL, 64.6 mmol).

The reaction was stirred at room temperature for 90 min, and then

the volatile compounds were removed in vacuo. The mixture was

extracted with ether (3 × 100 mL), and the ether extracts were

combined and washed with water (100 mL) and brine (10 mL) and

then dried (MgSO₄) and concentrated in vacuo to give the carboxylic

acid 20 as a pale yellow oil. The crude acid 20 was dissolved in

dry MeOH (89 mL) under Ar, and sodium methoxide (458 mg,

8.48 mmol) was added in one portion. The mixture was stirred for

15 min, concentrated in vacuo, and dried for 1 h under high vacuum.

Hz), 4.42 (1H, t, J ) 9.3 Hz), 4.05-4.02 (1H, br), 3.64 (1H, dd,

J ) 9.7, 5.9 Hz), 3.49 (1H, dd, J ) 9.7, 6.7 Hz), 2.59-2.44 (4H,

m), 2.42-2.35 (1H, m), 2.34-2.26 (2H, m), 2.19-2.09 (2H, m),

1.98 (3H, s), 1.72 (3H, s), 1.08-1.02 (24H, m); ¹³C NMR (100

MHz, CDCl₃) δ 212.0, 170.0, 140.9, 123.4, 87.3, 79.6, 77.3, 67.7,

43.3, 35.4, 34.5, 32.2, 22.4, 22.4, 20.1, 18.1, 16.3, 12.0; HRMS

(FAB) m/z calcd for C₂₅H₄₅O₅Si [M + H]⁺: 453.3036, found:

453.3017 (∆ 4.3 ppm). Anal. calcd for C₂₅H₄₄O₅Si: C, 66.33; H,

9.80. Found: C, 66.14; H, 9.85.

24: R_f) 0.4 (hexane-ethyl acetate, 4:1); [R]_D²¹-7.1 (c ) 1.1,

CHCl₃); ν_max(CHCl₃) 2943, 2892, 2866, 1729, 1643, 901, 883

1

cm^-1; H NMR (400 MHz, CDCl₃) δ 4.84 (1H, s), 4.67 (1H, s),

4.51-4.47 (1H, m), 4.16 (1H, d, J ) 5.6 Hz), 3.89 (1H, dd, J )

9.5, 4.5 Hz), 3.52 (1H, dd, J ) 9.5, 8.9 Hz), 2.83-2.75 (1H, m),

2.64-2.55 (1H, m), 2.35-2.18 (3H, m), 2.13 (1H, dd, J ) 13.7,

J. Org. Chem, Vol. 73, No. 3, 2008 1051

Clark et al.

3.7 Hz), 2.10-2.05 (1H, m), 2.01 (3H, s), 1.85 (1H, t, J ) 13.7

Hz), 1.78 (3H, s), 1.13 (3H, d, J ) 6.8 Hz), 1.12-1.02 (21H, m);

¹³C NMR (100 MHz, CDCl₃) δ 208.4, 169.9, 149.8, 110.2, 81.0,

79.2, 71.3, 67.3, 41.6, 41.4, 35.7, 34.3, 22.9, 22.2, 21.7, 18.6, 18.1,

12.0; HRMS (FAB) m/z calcd for C₂₅H₄₅O₅Si [M + H]⁺: 453.3036,

found: 453.2993 (∆ 9.6 ppm). Anal. calcd for C₂₅H₄₄O₅Si: C,

66.33; H, 9.80. Found C, 65.96; H, 9.65.

silica gel and purified by column chromatography on silica gel

(petroleum ether-ethyl acetate, 9:1 to 4:1) to give the alkene 26

(298 mg, 81%) as a colorless oil.

25

R_f) 0.51 (hexane-ethyl acetate, 4:1); [R]_D-6.6 (c ) 1.4,

CHCl₃); ν_max(CHCl₃) 2943, 2866, 1728, 1646, 1602, 884 cm^-1

.

¹H NMR (400 MHz, CDCl₃) δ 4.81 (1H, s), 4.67 (1H, s), 4.54

(1H, dd, J ) 13.2, 4.8 Hz), 4.20 (1H, dd, J ) 12.2, 6.0 Hz,), 3.88

(1H, dd, J ) 9.8, 5.6 Hz), 3.50 (1H, dd, J ) 9.8, 7.1 Hz), 3.09

(1H, dd, J ) 9.8, 5.3 Hz), 2.71 (1H, dd, J ) 13.9, 5.3 Hz), 2.55-

2.48 (1H, m), 2.39 (1H, dd, J ) 14.7, 4.8 Hz), 2.35-2.28 (1H, m),

2.05 (1H, dqd, J ) 7.1, 7.0, 5.6 Hz), 1.96 (3H, s), 1.85-1.78 (1H,

m), 1.77 (3H, s), 1.68 (1H, dd, J ) 13.9, 9.8 Hz), 1.64-1.56 (1H,

m), 1.40 (1H, dd, J ) 14.7, 13.2 Hz), 1.08-1.04 (21H, m), 0.92

(3H, d, J ) 7.0 Hz); ¹³C NMR (100 Hz, CDCl₃) δ 170.0, 147.2,

107.4, 83.4, 77.3, 72.6, 65.9, 62.8, 56.9, 43.3, 38.6, 33.5, 26.8, 22.5,

22.1, 20.8, 18.1, 13.1, 12.0; HRMS (FAB) m/z calcd for C₂₆H₄₇O₅-

Si [M + H]⁺: 467.3193, found: 467.3193 (∆ 0 ppm). Anal. calcd

for C₂₆H₄₆O₅Si: C, 66.91; H, 9.93. Found: C, 66.98; H, 9.92.

(1R,2R,4S,5Z,7R)-2-Methyl-8-methylene-5-{(1S)-1-methyl-2-

[(triisopropylsilyl)oxy]ethyl}-11-oxabicyclo[5.3.1]undec-5-ene-

2,4-diol (27) and (1R,6R)-1,5-Anhydro-3,6-dideoxy-6-methyl-2-

C-methyl-1-(3-methylenepent-4-en-1-yl)-7-O-(triisopropylsilyl)-

D-erythro-heptitol (28). Aluminum isopropoxide (490 mg, 2.40

mmol) was added to a solution of the epoxide 26 (112 mg, 0.240

mmol) in dry toluene (15 mL) at room temperature under N₂. The

reaction mixture was heated at reflux for 18 h and then allowed to

cool to room temperature. The reaction mixture was concentrated

in vacuo to ∼10% volume and diluted with ether (20 mL). A 0.5

M solution of HCl (15 mL) was added, and the mixture was

extracted with ether (3 × 15 mL). The ether extracts were combined

and washed with water (10 mL) and brine (10 mL), then dried

(MgSO₄) and concentrated in vacuo to give an oil. Purification by

column chromatography on silica gel (hexane-ethyl acetate, 3:1 to

2:1) gave the diol 27 (61 mg, 60%) and the diene 28 (40 mg, 39%,

5.5:1 mixture of diastereoisomers) as colorless oils.

