The Utility of Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes as Demonstrated by Modular Synthesis of Annonaceous Acetogenin Core Units and Their Pyrrolidine and Thiolane Analogues

2048

J . Org. Chem. 2000, 65, 2048-2064

Th e Utility of F u r a n -, P yr r ole-, a n d Th iop h en e-Ba sed 2-Silyloxy

Dien es As Dem on str a ted by Mod u la r Syn th esis of An n on a ceou s

Acetogen in Cor e Un its a n d Th eir P yr r olid in e a n d Th iola n e

An a logu es

Franca Zanardi,^†Lucia Battistini,^†Gloria Rassu,^‡Luciana Auzzas,^‡Luigi Pinna,^§

Lucia Marzocchi,^†Domenico Acquotti,^|and Giovanni Casiraghi*^,†

Dipartimento Farmaceutico, Universita` di Parma, I-43100 Parma, Italy, Istituto per l’Applicazione delle

Tecniche Chimiche Avanzate ai Problemi Agrobiologici del CNR, I-07100 Sassari, Italy, Dipartimento di

Chimica, Universita` di Sassari, I-07100 Sassari, Italy, and Centro Interdipartimentale di

Misure “G. Casnati”, Universita` di Parma, I-43100 Parma, Italy

Received October 7, 1999

We report a modular strategy for obtaining the core units of annonaceous acetogenins and their

nitrogen and sulfur analogues, which generates great structural diversity. This synthesis is based

on the application of a reiterative vinylogous addition protocol involving a unique triad of silyloxy

diene modules, 2-[(tert-butyldimethylsilyl)oxy]furan (TBSOF), N-(tert-butoxycarbonyl)-2-[(tert-

butyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert-butyldimethylsilyl)oxy]thiophene (TBSOT) and

suitable heteroatom-stabilized carbenium ions. By combining TBSOF, TBSOP, and TBSOT

nucleophilic synthons with certain tetrahydrofuran, pyrrolidine, and thiolane acceptors, the

construction of varied, adjacently linked oligo-heterocyclic motifs related to the core segments of

the annonaceous acetogenins is assured. At first, the reliability of the pivotal coupling maneuver

was certified, by assembling a collection of 18 model constructs, covering all oxygen, nitrogen, and

sulfur heteroatom combinations (i.e., compounds 7-9, 13-15, and 19-21). This uniformed protocol

was then suited to forge advanced bis-tetrahydrofuran, bis-pyrrolidine, and bis-thiolane scaffolds

encompassing the heterocyclic core portion of various binuclear annonaceous acetogenins and

relatives. The utility of this synthesis was demonstrated by the preparation of a repertoire of eight

isomeric bis-tetrahydrofuran units, 41-48, two bis-pyrrolidine units, 62 and 63, and four bis-thiolane

units, 78-81.

In tr od u ction

annonaceous acetogenins is an oxygenated core consisting

of either a tetrahydrofuran ring,³an assembly of tet-

rahydrofuran rings (both adjacent and not), or a bioge-

netically equivalent element (polyepoxide or epoxyolefin

moieties). This oxygenated core carries two alkyl chains,

one of which terminates with a γ-methyl-γ-lactone ring,

whereas both are generally oxygenated in the vicinity of

the central core and the lactone head (Figure 1). The

molecular diversity within the annonaceous acetogenins

is impressive, since the variability of the constitutional

elements (type of oxygen core and location of the oxygen

functions on the alkyl branches) is further magnified by

the diverse disposition of the numerous stereocenters

present.

The annonaceous acetogenins are a class of C₃₅or C₃₇

plant metabolites isolated, as to date, only from the

archaic family of the Annonaceae.¹Since 1982, when

uvaricin was first isolated from Uvaria acuminata,²this

class of compounds has grown to include over 250

individual representatives. The structural hallmark of

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

ipruniv.cce.unipr.it.

^†Dipartimento Farmaceutico, Universita` di Parma.

^‡CNR, Sassari.

^§Dipartimento di Chimica, Universita` di Sassari.

^|Centro Interdipartimentale di Misure, Universita` di Parma.

(1) For recent comprehensive reviews, see: Alali, F. Q.; Liu, X.-X.;

McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504-540. Cave´, A.; Figade`re,

B.; Laurens, A.; Cortes, D. In Progress in the Chemistry of Organic

Natural Products; Herz, W., Ed.; Springer-Verlag: Wien, New York,

1997; Vol. 70, pp 81-288. Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng,

L.; McLaughlin, J . L. In Recent Advances in Phytochemistry; Arnason,

J . T., Mata, R., Romeo, J . T., Eds.; Plenum Press: New York, 1995;

Vol. 29, Chapter 11, pp 249-310. Zeng, L.; Ye, Q.; Oberlies, N. H.;

Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J . L. Nat. Prod. Rep. 1996,

275-306. Cave´, A.; Cortes, D.; Figade`re, B.; Hocquemiller, R.; Lapre´-

vote, O.; Laurens, A.; Lebœuf, M. In Phytochemical Potential of

Tropical Plants; Downum, K. R., Romeo, J . T., Stafford, H. E., Eds.;

Plenum Press: New York, 1993; pp 167-202. Marshall, J . A.; Hinkle,

K. W.; Hagedorn, C. E. Recent Developments in the Synthesis of

Annonaceous Acetogenins. Isr. J . Chem. 1997, 37, 97-107. Zafra-Polo,

M. C.; Figade`re, B.; Gallardo, T.; Tormo, J . R.; Cortes, D. Phytochem-

istry 1998, 48, 1087-1117. Casiraghi, G.; Zanardi, F.; Battistini, L.;

Rassu, G.; Appendino, G. Chemtracts Org. Chem. 1998, 11, 803-827

and references therein.

The economic relevance of several plants from the

Annonaceae family is paralleled by the broad biological

activity of several of their acetogenins. Of special interest

is their cytotoxicity which, seemingly mediated by inhibi-

tion of mitochondrial respiratory complex I, ultimately

results in ATP depletion.⁴Furthermore, several annona-

ceous acetogenins display an anticancer activity several

orders of magnitude greater than that of some chemo-

therapeutic agents in current clinical use.^1,4However,

(3) Recently, a few tetrahydropyran-containing analogues have been

isolated and synthesized: Schaus, S.; Brånalt, J .; J acobsen, E. J . Org.

Chem. 1998, 63, 4876-4877. Neogi, P.; Doundoulakis, T.; Yazbak, A.;

Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120,

11279-11284. Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40,

723-726. Evans, P. A.; Murthy, V. S. Tetrahedron Lett. 1999, 40,

1253-1256.

(2) J olad, S. D.; Hoffmann, J . J .; Schram, K. H.; Cole, J . R.;

Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J . Org. Chem. 1982, 47,

3151-3153.

Published on Web 03/16/2000

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2049

Resu lts a n d Discu ssion

P la n n in g. As a continuation of our program targeted

at developing a methodology relevant to the asymmetric

synthesis of important multifunctional biomolecules, we

have devised a modular approach of assembling both

binuclear annonaceous acetogenins A and mononuclear

relatives B by exploiting furan-, pyrrole-, and thiophene-

based silyloxy dienes TBSOF, TBSOP, and TBSOT and

using glyceraldehyde H as the chiral starter molecule.

As shown in the retrosynthetic plan in Scheme 1,

disconnection of the generic C₃₇binuclear acetogenin A

along the bonds C11-C12 and C25-C26 defines the

subtarget lactone C as the basic scaffold of the C12-C25

core backbone, which contains the two adjacently linked

heterocycles. Attachment of the methyl butenolide frame

and the saturated aliphatic chain at the north and south

orthogonally masked termini (or vice versa) guarantees

formation of the acetogenin targets. Installation of the

lactone moiety within C may arise via a vinylogous

juncture of the silyloxy furan TBSOF to the “anomeric”

carbon of the binuclear intermediate D. The C16-C25

unit D, in turn, originates from E, an intermediate

common to the synthesis of mononuclear annonaceous

acetogenins of type B. Disconnection of E along the bond

C19-C20 reveals the mononuclear lactol-type synthon

F , which, in the forward sense, leads to E via vinylogous

coupling with one of the three silyloxy diene heterocycles

TBSOF, TBSOP, or TBSOT. Lactol F readily traces back

to G, which may derive from the vinylogous Mukaiyama

aldol addition between glyceraldehyde H and one of the

silyloxy diene modules already mentioned.

On the whole, this synthesis, which exploits a readily

available triad of four-carbon modules and uses a uniform

and reiterative chemistry, outlines the stepwise elonga-

tion of the easily accessible three-carbon “chiron” H via

three sequential vinylogous additions.⁶The choice of the

heteroatoms combined in the first and the second vinyl-

ogous aldol couplings, the chirality of the chosen aldehyde

starter H (R vs S), and the chirality transmittal during

the molecular growth (erythro vs threo, cis vs trans) all

ensure the generation of ample chemical diversity during

this synthesis. In addition, the synthetic flexibility can

be increased during the final union of subtargets C and

E to the butenolide and aliphatic fragments by simply

switching the poles onto which these side chains are

installed (C12 and C25 in C, or C16 and C25 in E). As a

result, preparation of a highly diverse repertoire of

natural annonaceous acetogenins, as well as their struc-

tural and stereochemical variants is, in principle, fea-

sible.

F igu r e 1. Representative adjacent bis-tetrahydrofuran ac-

etogenins of the Annonaceae.

their very narrow therapeutic index necessitates optimi-

zation if their toxicity is to be reduced. This, coupled with

the failure to identify a common pharmacophore, the

challenging chemical architecture of the natural products,

their limited availability and their resistance to chemical

modification, justifies the interest shown in the total

synthesis of these compounds.¹

The aim of this work is (1) to design an adaptable,

chemically uniform methodology for obtaining the mul-

tichiral heterocyclic annonaceous acetogenin core com-

ponents and (2) to exploit this methodology to assemble

a repertoire of adjacently linked bis-tetrahydrofuran

acetogenin scaffolds and their modified bis-pyrrolidine

and bis-thiolane unnatural relatives. The synthesis of

these densely functionalized chiral constructs provides

a new application for the triad of vinylogous heterocyclic

silyl enol ethers, 2-[(tert-butyldimethylsilyl)oxy]furan

(hereafter TBSOF), N-(tert-butoxycarbonyl)-2-[(tert-bu-

tyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert-bu-

tyldimethylsilyl)oxy]thiophene (TBSOT).⁵This paper de-

scribes a novel, unified strategy that allows for the

synthesis of 14 individual adjacently linked binuclear

acetogenin core units, comprising eight isomeric bis-

tetrahydrofuran representatives, 41-48, two bis-pyrrol-

idine analogues, 62-63, and four bis-thiolane congeners,

78-81.

In itia l Stu d ies.⁷The work initiated by assembling a

number of unsaturated and saturated model constructs

4-21 (Scheme 2) covering all the diverse X,Y heteroatom

combinations. In order for the coupling chemistry to be

(4) Holschneider, C. H.; J ohnson, M. T.; Knox, R. M.; Rezai, A.; Ryan,

W. J .; Montz, F. J . Cancer Chemother. Pharmacol. 1994, 34, 166-170.

Degli Esposti, M.; Ghelli, A.; Ratta, M.; Cortes, D.; Estornell, E.

Biochem. J . 1994, 301, 161-167. Oberlies, N. H.; J ones, J . L.; Corbett,

T. H.; Fotopoulos, S. S.; McLaughlin, J . L. Cancer Lett. 1995, 96, 55-

62. Morre´, D. J .; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin,

J . L. Life Sci. 1995, 56, 343-348. Oberlies, N. H.; Croy, V. L.; Harrison,

M. L.; McLaughlin, J . L. Cancer Lett. 1997, 115, 73-79. Wang, X.-W.;

Xie, H. Drugs Future 1999, 24, 159-165.

(5) For general reviews: Casiraghi, G.; Rassu, G. Synthesis 1995,

607-629. Casiraghi, G.; Rassu, G.; Zanardi, F.; Battistini, L. In

Advances in Asymmetric Synthesis; Hassner, A., Ed.; J AI Press:

Stamford; 1998; Vol. 3, pp 113-189. Rassu, G.; Zanardi, F.; Battistini,

L.; Casiraghi, G. Synlett 1999, 1333-1350.

(6) For leading references concerning the reactivity of vinylogous

carbon nucleophiles, see, for example: Christoffers, J . J . Org. Chem.

1998, 63, 4539-4540. Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H.

J . Am. Chem. Soc. 1998, 120, 813-814. Kru¨ger, J .; Carreira, E. M.

Tetrahedron Lett. 1998, 39, 7013-7016. Saito, S.; Yamamoto, H. Chem.

Eur. J . 1999, 5, 1959-1962. Martin, S. F.; Lopez, O. D. Tetrahedron

Lett. 1999, 40, 8949-8953. Hara, R.; Furukawa, T.; Kashima, H.;

Kusama, H.; Horiguchi, Y.; Kuwajima, I. J . Am. Chem. Soc. 1999, 121,

3072-3082. Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos,

K. R. J . Am. Chem. Soc. 1999, 121, 6816-6826.

(7) For a preliminary account of the work in this section, see:

Zanardi, F.; Battistini, L.; Rassu, G.; Pinna, L.; Mor, M.; Culeddu, N.;

Casiraghi, G. J . Org. Chem. 1998, 63, 1368-1369.

2050 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

Sch em e 1

uniform and validated, vinylogous Mukaiyama aldol-type

reactions of the silyloxy diene triad TBSOF, TBSOP, and

TBSOT with simple tetrahydrofuran, pyrrolidine, and

thiolane electrophilic modules 1-3 were investigated.

The results are summarized in Scheme 2 and Chart 1.

Efficient, stereoselective synthesis of the lactol-type

modules 1, 2, and 3 had been previously achieved using

the same silyloxy diene triad TBSOF, TBSOP, and

TBSOT and using 2,3-O-isopropylidene-^D-glyceraldehyde

as the chiral hydroxymethyl surrogate.⁸Addition of

TBSOF to the activated lactol 1 in the presence of 0.6

equiv of tert-(butyldimethylsiloxy)trifluoromethanesul-

fonate (TBSOTf) in CH₂Cl₂at -90 °C afforded a sepa-

rable 1:1 mixture of two epimeric butenolide intermedi-

ates 4tt and 4et, which were individually hydrogenated,

to provide the corresponding saturated 4,5-threo-5,8-

trans- and 4,5-erythro-5,8-trans-configured counterparts

7tt and 7et (67% combined yield for two steps).⁹The

saturated binuclear models 7-9, 13-15, and 19-21

shown in Chart 1 were assembled according to a set of

parallel protocols that reproduced the catalytic system

and procedure used for the all-oxygen series. The results

reveal that the nine processes behaved in the same way

under TBSOTf catalysis, irrespective of the heteroatom

composition, providing, after hydrogenation, reasonable

yields (46-74%) of the expected saturated adducts 7-9,

13-15, and 19-21. With the exception of the coupling

between TBSOP and 1, which gave rise to all four

possible stereoisomers, the other reactions displayed

partial or complete diastereocontrol, yielding either a

couple of stereoisomers or a single component, as indi-

cated.

Structural diagnosis of the different isomers isolated

proved nontrivial, especially for the scantily precedented

2,5-disubstituted pyrrolidine-containing units (e.g., 10-

15). Stereochemical assignment was mainly based on the

following data. (1) Ch ir o-Op tica l Evid en ce. As a

guideline, 4R-configured 4-hydroxyalkyl-substituted 2,3-

unsaturated butenolides and relatives are dextrorotatory,

(8) Rassu, G.; Zanardi, F.; Battistini, L.; Gaetani, E.; Casiraghi, G.

J . Med. Chem. 1997, 40, 168-180. Conveniently, preparation of 1 and

2 may also be achieved adopting conventional chemistry by starting

with commercially available (R)-dihydro-5-(hydroxymethyl)-2(3H)-

furanone and (R)-5-(hydroxymethyl)-2-pyrrolidinone, respectively. The

reaction sequence to 1 encompasses proper silylation of the free

hydroxyl (TBDPSCl, imidazole, DMF), followed by carbonyl reduction

to a lactol (DIBAL-H, CH₂Cl₂, -80 °C) and acetylation (Ac₂O, pyridine,

DMAP) (65% yield over three steps). For 2, the protocol includes

hydroxyl silylation, N-Boc protection (Boc₂O, DMAP, MeCN), carbonyl

reduction (LiEt₃BH, THF, -80 °C), and methylation (CH(OMe)₃, BF₃‚

OEt₂, Et₂O, 4 Å molecular sieves) (52% yield over four steps).

(9) The suffixes associated to conventional numbering in model

compounds 4-21 relate to the relative stereodisposition of the C4-

C5 and C5-C8 stereocenters: e.g., 4tt ) 4,5-threo-5,8-trans-4; 14ec

) 4,5-erythro-5,8-cis-14, etc.

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2051

Sch em e 2^a

tion of N-Boc-containing compounds exhibiting contro-

versial results, 4,5-erythro-configured butenolides and

relatives may be distinguished from their 4,5-threo

counterparts by the downfield chemical shift of the H3

proton within the unsaturated ring.¹³

Where controversy arose, as in the case of the N,N-

binuclear adducts 11 and 14, recourse to bidimensional

¹H NMR NOESY and ROESY experiments proved deci-

sive, allowing for the unequivocal assignment of the

stereostructures through analysis of interproton NOE

contact sequences. For example, for the saturated lac-

tams 14ec and 14et, whose ¹H NMR spectra were barely

readable due to considerable N-Boc rotameric contamina-

tion, analysis of the corresponding N-deprotected coun-

terparts, deBoc-14ec and deBoc-14et, was necessary.

