Total synthesis of (-)-salicylihalamide A and related congeners

Tetrahedron 58 (2002) 6455–6471

Total synthesis of (2)-salicylihalamide A and related congeners

a,b

Amos B. Smith, III^a,band Junying Zheng

,

*

^aDepartment of Chemistry, Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA 19104, USA

^bMonell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA 19104, USA

Received 1 April 2002; accepted 9 May 2002

Dedicated to Professor Yoshito Kishi, on the occasion of the 2001 Tetrahedron Prize, with admiration and respect for his

many seminal contributions to chemistry

Abstract—A concise, highly efﬁcient total synthesis of (2)-salicylihalamide A (1), a novel marine sponge metabolite, has been achieved.

Key features of the synthetic strategy include a highly E-selective ring-closing metathesis to construct the 12-membered salicylihalamide A

macrocycle and a practical method for installation of the labile ene-hepta-(Z,Z)-dienamide side chain involving N-acylation of enecabarmate

5, the latter derived from the corresponding a,b-unsaturated carboxylic acid 28 via acyl azide formation and thermal Curtius rearrangement.

Two structurally simpliﬁed analogs (3 and 4) were also prepared which displayed signiﬁcant, but attenuated cell growth inhibitory activity

against several human tumor cell lines. q 2002 Published by Elsevier Science Ltd.

1. Introduction

Salicylihalamides A and B (1 and 2; Fig. 1) comprise a novel

class of secondary metabolites isolated by Boyd and

co-workers¹in 1997 from the marine sponge Haliclona.

Detailed NMR studies revealed that salicylihalamide A (1)

possesses a medium-sized salicylate macrolide, in conjunc-

tion with a novel dienylenamide sidechain. The absolute

conﬁguration, 12S, 13R, 15S, was secured by De Brabander

and co-workers²in conjunction with their syntheses of both

(þ) and (2)-salicylihalamides A (1).³Salicylihalamide A

(1) displays potent cytotoxicity in the NCI 60-cell line

human tumor assay, with a mean GI₅₀value of 15 nM.¹The

COMPARE pattern-recognition analysis⁴revealed that the

mean-graph proﬁles do not correlate with any of the proﬁles

of known antitumor agents within the NCI database, thereby

suggesting a novel mechanism of action. Recent pharma-

cological studies however do indicate that salicylihalamide

A selectively inhibits mammalian vacuolar-type (H^þ)-

ATPase (V-ATPase).⁵Unfortunately, further biological

studies directed at deﬁning the mode of action of (2)-

salicylihalamide A (1) have been signiﬁcantly hampered by

the limited availability of material from natural sources.

Since the discovery of the salicylihalamides, a growing

number of structurally related, bioactive metabolites have

been isolated and characterized, including the apicularens,⁶

the lobatamides,⁷the oximidines,⁸CJ-12950,⁹and

CJ-13357,⁹all of which share the salicylic acid moiety

Figure 1.

Keywords: salicylihalamide; total synthesis; macrocycles; metathesis;

Curtius rearrangement.

and a similar highly unsaturated enamide side chain

common to the salicylihalamides. In the case of the

apicularens, the side chains are identical with those of the

*

Corresponding author. Tel.: þ1-215-898-2440; fax: þ1-215-898-5129;

e-mail: smithab@sas.upenn.edu

0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.

PII: S0040-4020(02)00657-9

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A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

salicylihalamides, while those of other members terminate

in various O-methyl oximes.

enecarbamate (3) with (Z,Z)-dienyl chloride 6 (Scheme

1).¹⁶For the construction of the macrocycle, we envisioned

ring closing metathesis (RCM).¹⁷Although at the outset of

this synthetic venture, ring closing metatheses had been

used to form 12-member macrolactones,¹⁷the high

E-selectivity could not be assured. Mitsunobu esteriﬁca-

tion¹⁸of alcohol 9 and O-methyl-6-allylsalicylic acid 8

would provide 7, the requisite diene substrate for the

metathesis process.

The unprecedented highly unsaturated enamide side chain

of the salicylihalamides, in conjunction with both the potent

cytotoxicities and their scarcity, has engendered consider-

able interest within the synthetic community, including

successful total syntheses by De Brabander,²Labrecque,¹⁰

Snider,¹¹Fu¨rstner,¹²and our group.¹³In addition, a number

of synthetic approaches towards the ring system¹⁴and

strategic procedures for construction of the labile enamide

side chain¹⁵have been disclosed. Herein, we describe a full

account of our total synthesis of the naturally occuring

enantiomer of (2)-salicylihalamide A (1), in conjunction

with the preparation of two functionally simpliﬁed analogs

(3 and 4). We have previously communicated the synthesis

of the unnatural enantiomer, (þ)-salicylihalamide A.¹³

Evaluation of the biological activities of (2)-salicylihal-

amide A (1) and the analogs (3 and 4) is also presented.

The synthesis of salicylic acid 8 was achieved as described

in Scheme 2. Exposure of known amide 10¹⁹(available in

two steps from O-methyl salicylic acid chloride) to iodine in

THF/H₂O (5:1) furnished iodolactone 11, which in turn was

converted to acid 8 by treatment with zinc in acetic acid.²⁰

2. Result and discussions

2.1. Total synthesis of (2)-salicylihalamide A

From the retrosynthetic perspective, we reasoned that the

sensitive enamide side chain would best be installed at a late

stage of the synthesis via N-acylation of an advanced

Scheme 2.

Our point of departure for the required coupling partner

alcohol 9 (Scheme 3), was known aldehyde (þ)-12,²¹

readily prepared from natural S-malic acid in three steps.

Roush crotylboration²²furnished alcohol (þ)-14 (90% de),

which was protected as the tert-butyldimethylsilyl ether

(þ)-15. A three-step homologation involving hydrobora-

tion,²³Swern oxidation²⁴and Wittig methylenation.²⁵led to

oleﬁns (þ)-18. Exposure to aqueous triﬂuoroacetic acid²⁶

then furnished diol (þ)-19, which was converted to the

terminal epoxide (þ)-20 exploiting the Kishi epoxide

protocol.²⁷Treatment of the latter with vinyl Grignard 22

in presence of a catalytic amount of CuI afforded secondary

alcohol (þ)-9.²⁸The required Grignard reagent (22) was

prepared from the known vinyltin 21²⁹by transmetalation

with n-BuLi³⁰and treatment with MgBr₂.³¹Interestingly,

attempts to open epoxide (þ)-20 with a variety of higher

order cuprates³²derived from the corresponding vinyl

lithium failed to furnish (þ)-9. From the synthetic

perspective, it is noteworthy that this sequence results in

introduction of the future C(17) and C(18) enamide carbons.

Esteriﬁcation of acid 8 with alcohol (þ)-9 exploiting the

Mitsunobu protocol¹⁸then furnished the oleﬁn metathesis

substrate (þ)-7, possessing the required stereogenic centers

at C(12, 13 and 15) for (2)-salicylihalamide A (1) (Scheme

4). Pleasingly, treatment of (þ)-7 (0.008 M in CH₂Cl₂) with

the Grubbs catalyst (Cy₃P)₂Cl₂RuvCHPh (10 mol%)

generated the salicylihalamide macrolide (2)-23 as a

mixture of double bond isomers (ca. 10:1), favoring the

desired E-congener. Similar ring-closing metathesis selec-

tivities were observed by De Brabander²and Labrecque¹⁰in

their total syntheses of (2)-salicylihalamide A (1).

Scheme 1.

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6457

Scheme 4.

Scheme 3.

Martin protocol.³⁵Treatment of enal (2)-25 with BBr₃

34

Although RCM-based macrocyclizations are known to be

reversible processes and usually provide E,Z-mixtures,

often favoring the thermodynamically more stable isomer,³³

De Brabander and co-workers have demonstrated that the

highly E-selective RCM in the case of salicylihalamide

macrolactone skeleton employing the ﬁrst generation

Grubbs catalyst derives from kinetic control.²

then cleanly removed the anisole methyl to provide phenol

(2)-26. Subsequent oxidation afforded acid (2)-27, which

in turn was converted to acid (þ)-28 after silylation of both

the C(3) hydroxyl and acid moieties with TBSOTf (Et₃N)

and base-mediated saponiﬁcation.³⁶

In anticipation of the N-acylation tactic to install the

salicylihalamide side chain, we turned to the synthesis of

acid chloride 6 (Scheme 5). Following the procedure of

Taylor and co-workers³⁷for the synthesis of the closely

related Z,Z-nonadienoic acid, ethyl lithium (prepared by

lithium–halogen exchange between t-BuLi and ethyl

iodide) was treated sequentially with the CuBr·SMe₂

complex (0.5 equiv.) and acetylene (1.5 equiv., introduced

Continuing with elaboration of the (2)-salicylihalamide A

(1), attempts to achieve removal of the anisole methyl and

PMB moieties in one step using various Lewis acid³⁴(i.e.,

BBr₃, BCl₃, TMSI) failed, furnishing instead allylic halide

by-products. The PMB protecting group could however be

removed with DDQ to provide primary allylic alcohol (2)-

24, which in turn was oxidized to enal (2)-25 via the Dess–

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A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

´

Hu¨nig’s base, i-BuOCOCl and then aqueous NaN₃a la

Weinstock,³⁸followed by warming to effect the facile

Curtius rearrangement and capture of the resultant iso-

cyanate with 2-(trimethylsilyl)-ethanol furnished enecarba-

mate (þ)-5 in excellent overall yield (86%). N-acylation

then proceeded smoothly via exposure of (þ)-5 to

NaHMDS, followed by acid chloride 6 to yield (þ)-30.¹⁶

From the synthetic perspective, this stepwise procedure

proved to be an efﬁcient, practical method for incorporation

of the salicylihalamide side chain. The Teoc and the aryl

TBS protecting groups were then removed by treatment

with TBAF. Interestingly, the secondary TBS ether proved

quite resistant. In the end, the secondary TBS moiety was

removed by treatment with HF·py in THF and pyridine

(3:1), as described by De Brabander,²to afford (2)-

salicylihalamide A (1), possessing spectra and chiroptic

properties identical in all respects to those reported of the

natural product [e.g., ¹H (500 MHz), ¹³C NMR (125 MHz),

IR, HRMS and [a ]²_D⁵¼222.88 (c 0.11, MeOH); lit.¹

[a ]²_D⁵¼2358 (c 0.70, MeOH)].

Scheme 5.

as a measured volume of gas) at 2408C to generate the

corresponding (Z )-alkenyl cuprate. Introduction of an

additional 2.5 equiv. of acetylene at 2108C resulted in the

addition of the (Z )-alkenyl cuprate to acetylene. The

resulting Z,Z-dienylcuprate was then trapped with carbon

dioxide to furnish dienyl acid 29 as a single isomer, albeit in

only 20% overall yield. Preparation of acid chloride 6 then

proceeded in a straightforward manner upon treatment with

oxalyl chloride in the presence of a catalytic amount of

DMF.

2.2. Analogs of the salicylihalamide A

The ﬁrst study on the structure–activity relationships (SAR)

of (2)-salicylihalamide A (1), reported recently by De

Brabander and co-workers,²revealed that the characteristic

N-acyl enamine functionality is essential for activity, and as

they propose may lead to covalent bond with the putative

binding protein via a protonation/addition reaction

sequence.³⁹Interestingly, analogs lacking the enoyl func-

tionality also displayed signiﬁcant cell growth inhibitory

activity.

With ample quantities of both 6 and (þ)-28 in hand, the

stage was set to incorporate the enamide side chain.

Towards this end, exposure of (þ)-28 (Scheme 6) to

In view of the potential of (2)-salicylihalamide A (1) as a

lead compound for cancer chemotherapy, we sought to

prepare a number of simpliﬁed analogs with similar or

hopefully improved cytotoxicity. At the outset, we chose to

investigate the importance of structural elements present on

the (2)-salicylihalamide A macrolactone ring. We therefore

selected analogs 3 and 4 (Fig. 1) as initial targets.⁴⁰

Construction of 3 and 4 began with known epoxide (2)-

31,⁴¹available in three steps (56% yield) from S-aspartic

acid (Scheme 7). Secondary alcohol (2)-33 was prepared by

treatment of epoxide (2)-31 with Grignard 32, available

from 1-bromo-5-hexene and magnesium. Esteriﬁcation of

salicylic acid 8 again exploiting the Mitsunobu protocol,¹⁸

provided diene (2)-34. In contrast to the high E-selectivity

observed in the total synthesis of 1, ring closing meta-

thesis¹⁷afforded an inseparable mixture (2:1/E:Z) of cyclic

congeners. Removal of the PMB group followed by careful

column chromatography then afforded the isomeric lactones

(2)-36 (E ) and (2)-37 (Z ). The Z-isomer (2)-37 was

hydrogenated to give lactone (þ)-38.

To access analog 3, we employed the E-isomer (2)-36

(Scheme 8). Oxidation with Dess–Martin periodinane³⁵

afforded aldehyde (2)-39. In accordance with the De

Brabander synthesis of (2)-salicylihalamide A (1),²

Horner–Wadsworth–Emmons homologation employing

allyl diethylphosphono-acetate delivered allyl ester (2)-40

as the E-isomer. The anisole methyl group was next

removed with BBr₃.³⁴Silylation of the resultant phenol to

Scheme 6.

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6459

Scheme 7.

afford (2)-42 was followed by removal of the allyl ester

with catalytic Pd(PPh₃)₄in the presence of morpholine to

furnish carboxylic acid (2)-43,⁴²which was readily

converted to enecarbamate (2)-44, exploiting the stepwise

introduction of the enamide side chain as employed to great

advantage in our synthesis of the (2)-salicylihalamide A

(1). Construction of (2)-3 was then achieved via

N-acylation with acid chloride 6 to furnish (2)-45, followed

by exposure to TBAF.

Scheme 8.

In a similar fashion, the saturated lactone (þ)-38 was

converted to analog (2)-4 (Scheme 9).

activity. Presumably their function is to orchestrate the

optimal orientation between the side chain and salicylate

substituents for receptor binding.

2.3. Biological evaluation

(2)-Salicylihalamide A (1) and the structurally simpler

analogs (2)-3 and (2)-4 were screened in vitro against a

series of cell lines for their growth inhibitory activity.

Representative cytotoxicity data are presented in Table 1.

3. Summary

We have achieved an efﬁcient total synthesis of (2)-

salicylihalamide A (1) in 20 steps from aldehyde (þ)-12,

with an overall yield of 7.4%. The synthesis features both a

highly E-selective RCM to form the macrolactone ring and

an efﬁcient, practical protocol for manipulation of the

labile enamide side chain. In addition, we prepared two

As illustrated, analogs (2)-3 and (2)-4 retained signiﬁcant,

albeit attenuated activity. Interestingly, removal of the

endocyclic oleﬁn reduces the activity (i.e., (2)-4 vs (2)-3).

These observations suggest that the structure elements on

the lactone ring may be important, but not critical for

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A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

structurally simpliﬁed analogs ((2)-3 and (2)-4), which

retain signiﬁcant cell growth inhibitory activity.

4. Experimental

4.1. Materials and methods

All reactions were carried out under argon with dry, freshly

distilled solvents, vacuum-ﬂamed glassware, and magnetic

stirring, unless otherwise stated. Diethyl ether (Et₂O) and

tetrahydrofuran (THF) were distilled from sodium/benzo-

phenone; benzene and toluene were distilled from sodium,

and dichloromethane (CH₂Cl₂) from calcium hydride.

Triethylamine, diisopropylethylamine and pyridine were

distilled from calcium hydride and stored over KOH.