(1R,3S,5S,7R,8R)-7-Methyl-3-{(1R)-1-methyl-2-[(triisopropyl-

silyl)oxy]ethyl}-11-oxo-4,12-dioxatricyclo[6.3.1.0^3,5]dodec-7-yl Ac-

etate (25). Purified m-CPBA (211 mg, 1.22 mmol) (Caution!

Explosion hazard.) was added to a solution of the alkene 23 (369

mg, 0.815 mmol) in dry CH₂Cl₂(40 mL) under N₂.⁴⁶The reaction

mixture was heated at reflux for 1 h and then allowed to cool to

room temperature. The reaction was quenched by the addition of a

saturated solution of sodium thiosulfate (20 mL), and the mixture

was extracted with CH₂Cl₂(3 × 20 mL). The organic extracts were

combined and washed with a saturated solution of sodium

bicarbonate (20 mL), water (20 mL), and brine (20 mL), then dried

(MgSO₄) and concentrated in vacuo. Purification by column

chromatography (hexane-ethyl acetate, 9:1 to 4:1) gave the epoxide

25 (305 mg, 80%, 22:1 mixture of diastereoisomers) as a white

23

solid: mp 83-85 °C; R_f) 0.37 (hexane-ethyl acetate, 4:1); [R]_D

-6.5 (c ) 0.46, CHCl₃); ν_max(CHCl₃) 2943, 2866, 1730, 882 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 4.46 (1H, dd, J ) 12.3, 6.1 Hz),

4.25 (1H, dd, J ) 13.9, 5.0 Hz), 3.83 (1H, dd, J ) 9.8, 5.8 Hz),

3.51 (1H, dd, J ) 9.8, 6.7 Hz), 3.12 (1H, dd, J ) 9.8, 5.3 Hz),

2.74 (1H, dd, J ) 14.2, 5.3 Hz), 2.63 (1H, dd, J ) 14.4, 5.0 Hz),

2.60-2.46 (2H, m), 2.17-2.08 (1H, m), 1.99 (3H, s), 1.96-1.84

(2H, m), 1.82 (3H, s), 1.66 (1H, dd, J ) 14.2, 10.0 Hz), 1.31 (1H,

dd, J ) 14.4, 13.9 Hz), 1.12-1.04 (21H, m), 0.90 (3H, d, J ) 7.0

Hz); ¹³C NMR (100 MHz, CDCl₃), δ 210.7, 170.0, 82.9, 76.8, 76.5,

65.6, 62.4, 56.8, 39.0, 36.8, 35.2, 33.4, 22.5, 22.1, 19.9, 18.1, 13.0,

11.9; HRMS (FAB) m/z calcd for C₂₅H₄₅O₆Si [M + H]⁺: 469.2985,

found: 469.2980 (∆ 1.1 ppm). Anal. calcd for C₂₅H₄₄O₆Si: C,

64.06; H, 9.46. Found: C, 63.84; H, 9.24.

27: R_f) 0.21 (hexane-ethyl acetate, 3:1); [R]_D²⁴-31 (c ) 1.0,

CHCl₃); ν_max(CHCl₃) 3382, 2945, 2868, 1656, 1601, 907, 883

(1R,3S,5S,7R,8R)-7-Methyl-11-methylene-3-{(1R)-1-methyl-

2-[(triisopropylsilyl)oxy]ethyl}-4,12-dioxatricyclo[6.3.1.0^3,5]dodec-

7-yl acetate (26). Using the Nysted reagent.²⁵Titanium(IV)

chloride (1.60 mL of a 1 M solution in CH₂Cl₂, 1.60 mmol) was

added to a solution of Nysted reagent {cyclo-dibromodi-µ-meth-

ylene-[µ-(tetrahydrofuran)]trizinc} (3.86 mL of a 20 wt % suspen-

sion in THF, 2.01 mmol) in THF (6 mL) at 0 °C under N₂. After

the mixture was stirred for 5 min, a solution of the ketone 25 (376

mg, 0.802 mmol) in THF (14 mL) was added at 0 °C under N₂.

The reaction was stirred for 90 min and warmed to room

temperature during this period. The reaction was then quenched

by the addition of 0.5 N HCl (20 mL), and the reaction mixture

was extracted with ether (3 × 20 mL). The ether extracts were

combined and washed with water (25 mL) and brine (20 mL), then

dried (MgSO₄) and concentrated in vacuo to give an oil. Purification

by column chromatography on silica gel (hexane-ethyl acetate, 19:1

to 4:1) afforded the alkene 26 (332 mg, 89%) as a colorless oil.

Using the Petasis protocol.²⁴Dimethyltitanocene (493 mg, 2.37

mmol) and the ketone 25 (370 mg, 0.789 mmol) were dissolved in

dry THF (40 mL) under Ar, and the resulting orange solution was

heated at reflux for 20 h. The mixture was cooled to room

temperature, and a saturated solution of sodium bicarbonate (30

mL) was added. The mixture was extracted with ether (3 × 40

mL), and the ether extracts were combined and washed with water

(40 mL) and brine (40 mL), then dried (MgSO₄) and concentrated

in vacuo to an orange oil. The crude product was dry-loaded onto

1

cm^-1; H NMR (400 MHz, CDCl₃) δ 5.51 (1H, ddt, J ) 9.3, 4.0,

2.0 Hz), 5.21 (1H, dd, J ) 2.0, 1.1 Hz), 4.81 (1H, s), 4.79 (2H, s),

4.13 (1H, s, OH), 3.80 (1H, dd, J ) 8.4, 4.5 Hz), 3.70 (1H, dd, J

) 7.2, 6.4 Hz), 3.30 (1H, dd, J ) 10.5, 8.4 Hz), 3.17 (1H, dqd, J

) 10.5, 7.1, 4.5 Hz), 2.71-2.62 (1H, m), 2.30-2.18 (2H, m), 2.08-

2.07 (1H, dd, J ) 14.0, 4.0 Hz), 2.04-1.95 (1H, m), 1.96 (1H, dd,

J ) 14.0, 9.3 Hz), 1.89-1.80 (1H, m), 1.35 (3H, s, CCH₃), 1.10-

1.04 (21H, m), 1.00 (3H, d, J ) 7.1 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 150.8, 146.9, 126.7, 108.4, 80.1, 76.2, 74.9, 71.7, 66.6,

48.3, 33.2, 28.4, 26.2, 22.9, 17.9, 17.6, 11.9; HRMS (ESI) m/z calcd

for C₂₄H₄₄O₄SiNa [M + Na]⁺: 447.2907, found: 447.2884 (∆ 2.3

ppm).