This analysis showed well resolved resonances for all

diagnostic protons. The compounds deBoc-14ec and

deBoc-14et were cleanly obtained in yields of 85% and

81%, respectively, upon exposure of the corresponding

protected derivatives 14ec and 14et to B-bromocat-

echolborane in CH₂Cl₂.¹⁴As shown in Figure 2, the

contacts H8/H6â, H9a/H6R, and H5/H6â for deBoc-14ec

and H8/H6â, H9a/H6R, and H5/H6R for deBoc-14et were

crucial for structural diagnosis. This study also revealed

the existence of a major conformation for both isomers,

where the H4 and H5 protons involving the inter-ring

juncture are located in an antiperiplanar relationship,

reflected by the large vicinal H4-H5 coupling constant

(J _4,5) 8.8 Hz for deBoc-14ec, and J _4,5) 7.1 Hz for deBoc-

14et). In particular, the slightly smaller value of the J _4,5

coupling constant for deBoc-14et, compared with that of

the deBoc-14ec isomer, may be attributed to the coexist-

ence of a minor conformation where the H4 and H5

protons are in a gauche relationship. This conclusion is

also supported by a significant NOE contact between

these two protons, which is almost negligible for the

deBoc-14ec isomer.

Taken together, these data allowed us to assign with

confidence the stereochemistry of all 18 compounds

shown in Chart 1.¹⁵Overall, our optimized synthetic

protocols and the set of criteria used for the structural

diagnosis of the various stereostructures represent the

sound foundations onto which the synthesis of C12-C25

acetogenin subtargets could be based.

Syn t h esis of Bis-Tet r a h yd r ofu r a n C12-C25

Un its.¹⁶Successful preparation of model structures 4-21

via the flexible synthesis just described prompted us to

exploit a similar methodology to assemble bis-tetrahy-

drofuran units of type C (Scheme 1), where X and Y are

atoms of oxygen. These scaffolds encompass the C12-

C25 core portion of a myriad of biologically important

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF.

while their 4S-configured counterparts are levorotatory.¹⁰

A more reliable piece of evidence came from circular

dichroic measurements, where positive or negative signs

of the Cotton effect of the π-π* transitions are directly

correlated to right-handed (P) or left-handed (M) helicity

of the chromofore.¹¹(2) Ba se-P r om oted C4 Ep im er -

iza tion . When an unsaturated adduct is exposed to Et₃N,

deprotonation at C4 takes place, directly assessing the

epimeric relationship for a given isomeric couple. Quite

unexpectedly, the N,N-couple 11ec and 11et proved

particularly base-resistant, thus preventing us from being

able to use this diagnostic criterion. (3) H4-H5 Vicin a l

Cou p lin g Con sta n ts [³J (H4,H5)]. Evaluation of H-

1

¹H coupling constants between the H4 and H5 protons

within both unsaturated and saturated products is a sure

guide for assigning the 4,5-threo/erythro relative disposi-

tion of the two heteroatom substituents, with erythro

compounds exhibiting larger J values than the corre-

sponding threo counterparts.¹²(4) H3 Ch em ica l Sh ift

Va lu es of Bu ten olid e-Typ e Ad d u cts. With the excep-

(12) For some representative binuclear fragments, a molecular

mechanics calculation was performed, simulating a rotation around

the C4-C5 bond. The calculation of the relative populations of anti

and gauche conformations allowed the prediction of the mean J values,

which were in good accordance with the experimental ones. See note

12 in ref 7.

(13) Figade`re, B.; Chaboche, C.; Peyrat, J .-F.; Cave´, A. Tetrahedron

Lett. 1993, 34, 8093-8096. J efford, C. W.; J aggi, D.; Boukouvalas, J .

Tetrahedron Lett. 1987, 28, 4037-4040.

(14) Boeckman, R. K. J r.; Potenza, J . C. Tetrahedron Lett. 1985, 26,

1411-1414.

(10) Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P.; Gasparri Fava,

G.; Ferrari Belicchi, M. Tetrahedron 1990, 46, 5807-5824.

(11) Gawronski, J . K.; van Oeveren, A.; van der Deen, H.; Leung,

C. W.; Feringa, B. L. J . Org. Chem. 1996, 61, 1513-1515. Cuiper, A.

D.; Brzostowska, M.; Gawronski, J . K.; Smeets, W. J . J .; Spek, A. L.;

Hiemstra, H.; Kellogg, R. M.; Feringa, B. L. J . Org. Chem. 1999, 64,

2567-2570.

(15) In the preliminary account of this work (ref 7) the stereostruc-

tures of compounds 14ec and 14et were misassigned as threo,trans

and threo,cis isomers, respectively.

(16) For easy reference, the atom numbering of the various target

and intermediary compounds adopted in Schemes 3-11 relate to the

conventional numbering of the generic C₃₇annonaceous acetogenin A

in Scheme 1.

2052 J . Org. Chem., Vol. 65, No. 7, 2000

Ch a r t 1. Syn th esized Sa tu r a ted Bin u clea r Mod els a n d Ster eoch em istr y

Zanardi et al.

adjacently linked bis-THF annonaceous acetogenins of

natural origin. Our project started with the preparation

of the C20-C25 lactol precursor 26, via BF₃‚OEt₂-

promoted vinylogous Mukaiyama aldol coupling of TB-

SOF to 2,3-O-isopropylidene-^D-glyceraldehyde (22) (Scheme

3). This addition produced the unsaturated butenolide

adduct 23, in high yield (75%) and with a high diaste-

reoselectivity (94%), which was converted to 24 by

catalytic hydrogenation and silylation (85%, two steps).

The precursor for this project, 26, was prepared from 24

by a sequence involving (1) selective acetonide deblocking,

(2) NaIO₄oxidative one-carbon shortening, (3) NaBH₄

reduction of the aldehyde formed, (4) protection of the

primary hydroxyl to 25, and (5) lactone-to-lactol reduction

followed by acetylation (54% yield from 24).

then carried out following the guidelines previously

disclosed (vide supra), with both epimers fully matching

the diagnostic chiro-optical, chemical, and spectral re-

quirements.

Completion of the bis-tetrahydrofuran C12-C25

acetogenin units was effected in a parallel manner

by reiterating the addition of TBSOF to the

threo,trans,threo lactol 31 (Scheme 5, left side) and its

erythro,trans,threo counterpart 32 (right side). Each

TBSOTf-catalyzed vinylogous addition did not display

substantial stereocontrol, affording all four expected

trinuclear butenolide isomers 33-36 and 37-40, respec-

tively. The unsaturated compounds 33-40 were indi-

vidually hydrogenated, leading to the final eight bis-THF

scaffolds 41-48 in yields g95% for this step.

Homologation of 26 to C16-C25 subunits 31 and 32

utilized the same furan-based silyloxy diene TBSOF

under TBSOTf catalysis (Scheme 4). The reaction was

conducted in CH₂Cl₂at -90 °C and furnished a 1:1

mixture of threo,trans,threo butenolide 27 and its

erythro,trans,threo C19-epimer 28 (70% combined yield).

After chromatographic separation, 27 and 28 were indi-

vidually subjected to parallel three-stage protocols, con-

sisting of hydrogenation to the corresponding saturated

adducts 29 and 30, followed by lactone-to-lactol reduction

and acetylation. In this case, bis-THF donor units 31 and

32 were formed in 78% and 71% isolated yields from 27

and 28. Stereochemical assignment for 27 and 28 was

Assignment of the relative stereochemistry for all the

components was based mainly on analysis of the unsat-

urated congeners 33-40. Thus, 33/36, 34/35, 37/40, and

38/39 are C15 epimeric couples (Et₃N-promoted epimer-

ization); 33, 35, 37, and 39 are 15R-configured (positive

[R]_Dvalues and π-π* CD Cotton effects), while 34, 36,

38, and 40 are 15S-configured (negative [R]_Dvalues and

π-π* CD Cotton effects); and 33, 34, 37, and 38 possess

a 15,16-threo relative configuration (J _15,16) 3.6-4.6 Hz),

while 35, 36, 39, and 40 possess a 15,16-erythro config-

uration (J _15,16) 6.5-7.9 Hz). Since the relative and

absolute configuration of the remainder three stereo-

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2053

Sch em e 3^a

a

Key: (a) BF₃‚OEt₂, CH₂Cl₂, -80 °C; (b) (i) H₂, Pd/C, THF, (ii)

TBSOTf, 2,6-lutidine, CH₂Cl₂; (c) (i) 80% aq AcOH, 50 °C, (ii) aq

NaIO₄, CH₂Cl₂, (iii) NaBH₄, MeOH, -30 to -15 °C, (iv) TBSOTf,

2,6-lutidine, CH₂Cl₂, 0 °C; (d) (i) DIBAL-H, CH₂Cl₂, -80 °C, (ii)

Ac₂O, pyridine, DMAP, CH₂Cl₂.

Sch em e 4^a

F igu r e 2. Possible minimum-energy conformations of isomers

deBoc-14ec and deBoc-14et consistent with the NOE peaks

reported. The structures represented were selected among

families of minimum energy conformations, obtained by geo-

metry optimization applying the Tripos force field, with the

molecular modeling program Sybyl 6.5 (Tripos Inc., St. Louis,

MO).

centers (C20, C23, and C24) were previously established,

the overall assignment could be made with confidence.

The lack of selectivity encountered during the synthe-

sis of compounds 41-48, though chemically unappealing,

guarantees the generation of chemical diversity. Thus,

41 could be the subtarget of asimicin, when the proper

butenolide appendage is attached to the north terminal

of the scaffold (C12) and the aliphatic chain to the south

terminal (C25). Interestingly, 44 could represent the core

component of both squamocin I and bullatacin, whereas

45 could be the scaffold of trilobacin via south-north

homologation. On the other hand, the remaining units

bearing “unnatural” stereochemistry could lead to a

number of novel bis-THF acetogenin candidates.

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF; (c) (i)

DIBAL-H, CH₂Cl₂, -80 °C, (ii) Ac₂O, pyridine, DMAP, CH₂Cl₂.

between the pyrrole-based TBSOP and ^D-glyceraldehyde

22. The reaction was performed in the presence of SnCl₄

in diethyl ether at -80 °C and furnished the crystalline

unsaturated adduct 49 as the major product in an 80%

isolated yield. Next, hydrogenation and protection of the

secondary hydroxyl led to the fully protected lactam

Syn th esis of Bis-P yr r olid in e C12-C25 Un its. Syn-

thesis of the bis-pyrrolidine scaffolds of type C (Scheme

1, X ) Y ) NBoc) called for C20-C25 N,O-acetal 53 as

the pivotal precursor. Thus, as depicted in Scheme 6, 53

arose from a vinylogous Mukaiyama-type aldol addition

2054 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

Sch em e 5^a

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF.

Sch em e 6^a

The advanced subunits 58 and 59 were obtained from

53 and TBSOP, as shown in Scheme 7. The vinylogous

Mannich addition was catalyzed by TBSOTf as usual and

furnished two out of four possible bicyclic constructs,

namely, erythro,cis,threo unsaturated lactam 54 and its

erythro,trans,threo diastereoisomer 55, in a 75% com-

bined yield (60:40 ratio).¹⁷Once separated by silica gel

chromatography, each isomer was saturated to 56 and

57 and transformed into C16-C25 subunits 58 and 59

by LiEt₃BH reduction and methylation (69% and 67%,

three steps). The final stages of this synthesis paralleled

the chemistry, previously disclosed, used for the bis-THF

units. Elongation of both 58 and 59 with furan-based

TBSOF (TBSOTf as a catalyst) proved highly diastereo-

selective (Scheme 8), butenolides 60 and 61 being solely

produced in 90% and 98% yields, respectively. As ex-

pected (vide infra), both reactions behaved similarly,

favoring a relative threo,trans arrangement for the newly

formed stereocenters at C15 and C16. Catalytic hydro-

genation of the individual compounds 60 and 61 eventu-

ally completed the diastereoselective synthesis of the bis-

pyrrolidine units 62 and 63 in 95% and 88% yields,

respectively.

a

Key: (a) SnCl₄, Et₂O, -80 °C; (b) (i) H₂, Pd/C, THF, (ii)

TBSOTf, 2,6-lutidine, CH₂Cl₂; (c) (i) 80% aq AcOH, 50 °C, (ii) aq

NaIO₄, CH₂Cl₂, (iii) NaBH₄, MeOH, -30 to -15 °C; (d) (i) TBSOTf,

2,6-lutidine, CH₂Cl₂, 0 °C, (ii) Boc₂O, DMAP, MeCN, 40 °C; (e)

LiEt₃BH, THF, -80 °C, (ii) (MeO)₃CH, BF₃‚OEt₂, Et₂O.

50 (78%)¹⁷which was sequentially exposed to 80% aque-

ous acetic acid, sodium periodate, and NaBH₄to deliver

pyrrolidinone 51 in a 70% yield. Suitable protection of

the primary hydroxyl and reprotection of the pyrrolidine

nitrogen gave rise to 52 (84%), which was promptly

converted to the N,O-acetal 53 via selective carbonyl

reduction (LiEt₃BH) followed by methylation (90%).

As with the model pyrrolidine compounds 11ec and

11et (and 14ec and 14et), direct NMR structural diag-

nosis for the binuclear compounds 54 and 55, and the

trinuclear congeners 60 and 61 (and related saturated

(17) Although TBSOTf is actually a reagent for cleaving N-Boc

linkages, no traces of N-deprotected compounds were found in this and

similar instances.

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2055

Sch em e 7^a

Sch em e 8^a

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF.

Sch em e 9^a

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF; (c)

LiEt₃BH, THF, -80 °C, (ii) (MeO)₃CH, BF₃‚OEt₂, Et₂O.

counterparts) proved difficult as the analysis was ham-

pered, in all instances, by conformational heterogeneity

reflecting rotameric coexistence. Nevertheless, guided by

chiro-optical considerations and in view of the strong

spectral analogy with the models 11ec and 11et, we were

able to assign an erythro,cis,threo configuration to 54 and

an erythro,trans,threo configuration to 55, whereas the

relative stereodisposition of the two additional stereo-

centers C15 and C16 of the trinuclear targets 60 and 61

(and 62 and 63), which lacked suitable comparison

models, was determined by circular dichroic measure-

ments, by examination of ¹H-¹H coupling constants

between H15 and H16, and by synthetic conjectures.¹⁸

Thus, a positive Cotton effect for compound 60 led us

to assign a 15R-absolute configuration, whereas a nega-

tive value for 61 defined its 15S-configuration. These

a

Key: (a) BF₃‚OEt₂, CH₂Cl₂, -80 °C; (b) (i) H₂, Pd/C, THF, (ii)

TBSOTf, 2,6-lutidine, CH₂Cl₂; (c) (i) 80% aq AcOH, 50 °C, (ii) aq

NaIO₄, CH₂Cl₂, (iii) NaBH₄, EtOH, -30 °C, (iv) TBSOTf, 2,6-

lutidine, CH₂Cl₂, 0 °C; (d) (i) NaBH₄, MeOH, -15 °C, (ii) Ac₂O,

pyridine, DMAP, CH₂Cl₂.

3

data, coupled with the observed J _15,16values (3.6 Hz for

60, 3.1 Hz for 61), established the final assignment

indicated.

With the two bis-pyrrolidine subtargets 62 and 63 at

hand, the exciting perspective of obtaining nitrogen

acetogenin analogues now emerged. Indeed, by tethering

a butenolide moiety to C12 and an alkyl chain to C25,

aza-trilobacin can easily be prepared from compound 62.

Syn th esis of Bis-Th iola n e C12-C25 Un its. Prepa-

ration of the disubstituted thiolane precursor 67, encom-

passing the C20-C25 frame of the bis-thiolane targets

78-81, echoes the previous experiments involving its

oxygen and nitrogen congeners 26 and 53 (vide supra).

Thus, as shown in Scheme 9, BF₃-mediated Mukaiyama

aldol addition of thiophene-based silyloxy diene TBSOT

to ^D-glyceraldehyde 22 afforded the expected adduct 64

(18) Owing to the high diastereoselectivity observed in the model

coupling reaction between TBSOF and N,O-acetal 2, favoring

threo,trans-configured adduct 10t t, one can reason that a similar

behavior is here followed, too. See also: Hanessian, S.; McNaughton-

Smith, G. Bioorg. Med. Chem. Lett. 1996, 6, 1567-1572. Martin, S.

F.; Barr, K. J .; Smith, D. W.; Bur, S. K. J . Am. Chem. Soc. 1999, 121,

6990-6997.

2056 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

Sch em e 10^a

Sch em e 11^a

a

Key: (a) TBSOTf, BF₃‚OEt₂, CH₂Cl₂, -90 °C; (b) H₂, Pd/C,

THF.