Dimethylsulfoxide (DMSO) was distilled from calcium

˚

hydride and stored over 4 A molecular sieves. All reactions

were monitored by thin layer chromatography (TLC) using

0.25 mm E. Merck precoated silica gel plates. Flash

chromatography was performed with the indicated solvents

and E. Merck silica gel 60 (particle size 0.040–0.063 mm).

Yields refer to chromatographically and spectroscopically

pure compounds, except as otherwise indicated. All melting

points were obtained on a Thomas–Hoover apparatus and

are corrected. Infrared spectra were recorded on a Perkin–

Elmer Model 283B spectrophotometer. Proton NMR spectra

were recorded on Bruker AM-500 or Bruker DRX-500

spectrometer; ¹³C NMR spectra were recorded on a Bruker

AM500 instrument. Chemical shifts are reported in d values

relative to tetramethylsilane. Optical rotations were

measured with a Perkin–Elmer Model 241 polarimeter in

the solvent indicated. High resolution mass spectra were

obtained at the University of Pennsylvania Mass

Spectrometry Center on either a VG Micromass 70/70H or

VG ZAB-E spectrometer.

4.1.1. Alkyl iodide 11. To a solution of 10 (150 mg,

0.607 mmol) in THF (3 mL) and H₂O (1 mL) was added I₂

(770 mg, 3.036 mmol). The solution was stirred at ambient

temperature for 24 h, then quenched with saturated Na₂S₂O₃

solution until the color of the iodine disappeared, added to

brine (20 mL) and extracted with Et₂O (2£20 mL). The

combined organic phases were dried over MgSO₄, ﬁltered,

and concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 2:1) provided 11 (126 mg, 65% yield) as a

light yellow oil: IR (CHCl₃): 2850 (s), 1720 (s), 1580 (s),

1470 (s), 1440 (s), 1275 (s), 1230 (s), 1070 (s), 1050 (s),

920 s), 750 (s), 650 (s) cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.47 (t, J¼8.4 Hz, 1H), 6.92 (d, J¼8.6 Hz, 1H), 6.80 (d,

J¼8.1 Hz, 1H), 4.45 (m, 1H), 3.93 (s, 3H), 3.45 (dd, J¼10.4,

4.8 Hz, 1H), 3.35 (dd, J¼10.5, 7.4 Hz, 1H), 3.15 (dd,

J¼15.9, 3.0 Hz, 1H), 3.04 (dd, J¼16.0, 10.8 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) d 161.2, 161.1, 140.5, 134.8,

119.5, 113.1, 111.2, 76.3, 56.2, 34.2, 5.1; high resolution

mass spectrum (ESI, Na) m/z 340.9668 [(MþNa)^þ; calcd

for C₁₁H₁₁IO₃Na: 340.9651].

Scheme 9.

Table 1. Biological evaluation of salicylihalamide A analogs 3 and 4

Cell type

Cell line

GI₅₀(£10²²mg/mL)

1

3

4

Pancreas-a

Breast adn

CNS gliobl

Lung-NSC

Colon

BXPC-3

MCF-7

SF268

NCI-H460

KM20L2

DU-145

8.0

7.4

8.0

7.3

3.8

8.1

46

57

11

56

15

87

88

48

37

65

71

78

4.1.2. Acid 8. To a solution of 11 (114 mg, 0.358 mmol) in

acetic acid (2 mL) was added zinc dust (235 mg,

3.584 mmol). The reaction mixture was stirred at 908C for

24 h and then cooled down to room temperature. The

mixture was ﬁltered and then the residue was washed with

Prostate

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6461

hot H₂O (3£10 mL). The ﬁltrate was extracted with ethyl

acetate (3£20 mL) and the combined organic phases were

washed with brine (10 mL), ﬁltered, and concentrated in

vacuo. Flash chromatography (methylene chloride/metha-

nol, 20:1) provided 8 (50 mg, 73% yield) as a white solid: IR

(CHCl₃): 2500–3600 (s), 1700 (s), 1580 (s), 1470 (s), 1400

(s), 1265 (s), 1220 (s), 970 (s), 910 (s), 750 (s), 650

(s) cm²¹; ¹H NMR (500 MHz, CDCl₃) d 7.32 (t, J¼8.1 Hz,

1H), 6.87 (d, J¼7.7 Hz, 1H), 6.84 (d, J¼8.3 Hz, 1H), 5.96

(m, 1H), 5.10 (dd, J¼17.3, 1.5 Hz, 1H), 5.07 (d, J¼10.4 Hz,

1H), 3.88 (s, 3H), 3.52 (d, J¼6.6 Hz, 2H); ¹³C NMR

(125 MHz, CDCl₃) d 172.6, 156.8, 139.6, 136.4, 131.1,

122.2, 122.0, 116.3, 109.3, 56.1, 37.8; high resolution mass

spectrum (CI, NH₃) m/z 193.0857 [(MþH)^þ; calcd for

C₁₁H₁₃O₃: 193.0865].

CDCl₃) d 140.4, 114.8, 112.3, 73.4, 72.9, 70.4, 42.8, 37.8,

30.0, 29.8, 25.8, 25.6, 18.0, 15.6, 8.2, 7.9, 24.5, 24.6; high

resolution mass spectrum (ESI, Na) m/z 343.2665

[(MþH)^þ; calcd for C₁₉H₃₉O₃Si: 343.2669].

4.1.5. Alcohol (1)-16. To a solution of (þ)-15 (690 mg,

2.014 mmol) in THF (40 mL) was added 9-BBN (12.1 mL,

0.5 M in THF, 6.042 mmol). The reaction mixture was

heated to reﬂux for 3 h and then cooled down to 08C. H₂O

(1 mL) was added slowly, followed by NaOH (2N, 8 mL)

and 30% H₂O₂(4 mL). The two phase mixture was warmed

up to room temperature and stirred for 1 h. The mixture was

diluted with H₂O (30 mL) and extracted with EtOAc

(2£50 mL). The combined organic phases were washed

with brine (50 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 6:1) afforded (þ)-16 (611 mg, 89% yield) as a

colorless oil: [a ]²_D³¼þ11.78 (c 0.60, CHCl₃); IR (neat):

3000–3600 (br, m), 2858 (s), 1463 (s), 1376 (m), 1395 (m),

1173 (s), 1099 (s), 1076 (s), 1057 (s), 919 (m), 836 (s), 774

4.1.3. Alcohol (1)-14. A solution of (R,R )-diisopropyl

tartrate (E )-crotylboronate 13²²(46.0 g, 0.152 mol) in dry

˚

toluene (1 L) was treated with powdered 4 A molecular

sieve (6 g) at 2788. A solution of (2)-12 (13.1 g,

0.076 mol) in dry toluene (50 mL) was cooled to 2788C

and added dropwise into the suspension via cannula. The

resultant reaction mixture was stirred at 2788C for 1 h

before an aqueous NaOH (2N, 70 mL) was added. The

mixture was warmed up to 08C, stirred for 30 min and

ﬁltered through a pad of celite. The aqueous layer was

extracted with Et₂O (3£250 mL) and the combined organic

phases were washed with brine (200 mL), dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Flash chroma-

tography (hexanes/ethyl acetate, 7:1) afforded (þ)-14

(15.2 g, 88% yield) as a colorless oil: [a ]²_D³¼þ9.48 (c

3.48, CHCl₃); IR (neat): 3150–3600 (br, m), 3074 (s), 2881

(s), 1693 (w), 1463 (m), 1418 (m), 1355 (m), 1173 (m), 1080

1

(s), 671 (w) cm²¹; H NMR (500 MHz, CDCl₃) d 4.14 (q,

J¼3.6 Hz, 1H), 4.04 (t, J¼7.1 Hz, 1H), 3.72 (m, 2H), 3.58

(m, 1H), 3.44 (t, J¼8.7 Hz, 1H), 2.19 (m, 1H), 1.87 (m, 1H),

1.82 (m, 1H), 1.71 (m, 1H), 1.60 (m, 4H), 1.52 (m, 1H), 0.97

(d, J¼6.9 Hz, 3H), 0.98 (s, 9H), 0.88 (m, 6H), 0.04 (s, 6H);

¹³C NMR (125 MHz, CDCl₃) d 112.5, 73.4, 73.3, 70.4, 60.0,

37.5, 34.2, 30.0, 29.7, 25.8, 18.0, 15.6, 8.1, 7.9, 24.5, 24.6;

high resolution mass spectrum (ESI, Na) m/z 361.2771

[(MþH)^þ; calcd for C₁₉H₄₁O₄Si: 361.2775].

4.1.6. Aldehyde (1)-17. A solution of dimethyl sulfoxide

(4.5 mL, 0.064 mol) in CH₂Cl₂(100 mL) at 2788C was

treated with oxalyl chloride (2.0 M in CH₂Cl₂, 15.8 mL,

0.032 mol). After 10 min, a solution of (þ)-16 (9.5 g,

0.026 mol) in CH₂Cl₂(40 mL) was added to the above

mixture. The resultant cloudy solution was stirred for an

additional 10 min at 2788C before triethylamine (14.7 mL,

0.105 mol) was added. The mixture was then warmed up to

ambient temperature and then added to saturated NaHCO₃

(150 mL) and extracted with ethyl acetate (2£200 mL). The

combined organic phases were washed with brine (100 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 10:1)

afforded (þ)-17 (9.1 g, 96% yield) as a colorless oil:

[a ]²_D³¼þ4.18 (c 0.70, CHCl₃); IR (neat): 2955 (s), 2882 (s),

2710 (w), 1727 (s), 1463 (m), 1254 (m), 1173 (m), 1078 (s),

1039 (s), 921 (m), 836 (s), 774 (s), 674 (w) cm²¹; ¹H NMR

(500 MHz, CDCl₃) d 9.77 (s, 1H), 4.18 (dt, J¼12.1, 4.7 Hz,

1H), 4.04 (dd, J¼13.6, 6.2 Hz, 1H), 3.68 (dd, J¼10.2,

3.7 Hz, 1H), 3.42 (t, J¼7.9 Hz, 1H), 2.52 (dd, J¼14.1,

3.2 Hz, 1H), 2.31 (m, 1H), 2.23 (m, 1H), 1.85 (m, 1H), 1.59

(m, 5H), 1.00 (d, J¼6.8 Hz, 3H), 0.90 (m, 6H), 0.89 (s, 9H),

0.05 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) d 202.5, 112.6,

73.2, 72.8, 70.4, 46.3, 37.8, 32.6, 30.0, 29.7, 25.8, 25.7,

18.0, 16.9, 8.2, 7.9, 24.4, 24.6; high resolution mass

spectrum (ESI, Na) m/z 381.2425 [(MþNa)^þ; calcd for

C₁₉H₃₈O₄SiNa: 381.2437].

1

(s), 917 (s), 852 (w), 763 (w) cm²¹; H NMR (500 MHz,

CDCl₃) d 5.80 (m, 1H), 5.08 (d, J¼5.7, 1.4 Hz, 1H), 4.25

(m, 1H), 4.10 (dd, J¼7.9, 5.9 Hz, 1H), 3.68 (m, 1H), 3.50 (t,

J¼8.0 Hz, 1H), 3.03 (d, J¼1.7 Hz, 1H), 2.07 (m, 1H), 1.64

(m, 4H), 1.05 (d, J¼6.9 Hz, 3H), 0.89 (m, 6H); ¹³C NMR

(125 MHz, CDCl₃) d 140.2, 115.4, 113.3, 76.0, 74.1, 70.3,

43.8, 36.8, 29.9, 29.5, 15.5, 8.1, 7.9; high resolution mass

spectrum (ESI, Na) m/z 251.1612 [(MþNa)^þ; calcd for

C₁₃H₂₄O₃Na: 251.1623].

4.1.4. TBS ether (1)-15. A solution of (þ)-14 (8.5 g,

0.037 mol) in CH₂Cl₂(500 mL) was treated with 2,6-

lutidine (8.67 mL, 0.074 mol) and tert-butyldimethylsilyl

triﬂuoromethanesulfonate (10.3 mL, 0.045 mmol) at

2788C. After 10 min, the reaction mixture was warmed

up to ambient temperature, added to brine-saturated

NaHCO₃(1:1, 200 mL), and extracted with CH₂Cl₂

(2£300 mL). The combined organic phases were washed

with brine (300 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 15:1) afforded (þ)-15 (12.4 g, 97% yield) as a

colorless oil: [a]²_D³¼þ11.0 (c 3.66, CHCl₃); IR (neat): 2957

(s), 2858.0 (s), 1643 (m), 1472 (m), 1360 (m), 1254 (s), 1099

(s), 1076 (s), 1040 (s), 915 (s), 836 (s), 774 (s), 668

1

(m) cm²¹; H NMR (500 MHz, CDCl₃) d 5.77 (m, 1H),

5.01 (m, 1H), 4.98 (dd, J¼11.1, 1.1 Hz, 1H), 4.15 (q,

J¼6.2 Hz, 1H), 4.03 (t, J¼7.8 Hz, 1H), 3.68 (m, 1H), 3.41

(t, J¼7.8 Hz, 1H), 2.36 (m, 1H), 1.69 (q, J¼6.9 Hz, 1H),

1.61 (m, 4H), 1.02 (d, J¼6.8 Hz, 3H), 0.90 (m, 6H), 0.89 (s,

9H), 0.06 (s, 6H), 0.05 (s, 3H); ¹³C NMR (125 MHz,

4.1.7. Oleﬁn (1)-18. A suspension of methyltriphenyl

phosphonium iodide (631 mg, 1.56 mmol) in THF (15 mL)

at 08C was treated with NaHMDS (1.0 M in THF, 1.61 mL,

1.61 mmol) for 30 min and then cooled down to 2788C. To

the resultant yellow solution was added (þ)-17 (373 mg,

6462

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

1.04 mmol) in THF (5 mL). The reaction mixture was

warmed up to room temperature and stirred for 1 h, poured

into brine (20 mL) and extracted with ethyl ether

(2£30 mL). The combined organic phases were dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Flash chroma-

tography (hexanes/ethyl acetate, 40:1) afforded (þ)-18

(298 mg, 81% yield) as a yellow oil: [a]²_D³¼þ16.58 (c

4.60, CHCl₃); IR (neat): 3076 (s), 2857 (s), 1640 (m), 1463

(s), 1376 (m), 1254 (s), 1173 (m), 1078 (s), 915 (s), 836 (s),

1H), 4.98 (t, J¼1.0 Hz, 1H), 3.72 (m, 1H), 3.03 (m, 1H),

2.72 (td, J¼4.9, 0.7 Hz, 1H), 2.42 (dd, J¼5.1, 2.7 Hz, 1H),

2.13 (m, 1H), 1.82 (m, 2H), 1.76 (m, 1H), 1.47 (m, 1H), 0.90

(s, 9H), 0.89 (d, J¼3.0 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) d 137.4, 115.6, 73.6, 50.0,

46.8, 38.3, 37.1, 35.7, 25.8, 18.0, 14.6, 24.6; high resolution

mass spectrum (CI, NH₃) m/z 271.2094 [(MþH)^þ; calcd for

C₁₅H₃₁O₂Si: 271.2093].