28 (5.5:1 mixture of diastereoisomers): R_f) 0.46 (hexane-ethyl

24

acetate, 3:1); [R]_D+19 (c ) 0.45, CHCl₃); ν_max(CHCl₃) 3422,

2944, 2867, 1595, 883 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 6.39

(1H, dd, J ) 17.7, 10.9 Hz, minor), 6.38 (1H, dd, J ) 17.6, 11.0

Hz, major), 5.27 (1H, ddt, J ) 17.6, 1.1, 0.5 Hz, major), 5.26 (1H,

ddt, J ) 17.8, 1.1, 0.5 Hz, minor), 5.07-5.03 (3H, m), 4.14 (1H,

ddd, J ) 10.2, 3.3, 1.8 Hz, minor), 4.05 (1H, ddd, J ) 9.6, 3.5, 2.5

Hz, major), 4.02 (1H, dd, J ) 3.9, 2.5 Hz, minor), 3.85 (1H, dd, J

) 9.8, 3.7 Hz, major), 3.74 (1H, dd, J ) 9.5, 4.1 Hz, minor), 3.72

(1H, dd, J ) 9.8, 5.1 Hz major), 3.46 (1H, dd, J ) 9.4, 2.9 Hz,

minor), 3.37 (1H, dd, J ) 9.2, 3.0 Hz, major), 2.48 (1H, ddd, J )

14.6, 10.4, 4.9 Hz), 2.30-2.23 (1H, m), 2.23-2.21 (1H, m, minor),

2.20 (1H, dd, J ) 13.6, 3.5 Hz, major), 2.10-2.07 (1H, m, minor),

2.05 (1H, dd, J ) 13.6, 9.6 Hz, major), 1.98 (1H, dd, J ) 13.6, 3.3

Hz, minor), 1.86-1.78 (2H, m), 1.77-1.68 (1H, m), 1.26 (3H, s,

major), 1.24 (3H, s, minor), 1.12-1.04 (21H, m), 1.01 (3H, d, J )

7.1 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 146.4, 139.1, 115.7, 113.3,

85.7, 78.2, 76.9, 69.0, 41.9, 37.7, 28.4, 26.6, 22.2, 18.1, 12.2, 11.9;

HRMS (CI, CH₄) m/z calcd for C₂₄H₄₇O₄Si [M + H]⁺: 427.3244,

found: 427.3256 (∆ 2.9 ppm).

(46) Commercial m-chloroperbenzoic acid was purified according to the

the procedure described in: Armarego, W. L. F.; Perkin, D. D. Purification

of Laboratory Chemicals, 4th ed.; 1996; p 145. A solution of m-

chloroperbenzoic acid in benzene was washed with aqueous pH 7.4 buffer,

and the solution was dried (MgSO₄). The solvent was removed at water

pump pressure on a rotary evaporator behind a blast screen. The solid

m-chloroperbenzoic acid was used without recrystallization.

1052 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

(1R,2R,4S,5Z,7R)-2-Methyl-8-methylene-5-{(1S)-1-methyl-2-

[(triisopropylsilyl)oxy]ethyl}-2,4-bis(triethylsilyloxy)-11-oxabicyclo-

[5.3.1]undec-5-ene (29). Triethylsilyl trifluoromethanesulfonate

(183 µL, 0.809 mmol) was added dropwise over 2 min to a solution

of the diol 27 (72 mg, 0.17 mmol) and 2,6-lutidine (296 µL, 2.54

mmol) in dry CH₂Cl₂(4 mL) at -78 °C under Ar. The mixture

was stirred at -78 °C for 30 min, and the reaction was then

quenched by the addition of water (3 mL) and a saturated solution

of copper sulfate (3 mL). The mixture was extracted with ether (3

× 5 mL), and the combined ether extracts were washed with water

(5 mL) and brine (5 mL), then dried (MgSO₄) and concentrated in

vacuo to give an oil. Purification by column chromatography on

silica gel (hexane-ethyl acetate, 19:1 to 9:1) gave the diene 29 (108

mmol) and TEMPO (0.9 mg, 5 mol %) in CH₂Cl₂(2.4 mL) at room

temperature. The solution was cooled to 0 °C, and a solution of

sodium hypochlorite (0.218 mmol) in a saturated solution of sodium

bicarbonate (115 µL) and brine (238 µL) was added over 5 min.

The reaction was stirred at 0 °C for 15 min and then quenched

with water (10 mL) and CH₂Cl₂(10 mL). The aqueous layer was

separated and extracted with CH₂Cl₂(2 × 10 mL). The organic

extracts were combined, dried (MgSO₄), and concentrated in vacuo

to give the aldehyde 31 as a clear oil. The aldehyde 31 was

dissolved in a mixture of t-butanol (545 µL) and 2-methyl-2-butene

(93 µL, 0.88 mmol) at room temperature. A solution of sodium

chlorite (80%, 74 mg, 0.82 mmol) and sodium dihydrogenortho-

phosphate dihydrate (111 mg, 0.712 mmol) in water (1.1 mL) was

added dropwise to this mixture over 5 min at room temperature.

The mixture was stirred at room temperature for 15 min and then

diluted with CH₂Cl₂(10 mL). The aqueous layer was separated

and extracted with CH₂Cl₂(2 × 5 mL), and the combined organic

extracts were then dried (MgSO₄) and concentrated in vacuo to

give the acid 32 as a yellow oil. The crude acid 32 was dissolved

in dry CH₂Cl₂(5 mL) under Ar, and a solution of trimethylsilyl-

diazomethane (2.0 M in ether, 273 µL, 0.546 mmol) was added

dropwise over 2 min at 0 °C. The reaction was allowed to stir for

20 min at 0 °C and then quenched by the addition of a saturated

solution of ammonium chloride (5 mL). The mixture was extracted

with CH₂Cl₂(2 × 10 mL), dried (MgSO₄), and concentrated in

vacuo to give a yellow oil. Purification by column chromatography

(hexane-ethyl acetate, 19:1 to 4:1) afforded the methyl ester 33

(20 mg, 26%) and the ketone 34 (34 mg, 48%) as colorless oils.