Synthesis of the sulfur subunits 72 and 73 proceeded

nicely from 68 and 69, via double-bond saturation to

thiolactones 70 and 71 (82% and 78%), followed by

lactone-to-lactol reduction (NaBH₄, MeOH, -15 °C) and

acetylation (66% and 70%, two steps). To establish the

lactone moiety, furnishing the C12-C15 portion of our

sulfur units, 72 and 73 were separately coupled to

TBSOF (TBSOTf/BF₃‚OEt₂as a catalyst mixture) to

provide trinuclear butenolides 74/75 and 76/77, respec-

tively (65% and 68% combined yields) (Scheme 11).

Each couple consisted of C15-epimers (Et₃N-promoted

equilibration) with a C(15R)-configuration for 74 and 77

(positive Cotton effects) and a C(15S)-configuration for

75 and 76 (negative Cotton effects). Once again, evalu-

ation of the vicinal coupling constant values between H15

and H16 for the four isomers 74-77 sustained the

relative arrangement of these two stereocenters, with

threo isomers 74 and 76 displaying smaller constants

(³J _15,16) 6.0 and 5.2 Hz) than the erythro counterparts

75 and 77 (³J _15,16) 9.8 and 9.6 Hz). Completion of

individual sulfur subtargets 78-81 was finally accom-

plished by catalytic hydrogenation of the respective

isolated precursors with 68%, 72%, 65%, and 70% yields.

It will not go unnoticed that scaffold 78 may well

constitute the basic substructure of either an asimicin-

or a parviflorin-sulfur analogue, whereas 79 may be used

to forge the core construct of unnatural thio-bullatacin.

a

Key: (a) TBSOTf, CH₂Cl₂, -90 °C; (b) H₂, Pd/C, THF; (c) (i)

NaBH₄, MeOH, -15 °C, (ii) Ac₂O, pyridine, DMAP, CH₂Cl₂.

(70%), which was catalytically hydrogenated and pro-

tected to saturated thiolactone 65 (72%, two steps). One-

carbon shortening of the lactone side chain was then

carried out, as per usual, by deacetonidation followed by

periodate fission. In the event, a six-carbon aldehyde was

formed (not shown), which was selectively reduced to an

alcohol (NaBH₄, EtOH, -30 °C) and protected to afford

thiolactone 66 in a 57% yield (four steps). Further

reduction of the carbonyl function within 66 was ef-

ficiently effected by exposure to NaBH₄in MeOH at -15

°C to furnish a thiolactol that was promptly acetylated

to 67 (71%, two steps). The binuclear subunits C16-C25,

72 and 73, were obtained by a vinylogous addition

involving TBSOT and 67 (Scheme 10), carried out in the

presence of catalytic TBSOTf at -90 °C, to give a 1:3

mixture of two epimeric unsaturated adducts 68 and 69

in a 80% combined yield. In this case, verification of

the threo,trans,threo arrangement for 68 and the

erythro,trans,threo arrangement for 69 proved straight-

forward and was based on the usual chemical, chiro-

1

optical, and H NMR spectroscopic criteria (vide supra).

For 68, dextrorotation coupled with a 6.2 Hz J _19,20

3

coupling constant indicated its C(19R)/C19-C20 threo

configuration, whereas for 69 levorotation and a large

H19-H20 coupling constant (9.3 Hz) corroborated its

C(19S)/C19-C20 erythro configuration.

Con clu sion

The synthesis of a repertoire of annonaceous acetoge-

nin core units has been accomplished, encompassing

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2057

TBS protection. Thus, a stirred solution of the lactone inter-

mediate (2.35 g, 10.9 mmol) in anhydrous CH₂Cl₂(30 mL) was

cooled with an ice bath and sequentially treated with 2,6-

lutidine (2.0 mL, 17.4 mmol) and TBSOTf (3.5 mL, 15.3 mmol),

under nitrogen atmosphere. The reaction mixture was allowed

to warm to room temperature and stirred for 1 h. The reaction

was then quenched with 5% aqueous citric acid and extracted

with CH₂Cl₂. The combined organic layers were dried (MgSO₄)

and concentrated under vacuum to afford a crude residue that

was purified by flash chromatography (hexanes/EtOAc 50:50).

eight members of the “natural” bis-tetrahydrofuran fam-

ily, two representatives of “unnatural” bis-pyrrolidine

analogues, and four bis-thiolane surrogates. This project

proved highly reliable, allowing all the synthetic paths

to be pursued with comparable efficacy according to the

same protocol. Starting from a common chiral substance,

D-glyceraldehyde 22, the parallel synthetic sequences

leading to 41-48, 62-63, and 78-81 entailed prepara-

tion of the mononuclear synthons 26, 53, and 67 (first

vinylogous addition, nine steps), elongation to the bi-

nuclear scaffolds 31-32, 58-59, and 72-73 (second

vinylogous addition, four steps), and, common to all

processes, installation of the terminal butenolide ring

(third vinylogous coupling, two steps). Through this

study, we have convincingly demonstrated both the

utility and malleability of the vinylogous version of the

Mukaiyama aldol and Mannich-type addition reactions

involving TBSOF, TBSOP, and TBSOT, an ideal triad of

five-membered heterocyclic building modules.

The possibility of totally synthesizing naturally occur-

ring acetogenins and, hopefully, nitrogen and sulfur

surrogates, using intermediates rationally selected from

our repertoire of trinuclear scaffolds, is an exciting

prospect that has now opened. The convergence of 62 into

aza-trilobacin is currently being studied in our labora-

tories, and the completed synthesis will be reported in

due course. With such a series of varied acetogenin

candidates we hope to provide impetus for a better

understanding of their important, yet not completely

understood, structure-activity relationship.

Protected lactone 24 (3.17 g, 88%) was obtained as a colorless

1

oil: [R]²⁰-9.5 (c 0.6, CHCl₃); H NMR (300 MHz, CDCl₃) δ

D

4.60 (dt, J ) 6.6, 3.6 Hz, 1H), 4.13 (m, 1H), 4.06 (dd, J ) 8.1,

6.3 Hz, 1H), 3.87 (dd, J ) 8.1, 6.9 Hz, 1H), 3.78 (dd, J ) 6.0,

3.6 Hz, 1H), 2.51 (m, 2H), 2.21 (m, 2H), 1.41 (s, 3H), 1.33 (s,

3H), 0.89 (s, 9H), 0.13 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

176.5, 109.0, 81.2, 76.3, 74.3, 66.6, 28.4, 26.5, 25.8 (3C), 27.2,

23.6, 18.1, -4.0 (2C). Anal. Calcd for C₁₆H₃₀O₅Si: C, 58.15; H,

9.15. Found: C, 58.20; H, 9.09.

La cton e 25. Protected lactone 24 (3.0 g, 9.1 mmol) was

dissolved in 10 mL of 80% aqueous acetic acid, and the

resulting mixture was warmed to 50 °C and allowed to stir

for 24 h. The reaction mixture was then concentrated under

vacuum, furnishing a crude diol intermediate (2.51 g, 95%) as

a white solid. To a stirred solution of the crude diol (2.51 g,

8.6 mmol) in CH₂Cl₂(30 mL) were added chromatography

grade SiO₂(15 g) and a 0.65 M aqueous NaIO₄solution (17.3

mL, 11.18 mmol). The resulting slurry was vigorously stirred

at room temperature for 45 min, after which time the reaction

mixture was filtered under suction and the silica was thor-

oughly washed with CH₂Cl₂and EtOAc. The filtrates were

evaporated, affording a crude aldehyde intermediate (2.13 g,

96%) as colorless crystals.

A stirred solution of the aldehyde intermediate (2.13 g, 8.24

mmol) in methanol (40 mL) under nitrogen atmosphere was

cooled to -30 °C and treated with NaBH₄(620 mg, 16.4 mmol).

After being stirred for 1 h at -30 °C, the temperature of the

reaction mixture was allowed to rise to -15 °C, while a further

portion of NaBH₄(312 mg, 8.24 mmol) was added. After 2 h

at -15 °C, the reaction mixture was quenched by addition of

acetone (10 mL) and 5% aqueous citric acid. The mixture was

then extracted with EtOAc, and the combined organic layers

were dried (MgSO₄), filtered, and concentrated under vacuum,

furnishing a crude alcohol that was purified by flash chroma-

tography (hexanes/EtOAc 50:50). A pure alcohol intermediate

was obtained (2.0 g, 94%) as a colorless solid: ¹H NMR (300

MHz, CDCl₃) δ 4.64 (ddd, J ) 7.7, 6.4, 3.8 Hz, 1H), 3.6-3.7

(m, 3H), 3.55 (dd, J ) 10.4, 4.1 Hz, 1H), 2.52 (ddd, J ) 17.7,

10.0, 6.4 Hz, 1H), 2.42 (ddd, J ) 17.6, 9.6, 7.6 Hz, 1H), 2.23

(dddd, J ) 12.7, 9.4, 7.7, 6.5 Hz, 1H), 2.01 (m, 1H), 0.84 (s,

9H), 0.07 (s, 3H), 0.05 (s, 3H).

Exp er im en ta l Section

Un sa tu r a ted La cton e 23. To a solution of TBSOF (3.05

mL, 15.4 mmol) in anhydrous CH₂Cl₂(60 mL) under argon

atmosphere was added 2,3-O-isopropylidene-^D-glyceraldehyde

(22) (2.60 g, 20.0 mmol), and the resulting mixture was cooled

to -80 °C. BF₃etherate (1.89 mL, 15.4 mmol), cooled to the

same temperature, was added dropwise to the stirring solution,

and the reaction was allowed to proceed for 6 h at -80 °C.

The reaction was then quenched at the same temperature by

the addition of saturated aqueous NaHCO₃, and after ambient

temperature was reached, the mixture was extracted with CH₂-

Cl₂. The combined organic layers were washed with brine,

dried (MgSO₄), filtered, and concentrated under vacuum to give

a solid crude residue that was subjected to flash chromato-

graphic purification (hexanes/EtOAc 60:40). Pure lactone 23

A stirred solution of the alcohol intermediate (2.0 g, 7.7

mmol) in anhydrous CH₂Cl₂(30 mL) was cooled with an ice

bath and sequentially treated with 2,6-lutidine (1.26 mL, 10.8

mmol) and TBSOTf (2.1 mL, 9.24 mmol), under nitrogen

atmosphere. After being stirred at 0 °C for 30 min, the reaction

mixture was quenched with 5% aqueous citric acid and

extracted with CH₂Cl₂. The combined organic layers were

dried, filtered, and concentrated under vacuum, providing an

oily crude residue that was subjected to flash chromatographic

purification (hexanes/EtOAc 85:15). Pure lactone 25 was

obtained (2.28 g) in 79% yield (68% overall yield from 24) as

a colorless oil: [R]²⁰_D-44.3 (c 0.8, CHCl₃); ¹H NMR (300 MHz,

CDCl₃) δ 4.65 (ddd, J ) 8.2, 5.1, 1.6 Hz, 1H), 3.58 (m, 2H),

3.49 (dd, J ) 13.7, 9.5 Hz, 1H), 2.49 (ddd, J ) 17.6, 10.3, 7.2

Hz, 1H), 2.36 (ddd, J ) 17.4, 9.9, 6.0 Hz, 1H), 2.19 (m, 1H),

2.03 (m, 1H), 0.82 (bs, 18H), -0.02 (bs, 12H); ¹³C NMR (75

MHz, CDCl₃) δ 177.7, 79.4, 74.9, 63.5, 28.3, 25.8 (3C), 25.6

(3C), 23.4, 18.1, 17.8, -3.7, -4.5, -5.0, -5.6. Anal. Calcd for

was obtained (2.47 g, 75%) as white crystals: mp 125 °C; [R]²⁰

D

+69.6 (c 1.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.59 (dd, J

) 5.8, 1.7 Hz, 1H), 6.17 (dd, J ) 5.8, 1.9 Hz, 1H), 5.27 (m,

1H), 4.18 (m, 2H), 4.05 (m, 1H), 3.67 (m, 1H), 2.94 (d, J ) 6.6

Hz, 1H), 1.42 (s, 3H), 1.37 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 176.4, 154.3, 122.1, 109.8, 84.2, 75.5, 72.9, 67.1, 26.7, 25.1.

Anal. Calcd for C₁₀H₁₄O₅: C, 56.07; H, 6.59. Found: C, 55.94;

H, 6.71.

La cton e 24. Palladium on carbon (10%, 0.3 g) was added

to a solution of R,â-unsaturated lactone 23 (2.4 g, 11.2 mmol)

in anhydrous THF (60 mL) in the presence of a small amount

of NaOAc (0.09 g) at room temperature. The reaction vessel

was evacuated by aspirator and thoroughly purged with

hydrogen (three times), and the resulting heterogeneous

mixture was stirred under a balloon of hydrogen. After 24 h,

the hydrogen was evacuated, the catalyst filtered off, and the

filtrate concentrated under vacuum to give a crude residue that

was subjected to flash chromatographic purification (EtOAc/

hexanes 60:40). There was obtained 2.35 g (97%) of a saturated

lactone as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.77

(td, J ) 7.5, 2.1 Hz, 1H), 4.14 (m, 2H), 4.01 (m, 1H), 3.53 (bs,

1H), 3.35 (bs, 1H), 2.5-2.7 (m, 2H), 2.31 (m, 2H), 1.41 (s, 3H),

1.35 (s, 3H). The saturated lactone was subjected to suitable

C

₁₈H₃₈O₄Si: C, 62.38; H, 11.05. Found: C, 62.19; H, 11.23.

Oxygen P r ecu r sor 26. To a stirred solution of lactone 25

(2.0 g, 5.3 mmol) in anhydrous CH₂Cl₂(30 mL) cooled at -80

°C was added DIBAL-H (7 mL of a 1.5 M solution in toluene,

10.6 mmol) dropwise. The reaction was stirred at -80 °C under

nitrogen atmosphere for 30 min and quenched at the same

2058 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

temperature by addition of methanol (15 mL) and water (15

mL). Once warmed to room temperature, the mixture was

extracted with CH₂Cl₂. The combined organic layers were dried

and concentrated, providing a crude lactol intermediate (1.94

g, 97%). The crude lactol (1.94 g, 5.14 mmol) was dissolved in

dry CH₂Cl₂(30 mL) under nitrogen atmosphere and sequen-

tially treated with pyridine (1.24 mL, 15.42 mmol), acetic

anhydride (0.9 mL, 0.28 mmol), and DMAP (catalytic) at room

temperature. After being stirred for 1 h, the mixture was

treated with further portions of pyridine (0.62 mL, 7.7 mmol),

Ac₂O (0.46 mL, 5.14 mmol), and DMAP (catalytic). After 2 h,

the reaction mixture was quenched with saturated aqueous

NaHCO₃and extracted with CH₂Cl₂(3 × 20 mL). The

combined organic layers were dried over MgSO₄and concen-

trated under vacuum. The residue was purified by flash

chromatography (hexanes/EtOAc 80:20) to give 26 (1.76 g,

82%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃, 75:25

anomeric mixture) δ 6.27 (dd, J ) 5.0, 1.1 Hz, 0.75H), 6.20

(dd, J ) 3.7, 1.1 Hz, 0.25H), 4.29 (m, 0.75H), 4.04 (m, 0.25H),

3.4-3.7 (m, 3H), 1.9-2.1 (m, 2H), 1.96 (s, 3 × 0.75), 1.94 (s, 3

× 0.25H), 1.8-1.9 (m, 2H), 0.85 (s, 9 × 0.25H) 0.84 (s, 9 ×

0.25H), 0.83 (s, 9 × 0.75H), 0.82 (s, 9 × 0.75H), 0.02 (s, 6H),

0.01 (s, 6H); ¹³C NMR (75 MHz, CDCl₃, major anomer) δ 170.2,

99.2, 80.2, 74.8, 64.4, 31.9, 25.8 (3C), 25.7 (3C), 24.3, 21.2, 18.2,

18.0, -4.4, -4.6, -5.5 (2C). Anal. Calcd for C₂₀H₄₂O₅Si₂: C,

57.37; H, 10.11. Found: C, 57.45; H, 10.24.

(td, J ) 6.8, 2.6 Hz, 1H), 4.06 (m, 1H), 4.00 (td, J ) 7.0, 2.5

Hz, 1H), 3.61 (dd, J ) 11.4, 8.5 Hz, 1H), 3.52 (m, 2H), 2.65

(ddd, J ) 17.3, 9.6, 7.6 Hz, 1H), 2.39 (dt, J ) 17.6, 7.9 Hz,

1H), 2.21 (m, 2H), 1.7-2.0 (m, 4H), 0.86 (s, 18H), 0.05 (s, 6H),

0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6,

81.2, 80.8, 80.4, 75.8, 64.9, 28.2, 27.9, 27.6, 26.0 (3C), 25.9 (3C),

24.6, 18.4, 18.1, -4.3, -4.8, -5.4 (2C). Anal. Calcd for

C

₂₂H₄₄O₅Si₂: C, 59.41; H, 9.97. Found: C, 59.35; H, 10.05.

