Studies on the synthesis of the quartromicins: Partial stereochemical assignment of quartromicins A3 and D3 and diastereoselective synthesis of the endo- and exo-spirotetronate subunits

Tetrahedron 58 (2002) 6433–6454

Studies on the synthesis of the quartromicins: partial

stereochemical assignment of quartromicins A₃and D₃

and diastereoselective synthesis of the endo- and

exo-spirotetronate subunits^q

*

William R. Roush, David A. Barda, Chris Limberakis and Roxanne K. Kunz

Department of Chemistry, University of Michigan, 930 North University, Ann Arbor, MI 48109-1055, USA

Received 16 April 2002; accepted 13 May 2002

Abstract—A partial stereochemical assignment of quartromicins A₃and D₃is presented, along with diastereoselective syntheses of the

endo- and exo-spirotetronates 1 and 2, corresponding to the galacto and agalacto fragments of the proposed quartromicin stereostructure.

The key steps of these syntheses are highly enantio- and diastereoselective Lewis acid catalyzed Diels–Alder reactions of 1,1,3,4-

1. Introduction

member of the quartromicin family was isolated by

scientists at Eli Lilly, and was reported to inhibit

phospholipase A₂(PLA₂).⁴PLA₂is a human enzyme that

catalyzes the hydrolysis of membrane phospholipids in the

synthesis of eicosanoids, an important step in the inﬂam-

matory response associated with arthritis, psoriasis, asthma,

and atherosclerosis.^5,6However, structural information

about the Eli Lilly isolate has not been reported.

The quartromicins^1–3are a structurally unique group of

spirotetronate natural products ﬁrst isolated from

actinomycetes species in 1991. The quartromicins possess

a novel 32-membered carbocyclic structure consisting of

four spirotetronic acid units connected by enone linkers in a

head-to-tail fashion. Quartromicins A₁, A₃, D₁and D₃are

C₂symmetric and contain two distinct spirotetronate

subunits.¹Two of the subunits contain a-galactopyranosyl

residues connected to the C(26) and C(26⁰)-hydroxymethyl

groups; we refer to these as the ‘galacto fragments’. The

remaining members of this class, quartromicins A₂and D₂,

differ from the C₂symmetric members in that the two

agalacto subunits (the subunits lacking galactopyranosyl

units) have different oxidation states for the C(8) and C(8⁰)

carbons. Reduction of quartromicins A₁and A₂, or D₁and

D₂, with NaBH₄provide quartromicins A₃and D₃,

respectively, thereby conﬁrming that all members of this

family have the same carbon skeleton.

The quartromicins possess a range of biological properties,

including activity against several important viral targets

including herpes simplex virus (HSV) type 1,²inﬂuenza,²

and human immunodeﬁciency virus (HIV).³An additional

^qA portion of this work was performed by D. A. Barda at Indiana

University.

Keywords: quartromicin stereochemical assignment; spirotetronate

antibiotics; Diels–Alder reactions of acyclic (Z)-dienes.

*

Corresponding author. Tel.: þ1-734-647-9278; fax: þ1-734-647-9279;

e-mail: roush@umich.edu

PII: S0040-4020(02)00656-7

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1

The H NMR data for the H(29) and H(11) resonances of

quartromicin D₃are remarkably similar to data we have

previously analyzed for the endo- and exo-spirotetronates

prepared in connection with studies on the synthesis of

chlorothricolide^9,10and kijanolide,^11,12the aglycones of the

spirotetronate natural products chlorothricin¹³and

1

kijanimicin.^14,15Selected H NMR data (CDCl₃) for the

endo- and exo-spirotetronates 5¹²and 6¹¹summarized

below show that when the C(23)-Me group is equatorial

(kijanolide numbering system), J_24a,23¼10.0 Hz and

J_24b,23¼6.7 Hz. However, when the C(23)-Me group is

axial, as in the exo-spirotetronate 6, J_24a,23¼7.4 Hz and

J_24b,23¼0 Hz. The data for 5 are very similar to the coupling

constants summarized above for the H(27)–H(29) relation-

ship in the quartromicin galacto fragment 3, while the data

for 6 are very similar to those reported for the H(9)–H(11)

coupling constants in the quartromicin agalacto fragment 4.

On the basis of these data, we assigned the secondary C(22)-

Me and C(9)-Me groups of 3 and 4 as equatorial and axial,

respectively.

The quartromicins are attractive targets for total synthesis,

given their unique structures and interesting biological

properties. However, no information on the stereochemistry

of the individual spirotetronate substructures, or of their

absolute stereochemistry, had been reported prior to the

initiation of our studies on this problem. We report herein a

partial stereochemical assignment of quartromicins A₃and

D₃, along with highly diastereoselective syntheses of the

spirotetronates 1 and 2 that correspond to the galacto and

agalacto fragments of quartromicins A₃and D₃,

respectively. Preliminary accounts of these studies have

appeared.^7,8

2. Results and discussion

2.1. A partial stereochemical assignment of

quartromicins A₃and D₃

Examination of the published ¹H NMR data^1,2for

quartromicins A₃and D₃reveals that the two spirotetronate

fragments have strikingly different NMR properties. The

quaternary methyl groups C(22)-Me and C(4)-Me are in

very different chemical environments in the galacto (3) and

agalacto fragments (4), as indicated by the large differences

in chemical shifts (d 0.83 and d 1.23, respectively). Most

diagnostic, however, is the very different appearance of the

ABX patterns for the methylene groups at C(29) and C(11),

respectively. In the galacto fragment 3, both H(29a) and

H(29b) exhibit coupling constants with H(27)

(J_29a,27¼11.0 Hz, J_29b,27¼5.8 Hz), whereas in the agalacto

fragment 4 the coupling constants J_11a,9and J_11b,9are 8.6

and 0 Hz, respectively.

Additional support for the conclusion that if the quartro-

micin agalacto fragment C(9)-Me group is axial, then J_11b,9

should be very small derives from NMR data for

spirotetronates 7 and 8. Spirotetronate 7 (J_20a,19¼7.5 Hz;

J_20b,19¼0 Hz) is a fragment of the antibiotic PA-46101A,

whose structure and stereochemistry are known on the basis

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6435

of an X-ray crystal structure analysis.¹⁶The stereostructure

of spiroacetal 8 (J_11a,9¼8.6 Hz; J_11b,9¼0 Hz) was also

assigned by X-ray methods.¹⁷

conﬁguration of the C(12) and C(30) spirotetronate centers

being opposite in the two structures.

Insight into the stereochemistry of the C(22)-Me and C(4)-

Me groups of the quartromicin galacto (3) and agalacto

fragment (4) derives from their strikingly different chemical

shifts (d 0.83 and d 1.23, respectively). The fact that the

quaternary methyl group in the PA-46101A spirotetronate 7

(d 1.24) is virtually identical to that in 4 led us to assign

C(9)-Me as axial in the agalacto fragment 4. The

considerable upﬁeld chemical shift of the C(22)-Me in the

galacto fragment 3 compared to C(9)-Me in 4 suggested that

this methyl group is equatorial in 3, and that the striking

difference in chemical shift may be attributed to anisotropic

shielding of C(22)-Me by the tetronic acid fragment in 3.

This analysis is consistent with the difference in chemical

shift of H(20) in the endo- and exo-spirotetronates 5 (d 3.17,

i.e. H(20)-equatorial) and 6 (d 3.45, i.e. H(20)-axial).

According to this analysis, we propose the stereostructures

of quartromicins A₃and D₃to be as depicted below. These

structures serve as the targets of the synthetic studies

described in the following sections of this paper.

Based on these data, we have concluded that the two methyl

groups are trans in both the galacto and agalacto fragments

3 and 4. The quartromicin spirotetronates therefore must

differ in the stereochemistry of the spirotetronate center.

1

Given the striking similarities of the H NMR data for the

agalacto fragment 4 and the PA-46101A spirotetronate 7,

we have assigned the stereochemistry of the C(12)

spirotetronate stereocenter to be as shown in the three-

dimensional structure presented for 4, in which C(12)-O is

axial and trans to the C(4)-Me and cis to the secondary

C(9)-Me group. By process of elimination, the stereo-

chemistry of the galacto spirotetronate C(30)-stereocenter

(see fragment 3) must have the C(30)-oxygen atom in an

axial position, cis to C(22)-Me and trans to the secondary

C(27)-Me group.

Although we have not assigned the absolute stereochemistry

of the two spirotetronate sub-structures, consideration of

possible biosynthetic sequences enables us to make a

tentative assignment of the relative stereochemistry

between the quartromicin fragments 3 and 4. It is attractive

to speculate that both spirotetronate units may be derived

from a common biosynthetic intermediate such as 9, in

which the stereochemistry of the C(9) or C(27)-methyl

groups has already been set in earlier biosynthetic

intermediates. It is conceivable that presumed intermediate

9 might undergo a Prins-type cyclization, such that

spirotetronates 10 (corresponding to the galacto fragment

3) and 12 (corresponding to the agalacto fragment 4) would

then be produced with identical absolute stereochemistry at

the carbons bearing the two methyl groups (C(22) and C(27)

in 10, and C(6) and C(9) in 12), and with the absolute

2.2. Synthesis and NMR analysis of all four

diastereomers of the quartromicin spirotetronate

subunits

In an attempt to verify our stereochemical assignment of the

quartromicin A₃and D₃galacto and agalacto spirotetronate

subunits, we developed syntheses of all four stereoisomers

of the core spirotetronate substructure.^17,18We initially

targeted spirotetronates 1 and 2 since these compounds

possess the stereochemistry that we assigned to the

quartromicin galacto and agalacto fragments, but we also

wished to gain access to spirotetronates 13 and 14 for

comparative spectroscopic analysis.

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three cycloadducts provided samples of spirotetronates 2,

ent-1, and ent-14.^17,21

The fact that spirotetronate 2, corresponding to the agalacto

fragment of the quartromicins, was ﬁrst prepared from the

exo-Diels–Alder adduct 8 prompts us to refer to 2 as an

‘exo’ spirotetronate. Similarly, 1 (corresponding to the

galacto fragment of the quartromicins) is referred to as an

‘endo’ spirotetronate, in view of the fact that it was ﬁrst

synthesized from the endo-Diels–Alder adduct 17. By

analogy, 14 is an ‘iso-endo’ spirotetronate. This nomen-

clature is also consistent with our subsequent ﬁnding that 1

and 2 may be synthesized from products of (formal) endo-

or exo-Diels–Alder reactions of an a-acetoxy acrylate

dienophile and a 1,1,3,4-tetrasubstituted diene.^8,22

While sufﬁcient quantities of ent-1, 2, and ent-14 were

prepared for spectroscopic analysis, it was clear that this

synthesis was too inefﬁcient for ultimate application to a

quartromicin total synthesis. Accordingly, a second gener-

ation synthesis was developed in which the stereochemistry

of the two methyl centers in the spirotetronate subunits is

controlled in early intermediates.¹⁸The Ireland enolate

Claisen rearrangement^23,24of 19 set the quaternary methyl

stereochemistry in 20. However, the subsequent enolate

hydroxylation was poorly selective. Elaboration of 22a via

an ozonolysis-intramolecular aldol sequence provided 23,

which was then elaborated to the fourth spirotetronate

diastereomer, the ‘iso-exo’ isomer 13. In fact, all four

spirotetronate diastereomers 1, 2, 13 and 14 were prepared

by this second generation sequence.²¹

Our ﬁrst generation strategy for the synthesis of 1 and 2

utilized an intramolecular Diels–Alder reaction of triene 16,

which was generated in situ from the sulfoxide derived from

15.¹⁷We had anticipated at the outset that this reaction

would provide a mixture of exo and endo Diels–Alder

adducts 8 and 17, which would then be elaborated to ent-1

and 2, respectively. In practice, however, the IMDA

reaction of 16 provided a mixture of three products 7, 17

and 18 in 23%, 3% and 13% yields, respectively. The third

cycloadduct 18 evidently derives from the IMDA cycliza-

tion of an oleﬁn isomer of 16, as the starting material 15 was

isomerically pure at the beginning of the experiment. Oleﬁn

isomerizations have previously been observed in IMDA

reactions of (Z )-dienes.^19,20Subsequent elaboration of the

Interestingly, ¹H NMR analysis of spirotetronate dia-

stereomers 1, 2, 13, and 14 revealed that all four structures

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6437

adopt conformations with the two methyl groups in

equatorial positions! This conclusion is easily veriﬁed by

inspection of the coupling constants involving H(9) and

H(11); in all cases J_11a,9¼8.3–10.8 Hz and J_11b,9¼6.3–

6.8 Hz. The data for these compounds support our earlier

conclusion that the C(4)-Me group will be shielded by the

tetronate unit if it is in an equatorial position. Indeed, the

chemical shifts of the equatorial C(4)-Me groups in 1 and 2

are in the range d 1.05–1.07, whereas the axial C(4)-Me

group appears at d 1.19–1.27 in diastereomers 13 and 14.

The fact that the synthetic spirotetronates 1 and 2 exist in

different conformations prompted us to consider the

possibility that all four of the spirotetronate units of

the quartromicins have identical stereochemistry, such that

the natural product exists with the two galacto fragments in

a dimethyl equatorial conformation (i.e. analogous to the

conformations depicted for 1 and 3), and with the two

agalacto fragments in ‘chair-inverted’ conformations as

depicted in structure 2. However, extensive molecular

modeling studies have failed to identify a sufﬁciently stable

quartromicin stereoisomer or conformer that would satisfy

these criteria. Accordingly, we regard this possibility as

highly unlikely at this time.²⁵

2.3. Diastereoselective syntheses of spirotetronates 1 and

2 via Diels–Alder reactions of acyclic (Z,E)-1,3-diene 24

In principle, the most straightforward approach to the

synthesis of spirotetronates 1 and 2 would involve Diels–

Alder reactions of an acyclic (Z)-substituted 1,3-diene (24)

and an appropriate a-acetoxy acrylate dienophile (cf. 25). If

this reaction could be induced to provide the endo- or exo-

Diels–Alder adducts 26 or 27 with good selectivity, then the

targeted spirotetronates 1 and 2 would be easily accessible.

In addition, if the isomeric diene 28 could serve as a viable

Diels–Alder reaction substrate, then the isomeric pair of

spirotetronates 14 and 13 would be accessible from the

endo- and exo-Diels–Alder adducts 29 and 30, respectively.

However, although oxygenated and other heteroatom (Z)-

substituted 1,3-dienes readily undergo cycloaddition with a

range of conventional and hetero dienophiles,^26,27acyclic

(Z )-alkyl substituted 1,3-dienes are generally regarded as

exceptionally poor substrates for Diels–Alder reactions.^28,

These NMR data establish that the secondary C(9)-Me

group adopts an equatorial position in all four of the

synthetic spirotetronates 1, 2, 13, and 14. Clearly, none of

these compounds has NMR properties consistent with the

agalacto fragment 4, in which the secondary C(9)-Me is in

an axial position. It is not clear at present why diastereomers

2 and 14 preferentially adopt conformations in which the

spirotetronate C(13) unit is axial with respect to the

cyclohexenyl ring. We presume that conformational con-

straints imposed by the quartromicin macrocycle cause the

conformation of the agalacto fragment within the natural

product to adopt a different conformation than 2.

29

Conventional wisdom generally precludes the use of

acyclic (Z)-substituted 1,3-dienes in synthetic applications

(other than in intramolecular Diels–Alder reactions).²⁰

However, scattered reports of successful thermal^30–32and

Lewis acid catalyzed^33–40Diels–Alder reactions of acyclic

(Z )-substituted 1,3-dienes suggested to us that the prospects

of using dienes such as 24 or 28 as intermediates in organic

synthesis might not be as bleak as has been widely assumed.