33: R_f) 0.45 (hexane-ethyl acetate, 3:1); [R]_D²⁸-4.0 (c ) 0.50,

CHCl₃); ν_max(CHCl₃) 2927, 2867, 1724, 883 cm^-1; ¹H NMR (500

MHz, CDCl₃) δ 5.36 (1H, d, J ) 9.6 Hz), 5.09 (1H, s), 4.30 (1H,

s), 3.81 (3H, s), 3.70 (1H, dd, J ) 9.2, 4.7 Hz), 3.65 (1H, dd, J )

13.2, 5.1, Hz), 3.36 (1H, dd, J ) 9.2, 7.6 Hz), 3.04 (1H, s), 2.89

(1H, dqd, J ) 7.6, 7.0, 4.7 Hz), 2.73 (1H, dd, J ) 14.7, 6.8 Hz),

2.30 (1H, dd, J ) 14.1, 9.6 Hz), 1.94-1.86 (1H, m), 1.81-1.73

(1H, m), 1.69 (1H, d, J ) 14.1 Hz), 1.65-1.59 (1H, m), 1.55 (3H,

s), 1.15 (3H, d, J ) 7.0 Hz), 1.06-1.03 (21H, m), 0.95 (9H, t, J )

7.9 Hz), 0.92 (9H, t, J ) 7.9 Hz), 0.60 (6H, q, J ) 7.9 Hz), 0.54

(6H, q, J ) 7.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 174.2, 148.4,

120.0, 80.5, 76.2, 75.5, 68.1, 67.1, 52.9, 49.6, 35.6, 28.0, 27.3, 19.4,

18.7, 18.1, 12.2, 7.1, 7.0, 7.0, 5.1; LRMS (CI, CH₄) m/z 715 (M⁺,

8.6%), 655 (4.6%), 542 (79.0%).

mg, 98%) as a colorless oil: R_f) 0.72 (hexane-ethyl acetate, 3:1);

[R]_D+26 (c ) 0.30, CHCl₃); ν_max2955, 2874, 1601, 882 cm^-1

;

24

¹H NMR (400 MHz, CDCl₃) δ 5.40 (1H, d, J ) 9.3 Hz), 5.05 (1H,

s), 4.78 (2H, s), 4.76 (1H, s), 3.73 (1H, dd, J ) 9.2, 4.7 Hz), 3.51

(1H, dd, J ) 12.7, 4.2 Hz), 3.44 (1H, dd, J ) 9.2, 7.4 Hz), 2.88

(1H, dqd, J ) 7.4, 7.0, 4.7 Hz), 2.64 (1H, br d, J ) 16.1 Hz), 2.34

(1H, dd, J ) 13.9, 9.3 Hz), 2.32-2.20 (1H, m), 1.92 (1H, dddd, J

) 13.8, 13.2, 12.7, 4.5), 1.85-1.77 (1H, m), 1.72 (1H, d, J ) 13.9

Hz), 1.51 (3H, s), 1.16 (3H, d, J ) 7.0 Hz), 1.09-1.04 (21H, m),

0.98 (9H, t, J ) 8.0 Hz), 0.94 (9H, t, J ) 7.8 Hz), 0.62 (6H, q, J

) 7.8 Hz) 0.58 (6H, q, J ) 8.0 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ 147.3, 145.9, 127.5, 108.1, 83.0, 76.1, 75.5, 68.1, 66.8, 50.4,

35.3, 27.9, 25.8, 20.9, 19.6, 18.2, 12.1, 7.2, 7.0, 7.0, 5.1; HRMS

(FAB) m/z calcd for C₃₆H₇₂O₄Si₃[M]⁺: 652.4738, found: 652.4709

(∆ 4.6 ppm). Anal. calcd for C₃₆H₇₂O₄Si₃: C, 66.19; H, 11.11.

Found C, 66.14; H, 11.21.

(1R,2R,4S,5Z,7R,8R)-8-(Hydroxymethyl)-2-methyl-5-{(1S)-1-

methyl-2-[(triisopropylsilyl)oxy]ethyl}-2,4-bis[(triethylsilyl)oxy]-

11-oxabicyclo[5.3.1]undec-5-en-8-ol (30). A solution of osmium

tetroxide (4% in H₂O, 42 µL, 5 mol %) was added to a solution of

the alkene 29 (89 mg, 0.14 mmol) and NMO (48 mg, 0.41 mmol)

in acetone (3 mL) and water (0.5 mL) at room temperature. The

reaction mixture was allowed to stir at room temperature for 24 h.

TLC analysis revealed that the reaction was incomplete, so

additional osmium tetroxide (4% in H₂O, 42 µL, 5 mol %) was

added, and the reaction was allowed to stir at room temperature

for a further 24 h. The reaction was quenched with sodium

metabisulfite (500 mg), diluted with water (5 mL), and extracted

with ether (3 × 10 mL). The ether extracts were combined and

washed with water (10 mL) and brine (10 mL), then dried (MgSO₄)

and concentrated in vacuo to give an oil. Purification by column

chromatography on silica gel (hexane-ethyl acetate, 9:1 to 4:1) gave

the diol 30 (75 mg, 80%) as a colorless oil: R_f) 0.28 (hexane-

18

34: R_f) 0.87 (hexane-ethyl acetate, 19:1); [R]_D+62 (c )

0.28, CHCl₃); ν_max(CHCl₃) 2957, 2875, 1723, 881 cm^-1; ¹H NMR

(400 MHz, CDCl₃) δ 5.34 (1H, d, J ) 8.9 Hz), 4.95 (1H, s), 4.62

(1H, s), 3.71 (1H, dd, J ) 9.3, 4.7 Hz), 3.68 (1H, dd, J ) 9.8, 5.7

Hz), 3.43 (1H, dd, J ) 9.3, 7.6 Hz), 2.88 (1H, dqd, J ) 7.6, 6.9,

4.7 Hz), 2.59 (1H, dt, J ) 18.4, 2.7 Hz), 2.38-2.28 (2H, m), 2.17-

2.12 (1H, m), 2.03-1.91 (1H, m), 1.78 (1H, d, J ) 14.2 Hz), 1.58

(3H, s), 1.13 (3H, d, J ) 6.9 Hz), 1.06-1.03 (21H, m), 0.96 (9H,

t, J ) 7.9 Hz), 0.94 (9H, t, J ) 7.9 Hz), 0.61 (6H, q, J ) 7.9 Hz),

0.58 (6H, q, J ) 7.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 209.4,

149.6, 119.4, 82.8, 80.2, 75.3, 67.7, 66.6, 50.7, 36.1, 36.0, 27.8,

20.6, 19.7, 18.1, 12.1, 7.1, 7.0, 7.0, 5.1.