Sa tu r a ted La cton e 30. The reaction was carried out

according to general procedure B, by starting with butenolide

28 (600 mg, 1.36 mmol). After flash chromatographic purifica-

tion (hexanes/EtOAc 80:20), pure lactone 30 was obtained (550

mg, 91%) as a colorless oil: [R]²⁰_D-11.0 (c 0.3, CHCl₃); ¹H NMR

(300 MHz, CDCl₃) δ 4.37 (dt, J ) 7.3, 6.0 Hz, 1H), 4.0-4.1 (m,

2H), 3.61 (dd, J ) 11.2, 8.3 Hz, 1H), 3.51 (dd, J ) 11.1, 4.8

Hz, 1H), 3.50 (m, 1H), 2.54 (ddd, J ) 17.7, 9.9, 6.4 Hz, 1H),

2.44 (ddd, J ) 17.6, 9.3, 7.5 Hz, 1H), 2.24 (m, 1H), 2.08 (m,

2H), 1.94 (m, 1H), 1.81 (m, 1H), 1.66 (m, 1H), 0.86 (s, 9H),

0.85 (s, 9H), 0.04 (s, 6H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 177.4, 82.0, 80.3, 79.9, 75.7, 64.7, 28.7, 28.1,

27.3, 25.9 (3C), 25.8 (3C), 23.8, 18.3, 18.1, -4.4, -4.8, -5.5

(2C). Anal. Calcd for C₂₂H₄₄O₅Si₂: C, 59.41; H, 9.97. Found:

C, 59.49; H, 10.09.

Oxygen Su bu n it 31. The above two-step protocol to

transform 25 into 26 was adopted, by starting with lactone

29 (560 mg, 1.26 mmol). After flash chromatographic purifica-

tion (hexanes/EtOAc 80:20), pure acetylated lactol 31 was

obtained (515 mg, 84%) as a colorless oil: ¹H NMR (300 MHz,

CDCl₃, major anomer) δ 6.31 (d, J ) 4.6 Hz, 1H), 4.18 (quint,

J ) 3.8 Hz, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.62 (m, 1H), 3.53

(m, 2H), 2.18 (m, 1H), 2.00 (m, 1H), 1.99 (s, 3H), 1.7-2.0 (m,

6H), 0.87 (s, 9H), 0.86 (s 9H), 0.04 (s, 6H), 0.03 (s, 3H), 0.02

(s, 3H); ¹³C NMR (75 MHz, CDCl₃, major anomer) δ 170.3, 99.1,

82.6, 81.2, 80.5, 75.3, 64.8, 31.9, 28.4, 27.5, 26.0 (3C), 25.8 (3C),

24.2, 22.6, 18.3, 18.2, -4.3, -4.8, -5.4 (2C). Anal. Calcd for

Un sa tu r a ted La cton es 27 a n d 28. Gen er a l P r oced u r e

A. To a stirred solution of acetyl lactol 26 (1.76 g, 4.2 mmol)

in anhydrous CH₂Cl₂(50 mL) under an inert atmosphere (N₂)

cooled to -90 °C were added dropwise enol ether TBSOF (1.0

g, 5.04 mmol) and TBSOTf (0.58 mL, 2.5 mmol). After being

stirred for 1 h at -90 °C, the reaction mixture was neutralized

at the same temperature by addition of Et₃N (2.5 mL of a 1.0

M solution in CH₂Cl₂, 2.5 mmol) and quenched with water.

After room temperature was reached, the mixture was ex-

tracted with CH₂Cl₂. The combined organic layers were dried

over MgSO₄, filtered, and concentrated under vacuum to

furnish an oily crude residue that was subjected to flash

chromatographic purification (hexanes/EtOAc 85:15). Two pure

stereoisomeric butenolides were obtained, namely, 27 (650 mg)

and 28 (648 mg), each in 35% yield.

C

₂₄H₄₈O₆Si₂: C, 58.97; H, 9.90. Found: C, 59.05; H, 9.78.

Oxygen Su bu n it 32. The above two-step protocol to

transform 25 into 26 was adopted, by starting with lactone

30 (550 mg, 1.24 mmol). After flash chromatographic purifica-

tion (hexanes/EtOAc 80:20), pure acetylated lactol 32 was

obtained (470 mg, 78%) as a colorless oil: ¹H NMR (300 MHz,

CDCl₃, 50:50 anomeric mixture) δ 6.26 (bd, J ) 4.5 Hz, 0.5H),

6.20 (t, J ) 2.6 Hz, 0.5H), 3.7-4.1 (m, 3H), 3.63 (m, 1H), 3.52

(m, 2H), 1.99 (s, 3 × 0.5H), 1.97 (s, 3 × 0.5H), 1.7-2.1 (m,

8H), 0.86 (s, 9H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02

(s, 6H); ¹³C NMR (75 MHz, CDCl₃, one anomer) δ 170.2, 99.2,

82.0, 80.9, 80.2, 75.7, 64.7, 31.9, 28.2, 27.1, 27.0, 25.9 (3C),

25.8 (3C), 21.2, 18.3, 18.1, -4.4, -4.8, -5.4 (2C). Anal. Calcd

for C₂₄H₄₈O₆Si₂: C, 58.97; H, 9.90. Found: C, 58.89; H, 9.76.

27: an oil; [R]²⁰+28.1 (c 0.3, CHCl₃); CD (CH₃OH, 1.4 ×

D

10^-4M) [θ]₂₁₅+3140 deg cm²dmol^-1

;

¹H NMR (300 MHz,

CDCl₃) δ 7.38 (dd, J ) 5.8, 1.6 Hz, 1H), 6.12 (dd, J ) 5.8, 2.0

Hz, 1H), 5.03 (dt, J ) 3.7, 1.8 Hz, 1H), 4.25 (td, J ) 6.9, 3.9

Hz, 1H), 4.07 (td, J ) 6.8, 3.2 Hz, 1H), 3.4-3.6 (m, 3H), 2.02

(m, 1H), 1.93 (m, 1H), 1.7-1.9 (m, 2H), 0.86 (s, 9H), 0.85 (s,

9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 172.2, 153.7, 122.8, 84.6, 80.6, 77.8,

75.6, 64.7, 27.6, 27.1, 26.0 (3C), 25.9 (3C), 18.3 (2C), -4.3, -4.8,

-5.4 (2C). Anal. Calcd for C₂₂H₄₂O₅Si₂: C, 59.68; H, 9.56.

Found: C, 59.71; H, 9.64.

Un sa tu r a ted Oxygen Un its 33, 34, 35, a n d 36. The

reaction was carried out according to general procedure A,

using TBSOF (250 mg, 1.26 mmol) and acetyl furanose 31 (500

mg, 1.02 mmol). After flash chromatographic purification

(hexanes/EtOAc 80:20), pure butenolides 33 (162 mg, 31%),

34 (70 mg, 13%), 35 (62 mg, 12%), and 36 (93 mg, 18%) were

obtained in a 74% combined yield.

28: an oil; [R]²⁰-40.7 (c 0.4, CHCl₃); CD (CH₃OH, 1.4 ×

D

10^-4M) [θ]₂₁₆-5660 deg cm²dmol^-1

;

¹H NMR (300 MHz,

CDCl₃) δ 7.57 (dd, J ) 5.8, 1.6 Hz, 1H), 6.12 (dd, J ) 5.8, 1.9

Hz, 1H), 4.82 (dt, J ) 7.1, 1.7 Hz, 1H), 4.14 (td, J ) 6.8, 3.5

Hz, 1H), 3.85 (app q, J ) 6.8 Hz, 1H), 3.61 (dd, J ) 11.4, 8.9

Hz, 1H), 3.52 (m, 2H), 2.10 (m, 1H), 1.97 (m, 1H), 1.7-1.9 (m,

2H), 0.87 (s, 9H), 0.85 (s, 9H), 0.07 (s, 3H), 0.04 (s, 6H), 0.03

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.0, 155.3, 122.0, 85.2,

80.3, 79.5, 75.5, 64.7, 29.2, 27.2, 25.9 (3C), 25.8 (3C), 18.4, 18.2,

-4.4, -4.8, -5.4 (2C). Anal. Calcd for C₂₂H₄₂O₅Si₂: C, 59.68;

H, 9.56. Found: C, 59.53; H, 9.69.

33: colorless oil; CD (CH₃OH, 4.9 × 10^-5M) [θ]₂₁₄+26920

1

deg cm²dmol^-1; H NMR (300 MHz, CDCl₃) δ 7.41 (dd, J )

5.8, 1.6 Hz, 1H), 6.15 (dd, J ) 5.6, 2.1 Hz, 1H), 5.06 (dt, J )

3.6, 1.8 Hz, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.88 (m, 2H), 3.6-

3.7 (m, 1H), 3.5-3.6 (m, 2H), 2.09 (m, 1H), 1.7-2.0 (m, 6H),

1.61 (m, 1H), 0.88 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s,

3H), 0.04 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 172.0, 153.6,

122.6, 84.3, 80.6, 80.2, 79.4, 77.8, 75.7, 65.0, 28.0, 27.7, 27.4,

26.0 (3C), 25.0 (3C), 24.0, 18.4, 18.2, -5.4 (4C); HRMS (CI,

CH₄) m/z 513.3081 (MH, 513.3068 calcd for C₂₆H₄₉O₆Si₂).

Sa tu r a ted La cton e 29. Gen er a l P r oced u r e B. Buteno-

lide 27 (600 mg, 1.36 mmol) was dissolved in anhydrous THF

(50 mL) and treated with 10% Pd on carbon (60 mg) and a

small amount of sodium acetate (15 mg) at room temperature.

The reaction vessel was evacuated and purged with hydrogen,

and the resulting heterogeneous mixture was stirred under a

balloon of hydrogen for 24 h. After hydrogen evacuation, the

catalyst was filtered off, and the filtrate was concentrated

under vacuum to afford a crude oily residue that was subjected

to flash chromatographic purification (hexanes/EtOAc 80:20).

Pure lactone 29 was obtained (560 mg, 93%) as a colorless oil:

34: an oil; CD (CH₃OH, 1.3 × 10^-5M) [θ]₂₁₅-15780 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.54 (dd, J ) 5.8, 1.6

;

Hz, 1H), 6.13 (dd, J ) 5.4, 2.0 Hz, 1H), 5.09 (dt, J ) 4.6, 1.7

Hz, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.85 (m, 2H), 3.6-3.7 (m,

1H), 3.5-3.6 (m, 2H), 2.10 (m, 1H), 1.6-2.0 (m, 7H), 0.88 (s,

9H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H); ¹³C

NMR (75 MHz, CDCl₃) δ 172.2, 153.7, 122.8, 84.3, 80.6, 80.2,

79.5, 77.9, 75.6, 64.9, 27.9, 27.7, 27.4, 26.0 (3C), 25.9 (3C), 24.7,

[R]²⁰-15.0 (c 0.3, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 4.43

D

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2059

18.3, 18.2, -4.3, -4.7, -5.4 (2C); HRMS (CI, CH₄) m/z

513.3074 (MH, 513.3068 calcd for C₂₆H₄₉O₆Si₂).

¹H NMR (300 MHz, CDCl₃) δ 4.43 (td, J ) 6.8, 2.2 Hz, 1H),

4.01 (m, 2H), 3.85 (m, 2H), 3.63 (m, 1H), 3.5-3.6 (m, 2H), 2.67

(dt, J ) 17.1, 8.7 Hz, 1H), 2.39 (dt, J ) 17.4, 7.8 Hz, 1H), 2.22

(m, 2H), 1.8-2.1 (m, 4H), 1.6-1.8 (m, 3H), 1.56 (m, 1H), 0.87

(s, 18H), 0.05 (s, 6H), 0.03 (s, 6H); ¹³C NMR (75 MHz, CDCl₃)

δ 177.9, 82.3, 81.3, 81.2, 80.8, 80.2, 75.8, 65.0, 28.6, 28.3, 28.2,

27.8, 27.7, 26.0 (3C), 25.9 (3C), 24.7, 18.4, 18.2, -4.3, -4.7,

-5.4 (2C); MS (CI, CH₄) m/z 515 [M + H]⁺. Anal. Calcd for

35: an oil; CD (CH₃OH, 1.2 × 10^-5M) [θ]₂₁₈+12530 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.64 (dd, J ) 5.9, 1.7

;

Hz, 1H), 6.12 (dd, J ) 5.4, 1.8 Hz, 1H), 4.86 (dt, J ) 7.9, 1.6

Hz, 1H), 3.8-4.1 (m, 4H), 3.5-3.7 (m, 3H), 2.10 (m, 1H), 1.7-

2.0 (m, 6H), 1.60 (m, 1H), 0.88 (s, 18H), 0.07 (s, 6H), 0.04 (s,

6H); ¹³C NMR (75 MHz, CDCl₃) δ 172.0, 155.0, 122.0, 84.9,

80.3, 80.0, 79.8, 78.2, 75.5, 64.7, 28.2, 27.6, 27.2, 26.0 (3C),

25.9 (3C), 24.3, 18.4, 18.2, -4.3, -4.7, -5.4 (2C); HRMS (CI,

CH₄) m/z 513.3042 (MH, 513.3068 calcd for C₂₆H₄₉O₆Si₂).

36: an oil; CD (CH₃OH, 3.9 × 10^-5M) [θ]₂₁₆-15180 deg cm²

C

₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79. Found: C, 60.48; H, 9.87.

Sa tu r a ted Oxygen Un it 42. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 34 (50 mg, 0.10 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 42 (48 mg)

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.60 (dd, J ) 6.0, 1.7

;

Hz, 1H), 6.14 (dd, J ) 5.9, 2.1 Hz, 1H), 4.89 (dt, J ) 6.8, 1.8

Hz, 1H), 3.9-4.1 (m, 4H), 3.5-3.8 (m, 3H), 2.10 (m, 1H), 1.7-

2.0 (m, 6H), 1.60 (m, 1H), 0.88 (s, 18H), 0.07 (s, 6H), 0.04 (s,

6H); ¹³C NMR (75 MHz, CDCl₃) δ 172.2, 154.9, 122.1, 84.7,

80.5, 80.1, 79.7, 78.1, 75.5, 64.7, 27.9, 27.7, 27.3, 26.0 (3C),

25.9 (3C), 24.1, 18.4, 18.1, -4.3, -4.8, -5.4 (2C); HRMS (CI,

CH₄) m/z 513.3051 (MH, 513.3068 calcd for C₂₆H₄₉O₆Si₂).

Un sa tu r a ted Oxygen Un its 37, 38, 39, a n d 40. The

reaction was carried out according to general procedure A,

using TBSOF (200 mg, 1.01 mmol) and acetyl furanose 32 (450

mg, 0.92 mmol). After flash chromatographic purification

(hexanes/EtOAc 80:20), pure butenolides 37 (84 mg, 18%), 38

(133 mg, 28%), 39 (75 mg, 16%), and 40 (48 mg, 10%) were

obtained in a 72% combined yield.

was obtained in 95% yield: an oil; [R]²⁰-7.1 (c 0.9, CHCl₃);

D

¹H NMR (300 MHz, CDCl₃) δ 4.45 (td, J ) 6.8, 2.8 Hz, 1H),

4.01 (m, 2H), 3.8-3.9 (m, 2H), 3.5-3.7 (m, 3H), 2.66 (dt, J )

17.2, 8.7 Hz, 1H), 2.38 (m, 1H), 2.2-2.3 (m, 2H), 1.8-2.1 (m,

4H), 1.6-1.8 (m, 3H), 1.52 (m, 1H), 0.87 (s, 18H), 0.05 (s, 9H),

0.03 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 83.0, 81.6,

81.4, 80.9, 80.6, 76.0, 65.0, 28.6, 28.3, 27.8, 27.5, 27.2, 26.0

(3C), 25.9 (3C), 24.3, 18.4, 18.2, -4.3, -4.7, -5.4 (2C); MS (CI,

CH₄) m/z 515 [M + H]⁺. Anal. Calcd for C₂₆H₅₀O₆Si₂: C, 60.66;

H, 9.79. Found: C, 60.76; H, 9.65.

Sa tu r a ted Oxygen Un it 43. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 35 (50 mg, 0.10 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 43 (49 mg)

37: an oil; [R]²⁰_D+4.4 (c 0.2, CHCl₃); CD (CH₃OH, 1.2 × 10^-4

M) [θ]₂₁₂+5870 deg cm²dmol^-1; ¹H NMR (300 MHz, CDCl₃) δ

7.47 (dd, J ) 5.8, 1.6 Hz, 1H), 6.13 (dd, J ) 5.8, 2.0 Hz, 1H),

5.05 (dt, J ) 4.0, 1.8 Hz, 1H), 4.21 (ddd, J ) 7.0, 5.9, 4.0 Hz,

1H), 3.99 (td, J ) 7.1, 3.9 Hz, 1H), 3.85 (m, 2H), 3.61 (dd, J )

11.8, 8.0 Hz, 1H), 3.52 (m, 1H), 3.51 (dd, J ) 11.5, 5.0 Hz,

1H), 1.7-2.0 (m, 6H), 1.5-1.7 (m, 2H), 0.87 (s, 9H), 0.86 (s,

9H), 0.05 (s, 6H), 0.02 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

172.1, 153.7, 122.8, 84.6, 80.7, 80.3, 79.8, 77.8, 75.8, 65.2, 28.1,

27.6, 26.8, 26.0 (3C), 25.9 (3C), 24.5, 18.4, 18.2, -4.4, -4.7,

-5.4 (2C); HRMS (CI, CH₄) m/z 513.3089 (MH, 513.3068 calcd

for C₂₆H₄₉O₆Si₂).

was obtained in 96% yield: an oil; [R]²⁰-33.3 (c 0.2, CHCl₃);

D

¹H NMR (300 MHz, CDCl₃) δ 4.36 (q, J ) 6.0 Hz, 1H), 4.00

(m, 2H), 3.86 (m, 2H), 3.6-3.7 (m, 1H), 3.5-3.6 (m, 2H), 2.4-

2.6 (m, 1H), 2.2-2.3 (m, 2H), 1.6-2.0 (m, 8H), 1.52 (m, 1H),

0.87 (s, 18H), 0.05 (s, 6H), 0.03 (s, 6H); ¹³C NMR (75 MHz,

CDCl₃) δ 177.6, 82.0, 81.5, 81.0, 80.3, 80.2, 76.1, 65.0, 28.7,

28.5, 28.2, 27.7, 27.4, 26.0 (6C), 23.9, 18.4, 18.2, -4.3, -4.7,

-5.4 (2C); MS (CI, CH₄) m/ z 515 [M + H]⁺. Anal. Calcd for

C

₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79. Found: C, 60.85; H, 9.54.