This prompted us to explore the scope of the Lewis acid

catalyzed Diels–Alder reactions of acyclic (Z )-substituted

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1,3-dienes and to apply this technology to the synthesis of 1

and 2.^8,22

THF solution of the Weinreb amide 33⁴²provided enone 34

in 76% yield. A (Z )-selective Wittig oleﬁnation reaction of

34 with ethyltriphenylphosphonium bromide and potassium

bis(trimethylsilyl)amide (KHMDS) in THF afforded diene

24 in 88% yield.⁴³

Diene 24 was prepared starting from the known vinyl iodide

31.⁴¹Protection of 31 as a tert-butyldimethylsilyl (TBS)

ether provided 32 in 97% yield. Treatment of 32 with

n-butyllithium at 2788C in THF followed by addition of a

Attempts to perform Diels–Alder reactions of 24 with

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6439

acrylate dienophiles (e.g. methyl acrylate) under Lewis acid

catalysis were unsuccessful. Therefore, we did not explore

the reactions of 24 with a-acetoxy acrylate 25. However,

treatment of diene 24 with 4 equiv. of a-acetoxy acrolein

(35)³⁹and 1 equiv. of MeAlCl₂in toluene at 2788C for 1 h

provided the Diels–Alder adduct 36 in 89% yield as a 96:4

mixture of endo and exo isomers.⁴⁴Oxidation of 36 to the

carboxylic acid was performed by using Masamune’s

method.⁴⁵Esteriﬁcation of the crude carboxylic acid by

treatment with trimethylsilyldiazomethane then provided

the originally targeted a-hydroxy ester 26. Finally,

deprotection of the side chain TBS ether by treatment of

26 with PPTs in EtOH provided 37 in 43% overall yield

from 36.

tion.⁴⁷After examining a wide range of conditions, best

results were obtained when 41 was treated with acetic

anhydride and NaOAc at 1258C. However, the desired

a-acetoxy aldehyde 42 (which was identiﬁed as the minor

product of the Diels–Alder reaction of 24 and 35) was

obtained in only 31–37% yield. Numerous attempts to

improve the efﬁciency of this reaction have thus far been

unsuccessful. We suspect that the intermediate a-hydroxy-

sulfenium ion undergoes a ring expansion via a pinacol-type

process. Attempts to suppress the presumed pinacol-like

rearrangement by acylation of the a-hydroxy sulﬁde prior to

MCPBA oxidation of the sulﬁde were unsuccessful—the

a-acetoxy sulﬁde proved to be remarkably inert to the action

of MCPBA. The conversion of 39 to 42 remains a

problematic step, and efforts to ﬁnd a higher yielding and

more efﬁcient alternative sequence continue in our labora-

tory. Finally, oxidation of 42 to 27 proceeded smoothly by

using the conditions deﬁned for the conversion of 36 to 26.

The exo-a-acetoxy ester 43 was then obtained in 55%

overall yield following standard deprotection of the propyl

side chain TBS ether.

Lewis acid catalyzed Diels–Alder reactions of 24 with other

dienophiles were also examined, in an effort to deﬁne a

reaction partner that could be used in the synthesis of the

formal exo-cycloadduct 27. The MeAlCl₂-catalyzed Diels–

Alder reaction of 24 and a-bromoacrolein was also highly

selective, and provided a 96:4 mixture of endo and exo

cycloadducts 39. We anticipated that it might be possible to

invert the stereochemistry of the very hindered a-bromo-

aldehyde stereocenter, thereby gaining access to the formal

exo-Diels–Alder adduct 42, by application of a strategy

demonstrated in the chlorothricolide and kijanolide

series.^43,46Thus, reduction of 39 with NaBH₄in MeOH

gave the corresponding bromohydrin that was treated

with NaOMe in MeOH. This provided the inverted spiro-

epoxide 40 in 72% yield. Epoxide 40 is very sterically

hindered and proved to be extremely unreactive towards a

range of oxygen nucleophiles at elevated temperatures

(e.g. NaOH, tert-BuOH, reﬂux; NaOAc, DMF, 1508C;

NaHCO₃, H₂O, N-methylpyrrolidinone, 1308C; KOAc,

HOAc, DMSO, 1008C; p-MeOC₆H₄OH, NaOH, dioxane,

1008C; p-MeOC₆H₄CH₂ONa, MeOC₆H₄CH₂OH, 1008C,

24 h; etc.). However, treatment of 40 with thiophenol and

NaOH in aqueous tert-BuOH at 808C effected smooth ring

opening. Oxidation of the thiophenyl sulﬁde intermediate

with MCPBA at low temperature then provided 41 as a

mixture of sulfoxide diastereomers in good overall yield.

We anticipated that sulfoxide 41 could be converted to the

formal exo-Diels–Alder adduct 42 by a Pummerer reac-

In order to demonstrate the generality of the Lewis acid

catalyzed Diels–Alder reactions of acyclic (Z)-dienes, we

have also synthesized and studied the reactions of the

isomeric diene 28. Protection of commercially available

pentynol 44 as a TBS ether followed by acylation of the

acetylide anion with Weinreb amide 33⁴²provided the

acetylenic ketone 46 in excellent yield. Treatment of 46

with Me₂CuLi in THF at 2788C provided a ca. 1:1 mixture

of the two trisubstituted oleﬁn isomers, from which 47 was

obtained in 45% yield by preparative HPLC separation.

Finally, Wittig oleﬁnation of 47 using MeCHvPPh₃then

provided 28 in near quantitative yield. Remarkably, the

MeAlCl₂-promoted Diels–Alder reactions of 28 with both

a-acetoxy acrolein (35) and a-bromoacrolein (38) were

highly endo selective, and provided cycloadducts 48 (from

35) and 49 (from 38) with $97:3 diastereoselectivity and in

84–88% yield.⁴⁴These results demonstrate that the Lewis

acid catalyzed Diels–Alder reactions of acyclic (Z)-dienes

have considerable generality, much more so than widely

believed by the organic chemistry community. Although

cycloadducts 48 and 49 have not been elaborated to

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spirotetronates 14 and 13, we suspect that this could be

accomplished by using procedures analogous to those

described here for the conversion of the diastereomeric

Diels–Alder adducts 36 and 39 to the spirotetronates 1 and

2.

enantiomeric lactones 55 and ent-55, respectively. Thus,

DIBAL reduction of 51 provided the exo aldehyde 52.

Deprotection of the TBS ether provided a hemiacetal that

was oxidized to give lactone (2)-55 by using PCC on silica

gel. Deprotection of the TBS ether of 54 and treatment of

the resulting alcohol with NaH then gave ent-(þ)-55 in 42%

yield.⁵⁰This correlation establishes that the two exo-Diels–

Alder adducts 51 and 54 are heterochirally related. In both

cases, the assigned stereostructures are consistent with the

well-established diastereofacial selectivity preferences of

N-acryloyl sultam and N-acryloyl oxazolidinone dieno-

philes.^49,51The exo-stereochemistry of 51, 52, and 55 was

veriﬁed by ¹H NOE studies.

Elaboration of the racemic hydroxy esters 37 and 43 to the

quartromicin endo and exo spirotetronates 1 and 2 has been

accomplished, as described subsequently. However, use of

spirotetronates 1 and 2 (or their immediate precursors) in an

eventual total synthesis of quartromicin D₃requires that

they be prepared as single enantiomers, in order to avoid

generation of racemic diastereomers during the late-stage

coupling sequence. Therefore, we have also explored the

reactions of diene 24 with chiral dienophiles. Best results

were obtained from MeAlCl₂-promoted Diels–Alder

reaction of 24 and N-acryloyl sultam 50⁴⁸that provided

the exo-cycloadduct 51 with 7:1 diastereoselectivity. In

contrast, the Lewis acid catalyzed Diels–Alder reaction of

24 and the N-acryloyl imide 53⁴⁹provided a 3:2 mixture of

exo and endo cycloadducts (only the structure of the exo

adduct 54 is shown). Stereochemical assignments in these

cases are based on the conversion of 51 and 54 to the

The reactions of 24 with the chiral dienophiles 50 and 53 are

the ﬁrst examples of enantioselective Diels–Alder reactions

of an acyclic (Z )-diene, and constitutes a signiﬁcant

expansion of the scope of Lewis acid mediated Diels–

Alder reactions of acyclic (Z )-dienes.²²Unfortunately,

attempts to perform Diels–Alder reactions of 24 with

chiral dienophiles (e.g. 50a⁵²and 53a) possessing a-sub-

stituents on the dienophilic double bond were not success-

ful. It is known that methacryloylsultams adopt ground state

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6441

conformations with the methyacrylate carbonyl substan-

tially out of plane of the dienophilic double bond.⁵³It is also

known that methacryloyl imides are only moderately

selective Diels–Alder dienophiles, with the a-methyl

group destabilizing the ground state s-cis conformation.^49,54

Consequently, we elected to use cycloadduct 51 or the

derived aldehyde 52 in syntheses of the key quartromicin

intermediates 37 and 43.

as substrates. Thus, oxidation of endo hydroxy ester 37 by

using the standard Swern protocol⁵⁹gave an aldehyde that

was oxidized to the a,b-unsaturated aldehyde via the

enamine, by using Williams’ procedure.⁶⁰Reduction of enal

60 by using lithium tri-tert-butoxyaluminum hydride

provided the corresponding allylic alcohol, that was

protected as a TBS ether to give 61 in high yield. Finally,

treatment of 61 with lithium hexamethyldisilazide

(LHDMS) in THF at 2788C with warming to 08C effected

Dieckmann closure. Addition of MOM-Cl to this reaction

mixture then provided the MOM protected endo spiro-

tetronate 1 in 80% overall yield. The exo spirotetronate 2

was prepared from the exo hydroxy ester 43 by using an

analogous reaction sequence.

Disappointingly, all attempts to hydroxylate enolates

generated from 51 or the derived methyl ester have not

succeeded. However, treatment of aldehyde 52 with TMS-

OTf and Et₃N in CH₂Cl₂at 238C provided the enol silane 56

as a 3:1 isomeric mixture (62% yield from the Diels–Alder

adduct 51). Treatment of enol silane 56 with bromo-

dimethylsulfonium bromide⁵⁵gave a 5:1 mixture of the

endo bromide 39 and its easily separated exo diastereomer

in 82% yield. Alternatively, exposure of enol silane 56 to a

solution of dimethyldioxirane in acetone provided the endo-

alcohol 57 in 78% yield with 10:1 diastereoselectivity.⁵⁶

Oxidation of the a-hydroxy aldehyde to the a-hydroxy ester

was best accomplished by using I₂, and KOH in MeOH.⁵⁷

The primary TBS ether was also cleaved under these

conditions, and a-hydroxy methyl ester 58 was obtained in

84% yield. All other oxidants examined for this reaction

failed to provide either the a-hydroxy acid or a-hydroxy

ester. Acylation of 58 by using Sc(OTf)₃in Ac₂O gave the

diacetate 59 in good yield.⁵⁸Finally, selective DIBAL

reduction of the unhindered primary acetate unit of 59 then

provided hydroxy ester 37 in 72% yield from 58.

3. Summary and future prospects

We have made a partial stereochemical assignment of

quartromicins A₃and D₃by analysis of published ¹H NMR

data of the natural product, and comparison with NMR data

for a series of known spirotetronate systems. We have also

developed highly stereoselective syntheses of the endo and

exo spirotetronates 1 and 2, that correspond to the galacto

and agalacto fragments of the natural product, by routes

involving highly diastereoselective Lewis acid catalyzed

Diels–Alder reactions of acyclic (Z )-diene 24. Syntheses of

1 and 2 are also potentially enantioselective, by virtue of the

exo-selective Diels–Alder reaction of 24 and acryloyl

sultam 50, and the elaboration of the major cycloadduct

51 to precursors of both 1 and 2. This work substantially

extends the scope of the Diels–Alder reaction in organic

synthesis.

Nevertheless, it is readily apparent that the elaboration of

the endo a-bromoaldehyde 39 to the exo a-acetoxy ester 27

constitutes a substantial bottle neck in our efforts to scale up

the synthesis of the exo-spirotetronate 2. Reasoning that if

an appropriate acyl anion equivalent were to add to the exo

face of ketone 63—from the same face as electrophilic

oxidants add to the silyl enol ether 56—then a much shorter

route to the exo a-hydroxy ester intermediate 27 might

become viable. Towards this end, we have recently

demonstrated that treatment of ketone 63 with

With highly diastereo- and enantioselective routes to 37 and

43 in hand, all that remained to complete syntheses of the

quartromicin endo and exo spirotetronate units was to

introduce the side chain double bond and to close the

spirotetronate units by Dieckmann cyclizations. This

chemistry has been developed by using racemic 37 and 43

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W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

H₂CvCHMgBr and CeCl₃in THF provided 64 with an exo-

vinyl substituent with excellent selectivity;⁶¹the stereo-

chemistry of 64 was conﬁrmed by ¹H NOE studies.

Similarly, treatment of 63 with 2-furyllithium and CeCl₃

provided the exo furyl alcohol 65 in excellent yield and with

5:1 diastereoselectivity. Efforts to oxidize 64 or 65 to useful

synthetic intermediates en route to 27 or 2 are in progress.⁶²

C(22) and C(14) of the quartromicin galacto and agalacto

fragments, respectively, as demonstrated by the synthesis of

the model 2-acyl spirotetronate 68 summarized below.

Second, we have demonstrated that the enone unit linking

C(32) of the galacto fragment with C(4⁰) of the agalacto

quadrant can be introduced by using a 2-lithiotetronate

intermediate.^63,64Thus, treatment of exo series enal 62

(racemic) with the anion generated by metallation of endo

spirotetronate 69 (also racemic; prepared by the Dieckmann

cyclization of 61 followed by treatment of the isolated

tetronic acid with CH₂N₂)⁶⁵provided the 1,2-addition

product 70 as a mixture of diastereomers in 59–66%

Preliminary studies on the coupling of the spirotetronates,

en route to completion of total syntheses of quartromicins

A₃and D₃also have been performed. First, we have

demonstrated that an aldol sequence may be a viable

strategy for introducing the (E,E )-dienone unit spanning

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6443

yield. Oxidation of this mixture with activated MnO₂then

provided enone 71 as a 1:1 mixture of racemic dia-

stereomers in excellent yield.

over 5 min via cannula. The reaction was allowed to warm

to 238C over 1.5 h. The reaction mixture was recooled to

2788C and quenched with 1N HCl (40 mL). The mixture

was poured into a mixture of 1N HCl (100 mL) and 1:1

hexanes–ether (500 mL). The aqueous layer was separated

and extracted with ether (100 mL). The combined organic

extracts were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated to dryness. The residue was

puriﬁed by ﬂash chromatography (25:1 hexanes–ether) to

give 3.80 g (76% yield) of 34 as a clear oil. R_f(10:1

hexanes–EtOAc)¼0.40; ¹H NMR (CDCl₃, 400 MHz) d

7.71–7.65 (m, 4H), 7.48–7.36 (m, 6H), 6.38 (d, J¼1.3 Hz,

1H), 4.21 (s, 2H), 3.62 (t, J¼6.4 Hz, 2H), 2.23 (m, 2H), 2.19

(d, J¼1.0 Hz, 3H), 1.73–1.65 (m, 2H), 1.11 (s, 9H), 0.90 (s,

9H), 0.05 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d 198.9,

160.9, 135.5, 132.9, 129.8, 127.8, 118.7, 70.2, 62.3, 37.8,

30.6, 26.8, 25.9, 19.9, 19.2, 18.3, 25.3; IR (neat) 3072,

3049, 2954, 2931, 2892, 2857, 1705, 1689, 1617, 1472,

1428, 1390, 1362, 1255, 1109, 1007, 941, 836 cm²¹; HRMS

(CI, NH₃) for C₂₆H₃₇O₃Si₂[M2C₄H₉]^þcalcd 453.2281,

found 453.2264 m/z. Anal. calcd for C₃₀H₄₆O₃Si₂: C, 70.53;

H, 9.08. Found: C, 70.30; H, 8.80.

This strategy should provide a convenient means to

synthesize advanced galacto-agalacto ‘dimers’ for use in

completion of a quartromicin total synthesis, once sufﬁcient

quantities of single enantiomer intermediates are in hand.

Additional progress towards this goal will be reported in due

course.