806 (m), 774 (s), 673 (m) cm²¹

;

¹H NMR (500 MHz,

4.1.10. Alcohol (1)-9. A 1.0 M solution of anhydrous

MgBr₂in ether/benzene (3:1) was prepared by addition of

1,2-dibromoethane (0.69 mL, 8 mmol) to a stirred suspen-

sion of magnesium turnings (0.2 g, 8.3 mmol) in Et_2-

O/benzene (3:1, 8 mL) at a rate sufﬁcient to maintain

gentle reﬂux and then stirred for 1 h. Simultaneously,

n-BuLi (1.6 M in hexanes, 0.333 mL, 0.532 mmol) was

added dropwise to 21 (248 mg, 0.532 mmol) in dry THF

(3 mL) at 2788C and the resultant mixture was stirred for

1 h at 2788C. To the mixture was added the 1.0 M freshly

prepared MgBr₂solution (532 mL, 0.532 mmol) dropwise

and the resulting suspension was stirred at 2788C. After

45 min, the mixture was transferred into a suspension of CuI

(6 mg, 0.026 mmol) in THF (1 mL) at 2788C via cannula

and allowed to stir for 30 min. A solution of (þ)-20 (58 mg,

0.212 mmol) in THF (1.5 mL) was added dropwise at

2788C. The reaction mixture was warmed up slowly to

room temperature, stirred for 1 h quenched with saturated

aqueous NH₄Cl (10 mL) and extracted with EtOAc

(2£30 mL). The combined organic phases were washed

with brine (10 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 6:1) afforded (þ)-9 (90 mg, 94% yield) as a

colorless oil: [a ]²_D³¼þ24.18 (c 1.6, CHCl₃); IR (neat):

3350–3600 (br, m), 2921 (s), 1612 (m), 1513 (s), 1249 (s),

1463 (s), 1068 (s), 1037 (s), 911 (s), 836 (s), 774 (s), 666.6

CDCl₃) d 5.75 (m, 1H), 5.00 (dd, J¼9.0, 1.1 Hz, 1H), 4.97

(d, J¼1.0, 1H), 4.20 (dt, J¼12.3, 5.7 Hz, 1H), 4.05 (dd,

J¼7.7, 5.4 Hz, 1H), 3.60 (dt, J¼7.3, 4.4 Hz, 1H), 3.44 (t,

J¼7.9 Hz, 1H), 2.12 (dt, J¼13.9, 7.0 Hz, 1H), 1.83–1.92

(m, 2H), 1.71 (m, 1H), 1.56 (m, 1H), 1.60 (m, 4H), 0.90 (s,

9H), 0.89 (m, 6H), 0.05 (m, 3H), 0.03 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) d 137.5, 115.6, 112.2, 73.6, 72.8, 70.3,

38.1, 37.0, 36.3, 30.0, 29.8, 25.8, 18.0, 14.5, 8.2, 7.9, 24.5,

24.6; high resolution mass spectrum (ES, Na) m/z 379.2613

[(MþNa)^þ; calcd for C₂₀H₄₀O₃SiNa: 379.2645].

4.1.8. Diol (1)-19. To a solution of (þ)-18 (185 mg,

0.519 mmol) in CH₂Cl₂(10 mL) was added 50% aqueous

triﬂuoroacetic acid (0.7 mL). The reaction mixture was

stirred vigorously at room temperature for 30 min (reaction

monitored by TLC) and then diluted with CH₂Cl₂(60 mL)

and H₂O (20 mL). The organic layer was washed with

saturated NaHCO₃(20 mL) and brine (20 mL), dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Flash chroma-

tography (hexanes/ethyl acetate, 2:1) afforded (þ)-19

(135 mg, 90% yield) as a white solid: [a ]²_D³¼þ10.88 (c

4.05, CHCl₃); IR (neat): 3100–3600 (br, s), 1640 (m), 1482

(m), 1441 (m), 1413 (m), 1377 (m), 1255 (s), 1066 (s), 1005

1

(m), 911 (m), 836 (s), 724 (s) cm²¹; H NMR (500 MHz,

CDCl₃) d 5.74 (m, 1H), 5.00 (m, 1H), 4.98 (t, J¼1.2 Hz,

1H), 3.92 (m, 1H), 3.84 (m, 1H), 3.62 (dd, J¼11.1, 3.6 Hz,

1H), 3.47 (dd, J¼11.1, 6.0 Hz, 1H), 1.97 (m, 1H), 1.88 (m,

1H), 1.78 (m, 1H), 1.60 (m, 1H), 1.47 (dt, J¼14.4, 3.0 Hz,

1H), 0.90 (s, 9H), 0.89 (d, J¼3.1 Hz, 3H), 0.11 (s, 3H), 0.10

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) d 136.9, 116.0, 75.7,

71.4, 66.9, 38.7, 37.9, 32.9, 25.8, 17.9, 13.1, 24.1, 24.8;

high resolution mass spectrum (ESI, Na) m/z 311.2031

[(MþNa)^þ; calcd for C₁₅H₃₂O₃SiNa: 311.2019].

(m) cm²¹

;

¹H NMR (500 MHz, CDCl₃) d 7.25 (d,

J¼8.3 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H), 5.62–5.80 (m,

3H), 5.00 (s, 1H), 4.97 (dd, J¼2.1, 1.0 Hz, 1H), 4.42 (s, 2H),

3.97 (d, J¼5.8 Hz, 2H), 3.88 (m, 1H), 3.80 (s, 3H), 3.79 (m,

1H), 3.23 (br, s, 1H), 2.23 (t, J¼6.3 Hz, 2H), 1.93 (m, 1H),

1.88 (m, 1H), 1.76 (m, 1H), 1.60 (m, 2H), 0.89 (s, 9H), 0.8

(d, J¼7.0 Hz, 3H), 0.11 (s, 3H), 0.09 (s, 2H); ¹³C NMR

(125 MHz, CDCl₃) d 159.1, 137.0, 130.4, 130.3, 129.3,

129.2, 115.9, 113.7, 75.8, 71.5, 70.5, 70.4, 55.2, 40.4, 38.8,

37.9, 35.9, 29.6, 25.8, 17.9, 13.2, 24.1, 24.7; high

resolution mass spectrum (ESI, Na) m/z 471.2901

[(MþNa)^þ; calcd for C₂₆H₄₄O₄SiNa: 471.2907].

4.1.9. Epoxide (1)-20. To a suspension of NaH (60%

dispersion in mineral oil, 59 mg, 1.456 mmol, washed twice

with hexanes) in THF (5 mL) at 08C was added a solution of

(þ)-19 (105 mg, 0.346 mmol) in THF (2 mL). The resulting

mixture was stirred at 08C for 30 min and then cooled down

4.1.11. Ester (1)-7. To a solution of (þ)-9 (450 mg,

1.016 mmol), 8 (975 mg, 5.081 mmol), triphenylphosphine

(665 mg, 2.541 mmol) in benzene (10 mL) was added

diethyl azodicarboxylate (0.409 mL, 2.591 mmol). After

24 h, the resultant mixture was added to brine (25 mL) and

extracted with ether (3£25 mL). The combined organic

phases were dried over MgSO₄, ﬁltered, and concentrated in

vacuo. Flash chromatography (hexanes/ethyl acetate, 20:1)

afforded (þ)-7 (499 mg, 84% yield) as a colorless oil:

[a ]²_D³¼þ14.88 (c 0.29, CHCl₃); IR (neat): 2855 (s), 1725

(s), 1584 (m), 1513 (m), 1470 (s), 1264 (s), 1248 (s), 1113

to 2788C.

A

solution of tosylimidazole (89 mg,

0.400 mmol) in THF (2 mL) was added dropwise via

cannula. The reaction mixture was warmed up to 08C and

stirred for 1 h before being quenched with saturated NH₄Cl

(20 mL). The mixture was poured into Et₂O (30 mL) and the

aqueous layer was extracted with Et₂O (2£20 mL). The

combined organic phases were washed with brine (10 mL),

dried over MgSO₄, ﬁltered, and concentrated. Flash

chromatography (hexanes/ethyl acetate, 20:1) afforded

(þ)-20 (75 mg, 81% yield) as

a

colorless oil:

1

[a ]²_D³¼þ9.78 (c 1.20, CHCl₃); IR (neat): 2856 (s), 1640

(m), 1066 (s), 835 (m), 807 (m), 774 (m) cm²¹; H NMR

(w), 1472 (m), 1407 (m), 1377 (m), 1360 (w), 1254 (s), 1070

(s), 910 (m), 835 (s), 774 (s), 665 (w) cm²¹; H NMR

(500 MHz, CDCl₃) d 7.30 (t, J¼8.1 Hz, 1H), 7.24 (d,

J¼8.2 Hz, 2H), 6.85 (d, J¼6.7 Hz, 2H), 6.81 (d, J¼7.8 Hz,

1H), 6.73 (d, J¼8.2 Hz, 1H), 5.92 (m, 1H), 5.68–5.80 (m,

1

(500 MHz, CDCl₃) d 5.76 (m, 1H), 5.01 (dd, J¼3.5, 2.0 Hz,

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6463

3H), 5.26 (m, 1H), 5.07 (t, J¼1.9 Hz, 1H), 5.02 (dd, J¼5.9,

1.7 Hz, 1H), 4.90 (dd, J¼9.1, 1 Hz, 1H), 4.62 (s, 1H), 4.03

(s, 1H), 3.69 (m, 1H), 3.85 (m, 1H), 3.80 (s, 3H), 3.78 (s,

3H), 3.35 (d, J¼6.5 Hz, 2H), 2.50 (m, 2H), 2.04 (m, 1H),

1.82 (m, 1H), 1.71 (m, 2H), 1.62 (m, 1H), 0.92 (s, 9H), 0.88

(d, J¼6.9 Hz, 3H), 0.13 (s, 3H), 0.08 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) d 167.6, 159.1, 156.3, 138.3, 137.3,

136.3, 130.5, 129.8, 129.3, 129.0, 124.1, 121.5, 116.3,

115.6, 113.7, 108.7, 72.7, 72.2, 71.4, 70.2, 55.5, 55.2, 39.2,

37.9, 37.3, 37.2, 36.4, 25.9, 25.8, 18.0, 13.6, 24.3, 24.5;

high resolution mass (ESI, Na) m/z 645.3582 [(MþNa)^þ;

calcd for C₃₇H₅₄O₆SiNa: 645.3587].

0.91 (s, 9H), 0.85 (d, J¼6.8 Hz, 3H), 0.22 (s, 3H), 0.12 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) d 168.0, 156.6, 139.0,

131.7, 131.2, 129.9, 128.4, 128.3, 124.7, 122.7, 109.5, 74.5,

72.3, 63.6, 55.7, 38.8, 37.8, 37.7, 37.2, 36.7, 25.9, 18.0,

13.1, 24.3, 24.5; high resolution mass spectrum (ESI, Na)

m/z 497.2699 [(MþNa)^þ; calcd for C₂₇H₄₂O₅SiNa:

497.2700].

4.1.14. Enal (2)-25. To a solution of (2)-24 (53 mg,

0.112 mmol) in CH₂Cl₂(10 mL) was added Dess–Martin

periodinane (105 mg, 0.246 mmol). The reaction mixture

was stirred at room temperature for 30 min before being

quenched with aqueous Na₂S₂O₃(15%, 5 mL) and Satu-

rated NaHCO₃(5 mL). The mixture was diluted with EtOAc

(100 mL) and the organic phase was washed with brine

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

vacuo. Flash chromatography (hexanes/ethyl acetate, 4:1)

provided (2)-25 (51 mg, 98% yield) as a colorless oil:

[a ]²_D³¼250.68 (c 0.58, CHCl₃); IR (neat): 2854 (s), 1727

(s), 1649 (s), 1584 (m), 1469 (s), 1273 (s), 1251 (s), 1251 (s),

4.1.12. Lactone (2)-23. To a solution of the Grubbs catalyst

(Cy₃P)₂Cl₂RuvCHPh (17.2 mg, 0.021 mmol, 10 mol%) in

dry CH₂Cl₂(26 mL) was added a solution of (þ)-7 (130 mg,

0.209 mmol) in CH₂Cl₂(3 mL). The reaction mxture was

stirred for 40 min at ambient temperature and poured into

H₂O (20 mL). The organic phase was washed with brine

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

vacuo. Flash chromatography (hexanes/ethyl acetate, 15:1)

afforded (2)-23 (112 mg, 85%) as a colorless oil (contain a

small amount of Z-isomer): [a]²_D³¼241.58 (c 0.55, CHCl₃);

IR (neat): 2853 (s), 1724 (s), 1584 (m), 1513 (s), 1469 (s),

1275 (s), 1249 (s), 1071 (s), 970 (m), 835 (s), 807 (m), 775

(m) cm²¹; ¹H NMR (500 MHz, CDCl₃) d 7.25 (dd, J¼4.9,

2.9 Hz, 2H), 6.86 (dd, J¼4.9, 2.9 Hz, 2H), 7.21 (t,

J¼8.3 Hz, 1H), 6.78 (d, J¼8.4 Hz, 1H), 6.74 (d,

J¼7.6 Hz, 1H), 5.75–5.85 (m, 1H), 5.62–5.71 (m, 1H),

5.41 (ddt, J¼13.2, 10.8, 2.1 Hz, 1H), 5.25–5.34 (m, 2H),

4.42 (d, J¼3.2 Hz, 2H), 4.25 (dt, J¼8.5, 4.9 Hz, 1H), 3.97

(m, 1H), 3.80 (, 3H), 3.74 (s, 3H), 3.71 (dd, J¼16.3, 9.4 Hz,

1H), 3.30 (dd, J¼16.3, 2.0 Hz, 1H), 2.41–2.52 (m, 1H),

2.28–2.37 (m, 1H), 2.21–2.29 (m, 1H), 1.80 (m, 1H), 1.68

(dd, J¼14.9, 8.3 Hz, 2H), 1.43 (dd, J¼15.2, 7.8 Hz, 1H),

0.90 (s, 9H), 0.83 (d, J¼6.8 Hz, 3H), 0.23 (s, 3H), 0.12 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) d 170.0, 159.1, 156.6,

139.0, 131.2, 130.4, 129.9, 129.4, 129.3, 129.2, 128.4,

124.6, 122.6, 113.7, 109.3, 74.6, 72.3, 71.4, 70.3, 55.5, 55.2,

39.0, 37.8, 37.7, 37.3, 36.7, 25.9, 17.9, 13.0, 24.3, 24.5;

high resolution mass spectrum (ESI, Na) m/z 617.3265

[(MþNa)^þ; calcd for C₃₅H₅₀O₆SiNa: 617.3275].

1

1070 (s), 971 (m), 836 (m), 775 (m), 734 (w) cm²¹; H

NMR (500 MHz, CDCl₃) d 9.57 (d, J¼7.8 Hz, 1H), 7.23 (t,

J¼8.1, 1H), 6.92 (dt, J¼15.6, 7.0 Hz, 1H), 6.19 (dd, J¼15.7,

7.8 Hz, 1H), 5.35–5.47 (m, 2H), 5.26–5.33 (m, 1H), 4.24

(dd, J¼8.8, 3.8 Hz, 1H), 3.77 (s, 1H), 3.70 (dd, J¼16.3,

9.5 Hz, 1H), 3.32 (ddt, J¼13.9, 4.2, 2.1 Hz, 1H), 2.73 (m,

1H), 2.58 (m, 1H), 2.28 (m, 1H), 1.82 (m, 1H), 1.75 (dd,

J¼15.1, 8.1 Hz, 1H), 1.67 (dd, J¼14.2, 11.5 Hz, 1H), 1.38

(dd, J¼15.1, 8.9 Hz, 1H), 0.91 (s, 9H), 0.83 (d, J¼6.8 Hz,

2H), 0.23 (s, 3H), 0.13 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) d 193.4, 167.8, 156.5, 153.5, 139.1, 134.7, 131.3,

130.1, 128.4, 124.1, 122.8, 109.4, 72.8, 72.3, 55.7, 39.3,

37.8. 37.7, 37.3, 37.1, 25.8, 18.0, 13.0, 24.3, 24.5; high

resolution mass spectrum (ES, Na) m/z 495.2551

[(MþNa)^þ; calcd for C₂₇H₄₀O₅SiNa: 495.2543].