Sa tu r a ted Oxygen Un it 44. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 36 (80 mg, 0.16 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 44 (76 mg)

38: an oil; [R]²⁰-17.2 (c 0.2, CHCl₃); CD (CH₃OH, 1.8 ×

D

10^-4M) [θ]₂₁₆-6490 deg cm²dmol^-1

;

¹H NMR (300 MHz,

was obtained in 95% yield: an oil; [R]²⁰-7.1 (c 0.7, CHCl₃);

D

CDCl₃) δ 7.38 (dd, J ) 5.8, 1.6 Hz, 1H), 6.15 (dd, J ) 5.8, 2.0

Hz, 1H), 5.02 (dt, J ) 3.8, 1.8 Hz, 1H), 4.28 (m, 1H), 4.00 (m,

1H), 3.85 (m, 2H), 3.5-3.7 (m, 3H), 1.7-2.1 (m, 6H), 1.5-1.7

(m, 2H), 0.86 (s, 9H), 0.85 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H),

0.02 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 172.0, 153.8, 122.6,

84.3, 80.9, 80.2, 79.7, 77.9, 75.7, 65.0, 28.1, 27.7, 27.0, 26.0

(3C), 25.9 (3C), 24.6, 18.4, 18.2, -4.3, -4.7, -5.4 (2C); HRMS

(CI, CH₄) m/z 513.3055 (MH, 513.3068 calcd for C₂₆H₄₉O₆Si₂).

39: an oil; CD (CH₃OH, 1.3 × 10^-4M) [θ]₂₁₉+ 11170 deg

¹H NMR (300 MHz, CDCl₃) δ 4.40 (app q, J ) 6.2 Hz, 1H),

4.01 (m, 2H), 3.8-4.0 (m, 2H), 3.64 (m, 1H), 3.54 (m, 2H), 2.4-

2.6 (m, 2H), 2.2-2.4 (m, 1H), 2.0-2.2 (m, 1H), 1.6-2.0 (m, 7H),

1.54 (m, 1H), 0.87 (s, 18H), 0.05 (s, 12H); ¹³C NMR (75 MHz,

CDCl₃) δ 177.3, 82.2, 82.0, 81.4, 80.2 (2C), 75.8, 65.0, 28.6, 28.2,

28.1 (2C), 27.6, 26.0 (3C), 25.9 (3C), 24.1, 18.4, 18.2, -4.3, -4.8,

-5.4 (2C); MS (CI, CH₄) m/ z 515 [M + H]⁺. Anal. Calcd for

C

₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79. Found: C, 60.83; H, 9.58.

Sa tu r a ted Oxygen Un it 45. The reaction was carried out

1

cm²dmol^-1; H NMR (300 MHz, CDCl₃) δ 7.56 (dd, J ) 5.8,

according to general procedure B, by starting with unsaturated

lactone 37 (70 mg, 0.14 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 45 (67 mg)

1.6 Hz, 1H), 6.13 (dd, J ) 5.7, 1.9 Hz, 1H), 4.86 (dt, J ) 6.5,

1.8 Hz, 1H), 4.02 (m, 1H), 3.8-4.0 (m, 3H), 3.61 (m, 1H), 3.53

(m, 2H), 1.9-2.1 (m, 3H), 1.7-1.9 (m, 3H), 1.5-1.7 (m, 2H),

0.87 (s, 9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s,

3H), 0.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.2, 155.2,

122.0, 84.9, 80.7, 80.3, 79.8, 78.0, 75.7, 65.0, 28.1, 27.9, 27.4,

26.0 (3C), 25.9 (3C), 23.9, 18.4, 18.2, -4.3, -4.7, -5.4 (2C);

HRMS (CI, CH₄) m/z 513.3084 (MH, 513.3068 calcd for

was obtained in 96% yield: an oil; [R]²⁰-28.0 (c 0.3, CHCl₃);

D

¹H NMR (300 MHz, CDCl₃) δ 4.48 (ddd, J ) 7.9, 5.0, 2.8 Hz,

1H), 3.95 (m, 2H), 3.78 (m, 2H), 3.61 (m, 1H), 3.53 (m, 2H),

2.61 (ddd, J ) 17.4, 10.0, 7.4 Hz, 1H), 2.39 (ddd, J ) 17.2, 9.7,

6.0 Hz, 1H), 2.1-2.3 (m, 2H), 1.8-2.0 (m, 4H), 1.5-1.8 (m,

4H), 0.87 (s, 18H), 0.05 (s, 6H), 0.03 (s, 6H); ¹³C NMR (75 MHz,

CDCl₃) δ 177.7, 82.3, 81.2, 80.7, 80.5, 80.2, 75.9, 65.2, 29.4,

28.8, 28.2, 27.7, 26.8, 26.0 (3C), 25.9 (3C), 24.6, 18.4, 18.2, -4.4,

-4.7, -5.4 (2C); MS (CI, CH₄) m/ z 515 [M + H]⁺. Anal. Calcd

for C₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79. Found: C, 60.48; H, 9.89.

Sa tu r a ted Oxygen Un it 46. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 38 (100 mg, 0.19 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 46 (97 mg)

C

₂₆H₄₉O₆Si₂).

40: an oil; CD (CH₃OH, 1.1 × 10^-4M) [θ]₂₂₀-10500 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.59 (dd, J ) 5.5, 1.4

;

Hz, 1H), 6.12 (dd, J ) 5.7, 1.9 Hz, 1H), 4.84 (m, 1H), 4.02 (m,

1H), 3.8-4.0 (m, 3H), 3.60 (m, 1H), 3.50 (m, 2H), 1.9-2.1 (m,

3H), 1.7-1.9 (m, 3H), 1.5-1.7 (m, 2H), 0.88 (s, 9H), 0.86 (s,

9H), 0.05 (s, 6H), 0.02 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

172.3, 155.3, 122.4, 84.7, 80.6, 80.3, 79.5, 78.1, 75.8, 64.9, 28.2,

27.6, 27.2, 26.0 (3C), 25.9 (3C), 23.6, 18.3, 18.2, -4.3, -4.7,

-5.4 (2C); HRMS (CI, CH₄) m/z 513.3087 (MH, 513.3068 calcd

for C₂₆H₄₉O₆Si₂).

Sa tu r a ted Oxygen Un it 41. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 33 (130 mg, 0.25 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 41 (124 mg)

was recovered in 95% yield: an oil; [R]²⁰_D-10.0 (c 0.4, CHCl₃);

was obtained in 97% yield: an oil; [R]²⁰-10.5 (c 0.5, CHCl₃);

D

¹H NMR (300 MHz, CDCl₃) δ 4.46 (ddd, J ) 7.8, 5.1, 2.4 Hz,

1H), 3.9-4.1 (m, 2H), 3.7-3.9 (m, 2H), 3.5-3.7 (m, 3H), 2.68

(ddd, J ) 17.4, 9.9, 7.5 Hz, 1H), 2.43 (ddd, J ) 17.1, 9.6, 6.6

Hz, 1H), 2.23 (m, 2H), 1.6-2.1 (m, 8H), 0.88 (s, 18H), 0.07 (s,

12H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7, 82.8, 81.4, 81.1, 80.8,

80.1, 75.8, 65.0, 29.4, 28.4, 28.2, 27.8, 27.4, 26.0 (3C), 25.9 (3C),

24.7, 18.4, 18.2, -4.3, -4.7, -5.4 (2C); MS (CI, CH₄) m/z 515

2060 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

[M + H]⁺. Anal. Calcd for C₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79.

Found: C, 60.50; H, 9.85.

9.8 Hz, 1H), 2.38 (ddd, J ) 17.8, 10.3, 2.0 Hz, 1H), 2.16 (m,

1H), 1.98 (m, 1H), 1.52 (s, 9H), 1.30 (s, 3H), 1.26 (s, 3H), 0.85

(s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 174.4, 149.8, 109.8, 82.3, 75.2, 71.1, 68.6, 60.2, 31.8, 29.4,

28.0 (3 C), 26.2, 25.4 (3 C), 24.9, 17.6, -4.2, -5.0. Anal. Calcd

for C₂₁H₃₉NO₆Si: C, 58.71; H, 9.15; N, 3.26. Found: C, 58.79;

H, 9.20; N, 3.12.

La cta m 51. Pure lactam 50 (2.0 g, 4.65 mmol) was dissolved

in 15 mL of 80% aqueous acetic acid, and the resulting mixture

was warmed to 50 °C and allowed to stir for 24 h. The reaction

was then concentrated under vacuum, furnishing a crude diol

intermediate, which was subjected to flash chromatographic

purification (EtOAc/MeOH 95:5 to 80:20). A pure diol inter-

mediate was obtained (1.2 g, 90%) as white crystals, which

was dissolved in CH₂Cl₂(15 mL) and treated with chroma-

tography-grade SiO₂(6 g) and a 0.65 M aqueous NaIO₄solution

(8.3 mL, 5.4 mmol). The resulting slurry was vigorously stirred

at room temperature for 2 h, after which time the reaction

mixture was filtered under suction and the silica was thor-

oughly washed with CH₂Cl₂and EtOAc. The filtrates were

evaporated, affording a crude aldehyde intermediate (1.04 g,

98%) as a pale yellow oil.

Sa tu r a ted Oxygen Un it 47. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 39 (60 mg, 0.12 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 47 (57 mg)

was obtained in 95% yield: an oil; ¹H NMR (300 MHz, CDCl₃)

δ 4.41 (q, J ) 6.2 Hz, 1H), 4.04 (m, 2H), 3.87 (m, 2H), 3.64

(dd, J ) 11.8, 8.0 Hz, 1H), 3.5-3.6 (m, 2H), 2.4-2.6 (m, 2H),

2.2-2.4 (m, 2H), 1.6-2.2 (m, 4H), 1.6-1.9 (m, 4H), 0.89 (s,

18H), 0.07 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 82.4,

81.8, 81.5, 81.1, 80.1, 75.8, 65.0, 29.2, 28.3, 28.2, 28.0, 27.4,

26.0 (3C), 25.9 (3C), 23.9, 18.4, 18.2, -4.3, -4.7, -5.3 (2C);

MS (CI, CH₄) m/ z 515 [M + H]⁺. Anal. Calcd for C₂₆H₅₀O₆Si₂:

C, 60.66; H, 9.79. Found: C, 60.85; H, 9.59.

Sa tu r a ted Oxygen Un it 48. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 40 (40 mg, 0.08 mmol). After flash chromatographic

purification (hexanes/EtOAc 70:30), pure lactone 48 (36 mg)

was obtained in 92% yield: an oil; ¹H NMR (300 MHz, CDCl₃)

δ 4.39 (q, J ) 6.2 Hz, 1H), 4.00 (m, 2H), 3.86 (m, 2H), 3.5-3.7

(m, 3H), 2.4-2.6 (m, 2H), 2.2-2.4 (m, 2H), 1.9-2.2 (m, 4H),

1.5-1.8 (m, 4H), 0.87 (s, 9H), 0.86 (s, 9H), 0.06 (s, 12H); ¹³C

NMR (75 MHz, CDCl₃) δ 176.2, 82.2, 81.8, 81.5, 80.9, 80.1,

75.9, 64.9, 29.4, 29.2, 28.3, 27.7, 27.3, 26.0 (3C), 25.9 (3C), 23.7,

18.3, 18.2, -4.3, -4.7, -5.4 (2C); MS (CI, CH₄) m/ z 515 [M +

H]⁺. Anal. Calcd for C₂₆H₅₀O₆Si₂: C, 60.66; H, 9.79. Found:

C, 60.77; H, 9.64.

A stirred solution of this aldehyde intermediate (1.04 g, 4.04

mmol) in methanol (20 mL) under nitrogen atmosphere was

cooled to -30 °C and treated with NaBH₄(306 mg, 8.08 mmol).

After being stirred for 1 h at -30 °C, the temperature of the

reaction mixture was allowed to raise to -15 °C, while further

portion of NaBH₄(155 mg, 4.04 mmol) was added. After 2 h

at -15 °C, the reaction mixture was quenched by addition of

acetone (5 mL) and 5% aqueous citric acid solution. The

mixture was then extracted with CH₂Cl₂, and the organic layer

was dried (MgSO₄), filtered, and concentrated under vacuum,

furnishing a crude residue that was purified by flash chroma-

tography (EtOAc/MeOH 98:2). Pure lactam 51 was recovered

(840 mg, 80% corresponding to a 70% overall yield from 50)

Un sa tu r a ted La cta m 49. To a solution of TBSOP (2.45 g,

8.2 mmol) in anhydrous Et₂O (50 mL) under argon atmosphere

was added protected ^D-glyceraldehyde 22 (1.39 g, 10.7 mmol),

and the resulting mixture was cooled to -80 °C. A 0.1 M Et₂O

solution of SnCl₄(0.82 mL, 8.2 mmol), cooled to the same

temperature, was added dropwise to the stirring solution, and

the reaction was allowed to proceed for 5 h at -80 °C. The

reaction mixture was then quenched at the same temperature

by the addition of solid NaHCO₃(2.7 g) followed by water (30

mL) and, after reaching room temperature, the mixture was

extracted with CH₂Cl₂. The combined organic layers were

washed with brine, dried (MgSO₄), and concentrated under

vacuum to furnish a crude residue, which was purified by

crystallization from CH₂Cl₂/hexane. Pure lactam 49 was

obtained (2.06 g) in 80% yield, accompanied by its C4-epimer

(4.7% yield), which was obtained in a pure form by flash

chromatography of the mother residue (hexanes/EtOAc 50:50).

as white crystals: mp 92-94 °C; [R]²⁰-22.2 (c 0.5, CHCl₃);

D

¹H NMR (300 MHz, CDCl₃) δ 6.28 (bs, 1H), 3.82 (dt, J ) 7.4,

5.2 Hz, 1H), 3.5-3.6 (m, 3H), 2.73 (bs, 1H), 2.30 (m, 2H), 2.16

(m, 1H), 1.82 (m, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 178.4, 75.3, 63.7, 56.2, 30.0, 25.7

(3C), 23.5, 17.9, -4.4, -4.8. Anal. Calcd for C₁₂H₂₅NO₃Si: C,

55.56; H, 9.71; N, 5.40. Found: C, 55.69; H, 9.88; N, 5.32.

La cta m 52. A stirred solution of carbinol 51 (830 mg, 3.2

mmol) in anhydrous CH₂Cl₂(15 mL) was cooled with an ice

bath and sequentially treated with 2,6-lutidine (0.5 mL, 4.48

mmol) and TBSOTf (0.88 mL, 3.84 mmol) under nitrogen

atmosphere. After being stirred at 0 °C for 1 h, the reaction

mixture was quenched with 5% aqueous citric acid and

extracted with CH₂Cl₂. The combined organic layers were

dried, filtered, and concentrated under vacuum, providing a

crude residue that was purified by flash chromatography

(EtOAc/hexanes 80:20). A pure silylated lactam intermediate

was obtained (1.0 g, 2.68 mmol, 85%) that was dissolved in

CH₃CN (20 mL) and sequentially treated with Boc₂O (385 mg,

2.68 mmol) and DMAP (16 mg, 0.13 mmol). The reaction

mixture was warmed to 40 °C and allowed to stir under

nitrogen atmosphere for 2 h, during which time two further

portions of Boc₂O (385 mg, 2.68 mmol each) and DMAP (16

mg, 0.13 mmol) were added. The reaction mixture was then

concentrated under vacuum, providing a crude residue that

was purified by flash chromatography (hexanes/EtOAc 85:15).

Pure protected lactam 52 was obtained (1.27 g) in almost

Compound 49: white solid; mp 138-140 °C; [R]²⁰+197.6 (c

D

1

0.83, CHCl₃); H NMR (300 MHz, CDCl₃) δ 7.43 (dd, J ) 6.3,

2.1 Hz, 1H), 6.13 (dd, J ) 6.3, 1.5 Hz, 1H), 4.81 (dt, J ) 5.7,

2.4 Hz, 1H), 4.09 (ddd, J ) 6.0, 5.7, 3.9 Hz, 1H), 4.01 (q, J )

6.0, 1H), 3.94 (dd, J ) 8.1, 6.0 Hz, 1H), 3.86 (dd, J ) 8.1, 6.0

Hz, 1H), 3.63 (d, J ) 3.9 Hz, 1H), 1.57 (s, 9H), 1.37 (s, 3H),

1.32 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 168.9, 150.9, 148.2,

126.9, 109.2, 83.8, 75.6, 72.6, 66.4, 65.6, 28.0 (3 C), 26.4, 25.1.