25

ethyl acetate, 3:1); [R]_D+2.3 (c ) 1.13, CHCl₃). ν_max(CHCl₃)

3572, 2955, 2874, 1602, 883 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ

5.40 (1H, d, J ) 9.7 Hz), 5.29 (1H, s), 4.33 (1H, s), 3.75 (1H, dd,

J ) 9.3, 4.6, Hz), 3.64 (1H, dd, J ) 13.1, 5.1 Hz), 3.60 (2H, d, J

) 6.1 Hz), 3.43 (1H, dd, J ) 9.3, 7.4 Hz), 3.11 (1H, br), 2.90 (1H,

dqd, J ) 7.4, 7.0, 4.6 Hz), 2.31 (1H, dd, J ) 13.9, 9.7 Hz), 2.24

(1H, t, J ) 6.1 Hz), 1.95-1.83 (1H, m), 1.78-1.66 (3H, m), 1.55

(3H, s), 1.58-1.53 (1H, m), 1.16 (3H, d, J ) 7.0 Hz), 1.09-1.04

(21H, m), 0.96 (9H, t, J ) 8.0 Hz), 0.93 (9H, t, J ) 7.9 Hz), 0.61

(6H, q, J ) 7.9 Hz), 0.56 (6H, q, J ) 8.0 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 148.0, 120.2, 80.5, 75.6, 74.7, 73.8, 68.2, 67.0,

66.8, 49.5, 35.6, 28.4, 28.1, 19.6, 19.0, 18.1, 12.1, 7.1, 7.0, 6.9,

5.0; HRMS (FAB) calcd for C₃₆H₇₄O₆Si₃[M⁺]: 686.4793, found:

686.4789 (∆ 0.6 ppm). Anal. calcd for C₃₆H₇₄O₆Si₃: C, 62.92; H,

10.85. Found C, 62.61; H, 10.61.

Methyl (1R,2R,4S,5S,6S,7R,8S)-5,6,8-Trihydroxy-2-methyl-5-

{(1R)-1-methyl-2-[(triisopropylsilyl)oxy]ethyl}-2,4-bis[(triethyl-

silyl)oxy]-11-oxabicyclo[5.3.1]undecane-8 -carboxylate (35). Os-

mium tetroxide (4% in water, 341 µL, 0.0536 mmol) was added to

a solution of the alkene 33 (40 mg, 0.056 mmol) and NMO (20

mg, 0.17 mmol) in acetone (2 mL), water (0.4 mL), and pyridine

(14 µL, 0.17 mmol) at room temperature. The reaction was stirred

at room temperature for 3 h, then quenched by the addition of solid

sodium metabisulfite (200 mg). The reaction mixture was diluted

with water (10 mL) and ether (10 mL), and the aqueous layer was

then removed and extracted with ether (2 × 10 mL). The ether

extracts were combined and washed with a saturated solution of

sodium thiosulfate (10 mL) and a saturated solution of copper

sulfate (10 mL) and brine (10 mL), then dried (MgSO₄) and

concentrated in vacuo to give a brown oil. Purification by column

Methyl (1R,2R,4S,5Z,7R,8S)-8-Hydroxy-2-methyl-5-{(1S)-1-

methyl-2-[(triisopropylsilyl)oxy]ethyl}-2,4-bis[(triethylsilyl)-

oxy]-11-oxabicyclo[5.3.1]undec-5-ene-8-carboxylate (33) and

(1R,2R,4S,5Z,7R,1′S)-2-Methyl-5-{(1S)-1-methyl-2-[(triisopro-

pylsilyl)oxy]ethyl}-2,4-bis[(triethylsilyl)oxy]-11-oxabicyclo[5.3.1]-

undec-5-en-8-one (34). A saturated solution of sodium bicarbonate

(216 µL) containing tetra-n-butylammonium bromide (1.8 mg, 5

mol %) was added to a solution of the alcohol 30 (75 mg, 0.11

J. Org. Chem, Vol. 73, No. 3, 2008 1053

Clark et al.

chromatography (hexane-ethyl acetate, 1:1) gave the triol ester 35

(35 mg, 84%) as an oil: R_f) 0.16 (petroleum ether-ethyl acetate,

19.8, 18.0, 12.7, 11.8, 7.2, 7.1, 7.0, 5.6; HRMS (CI, NH₄) m/z calcd

for C₃₆H₇₄O₇Si₃[M]⁺: 702.4742, found: 702.4756 (∆ 2.0 ppm).

19

3:1); [R]_D+230 (c ) 0.50, CHCl₃); ν_max(CHCl₃) 2956, 2873,

(3R,3aR,6R,8S,9S,9aR)-6-Methyl-9-{(1R)-1-methyl-2-[(triiso-

propylsilyl)oxy]ethyl}-6,8-bis[(triethylsilyl)oxy]hexahydro-3,5-

(ethanylylidene)furo[3,2-b]oxocine-3,9(2H)-diol (41). Ruthenium-

(III) chloride hydrate (3.2 mg, 0.014 mmol) was added to a solution

of the diol 39 (11 mg, 0.016 mmol) and sodium m-periodate (14

mg, 0.064 mmol) in CCl₄(0.5 mL), acetonitrile (0.5 mL), and water

(0.75 mL) at room temperature. The mixture was stirred at room

temperature for 5 h and then diluted with CH₂Cl₂(10 mL). The

aqueous and organic layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 5 mL). The organic extracts were

combined and washed with brine (5 mL), then dried (MgSO₄) and

concentrated in vacuo. Purification by column chromatography on

silica gel (petroleum ether-ethyl acetate, 9:1 to 4:1) gave recovered

diol 39 (9 mg) and the alkene 41 (2 mg) as a colorless oil: R_f)