4.1.15. Phenol (2)-26. A suspension of (2)-25 (57 mg,

0.121 mmol) in CH₂Cl₂(57 mL) at 2788C was treated with

BBr₃(1.0 M in CH₂Cl₂, 362 mL, 0.362 mmol). The mixture

was stirred at 2788C for 3 h, and then quenched with

saturated NH₄Cl (20 mL). The mixture was allowed to

warm up to room temperature and diluted with CH₂Cl₂

(50 mL). The organic layer was washed brine (20 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 4:1) provided

(2)-26 (45 mg, 82% yield) as a colorless oil: [a]²_D³¼211.48

(c 0.50, CHCl₃); IR (neat): 3000–3500 (br, s), 2852 (s),

1727 (s), 1693 (s), 1606 (m), 1587 (m), 1463 (s), 1379 (m),

1359 (s), 1250 (s), 1062 (s), 970 (m), 836 (s), 806 (m), 775.9

(s), 663 (m) cm²¹; ¹H NMR (500 MHz, CDCl₃) d 10.92 (br,

s, 1H), 9.53 (d, J¼7.6 Hz, 1H), 7.31 (t, J¼7.6 Hz, 1H), 6.89

(dd, J¼8.3, 1.0 Hz, 1H), 6.82 (dt, J¼15.7, 7.3 Hz, 1H), 6.71

(dd, J¼7.4, 0.9 Hz, 1H), 6.22 (dd, J¼15.6, 7.8 Hz, 1H), 5.52

(dt, J¼10.7, 4.9 Hz, 1H), 5.45 (dt, J¼14.0, 2.0 Hz, 1H), 5.11

(m, 1H), 3.71 (dd, J¼16.7, 5.7 Hz, 1H), 3.62 (dd, J¼8.2,

3.0 Hz, 1H), 3.40 (d, J¼16.5 Hz, 1H), 2.73 (ddd, J¼7.3, 6.1,

1.4 Hz, 2H), 2.33 (m, 1H), 2.01 (dd, J¼14.7, 10.8 Hz, 1H),

1.74 (m, 2H), 1.39 (ddd, J¼10.3, 8.4, 1.8 Hz, 1H), 0.92

(d, J¼6.3 Hz, 1H), 0.89 (s, 9H), 0.03 (s, 3H), 20.03 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) d 193.2, 170.7, 162.7,

151.8, 142.1, 135.5, 134.2, 132.6, 126.6, 123.6, 116.7,

112.9, 73.3, 71.3, 39.1, 38.6, 38.3, 37.2, 36.4, 29.6, 25.7,

17.9, 3.7, 24.6, 25.0; high resolution mass spectrum (ES,

4.1.13. Alcohol (2)-24. To a solution of (2)-23 (83 mg,

0.140 mmol) in CH₂Cl₂(20 mL) was added DDQ (95 mg,

0.419 mmol) followed by pH 7 buffer (1 mL). The reaction

mixture was allowed to stir at room temperature for 45 min

before being quenched with saturated NaHCO₃(20 mL).

The mixture was diluted with CH₂Cl₂(100 mL) and the

organic phase was washed with brine (20 mL), dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Flash chroma-

tography (hexanes/ethyl acetate, 4:1) afforded (2)-24

(63 mg, 98% yield) as a colorless oil: [a]²_D³¼253.88 (c

0.45, CHCl₃); IR (neat): 3100–3600 (br, m), 2854 (s), 1723

(s), 1583 (m), 1469 (s), 1438 (m), 1275 (s), 1253 (s), 1072

1

(s), 970 (m), 835 (s), 775 (m) cm²¹; H NMR (500 MHz,

CDCl₃) d 7.21 (t, J¼8.0 Hz, 1H), 6.79 (d, J¼8.4 Hz, 1H),

6.75 (d, J¼7.6 Hz, 1H), 5.72–5.83 (m, 2H), 5.40 (ddt,

J¼13.7, 10.4, 3.0 Hz, 1H), 5.22–5.34 (m, 2H), 4.23 (dd,

J¼8.6, 3.6 Hz, 1H), 4.11 (d, J¼4.8 Hz, 1H), 3.80 (s, 3H),

3.68 (dd, J¼16.2, 4.4 Hz, 1H), 3.30 (dt, J¼16.2, 2.1 Hz,

1H), 2.45 (m, 1H), 2.21–2.35 (m, 2H), 1.82 (m, 1H), 1.68

(dd, J¼15.2, 8.4 Hz, 2H), 1.40 (dd, J¼15.2, 8.8 Hz, 1H),

6464

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

Na) m/z 481.2380 [(MþNa)^þ; calcd for C₂₆H₃₈O₅SiNa:

mass spectrum (ESI, Na) m/z 611.3209 [(MþNa)^þ; calcd

481.2387].

for C₃₂H₅₂O₆Si₂Na: 611.3200].

4.1.16. Acid (2)-27. A solution of (2)-26 (32 mg,

0.068 mmol) in t-butanol (2 mL) and 2-methyl-2-butene

(1 mL) was treated with sodium chlorite (156 mg,

1.72 mmol) and NaH₂PO₄·2H₂O (402 mg, 2.58 mmol) in

water (2 mL). The resultant mixture was stirred vigorously

for 1 h, added to brine (20 mL), and extracted with ethyl

acetate (4£20 mL). The combined organic phases were

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 1:2) provided

(2)-27 (31 mg, 97% yield) as a yellow oil: [a]²_D³¼218.98 (c

0.25, CHCl₃); IR (neat): 2500–3510 (br, m), 1698 (s), 1657

(s), 1606 (m), 1463 (s), 1291 (s), 1249 (s), 1063 (s), 970 (m),

4.1.18. Dienyl acid 29. tert-Butyllithium (100 mL, 1.7 M in

pentane, 170.0 mmol) was added dropwise to a solution of

iodoethane (13.3 g, 85.0 mmol) in Et₂O (100 mL) at

2788C. The solution was stirred at 2788C for 10 min and

then at room temperature for 1 h. The resulting solution was

added via cannula to a suspesion of CuBr·SMe₂(8.7 g,

42.5 mmol) in Et₂O (150 mL) at 2408C. The mixture was

stirred at 2358C for 20 min and cooled down to 2408C.

Gaseous acetylene (2.86 L, 127.5 mmol) was slowly passed

into the solution through a syringe needle. The resulting

solution was stirred at 2308C for 15 min and then warmed

up to 2108C. The temperature was carefully maintained

between 215 and 2108C, while more acetylene gas (4.8 L,

212.5 mmol) was added over 15 min. The resulting mixture

was cooled down to 2408C and HMPA (5.9 mL,

34.0 mmol), (EtO)₃P (50 mL) were added dropwise.

Gaseous CO₂was bubbled through while the reaction

mixture was warmed up to 108C. Saturated NH₄Cl (150 mL)

and HCl (3N, 50 mL) was added and the organic layer was

extracted with Et₂O (2£300 mL). The combined organic

phases were washed with brine (100 mL), dried over

MgSO₄, ﬁltered and concentrated in vacuo. Flash chroma-

tography (methylene chloride/methanol, 30:1) provided a

crude brown residue. Vaccum distillation of the crude

residue gave 29 (1.07 g, 21% yield) as a light yellow oil: bp

80–858C/0.5 mm Hg; IR (CHCl₃): 2100–3500 (br, s), 1690

(s), 1635 (s), 1595 (s), 1450 (s), 1290 (s), 1245 (s), 1010 (m),

939 (m), 836 (s), 805 (m), 775 (s) cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 10.92 (br, s, 1H), 7.30 (t, J¼7.5 Hz,

1H), 7.07 (dt, J¼15.1, 72 Hz, 1H), 6.89 (dd, J¼8.6, 1.0 Hz,

1H), 6.71 (dd, J¼7.6, 1.0 Hz, 1H), 5.93 (d, J¼15.7 Hz, 1H),

5.41–5.53 (m, 2H), 5.06 (m, 1H), 3.69 (dd, J¼16.5, 5.8 Hz,

1H), 3.60 (dd, J¼8.1, 2.8 Hz, 1H), 3.40 (dd, J¼16.0, 1.6 Hz,

1H), 2.56–2.68 (m, 2H), 2.26–2.35 (m, 1H), 2.01 (dd,

J¼15.5, 10.9 Hz, 1H), 1.82 (m, 2H), 1.37 (ddd, J¼14.0, 6.4,

1.0 Hz, 1H), 0.89 (d, J¼8.1 Hz, 1H), 0.87 (s, 9H), 0.03 (s,

3H), 20.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) d 170.6,

169.7, 162.7, 145.8, 142.3, 134.1, 132.7, 126.5, 123.6,

123.5, 116.6, 112.9, 73.4, 71.2, 39.0, 38.3, 38.0, 37.2, 36.2,

25.8, 25.7, 17.9, 13.7, 24.5, 24.6, 24.9, 25.0; high

resolution mass spectrum (ESI, Na) m/z 497.2358

[(MþNa)^þ; calcd for C₂₆H₃₈O₆SiNa: 497.2336].

900 (m), 850 (m), 823 (m), 670 (m) cm²^{1 1}H NMR

;

4.1.17. Acid (1)-28. To a solution of (2)-27 (48 mg,

0.098 mmol) in CH₂Cl₂(4 mL) was added Et₃N (82 mL,

0.590 mmol) followed by TBSOTf (68 mL, 0.294 mmol).

The reaction mixture was stirred at ambient temperature for

2 h before being quenched with HCl (1N, 10 mL). The

aqueous phase was extracted with CH₂Cl₂(2£20 mL). The

combined organic phases were washed with brine (10 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was dissolved in MeOH (3 mL) and THF (1 mL). A

solution of K₂CO₃(200 mg) in H₂O (1 mL) was added and

the mixture was stirred at ambient temperature for 5 min.

The reaction was quenched with HCl (1N, 10 mL) and the

aqueous phase was extracted with ethyl acetate (2£30 mL).

The combined organic phases were washed with brine

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

vacuo. Flash chromatography (hexanes/ethyl acetate, 2:1)

provided (þ)-28 (21 mg, 83% yield) as a colorless oil:

[a ]²_D³¼þ6.98 (c 0.30, CHCl₃); IR (neat): 2400–3300 (br, s),

2951 (s), 1727 (s), 1700 (s), 1653 (m), 1581 (m), 1457 (s),

(500 MHz, CDCl₃) d 7.22 (t, J¼11.1 Hz, 1H), 7.05 (t,

J¼11.5 Hz, 1H), 5.96 (dd, J¼10.8, 7.3 Hz, 1H), 5.67 (d,

J¼11.4 Hz, 1H), 2.30 (dt, J¼13.6, 6.0 Hz, 2H), 1.03 (t,

J¼7.6 z, 3H); ¹³C NMR (125 MHz, CDCl₃) d 172.0, 144.2,

141.0, 123.8, 116.5, 20.8, 13.8; high resolution mass

spectrum (CI, NH₃) m/z 127.0756 [(MþH)^þ; calcd for

C₇H₁₁O₂: 127.0760].

4.1.19. Dienyl acid chloride 6. A solution of 29 (230 mg,

1.825 mmol) in dry benzene (3 mL) was treated with oxalyl

chloride (0.321 mL, 3.651 mmol). A trace ammount of

DMF was added. The resultant mixture was stirred at room

temperature for 1 h and then concentrated in vacuo. The

residue was azeotropically dried with benzene (2£1 mL) to

afford the corresponding acid chloride 6 as a yellow oil

(253 mg, 95%). The acid chloride 6 was used immediately

in the following step: IR (CHCl₃): 3000 (m), 1735 (s), 1625

(s), 1620 (s), 1575 (s), 1430 (m), 1190 (m), 955 (s), 860 (s),

810 (m), 690 (m), 610 (m) cm²^{1 1}H NMR (500 MHz,

;

1

1281 (s), 1253 (s), 1113 (m), 1066 (s), 1036 (m) cm²¹; H

CDCl₃) d 7.01 (m, 2H), 6.25 (m, 1H), 5.97 (m, 1H), 2.32 (dt,

J¼15.5, 6.6 Hz, 2H), 1.07 (t, J¼7.8 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) d 163.8, 148.9, 142.2, 123.7, 122.0,

21.3, 13.7; high resolution mass spectrum (CI, NH₃) m/z

145.0416 [(MþH)^þ; calcd for C₇H₁₀ClO: 145.0420].

NMR (500 MHz, CDCl₃) d 7.11 (t, J¼7.8 Hz, 1H), 7.02 (dt,

J¼15.7, 7.2 Hz, 1H), 6.74 (d, J¼7.5 Hz, 1H), 6.72 (d,

J¼8.2 Hz, 1H), 5.93 (d, J¼15.7 Hz, 1H), 5.28–5.44 (m,

1H), 3.64 (dd, J¼16.1, 9.0 Hz, 1H), 3.31 (ddd, J¼16.6, 3.0,

1.0 Hz, 1H), 2.60 (t, J¼6.5 Hz, 2H), 2.26 (d, J¼12.9 Hz,

1H), 1.76–1.85 (m, 1H), 1.69 (dt, J¼15.0, 10.7 Hz, 2H),

1.41 (dd, J¼15.1, 8.9 Hz, 1H), 0.96 (s, 9H), 0.91 (s, 9H),

0.83 (d, J¼6.7 Hz, 3H), 0.22 (s, 3H), 0.19 (s, 3H), 0.16 (s,

3H), 0.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) d 170.0,

168.1, 152.7, 146.1, 138.7, 131.3, 129.5, 128.3, 127.3,

123.3, 123.1, 117.7, 72.3, 71.9, 38.4, 38.0, 37.9, 37.0, 36.2,

25.9, 25.7, 13.0, 24.2, 24.4, 24.5, 24.6; high resolution

4.1.20. Enecarbamate (1)-5. To a solution of (þ)-28

(21 mg, 0.036 mmol) in acetone (2 mL) was sequentially

added N,N-diisopropylethylamine (10.2 mg, 14 mL,

0.078 mmol) and isobutylchloroformate (9.6 mg, 9 mL,

0.072 mmol) at 08C. The reaction mixture was stirred at

room temperature for 1 h, and then a solution of sodium

azide (23 mg, 0.347 mmol) in distilled H₂O (1 mL) was

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6465

added. The resulting mixture was stirred at room tempera-

ture for an additional 30 min. Brine (10 mL) was added and

the aqueous phase extracted with ethyl acetate (2£20 mL).