Anal. Calcd for C₁₅H₂₃NO₆: C, 57.50; H, 7.40; N, 4.47. Found:

C, 57.31; H, 7.35; N, 4.32.

La cta m 50. The above hydrogenation procedure to trans-

form 23 into 24 was adopted, using unsaturated lactam 49

(2.0 g, 6.38 mmol), Pd on carbon (10%, 200 mg), and NaOAc

(80 mg) in dry THF (30 mL). After flash chromatographic

purification (hexanes/EtOAc 60:40), a saturated lactam inter-

mediate was obtained (1.85 g) in 92% yield as a white solid.

This lactam intermediate (1.85 g, 5.87 mmol) was dissolved

in anhydrous CH₂Cl₂(16 mL) and sequentially treated with

2,6-lutidine (1.1 mL, 9.4 mmol) and TBSOTf (1.89 mL, 8.22

mmol), under stirring at room temperature. After 1 h, the

reaction mixture was quenched with 5% citric acid and

extracted with CH₂Cl₂. The combined organic layers were dried

(MgSO₄) and concentrated under vacuum to afford a crude

residue that was purified by flash chromatography (hexanes/

EtOAc 70:30). Protected lactam 50 was obtained (2.14 g, 85%,

quantitative yield (84% from 51) as a pale yellow oil: [R]²⁰

D

+20.1 (c 0.4, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 4.19 (ddd,

J ) 9.3, 4.3, 1.7 Hz, 1H), 4.11 (q, J ) 5.4 Hz, 1H), 3.57 (dd, J

) 10.6, 5.5 Hz, 1H), 3.52 (dd, J ) 10.6, 5.4 Hz, 1H), 2.52 (ddd,

J ) 17.8, 10.9, 9.8 Hz, 1H), 2.35 (ddd, J ) 17.8, 10.2, 2.5 Hz,

1H), 2.18 (dddd, J ) 13.5, 9.6, 2.2, 2.2 Hz, 1H), 1.94 (m, 1H),

1.50 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.08 (s, 3H), 0.07 (s,

3H), 0.01 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 174.8, 150.0,

82.6, 71.6, 64.0, 60.0, 32.0, 29.6 (3C), 25.9 (3C), 25.7 (4C), 18.0,

17.9, -4.6, -4.9, -5.6, -5.7. Anal. Calcd for C₂₃H₄₇NO₅Si₂:

C, 58.31; H, 10.00; N, 2.96. Found: C, 58.26; H, 10.12; N, 2.84.

Nitr ogen P r ecu r sor 53. To a stirred solution of lactam

52 (1.27 g, 2.68 mmol) in anhydrous THF (20 mL) cooled at

corresponding to a 78% overall yield from 49) as a pale yellow

1

oil: [R]²⁰+38.1 (c 0.8, CHCl₃); H NMR (300 MHz, CDCl₃) δ

D

4.19 (ddd, J ) 9.2, 3.7, 1.3 Hz, 1H), 4.10 (dd, J ) 8.5, 3.7 Hz,

1H), 4.07 (dd, J ) 8.0, 5.9 Hz, 1H), 3.95 (dt, J ) 8.5, 6.1 Hz,

1H), 3.71 (dd, J ) 8.1, 6.2 Hz, 1H), 2.57 (ddd, J ) 17.8, 11.5,

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2061

-80 °C was added LiEt₃BH (4.02 mL of a 1.0 M solution in

THF, 4.02 mmol) dropwise. After being stirred at -80 °C under

nitrogen atmosphere for 2 h, the reaction mixture was treated

with further portion of LiEt₃BH (4.02 mL of a 1.0 M solution

in THF, 4.02 mmol) and allowed to stirr at -80 °C for an

additional 2 h. Methanol (10 mL), water (10 mL), and potas-

sium sodium tartrate tetrahydrate were added, and once

warmed to room temperature, the mixture was extracted with

EtOAc. The combined organic layers were dried and concen-

trated, providing a crude aminal intermediate (1.27 g, quan-

titative) as a colorless oil. This N,O-acetal (1.27 g, 2.67 mmol)

was dissolved at room temperature in dry Et₂O (12 mL) under

nitrogen atmosphere and sequentially treated with activated

2-3 µm molecular sieves (80 mg), methyl orthoformate (590

µL, 5.34 mmol), and BF₃‚OEt₂(100 µL). After being stirred

for 2 h, the reaction was quenched with brine and Et₃N (some

drops) and extracted with Et₂O. The combined organic layers

were washed with water, dried, and concentrated under

vacuum to furnish a crude oily residue that was purified by

flash chromatography (hexanes/EtOAc 85:15). Pure methyl

18.4, 18.0, -4.3, -4.8, -5.3, -5.5. Anal. Calcd for C₃₂H₆₀N₂O₇-

Si₂: C, 59.96; H, 9.43; N, 4.36. Found: C, 59.84; H, 9.36; N,

4.28.

Sa tu r a ted La cta m 56. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactam 54 (650 mg, 1.01 mmol). After flash chromatographic

purification (hexanes/EtOAc 75:25), pure lactam 56 was

obtained (640 mg, 98%) as a colorless oil: [R]²⁰+19.5 (c 0.3,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃, 50:50 mixture of rotamers)

δ 4.60 (dt, J ) 6.7, 4.2 Hz, 0.5H), 4.35 (m, 0.5H), 4.27 (m, 0.5H),

4.13 (m, 1H), 3.93 (m, 0.5H), 3.84 (dd, J ) 8.0, 4.7 Hz, 0.5H),

3.78 (dd, J ) 8.2, 4.6 Hz, 0.5H), 3.42 (m, 2H), 2.77 (ddd, J )

17.5, 11.4, 8.9 Hz, 0.5H), 2.60 (ddd, J ) 17.4, 12.1, 8.6 Hz,

0.5H), 2.38 (m, 1H), 2.20 (m, 1H), 1.8-2.1 (m, 3H), 1.65 (m,

2H), 1.53 (s, 9 × 0.5H), 1.51 (s, 9 × 0.5H), 1.46 (s, 9 × 0.5H),

1.43 (s, 9 × 0.5H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.02

(s, 6H); ¹³C NMR (75 MHz, CDCl₃, one rotamer) δ 173.4,

154.0, 150.1, 83.0, 80.1, 70.0, 64.1, 61.1, 59.7, 59.4, 31.5, 28.1

(3C), 28.0 (3C), 26.0 (3C), 25.8 (3C), 24.2, 22.9, 22.4, 18.4, 18.0,

-4.4, -4.7, -5.4 (2C). Anal. Calcd for C₃₂H₆₂N₂O₇Si₂: C, 59.77;

H, 9.72; N, 4.36. Found: C, 59.61; H, 9.80; N, 4.44.

N,O-acetal 53 was obtained (1.18 g) in 90% yield (two steps)

1

as a colorless oil: [R]²⁰+35.9 (c 1.6, CHCl₃); H NMR (300

Sa tu r a ted La cta m 57. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactam 55 (450 mg, 0.7 mmol). After flash chromatographic

purification (hexanes/EtOAc 75:25), pure lactam 57 was

D

MHz, CDCl₃) δ 5.17 (m, 1H), 4.27 (m, 1H), 3.84 (m, 1H), 3.70

(bd, J ) 10.6 Hz, 1H), 3.50 (dd, J ) 10.8, 8.2 Hz, 1H), 3.31 (s,

3H), 1.9-2.0 (m, 2H), 1.78 (m, 1H), 1.63 (m, 1H), 1.47 (s, 9H),

0.87 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H), 0.01 (s,

3H), -0.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.2, 90.0,

79.5, 71.5, 64.0, 60.0, 54.9, 31.7, 28.4 (3C), 26.0 (3C), 25.8 (3C),

obtained (433 mg, 96%) as a colorless oil: [R]²⁰+14.7 (c 0.3,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃, major rotamer) δ 4.96 (bd,

J ) 9.4 Hz, 1H), 4.30 (m, 1H), 4.02 (bd, J ) 6.2 Hz, 1H), 3.74

(m, 1H), 3.3-3.5 (m, 2H), 2.58 (m, 1H), 2.42 (ddd, J ) 18.1,

10.7, 3.0 Hz, 1H), 2.1-2.3 (m, 2H), 1.5-1.8 (m, 4H), 1.53 (s,

9H), 1.50 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.06 (s, 6H), 0.01

(s, 6H); ¹³C NMR (75 MHz, CDCl₃, major rotamer) δ 174.4,

154.0, 150.8, 82.9, 80.0, 72.3, 64.1, 63.1, 60.2, 57.4, 31.9, 28.7

(3C), 28.0 (3C), 26.0 (3C), 25.8 (3C), 25.0, 24.8, 21.2, 18.4, 18.0,

-4.3, -4.8, -5.4, -5.5. Anal. Calcd for C₃₂H₆₂N₂O₇Si₂: C,

59.77; H, 9.72; N, 4.36. Found: C, 59.65; H, 9.61; N, 4.30.

Nitr ogen Su bu n it 58. N,O-Acetal 58 was prepared accord-

ing to the two-step procedure used to trasform 52 into 53, by

starting with lactam 56 (620 mg, 0.96 mmol). After flash

chromatographic purification (hexanes/EtOAc 75:25), methyl

aminal 58 was obtained (445 mg, 70%, two steps) as a mixture

23.0, 18.0, 17.9, -4.3, -4.8, -5.5 (2C). Anal. Calcd for C₂₄H₅₁

-

NO₅Si₂: C, 58.85; H, 10.49; N, 2.86. Found: C, 58.71; H, 10.53;

N, 2.75.

Un sa tu r a ted La cta m s 54 a n d 55. Gen er a l P r oced u r e

C. To a solution of methyl aminal 53 (1.18 g, 2.41 mmol) in

anhydrous CH₂Cl₂(30 mL) cooled to -90 °C under an inert

atmosphere (N₂) was added TBSOTf (0.33 mL, 1.45 mmol)

dropwise. The resulting mixture was allowed to stir at -90

°C for 15 min, after which time it was treated with 856 mg

(2.89 mmol) of silylenol ether TBSOP. After being stirred for

an additional 1 h at -90 °C, the reaction mixture was

neutralized at the same temperature with Et₃N (1.45 mL of a

1.0 M solution in CH₂Cl₂, 1.45 mmol) and quenched by the

addition of water. After room temperature was reached, the

mixture was extracted with CH₂Cl₂. The combined organic

layers were dried over MgSO₄, filtered, and concentrated under

vacuum to provide an oily residue that was purified by flash

chromatography (hexanes/EtOAc 75:25). Pure unsaturated

lactams 54 (695 mg, 45%) and 55 (460 mg, 30%) were obtained.

1

of anomers and rotamers: colorless oil; H NMR (300 MHz,

CDCl₃, major isomer) δ 5.16 (m, 1H), 4.68 (m, 1H), 4.3-4.5

(m, 2H), 3.84 (m, 1H), 3.3-3.6 (m, 2H), 3.26 (s, 3H), 1.5-2.0

(m, 8H), 1.45 (s, 18H), 0.86 (s, 9H), 0.85 (s, 9H), 0.05 (s, 3H),

0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃, major isomer) δ 154.3, 154.0, 89.9, 83.1, 80.0, 71.5, 64.1,

61.2, 59.5, 59.2, 55.0, 31.4, 28.1 (3C), 28.0 (3C), 26.0 (3C), 25.9

(3C), 24.0, 22.7, 22.4, 18.3, 18.1, -4.5, -4.7, -5.5 (2C). Anal.

Calcd for C₃₃H₆₆N₂O₇Si₂: C, 60.14; H, 10.09; N, 4.25. Found:

C, 60.27; H, 10.22; N, 4.16.

54: [R]²⁰+77.9 (c 0.3, CHCl₃); CD (CH₃OH, 1.3 × 10^-4M)

D

[θ]₂₂₇+11474 deg cm²dmol^-1; ¹H NMR (300 MHz, CDCl₃, 60:

40 rotameric mixture) δ 7.01 (dd, J ) 6.0, 2.0 Hz, 0.4H), 7.00

(dd, J ) 6.1, 2.0 Hz, 0.6H), 6.14 (dd, J ) 5.8, 1.5 Hz, 0.4H),

6.13 (dd, J ) 6.0, 1.6 Hz, 0.6H), 5.57 (dt, J ) 5.1, 1.8 Hz, 0.6H),

5.28 (dt, J ) 5.4, 1.9 Hz, 0.4H), 4.70 (dd, J ) 7.8, 5.2 Hz, 0.6H),

4.61 (dd, J ) 8.5, 5.6 Hz, 0.4H), 4.31 (q, J ) 5.2 Hz, 0.4H),

4.20 (dt, J ) 6.4, 4.7 Hz, 0.6H), 3.90 (dd, J ) 8.3, 4.2 Hz, 0.4H),

3.80 (dd, J ) 8.0, 4.8 Hz, 0.6H), 3.3-3.5 (m, 2H), 2.00 (m, 1H),

1.2-1.8 (m, 3H), 1.54 (s, 9 × 0.6H), 1.53 (s, 9 × 0.4H), 1.49 (s,

9 × 0.4H), 1.48 (s, 9 × 0.6H), 0.86 (s, 9H), 0.84 (s, 9H), 0.07 (s,

3H), 0.05 (s, 3H), 0.01 (s, 6H); ¹³C NMR (75 MHz, CDCl₃, major

rotamer) δ 177.5, 153.5, 150.8, 147.8, 128.0, 83.2, 80.3, 72.1,

64.2, 61.9, 61.3, 58.5, 28.6 (3C), 28.1 (3C), 26.0 (3C), 25.7 (3C),

25.6, 25.1, 18.5, 18.0, -3.6, -4.4, -5.3 (2C). Anal. Calcd for

Nitr ogen Su bu n it 59. N,O-Acetal 59 was prepared accord-

ing to the two-step procedure to trasform 52 into 53, by

starting with lactam 57 (410 mg, 0.64 mmol). After flash

chromatographic purification (hexanes/EtOAc 80:20), com-

pound 59 was obtained (294 mg, 70%, two steps) as a mixture

1

of anomers and rotamers: colorless oil; H NMR (300 MHz,

CDCl₃, major isomer) δ 5.20 (m, 1H), 4.62 (m, 1H), 4.3-4.5

(m, 2H), 3.91 (m, 1H), 3.3-3.6 (m, 2H), 3.30 (s, 3H), 1.5-2.0

(m, 8H), 1.44 (s, 18H), 0.86 (s, 18H), 0.05 (s, 6H), 0.03 (s, 6H);

¹³C NMR (75 MHz, CDCl₃, major isomer) δ 154.5, 154.1, 89.5,

83.0, 79.9, 72.1, 64.1, 61.6, 60.0, 57.3, 55.1, 31.7, 28.5 (3C),

28.0 (3C), 26.0 (3C), 25.9 (3C), 25.0, 24.5, 21.9, 18.4, 18.0, -4.3,

-4.7, -5.5 (2C). Anal. Calcd for C₃₃H₆₆N₂O₇Si₂: C, 60.14; H,

10.09; N, 4.25. Found: C, 60.01; H, 10.15; N, 4.15.

C

₃₂H₆₀N₂O₇Si₂: C, 59.96; H, 9.43; N, 4.36. Found: C, 60.07;

H, 9.51; N, 4.32.

55: CD (CH₃OH, 1.3 × 10^-4M) [θ]₂₂₅-10270 deg cm²dmol^-1

;

Un sa tu r a ted Nitr ogen Un it 60. The reaction was carried

out according to general procedure C, using TBSOF (0.21 mL,

1.01 mmol) and methyl pyrrolidinose 58 (445 mg, 0.68 mmol).

After flash chromatographic purification (hexanes/EtOAc 65:

35), pure butenolide 60 (435 mg, 90%) was obtained as a white

¹H NMR (300 MHz, CDCl₃, major rotamer) δ 7.01 (dd, J )

6.1, 2.1 Hz, 1H), 6.04 (dd, J ) 6.0, 1.7 Hz, 1H), 5.74 (q, J )

1.8 Hz, 1H), 4.20 (m, 2H), 3.72 (dd, J ) 8.4, 4.9 Hz, 1H), 3.43

(dd, J ) 10.1, 3.8 Hz, 1H), 3.35 (dd, J ) 10.1, 7.1 Hz, 1H),

2.06 (m, 1H), 1.3-1.8 (m, 3H), 1.52 (s, 9H), 1.50 (s, 9H), 0.85

(s, 9H), 0.83 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H),

-0.01 (s, 3H); ¹³C NMR (75 MHz, CDCl₃, major rotamer) δ

169.6, 154.1, 150.1, 149.4, 127.2, 82.9, 80.2, 72.3, 64.1, 61.9,

60.7, 59.7, 28.7 (3C), 28.0 (3C), 26.0 (3C), 25.7 (3C), 25.2, 22.8,

waxy solid: [R]²⁰+74.0 (c 0.6, CHCl₃); CD (CH₃OH, 1.1 ×

D

10^-4M) [θ]₂₁₇+11932 deg cm²dmol^-1

;

¹H NMR (300 MHz,

CDCl₃) δ 7.43 (dd, J ) 5.8, 1.3 Hz, 1H), 5.97 (dd, J ) 5.7, 1.9

Hz, 1H), 5.65 (dt, J ) 3.6, 1.8 Hz, 1H), 4.3-4.4 (m, 2H), 3.6-

3.9 (m, 3H), 3.3-3.5 (m, 2H), 1.5-2.2 (m, 8H), 1.47 (s, 9H),

2062 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

1.42 (s, 9H), 0.84 (s, 9H), 0.83 (s, 9H), 0.05 (s, 3H), 0.03 (s,

6H), -0.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.2, 154.8,

153.8, 153.3, 120.6, 83.1, 80.0, 79.8, 72.1, 64.3, 61.3, 60.9, 60.5,

58.5, 29.6, 28.6 (3C), 28.2 (3C), 27.5, 25.9 (3C), 25.7 (3C), 23.9,

23.7, 18.4, 17.9, -4.3, -4.6, -5.4, -5.6. Anal. Calcd for

12.5 mmol) and TBSOTf (2.5 mL, 10.9 mmol) under stirring

at room temperature. After 4 h, the reaction mixture was

quenched with 5% citric acid, and extracted with CH₂Cl₂. The

combined organic layers were dried (MgSO₄) and concentrated

under vacuum, to afford a crude residue that was purified by

flash chromatography (hexanes/EtOAc 70:30). Protected thi-

olactone 65 was obtained (2.16 g, 80%, corresponding to a 72%

C

₃₆H₆₆N₂O₈Si₂: C, 60.81; H, 9.36; N, 3.94. Found: C, 60.87;

H, 9.41; N, 3.82.