4. Experimental⁶⁶

4.1. General

4.1.1. (E )-5-[(tert-Butyldimethylsilyl)oxy]-1-iodo-2-

methyl-1-pentene (32). To a 2788C solution of (E)-1-

iodo-2-methyl-penten-5-ol (31) (8.89 g, 39.3 mmol) and

2,6-lutidine (6.87 mL, 59.0 mmol) in CH₂Cl₂(60 mL) was

added TBS-OTf (9.48 mL, 41.3 mmol) dropwise. The

reaction mixture was allowed to stir for 1.5 h, then

additional TBS-OTf (0.451 mL, 1.97 mmol) was added

and the mixture was stirred for another 0.5 h. The mixture

was poured into saturated NaHCO₃solution and extracted

with 1:1 hexanes–ether (300 mL). The organic layer was

washed with 1N HCl and brine, dried over MgSO₄, ﬁltered,

and concentrated to dryness. The residue was puriﬁed by

ﬂash chromatography (50:1 hexanes–ether) to give 12.9 g

(97% yield) of 32 as a clear oil. ¹H NMR (CDCl₃, 400 MHz)

d 5.88 (d, J¼4.0 Hz, 1H), 3.58 (t, J¼6.2 Hz, 2H), 2.30–2.23

(m, 2H), 1.83 (s, 3H), 1.68–1.60 (m, 2H), 0.89 (s, 9H), 0.04

(s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d 147.7, 74.7, 62.1,

35.8, 30.8, 25.9, 23.9, 18.3; IR (neat) 3057, 2953, 2931,

2891, 2857, 1618, 1470, 1387, 1361, 1255, 1186, 1142,

1104, 1106, 955, 836 cm²¹; HRMS (CI, NH₃) for C₈H₁₆OISi

[M2C₄H₉]^þcalcd 283.0017, found 283.0026 m/z.

4.1.3. (2Z,4E )-8-[(tert-Butyldimethylsilyl)oxy]-3-[[(tert-

butyldiphenylsilyl)-oxy]-methyl]-5-methyl-2,4-octadiene

(24). To a 2788C suspension of Ph₃PEt^þBr²(2.06 g,

5.54 mmol) in THF (15 mL) was added a 0.5 M solution of

potassium hexamethyldisilylazide (KHMDS) in toluene

(10.7 mL, 5.33 mmol). The reaction was allowed to warm

to 08C and stir for 30 min. The dark orange reaction solution

was recooled to 2788C and a solution of enone 34 (1.09 g,

2.13 mmol) in THF (6 mL) was added dropwise via

cannula. The reaction mixture was allowed to warm to

08C and stir for 2 h. The dark mixture was recooled to

2788C and was poured into a mixture of 1N HCl (30 mL)

and 1:1 hexanes–ether (100 mL). The aqueous layer was

separated and extracted with ether. The combined organic

extracts were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated to dryness. The residue was

puriﬁed by ﬂash chromatography (50:1 hexanes–ether) to

give 0.98 g (88% yield) of 24 as a clear oil. ¹H NMR

(CDCl₃, 400 MHz) d 7.72–7.67 (m, 4H), 7.45–7.35 (m,

6H), 5.79 (d, J¼1.0 Hz, 1H), 5.36 (br q, J¼6.7 Hz, 1H), 4.24

(s, 2H), 3.64 (t, J¼6.5 Hz, 2H), 2.11 (m, 2H), 1.77 (d,

J¼1.3 Hz, 3H), 1.73–1.65 (m, 2H), 1.52 (br d, J¼7.0 Hz,

3H), 1.04 (s, 9H), 0.92 (s, 9H), 0.07 (s, 6H); ¹³C NMR

4.1.2. (E)-1-[(tert-Butyldimethylsilyl)oxy]-7-[(tert-butyl-

diphenylsilyl)oxy]-4-methyl-3-hepten-2-one (34). To a

2788C solution of vinyl iodide 32 (3.31 g, 9.74 mmol) in

THF (85 mL) was added a 2.5 M solution of n-BuLi in

hexanes (4.09 mL, 10.2 mmol) over 3 min. The reaction

was stirred at 2788C for 5 min then a solution of Weinreb’s

amide 33 (3.83 g, 10.7 mmol) in THF (15 mL) was added

6444

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

(CDCl₃, 100 MHz) d 136.8, 136.8, 135.7, 134.0, 129.5,

127.5, 125.7, 124.6, 63.0, 61.8, 36.6, 31.3, 26.8, 26.8, 26.0,

19.3, 18.4, 17.8, 13.3, 25.2; IR (neat) 3071, 3048, 2953,

2931, 2892, 2857, 1959, 1891, 1822, 1651, 1589, 1471,

(2.28 mL of a 2.0 M solution in hexanes, 4.56 mmol). The

reaction mixture was then warmed to 238C and stirred for

30 min. The solution was then cooled to 08C, and saturated

aqueous NaHCO₃(6.5 mL) was added cautiously. The

mixture was then partitioned between EtOAc (100 mL) and

saturated aqueous NaCl (30 mL), and the layers were

separated. The aqueous layer was extracted with EtOAc

(3£50 mL). The combined organic layers were dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by ﬂash chromatography (10:1

hexanes–EtOAc) to deliver 443 mg (58%) of a-acetoxy

1428, 1388, 1361, 1254, 1189, 1109, 1006, 954, 835 cm²¹

;

HRMS (CI, NH₃) for C₃₂H₅₀O₂Si₂[M]^þcalcd 522.3349,

found 522.3360 m/z.

4.1.4. (1S,2S,5S )-1-Acetoxy-2-[[(tert-butyldimethylsilyl)-

oxy]-propyl]-4-[[(tert-butyldiphenylsilyl)oxy]-methyl]-

2,5-dimethyl-3-cyclohexene-1-carboxaldehyde (36). To a

2788C solution of diene 24 (588 mg, 1.13 mmol) and

a-acetoxy acrolein (321 mg, 2.82 mmol) in toluene (10 mL)

was added MeAlCl₂(1.36 mL of a 1.0 M solution in

hexanes, 1.36 mmol) dropwise. The reaction mixture was

stirred at 2788C for 90 min, then quenched by the cautious

addition of saturated NaHCO₃solution (4 mL). The mixture

was diluted with ether (50 mL) and saturated NaCl solution

(10 mL). The layers were separated, then the aqueous layer

was extracted with ether (3£30 mL). The combined organic

extracts were dried over MgSO₄, ﬁltered, and concentrated

in vacuo. ¹H NMR analysis of the crude product indicated a

96:4 mixture of endo–exo cycloadducts. Puriﬁcation of the

crude product by ﬂash chromatography (10:1–5:1

hexanes–ether) gave 638 mg (89%) of 36. An analytical

sample of the major cycloadduct was obtained by hplc (7%

1

methyl ester 26. H NMR (CDCl₃, 400 MHz) d 7.76–7.69

(m, 4H), 7.47–7.36 (m, 6H), 5.28 (d, J¼1.1 Hz, 1H), 4.30

(A of AB, J¼12.7 Hz, 1H), 4.07 (B of AB, J¼12.9 Hz, 1H),

3.74 (s, 3H), 3.54 (t, J¼6.2 Hz, 2H), 2.69 (dd, J¼14.5,

5.5 Hz, 1H), 2.23 (m, 1H), 2.04 (s, 3H), 1.95 (dd, J¼14.5,

11.7 Hz, 1H), 1.56–1.40 (m, 3H), 1.21 (s, 3H), 1.10 (m,

1H), 1.07 (d, J¼7.7 Hz, 3H), 1.06 (s, 9H), 0.89 (s, 9H), 0.03

(s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d 171.1, 170.2, 138.2,

135.5, 135.4, 133.9, 133.7, 129.6, 129.6, 128.0, 127.6,

127.5, 84.1, 65.7, 63.4, 51.8, 41.0, 35.7, 33.1, 27.3, 27.3,

26.7, 25.9, 20.9, 19.9, 19.3, 18.2, 18.1, 25.3; IR (neat)

3072, 3051, 2956, 2933, 2888, 2857, 1744, 1471, 1428,

1369, 1257, 1199, 1109, 1066, 940, 836 cm²¹; HRMS (CI,

NH₃) for C₃₄H₄₉O₆Si₂[M2C₄H₉]^þcalcd 609.3067, found

609.3074 m/z.

1

EtOAc–hexanes). H NMR (CDCl₃, 400 MHz) d 9.71 (s,

1H), 7.73–7.63 (m, 4H), 7.47–7.37 (m, 6H), 5.25 (br s, 1H),

4.28 (A of AB, J¼12.8 Hz, 1H), 4.05 (B of AB, J¼12.8 Hz,

1H), 3.50 (t, J¼6.3 Hz, 2H), 2.47 (dd, J¼14.6, 6.0 Hz, 1H),

2.28 (m, 1H), 2.08 (s, 3H), 1.94 (dd, J¼14.6, 11.4 Hz, 1H),

1.52–1.36 (m, 4H), 1.21 (s, 3H), 1.06 (d, J¼7.0 Hz, 3H),

1.04 (s, 9H), 0.86 (s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 199.5, 170.7, 138.5, 135.5, 135.4, 133.8, 133.7,

129.7, 129.6, 128.1, 127.6, 127.6, 87.3, 65.7, 63.4, 40.9,

35.7, 30.6, 27.3, 27.0, 26.7, 25.9, 20.7, 20.5, 19.3, 18.3,

25.3; IR (neat) 3071, 3049, 2955, 2931, 2889, 2857, 2714,

1960, 1893, 1822, 1735, 1589, 1471, 1428, 1369, 1257,

1237, 1197, 1109, 1066, 1008, 941, 880, 836 cm²¹; HRMS

(CI, NH₃) for C₃₃H₄₇O₅Si₂[M2C₄H₉]^þcalcd 579.2962,

found 579.2965 m/z.

4.1.6. Methyl (1S,2S,5S )-1-acetoxy-4-{[(tert-butyldi-

methylsilyl)oxy]-methyl}-2,5-dimethyl-2-[3-(hydroxy)-

propyl]-cyclohex-3-enoate (37). A solution of 26 (0.115 g,

0.172 mmol) and pyridinium p-toluenesulfonate (0.147 g,

0.586 mmol) in EtOH (9.7 mL) was stirred for 15 h. The

reaction mixture was concentrated in vacuo and diluted with

Et₂O. The mixture was washed with saturated aqueous

NaHCO₃solution, 1N HCl, saturated aqueous NaHCO₃

solution, and then dried over MgSO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by silica

gel ﬂash chromatography (2:1–3:1 ether–hexanes) to give

87 mg (92%) of 37 as a clear colorless oil. ¹H NMR (CDCl₃,

400 MHz) d 7.72–7.67 (m, 4H), 7.46–7.36 (m, 6H), 5.26

(d, J¼1.3 Hz, 1H), 4.28 (A of AB, J¼12.7 Hz, 1H), 4.06 (B

of AB, J¼13.0 Hz, 1H), 3.74 (s, 3H), 3.55 (dt, J¼6.4,

1.7 Hz, 2H), 2.67 (dd, J¼14.7, 5.5 Hz, 1H), 2.20 (m, 1H),

2.03 (s, 3H), 1.93 (dd, J¼14.6, 11.6 Hz, 1H), 1.58–1.39 (m,

3H), 1.20 (s, 3H), 1.12 (m, 1H), 1.04 (d, J¼6.7 Hz, 3H), 1.04

(s, 9H); ¹³C NMR (CDCl₃, 100 MHz) d 171.4, 170.2, 138.4,

135.5, 135.4, 133.8, 129.6, 127.7, 127.6, 127.5, 83.9, 65.6,

63.3, 51.9, 40.9, 35.6, 33.1, 27.3, 26.7, 20.9, 20.0, 19.3, 18.1;

IR (neat) 3390 br, 3072, 3053, 3018, 2956, 2931, 2860, 1742,

1460, 1429, 1369, 1264, 1238, 1198, 1154, 1109, 1089, 1062,

1030, 986, 876, 825 cm²¹; HRMS (CI, NH₃) for C₂₈H₃₅O₆Si

[M2C₄H₉]^þcalcd 495.2203, found 495.2188 m/z.

4.1.5. Methyl (1S,2S,5S )-1-acetoxy-2-{3-[(tert-butyldi-

methylsilyl)oxy]-propyl}-4-{[(tert-butyldiphenylsilyl)-

oxy]-methyl}-2,5-dimethyl-cyclohex-3-enoate (26). To a

solution of a-acetoxy aldehyde 36 (728 mg, 1.14 mmol) in

tert-butanol (20 mL) and acetone (6.8 mL) was added

KH₂PO₄(5.47 mL of a 1.25 M solution, 6.84 mmol). The

resulting suspension was cooled to 08C and an aqueous

solution of KMnO₄(9.1 mL of a 0.5 M solution, 4.56 mmol)

was delivered dropwise. The stirred reaction was kept at 08C

for 15 min and at rt for an additional 60 min. The purple

mixture was cooled to 08C, poured into a solution of

Na₂S₂O₃(80 mL of a 10% solution (by mass)), and diluted

with EtOAc (200 mL). The layers were separated, and the

aqueous layer was extracted with EtOAc (4£200 mL). The

combined organic layers were dried over MgSO₄, ﬁltered,

and concentrated under reduced pressure to afford a white

foam (699 mg). The crude carboxylic acid was used in the

next step without further puriﬁcation.

4.1.7. (1S,2S,5S )-1-Bromo-2-[[(tert-butyldimethylsilyl)-

oxy]-propyl]-4-[[(tert-butyldiphenylsilyl)oxy]-methyl]-

2,5-dimethyl-3-cyclohexene-1-carboxaldehyde (39). To a

2788C solution of diene 24 (2.93 g, 5.60 mmol) and

a-bromo acrolein (38) (1.51 g, 11.2 mmol) in toluene

(160 mL) was added a 1.0 M solution of MeAlCl₂in hexane

(6.16 mL, 6.16 mmol) dropwise. The reaction mixture was

stirred at 2788C for 90 min, then quenched by the cautious

addition of saturated NaHCO₃(45 mL). The mixture was

diluted with ether (250 mL) and saturated NaCl solution

To a 08C solution of the crude carboxylic acid (,699 mg) in

THF (7.8 mL) and MeOH (3.9 mL) was added TMSCHN₂

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6445

(90 mL). The layers were separated, then the aqueous layer

was extracted with ether (3£200 mL). The combined

organic extracts were dried over anhydrous MgSO₄, ﬁltered,

and concentrated in vacuo. Puriﬁcation of the crude product

by ﬂash chromatography (30:1 hexanes–ether) gave 3.35 g

(91%) of 39 (endo and exo isomers, 96:4) as a clear colorless

oil. An analytical sample of the major cycloadduct 39 was

aqueous layer was extracted with ether (3£35 mL). The

combined organic layers were washed with saturated NaCl

(20 mL), dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The resulting oil was puriﬁed by

ﬂash chromatography (10:1 hexanes–ether) to deliver

403 mg (79%) of epoxide 40. ¹H NMR (CDCl₃,

500 MHz) d 7.70–7.66 (m, 4H) 7.44–7.35 (m, 6H), 5.45

(d, J¼1.0 Hz, 1H), 4.21 (A of AB, J¼12.9 Hz, 1H), 4.11 (B

of AB, J¼12.9 Hz, 1H), 3.58–3.50 (m, 2H), 2.74 (d,

J¼4.4 Hz, 1H), 2.44–2.40 (m, 1H), 2.40 (d, J¼4.4 Hz, 1H),

1.75 (dd, J¼13.2, 5.6 Hz, 1H), 1.61–1.49 (m, 3H), 1.43–

1.26 (m, 2H), 1.06 (s, 9H), 1.05 (d, J¼7.3 Hz, 3H), 0.89 (s,

3H), 0.87 (s, 9H), 0.03 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 139.3, 135.5, 135.5, 133.8, 133.7, 129.6,

129.6, 127.6, 127.6, 127.6, 65.8, 63.9, 61.8, 49.2, 37.0, 36.8,

34.0, 30.7, 28.2, 26.8, 26.0, 24.1, 19.5, 19.3, 19.3, 18.3,

25.2, 25.3; IR (ﬁlm) 3070, 3049, 2956, 2930, 2894, 2857,

1721, 1472, 1463, 1428, 1390, 1362, 1255, 1112, 1057,

1005, 938, 835, 776, 740, 702, 613 cm²¹; HRMS (70 eV)

for C₃₅H₅₄O₃Si₂calcd 578.3612, found 578.3595 m/z.