The combined organic phases were dried over MgSO₄,

ﬁltered and concentrated in vacuo. The residue was

azeotropically dried with benzene (2£1 mL) and then

dissolved in toluene (2 ml) and heated at reﬂux for

15 min. 2-(trimethylsilyl)-ethanol was added in one portion

and the mixture was heated at reﬂux for an additional

10 min. The mixture was then cooled to room temperature

and concentrated in vacuo. Flash chromatography (hexane/

ethyl acetate, 20:1) afforded (þ)-5 (21.6 mg, 86%) as a

colorless oil: [a ]²_D³¼þ17.08 (c 0.35, CH₂Cl₂); IR (neat):

3200–3400 (br, m), 2856 (s), 1725 (s), 1681 (m), 1581 (m),

1504 (m), 1462 (s), 1259 (s), 1066 (s), 836 (s), 804 (s), 665

(7.8 mg, 0.010 mmol) in THF (1 mL) was treated with

tetrabutylammonium ﬂuoride (1.0 M in THF, 60 ml,

0.060 mmol). The resultant brown solution was stirred for

10 min at 08C, added to H₂O (5 ml), and extracted with ethyl

ether (2£15 mL). The combined organic phases were dried

over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was dissolved in a solution of HF·py (0.1 g) in

pyridine (0.3 mL) and THF (0.9 mL). The reaction mixture

was allowed to stir at room temperature. After 48 h, the

reaction was carefully quenched with saturated aqueous

NaHCO₃(10 mL) extracted with EtOAc (2£20 mL). The

combined organic phases were washed with brine (5 mL),

dried over MgSO₄, ﬁltered and concentrated in vacuo. Flash

chromatography (hexanes/ethyl acetate, 1:1) afforded (2)-1

(2.6 mg, 56% yield) as a white solid: [a ]²_D³¼222.88 (c 0.11,

MeOH); IR (neat): 3280 (br, m), 2964 (s), 1695 (s),1605 (s),

1

(s) cm²¹; H NMR (500 MHz, C₆D₆) d 6.91 (t, J¼8.0 Hz,

1H), 6.80–6.89 (m, 1H), 6.70 (d, J¼8.1, 1H), 6.56 (d,

J¼7.6 Hz, 1H), 5.69 (d, J¼10.8 Hz, 1H), 5.40–5.47 (m,

1H), 5.31–5.40 (m, 2H), 4.61–4.78 (m, 1H), 4.49 (m, 1H),

4.16 (t, J¼8.2 Hz, 2H), 3.70 (dd, J¼16.1, 8.3 Hz, 1H), 3.20

(dd, J¼16.2, 4.1 Hz, 1H), 2.33–2.47 (m, 2H), 2.11 (m, 1H),

1.68 (m, 1H), 1.59–1.70 (m, 2H), 1.50–1.59 (m, 1H), 1.10 (s,

9H), 1.03 (s, 9H), 0.82–0.90 (m, 5H), 0.28 (s, 6H), 0.16 (s,

3H), 0.11 (s, 3H), 20.11 (s, 9H); ¹³C NMR (125 MHz, C₆D₆)

d 167.9, 153.2, 153.0, 138.7, 131.2, 129.6, 128.9, 128.8,

126.7, 123.3, 118.1, 104.0, 74.2, 72.1, 63.0, 38.3, 38.1, 37.5,

36.2, 35.9, 26.0, 25.7, 18.3, 18.1, 17.6, 1.1, 21.9, 24.2, 24.3,

24.6, 24.7; high resolution mass spectrum (ES, Na) m/z

726.4037 [(MþNa)^þ; calcd for C₃₇H₆₅NO₆Si₃Na: 726.4017].

1520 (s), 1460 (s), 1245 (s), 1120 (s), 972 (s), 735 (s) cm²¹

;

¹H NMR (500 MHz, CD₃OD) d 7.30 (t, J¼12.0 Hz, 1H),

7.12 (t, J¼7.9 Hz, 1H), 6.87 (t, J¼11.1 Hz, 1H), 6.80 (d,

J¼14.7 Hz, 1H), 6.73 (d, J¼8.2 Hz, 1H), 6.64 (d, J¼7.5 Hz,

1H), 5.81 (dd, J¼10.8, 7.4 Hz, 1H), 5.68 (d, J¼11.7 Hz,

1H), 5.22–5.48 (m, 4H), 4.12 (dd, J¼9.3, 3.4 Hz, 1H), 3.56

(dd, J¼16.6, 8.3 Hz, 1H), 3.35 (dd, J¼16.6, 7.7 Hz, 1H),

2.34–2.46 (m, 2H), 2.28 (m, 2H), 1.81–1.91 (m, 1H), 1.70–

1.80 (m, 2H), 1.35 (m, 1H), 1.02 (t, J¼7.4, 3H), 0.85 (d,

J¼6.8 Hz, 3H); ?¹³C NMR (125 MHz, CD₃OD) d 171.0,

165.9, 157.1, 142.6, 140.7, 137.7, 131.7, 131.6, 130.7,

126.2, 125.3, 123.0, 122.5, 120.3, 110.4, 76.0, 72.0, 38.9,

38.8, 38.6, 37.6, 36.6, 21.5, 14.4, 13.6; high resolution mass

spectrum (ESI, Na) m/z 462.2256 [(MþNa)^þ; calcd for

C₂₆H₃₃NO₅Na: 462.2256].

4.1.21. Enamide (1)-30. A solution of (þ)-5 (8.4 mg,

0.012 mmol) in dry THF (1 mL) was treated with sodium

bis(trimethylsilyl)amide (1.0 M in THF, 18 mL,

0.018 mmol) for 5 min at 08C. A solution of 6 (3 mg,

0.024 mmol) in dry benzene (0.2 mL) was added. The

resulting mixture was stirred at 08C for 10 min before being

quenched with saturated NH₄Cl (3 mL) and extracted with

ether (2£15 mL). The combined organic phases were

washed with brine, dried over MgSO₄, ﬁltered and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 10:1) provided (þ)-30 (7.8 mg, 81%) as a

colorless oil: [a ]²_D³¼þ19.18 (c 0.45, CH₂Cl₂); IR (neat):

3587 (m), 2926 (s), 2854 (s), 1728 (s), 1581 (m), 1456 (m),

1382 (m), 1260 (s), 1066 (s), 969 (m), 860 (m), 803

(s) cm²¹; ¹H NMR (500 MHz, C₆D₆) d 7.54 (t, J¼11.5 Hz,

1H), 6.90 (t, J¼7.9 Hz, 1H), 6.65–6.75 (m, 2H), 6.53–6.62

(m, 2H), 6.45 (d, J¼11.4 Hz, 1H), 5.89 (dt, J¼14.1, 7.4 Hz,

1H), 5.54–5.65 (m, 2H), 5.33–5.45 (m, 2H), 4.51–4.59 9m,

1H), 4.18 (t, J¼7.6 Hz, 2H), 3.69 (dd, J¼16.0, 8.1 Hz, 1H),

3.19 (dd, J¼16.0, 4.0 Hz, 1H), 2.53–2.69 (m, 2H), 2.10–

2.19 (m, 1H), 1.85–1.96 (m, 1H), 1.75–1.85 (m, 2H), 1.65–

1.75 (m, 2H), 1.12 (s, 9H), 1.02 (s, 9H), 0.92 (d, J¼6.6 Hz,

3H), 0.88–0.97 (m, 2H), 0.73 (t, J¼7.5 Hz, 3H), 0.28 (s,

9H), 0.16 (s, 3H), 0.11 (s, 3H), 20.10 (s, 6H); ¹³C NMR

(125 MHz, C6D6) d 70.0, 166.9, 153.6, 153.0, 142.3, 138.8,

137.0, 131.2, 129.2, 128.6, 127.0, 124.9, 123.3, 121.1,

121.0, 118.0, 73.6, 72.1, 65.0, 38.3, 38.0, 37.5, 37.0, 36.2,

26.0, 25.7, 20.6, 18.3, 18.1, 17.4, 13.7, 1.1, 22.0, 24.2,

24.3, 24.6, 24.7; high resolution mass spectrum (ESI, Na)

m/z 834.4618 [(MþNa)^þ; calcd for C₄₄H₇₃NO₇Si₃Na:

834.4618].

4.1.23. Alcohol (2)-33. To a suspension of magnesium

turnings (0.61 g, 0.025 mol) in Et₂O (10 mL) was added two

drops of 1,2-dibromoethane and the mixture was heated to

reﬂux for 10 min and then cooled down to room

temperature. 5-bromo-1-pentene (3.0 g, 0.02 mol) was

added dropwise and the resultant mixture was reﬂuxed for

2 h, cooled down to room temperature. This Grignard

reagent 32 was transferred into THF (20 mL) and cooled

down to 2788C. A solution of Li₂CuCl₄(0.1 M in THF,

4.49 mL, 0.449 mmol) was added and the mixture was

stirred at 2788C for 15 min. A solution of (þ)-31 (1.87 g,

0.009 mol) in THF (10 mL) was added dropwise via

cannula. The reaction mixture was stirred at 2788C for

5 min and slowly warmed up to room temperature,

quenched with saturated NH₄Cl (20 mL). The aqueous

phase was extracted with Et₂O (3£40 mL) and the

combined organic phases were washed with brine

(40 mL), dried over MgSO₄, ﬁltered and concentrated in

vacuo. Flash chromatography (hexanes/ethyl acetate, 6:1)

afforded (2)-33 (2.16 g, 88% yield) as a colorless oil:

[a ]²_D³¼211.98 (c 0.82, CHCl₃); IR (neat): 3450 (br, m),

3010 (s), 1610 (s), 1505 (s), 1240 (s), 1080 (s), 900 (m), 750

1

(s), 660 (s) cm²¹; H NMR (500 MHz, CDCl₃) d 7.24 (d,

J¼8.5 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 5.80 (m, 1H), 4.99

(dd, J¼17.2, 1.0 Hz, 1H), 4.91 (dd, J¼10.2, 1.0 Hz, 1H),

4.44 (s, 2H), 3.80 (s, 3H), 3.79 (m, 1H), 3.70 (m, 1H), 3.62

(m, 1H), 2.80 (br, s, 1H), 2.05 (m, 2H), 1.71 (m, 2H), 1.25–

1.50 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) d 159.3, 138.9,

130.0, 129.2, 114.3, 113.9, 72.9, 71.4, 68.9, 55.2, 37.2, 36.4,

33.7, 28.9, 25.7; high resolution mass spectrum (ESI, Na)

m/z 278.1877 [(MþH)^þ; calcd for C₁₇H₂₇O₃: 278.1882].

4.1.22. Salicylihalamide A (2)-1. A solution of (þ)-30

6466

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

4.1.24. Ester (2)-34. To a solution of (2)-33 (450 mg,

1.016 mmol), 206 (975 mg, 5.081 mmol), triphenyl-

phosphine (665 mg, 2.541 mmol) in benzene (10 mL) was

added diethyl azodicarboxylate (0.409 mL, 2.591 mmol).

After 24 h, the resultant mixture was added to brine (25 mL)

and extracted with ether (2£25 mL). The combined organic

phases were dried over MgSO₄, ﬁltered, and concentrated in

vacuo. Flash chromatography (hexanes/ethyl acetate, 20:1)

afforded (2)-34 (535 mg, 89% yield) as a colorless oil:

[a ]²_D³¼27.88 (c 0.50, CHCl₃); IR (neat): 3000 (s), 2920 (m),

1720 (s), 1590 (m), 1510 (s), 1470 (s), 1430 (m), 1260 (s),

3.76 (dd, J¼14.7, 10.9 Hz, 1H), 3.17 (dd, J¼14.7, 2.7 Hz,

1H), 2.43 (m, 1H), 2.30 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H),

1.93 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.33–1.48 (m,

3H); ¹³C NMR (125 MHz, CDCl₃) d 168.0, 155.8, 139.6,

130.4, 130.1, 129.5, 122.2, 108.4, 74.5, 60.5, 55.7, 35.0,

31.4, 30.2, 29.6, 26.5, 24.0, 18.0; high resolution mass

spectrum (ESI, Na) m/z 327.1580 [(MþNa)^þ; calcd for

C₁₈H₂₄O₄: 327.1572].

4.1.26. Alcohol (1)-38. To a suspension of Pd(OH)₂/C

(20 mg) in MeOH (2 mL) was added a solution of (2)-37

(80 mg, 0.2632 mmol) in MeOH (5 mL). The mixture was

allowed to stir at ambient temperature under H₂atmosphere.

After 8 h, the mixture was ﬁltered and the concentrated in

vacuo. Flash chromatography (hexanes/ethyl acetate, 2:1)

provided (þ)-38 (72 mg, 89% yield) as a colorless oil.

[a ]²_D³¼þ1.28 (c 0.33, CHCl₃); IR (neat): 3520 (br, s), 2990

(m), 2920 (s), 1710 (s), 1590 (s), 1460 (s), 1430 (m), 1260

(s), 1110 (s), 1070 (s), 890 (w) cm²¹; ¹H NMR (500 MHz,

CDCl₃) d 7.27 (t, J¼8.0 Hz, 1H), 6.81 (d, J¼7.6 Hz, 1H),

6.73 (d, J¼8.3 Hz, 1H), 5.38 (m, 1H), 3.80 (s, 3H), 3.71–

3.86 (m, 2H), 2.73 (m, 1H), 2.58 (m, 1H), 2.49 (br, s, 1H),

2.10 (m, 1H), 1.96 (m, 1H), 1.80 (m, 1H), 1.59–1.70 (m,

4H), 1.50 (m, 1H), 1.35–1.47 (m, 3H), 1.20–1.32 (m, 3H);

¹³C NMR (125 MHz, CDCl₃) d 168.7, 155.9, 141.9, 130.3,

124.4, 122.4, 108.2, 74.5, 59.8, 55.7, 36.1, 30.3, 26.2, 25.0,

23.7, 20.7; high resolution mass spectrum (ESI, Na) m/z

329.1713 [(MþNa)^þ; calcd for C₁₈H₂₆O₄Na: 329.1729].

1200 (s), 1110 (s), 750 (s), 660 (s) cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.27 (m, 3H), 6.88 (d, J¼8.2 Hz,

2H), 6.82 (d, J¼7.7 Hz, 1H), 6.74 (d, J¼8.3 Hz, 1H), 5.89–

6.00 (m, 1H), 5.77–5.86 (m, 1H), 5.32 (m, 1H), 4.93–5.12

(m, 4H), 4.45 (m, 1H), 3.81 (m, 3H), 3.77 (m, 3H), 3.60 (m,

2H), 3.38 (d, J¼6.5 Hz, 2H), 2.04 (m, 2H), 1.93 (m, 2H),

1.62–1.75 (m, 2H), 1.33–1.51 (m, 4H); ¹³C NMR

(125 MHz, CDCl₃) d 168.7, 159.1, 156.2, 138.7, 138.2,

136.3, 130.5, 130.1, 129.2, 124.2, 121.6, 116.3, 114.4,

113.8, 113.7, 108.9, 72.9, 72.7, 66.5, 55.6, 55.2, 37.2, 34.3,

34.2, 33.6, 28.8, 24.6; high resolution mass spectrum (ESI,

Na) m/z 475.2448 [(MþNa)^þ; calcd for C₂₈H₃₆O₅Na:

475.2460].