Un sa tu r a ted Nitr ogen Un it 61. The reaction was carried

out according to general procedure C, using TBSOF (0.14 mL,

0.66 mmol) and methyl pyrrolidinose 59 (290 mg, 0.44 mmol).

After flash chromatographic purification (hexanes/EtOAc 65:

35), pure butenolide 61 (307 mg, 98%) was obtained as a white

overall yield from 64) as a golden oil: [R]²⁰-57.3 (c 3.3,

D

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 4.14 (ddd, J ) 9.9, 5.7,

4.8 Hz, 1H), 4.02 (m, 2H), 3.93 (dd, J ) 5.4, 4.8 Hz, 1H), 3.84

(m, 1H), 2.61 (m, 2H), 2.29 (m, 1H), 2.09 (m, 1H), 1.42 (s, 3H),

1.33 (s, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 207.8, 109.2, 77.8, 74.7, 66.4, 54.9, 42.3,

28.5, 26.5, 25.8 (3 C), 25.1, 18.3, -3.6, -3.9. Anal. Calcd for

waxy solid: [R]²⁰-29.0 (c 0.7, CHCl₃); CD (CH₃OH, 1.0 ×

D

10^-4M) [θ]₂₁₃-17656 deg cm²dmol^-1

;

¹H NMR (300 MHz,

CDCl₃) δ 7.43 (m, 1H), 6.03 (m, 1H), 5.66 (m, 1H), 4.2-4.4 (m,

3H), 4.05 (m, 1H), 3.75 (m, 1H), 3.3-3.5 (m, 2H), 1.5-2.1 (m,

8H), 1.44 (s, 18H), 1.84 (s, 18H), 0.05 (s, 6H), -0.01 (s, 6H);

¹³C NMR (75 MHz, CDCl₃) δ 172.7, 154.3, 153.6, 153.4, 120.9,

83.1, 80.3, 79.4, 72.4, 64.0, 62.6, 60.9 (2C), 58.4, 31.9, 29.2,

28.5 (3C), 28.3 (3C), 25.9 (3C), 25.7 (3C), 24.6, 22.2, 18.3, 17.9,

-4.4, -4.8, -5.5, -5.6. Anal. Calcd for C₃₆H₆₆N₂O₈Si₂: C,

60.81; H, 9.36; N, 3.94. Found: C, 60.90; H, 9.48; N, 4.01.

Sa tu r a ted Nitr ogen Un it 62. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 60 (400 mg, 0.56 mmol). After flash chromatographic

purification (hexanes/EtOAc 55:45), pure lactone 62 (380 mg,

C

₁₆H₃₀O₄SSi: C, 55.45; H, 8.73. Found: C, 55.39; H, 8.88.

Th iola cton e 66. Protected thiolactone 65 (2.0 g, 5.77 mmol)

was dissolved in 7 mL of 80% aqueous acetic acid, and the

resulting mixture was warmed to 50 °C and allowed to stir

for 24 h. The reaction mixture was concentrated under

vacuum, furnishing a crude residue, which was purified by

flash chromatography eluting with ethyl acetate. A white

crystalline diol intermediate was obtained (1.5 g) in 85%

isolated yield. To a stirred solution of this pure diol (1.5 g, 4.9

mmol) in CH₂Cl₂(35 mL) were added chromatography grade

SiO₂(15 g) and a 0.65 M aqueous NaIO₄solution (15 mL, 9.8

mmol). The resulting slurry was vigorously stirred at room

temperature for 1 h, after which time the reaction mixture

was filtered under suction and the silica thoroughly washed

with CH₂Cl₂. The filtrates were evaporated, affording a crude

aldehyde intermediate (1.08 g, 80%) as a yellow oil. A stirred

solution of this aldehyde (1.08 g, 3.92 mmol) in 95% ethanol

(50 mL) under nitrogen atmosphere was cooled to -30 °C and

treated with NaBH₄(74 mg, 1.96 mmol). After 1 h, the reaction

mixture was quenched by addition of 5% aqueous citric acid

solution until neutral. The mixture was extracted with CH₂-

Cl₂, and the organic layer was dried (MgSO₄), filtered, and

concentrated under vacuum, furnishing a crude residue that

was purified by flash chromatography (hexanes/EtOAc 60:40).

A pure alcohol intermediate was recovered in 88% yield as

95%) was obtained as a yellow transparent oil: [R]²⁰+37.1

D

(c 0.4, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.19 (td, J ) 8.0,

4.4 Hz, 1H), 4.2-4.4 (m, 2H), 3.90 (m, 2H), 3.78 (m, 1H), 3.3-

3.5 (m, 2H), 2.4-2.5 (m, 2H), 2.0-2.2 (m, 2H), 1.5-2.0 (m, 8H),

1.45 (s, 9H), 1.44 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.06 (s,

6H), -0.01 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 174.0, 154.1,

152.0, 79.8, 79.7, 79.6, 72.3, 64.4, 61.3, 61.2, 60.3, 58.4, 30.1,

28.9, 28.7 (3C), 28.4 (3C), 27.2, 26.0 (3C), 25.8 (3C), 25.2, 23.8,

23.6, 18.0 (2C), -4.2, -4.6, -5.4, -5.5; MS (CI, CH₄) m/ z 713

[M + H]⁺. Anal. Calcd for C₃₆H₆₈N₂O₈Si₂: C, 60.63; H, 9.61;

N, 3.93. Found: C, 60.51; H, 9.49; N, 3.86.

Sa tu r a ted Nitr ogen Un it 63. The reaction was carried out

according to general procedure B, by starting with unsaturated

lactone 61 (290 mg, 0.41 mmol). After flash chromatographic

purification (hexanes/EtOAc 60:40), pure lactone 63 (256 mg,

88%) was obtained as a colorless oil: ¹H NMR (300 MHz,

CDCl₃) δ 5.09 (m, 1H), 4.0-4.4 (m, 4H), 3.76 (m, 1H), 3.3-3.5

(m, 2H), 2.48 (m, 2H), 1.5-2.2 (m, 10H), 1.45 (s, 18H), 0.85 (s,

18H), 0.05 (s, 6H), -0.01 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

175.2, 152.5, 151.9, 81.6, 81.4, 79.5, 72.9, 65.6, 63.1, 61.2, 60.5,

59.6, 30.7, 29.3, 28.5 (3C), 28.2 (3C), 28.0, 26.1 (3C), 25.8 (3C),

25.4, 24.1, 23.4, 18.2, 18.1, -4.5 (2C), -5.2, -5.4; MS (CI, CH₄)

m/ z 713 [M + H]⁺. Anal. Calcd for C₃₆H₆₈N₂O₈Si₂: C, 60.63;

H, 9.61; N, 3.93. Found: C, 60.68; H, 9.54; N, 3.87.

1

white crystals: mp 63-64 °C; H NMR (300 MHz, CDCl₃) δ

4.17 (ddd, J ) 9.3, 7.4, 6.0 Hz, 1H), 3.81 (dt, J ) 7.2, 3.6 Hz,

1H), 3.63 (m, 2H), 2.62 (ddd, J ) 16.9, 8.2, 4.4 Hz, 1H), 2.54

(ddd, J ) 17.1, 10.1, 6.7 Hz, 1H), 2.28 (dddd, J ) 12.7, 6.8,

5.9, 4.2 Hz, 1H), 2.03 (bs, 1H), 1.91 (dddd, J ) 12.7, 10.4, 9.4,

8.2 Hz, 1H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). A stirred

solution of the carbinol intermediate (950 mg, 3.44 mmol) in

anhydrous CH₂Cl₂(30 mL) was cooled with an ice-bath and

sequentially treated with 2,6-lutidine (0.64 mL, 5.5 mmol) and

TBSOTf (1.11 mL, 4.82 mmol), under nitrogen atmosphere.

After being stirred at 0 °C for 45 min, the reaction mixture

was quenched with 5% aqueous citric acid and extracted with

CH₂Cl₂. The combined orgainc layers were dried, filtered, and

concentrated under vacuum, providing a crude residue that

was purified by flash chromatography (hexanes/EtOAc 80:20).

Pure thiolactone 66 was obtained (1.29 g) in 96% yield (57%

Un sa tu r a ted Th iola cton e 64. Thiolactone 64 was pre-

pared according to the procedure described for 23, by employ-

ing 2.71 g (12.6 mmol) of TBSOT, 2.13 g (16.4 mmol) of

D-glyceraldehyde 22 and 1.55 mL (12.6 mmol) of BF₃etherate

in CH₂Cl₂(50 mL) at -80 °C for 4 h. After flash chromato-

graphic purification (hexanes/EtOAc 50:50), thiolactone 64 was

recovered in 70% yield (2.0 g), accompanied by a minor amount

overall yield from 65) as white crystals: mp 44-45 °C; [R]²⁰

D

-60.3 (c 1.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 4.15 (dt, J

) 8.2, 5.8 Hz, 1H), 3.80 (dt, J ) 6.7, 4.8 Hz, 1H), 3.61 (dd, J

) 10.4, 4.3 Hz, 1H), 3.48 (dd, J ) 10.3, 6.7 Hz, 1H), 2.61 (ddd,

J ) 16.9, 7.8, 5.1 Hz, 1H), 2.50 (ddd, J ) 16.9, 9.4, 7.5 Hz,

1H), 2.27 (dddd, J ) 13.3, 7.3, 6.3, 5.1 Hz, 1H), 2.03 (dddd, J

) 12.8, 9.4, 9.4, 8.0 Hz, 1H), 0.85 (s, 9H), 0.84 (s, 9H), 0.05 (s,

3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 208.6, 75.6, 65.8, 54.4, 42.2, 28.2, 25.8 (3C), 25.7 (3C),

18.1, 17.9, -4.2, -4.8, -5.6 (2C). Anal. Calcd for C₁₈H₃₈O₃-

SSi₂: C, 55.33; H, 9.80. Found: C, 55.26; H, 9.91.

of its C4-epimer. Compound 64: an oil; [R]²⁰+67.0 (c 2.5,

D

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 7.54 (dd, J ) 6.1, 2.9

Hz, 1H), 6.31 (dd, J ) 6.1, 1.9 Hz, 1H), 4.91 (m, 1H), 3.8-4.2

(m, 4H), 2.74 (bs, 1H), 1.41 (s, 3H), 1.32 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 199.6, 156.7, 133.4, 110.0, 78.1, 72.9, 67.1, 58.4,

26.7, 24.9. Anal. Calcd for C₁₀H₁₄O₄S: C, 52.16; H, 6.13.

Found: C, 52.24; H, 6.01.

Th iola cton e 65. The above hydrogenation procedure to

transform 23 into 24 was adopted, using unsaturated thiolac-

tone 64 (2.0 g, 8.7 mmol), 10% Pd on carbon (200 mg), and

NaOAc (70 mg) in dry THF (45 mL). After 24 h, the hydrogen

was evacuated and the catalyst was filtered on a Celite pad

and thoroughly washed with methanol. The filtrates were

concentrated and subjected to flash chromatographic purifica-

tion (hexanes/EtOAc 50:50) giving a saturated thiolactone

intermediate (1.8 g, 90% yield) as white crystals. This inter-

mediate (1.8 g, 7.8 mmol) was dissolved in anhydrous CH₂Cl₂

(50 mL) and sequentially treated with 2,6-lutidine (1.45 mL,

Su lfu r P r ecu r sor 67. NaBH₄(61 mg, 1.61 mmol) was

added to a stirred solution of thiolactone 66 (1.25 g, 3.21 mmol)

in methanol (50 mL) cooled at -15 °C. After being stirred at

the same temperature under nitrogen atmosphere for 1 h, five

additional portions of NaBH₄(5 × 61 mg, 5 × 1.61 mmol) were

added over a period of 6 h. The reaction mixture was quenched

at -15 °C with 5% aqueous citric acid and water until neutral

pH was reached, and a spatula tip of sodium and potassium

tartrate was added. Once warmed to room temperature, the

Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes

J . Org. Chem., Vol. 65, No. 7, 2000 2063

mixture was extracted with CH₂Cl₂. The organic layers were

dried and concentrated, providing a yellow crude residue that

was subjected to flash chromatographic purification (hexanes/

EtOAc 85:15). A pure thiolactol intermediate was obtained

(904 mg, 2.31 mmol, 72%), which was readily dissolved in dry

CH₂Cl₂(40 mL) under argon atmosphere, and sequentially

treated with pyridine (0.4 mL, 4.62 mmol), acetic anhydride

(0.65 mL, 6.93 mmol), and DMAP (14 mg, 0.12 mmol) at room

temperature. After being stirred for 1 h, the mixture was

quenched with saturated aqueous NaHCO₃and extracted with

CH₂Cl₂. The combined organic layers were dried (MgSO₄), and

concentrated in vacuo. The yellowish crude extract was puri-

fied by flash chromatography (hexanes/EtOAc 85:15) to provide

acetyl thiolactol 67 (985 mg, 98%) as a golden yellow oil: ¹H

NMR (300 MHz, CDCl₃, 1:1 anomeric mixture) δ 6.13 (dd, J

) 4.6, 2.2 Hz, 0.5H), 6.06 (d, J ) 3.2 Hz, 0.5H), 4.17 (dt, J )

8.3, 6.0 Hz, 0.5H), 3.81 (dt, J ) 6.7, 5.2 Hz, 0.5H), 3.6-3.8 (m,

1H), 3.59 (dd, J ) 10.4, 4.5 Hz, 0.5H), 3.45-3.55 (m, 3 × 0.5H),

2.61 (ddd, J ) 16.9, 9.1, 5.1 Hz, 0.5H), 2.52 (ddd, J ) 16.9,

9.4, 7.5 Hz, 0.5H), 1.8-2.3 (m, 3H), 0.87 (s, 9 × 0.5H), 0.86 (s,

9 × 0.5H), 0.85 (s, 9 × 0.5H), 0.84 (s, 9 × 0.5H), 0.08 (s, 3 ×

0.5H), 0.07 (s, 3 × 0.5H), 0.06 (s, 3 × 0.5H), 0.05 (s, 3 × 0.5H),

0.04 (s, 3 × 0.5H), 0.03 (s, 3 × 0.5H), 0.02 (s, 3 × 0.5H), 0.01

(s, 3 × 0.5H); ¹³C NMR (75 MHz, CDCl₃, 1:1 anomeric mixture)

δ 170.2, 82.9, 75.5 and 75.3, 66.6 and 65.9, 54.6 and 53.1, 42.3

and 41.7, 30.2 and 28.4, 25.9 (3C), 25.7 (3C), 21.3, 19.1, 18.2,

-4.1, -4.4, -4.7, -5.4. Anal. Calcd for C₂₀H₄₂O₄SSi₂: C, 55.25;

H, 9.74. Found: C, 55.38; H, 9.82.

66.7, 56.9, 54.2, 53.3, 41.7, 37.3, 32.8, 32.0, 25.9 (3C), 25.5 (3C),

18.3, 18.1, -4.0, -4.6, -5.0, -5.5. Anal. Calcd for C₂₂H₄₄O₃S₂-

Si₂: C, 55.41; H, 9.30. Found: C, 55.29; H, 9.21.

Su lfu r Su bu n it 72. Acetyl thiolactol 72 was prepared

according to the two-step procedure utilized to transform 66

into 67, by starting with thiolactone 70 (286 mg, 0.6 mmol).

After flash chromatographic purification (hexanes/EtOAc 85:

15), acetyl thiolactol 72 was obtained (205 mg, 66%, two steps)

as an oil: ¹H NMR (300 MHz, CDCl₃, 1:1 anomeric mixture)

δ 6.14 (dd, J ) 4.7, 2.2 Hz, 0.5H), 6.08 (bd, J ) 4.0 Hz, 0.5H),

3.61 (m, 3H), 3.50 (m, 3H), 2.22 (m, 2H), 1.9-2.1 (m, 2H), 2.01

(s, 3H), 1.6-1.8 (m, 2H), 1.5-1.6 (m, 2H), 0.87 (s, 18H), 0.08

(s, 3H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR (75

MHz, CDCl₃, 1:1 anomeric mixture) δ 170.2, 82.8, 76.1 and

75.9, 66.7 and 66.0, 56.4 and 56.2, 54.2 and 54.0, 53.1 and 52.8,

41.0 and 39.7, 34.8 and 33.9, 32.8 and 31.7, 32.5 and 31.0, 25.8

(3C), 25.7 (3C), 21.2, 18.3, 18.2, -4.2, -4.4, -4.7, -5.3. Anal.