1

1722, 1608, 872, 832 cm^-1; H NMR (400 MHz, CDCl₃) δ 4.88

(1H, d, J ) 5.9 Hz), 4.46 (1H, d, J ) 10.1 Hz), 4.36 (1H, d, J )

10.1 Hz), 4.29 (1H, dd, J ) 9.7, 6.4 Hz), 3.78 (1H, dd, J ) 9.7,

8.1 Hz), 3.72 (1H, dd, J ) 10.1, 7.3 Hz), 3.40 (1H, br), 3.35 (3H,

s), 2.78-2.68 (3H, m), 1.88-1.80 (2H, m), 1.78 (1H, d, J ) 15.1

Hz), 1.67-1.58 (1H, m), 1.55 (3H, s), 1.17 (3H, d, J ) 7.1 Hz),

1.15-1.11 (21H, m), 0.97 (9H, t, J ) 7.9 Hz), 0.77 (9H, t, J ) 7.9

Hz), 0.60 (6H, q, J ) 7.9 Hz), 0.56-0.39 (6H, m); ¹³C NMR (100

MHz, CDCl₃) δ 176.1, 98.2, 89.5, 80.7, 77.9, 75.5, 75.0, 73.6, 66.7,

52.5, 47.3, 42.9, 29.7, 27.0, 19.2, 18.3, 14.9, 12.4, 7.2, 7.1, 7.0,

5.5.

(1R,2S,4S,5S,7R,8R,11R)-11-(Hydroxymethyl)-7-methyl-4-

{(1R)-1-methyl-2-[(triisopropylsilyl)oxy]ethyl}-5,7-bis[(triethyl-

silyl)oxy)]-3,12-dioxatricyclo[6.3.1.0^2,4]dodecan-11-ol (38). m-

CPBA (50-55%, 66 mg, 0.19 mmol) was added to a solution of

the alkene 30 (87 mg, 0.13 mmol) in dry CH₂Cl₂(10 mL) at 0 °C

under Ar. The reaction vessel was then removed from the ice bath

and the mixture was stirred for 4 h. The reaction was quenched by

the addition of a saturated solution of sodium thiosulfate (10 mL),

and the reaction mixture was extracted with CH₂Cl₂(3 × 10 mL).

The organic extracts were combined and washed with a saturated

solution of sodium bicarbonate (10 mL), water (10 mL), and brine

(10 mL), then dried (MgSO₄) and concentrated in vacuo to give an

oil. Purification by column chromatography (isohexane-ethyl

acetate, 9:1 to 4:1) gave the epoxide 38 (76.5 mg, 86%) as a

colorless, viscous oil: R_f) 0.29 (isohexane-ethyl acetate, 4:1).

23

0.43 (petroleum ether-ethyl acetate, 4:1): [R]_D+39 (c ) 0.23,

CHCl₃); ν_max(CHCl₃) 3446, 2952, 2874, 1678, 1601, 883 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 5.20 (1H, dd, J ) 7.8, 3.9 Hz),

4.68 (1H, br), 4.56 (1H, d, J ) 3.6 Hz), 4.48 (1H, d, J ) 8.1 Hz),

4.15 (1H, d, J ) 3.6 Hz), 3.86 (1H, dd, J ) 11.6, 10.4 Hz), 3.70

(1H, d, J ) 9.3 Hz), 3.71-3.67 (1H, m), 3.41 (1H, dd, J ) 9.3,

2.0 Hz), 2.83 (1H, dd, J ) 13.7, 8.1 Hz), 2.56-2.47 (1H, m), 2.37

(1H, dd, 12.9, 7.8 Hz), 2.34-2.27 (1H, m), 1.64 (1H, d, J ) 13.7

Hz), 1.47 (3H, s), 1.12-1.04 (21H, m), 0.98 (12H, t, J ) 7.9 Hz),

0.95 (9H, t, J ) 8.0 Hz), 0.76-0.62 (6H, m) 0.60 (6H, q, J ) 7.9

Hz); ¹³C NMR (125 MHz, CDCl₃) δ 164.8, 96.6, 88.9, 86.8, 83.5,

80.1, 79.5, 76.7, 75.3, 68.4, 50.7, 41.2, 32.4, 25.2, 18.0, 13.0, 11.8,

7.2, 7.1, 7.0, 5.3. HRMS (ESI) m/z calcd for C₃₆H₇₂O₇Si₃[M]⁺:

700.4586, found: 700.4528 (∆ 8.2 ppm).

18

[R]_D+54 (c ) 0.98, CHCl₃); ν_max(CHCl₃) 3568, 2955, 2874,

1

883 cm^-1; H NMR (400 MHz, CDCl₃) δ 4.24 (1H, d, J ) 9.9

(3S,3aR,5R,6R,8S,9S,9aR)-3,9-Dihydroxy-6-methyl-9-{(1R)-

1-methyl-2-[(triisopropylsilyl)oxy]ethyl}-6,8-bis[(triethylsilyl)-

oxy]octahydro-2H-3,5-ethanofuro[3,2-b]oxocin-2-one (37) and

(1R,2S,4S,5S,7R,8R)-7-Methyl-4-{(1R)-1-methyl-2-[(triisopropyl-

silyl)oxy]ethyl}-5,7-bis[(triethylsilyl)oxy]-3,12-dioxatricyclo-

[6.3.1.0^2,4]dodecan-11-one (43). Tetra-n-butylammonium bromide

(1.5 mg, 5.0 mol %) was dissolved in a saturated solution of sodium

bicarbonate (180 µL), and the mixture was then added to a solution

of the alcohol 38 (64 mg, 0.091 mmol) and TEMPO (0.7 mg, 5

mol %) in CH₂Cl₂(2 mL) at room temperature. The mixture was

cooled to 0 °C, and a solution of sodium hypochlorite (271 mg,

0.182 mmol) dissolved in a saturated solution of sodium bicarbonate

(96 µL) and brine (198 µL) was added over 10 min. The reaction

was stirred at 0 °C for 15 min and then quenched by the addition

of water (10 mL) and CH₂Cl₂(10 mL). The aqueous and organic

phases were separated, and the aqueous layer was extracted with

CH₂Cl₂(2 × 10 mL). The organic extracts were combined, dried

(MgSO₄), and concentrated in vacuo to afford the crude aldehyde

(69 mg) as a colorless oil.

The aldehyde was dissolved in a mixture of t-butanol (455 µL)

and 2-methyl-2-butene (77 µL, 0.73 mmol) at room temperature.