4.1.25. Lactone (2)-36 and (2)-37. To a solution of the

(49 mg,

Grubbs

catalyst

(Cy₃P)₂Cl₂RuvCHPh

0.0597 mmol, 10 mol%) in dry CH₂Cl₂(80 mL) was

added a solution of (2)-34 (270 mg, 0.597 mmol) in

CH₂Cl₂(6 mL). The reaction mxture was stirred for 24 h

at ambient temperature and poured into H₂O (20 mL). The

organic phase was washed with brine (50 mL), dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Flash chroma-

tography (hexanes/ethyl acetate, 9:1) afforded 35 (250 mg,

92%) as a colorless oil which was directly used for the next

step. To a solution of 35 (250 mg, 0.589 mmol) in CH₂Cl₂

(20 mL) was added DDQ (267 mg, 1.178 mmol) followed

by pH 7 buffer (1 mL). The reaction mixture was allowed to

stir at room temperature for 40 min before being quenched

with saturated NaHCO₃(20 mL). The mixture was diluted

with CH₂Cl₂(100 mL) and the organic phase was washed

with brine (20 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexane-

s/ethyl acetate, 2:1) afforded (2)-36 (110 mg) and (2)-37

(56 mg) as colorless oil: (2)-36: [a]²_D³¼250.08 (c 1.17,

CHCl₃); IR (neat): 3530 (br, m), 3000 (m), 2920 (s), 1710

(s), 1580 (s), 1470 (s), 1270 (s), 1120 (s), 1070 (s), 970 (s),

4.1.27. Aldehyde (2)-39. To a solution of (2)-36 (82 mg,

0.270 mmol) in CH₂Cl₂(10 mL) was added Dess–Martin

periodinane (172 mg, 0.405 mmol). The reaction mixture

was stirred at room temperature for 30 min before being

quenched with aqueous Na₂S₂O₃(15%, 5 mL) and saturated

NaHCO₃(5 mL). The mixture was diluted with CH₂Cl₂

(100 mL) and the organic phase was washed with brine

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

vacuo. Flash chromatography (hexanes/ethyl acetate, 4:1)

provided (2)-39 (73 mg, 90% yield) as a colorless oil:

[a ]²_D³¼255.58 (c 0.47, CHCl₃); IR (neat): 2920 (m), 2830

(m), 1720 (s), 1590 (m), 1580 (m), 1460 (s), 1430 (m), 1270

(s), 1250 (m), 1110 (s), 1060 (s), 960 (m), 620 (w) cm²¹; ¹H

NMR (500 MHz, CDCl₃) d 9.89 (t, J¼2.5 Hz, 1H), 7.27 (t,

J¼9.0 Hz, 1H), 6.80 (d, J¼8.0 Hz, 2H), 5.50 (m, 1H), 5.38–

5.49 (m, 1H), 5.25–5.35 (m, 1H), 3.77 (s, 3H), 3.72 (dd,

J¼14.5, 10.3 Hz, 1H), 3.16 (dd, J¼14.5, 3.0 Hz, 1H), 2.71

(m, 2H), 2.21 (m, 1H), 1.63–1.79 (m, 4H), 1.50 (m, 1H),

1.24 (m, 1H), 1.14 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) d

167.8, 156.9, 139.6, 132.4, 130.5, 129.0, 123.5, 122.4,

109.4, 67.9, 55.6, 47.7, 37.7, 32.8, 32.6, 24.5, 19.8; high

resolution mass spectrum (CI, NH₃); m/z 303.1595

[(MþH)^þ; calcd for C₁₈H₂₃O₄: 303.1596].

630 (w) cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.27 (t,

;

J¼8.1 Hz, 1H), 6.80 (m, 2H), 5.35–5.45 (m, 1H), 5.20–

5.33 (m, 2H), 3.80 (s, 3H), 3.70–3.90 (m, 2H), 3.14 (d,

J¼11.7 Hz, 1H), 2.82–3.00 (br, s, 1H), 2.12–2.21 (m, 1H),

1.75–1.90 (m, 2H), 1.52–1.77 (m, 4H), 1.44 (m, 1H), 1.25

(m, 1H), 1.06 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) d

168.8, 156.7, 140.1, 132.0, 130.5, 128.9, 123.6, 122.8,

109.7, 71.2, 59.0, 55.8, 37.7, 37.2, 33.0, 32.8, 24.6, 19.7;

high resolution mass spectrum (ESI, Na) m/z 327.1556

[(MþNa)^þ; calcd for C₁₈H₂₄O₄Na: 327.1572]. (2)-37:

[a ]²_D³¼276.08 (c 0.25, CHCl₃); IR (neat): 3495 (br, m),

2923 (s), 2855 (s), 1714 (s), 1587 (s), 1470 (s), 1262 (s),

4.1.28. Allyl ester (2)-40. To a suspension of NaH (60%

dispersion in mineral oil, 14 mg, 0.335 mmol) in THF

(5 mL) at 08C was added a solution of allyl diethyl-

phosphonoacetate (75 mg, 0.318 mmol) in THF (2 mL).

The resulting mixture was stirred at 08C for 30 min. A

solution of (2)-39 (92 mg, 0.303 mmol) in THF (3 mL) was

added dropwise. The resultant mixture was warmed up to

room temperature and stirred for 1 h before being quenched

with saturated NH₄Cl (5 mL). The aqueous layer was

extracted with Et₂O (2£20 mL). The combined organic

1072 (s), 1055 (s), 761 (m), 696 (m) cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.31 (t, J¼8.0 Hz, 1H), 6.91 (d,

J¼7.7 Hz, 1H), 6.73 (d, J¼8.4 Hz, 1H), 5.43 (t, J¼10.7 Hz,

1H), 5.34 (m, 1H), 5.17 (m, 1H), 3.83 (s, 3H), 3.78 (m, 2H),

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6467

phases were washed with brine (10 mL), dried over MgSO₄,

ﬁltered, and concentrated in vacuo. Flash chromatography

(hexanes/ethyl acetate, 4:1) provide (2)-40 (55 mg, 96%

yield) as a colorless oil: [a]²_D³¼227.48 (c 0.39, CHCl₃); IR

(neat): 2930 (m), 1720 (s), 1583 (m), 1470 (m), 1438 (m),

1275 (s), 1257 (m), 1171 (m), 1117 (m), 1069 (m), 977 (m),

J¼8.3 Hz, 1H), 5.95 (m, 1H), 5.93 (m, 1H), 5.35 (dd,

J¼17.6, 1.6 Hz, 1H), 5.30 (m, 1H), 5.27 (d, J¼10.6 Hz, 1H),

5.00 (m, 1H), 4.63 (d, J¼5.7 Hz, 1H), 3.70 (dd, J¼14.4,

10.2 Hz, 1H), 3.14 (dd, J¼14.4, 2.5 Hz, 1H), 2.78 (m, 1H),

2.50 (m, 1H), 2.19 (m, 1H), 1.62–1.74 (m, 2H), 1.55–1.62

(m, 2H), 1.45 (m, 1H), 1.26 (m, 1H), 1.03 (m, 1H), 0.95 (s,

9H), 0.21 (s, 3H), 0.20 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) d 168.2, 165.6, 152.8, 144.1, 140.0, 132.2, 131.6,

129.8, 129.5, 126.5, 123.8, 122.8, 118.1, 117.6, 71.6, 65.0,

37.9, 37.0, 32.8, 31.9, 25.7, 24.7, 19.4, 18.5, 23.9, 24.0;

high resolution mass spectrum (ESI, Na) m/z 507.2563

[(MþNa)^þ; calcd for C₂₈H₄₀O₅SiNa: 507.2543].

935 (w) cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.26 (t,

;

J¼8.2 Hz, 1H), 7.14 (dt, J¼15.7, 7.3 Hz, 1H), 7.81 (d,

J¼8.4 Hz, 1H), 7.79 (d, J¼7.5 Hz, 1H), 5.96 (m, 1H), 5.95

(d, J¼15.7 Hz, 1H), 5.42 (m, 1H), 5.30 (dd, J¼17.1, 1.5 Hz,

1H), 5.29 (m, 1H), 5.24 (dd, J¼10.5, 1.5 Hz, 1H), 5.17 (m,

1H), 3.83 (s, 3H), 3.75 (dd, J¼14.4, 10.5 Hz, 1H), 3.15 (dd,

J¼14.4, 10.5 Hz, 1H), 2.69 (m, 1H), 2.56 (m, 1H), 2.20 (m,

1H), 1.60–1.75 (m, 3H), 1.54 (m, 1H), 1.47 (m, 1H), 1.20–

1.34 (m, 2H), 1.10 (m, 1H); ¹³C NMR (125 MHz,

CDCl₃)??? d 167.9, 165.8, 156.9, 145.0, 139.6, 132.3,

132.2, 130.0, 129.1, 123.4, 122.4, 118.1, 109.4, 71.0, 64.9,

55.6, 37.7, 36.6, 32.9, 32.1, 24.6, 19.7; high resolution mass

spectrum (ESI, Na) m/z 407.1843 [(MþH)^þ; calcd for

C₂₃H₂₈O₅Na: 407.1834].

4.1.31. Acid (2)-43. To a solution of (2)-42 (45 mg,

0.093 mmol) in dry THF (6 mL) was added a solution of

Pd(PPh₃)₄(11 mg, 0.0093 mmol) and morpholine (81 mL,

0.93 mmol) at ambient temperature. The reaction mixture

was allowed to stir for 12 h. HCl (1N, 10 mL) was added

and the aqueous phase was extracted with Et₂O (2£50 mL).

The combined organic phases were washed with brine

(40 mL), dried over MgSO₄, ﬁltered, and concentrated in

vacuo. Flash chromatography (hexanes/ethyl acetate, 4:1)

afforded (2)-43 (35 mg, 85% yield) as a colorless oil:

[a ]²_D³¼216.08 (c 0.15, CHCl₃); IR (neat): 2930 (s), 1721

(s), 1698 (s), 1655 (m), 1463 (s), 1435 (m), 1288 (s), 1257

(s), 1113 (m), 840 (s), 785 (m) cm²¹; ¹H NMR (500 MHz,

CDCl₃) d 7.15 (t, J¼7.8 Hz, 1H), 7.05 (m, 1H), 6.78 (d,

J¼7.4 Hz, 1H), 6.74 (d, J¼8.3 Hz, 1H), 5.91 (d, J¼15.6 Hz,

1H), 5.40 (m, 1H), 5.31 (m, 1H), 5.01 (m, 1H), 3.72 (dd,

J¼14.4, 10.4 Hz, 1H), 3.16 (dd, J¼14.4, 2.4 Hz, 1H), 2.80

(m, 1H), 2.54 (m, 1H), 2.20 (m, 1H), 1.68 (m, 2H), 1.59 (m,

2H), 1.46 (m, 1H), 1.30 (m, 1H), 1.05 (m, 1H), 0.97 (s, 9H),

0.21 (s, 3H), 0.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) d

171.1, 168.3, 152.8, 146.6, 139.8, 131.6, 129.6, 126.5,

123.3, 122.8, 117.6, 71.5, 37.9, 37.1, 32.8, 32.0, 25.8, 24.7,

19.4, 18.5, 2 3.9, 24.0; high resolution mass spectrum

(ESI, Na) m/z 467.2335 [(MþNa)^þ; calcd for C₂₅H₃₆O₅Si:

467.2330].

4.1.29. Phenol (2)-41. A solution of (2)-40 (43 mg,

0.112 mmol) in CH₂Cl₂(40 mL) at 2788C was treated

with BBr₃(1.0 M in CH₂Cl₂, 336 mL, 0.336 mmol). The

mixture was stirred at 2788C for 2 h, and then quenched

with saturated NH₄Cl (20 mL). The mixture was allowed to

warm up to room temperature and diluted with CH₂Cl₂

(50 mL). The organic layer was washed brine (20 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 4:1) provided

(2)-41 (36 mg, 87% yield) as a colorless oil: [a ]²_D³¼221.38

(c 0.40, CHCl₃); IR (neat): 3386 (br, m), 2929 (m), 1722 (s),

1698 (s), 1651 (m), 1588 (m), 1465 (m), 1292 (s), 1257 (s),

1

1116 (m), 1062 (m), 974 (m) cm²¹; H NMR (500 MHz,

CDCl₃) d 8.75–9.05 (br, s, 1H), 7.29 (t, J¼7.8 Hz, 1H), 7.03

(dt, J¼15.7, 7.9 Hz, 1H), 6.88 (d, J¼8.4 Hz, 1H), 6.77 (d,

J¼7.4 Hz, 1H), 6.00 (dt, J¼15.6, 1.4 Hz, 1H), 5.95 (m, 1H),

5.25 (d, J¼17.2 Hz, 1H), 5.29–5.42 (m, 3H), 5.28 (d,

J¼10.5 Hz, 1H), 4.68 (dt, J¼5.6, 1.4 Hz, 2H), 3.73 (dd,

J¼15.3, 6.5 Hz, 1H), 3.50 (dd, J¼15.3, 4.4 Hz, 1H), 2.62

(td, J¼6.1, 1.3 Hz, 2H), 2.10 (m, 1H), 1.96 (m, 1H), 1.60–

1.77 (m, 2H), 1.25–1.60 (m, 4H); ¹³C NMR (125 MHz,

CDCl₃) d 168.4, 165.5, 159.2, 143.5, 142.9, 133.0, 132.2,

130.8, 130.5, 124.3, 123.0, 118.1, 116.1, 73.2, 65.1, 65.0,

38.7, 37.5, 32.8, 32.7, 25.0. 20.6, 20.5; high resolution mass

spectrum (ESI, Na) m/z 393.1782 [(MþNa)^þ; calcd for

C₂₂H₂₆O₅Na: 393.1778].

4.1.32. Enecarbamate (2)-44. To a solution of (2)-43

(40 mg, 0.090 mmol) in dry acetone (4 mL) was sequen-

tially added N,N-diisopropylethylamine (24 mg, 32 mL,

0.094 mmol) and isobutylchloroformate (27 mg, 27 mL,

0.092 mmol) at 08C. The reaction mixture was stirred at

room temperature for 1 h, and then a solution of sodium

azide (58 mg, 0.902 mmol) in distilled H₂O (2 mL) was

added. The resulting mixture was stirred at ambient

temperature for an additional 30 min. Brine (10 mL) was

added and the aqueous phase extracted with ethyl acetate

(2£20 mL). The combined organic phases were dried over

MgSO₄, ﬁltered and concentrated in vacuo. The residue was

azeotropically dried with benzene (2£2 mL) and then

dissolved in dry toluene (2 ml) and heated at reﬂux for

15 min. 2-(Trimethylsilyl)-ethanol (130 mL, 0.902 mmol)

was added in one portion and the mixture was heated at

reﬂux for an additional 10 min. The mixture was then

cooled to ambient temperature and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 20:1)

afforded (2)-44 (40.6 mg, 81%) as a colorless oil:

[a ]²_D³¼215.48 (c 0.80, CH₂Cl₂); IR (neat): 3334 (br, m),

2950 (s), 1715 (s), 1681 (s), 1519 (m), 1463 (s), 1291 (s),

4.1.30. TBS ether (2)-42. A solution of (2)-41 (39 mg,

0.105 mmol) in CH₂Cl₂(8 mL) was treated with triethyl-

amine (45 mL, 0.316 mmol) and tert-butyldimethylsilyl

triﬂuoromethanesulfonate (29 mL, 0.126 mmol) at 2788C.