1

obtained by hplc (5% EtOAc–hexanes). H NMR (CDCl₃,

400 MHz) d 9.68 (s, 1H), 7.74–7.68 (m, 4H), 7.47–7.35 (m,

6H), 5.32 (d, J¼1.6 Hz, 1H), 4.24 (A of AB, J¼13.3 Hz,

1H), 4.13 (B of AB, J¼13.3 Hz, 1H), 3.51 (t, J¼6.0 Hz,

2H), 2.73–2.62 (m, 1H), 2.25 (dd, J¼15.2, 6.0 Hz, 1H),

1.99 (dd, J¼14.9, 10.5 Hz, 1H), 1.58–1.44 (m, 3H), 1.38

(s, 3H), 1.36–1.26 (m, 1H), 1.08 (d, J¼7.0 Hz, 3H), 1.06

(s, 9H), 0.87 (s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 191.7, 138.8, 135.6, 135.4, 133.7, 133.7, 129.6,

127.7, 127.6, 127.1, 79.5, 65.3, 63.1, 40.5, 36.9, 35.9, 29.3,

28.5, 26.7, 25.9, 24.9, 19.3, 18.4, 18.2, 25.3; IR (neat)

3070, 3048, 2955, 2931, 2885, 2856, 2728, 1958, 1893,

1827, 1721, 1589, 1471, 1428, 1388, 1362, 1304, 1255,

1186, 1110, 1064, 1006, 938, 835 cm²¹; HRMS (CI, NH₃)

for C₃₁H₄₄BrO₃Si₂[M2C₄H₉]^þcalcd 601.1992, found

601.1988 m/z.

4.1.9. (1R,2S,5S )-4-{[(tert-Butyldiphenylsilyl)oxy]-

methyl}-2,5-dimethyl-1-(phenylsulﬁnyl)-methyl-3-cyclo-

hexenol (41). To a solution of epoxide 40 (952 mg,

1.64 mmol) and thiophenol (505 mL, 4.92 mmol) in tert-

butyl alcohol (9.52 mL) was added an aqueous solution of

NaOH (9.52 mL, 4.76 mmol). This mixture was then heated

at 808C for 16 h. The mixture was then cooled to 08C and

saturated NH₄Cl (17 mL) and Et₂O (90 mL) were added.

The layers were separated, then the aqueous layer was

extracted with ether (2£90 mL). The combined organic

layers were dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The resulting oil was puriﬁed by

ﬂash chromatography (20:1–10:1 hexanes–ether) to deliver

4.1.8. (1R,2S,3S)-2-{3-[(tert-butyldimethylsilyl)oxy]-pro-

pyl}-4-{[tert-butyl-diphenylsilyl)-oxy]-methyl}-2,5-

dimethyl-1-oxaspiro[2.5]oct-5-ene (40). To a 08C solution

of a-bromo aldehyde 39 (1.32 g, 2.01 mmol) in MeOH

(30 mL) was added NaBH₄(76 mg, 2.01 mmol) in one

portion. The reaction mixture was allowed to warm to 238C

over 25 min. The mixture was diluted with ether (250 mL)

and the resulting solution was cooled to 08C, and then

poured into a cold solution of 1N HCl (20 mL). The layers

were separated, and the aqueous layer was extracted with

ether (3£40 mL). The combined organic layers were

washed with a saturated NaCl solution (30 mL), dried

over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was puriﬁed by ﬂash chromatography (5:1

hexanes–ether) to afford 1.20 g (91%) of bromo alcohol.

¹H NMR (CDCl₃, 400 MHz) d 7.75–7.70 (m, 4H), 7.46–

7.36 (m, 6H), 5.32 (d, J¼1.6 Hz, 1H), 4.24 (A of AB,

J¼13.0 Hz, 1H), 4.13 (B of AB, J¼13.4 Hz, 1H), 4.03 (A of

AB, J¼12.4 Hz, 1H), 3.62 (B of AB, J¼12.4 Hz, 1H), 3.56

(dt, J¼2.2, 6.0 Hz, 2H), 2.66 (m, 1H), 2.42 (dd, J¼14.6,

6.0 Hz, 1H), 2.05 (br s, 1H), 1.65 (dd, J¼14.6, 9.8 Hz, 1H),

1.56 (m, 2H), 1.45 (m, 2H), 1.34 (s, 3H), 1.06 (s, 9H), 1.05

(d, J¼5.1 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR

(CDCl₃, 100 MHz) d 137.9, 135.6, 135.5, 133.9, 133.8,

129.5, 128.8, 127.6, 127.6, 88.3, 68.0, 65.5, 63.5, 42.3, 39.2,

36.3, 29.9, 28.5, 26.7, 25.9, 25.2, 19.3, 18.5, 18.2, 25.3; IR

(neat) 3562, 3463, 3070, 3049, 2955, 2931, 2892, 2857,

1470, 1428, 1388, 1362, 1254, 1107, 1059, 1006, 940,

1

948 mg (84%) of sulﬁde. H NMR (CDCl₃, 500 MHz) d

7.66–7.64 (m, 4H), 7.43–7.34 (m, 7H), 7.27–7.24 (m, 3H),

7.20–7.17 (m, 1H), 5.30 (s, 1H), 4.16 (A of AB, J¼12.9 Hz,

1H), 4.07 (B of AB, J¼12.9 Hz, 1H), 3.58–3.55 (m, 2H),

3.18–3.10 (m, 2H), 2.22 (m, 1H), 2.13 (s, 1H), 1.94 (dd,

J¼13.4, 6.3 Hz, 1H), 1.8–1.2 (m, 5H), 1.05 (s, 9H), 0.98 (s,

3H), 0.95 (d, J¼6.8 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); ¹³C

NMR (CDCl₃, 100 MHz) d 138.2, 137.2, 135.5, 135.5,

133.8, 133.8, 130.1, 129.8, 129.6, 129.6, 128.9, 127.6, 127.6,

126.3, 75.3, 65.5, 64.1, 43.1, 41.6, 39.1, 35.2, 30.2, 28.0,

26.8, 26.0, 19.7, 19.3, 18.9, 18.3, 25.2; IR (neat) 3524, 3072,

3051, 3017, 2930, 2956, 2885, 2857, 1957, 1887, 1822,

1774, 1718, 1655, 1584, 1472, 1462, 1428, 1361, 1255,

1112, 1057, 836, 776, 739, 702 cm²¹; HRMS (FAB, MþNa)

for C₄₁H₆₀O₃NaSi₂S calcd 711.3699, found 711.3735 m/z.

To a 2788C solution of sulﬁde (930 mg, 1.35 mmol) in

CH₂Cl₂(15 mL) was added a solution of ,57% m-CPBA

(409 mg, 1.35 mmol) in CH₂Cl₂(3 mL). The resulting white

suspension was stirred at 2788C for 25 min. Saturated

Na₂S₂O₃(12 mL) was added cautiously, and the mixture

was allowed to warm to rt. Et₂O (70 mL) was then added

and the layers were separated. The aqueous layer was

extracted with Et₂O (3£70 mL). The combined organic

layers were washed with saturated NaHCO₃(40 mL) and

saturated NaCl (40 ml), dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The crude product

was then puriﬁed by ﬂash chromatography (2:1–1:1

836 cm²¹

;

HRMS (FAB, Na) for C₃₅H₅₄O₃Si₂Na

[M2HBrþNa]^þcalcd 601.3509, found 601.3478 m/z.

A 08C solution of bromo alcohol prepared above (582 mg,

0.882 mmol) in MeOH (15 mL) was treated with NaOMe

(1.76 mL of a 1.0 M solution in MeOH, 1.76 mmol)

dropwise. The reaction mixture was allowed to warm to

238C for 2 h. The solution was then concentrated under

reduced pressure to afford a residue. The resulting residue

was cooled to 08C; ether (120 mL) and water (20 mL) were

added sequentially. The layers were separated, and the

1

hexanes–ether) to give 854 mg (90%) of sulfoxide 41. H

6446

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

NMR (CDCl₃, 500 MHz) d 7.62–7.59 (m, 4H), 7.54–7.45

(m, 5H), 7.40–7.34 (m, 2H), 7.31–7.26 (m, 4H), 5.17 (s,

1H), 4.27 (A of AB, J¼12.5 Hz, 1H), 4.04 (B of AB,

J¼12.5 Hz, 1H), 3.58–3.51 (m, 2H), 2.96 (dd, J¼13.2,

1.7 Hz, 1H), 2.67 (d, J¼13.2 Hz, 1H), 2.54 (m, 1H), 2.45

(dd, J¼14.2, 6.1 Hz, 1H), 2.05 (pseudo t, J¼13.4 Hz, 1H),

1.59–1.41 (m, 4H), 1.14 (d, J¼6.8 Hz, 4H), 1.06 (s, 9H),

0.87 (s, 9H), 0.84 (s, 3H), 0.02 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 143.6, 137.6, 135.5, 135.4, 133.8, 133.6, 131.4,

130.6, 129.7, 129.6, 129.5, 127.6, 123.9, 75.8, 65.8, 64.0,

62.5, 42.2, 38.9, 33.8, 30.2, 28.0, 26.9, 26.0, 19.4, 19.3,

19.0, 18.3, 25.2; IR (ﬁlm) 3424, 3071, 3049, 2956, 2930,

2857, 1956, 1889, 1827, 1589, 1472, 1463, 1444, 1428,

1389, 1361, 1255, 1106, 1093, 1056, 1007, 835, 776, 741,

702, 690, 614 cm²¹; HRMS (CI, CH₄) for C₄₁H₆₁O₄Si₂S

calcd 705.3829, found 705.3813 m/z.

dried over MgSO₄, ﬁltered, and concentrated under reduced

pressure to afford a white foam (370 mg). The crude

carboxylic acid was used in the next step without further

puriﬁcation.

To a 08C solution of the crude carboxylic acid (,370 mg) in

THF (4.1 mL) and MeOH (2.1 mL) was added TMSCHN₂

(1.17 mL of a 2.0 M solution in hexanes, 2.34 mmol). The

reaction mixture was then warmed to 238C and stirred for

30 min. The solution was then cooled to 08C, and saturated

aqueous NaHCO₃(3.2 mL) was added cautiously. EtOAc

(50 mL) was added, and the layers were separated. The

aqueous layer was extracted with EtOAc (3£25 mL). The

combined organic layers were dried over MgSO₄, ﬁltered,

and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (20:1–10:1 hexanes–

EtOAc) to deliver 241 mg of a mixture (5:1) of the

a-acetoxy methyl ester and a-acetoxy aldehyde. Further

puriﬁcation by HPLC (9% EtOAc–91% hexanes) afforded

36 mg (10% recovery) of 42 and 203 mg (52, 58% based on

4.1.10. (1R,2S,5S )-1-Acetoxy-2-{3-[(tert-butyldimethyl-

silyl)oxy]-propyl}-4-{[(tert-butyl-diphenylsilyl)-oxy}-

methyl]-2,5-dimethyl-cyclohex-3-enal (42).

A stirred

1

mixture of sulfoxide 41 (832 mg, 1.18 mmol) and NaOAc

(484 mg, 5.90 mmol) in acetic anhydride (12.5 ml) was

heated to 1258C over 45 min. The reaction mixture was then

stirred at 1258C for 17 h. After cooling the resulting brown

mixture to 238C, toluene (100 mL) was added and the

mixture was concentrated under reduced pressure. This

procedure was repeated with an additional portion of

toluene (100 mL). Ether (80 mL) and saturated NaHCO₃

(25 mL) were added to the brown residue. The layers were

separated, and the aqueous layer was extracted with ether

(3£80 mL). The combined extracts were dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The

resulting brown oil was puriﬁed via ﬂash chromatography

(15:1–10:1 hexanes–ether) to deliver 231 mg (31%) of

recovered aldehyde) of methyl ester 27. H NMR (CDCl₃,

500 MHz) d 7.70–7.66 (m, 4H), 7.44–7.35 (m, 6H), 5.48 (s,

1H), 4.19 (A of AB, J¼13.2, 1.2 Hz, 1H), 4.12 (B of AB,

J¼13.2, 1.2 Hz, 1H), 3.70 (s, 3H), 3.61–3.57 (m, 2H),

2.52–2.47 (m, 2H), 2.34 (m, 1H), 2.02 (s, 3H), 1.73–1.44

(m, 4H), 1.06 (s, 9H), 0.96 (d, J¼7.1 Hz, 3H), 0.89 (s, 9H),

0.89 (s, 3H), 0.05 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d

171.3, 170.4, 138.0, 135.5, 135.5, 133.7, 133.7, 129.6,

129.6, 127.6, 127.6, 127.6, 125.4, 84.6, 65.8, 64.0, 51.8,

40.2, 31.6, 31.3, 27.8, 27.8, 26.8, 25.9, 23.6, 21.6, 19.5,

19.3, 18.3, 25.3; IR (ﬁlm) 3072, 3050, 2955, 2932, 2889,

2858, 1745, 1590, 1472, 1463, 1429, 1368, 1250, 1112, 836,

776, 703, 611 cm²¹; HRMS (FAB, MþNa) for C₃₈H₅₈O_6-

NaSi₂calcd 689.3670, found 689.3655 m/z.

1

aldehyde 42. H NMR (CDCl₃, 500 MHz) d 9.59 (s, 1H),

7.68–7.65 (m, 4H), 7.44–7.36 (m, 6H), 5.42 (s, 1H), 4.18

(A of AB, J¼13.4, 0.7 Hz, 1H), 4.12 (B of AB, J¼13.4,

0.7 Hz, 1H), 3.67–3.58 (m, 2H), 2.66–2.59 (m, 2H), 2.09

(s, 3H), 1.92 (m, 1H), 1.66–1.51 (m, 4H), 1.06 (s, 9H), 0.98

(d, J¼6.8 Hz, 3H), 0.96 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H);

¹³C (CDCl₃, 100 MHz) d 199.0, 170.6, 138.7, 135.5, 135.5,

133.7, 133.6, 129.7, 129.6, 127.7, 127.6, 126.3, 87.5, 65.5,

63.7, 40.4, 34.4, 30.9, 28.4, 27.4, 26.8, 25.9, 21.9, 21.3,

19.9, 19.3, 18.3, 25.2, 25.3; IR (ﬁlm) 3072, 3050, 2965,

2931, 2891, 2857, 2737, 1736, 1590, 1472, 1463, 1368,

1247, 1106, 836, 702 cm²¹; HRMS (FAB, MþNa) for

C₃₇H₅₆O₅NaSi₂calcd 659.3564, found 659.3583 m/z.

4.1.12. Methyl (1R,2S,3S )-1-acetoxy-4-{[(tert-butyl-

diphenylsilyl)oxy]-methyl}-2,5-dimethyl-2-[3-(hydroxy)-

propyl]-cyclohex-3-enoate (43). A solution of silyl ether

27 (154 mg, 0.231 mmol) and pyridinium p-tolueneulfonate

(PPTS) (232 mg, 0.924 mmol) in 95% EtOH (12.5 mL) was

stirred at 238C for 18 h. The solution was concentrated

under reduced pressure to afford a white residue. Ether

(25 mL) was added and the resulting suspension was

ﬁltered. The excess PPTS was then washed with additional

portions of ether (2£25 mL). The combined ﬁltrates were

washed with saturated NaHCO₃(10 mL), HCl (10 mL of a

1 M solution), saturated NaHCO₃(10 mL), and saturated

NaCl (10 mL), dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The resulting clear oil was puriﬁed

via ﬂash chromatography (2:1–1:1 hexanes–EtOAc) to

afford 120 mg (94%) of 43. ¹H NMR (CDCl₃, 500 MHz) d

7.69–7.66 (m, 4H), 7.44–7.36 (m, 6H), 5.47 (s, 1H), 4.19

(A of AB, J¼13.2 Hz, 1H), 4.13 (B of AB, J¼13.2 Hz, 1H),

3.71 (s, 3H), 3.61 (pseudo t, J¼6.3 Hz, 2H), 2.50–2.46 (m,

2H), 2.35 (dd, J¼18.1, 5.4 Hz, 1H), 2.02 (s, 3H), 1.77–1.54

(m, 5H), 1.06 (s, 9H), 0.94 (d, J¼7.1 Hz, 3H), 0.90 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) d 171.3, 170.4, 138.3, 135.5,

135.5, 133.7, 133.7, 129.6, 129.6, 127.6, 127.6, 125.1, 84.5,

65.6, 63.8, 51.9, 40.2, 31.5, 31.2, 28.0, 27.7, 26.8, 23.7,

21.6, 19.5, 19.3; IR (ﬁlm) 3459, 3070, 3049, 2956, 2932,

2857, 1742, 1462, 1428, 1369, 1244, 1112, 1066, 823, 740,

703 cm²¹; HRMS (FAB, MþNa) for C₃₂H₄₄O₆NaSi calcd

575.2805, found 575.2808 m/z.