A solution of sodium chlorite (80%, 62 mg, 0.55 mmol) and sodium

dihydrogenorthophosphate dihydrate (92 mg, 0.59 mmol) in water

(910 µL) was then added dropwise over 5 min at room temperature.

The mixture was stirred at room temperature for 15 min and then

diluted with CH₂Cl₂(10 mL). The phases were separated, and the

aqueous layer was extracted with CH₂Cl₂(2 × 5 mL). The organic

extracts were combined, dried (MgSO₄), and concentrated in vacuo

to give the crude carboxylic acid 42 (69 mg) as a yellow oil.

Hz), 4.01 (1H, s), 3.83 (1H, dd, J ) 9.6, 4.5 Hz), 3.66 (2H, s),

3.61 (1H, dd, J ) 12.4, 4.0 Hz), 3.32 (1H, dd, J ) 9.6, 8.0 Hz),

3.00 (1H, s), 2.98 (1H, br), 2.65 (1H, dqd, J ) 8.0, 7.0, 4.5 Hz),

2.45 (1H, dd, J ) 14.6, 9.9 Hz), 2.21 (1H, br), 1.95-1.88 (1H,

m), 1.84-1.50 (3H, m), 1.60 (1H, d, J ) 14.6 Hz), 1.46 (3H, s),

1.17 (3H, d, J ) 7.0 Hz), 1.06-1.05 (21H, m), 0.98 (9H, t, J )

7.8 Hz), 0.93 (9H, t, J ) 7.8 Hz), 0.64 (6H, q, J ) 7.8 Hz), 0.58

(6H, q, J ) 7.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 79.2, 75.3,

75.2, 73.7, 72.1, 69.0, 66.8, 65.2, 60.7, 46.0, 33.5, 27.9, 27.1, 18.9,

18.0, 16.6, 12.0, 7.0, 6.8, 6.8, 4.9; HRMS (CI, CH₄) m/z calcd for

C₃₆H₇₄O₇Si₃[M⁺]: 702.4742, found: 702.4705 (∆ 5.3 ppm).

(3R,3aR,5R,6R,8S,9S,9aR)-6-Methyl-9-{(1R)-1-methyl-2-[(tri-

isopropylsilyl)oxy]ethyl}-6,8-bis[(triethylsilyl)oxy]hexahydro-

2H-3,5-ethanofuro[3,2-b]oxocine-3,9(3aH)-diol (39). Camphor

sulfonic acid (CSA) (2.5 mg, 0.011 mmol) was added to a solution

of the epoxide 38 (15.0 mg, 0.0213 mmol) in dry CH₂Cl₂(2 mL)

at room temperature under N₂. The reaction was heated to 40 °C

and stirred at this temperature for 16 h. The reaction was allowed

to cool to room temperature and then quenched by the addition of

water (1 mL) and a saturated solution of sodium bicarbonate (1

mL). The mixture was extracted with CH₂Cl₂(2 × 10 mL), and

the combined organic extracts were washed with brine (5 mL), then

dried (MgSO₄) and concentrated in vacuo to give an oil. Purification

by column chromatography on silica gel (isohexane-ethyl acetate,

9:1 to 4:1) gave the tricyclic diol 39 (11.3 mg, 75%) as a colorless

oil: R_f) 0.69 (isohexane-ethyl acetate, 4:1); [R]_D¹⁹+18 (c ) 1.0,

CHCl₃); ν_max(CHCl₃) 3598, 3446, 2950, 2874, 910, 881 cm^-1; ¹H

NMR (400 MHz, CDCl₃) δ 4.71 (1H, s), 4.38 (1H, d, J ) 4.7 Hz),

4.36 (1H, d, J ) 5.3 Hz), 3.96 (1H, d, J ) 9.3 Hz), 3.96-3.92

(1H, m), 3.86 (1H, d, J ) 4.7 Hz), 3.71 (1H, dd, J ) 10.1, 4.5

Hz), 3.66 (1H, dd, J ) 11.2, 6.7 Hz), 3.37 (1H, dd, J ) 9.3, 1.1

Hz), 2.93 (1H, dd, J ) 14.7, 5.3 Hz), 2.49-2.38 (1H, m), 1.93

(1H, dd, J ) 9.5, 4.9 Hz), 1.86-1.78 (1H, m), 1.70-1.57 (2H, m),

1.48 (3H, s), 1.33 (1H, d, J ) 14.7 Hz), 1.11-1.04 (24H, m), 0.98

(9H, t, J ) 7.8 Hz), 0.93 (9H, t, J ) 7.8 Hz), 0.72-0.55 (6H, m),

0.55 (6H, q, J ) 7.8 Hz); ¹³C NMR (126 MHz, CDCl₃) δ 88.0,

84.4, 80.9, 79.5, 78.9, 78.7, 76.3, 76.2, 68.4, 43.6, 41.1, 32.1, 27.6,

The acid 42 (69 mg) was dissolved in dry CH₂Cl₂(2 mL) and

CSA (21 mg, 0.090 mmol) was added at room temperature under

Ar. The reaction was stirred at room temperature for 45 min and

then quenched by the addition of water (2 mL) and a saturated

solution of sodium bicarbonate (2 mL). The phases were separated,

and the aqueous layer was extracted with CH₂Cl₂(3 × 5 mL). The

organic extracts were then combined, dried (MgSO₄), and concen-

trated in vacuo to give an oil. Purification by column chromatog-

raphy on silica gel (hexane-ethyl acetate, 98:2 to 4:1) gave the

1054 J. Org. Chem., Vol. 73, No. 3, 2008

Construction of Tricyclic Core of Neoliacinic Acid

lactone 37 (24.4 mg, 37%) and the ketone 43 (27 mg, 44%) as

to a solution of the triol ester 35 (12 mg, 0.016 mmol) in dry ether

(2 mL) at room temperature under Ar. The reaction mixture was

stirred at room temperature for 12 h. The reaction was quenched

by the addition of 0.5 M HCl (10 mL) and extracted with ethyl

acetate (3 × 10 mL). The ethyl acetate extracts were combined

and washed with brine (5 mL), then dried (MgSO₄) and concentrated

in vacuo to a clear oil. Purification by column chromatography on

silica gel (hexane-ethyl acetate, 9:1) gave the lactone 47 (7 mg,

61%) as a colorless oil: R_f) 0.78 (petroleum ether-ethyl acetate,

colorless oils.