After 10 min, the solution was warmed up to ambient

temperature, added to brine-saturated NaHCO₃(1:1,

20 mL), and extracted with ether (3£20 mL). The combined

organic phases were dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 20:1) afforded (2)-42 (45 mg, 88% yield) as a

colorless oil: [a]²_D³¼213.38 (c 0.85, CHCl₃); IR (neat):

2930 (s), 1723 (s), 1580 (m), 1462 (s), 1290 (s), 1258 (s),

1

1167 (m), 1065 (m), 973 (m), 841 (s), 785 (m) cm²¹; H

NMR (500 MHz, CDCl₃) d 7.12 (t, J¼7.8 Hz, 1H), 6.94 (dt,

1253 (s), 1230 (s), 839 (s), 785 (m) cm²¹

;

¹H NMR

J¼15.6, 7.5 Hz, 1H), 6.76 (d, J¼7.5 Hz, 1H), 6.74 (d,

(500 MHz, C₆D₆) d 7.01 (t, J¼8.1 Hz, 1H), 6.94 (t,

6468

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

J¼12.0 Hz, 1H), 6.77 (d, J¼8.3 Hz, 1H), 6.71 (d, J¼7.6 Hz,

1H), 6.00 (d, J¼9.3 Hz, 1H), 5.51 (m, 1H), 5.40 (m, 1H),

5.12 (m, 1H), 4.84 (m, 1H), 4.32 (t, J¼8.1 Hz, 1H), 4.08 (dd,

J¼14.4, 10.4, Hz, 1H), 3.17 (dd, J¼14.4, 2.2 Hz, 1H), 2.80

(m, 1H), 2.43 (m, 1H), 2.15 (m, 1H), 1.60–1.78 (m, 2H),

1.50–1.62 (m, 2H), 1.05 (s, 9H), 0.95–1.00 (m, 3H), 0.24

(s, 3H), 0.20 (s, 3H), 0.03 (s, 9H); ¹³C NMR (125 MHz,

C₆D₆) d 167.9, 153.2, 153.1, 140.1, 131.6, 129.8, 129.5,

126.3, 122.9, 117.7, 104.9, 73.2, 63.1, 38.1, 34.9, 33.0, 31.6,

25.7, 24.9, 19.5, 18.4, 17.7, 21.89, 24.2, 24.3; high

resolution mass spectrum (ESI, Na) m/z 582.3054

[(MþNa)^þ; calcd for C₃₀H₄₉NO₅Si₂Na: 582.3047].

10.5 Hz, 1H), 3.12 (dq, J¼14.4, 2.5 Hz, 1H), 2.35–2.49 (m,

2H), 2.28 (apparent, pt, J¼7.5, 1.5 Hz, 2H), 2.11–2.19 (m,

1H), 1.58–1.69 (m, 4H), 1.51–1.58 (m, 1H), 1.40–1.49 (m,

1H), 1.25–1.34 (m, 1H), 1.06–1.15 (m, 1H), 1.02 (t,

J¼7.4 Hz, 3H); ¹³C NMR (125 MHz, CD₃OD) d 170.4,

165.9, 156.6, 142.5, 141.1, 137.6, 133.5, 131.6, 130.6,

126.1, 125.4, 123.2, 122.2, 120.4, 115.4, 110.5, 73.9, 38.9,

36.3, 33.7, 33.1, 25.9, 21.5, 21.0, 14.4; high resolution mass

spectrum (ESI, Na) m/z 432.2149 [(MþNa)^þ; calcd for

C₂₅H₃₁NO₄Na: 432.2151].

4.1.35. Aldehyde (1)-46. To a solution of (þ)-38 (85 mg,

0.278 mmol) in CH₂Cl₂(10 mL) was added Dess–Martin

periodinane (142 mg, 0.333 mmol). The reaction mixture

was stirred at ambient temperature for 30 min before being

quenched with Na₂S₂O₃(15%, 5 mL) and saturated

NaHCO₃(5 mL). The mixture was diluted with CH₂Cl₂

(100 mL) and the organic phase was washed with brine

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

vacuo. Flash chromatography (hexanes/ethyl acetate, 4:1)

provided (þ)-46 (76 mg, 90% yield) as a colorless oil:

[a ]²_D³¼þ8.778 (c 0.46, CHCl₃); IR (neat): 2990 (m), 2920

(s), 1720 (s), 1590 (s), 1460 (s), 1430 (m), 1270 (br, s), 1105

4.1.33. Enamide (2)-45. A solution of (2)-44 (14 mg,

0.025 mmol) in dry THF (1 mL) was treated with sodium

bis(trimethylsilyl)amide (1.0 M in THF, 30 mL,

0.030 mmol) for 5 min at 08C. A solution of 6 (6.4 mg,

0.050 mmol) in dry benzene (0.1 mL) was added. The

resulting mixture was stirred at 08C for 10 min before being

quenched with saturated NH₄Cl (3 mL) and extracted with

ether (2£15 mL). The combined organic phases were

washed with brine (10 mL), dried over MgSO₄, ﬁltered

and concentrated in vacuo. Flash chromatography (hexane-

s/ethyl acetate, 10:1) provided (2)-45 (12.5 mg, 75%) as a

colorless oil: [a ]²_D³¼243.88 (c 0.60, CH₂Cl₂); IR (neat):

2954 (s), 1722 (s), 1594 (m), 1580 (m), 1463 (s), 1290 (s),

1255 (s), 1230 (m), 1117 (m), 1063 (m), 840 (s), 784

(m) cm²¹; ¹H NMR (500 MHz, C₆D₆) d 7.53 (t, J¼11.3 Hz,

1H), 6.92 (t, J¼8.0 Hz, 1H), 6.74 (td, J¼11.8 Hz, 1.2 Hz,

1H), 6.65 (d, J¼8.2 Hz, 1H), 6.61 (d, J¼8.5 Hz, 1H), 6.50–

6.58 (m, 2H), 5.81 (m, 1H), 5.61 (dd, J¼18.2, 9.5 Hz, 1H),

5.35–5.42 (m, 1H), 5.21–5.31 (m, 1H), 5.14 (m, 1H), 4.15–

4.21 (m, 2H), 3.98 (dd, J¼14.1, 10.4 Hz, 1H), 3.06 (dt,

J¼14.1, 2.5 Hz, 1H), 2.88 (m, 1H), 2.55 (m, 1H), 2.02 (br, d,

J¼8.6 Hz, 1H), 1.85–1.94 (m, 2H), 1.60–1.72 (m, 2H),

1.46–1.60 (m, 2H), 1.30–1.46 (m, 3H), 0.95 (s, 9H), 0.86–

0.93 (m, 2H), 0.72 (t, J¼7.5 Hz, 3H), 0.13 (s, 3H), 0.09 (s,

3H), 20.12 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) d 168.1,

167.2, 154.0, 153.4, 142.8, 140.4, 137.4, 131.8, 130.0,

129.8, 127.8, 126.9, 125.2, 123.2, 122.7, 121.1, 118.0, 72.9,

65.4, 38.3, 35.6, 33.3, 32.0, 26.0, 25.2, 20.9, 19.8, 18.7,

17.6, 13.9, 21.7, 23.8, 24.0; high resolution mass

spectrum (ESI, Na) m/z 690.3644 [(MþNa)^þ; calcd for

C₃₇H₅₇NO₆Si₂Na: 690.3622].

1

(s), 1070 (s) cm²¹; H NMR (500 MHz, CDCl₃) d 9.87 (s,

1H), 7.27 (t, J¼8.1 Hz, 1H), 6.81 (d, J¼7.7 Hz, 1H), 5.68

(m, 1H), 3.79 (s, 3H), 2.84 (m, 1H), 2.71 (m, 1H), 2.60 (m,

2H), 2.11 (m, 1H), 1.60–1.78 (m, 4H), 1.55 (m, 1H),

1.40–1.53 (m, 3H), 1.20–1.40 (m, 3H); ¹³C NMR

(125 MHz, CDCl₃) d 200.4, 168.2, 156.2, 141.6. 130.3,

124.2, 121.9, 121.8, 108.1, 70.7, 55.6, 46.9, 30.3, 30.2, 30.0,

26.4, 25.1, 23.9, 20.8; high resolution mass spectrum (ESI,

Na) m/z 327.1679 [(MþNa)^þ; calcd for C₁₈H₂₄O₄Na:

327.1673].

4.1.36. Allyl ester (2)-47. To a suspension of NaH (60%

dispersion in mineral oil, 20 mg, 0.489 mmol) in THF

(5 mL) at 08C was added a solution of allyl diethyl-

phosphonoacetate (110 mg, 0.500 mmol) in THF (2 mL).

The resulting mixture was stirred at 08C for 30 min. A

solution of (þ)-46 (136 mg, 0.444 mmol) in THF (3 mL)

was precooled to 08C and added dropwise. The resultant

mixture was warmed up to ambient temperature and stirred

for 1 h before being quenched with saturated NH₄Cl (5 mL).

The aqueous layer was extracted with Et₂O (2£20 mL). The

combined organic phases were washed with brine (10 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 4:1) provided

(2)-47 (81 mg, 95% yield) as a colorless oil: [a ]²_D³¼29.38

(c 0.70, CHCl₃); IR (neat): 2936 (s), 2857 (m), 1722 (s),

1656 (m), 1583 (m), 1469 (s), 1273 (s), 1172 (s), 1113 (s),

4.1.34. Analog (2)-3. A solution of (2)-45 (4.9 mg,

0.0073 mmol) in THF (1 mL) was treated with tetrabutyl-

ammonium ﬂuoride (1.0 M in THF, 22 ml, 0.022 mmol) at

08C. The resultant brown solution was stirred for 10 min at

08C, added to H₂O (5 ml) and extracted with ethyl ether

(2£15 mL). The combined organic phases were washed

with brine (10 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 2:1) afforded (2)-3 (2.6 mg, 85% yield) as a

white solid: [a ]²_D³¼260.08 (c 0.26, MeOH); IR (neat): 3282

(br, s), 2927 (s), 1719 (m), 1649 (s), 1588 (s), 1464 (s), 1294

(s), 1256 (s), 1217 (s), 1060 (m), 972 (m), 955 (m) cm²¹; ¹H

NMR (500 MHz, CD₃OD) d 7.31 (t, J¼12.0 Hz, 1H), 7.12

(t, J¼7.8 Hz, 1H), 6.86 (td, J¼11.6, 1.1 Hz, 1H), 6.81 (d,

J¼14.3 Hz, 1H), 6.72 (d, J¼8.2 Hz, 1H), 6.68 (d, J¼7.4 Hz,

1H), 5.81 (apparent q, J¼13.8 Hz, 1H), 5.69 (d, J¼11.5 Hz,

1H), 5.38 (dt, J¼14.5, 7.5 Hz, 1H), 5.30–5.39 (m, 1H),

5.18–5.25 (m, 1H), 4.92–5.04 (m, 1H), 3.67 (dd, J¼14.1,

1

1073 (m), 957 (m), 928 (w) cm²¹; H NMR (500 MHz,

CDCl₃) d 7.29 (t, J¼7.9 Hz, 1H), 7.10 (dt, J¼15.7, 7.0 Hz,

1H), 6.80 (d, J¼7.7 Hz, 1H), 6.73 (d, J¼8.2 Hz, 1H), 5.95

(m, 1H), 5.31 (dd, J¼17.2, 1.5 Hz, 1H), 5.26 (m, 1H), 5.24

(dd, J¼11.2, 1.5 Hz, 1H), 4.65 (dt, J¼5.8, 1.3 Hz, 2H), 3.81

(s, 3H), 2.73 (m, 1H), 2.66 (m, 1H), 2.50–2.63 (m, 2H), 2.01

(m, 1H), 1.60–1.74 (m, 4H), 1.50 (m, 1H), 1.35–1.50 (m,

3H), 1.33 (m, 1H), 1.27 (m, 2H); ¹³C NMR (125 MHz,

CDCl₃) d 168.3, 165.8, 156.2, 145.1, 141.5, 132.3, 130.1,

123.3, 121.8, 118.1, 108.0, 73.9, 64.9, 55.6, 35.9, 30.3, 30.1,

26.4, 25.3, 23.9, 20.7; high resolution mass spectrum (ESI,

Na) m/z 409.1888 [(MþNa)^þ; calcd for C₂₃H₃₀O₅Na:

409.2089].

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

6469

4.1.37. Phenol (2)-48. A solution of (2)-47 (74 mg,

0.192 mmol) in CH₂Cl₂(70 mL) at 2788C was treated

with BBr₃(1.0 M in CH₂Cl₂, 0.576 mL, 0.576 mmol). The

mixture was stirred at 2788C for 2 h, and then quenched

with saturated NH₄Cl (20 mL). The mixture was allowed to

warm up to room temperature and diluted with CH₂Cl₂

(80 mL). The organic layer was washed brine (20 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 4:1) provided

(2)-48 (55 mg, 83% yield) as a colorless oil: [a ]²_D³¼252.58

(c 0.55, CHCl₃); IR (neat): 2932 (s), 1723 (s), 1652 (s), 1605

(s), 1448 (s), 1367 (m), 1290 (s), 1246 (s), 1114 (m), 989

(m), 814 (m), 713 (m) cm²¹; ¹H NMR (500 MHz, CDCl₃) d

10.88 (s, 1H), 7.28 (t, J¼7.9 Hz, 1H), 6.94 (dt, J¼15.6,

7.4 Hz, 1H), 6.81 (d, J¼8.3 Hz, 1H), 6.72 (d, J¼7.5 Hz,

1H), 5.95 (m, 1H), 5.92 (d, J¼15.6 Hz, 1H), 5.37 (dd,

J¼17.2, 1.1 Hz, 1H), 5.23 (d, J¼10.1 Hz, 1H), 5.25 (m, 1H),

4.61 (d, J¼5.7 Hz, 2H), 3.40 (td, J¼12.3, 2.4 Hz, 1H), 2.62

(m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 1.95 (m, 1H), 1.78 (m,

1H), 1.50–1.70 (m, 4H), 1.29–1.50 (m, 6H); ¹³C NMR

(125 MHz, CDCl₃) d 171.6, 165.5, 162.4, 146.4, 143.3,

134.1, 132.2, 124.2, 122.5, 118.1, 115.5, 112.2, 76.3, 65.0,

37.2, 33.1, 31.2, 28.8, 27.0, 24.7, 24.2, 21.1; high resolution

mass spectrum (ESI, Na) m/z 395.1942 [(MþNa)^þ; calcd

for C₂₂H₂₈O₅Na: 395.1935].

(c 0.28, CHCl₃); IR (neat): 2930 (s), 2858 (s), 1726 (s), 1698

(s), 1464 (s), 1277 (s), 1261 (s), 1107 (m), 1058 (m), 839 (s),

784 (m) cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.14 (t,

;

J¼7.8 Hz, 1H), 7.02 (dt, J¼15.6, 7.8 Hz, 1H), 6.81 (d,

J¼7.7 Hz, 1H), 6.68 (d, J¼8.2 Hz, 1H), 5.94 (d, J¼15.6 Hz,

1H), 5.23 (m, 1H), 2.73 (m, 1H), 2.51–2.68 (m, 3H), 2.02

(m, 1H), 1.59–1.72 (m, 4H), 1.30–1.58 (m, 7H), 0.97 (s,

9H), 0.22 (s, 3H), 0.20 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) d 170.5, 168.2, 152.2, 146.4, 141.6, 129.8, 126.9,

123.3, 122.2, 116.3, 73.5, 36.1, 30.8, 30.1, 29.3, 26.1, 25.9,

25.7, 23.2, 21.0, 18.2, 24.1, 24.4; high resolution mass

spectrum (ESI, Na) m/z 469.2352 [(MþNa)^þ; calcd for

C₂₅H₃₈O₅SiNa: 469.2386].

4.1.40. Enecarbamate (1)-51. To a solution of (þ)-50

(25 mg, 0.056 mmol) in acetone (3 mL) was sequentially

20 mL,

added

N,N-diisopropylethylamine

(15 mg,

0.117 mmol) and isobutylchloroformate (15 mg, 15 mL,

0.112 mmol) at 08C. The reaction mixture was stirred at

room temperature for 1 h and then a solution of sodium

azide (36 mg, 0.560 mmol) in distilled H₂O (1.5 mL) was

added. The resulting mixture was stirred at room tempera-

ture for an additional 30 min. Brine (10 mL) was added and

the aqueous phase extracted with ethyl acetate (2£30 mL).