4.1.11. Methyl (1R,2S,3S )-1-acetoxy-2-{3-[(tert-butyl-

dimethylsilyl)oxy]-propyl}-4-{[(tert-butyldiphenylsilyl)-

oxy]-methyl}-2,5-dimethyl-cyclohex-3-enoate (27). To a

solution of a-acetoxy aldehyde 42 (372 mg, 0.548 mmol) in

tert-butanol (10.2 mL) and acetone (3.48 mL) was added

KH₂PO₄(2.80 mL of a 1.25 M solution, 3.50 mmol). The

resulting suspension was cooled to 08C and an aqueous

solution of potassium permanganate (4 mL of a 0.5 M

solution, 2.00 mmol) was delivered dropwise. The stirred

reaction was kept at 08C for 15 min and at 238C for an

additional 60 min. The purple mixture was cooled to 08C,

poured into a solution of Na₂S₂O₃(40 mL of a 10% solution

(by mass)), and diluted with EtOAc (100 mL). The layers

were separated, and the aqueous layer was extracted with

EtOAc (4£100 mL). The combined organic layers were

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6447

4.1.13. 5-[(tert-Butyldimethylsilyl)oxy]-1-pentyne (45).

To 2788C solution of 1-pentyn-5-ol (1.86 mL,

combined extracts were dried over MgSO₄, ﬁltered, and

concentrated to dryness. The residue was puriﬁed by column

chromatography (50:1–20:1 hexanes–ether) to partially

separate the double bond isomers. The mixed fractions were

combined and puriﬁed by hplc. The conditions of the hplc

separation were 4% EtOAc in hexanes elution at 15 mL/min

on a Dynamax 60-A 8 mm silica gel 21.4 mm ID£25 cm L

preparative column. The retention time for 47¼10.54 min

and the retention time for 34¼13.12 min. The combined

fractions containing the less polar compound gave 1.80 g

(45% yield) of 47 as a clear oil. A comparable amount of the

more polar enone isomer 34 containing 5% of 47 was also

obtained. Data for (Z)-enone 47: R_f(10:1 hexanes–

a

20.0 mmol) and 2,6-lutidine (3.49 mL, 30.0 mmol) in

CH₂Cl₂(80 mL) was added TBS-OTf (5.05 mL,

22.0 mmol) dropwise. The reaction was stirred for 1.5 h

before it was poured into saturated NaHCO₃solution and

diluted with ether. The layers were separated and the

organic layer was washed with 1N HCl, brine and dried over

MgSO₄. The mixture was ﬁltered and concentrated to

dryness to give 3.75 g (95% yield) of 45 as a clear oil. This

material was used directly in the next step without further

puriﬁcation. ¹H NMR (CDCl₃, 400 MHz) d 3.69 (t,

J¼6.0 Hz, 2H), 2.27 (dt, J¼2.6, 7.1 Hz, 2H), 1.93 (t,

J¼2.6 Hz, 1H), 1.72 (tt, J¼7.0, 6.0 Hz, 2H), 0.89 (s, 9H),

0.06 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d 84.3, 68.2, 61.5,

31.5, 25.9, 18.3, 14.9, 25.3; IR (neat) 3314, 2955, 2932,

2897, 2858, 2120, 1472, 1434, 1388, 1361, 1255, 1107, 1072,

980, 942, 835 cm²¹; HRMS (CI, NH₃) for C₇H₁₃OSi

[M2C₄H₉]^þcalcd 141.0736, found 141.0733 m/z.

1

EtOAc)¼0.43; H NMR (CDCl₃, 400 MHz) d 7.69–7.63

(m, 4H), 7.46–7.35 (m, 6H), 6.32 (s, 1H), 4.18 (s, 2H), 3.65

(t, J¼6.7 Hz, 2H), 2.63 (m, 2H), 1.91 (d, J¼1.0 Hz, 3H),

1.67 (m, 2H), 1.10 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C

NMR (CDCl₃, 100 MHz) d 198.1, 161.6, 135.5, 133.0,

129.8, 127.8, 119.5, 70.2, 63.1, 31.3, 30.6, 26.8, 26.0, 25.9,

19.3, 18.3, 25.3; IR (neat) 3072, 3049, 2955, 2932, 2891,

2857, 1960, 1893, 1820, 1707, 1687, 1616, 1472, 1429,

1389, 1362, 1255, 1156, 1111, 1001, 939, 836 cm²¹; HRMS

(CI, NH₃) for C₂₆H₃₇O₃Si₂[M2C₄H₉]^þcalcd 453.2281,

found 453.2292 m/z. Anal. calcd for C₃₀H₄₆O₃Si₂: C, 70.53;

H, 9.08. Found: C, 70.04; H, 8.96.

4.1.14. 7-[(tert-Butyldimethylsilyl)oxy]-1-[(tert-butyl-

diphenylsilyl)oxy]-3-heptyn-2-one (46). To a 2788C

solution of 45 (1.57 g, 7.92 mmol) in THF (25 mL) was

added a 2.5 M solution of n-BuLi in hexanes (3.33 mL,

8.32 mmol). The reaction mixture was stirred for 20 min

and then a solution of Weinreb amide 33 (3.11 g,

8.71 mmol) in THF (5 mL) was added via cannula. The

reaction was allowed to warm to 08C and stirred for 2 h. The

reaction mixture was then recooled to 2788C and treated

with 5 mL 0.5N HCl. The mixture was allowed to warm to

ambient temperature and stirred for 30 min. The mixture

was diluted with ether and a saturated solution of NaHCO₃.

The aqueous layer was separated and extracted with ether

(3£30 mL). The combined ethereal extracts were washed

with brine, dried over MgSO₄, ﬁltered and concentrated to

dryness. The residue was puriﬁed by column chromato-

graphy (20:1 hexanes–ether) to give 3.87 g (98% yield) of

46 as a clear oil. ¹H NMR (CDCl₃, 400 MHz) d 7.71–7.66

(m, 4H), 7.47–7.37 (m, 6H), 4.30 (s, 2H), 3.65 (t, J¼5.9 Hz,

2H), 2.45 (t, J¼7.2 Hz, 2H), 1.75 (tt, J¼7.0, 6.0 Hz, 2H),

1.11 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 185.9, 135.5, 132.7, 129.9, 127.8, 97.0, 78.9,

70.5, 61.2, 30.6, 26.6, 25.9, 19.3, 18.2, 15.6, 25.4; IR (neat)

3072, 3049, 2955, 2932, 2891, 2858, 2210, 1698, 1676,

1589, 1472, 1428, 1390, 1362, 1322, 1255, 1187, 1136,

1111, 1071, 1006, 973, 944, 835 cm²¹; HRMS (CI, NH₃)

for C₂₅H₃₃O₃Si₂[M2C₄H₉]^þcalcd 437.1968, found

437.1963 m/z. Anal. calcd for C₂₉H₄₂O₃Si₂: C, 70.39; H,

8.56. Found: C, 70.18; H, 8.43.

4.1.16. (2Z,4Z )-8-[(tert-butyldimethylsilyl)oxy]-3-[[(tert-

butyldiphenylsilyl)oxy]-methyl]-5-methyl-2,4-octadiene

(28). To a 2788C suspension of ethyltriphenylphosphonium

bromide (4.13 g, 11.1 mmol) in THF (30 mL) was added a

0.5 M solution of potassium hexamethyldisilylazide

(KHMDS) in toluene (21.4 mL, 10.7 mmol). The reaction

was allowed to warm to 08C and stirred for 30 min. The

resulting dark orange reaction mixture was recooled to

2788C and a solution of enone 47 (2.19 g, 4.28 mmol) in

THF (15 mL) was added dropwise via cannula. The reaction

was allowed to warm to 08C and stirred for 2 h. The dark

mixture was recooled to 2788C and was poured into a

mixture of 1N HCl (60 mL) and 1:1 hexanes–ether

(200 mL). The aqueous layer was separated and extracted

with ether. The combined organic extracts were washed

with brine, dried over MgSO₄, ﬁltered, and concentrated to

dryness. The residue was puriﬁed by ﬂash chromatography

(50:1 hexanes–ether) to give 2.22 g (99% yield) of 28 as a

clear oil. ¹H NMR (CDCl₃, 400 MHz) d 7.73–7.68 (m, 4H),

7.46–7.38 (m, 6H), 5.79 (br s, 1H), 5.36 (br q, J¼7.0 Hz,

1H), 4.23 (s, 2H), 3.62 (t, J¼6.7 Hz, 2H), 2.25–2.19 (m,

2H), 1.79 (d, J¼1.3 Hz, 3H), 1.68–1.60 (m, 2H), 1.54 (br d,

J¼7.0 Hz, 3H), 1.05 (s, 9H), 0.91 (s, 9H), 0.06 (s, 6H); ¹³C

NMR (CDCl₃, 100 MHz) d 137.2, 136.7, 135.7, 134.0,

129.5, 127.5, 126.5, 123.8, 63.4, 62.0, 32.0, 29.2, 26.8, 26.0,

23.7, 19.3, 18.3, 13.3, 25.3; IR (neat) 3071, 3048, 2954,

2931, 2891, 2856, 1959, 1899, 1823, 1651, 1590, 1471,

1428, 1387, 1362, 1254, 1191, 1108, 1006, 941, 877,

835 cm²¹; HRMS (CI, NH₃) for C₃₂H₅₀O₂Si₂[M]^þcalcd

522.3349, found 522.3351 m/z.

4.1.15. (2Z )-1-[(tert-Butyldimethylsilyl)oxy]-7-[(tert-

butyldiphenylsilyl)oxy]-4-methyl-3-hepten-2-one (47).

To a 08C suspension of dry copper (I) iodide (3.72 g,

19.6 mmol) in THF (60 mL) was added a 1.4 M solution of

MeLi in Et₂O (16.8 mL, 23.5 mmol) dropwise. The solution

was stirred for 20 min, then was cooled to 2788C. To this

solution was added a solution of alkynyl ketone 46 (3.87 g,

7.82 mmol) in THF (20 mL) via cannula. The resulting

mixture was stirred at 2788C for 15 min. The reaction was

quenched at 2788C by addition of a saturated solution of

NH₄Cl (20 mL) and allowed to warm to 238C. The mixture

was diluted with ether and saturated NH₄Cl solution. The

aqueous layer was separated and extracted with ether. The

4.1.17. (1S,2R,5S )-1-Acetoxy-2-[[(tert-butyldimethyl-

silyl)oxy]-propyl]-4-[[(tert-butyldiphenylsilyl)oxy]-

methyl]-2,5-dimethyl-3-cyclohexene-1-carboxaldehyde

(48). The Diels–Alder reaction of diene 28 (0.052 g,

0.0994 mmol) and a-acetoxy acrolein (35) (0.027 g,

0.237 mmol) in the presence of SnCl₄(14 mL,

6448

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

0.119 mmol) was performed according to the procedure

described for the preparation of 36. Puriﬁcation of the crude

product (essentially pure 48; $98:2 by H NMR analysis)

by column chromatography (5:1 hexanes–ether) gave

0.056 g (88% yield) of 48 as a clear oil. An analytical

1

sample was obtained by hplc (7% EtOAc–hexanes). H

NMR (CDCl₃, 400 MHz) d 9.76 (s, 1H), 7.73–7.65 (m, 4H),

7.46–7.35 (m, 6H), 5.48 (br s, 1H), 4.26 (A of AB,

J¼13.0 Hz, 1H), 4.07 (B of AB, J¼13.0 Hz, 1H), 3.67–3.54

(m, 2H), 2.43 (dd, J¼14.6, 5.7 Hz, 1H), 2.23 (m, 1H), 2.10

(s, 3H), 1.92 (dd, J¼14.6, 11.4 Hz, 1H), 1.85–1.76 (m, 1H),

1.66–1.48 (m, 3H), 1.05 (s, 9H), 1.03 (d, J¼7.0 Hz, 3H),

0.94 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 199.9, 170.7, 137.8, 135.5, 135.4, 133.8, 133.7,

129.6, 127.6, 127.6, 126.9, 87.9, 65.5, 63.7, 41.1, 32.3, 31.3,

27.7, 27.2, 26.7, 25.9, 23.6, 20.8, 19.3, 18.3, 18.2, 25.3; IR

(neat) 3072, 3047, 2956, 2932, 2891, 2857, 2732, 1735,

1468, 1428, 1368, 1255, 1199, 1109, 1054, 1009, 941,

836 cm²¹; HRMS (CI, NH₃) for C₃₃H₄₇O₅Si₂[M2C₄H₉]^þ

calcd 579.2962, found 579.2989 m/z.

with saturated aqueous NaHCO₃and brine, dried over

MgSO₄, ﬁltered and concentrated. The diastereomeric

products (7:1 mixture) were separated by silica gel ﬂash

chromatography (10:1 hexanes–EtOAc) to give a combined

yield of 66% (990 mg). Data for the major cycloadduct:

[a ]²_D⁵¼261.1 (c¼2.0, CHCl₃); R_f¼0.24 (10:1 hexanes–

EtOAc); ¹H NMR (CDCl₃, 500 MHz) d 7.70–7.66 (m, 4H),

7.46–7.35 (m, 6H), 5.36 (X of ABX, J¼1.0 Hz, 1H), 4.16

(A of ABX, J¼13.2, 0.7 Hz, 1H), 4.06 (B of ABX, J¼13.9,

0.7 Hz, 1H), 3.92 (dd, J¼7.8, 4.9 Hz, 1H), 3.55–3.60 (m,

1H), 3.48 (A of AB, J¼13.7 Hz, 1H), 3.47–3.42 (m, 1H),

3.41 (A of AB, J¼13.7 Hz, 1H), 3.26 (dd, J¼11.2, 2.7 Hz,

1H), 2.36–2.30 (m, 1H), 2.08 (dd, J¼7.8, 7.9 Hz, 1H),

2.05–1.85 (m, 5H), 1.72–1.65 (m, 1H), 1.64 (app dt,

J¼13.3, 3.0 Hz, 1H), 1.46–1.29 (m, 5H), 1.19 (s, 3H), 1.05

(s, 9H), 1.03 (s, 3H), 0.99 (d, J¼7.3 Hz, 3H), 0.97 (s, 3H),

0.86 (s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃, 125 MHz) d

174.7, 138.9, 135.56, 135.52, 133.9, 133.7, 129.5, 128.9,

127.6, 127.57, 65.9, 65.4, 63.7, 53.4, 47.8, 47.7, 44.2, 38.9,

38.6, 37.9, 32.9, 30.2, 28.3, 27.4, 26.8, 25.9, 23.9, 20.9,

19.9, 19.3, 19.2, 18.3; IR (thin ﬁlm) 3071, 3049, 2958, 2930,

2890, 2857, 1697, 1471, 1462, 1428, 1390, 1361, 1333,

1261, 1235, 1202, 1131, 1111, 1066, 1051, 999, 980, 939,

836, 775, 737, 702 cm²¹; HRMS (FAB) for C₄₅H₆₉NO_5-

SSi₂[MþNa]^þcalcd 814.4333, found 814.4296 m/z.

1

4.1.18. (1S,2R,5S )-1-Bromo-2-[[(tert-butyldimethylsilyl)-

oxy]-propyl]-4-[[(tert-butyldiphenylsilyl)oxy]-methyl]-

2,5-dimethyl-3-cyclohexene-1-carboxaldehyde (49). The

reaction of diene 28 (0.051 g, 0.0975 mmol) and a-bromo

acrolein (38) (0.034 g, 0.252 mmol) in the presence of

MeAlCl₂(107 mL of

a

1.0 M hexanes solution,

0.107 mmol) was performed according to the procedure

described for the preparation of 39. Puriﬁcation of the crude

product (a 97:3 mixture of endo–exo cycloadducts accord-

ing to ¹H NMR analysis) by column chromatography (10:1

hexanes–ether) gave 0.054 g (84% yield) of 49 (endo and

exo isomers) as a clear oil. An analytical sample of the

major cycloadduct 49 was obtained by hplc (5% EtOAc–

hexanes). ¹H NMR (CDCl₃, 400 MHz) d 9.73 (s, 1H), 7.73–

7.67 (m, 4H), 7.46–7.35 (m, 6H), 5.58 (d, J¼1.3 Hz, 1H), 4.22

(A of AB, J¼13.5 Hz, 1H), 4.14 (B of AB, J¼13.5 Hz, 1H),

3.63 (m, 2H), 2.63 (m, 1H), 2.19 (dd, J¼14.9, 6.0 Hz, 1H),

2.01 (dd, J¼14.9, 10.5 Hz, 1H), 1.86–1.75 (m, 2H), 1.66–

1.53 (m, 2H), 1.06 (s, 12H), 1.05 (d, J¼7.3 Hz, 3H), 0.90 (s,

9H), 0.06 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) d 193.0,

138.1, 135.6, 135.4, 133.7, 129.6, 127.7, 127.6, 125.6, 79.7,

65.1, 63.4, 40.4, 37.0, 36.4, 29.4, 27.9, 26.8, 26.0, 23.7, 19.3,

18.4, 18.3, 25.3; IR (neat) 3070, 3046, 2956, 2932, 2893,

2857, 1722, 1471, 1428, 1388, 1362, 1254, 1191, 1112, 1078,

1058, 1006, 836 cm²¹; HRMS (CI, NH₃) for C₃₁H₄₄O₃Si₂

[M2C₄H₉]^þcalcd 599.2012, found 599.1992 m/z.