Calcd for C₂₄H₄₈O₄S₂Si₂: C, 55.34; H, 9.29. Found: C, 55.27;

H, 9.21.

Su lfu r Su bu n it 73. Acetyl thiolactol 73 was prepared

according to the two-step procedure utilized to transform 66

into 67, by starting with thiolactone 71 (535 mg, 1.12 mmol).

After flash chromatographic purification (hexanes/EtOAc 85:

15), acetyl thiolactol 73 was obtained (409 mg, 70%, two steps)

as an oil: ¹H NMR (300 MHz, CDCl₃, 1:1 anomeric mixture)

δ 6.11 (m, 1H), 3.6-3.9 (m, 3H), 3.3-3.6 (m, 3H), 2.29 (m, 2H),

1.9-2.2 (m, 2H), 2.03 (s, 3H), 1.5-1.9 (m, 4H), 0.90 (s, 9H),

0.89 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.02 (s,

3H); ¹³C NMR (75 MHz, CDCl₃, 1:1 anomeric mixture) δ 170.3,

83.0, 76.3 and 76.1, 66.6 and 65.9, 56.8 and 56.5, 54.4 and 54.0,

53.3 and 53.1, 41.9 and 41.5, 36.9 and 35.4, 32.8 and 32.1, 32.0

and 29.4, 25.9 (3C), 25.7 (3C), 21.4, 18.3, 18.1, -4.0, -4.6, -5.0,

Un sa tu r a ted Th iola cton es 68 a n d 69. The reaction was

carried out according to general procedure A, using acetyl

lactol 67 (985 mg, 2.27 mmol) and TBSOT (583 mg, 2.72

mmol). After flash chromatographic purification (hexanes/

EtOAc/Et₂O 75:10:15), pure thiobutenolides 68 (350 mg, 27%)

and 69 (685 mg, 53%) were obtained.

-5.5. Anal. Calcd for

C₂₄H₄₈O₄S₂Si₂: C, 55.34; H, 9.29.

Found: C, 55.20; H, 9.39.

68: an oil; CD (CH₃OH, 1.0 × 10^-4M) [θ]₂₁₄+4350 deg cm²

Un sa tu r a ted Su lfu r Un its 74 a n d 75. The reaction was

carried out according to general procedure A, using TBSOF

(96 µL, 0.46 mmol), acetyl thiolactol 72 (200 mg, 0.38 mmol),

and TBSOTf (53 µL, 0.23 mmol) and BF₃etherate (30 µL, 0.23

mmol) as the Lewis acid promoter mixture. After flash

chromatographic purification (hexanes/EtOAc 75:25), pure

butenolides 74 (54 mg, 26%) and 75 (80 mg 39%) were

obtained.

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.57 (dd, J ) 6.2, 2.6

;

Hz, 1H), 6.32 (dd, J ) 6.2, 1.9 Hz, 1H), 4.65 (dt, J ) 6.2, 2.1

Hz, 1H), 3.6-3.8 (m, 3H), 3.5-3.6 (m, 2H), 2.30 (m, 1H), 2.10

(m, 1H), 1.6-1.9 (m, 2H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s,

6H), 0.03 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 199.0, 155.7,

133.8, 76.3, 66.7, 59.1, 54.5, 50.5, 33.8, 33.2, 25.9 (3C), 25.6

(3C), 18.3, 18.1, -3.6, -4.0, -4.6, -5.5. Anal. Calcd for

C

₂₂H₄₂O₃S₂Si₂: C, 55.65; H, 8.92. Found: C, 55.50; H, 8.99.

74: an oil; CD (CH₃OH, 0.5 × 10^-4M) [θ]₂₁₁+9170 deg cm²

69: an oil; CD (CH₃OH, 1.0 × 10^-4M) [θ]₂₃₀-4275 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.44 (dd, J ) 5.7, 1.6

;

dmol^-1

;

¹H NMR (300 MHz, CDCl₃) δ 7.45 (dd, J ) 6.1, 2.6

Hz, 1H), 6.17 (dd, J ) 5.8, 1.9 Hz, 1H), 5.10 (dt, J ) 6.0, 1.9

Hz, 1H), 3.5-3.9 (m, 7H), 1.6-2.3 (m, 8H), 0.87 (s, 9H), 0.86

Hz, 1H), 6.27 (dd, J ) 6.0, 1.8 Hz, 1H), 4.45 (dt, J ) 9.3, 2.3

Hz, 1H), 3.77 (m, 1H), 3.65 (m, 2H), 3.4-3.6 (m, 2H), 2.30 (m,

1H), 2.10 (m, 1H), 1.6-1.9 (m, 2H), 0.87 (s, 9H), 0.86 (s, 9H),

0.08 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 199.2, 158.0, 132.9, 76.3, 66.6, 60.6, 54.6,

51.6, 36.9, 32.5, 25.9 (3C), 25.7 (3C), 18.2, 18.1, -4.0, -4.6,

-5.4, -5.5. Anal. Calcd for C₂₂H₄₂O₃S₂Si₂: C, 55.65; H, 8.92.

Found: C, 55.70; H, 9.03.

Sa tu r a ted Th iola cton e 70. The reaction was carried out

according to general procedure B, by starting with thiobuteno-

lide 68 (350 mg, 0.73 mmol). After flash chromatographic

purification (hexanes/EtOAc/Et₂O 80:10:10), pure thiolactone

70 was obtained (286 mg, 82%) as an oil: ¹H NMR (300 MHz,

CDCl₃) δ 3.98 (td, J ) 8.1, 5.8 Hz, 1H), 3.55-3.70 (m, 3H),

3.45-3.55 (m, 2H), 2.58 (m, 1H), 2.30 (m, 1H), 1.8-2.2 (m,

3H), 1.5-1.8 (m, 3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.04 (s, 3H),

0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 207.5, 76.4, 66.8, 56.5, 54.0, 53.0, 41.2, 35.6, 32.9,

32.5, 25.9 (3C), 25.6 (3C), 18.3, 18.1, -4.0, -4.3, -4.6, -5.4.

Anal. Calcd for C₂₂H₄₄O₃S₂Si₂: C, 55.41; H, 9.30. Found: C,

55.37; H, 9.42.

Sa tu r a ted Th iola cton e 71. The reaction was carried out

according to general procedure B, by starting with thiobuteno-

lide 69 (685 mg, 1.44 mmol). After flash chromatographic

purification (hexanes/EtOAc/Et₂O 80:10:10), pure thiolactone

71 was obtained (535 mg, 78%) as an oil: ¹H NMR (300 MHz,

CDCl₃) δ 3.82 (ddd, J ) 9.9, 8.0, 5.7 Hz, 1H), 3.72 (m, 1H),

3.63 (m, 1H), 3.4-3.6 (m, 3H), 2.57 (m, 1H), 2.28 (m, 1H), 1.9-

2.2 (m, 3H), 1.6-1.8 (m, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07

(s, 6H), 0.04 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 207.7, 76.4,

(s, 9H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³

C

NMR (75 MHz, CDCl₃) δ 199.0, 155.8, 133.5, 84.6, 76.3, 66.4,

54.5, 54.1, 54.0, 53.9, 32.7, 32.0, 29.4, 28.7, 26.0 (6C), 18.2,

18.0, -4.2, -4.4, -4.7, -5.3; HRMS (CI, CH₄) m/z 545.2594

(MH, 545.2611 calcd for C₂₆H₄₉O₄S₂Si₂).

75: an oil; CD (CH₃OH, 2.0 × 10^-4M) [θ]₂₃₉-7002 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.45 (dd, J ) 5.7, 1.6

;

Hz, 1H), 6.11 (dd, J ) 5.8, 2.0 Hz, 1H), 4.80 (dt, J ) 9.8, 1.9

Hz, 1H), 3.4-3.8 (m, 7H), 1.6-2.4 (m, 8H), 0.87 (s, 9H), 0.86

(s, 9H), 0.08 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³

C

NMR (75 MHz, CDCl₃) δ 199.2, 157.8, 133.0, 85.2, 76.1, 66.6,

54.6, 53.9 (2C), 53.7, 32.8, 32.1, 29.7, 28.5, 26.2 (3C), 25.9 (3C),

18.2, 18.1, -4.3, -4.6, -5.4 (2C); HRMS (CI, CH₄) m/z

545.2599 (MH, 545.2611 calcd for C₂₆H₄₉O₄S₂Si₂).

Un sa tu r a ted Su lfu r Un its 76 a n d 77. The reaction was

carried out according to general procedure A, using TBSOF

(190 µL, 0.92 mmol), acetyl thiolactol 73 (400 mg, 0.77 mmol),

and TBSOTf (105 µL, 0.46 mmol) and BF₃etherate (60 µL,

0.46 mmol) as the Lewis acid promoter mixture. After flash

chromatographic purification (hexanes/EtOAc 75:25), pure

butenolides 76 (113 mg, 27%) and 77 (172 mg, 41%) were

obtained.

76: an oil; CD (CH₃OH, 0.5 × 10^-5M) [θ]₂₄₀-750 deg cm²

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.50 (dd, J ) 5.9, 1.6

;

Hz, 1H), 6.17 (dd, J ) 5.7, 1.7 Hz, 1H), 5.10 (dt, J ) 5.2, 1.7

Hz, 1H), 3.4-3.8 (m, 7H), 2.1-2.4 (m, 2H), 1.9-2.1 (m, 3H),

1.4-1.7 (m, 3H), 0.88 (s, 18H), 0.05 (s, 6H), 0.03 (s, 3H), 0.02

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 199.0, 155.7, 133.7, 84.7,

76.3, 66.1, 54.5, 54.0, 53.8, 53.6, 32.9, 29.9, 29.0, 28.2, 26.1

2064 J . Org. Chem., Vol. 65, No. 7, 2000

Zanardi et al.

(3C), 26.0 (3C), 18.2, 18.1, -4.5, -4.6, -5.3, -5.4; HRMS (CI,

CH₄) m/z 545.2632 (MH, 545.2611 calcd for C₂₆H₄₉O₄S₂Si₂).

77: an oil; CD (CH₃OH, 1.1 × 10^-4M) [θ]₂₂₀+3520 deg cm²

obtained as an oil: ¹H NMR (300 MHz, CDCl₃) δ 4.36 (m, 1H),

3.5-3.9 (m, 7H), 2.1-2.7 (m, 4H), 1.5-2.1 (m, 8H), 0.87 (s,

9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.01

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 82.0, 76.0, 66.1,

54.5, 54.3, 54.2, 53.4, 37.1, 34.5, 31.9, 31.7, 28.6, 28.3, 26.0

(3C), 25.9 (3C), 18.2, 18.1, -4.3, -4.6, -5.0, -5.3; MS (CI, CH₄)

m/ z 547 [M + H]⁺. Anal. Calcd for C₂₆H₅₀O₄S₂Si₂: C, 57.09;

H, 9.21. Found: C, 57.00; H, 9.17.

Sa tu r a ted Su lfu r Un it 81. The reaction was carried out

according to general procedure B, by starting with 77 (150 mg,

0.27 mmol). After flash chromatographic purification (hexanes/

EtOAc 75:25), pure lactone 81 (105 mg, 70%) was obtained as

an oil: ¹H NMR (300 MHz, CDCl₃) δ 4.04 (td, J ) 6.7, 1.8 Hz,

1H), 3.64 (m, 2H), 3.49 (m, 3H), 3.36 (m, 2H), 2.2-2.4 (m, 2H),

1.9-2.1 (m, 2H), 1.4-1.9 (m, 8H), 0.87 (s, 9H), 0.86 (s, 9H),

0.05 (s, 6H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 178.0, 81.0, 75.4, 67.0, 54.4, 54.3, 54.1, 53.6, 37.3,

34.0, 32.7, 31.9, 29.2, 28.4, 25.9 (3C), 25.8 (3C), 18.3, 18.1, -4.2,

-4.5, -5.1, -5.2; MS (CI, CH₄) m/ z 547 [M + H]⁺. Anal. Calcd

for C₂₆H₅₀O₄S₂Si₂: C, 57.09; H, 9.21. Found: C, 57.18; H, 9.18.

dmol^{-1 1}H NMR (300 MHz, CDCl₃) δ 7.49 (dd, J ) 5.5, 1.5

;

Hz, 1H), 6.12 (dd, J ) 5.6, 2.1 Hz, 1H), 4.81 (dt, J ) 9.6, 2.0

Hz, 1H), 3.4-3.8 (m, 7H), 2.1-2.4 (m, 2H), 1.95-2.10 (m, 3H),

1.6-1.9 (m, 3H), 0.90 (s, 18H), 0.08 (s, 6H), 0.05 (s, 6H); ¹³C

NMR (75 MHz, CDCl₃) δ 199.1, 157.6, 132.9, 85.1, 76.0, 66.5,

54.7, 53.8, 53.7, 53.4, 32.7, 29.8, 29.2, 28.4, 25.9 (3C), 25.8 (3C),

18.3, 18.1, -4.2, -4.5, -5.1, -5.2; HRMS (CI, CH₄) m/z

545.2587 (MH, 545.2611 calcd for C₂₆H₄₉O₄S₂Si₂).

Sa tu r a ted Su lfu r Un it 78. The reaction was carried out

according to general procedure B, by starting with 74 (50 mg,

0.09 mmol). After flash chromatographic purification (hexanes/

EtOAc 75:25), pure lactone 78 (34 mg, 68%) was obtained as

an oil: ¹H NMR (300 MHz, CDCl₃) δ 4.28 (m, 1H), 3.6-3.9

(m, 7H), 2.2-2.8 (m, 4H), 1.6-2.2 (m, 8H), 0.86 (s, 9H), 0.84

(s, 9H), 0.05 (s, 6H), 0.02 (s, 6H); ¹³C NMR (75 MHz, CDCl₃)

δ 177.6, 81.5, 75.9, 66.0, 54.3, 54.2 (2C), 54.1, 37.0, 34.1, 31.0,

29.7, 28.5, 28.2, 26.0 (6C), 18.2, 18.0, -4.5 (2C), -5.0, -5.2;

MS (CI, CH₄) m/ z 547 [M + H]⁺. Anal. Calcd for C₂₆H₅₀O₄S₂-

Si₂: C, 57.09; H, 9.21. Found: C, 56.94; H, 9.33.

Ackn owledgm en t. We thank the Ministero dell’Uni-

versita` e della Ricerca Scientifica e Tecnologica, Italy

(COFIN 1998-1999), for financial support of this work.

Thanks are due to the Centro Interdipartimentale di

Misure G. Casnati, Universita` di Parma, for instrumen-

tal facilities. We are indebted to Prof. Marco Mor and

Dr. Silvia Rivara, Dipartimento Farmaceutico, Univer-

sita` di Parma, for molecular mechanics calculations on

model compounds deBoc-14ec and deBoc-14et.

Sa tu r a ted Su lfu r Un it 79. The reaction was carried out

according to general procedure B, by starting with 75 (80 mg,

0.15 mmol). After flash chromatographic purification (hexanes/

EtOAc 75:25), pure lactone 79 (58 mg, 72%) was obtained as

an oil: ¹H NMR (300 MHz, CDCl₃) δ 4.11 (td, J ) 7.0, 2.1 Hz,

1H), 3.61 (m, 2H), 3.3-3.5 (m, 5H), 2.1-2.5 (m, 2H), 1.9-2.1

(m, 2H), 1.5-2.0 (m, 8H), 0.87 (s, 9H), 0.85 (s, 9H), 0.05 (s,

3H), 0.03 (s, 6H), 0.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ

177.6, 81.5, 76.0, 66.3, 54.6, 53.9, 53.6, 52.9, 37.9, 34.1, 32.5,

32.2, 30.1, 28.6, 26.2 (3C), 26.0 (3C), 18.2, 18.1, -4.1, -4.6 (2C),

-5.0; MS (CI, CH₄) m/ z 547 [M + H]⁺. Anal. Calcd for

Su p p or tin g In for m a tion Ava ila ble: General experimen-

tal details and materials, as well as complete experimental

procedures and characterization data for compounds 1-22.

This material is available free of charge via the Internet at

http://pubs.acs.org.

C

₂₆H₅₀O₄S₂Si₂: C, 57.09; H, 9.21. Found: C, 57.13; H, 9.15.

Sa tu r a ted Su lfu r Un it 80. The reaction was carried out

according to general procedure B, by starting with 76 (100

mg, 0.18 mmol). After flash chromatographic purification

(hexanes/EtOAc 75:25), pure lactone 80 (65 mg, 65%) was

J O991568X

Article Doi

The Utility of Furan-, Pyrrole-, and Thiophene-Based 2-Silyloxy Dienes as Demonstrated by Modular Synthesis of Annonaceous Acetogenin Core Units and Their Pyrrolidine and Thiolane Analogues

DOI: 10.1021/jo991568x

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