22

37: R_f) 0.75 (petroleum ether-ethyl acetate, 3:1); [R]_D-17

(c ) 1.0, CHCl₃); ν_max(CHCl₃) 3422, 2952, 2874, 1777 cm^-1; ¹H

NMR (400 MHz, CDCl₃) δ 4.94 (1H, s), 4.73 (2H, s), 4.45 (1H, d,

J ) 5.0 Hz), 4.03 (1H, dd, J ) 11.9, 11.5 Hz), 3.83-3.76 (2H,

m), 2.57-2.51 (1H, m, CHCH₃), 2.46 (1H, s), 2.44 (1H, dd, J )

15.2, 5.0), 2.10-2.04 (1H, m), 1.98-1.89 (1H, m), 1.73 (1H, ddd,

J ) 14.3, 11.9, 2.3 Hz), 1.50 (3H, s), 1.40 (1H, d, J ) 15.2 Hz),

1.16-1.10 (1H, m), 1.07-1.04 (21H, m), 1.03 (3H, d, J ) 7.4

Hz), 0.98 (9H, t, J ) 7.9 Hz), 0.90 (9H, t, J ) 7.9 Hz), 0.80-0.60

(6H, m), 0.54 (6H, q, J ) 7.9 Hz); ¹H NMR (400 MHz, C₆D₆) key

signals δ 5.16 (1H, d, J ) 5.3 Hz, OCHCHOCdO/OCHCHOCd

23

3:1); [R]_D+7.1 (c ) 0.17, CHCl₃); ν_max(CHCl₃) 3378, 2960,

2873, 1785, 1602 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 5.69 (1H,

s), 4.70 (1H, d, J ) 10.3 Hz), 4.61 (1H, d, J ) 10.3 Hz), 4.31 (1H,

dd, 11.6, 9.8 Hz), 4.09 (1H, d, J ) 8.1 Hz), 3.82 (1H, dd, J )

10.8, 7.7 Hz), 3.59 (1H, dd, J ) 9.8, 4.6 Hz), 2.80 (1H, dqd, J )

11.6, 7.1, 4.6 Hz), 2.63 (1H, s), 2.53-2.48 (1H, m), 2.35 (1H, dd,

J ) 15.8, 8.1 Hz), 1.97-1.71 (3H, m), 1.65 (1H, d, J ) 15.8 Hz),

1.51 (3H, s), 1.07-1.05 (21H, m), 0.99 (9H, t, J ) 7.9 Hz), 0.94

(3H, d, J ) 7.1 Hz), 0.92 (t, 9H, J ) 7.9 Hz,), 0.77-0.63 (6H, m),

0.56 (6H, q, J ) 7.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 177.7,

79.2, 78.9, 78.5, 76.1, 75.5, 75.4, 71.5, 68.9, 48.2, 36.8, 29.8, 28.6,

20.7, 17.9, 17.9, 12.9, 11.7, 7.1, 6.9, 5.3; HRMS (ESI) m/z calcd

for C₃₆H₇₂O₈Si₃[M]⁺: 716.4535, found: 716.4604 (∆ 9.6 ppm).

O), 5.13 (1H, d, J ) 5.3 Hz, OCHCHOCdO/OCHCHOCdO); ¹³

C

NMR (125 MHz, CDCl₃) δ 178.3, 85.2, 81.5, 79.5, 78.4, 76.2, 76.1,

75.9, 68.0, 44.0, 40.7, 27.6, 27.4, 21.9, 18.0, 12.2, 11.7, 7.2, 7.1,

6.9, 5.6; HRMS (CI, CH₄) m/z calcd for C₃₆H₇₂O₈Si₃[M]⁺:

716.4535, found: 716.4463.

43: R_f) 0.50 (petroleum ether-ethyl acetate, 19:1); [R]_D²⁰+2.2

(c ) 1.0, CHCl₃); ν_max(CHCl₃) 2954, 2875, 1731 cm^-1; ¹H NMR

(400 MHz, CDCl₃) δ 4.38 (1H, s), 4.18 (1H, d, J ) 8.8 Hz), 3.68

(1H, dd, J ) 9.7, 4.6 Hz), 3.66 (1H, dd, J ) 10.6, 3.6 Hz), 3.32

(1H, dd, J ) 9.7, 6.9 Hz), 3.09 (1H, s), 2.62-2.53 (3H, m), 2.41-

2.28 (2H, m), 1.89-1.76 (1H, m), 1.65 (1H, d, J ) 14.7 Hz), 1.49

(3H, s), 1.19 (3H, d, J ) 7.0 Hz), 1.08-1.00 (21H, m), 0.98 (9H,

t, J ) 7.9 Hz), 0.95 (9H, t, J ) 7.9 Hz), 0.64 (6H, q, J ) 7.9 Hz,),

0.59 (6H, q, J ) 7.9 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 209.4,

82.1, 78.9, 74.9, 72.2, 69.5, 64.4, 63.9, 46.1, 35.7, 33.9, 26.8, 19.7,

18.1, 17.0, 12.0, 7.1, 7.0, 6.9, 5.1; HRMS (CI, NH₃) m/z calcd for

C₃₅H₇₀O₆Si₃[M]⁺: 670.4480, found: 670.4512 (∆ 4.7 ppm).

(3S,3aR,5R,6R,8S,9S,9aS)-3,9-Dihydroxy-6-methyl-9-{(1R)-1-

methyl-2-[(triisopropylsilyl)oxy]ethyl}-6,8-bis[(triethylsilyl)oxy]-

octahydro-2H-3,5-ethanofuro[3,2-b]oxocin-2-one (47). Potassium

trimethylsilanolate (21 mg, 0.16 mmol) was added in one portion

Acknowledgment. The University of Nottingham, Syngenta,

and Merck Sharp and Dohme are gratefully acknowledged for

studentship funding (for C.A.B. and A.G.D.). This work was

supported by EPSRC (U.K.) (Grant GR/L62856/01).

Supporting Information Available: ¹H and ¹³C NMR spectra

for 7, 8, 11-13, 15-19, 21, 23-30, 33-35, 37-39, 41, 43, and

47. This material is available free of charge via the Internet at

http://pubs.acs.org.

JO702111U

J. Org. Chem, Vol. 73, No. 3, 2008 1055

Article Doi

Stereoselective construction of the tricyclic core of neoliacinic acid

DOI: 10.1021/jo702111u

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Full text of DOI:10.1021/jo702111u

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