4.1.19. (1⁰S,2⁰S,5⁰S )-[2⁰-[3-(tert-butyldimethyl-silanyl-

oxy)-propyl]-4⁰-(tert-butyldiphenyl-silanyloxymethyl)-

2⁰,5⁰-dimethyl-cyclohex-3-enyl]-(10,10-dimethyl-3,3-

dioxo-3l⁶-thia-4-aza-tricyclo[5.2.1.0^0,0]dec-4yl)-metha-

none (51). To a mixture of diene 24 (993 mg, 1.90 mmol)

and N-acryloyl sultam 50 (614 mg, 2.28 mmol) in CH₂Cl₂

(10 mL) cooled to 2788C was added methylaluminum

dichloride (3.65 mL, 1.0 M hexanes solution). The resulting

yellow solution was stirred at 2788C for 1 h and then

warmed to 08C over 1 h; the reaction mixture was quenched

slowly with saturated aqueous NaHCO₃and allowed to

warm to 238C. After diluting with Et₂O (10 mL), the white

solids were dissipated with 1N HCl (3 mL) and the layers

were separated. The aqueous layer was extracted with Et₂O

(3£20 mL) and the combined organic extracts were washed

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6449

4.1.20. (1S,2S,5S )-2-[3-(tert-Butyldimethylsilanyloxy)-

propyl]-4-(tert-butyldiphenylsilanyloxymethyl)-2,5-

dimethyl-cyclohex-3-enecarbaldehyde (52). A solution of

cyclohexene 51 (265 mg, 0.334 mmol) in CH₂Cl₂(4 mL)

was cooled to 2788C and DIBAL-H (388 mL, 1.0 M

solution in CH₂Cl₂) was added dropwise. After stirring the

reaction mixture at 2788C for 1.5 h, MeOH (8 mL) and 1N

HCl (5 mL) were added. The mixture was allowed to warm

to 238C and poured into a mixture of CH₂Cl₂(10 mL) and

H₂O (8 mL); the layers were separated and the aqueous

layer was extracted with CH₂Cl₂(3£15 mL). The combined

organic extracts were washed with brine, dried over MgSO₄,

ﬁltered and concentrated. The desired aldehyde 52 was

isolated following silica gel ﬂash chromatography (5:1

hexanes–EtOAc) (145 mg, 75%) as a colorless oil along

with a small amount of the over-reduced alcohol (13 mg,

7%). Data for aldehyde 52: [a ]²_D⁵¼218.3 (c¼2.0, CHCl₃);

R_f¼0.29 (15:1 hexanes–Et₂O); ¹H NMR (CDCl₃,

500 MHz) d 9.85 (d, J¼1.0 Hz, 1H), 7.70–7.63 (m, 4H),

7.46–7.36 (m, 6H), 5.29 (X of ABX, J¼1.0 Hz, 1H), 4.14

(A of ABX, J¼13.5, 1.3 Hz, 1H), 4.07 (B of ABX, J¼13.2,

1.0 Hz, 1H), 3.6 (t, J¼6.3 Hz, 2H), 2.53 (app dt, J¼11.9,

2.6 Hz, 1H), 2.35 (m, 1H), 1.89 (ddd, J¼13.5, 12.1, 5.7 Hz,

1H), 1.68–1.56 (m, 3H), 1.50–1.42 (m, 2H), 1.06 (s, 9H),

0.99 (s, 3H), 0.95 (d, J¼7.1 Hz, 3H), 0.89 (s, 9H), 0.04 (s,

6H); ¹³C NMR (CDCl₃, 125 MHz) d 206.0, 140.0, 135.6,

135.5, 133.8, 133.6, 129.6, 127.6, 127.5, 65.9, 63.7, 49.0,

37.6, 36.8, 27.9, 27.7, 26.8, 26.7, 25.9, 25.8, 24.1, 19.2,

18.4, 25.3; IR (thin ﬁlm) 3071, 2957, 2930, 2858, 1724,

1589, 1462, 1428, 1387, 1361, 1271, 1257, 1112, 1072, 939,

835, 775, 740, 702 cm²¹; HRMS (ES) for C₃₅H₅₄O₃Si₂Na

[MþNa]^þcalcd 601.3509, found 601.3502 m/z.

(CDCl₃, 125 MHz) d 176.7, 139.2, 135.6, 135.5, 133.7,

133.6, 130.6, 129.64, 129.63, 127.62, 127.60, 68.6, 65.8,

43.0, 41.8, 34.9, 29.7, 27.9, 26.8, 25.5, 20.2, 19.33, 19.30;

IR (thin ﬁlm) 3070, 2959, 2930, 2856, 1734, 1472, 1460,

1427, 1389, 1367, 1286, 1175, 1163, 1124, 1112, 1087,

1070, 1038, 998, 938, 869, 823 cm²¹; HRMS (CI, NH₃) for

C₂₉H₃₉O₃Si [MþH]^þcalcd 463.2668, found 463.2678 m/z.

4.1.22. (1⁰R,2⁰R,4S,5⁰R )-3-[2⁰-[3-(tert-Butyldimethyl-

silanyloxy)-propyl]-4⁰-(tert-butyldiphenyl-silanyloxy-

methyl)-2⁰,5⁰-dimethyl-cyclohex-3⁰-enecarbonyl]-4-iso-

propyl-oxazolidin-2-one (54). To a solution of diene 24

(258 mg, 0.493 mmol) and N-acryloyl oxazolidinone 53

(98 mg, 0.535 mmol) in CH₂Cl₂(5 mL) cooled to 2788C

was added MeAlCl₂(1.07 mL of a 1.0 M solution in

hexanes, 1.07 mmol). The resulting yellow solution was

stirred at 2788C for 2 h and then warmed to 08C over 1 h;

the reaction mixture was quenched slowly with saturated

aqueous NaHCO₃and allowed to warm to 238C. After

diluting with Et₂O (10 mL), the white solids were dissipated

with 1N HCl (3 mL) and the layers were separated. The

aqueous layer was extracted with Et₂O (3£20 mL) and the

combined organic extracts were washed with saturated

aqueous NaHCO₃and brine, dried over MgSO₄, ﬁltered and

concentrated. The diastereomeric products (3:2 mixture,

289 mg, 83%) were inseparable by silica gel ﬂash

chromatography (4:1 hexanes–EtOAc) or HPLC puriﬁ-

cation. Data for the mixture: [a ]²_D⁵¼þ30.4 (c¼3.4, CHCl₃);

R_f¼0.25 (10:1 hexanes–EtOAc); ¹H NMR (CDCl₃,

400 MHz) d 7.71–7.67 (m, 4H), 7.44–7.35 (m, 6H), 5.48

(s, 0.7H), 5.36 (s, 1H), 4.55–4.49 (m, 1.8H), 4.32–4.05 (m,

10H), 3.60–3.46 (m, 5H), 2.38–2.03 (m, 3.8H), 1.78–1.20

(m, 15H), 1.14 (s, 3H), 1.05 (s, 9H), 1.04 (s, 6H), 0.92 (s,

15H), 0.87 (m, 10H), 0.10 (s, 6H), 0.30 (s, 4H); ¹³C NMR

(CDCl₃, 125 MHz) (combined data for the two isomers) d

175.5, 175.1, 153.9, 153.8, 138.8, 138.6, 135.6, 135.54,

135.51, 133.9, 133.8, 133.7, 130.3, 129.7, 129.6, 129.5,

128.3, 127.63, 127.60, 127.58, 66.0, 65.7, 64.0, 63.9, 62.54,

62.53, 58.5, 58.45, 46.8, 39.9, 38.3, 38.0, 37.6, 34.6, 32.3,

31.2, 30.7, 28.6, 28.5, 28.47, 27.8, 27.7, 26.8, 26.79, 26.5,

26.0, 25.98, 25.9, 23.8, 19.3, 19.26, 18.9, 18.3, 18.28, 18.2,

18.15, 14.7, 25.3, 25.34; IR (thin ﬁlm) 2957, 2930, 2857,

1781, 1697, 1462, 1428, 1384, 1361, 1299, 1255, 1201,

1104, 1057, 1025, 940, 835, 775, 740, 702 cm²¹; HRMS

(ES) for C₄₁H₆₃NO₅Si₂Na [MþNa]^þcalcd 728.4143, found

728.4153 m/z.

4.1.21. (5aR,8R,9aR )-7-(tert-Butyl-diphenyl-silanyloxy-

methyl)-5a,8-dimethyl-4,5,5a,8,9,9a-hexahydro-3H-ben-

zo[c ]oxepin-1-one (55). To a solution of aldehyde 52

(89 mg, 0.154 mmol) in absolute EtOH (2.5 mL) was added

pyridinium p-toluenesulfonate (15 mg, 0.119 mmol). The

reaction mixture was diluted with H₂O and Et₂O after

stirring for 18 h at 238C; the layers were separated and the

aqueous layer was extracted with Et₂O (3£10 mL). The

organic extracts were combined and washed with brine,

dried over MgSO₄, ﬁltered and concentrated. The crude

lactol product was dissolved in CH₂Cl₂(700 mL) and added

to a suspension of PCC (14 mg, 0.065 mmol) and silica gel

(14 mg) in CH₂Cl₂(500 mL). After stirring overnight at

238C a second portion of PCC was added (14 mg) and the

reaction mixture was stirred for an additional 3 h at 238C.

Finally, saturated aqueous NaHCO₃was added followed by

Et₂O and H₂O. The layers were separated and the aqueous

layer was extracted with Et₂O (3£10 mL); the organic

extracts were combined and washed with brine, dried over

MgSO₄, ﬁltered and concentrated. The crude product was

puriﬁed by silica gel ﬂash chromatography (6:1 hexanes–

EtOAc) to give lactone 55 as a clear oil. [a]²_D⁵¼2109.7

1

(c¼2.0, CHCl₃); R_f¼0.30 (4:1 hexanes–EtOAc); H NMR

(C₆D₆, 500 MHz) d 7.80–7.75 (m, 4H), 7.26–7.21 (m, 6H),

5.18 (br s, 1H), 4.12 (A of ABX, J¼13.5, 1.7 Hz, 1H), 4.08

(B of ABX, J¼13.2, 1.2 Hz, 1H), 3.68–3.64 (m, 1H), 3.47

(app t, J¼12.0 Hz, 1H), 2.58 (dd, J¼12.5, 3.1 Hz, 1H),

2.21–2.12 (m, 2H), 1.71 (dd, J¼12.7, 2.7 Hz, 1H), 1.60–

1.50 (m, 1H), 1.26–1.22 (m, 1H), 1.18 (s, 9H), 1.08–0.97

(m, 2H), 0.88 (s, 3H), 0.81 (d, J¼7.3 Hz, 3H); ¹³C NMR

4.1.23. (4S,1⁰R,2⁰R,5⁰R )-3-[4⁰-(tert-Butyldiphenyl-silanyl-

oxymethyl)-2⁰-(3-hydroxypropyl)-2⁰,5⁰-dimethyl-cyclo-

hex-3⁰-enecarbonyl]-4-isopropyl-oxazolidin-2-one. A solu-

tion of cyclohexene isomers 54 (125 mg, 0.177 mmol) and

pyridinium p-toluenesulfonate (36 mg, 0.143 mmol) in

absolute EtOH (2.2 mL) was stirred at 238C for 18 h. The

6450

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

mixture was poured into 5 mL of H₂O and extracted with

Et₂O. The combined organic extracts were washed with

brine, dried over MgSO₄, ﬁltered and concentrated.

Puriﬁcation of the crude product by gradient silica gel

ﬂash chromatography (2:1 hexanes–EtOAc !2:1 EtOAc–

hexanes) yielded 87 mg of the major isomer as a colorless

foam (83%). [a]²_D⁵¼þ38.8 (c¼4.5, CHCl₃); R_f¼0.57 (1:1

dimethyl-cyclohex-3-enylidenemethoxy-trimethylsilane

(56). To a solution of aldehyde 52 (669 mg, 1.16 mmol) and

Et₃N (2.15 mL, 15.4 mmol) in CH₂Cl₂(9.4 mL) was added

TMS-OTf (2 mL, 11.1 mmol). After allowing the reaction

mixture to stir at 238C for 2 h, it was cooled to 08C and

saturated aqueous Na₂S₂O₃(10 mL) was carefully added.

Following dilution with hexanes (10 mL) the layers were

separated and the aqueous layer was extracted with hexanes

(2£10 mL). The combined organic layers were washed with

brine, dried over MgSO₄, ﬁltered and concentrated.

Puriﬁcation of the crude product by silica gel ﬂash

chromatography (15:1 hexanes–EtOAc) yielded 663 mg

of 56 as a 3:1 mixture of E(O) and Z(O) enol silanes (88%).

An analytically pure sample of the major E(O) isomer was

obtained by HPLC puriﬁcation (1% EtOAc–hexanes):

[a ]²_D³¼24.6 (c¼2.7, CHCl₃); R_f¼0.26 (50:1 hexanes–

1

hexanes–EtOAc); H NMR (CDCl₃, 500 MHz) d 7.71–

7.67 (m, 4H), 7.45–7.36 (m, 6H), 5.32 (X of ABX,

J¼1.0 Hz, 1H), 4.55 (app dt, J¼3.4, 6.7 Hz, 1H), 4.33 (dd,

J¼12.0, 2.6 Hz, 1H), 4.27 (app t, J¼8.8 Hz, 1H), 4.19 (dd,

J¼9.0, 3.4 Hz, 1H), 4.16 (A of ABX, J¼13.5, 1.2 Hz, 1H),

4.08 (B of ABX, J¼13.2, 1.0 Hz, 1H), 3.62–3.52 (m, 2H),

2.38–2.30 (m, 2H), 2.10 (ddd, J¼13.1, 5.3, 4.7 Hz, 1H),

1.76–1.68 (m, 1H), 1.54–1.34 (m, 4H), 1.06 (s, 9H), 1.05

(s, 3H), 1.01 (d, J¼7.0 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H),

0.92 (d, J¼7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) d

175.3, 154.2, 139.2, 135.54, 135.50, 133.8, 133.7, 129.6,

129.4, 127.6, 127.56, 65.9, 63.3, 62.6, 58.5, 39.2, 38.3, 37.6,

31.2, 28.5, 28.3, 27.8, 26.8, 24.4, 19.3, 18.1, 14.6; IR (thin

ﬁlm) 3517, 3071, 2960, 2931, 2858, 1777, 1699, 1486,

1462, 1427, 1386, 1300, 1202, 1143, 1112, 1058, 1024, 938,

874, 822, 793, 734, 702 cm²¹; HRMS (FAB) for C₃₅H_49-

O₅NSiNa [MþNa]^þcalcd 614.3278, found 614.3267 m/z.

Data for the minor diastereomer: [a ]²_D⁵¼þ49.3 (c¼1.0,

CHCl₃); R_f¼0.37 (1:1 hexanes–EtOAc); ¹H NMR (CDCl₃,

500 MHz) d 7.70–7.67 (m, 4H), 7.44–7.37 (m, 6H), 5.48

(d, J¼1.4 Hz, 1H), 4.52 (app dt, J¼3.4, 7.0 Hz, 1H), 4.25

(app t, J¼9.0 Hz, 1H), 4.20–4.08 (m, 4H), 3.62–3.55 (m,

2H), 2.36–2.28 (m, 2H), 1.77–1.72 (m, 2H), 1.67–1.50 (m,

2H), 1.35–1.29 (m, 2H), 1.15 (s, 3H), 1.04 (s, 9H), 0.96 (d,

J¼7.1 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H), 0.92 (d, J¼7.1 Hz,

3H); ¹³C NMR (CDCl₃, 100 MHz) d 175.3, 153.8, 138.9,

135.5, 135.49, 133.8, 133.7, 129.9, 129.6, 127.63, 127.60,

65.6, 63.9, 62.6, 58.5, 46.7, 37.6, 34.6, 32.4, 30.7, 28.6,

27.9, 26.8, 26.7, 19.3, 18.9, 18.2, 14.7; IR (thin ﬁlm) 3435,

3072, 2959, 2931, 2858, 1780, 1691, 1647, 1460, 1428,

1385, 1361, 1299, 1278, 1202, 1112, 1056, 823, 822, 743,

702 cm²¹; HRMS (ES) for C₃₅H₄₉O₅NSiNa [MþNa]^þ

calcd 614.3278, found 614.3279 m/z.