The combined organic phases were dried over MgSO₄,

ﬁltered and concentrated in vacuo. The residue was

azeotropically dried with benzene (2£1 mL) and dissolved

in toluene (2 ml) and heated at reﬂux for 15 min.

2-(trimethylsilyl)-ethanol (80 mL, 0.560 mmol) was added

in one portion and the mixture was heated at reﬂux for an

additional 10 min. The mixture was cooled to room

temperature and concentrated in vacuo. Flash chromato-

graphy (hexanes/ethyl acetate, 20:1) afforded (þ)-51

(24.6 mg, 78%) as a colorless oil: [a ]²_D³¼þ4.88 (c 0.95,

CH₂Cl₂); IR (neat): 2952 (s), 1722 (s), 1681 (s), 1520 (m),

1464 (s), 1277 s), 1252 (s), 1112 (m), 1057 (m), 838 (s), 783

(m) cm²¹; ¹H NMR (500 MHz, C₆D₆) d 7.00 (t, J¼8.0 Hz,

1H), 6.82 (m, 1H), 6.70 (d, J¼7.7 Hz, 1H), 6.88 (d,

J¼7.2 Hz, 1H), 5.92 (br, d, J¼9.6 Hz, 1H), 5.25 (m, 1H),

4.64 (m, 1H), 4.23 (t, J¼8.3 Hz, 2H), 2.76 (m, 1H), 2.50 (m,

2H), 2.28 (m, 1H), 1.95 (m, 1H), 1.71 (m, 1H), 1.44–1.67

(m, 4H), 1.17–1.44 (m, 6H), 1.03 (s, 9H), 0.92 (t, J¼8.3 Hz,

2H), 0.18 (s, 3H), 0.14 (s, 3H), 20.10 (s, 9H); ¹³C NMR

(125 MHz, C₆D₆) d 167.8, 153.3, 152.6, 141.8, 129.5, 128.3,

126.4, 122.4, 116.6, 104.6, 75.3, 63.1, 33.8, 30.9, 30.2, 28.8,

26.2, 26.1, 25.7, 23.3, 21.4, 18.2, 17.7, 21.9, 24.2, 24.6;

high resolution mass spectrum (ESI, Na) m/z 584.3292

[(MþNa)^þ; calcd for C₃₀H₅₁NO₅SiNa: 584.3304].

4.1.38. TBS ether (1)-49. A solution of (2)-48 (69 mg,

0.185 mmol) in CH₂Cl₂(8 mL) was treated with triethyl-

amine (78 mL, 0.556 mmol) and butyldimethylsilyl

triﬂuoromethanesulfonate (65 mL, 0.278 mmol) at 2788C.

After 10 min, the solution was warmed up to ambient

temperature, added to brine-saturated NaHCO₃(1:1,

20 mL), and extracted with Et₂O (2£20 mL). The combined

organic phases were dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 20:1) afforded (þ)-49 (81 mg, 90% yield) as a

colorless oil: [a ]²_D³¼þ15.18 (c 1.20, CHCl₃); IR (neat):

2930 (s), 1726 (s), 1657 (m), 1581 (m), 1464 (s), 1260 (s),

1169 (m), 1106 (m), 839 (s), 784 (m) cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.14 (t, J¼7.9 Hz, 1H), 6.91 (dt,

J¼15.6, 7.4 Hz, 1H), 6.80 (d, J¼7.7 Hz, 1H), 6.67 (d,

J¼8.1 Hz, 1H), 5.94 (m, 1H), 5.93 (d, J¼15.6 Hz, 1H), 5.32

(dd, J¼17.2, 1.6 Hz, 1H), 5.24 (d, J¼10.4 Hz, 1H), 5.23 (m,

1H), 4.62 (dt, J¼5.7, 1.4 Hz, 1H), 2.69 (m, 1H), 2.50–2.65

(m, 3H), 2.00 (m, 1H), 1.60–1.71 (m, 4H), 1.35–1.59 (m,

5H), 1.30 (m, 2H), 0.95 (s, 9H), 0.21 (s, 3H), 0.20 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) d 168.1, 165.6, 152.2, 143.9,

141.6, 132.2, 129.7, 127.0, 123.9, 122.2, 118.2, 116.2, 73.6,

65.0, 36.0, 30.8, 30.2, 29.1, 26.1, 25.8, 25.7, 23.3, 21.0,

18.2, 24.0, 24.4; high resolution mass spectrum (ESI, Na)

m/z 509.2711 [(MþNa)^þ; calcd for C₂₈H₄₂O₅SiNa:

509.2699].

4.1.41. Enamide (1)-52. A solution of (þ)-51 (17 mg,

0.0303 mmol) in dry THF (2 mL) was treated with sodium

bis(trimethylsilyl)amide (1.0 M in THF, 36 mL,

0.0364 mmol) for 5 min at 08C. A solution of 6 (7.7 mg,

0.0606 mmol) in dry benzene (0.2 mL) was added. The

resulting mixture was stirred at 08C for 10 min before being

quenched with saturated NH₄Cl (5 mL) and extracted with

Et₂O (2£20 mL). The combined organic phases were

washed with brine (10 mL), dried over MgSO₄, ﬁltered

and concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 10:1) provided (þ)-52 (15.4 mg, 76%) as a

colorless oil: [a ]²_D³¼þ6.08 (c 0.20, CH₂Cl₂); IR (neat): 2953

(s), 1726 (s), 1692 (m), 1580 (m), 1464 (s), 1278 (s), 1252

4.1.39. Acid (1)-50. To a solution of (þ)-49 (70 mg,

0.093 mmol) in dry THF (10 mL) was added a solution of

Pd(PPh₃)₄(16 mg, 0.015 mmol) and morpholine (126 mL,

1.44 mmol) at room temperature. The reaction mixture was

allowed to stir for 3 h. HCl (1N, 10 mL) was added and the

aqueous phase was extracted with Et₂O (2£50 mL). The

combined organic phases were washed with brine (20 mL),

dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Flash chromatography (hexanes/ethyl acetate, 4:1) afforded

(þ)-50 (52 mg, 82% yield) as a colorless oil: [a ]²_D³¼þ13.88

1

(s), 1110 (m), 1053 (m), 839 (s), 783 (m) cm²¹; H NMR

6470

A. B. Smith, III, J. Zheng / Tetrahedron 58 (2002) 6455–6471

M. R. J. Org. Chem. 1997, 62, 8188–8192. Erickson, K. L.;

Beutler, J. A.; Cardellina, II, J. A.; Boyd, M. R. J. Org. Chem.

2001, 66, 1532.

(500 MHz, C₆D₆) d 7.56 (t, J¼10.1 Hz, 1H), 6.98 (t,

J¼7.9 Hz, 1H), 6.74 (t, J¼11.7 Hz, 1H), 6.67 (d, J¼8.1 Hz,

1H), 6.51 (d, J¼11.5 Hz, 1H), 6.49 (d, J¼14.2 Hz, 1H),

5.70–5.79 (m, 1H), 5.61 (dd, J¼18.2, 9.5 Hz, 1H),

5.33–5.40 (m, 1H), 4.12–4.21 (m, 2H), 2.63–2.79 (m,

2H), 2.43–2.52 (m, 2H), 1.97–2.05 (m, 1H), 1.88–1.95 (m,

2H), 1.62–1.72 (m, 2H), 1.54–1.62 (m, 2H), 1.42–1.50 (m,

1H), 1.26–1.40 (m, 4H), 1.11–1.21 (m, 2H), 1.01 (s, 9H),

0.84–0.90 (m, 2H), 0.62 (t, J¼7.6 Hz, 3H), 0.18 (s, 3H),

0.12 (s, 3H), 20.13 (s, 6H); ¹³C NMR (125 MHz, C₆D₆) d

168.0, 167.2, 154.0, 152.9, 142.8, 142.1, 137.5, 129.8,

128.3, 127.8, 127.0, 125.2, 122.6, 122.4, 121.1, 116.8, 74.9,

65.3, 34.7, 31.2, 30.6, 29.2, 26.2, 26.0, 23.8, 21.4, 21.0,

18.5, 17.6, 13.9, 21.7, 24.0, 24.2; high resolution mass

spectrum (ESI, Na) m/z 692.3760 [(MþNa)^þ; calcd for

C₃₇H₅₉NO₆Si₂Na: 692.3779].

2. Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem. Int. Ed.

2000, 39, 4308–4310. Wu, Y.; Seguil, O. R.; De Brabander,

J. K. Org. Lett. 2000, 26, 4241–4244. Wu, Y.; Liao, X.; Wang,

R.; Xie, X.; De Brabander, J. K. J. Am. Chem. Soc. 2002, 124,

3245–3253.

3. The absolute stereochemistry, initially assigned by Boyd and

co-workers based on Mosher ester analysis, was reassigned by

De Brabander et al., see: Ref. 2.

4. Paull, K. D.; Hamel, E.; Malspeis, L. Prediction of

Biochemical Mechanism of Action from the In vitro

Antitumor Screen of the National Cancer Institute. In Cancer

Chemotherapeutic Agents; Foye, W. O., Ed.; American

Chemical Society: Washington, DC, 1995.

5. Boyd, M. R.; Farina, C.; Belﬁore, P.; Gagliardi, S.; Kim, J. M.;

Kayakawa, Y.; Beutler, J. A.; Mckee, T. C.; Bowman, B. J.;

Bowman, E. J. J. Pharmacol. Exp. Ther. 2001, 297, 114–120.

6. Kunze, B.; Jansen, R.; Sasse, F.; Hoﬂe, H.; Reichenbach, H.

J. Antbiot. 1998, 51, 1075–1080. Jansen, R.; Kunze, B.; Sasse,

F.; Reichenbach, H.; Hoﬂe, H. J. Org. Chem. 2000, 913–919.

7. McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, II,

J. H.; Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R.; Boyd,

M. R. J. Org. Chem. 1998, 63, 7805–7810. Suzumura, K. I.;

Takahashi, I.; Matsumoto, H.; Nagai, K.; Setiawan, B.;

Rantiatmodjo, R. M.; Suzuki, K. I.; Nagano, N. Tetrahedron

Lett. 1997, 38, 7573–7576.

4.1.42. Analog (2)-4. A solution of (þ)-52 (7.8 mg,

0.0117 mmol) in THF (1 mL) was treated with tetrabutyl-

ammonium ﬂuoride (1.0 M in THF, 35 ml, 0.0351 mmol) at

08C. The resultant brown solution was stirred for 10 min at

08C, added to H₂O (5 ml), and extracted with ethyl ether

(2£15 mL). The combined organic phases were washed

with brine (10 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Flash chromatography (hexanes/

ethyl acetate, 2:1) afforded (2)-4 (4.1 mg, 86% yield) as a

white solid: [a]²_D³¼215.98 (c 0.37, CH₂Cl₂); IR (neat):

2953 (s), 1726 (s), 1692 (m), 1580 (m), 1464 (s), 1278 (s),

1

1252 (s), 1110 (m), 1.53 (m), 839 (s), 783 (m) cm²¹; H

8. Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.

J. Org. Chem. 1999, 64, 153–155.

NMR (500 MHz, CD₃OD) d 7.56 (t, J¼10.1 Hz, 1H), 6.98

(t, J¼7.9 Hz, 1H), 6.74 (t, J¼11.7 Hz, 1H), 6.67 (d,

J¼7.7 Hz, 1H), 6.62 (d, J¼8.1 Hz, 1H), 6.51 (d,

J¼11.5 Hz, 1H), 6.49 (d, J¼14.2 Hz, 1H), 5.70–5.79 (m,

1H), 5.61 (dd, J¼18.2, 9.5 Hz, 1H), 5.33–5.40 (m, 1H),

4.12–4.21 (m, 2H), 2.63–2.79 (m, 2H), 2.43–2.52 (m, 2H),

1.97–2.05 (m, 1H), 1.88–1.95 (m, 2H), 1.62–1.72 (m, 2H),

1.54–1.62 (m, 2H), 1.42–1.50 (m, 1H), 1.26–1.40 (m, 4H),

1.11–1.21 (m, 2H), 1.01 (s, 9H), 0.84–0.90 (m, 2H), 0.62 (t,

J¼7.6 Hz, 3H), 0.18 (s, 3H), 0.12 (s, 3H), 20.13 (s, 9H);

¹³C NMR (125 MHz, CD₃OD) d 168.0, 167.2, 154.0, 152.9,

142.8, 142.1, 137.5, 129.8, 128.3, 127.8, 127.0, 125.2,

122.6, 122.4, 121.1, 116.8, 74.9, 65.3, 34.7, 31.2, 30.6, 29.2,

26.6, 26.2, 26.0, 23.8, 21.4, 21.0, 18.5, 17.6, 13.9, 21.7,

24.0, 24.2; high resolution mass spectrum (ESI, Na) m/z

434.2307 [(MþNa)^þ; calcd for C₂₅H₃₃NO₄Na: 434.2286].

9. Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara,

T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kijima, N. J.

J. Antibiot. 1998, 51, 14–20.

10. Labrecque, D.; Chatton, S.; Sej, R.; Blais, C.; Lamothe, S.

Tetrahedron Lett. 2001, 42, 2645–2648.

11. Snider, B. B.; Song, F. Org. Lett. 2001, 42, 2645–2648.

12. Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur.

J. 2001, 7, 5286–5298.

13. Preliminary communication: Smith, A. B.; Zheng, J. Synlett.

2001, 1019–1023, Spec. Issue.

14. For synthetic studies on the salicylihlamides lactone core, see:

Furstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2,

3731–3734. Feutrill, J. T.; Holloway, G. A.; Hilli, F.; Hugel,

H. M.; Rizzacasa, M. A. Tetrahedron Lett. 2000, 41,

8569–8572. Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi,

F.; Flaherty, P. T.; Mossman, C. J.; Roy, S.; Yang, K. Chem.

Commun. 2001, 255–256.

Acknowledgments

15. For investigations into syntheses of the salicylihalamide and

oximidine side chains, see: Snider, B. B.; Song, F. Org. Lett.

2000, 2, 407–408. Kuramochi, K.; Watanabe, H.; Kitahara, T.

Synlett. 2000, 397–399. Shen, R.; Porco, Jr J. A. Org. Lett.

2000, 2, 1333–1336. Stefanuti, I.; Smith, S. A.; Taylor, R. J.

K. Tetrahedron Lett. 2000, 41, 3735–3738. Fu¨rstner, A.;

Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3,

3955–3957.

Financial support was provided by the National Institutes of

Health (National Cancer Institute) through grant CA19033.

We thank Professor George R. Pettit for the biological

assays of the natural product and analogs. In addition, we

thank Dr George T. Furst and Dr Rakesh K. Kohli of the

University of Pennsylvania Spectroscopic Service Center

for assistance in securing and interpreting high-ﬁeld NMR

spectra and mass spectra, respectively.

16. Shimasaki, H.; Kagechika, H.; Fukasawa, H.; Kawachi, E.;

Shudo, K. Chem. Pharm. Bull. 1995, 43(1), 100–107.

17. For reviews, see: Trnka, T.; Grubbs, R. H. Acc. Chem. Res.

2001, 34, 18–29. Fu¨rstner, A. Angew. Chem. 2000, 112,

3140–3172. Fu¨rstner, A. Angew. Chem. Int. Ed. 2000, 39,

3012–3043. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,

4413–4450. Fu¨rstner, A. Top. Organomet. Chem. 1998, 1,

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Article Doi

Total synthesis of (-)-salicylihalamide A and related congeners

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