1

Et₂O); H NMR (C₆D₆, 500 MHz) d 7.85–7.81 (m, 4H),

7.28–7.22 (m, 6H), 6.45 (s, 1H), 5.39 (s, 1H), 4.24 (A of

ABX, J¼12.9, 1.0 Hz, 1H), 4.14 (B of ABX, J¼13.2,

1.0 Hz, 1H), 3.62–3.58 (m, 1H), 3.56–3.51 (m, 1H), 2.67

(dd, J¼13.4, 4.4 Hz, 1H), 2.48 (ddd, J¼13.2, 5.3, 1.4 Hz,

1H), 2.38–2.31 (m, 1H), 1.83–1.70 (m, 2H), 1.57–1.42 (m,

2H), 1.20 (s, 12H), 1.01 (d, J¼5.6 Hz, 3H), 0.99 (s, 9H),

0.17 (s, 9H), 0.08 (s, 6H); ¹³C NMR (CDCl₃, 125 MHz) d

140.1, 135.6, 135.5, 134.0, 133.9, 133.3, 130.8, 129.51,

129.50, 127.6, 127.5, 123.2, 66.0, 63.8, 38.3, 36.6, 30.5,

29.7, 28.3, 27.7, 26.8, 26.0, 19.3, 19.2, 18.3, 20.4, 25.26,

25.27; IR (thin ﬁlm) 3071, 3050, 2956, 2930, 2894, 2857,

1660, 1589, 1472, 1462, 1428, 1389, 1361, 1253, 1163,

1144, 1112, 1055, 1006, 973, 953, 937, 878, 842, 775, 739,

701 cm²¹; HRMS (ES) for C₃₈H₆₂O₃Si₃Na [MþNa]^þcalcd

673.3905, found 673.3909 m/z. Anal. calcd for

C₃₈H₆₂O₃Si₃: C, 70.09; H, 9.60. Found: C, 70.07; H, 9.82.

4.1.26. (1S,2S,5S )-1-Bromo-2-[3-(tert-butyldimethyl-

silanyloxy)-propyl]-4-(tert-butyldiphenylsilanyloxy-

methyl)-2,5-dimethyl-cyclohex-3-enal (39). To a solution

of enol silane 56 (28 mg, 0.043 mmol) in carbon tetra-

chloride (600 mL) cooled to 08C was added bromodimethyl-

sulfonium bromide in one portion. The heterogeneous

mixture became clear and homogeneous after stirring for

15 min at 08C. Triethylamine (50 mL) was added carefully

and the reaction mixture was diluted with CH₂Cl₂(5 mL),

saturated aqueous NaHCO₃(3 mL), and H₂O (8 mL). The

layers were separated and the aqueous layer was extracted

with CH₂Cl₂(3£8 mL). The combined organic extracts

were washed with 1N HCl and brine, dried over MgSO₄,

ﬁltered and concentrated. The diastereomeric products (5:1

mixture) were separated by silica gel ﬂash chromatography

(15:1 hexanes–EtOAc). The major product (23 mg, 82%)

was spectroscopically identical to the data reported here for

racemic 39; [a]²_D³¼þ70.4 (c¼3.0, CHCl₃).

4.1.24. (5aR,8R,9aR )-7-(tert-Butyldiphenyl-silanyloxy-

methyl)-5a,8-dimethyl-4,5,5a,8,9,9a-hexahydro-3H-ben-

zo[c ]oxepin-1-one (ent-55). To a suspension of sodium

hydride (60% dispersion, washed with hexanes) in THF

(13.5 mg in 2 mL, 0.338 mmol) cooled to 08C was added via

cannulation a solution of the cyclohexene alcohol in THF

(140 mg in 4 mL, 0.237 mmol). The resulting mixture was

stirred at 08C for 4 h and then quenched by the addition of

1N HCl (5 mL). The reaction was diluted with EtOAc and

H₂O, the layers were separated and the aqueous layer was

extracted with EtOAc (2£12 mL). The combined organic

layers were washed with saturated aqueous NaHCO₃and

brine, dried over MgSO₄, ﬁltered and concentrated. After

silica gel ﬂash chromatography of the crude product (2:1

hexanes–EtOAc), lactone ent-55 was obtained as a clear oil

(55 mg, 50%). This material was spectroscopically identical

to 55 and differed only in the sign of optical rotation;

[a ]²_D⁵¼þ87.9 (c¼4.2, CHCl₃).

4.1.27. (1S,2S,5S )-2-[3-(tert-Butyldimethyl-silanyloxy)-

propyl]-4-(tert-butyldiphenyl-silanyloxymethyl)-1-

hydroxy-2,5-dimethyl-cyclohex-3-enecarbaldehyde (57).

To a solution of enol silane 56 (214 mg, 0.33 mmol) in

CH₂Cl₂cooled to 08C was added dimethyldioxirane

(5.8 mL of a 0.06 M solution in acetone, 0.348 mmol)

dropwise. After stirring the reaction mixture at 08C for

10 min the mixture was concentrated in vacuo and the

resulting oil was diluted with Et₂O (15 mL) and 1N HCl

(5 mL). The layers were separated and the aqueous layer

4.1.25. (1S,2S,5S )-2-[3-(tert-Butyldimethyl-silanyloxy-

propyl)]-4-(tert-butyldiphenyl-silanyloxymethyl)-2,5-

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6451

was extracted with Et₂O (3£10 mL). The combined organic

layers were washed with brine, dried over MgSO₄, ﬁltered

and concentrated to obtain a 10:1 mixture of diastereomers.

The major isomer was separated from the minor dia-

stereomer by silica gel ﬂash chromatography (12:1

hexanes–EtOAc) to give a 78% combined yield (152 mg).

Data for major diastereomer 57: [a ]²_D⁴¼þ11.7 (c¼3.7,

CHCl₃); R_f¼0.60 (6:1 hexanes–EtOAc); ¹H NMR (CDCl₃,

500 MHz) d 9.77 (d, J¼1.0 Hz, 1H), 7.71–7.68 (m, 4H),

7.45–7.37 (m, 6H), 5.46 (d, J¼1.4 Hz, 1H), 4.23 (app dt,

J¼13.2, 1.2 Hz, 1H), 4.16 (d, J¼13.7 Hz, 1H), 3.58–3.54

(m, 2H), 3.16 (d, J¼1.0 Hz, 1H), 2.60–2.52 (m, 1H), 1.83

(dd, J¼13.6, 6.6 Hz, 1H), 1.78 (dd, J¼13.7, 8.3 Hz, 1H),

1.60–1.39 (m, 4H), 1.07 (s, 9H), 1.02 (d, J¼7.4 Hz, 3H), 1.0

(s, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (CDCl₃,

125 MHz) d 205.5, 138.5, 135.55, 135.51, 133.71, 133.70,

129.63, 129.61, 127.64, 127.60, 127.4, 80.4, 65.5, 63.4,

41.5, 36.0, 35.9, 27.7, 27.2, 26.8, 25.9, 20.5, 19.3, 19.2,

18.3, 25.3; IR (thin ﬁlm) 3510, 3071, 3049, 2955, 2930,

2857, 1717, 1589, 1472, 1428, 1389, 1361, 1255, 1111,

1060, 1006, 938, 835, 776, 740, 702 cm²¹; HRMS (ES) for

C₃₅H₅₄O₄Si₂Na [MþNa]^þcalcd 617.3458, found 617.3462

m/z.

58 (25 mg, 0.049 mmol) in acetic anhydride (400 mL)

cooled to 08C was added a solution of scandium triﬂate in

CH₃CN (13 mg in 100 mL, 0.026 mmol). The reaction

mixture was immediately diluted with saturated aqueous

NaHCO₃(1 mL) and Et₂O (2 mL), and allowed to warm to

238C and stirred for 1 h until the effervescence subsided.

The mixture was further diluted with Et₂O (5 mL) and H₂O

(5 mL), the layers were separated and the aqueous layer was

extracted with Et₂O (3£5 mL). The combined organic

layers were washed with brine, dried over MgSO₄, ﬁltered

and concentrated. The crude product was puriﬁed by silica

gel ﬂash chromatography (4:1 hexanes–EtOAc) to obtain

59 as a slightly yellow oil (25 mg, 76%). [a ]²_D⁴¼þ22.3

1

(c¼1.6, CHCl₃); R_f¼0.63 (3:1 hexanes–EtOAc); H NMR

(CDCl₃, 500 MHz) d 7.71–7.68 (m, 4H), 7.45–7.37 (m,

6H), 5.24 (br s, 1H), 4.29 (A of AB, J¼12.7 Hz, 1H), 4.06

(B of AB, J¼12.9 Hz, 1H), 3.98 (t, J¼6.9 Hz, 2H), 3.75 (s,

3H), 2.68 (dd, J¼14.7, 5.4 Hz, 1H), 2.25–2.17 (m, 1H),

2.04 (s, 3H), 2.03 (s, 3H), 1.91 (dd, J¼14.7, 12.7 Hz, 1H),

1.64–1.57 (m, 2H), 1.46–1.39 (m, 1H), 1.20 (s, 3H), 1.12–

1.07 (m, 1H), 1.06 (d, J¼6.1 Hz, 3H), 1.05 (s, 9H); ¹³C

NMR (CDCl₃, 125 MHz) d 171.4, 171.3, 170.4, 139.0,

135.8, 135.7, 134.1, 134.0, 129.92, 129.90, 127.9, 127.8,

127.7, 84.0, 65.9, 52.2, 41.2, 35.9, 33.4, 27.5, 26.9, 23.7,

21.2, 20.3, 19.5, 18.4; IR (thin ﬁlm) 3071, 3048, 2956, 2932,

2857, 1742, 1589, 1471, 1458, 1428, 1368, 1238, 1200,

1111, 1063, 879, 824, 743, 704 cm²¹; HRMS (ES) for

C₃₄H₄₆O₇SiNa [MþNa]^þcalcd 617.2911, found 617.2908

m/z.

4.1.28. (1S,2S,5S )-4-(tert-Butyldiphenylsilanyloxy-

methyl)-1-hydroxy-2-(3-hydroxy-propyl)-2,5-dimethyl-

cyclohex-3-enecarboxylic acid methyl ester (58). A

solution of aldehyde 57 (43 mg, 0.072 mmol) in MeOH

(720 mL) was cooled to 08C and methanolic solutions of

KOH (720 mL of a 0.78 M solution, 0.562 mmol) and I₂

(360 mL of a 0.78 M solution, 0.281 mmol) were added

successively. The resulting dark brown mixture was stirred

at 08C for 45 min, after which time a second portion of KOH

(60 mL, 0.047 mmol) and I₂(24 mL, 0.019 mmol) solutions

were again added successively. The starting material was

completely consumed 15 min after the second addition of

potassium hydroxide and iodine (total reaction time¼1 h).

The reaction mixture was diluted with 2N H₂SO₄(5 mL)

and Et₂O (8 mL) and stirred at 238C for 30 min. The layers

were separated and the aqueous layer was extracted with

Et₂O (3£10 mL). The combined organic layers were

washed with saturated aqueous Na₂S₂O₃and brine, dried

over MgSO₄, ﬁltered and concentrated. Following silica gel

ﬂash chromatography (10:1 hexanes–EtOAc), a colorless

oil was obtained (31 mg, 84%). [a ]²_D⁴¼þ73.4 (c¼1.9,

4.1.30. Methyl (1S,2S,5S )-1-acetoxy-4-(tert-butyldi-

phenylsilanyloxymethyl)-2,5-dimethyl-cyclohex-3-eno-

ate (37). A solution of diacetate 59 (22 mg, 0.037 mmol) in

THF (185 mL) was cooled to 2788C and DIBAL-H (185 mL

of a 1.0 M solution in THF, 0.185 mmol) was added slowly

down the side of the ﬂask. The resulting mixture was stirred

at 2788C for 30 min and then warmed to 2458C over

20 min; pH 7 buffer was then added (3 mL) and Et₂O

(5 mL). This mixture was allowed to warm to 238C, diluted

with saturated aqueous Rochelle’s salt (10 mL) and stirred

overnight for 18 h. The layers were separated, the aqueous

layer was extracted with Et₂O (3£5 mL) and the combined

organic extracts were dried over MgSO₄, ﬁltered and

concentrated. Following puriﬁcation by silica gel ﬂash

chromatography (2:1 hexanes–EtOAc) a clear oil was

isolated (19 mg, 95%) which was spectroscopically

identical to the data reported here for racemic 37;

[a ]²_D⁵¼þ79.4 (c¼0.6, CHCl₃).

1

CHCl₃); R_f¼0.33 (1:1 hexanes–EtOAc); H NMR (C₆D₆,

500 MHz) d 7.88–7.83 (m, 4H), 7.28–7.23 (m, 6H), 5.40

(d, J¼1.7 Hz, 1H), 4.32 (app dt, J¼13.1, 1.3 Hz, 1H), 4.20

(d, J¼13.4 Hz, 1H), 3.28 (s, 3H), 3.27–3.24 (m, 2H), 3.09

(s, 1H), 2.74–2.66 (m, 1H), 2.06 (dd, J¼13.2, 13.7 Hz, 1H),

1.94 (dd, J¼13.7, 5.9 Hz, 1H), 1.58–1.44 (m, 2H), 1.38–

1.30 (m, 2H), 1.02 (s, 9H), 1.12 (s, 3H), 0.92 (d, J¼7.1 Hz,

3H), 0.58 (s, 1H); ¹³C NMR (CDCl₃, 125 MHz) d 175.6,

138.5, 135.6, 135.5, 133.82, 133.81, 129.59, 129.58, 127.62,

127.57, 126.8, 78.2, 65.4, 63.6, 52.2, 41.5, 36.9, 36.7, 28.0,

27.2, 26.8, 19.7, 19.3, 18.5; IR (thin ﬁlm) 3436, 3071, 2954,

2857, 1723, 1589, 1472, 1456, 1428, 1389, 1259, 1151, 1111,

1058, 869, 823, 741, 702 cm²¹; HRMS (ES) for C₃₀H₄₂O_5-

SiNa [MþNa]^þcalcd 533.2699, found 533.2694 m/z.

4.1.31. Methyl (1S,2S,5S )-1-acetoxy-4-{[(tert-butyl-

diphenylsilyl)oxy]-methyl}-2,5-dimethyl-2-[(E )-3-(for-

myl)-vinyl]-cyclohex-3-enoate (60). To a 2788C solution

of DMSO (47 mL, 0.66 mmol) in CH₂Cl₂(0.5 mL) was

added oxalyl chloride (29 mL, 0.33 mmol) dropwise. The

reaction mixture was stirred for 20 min, then 37 (91 mg,

0.165 mmol) was added in CH₂Cl₂(1.15 mL) via cannula.

The reaction was allowed to warm to 08C and stirred for 1 h.

The reaction mixture was diluted with Et₂O and washed

with saturated aqueous NaHCO₃, 1 M NaHSO₄(2£), and

saturated aqueous NaHCO₃. The ethereal layer was dried

over MgSO₄, ﬁltered and concentrated in vacuo. The

residue was puriﬁed by silica gel ﬂash chromatography

(2:1 hexanes–ether) to give 82 mg (91%) of aldehyde as a

4.1.29. Methyl (1S,2S,5S )-1-acetoxy-2-(3-acetoxy-pro-

pyl)-4-(tert-butyl-diphenylsilanyloxymethyl)-2,5-

dimethyl-cyclohex-3-enecarboxyate (59). To a solution of

6452

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

clear colorless oil. ¹H NMR (CDCl₃, 400 MHz) d 9.69 (br s,

1H), 7.71–7.66 (m, 4H), 7.46–7.34 (m, 6H), 5.19 (br s, 1H),

4.26 (A of AB, J¼13.0 Hz, 1H), 4.08 (B of AB, J¼13.1 Hz,

1H), 3.76 (s, 3H), 2.70 (dd, J¼14.8, 5.4 Hz, 1H), 2.41 (m,

2H), 2.19 (m, 1H), 2.03 (s, 3H), 1.94 (dd, J¼14.8, 11.7 Hz,

1H), 1.76 (ddd, J¼13.7, 9.5, 6.7 Hz, 1H), 1.40 (ddd, J¼13.4,

9.8, 5.3 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 9H), 1.04 (d,

J¼7.7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) d 201.6,

170.9, 170.0, 139.7, 135.5, 135.4, 133.7, 133.6, 129.7,

127.6, 126.4, 83.5, 65.4, 52.0, 40.5, 39.0, 33.1, 31.3, 27.3,

26.7, 20.9, 20.2, 19.2, 18.0; IR (neat) 3071, 3050, 2957,

2935, 2857, 1740, 1452, 1429, 1368, 1263, 1239, 1198,

1180, 1109, 1061, 1029, 1012, 938, 824 cm²¹; HRMS (CI,

NH₃) for C₂₈H₃₃O₆Si [M2C₄H₉]^þcalcd 493.2046, found

493.2058 m/z.

9H), 1.02 (d, J¼7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz)

d 193.4, 170.2, 169.9, 159.2, 141.4, 135.5, 135.4, 133.6,

133.5, 133.0, 129.8, 127.7, 127.7, 124.0, 82.0, 65.0, 52.2,

45.5, 33.3, 27.5, 26.7, 20.8, 20.5, 19.3, 17.9; IR (neat) 3072,

3050, 2956, 2930, 2856, 2736, 1743, 1692, 1632, 1459,

1429, 1370, 1261, 1233, 1203, 1155, 1108, 1034, 985,

824 cm²¹; HRMS (CI, NH₃) for C₂₈H₃₁O₆Si [M2C₄H₉]^þ

calcd 491.1890, found 491.1890 m/z.

4.1.32. Methyl (1S,2S,5S )-1-acetoxy-2-{3-[(tert-butyl-

dimethylsilyl)oxy]-propenyl}-4-{[(tert-butyldiphenyl-

silyl)oxy]-methyl]-2,5-dimethyl-cyclohex-3-enoate (61).

To a 2208C solution of aldehyde 60 (136 mg, 0.25 mmol)

in THF (4.25 mL) was added LiAlH(tert-BuO)₃(322 mL of

1.0 M solution in THF, 0.32 mmol). The reaction was

stirred at 2208C for 90 min, whereupon MeOH (200 mL)

and saturated aqueous NaHCO₃(2 mL) were added

sequentially. The mixture was then partitioned between

ether (40 mL) and saturated aqueous NaCl (10 mL). The

layers were separated; the aqueous layer was extracted with

ether (3£30 mL). The combined organic layers were dried

(MgSO₄), ﬁltered, and concentrated under reduced pressure.

The resulting foam was puriﬁed by ﬂash chromatography

(2:1 hexanes–EtOAc) to afford 127 mg (93%) of the allylic

alcohol. ¹H NMR (CDCl₃, 500 MHz) d 7.72–7.68 (m, 4H),

7.46–7.36 (m, 6H), 5.57 (dt, J¼15.4, 5.4 Hz, 1H), 5.43 (dt,

J¼15.4, 1.3 Hz, 1H), 5.15 (d, J¼1.2 Hz, 1H), 4.31 (A of

AB, J¼12.8 Hz, 1H), 4.12 (B of AB, J¼13.1 Hz, 1H), 4.09

(d, J¼5.3 Hz, 2H), 3.72 (s, 3H), 2.57 (dd, J¼14.4, 5.4 Hz,

1H), 2.20 (m, 1H), 2.04 (s, 3H), 1.88 (dd, J¼14.4, 11.8 Hz,

1H), 1.61 (br s, 1H), 1.29 (s, 3H), 1.04 (s, 9H), 1.04 (d,

J¼6.8 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) d 170.8,

170.1, 139.5, 135.5, 135.4, 135.0, 133.8, 133.7, 131.4,

129.7, 129.6, 127.6, 127.6, 126.4, 82.9, 65.4, 63.2, 51.9,

44.4, 32.8, 27.4, 26.7, 21.2, 20.9, 19.3, 18.1; IR (neat) 3467

br, 3072, 3048, 2957, 2934, 2858, 1742, 1458, 1429, 1369,

1262, 1200, 1159, 1107, 1058, 1028, 985, 824 cm²¹; HRMS

(CI, NH₃) for C₂₈H₃₃O₆Si [M2C₄H₉]^þcalcd 493.2046,

found 493.2064 m/z.

A stirred mixture of aldehyde (188 mg, 0.341 mmol),

˚

piperidine (41 mL, 0.409 mmol), and 4 A molecular sieves

(254 mg) in toluene (2.6 mL) was heated at 808C for 3 h.

The white suspension was then cooled to 238C and ﬁltered

through a plug of Celite. The Celite was washed with THF

(2£10 mL). The combined ﬁltrates were then concentrated

under reduced pressure to afford 286 mg of the crude

enamine. The enamine was immediately used in the next

step without further puriﬁcation.

To a 2988C solution of the crude enamine in THF (2.6 mL),

PhSeCl (78 mg, 0.409 mmol) in THF (400 mL) was added

dropwise over 5 min. The reaction mixture was stirred at

2988C for 5 min and then at 2788C for 20 min. H₂O

(1.2 mL) and ether (10 mL) were added cautiously, but

sequentially. The mixture was allowed to reach 238C where

it was stirred vigorously for 3 h. The mixture was then

poured into ether (30 mL) and saturated NaCl (10 mL). The

layers were separated, and the aqueous layer was extracted

with ether (3£20 mL). The combined organic layers were

washed with saturated NaHCO₃(10 mL) and saturated NaCl

(10 mL), dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure to afford 243 mg of a 1:1 mixture

a-selenoaldehyde diastereomers. The crude product was

used in the next step without any additional puriﬁcation.

To a 2788C solution of allylic alcohol (51 mg, 0.093 mmol)

and 2,6-lutidine (54 mL, 0.46 mmol) in CH₂Cl₂(2 mL) was

added TBS-OTf (43 mL, 0.185 mmol) dropwise. The

reaction mixture was stirred for 1.5 h, quenched with

saturated aqueous NaHCO₃, and diluted with Et₂O. The

layers were separated, and the aqueous layer was extracted

with Et₂O. The combined organic extracts were washed

with 1N HCl, saturated aqueous NaHCO₃, dried over

MgSO₄, ﬁltered, and concentrated in vacuo. The residue

was puriﬁed by silica gel ﬂash chromatography (4:1

hexanes–Et₂O) to give 57 mg (93%) of 61 as a clear

colorless oil. ¹H NMR (CDCl₃, 400 MHz) d 7.73–7.69 (m,

4H), 7.46–7.36 (m, 6H), 5.43 (dt, J¼15.2, 4.6 Hz, 1H), 5.39

(dt, J¼15.2, 4.6 Hz, 1H), 5.16 (d, J¼1.4 Hz, 1H), 4.23 (A of

AB, J¼12.9 Hz, 1H), 4.12 (dd, J¼4.5, 1.2 Hz, 2H), 4.11 (B

of AB, J¼12.9 Hz, 1H), 3.71 (s, 3H), 2.58 (dd, J¼14.4,

5.4 Hz, 1H), 2.21 (m, 1H), 2.04 (s, 3H), 1.89 (dd, J¼14.4,

11.7 Hz, 1H), 1.29 (s, 3H), 1.04 (s, 9H), 1.04 (d, J¼7.1 Hz,

3H), 0.89 (s, 9H), 0.05 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 170.6, 170.2, 139.2, 135.5, 133.9, 133.7,

133.1, 131.8, 129.6, 127.6, 126.8, 82.9, 65.5, 63.5, 51.8,

44.5, 32.7, 27.4, 26.7, 25.9, 21.3, 20.9, 19.3, 18.3, 18.1,

25.2; IR (neat) 3072, 3053, 2954, 2857, 1745, 1470, 1429,

To 08C suspension of the crude a-selenoaldehydes in

MeOH–THF–H₂O (2:1:1, 12.7 mL) was added NaIO₄

(146 mg, 0.683 mmol). The reaction was stirred at 238C

for 1 h, then cooled to 08C and an additional portion of

NaIO₄(145 mg, 0.678 mmol) was added. The yellow

mixture was stirred for an additional 1 h. The suspension

was cooled to 08C, and ether (50 mL) and saturated

Na₂S₂O₃(10 mL) were added sequentially. The layers

were separated; the aqueous layer was extracted with ether

(3£30 mL). The combined organic layers were washed with

H₂O (20 mL) and saturated NaCl (20 mL), dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by ﬂash chromatography (10:1–

4:1 hexanes–EtOAc) to deliver 162 mg (86% for three

1

steps) of a,b-unsaturated aldehyde 60. H NMR (CDCl₃,

400 MHz) d 9.51 (d, J¼7.7 Hz, 1H), 7.72–7.65 (m, 4H),

7.47–7.36 (m, 6H), 6.55 (d, J¼15.7 Hz, 1H), 6.02 (dd,

J¼15.7, 6.7 Hz, 1H), 5.18 (br s, 1H), 4.28 (A of AB,

J¼13.6 Hz, 1H), 4.14 (B of AB, J¼13.7 Hz, 1H), 3.73 (s,

3H), 2.67 (dd, J¼14.8, 5.4 Hz, 1H), 2.20 (m, 1H), 2.07 (s,

3H), 1.82 (dd, J¼14.8, 11.7 Hz, 1H), 1.36 (s, 3H), 1.04 (s,

W. R. Roush et al. / Tetrahedron 58 (2002) 6433–6454

6453

1368, 1258, 1110, 1058, 987, 836 cm²¹; HRMS (CI, NH₃)

for C₃₄H₄₇O₆Si₂[M2C₄H₉]^þcalcd 607.2911, found

607.2897 m/z.

Health to W. R. R. (GM 26782), a US Department

of Education GAANN Fellowship (P200A980233-00) to

R. K. K., and a Kratz Fellowship to DAB is gratefully

acknowledged.

4.1.33. (5S,6S,9S )-6-{3-[(tert-Butyldimethylsilyl)oxy]-

propenyl}-8-{[(tert-butyldiphenylsilyl)oxy]-methyl}-6,9-

dimethyl-4-{[(methoxy)methyl]-oxy}-1-oxaspiro[4.5]-

deca-3,7-dien-2-one (1). To a 2788C of 61 (57 mg,

0.0857 mmol) in THF (2 mL) was added LHMDS

(0.129 mmol of a 1.0 M solution in THF, 0.129 mmol).

The reaction mixture was stirred for 1 h, then warmed to 08C

and stirred for 1 h longer, then MOM-Cl (13 mL,

0.171 mmol) was added. The reaction was stirred for 1 h,

then diluted with Et₂O and saturated aqueous NaHCO₃

solution. After the layers were separated, the aqueous layer

was extracted with Et₂O. The combined organic extracts

were dried over MgSO₄, ﬁltered and concentrated in vacuo.

The residue was puriﬁed by silica gel ﬂash chromatography

(1:1 hexanes–Et₂O) to give 32 mg (55%) of 1 and 21 mg of

recovered starting material (37%) as clear colorless oils.

References

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Konishi, M.; Oki, T. J. Am. Chem. Soc. 1991, 113, 8947.

2. Tsunakawa, M.; Tenmyo, O.; Tomita, K.; Naruse, N.; Kotake,

C.; Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 180.

3. Tanabe-Tochikura, A.; Nakashima, H.; Murakami, T.;

Tenmyo, O.; Oki, T.; Yamamoto, N. Antiviral Chem.

Chemother. 1992, 3, 345.

4. Eli Lilly and Co., European Patent Application 92307089,

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5. Farooqui, A. A.; Litsky, M. L.; Farooqui, T.; Horrocks, L. A.

Brain Res. Bull. 1999, 49, 139.

1

Data for 1: H NMR (CDCl₃, 400 MHz) d 7.75–7.69 (m,

6. Balsinde, J.; Balboa, M. A.; Insel, P. A.; Dennis, E. A. Ann.

Rev. Pharmacol. Toxicol. 1999, 39, 175.

4H), 7.46–7.39 (m, 6H), 5.73 (br d, J¼15.4 Hz, 1H), 5.49

(dt, J¼15.4, 4.9 Hz, 1H), 5.34 (d, J¼1.6 Hz, 1H), 5.24 (s,

1H), 5.10 (s, 2H), 4.21 (br s, 2H), 4.18 (d, J¼4.4 Hz, 2H),

3.47 (s, 3H), 2.60 (m, 1H), 1.99 (dd, J¼13.6, 6.3 Hz, 1H),

1.73 (dd, J¼13.6, 6.3 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 9H),

1.00 (d, J¼6.9 Hz, 3H), 0.90 (s, 9H), 0.06 (d, J¼0.9 Hz,

6H); ¹³C NMR (CDCl₃, 100 MHz) d 180.3, 172.0, 139.3,

135.5, 133.9, 134.4, 133.6, 130.3, 129.6, 127.7, 127.6,

125.8, 96.7, 87.2, 65.1, 63.7, 57.3, 44.0, 36.4, 28.7, 26.8,

25.9, 20.3, 19.3, 18.6, 18.4, 25.1; IR (neat) 3070, 3048,

2957, 2930, 2890, 2857, 1759, 1627, 1470, 1351, 1335,

1252, 1112, 1090, 1009, 995, 911, 836 cm²¹; HRMS (CI,

NH₃) for C₃₅H₄₇O₆Si₂[M2C₄H₉]^þcalcd 619.2911, found

619.2908 m/z.

7. Roush, W. R.; Barda, D. A. Org. Lett. 2002, 4, 1539.

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52, 4135.

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4.1.34. (5R,6S,9S )-6-{3-[(tert-Butyldimethylsilyl)oxy]-

propenyl}-8-{[(tert-butyldiphenylsilyl)oxy]-methyl}-6,9-

dimethyl-4-{[(methoxy)methyl]-oxy}-1-oxaspiro[4.5]-

deca-3,7-dien-2-one (2). Spirotetronate 2 was synthesized

from 43 by using a sequence similar to that described for the

conversion of 37 to 1.^{21 1}H NMR (CDCl₃, 400 MHz) d

7.73–7.66 (m, 4H), 7.47–7.35 (m, 6H), 5.75 (dt, J¼15.7,

1.3 Hz, 1H), 5.46 (dt, J¼15.6, 5.5 Hz, 1H), 5.32 (d,

J¼1.1 Hz, 1H), 5.20 (s, 1H), 5.00 (A of AB, J¼6.0 Hz,

1H), 4.99 (B of AB, J¼6.0 Hz, 1H), 4.31 (A of AB,

J¼12.5 Hz, 1H), 4.19–4.14 (m, 3H), 3.36 (s, 3H), 2.76 (m,

1H), 2.04 (dd, J¼13.4, 10.4 Hz, 1H), 1.83 (dd, J¼13.4,

6.6 Hz, 1H), 1.06 (s, 9H), 1.05 (d, J¼7.9 Hz, 3H), 1.05 (s,

3H), 0.88 (s, 9H), 0.05 (s, 6H); ¹³C NMR (CDCl₃,

100 MHz) d 181.7, 171.9, 141.5, 140.7, 135.5, 135.4,

133.7, 133.6, 131.6, 129.8, 129.6, 127.7, 127.6, 125.8, 96.7,

91.9, 87.7, 65.5, 63.9, 57.3, 43.2, 37.7, 29.5, 26.8, 25.9,

21.8, 19.4, 19.0, 18.3, 25.0; IR (neat) 3072, 3047, 3021,

2956, 2928, 2856, 1761, 1626, 1462, 1428, 1357, 1331,

1259, 1159, 1111, 1093, 1058, 1011, 920, 835 cm²¹; HRMS

(CI, NH₃) for C₃₅H₄₇O₆Si₂[M2C₄H₉]^þcalcd 619.2911,

found 619.2930.

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Acknowledgments

Financial support provided by the National Institutes of

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Article Doi

Studies on the synthesis of the quartromicins: Partial stereochemical assignment of quartromicins A3 and D3 and diastereoselective synthesis of the endo- and exo-spirotetronate subunits

DOI: 10.1016/S0040-4020(02)00656-7

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