Total synthesis of (+)-Sieboldine a: Evolution of a pinacol-terminated cyclization strategy

Article

pubs.acs.org/joc

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-

Terminated Cyclization Strategy

Stephen M. Canham,^†David J. France,^‡and Larry E. Overman*

Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States

S

* Supporting Information

ABSTRACT: This article describes synthetic studies that

culminated in the ﬁrst total synthesis of the Lycopodium

alkaloid sieboldine A. During this study, a number of pinacol-

terminated cationic cyclizations were examined to form the cis-

hydrindanone core of sieboldine A. Of these, a mild Au(I)-

promoted 1,6-enyne cyclization that was terminated by a

semipinacol rearrangement proved to be most eﬃcient.

Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety

of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by

forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor.

(IC₅₀1.6 μM), and also exhibited modest cytoxicity toward

murine lymphoma L1210 cells (IC₅₀5.1 μg/mL).⁴

INTRODUCTION

■

The Lycopodium family of alkaloids displays a diverse array of

complex molecular structures, which for years have served to

stimulate innovation in organic synthesis.¹Although the

biological proﬁle of only a few alkaloids of this family has

been studied in detail, several are known to exhibit important

biological activities. Notably (−)-huperzine A (1), an

acetylcholinesterase inhibitor, is currently undergoing clinical

evaluation for the treatment of Alzheimer’s disease and

schizophrenia (Figure 1).^2,3

Motivated largely by its distinctive structure, (+)-sieboldine

A (2) was selected as a worthy target for total synthesis.

Sieboldine A contains an unprecedented N-hydroxyazacyclo-

nonane ring embedded in a bicyclo[5.2.1]decane-N,O-acetal,

the fragment shown in red in Figure 1. These functionalities

were previously unknown in natural products and in the

chemical literature as a whole. Sieboldine A also contains a cis-

hydrindane, the distinctive structural feature of the fawcetti-

mine class of Lycopodium alkaloids.¹Herein, we describe the

evolution of a synthetic sequence that culminated in the ﬁrst

total synthesis of (+)-sieboldine A (2) in 2010.⁵In 2011, Tu

and co-workers reported the total synthesis of ( )-alopecur-

idine and its conversion to ( )-sieboldine A by the biomimetic

sequence ﬁrst postulated by Kobayashi.^4,6

RESULTS AND DISCUSSION

■

Synthesis Plan. Our synthetic planning was inﬂuenced by

the anticipated sensitivity of the hydroxylamine N,O-acetal

functionality of sieboldine A (2). As a result, we envisaged

forming the N-hydroxyazacyclononane ring at a late stage in the

synthesis by intramolecular condensation of a tethered

hydroxylamine side chain with the ﬁve-membered lactol 4 (X

= OH) or a derivative (Scheme 1).⁷Spirotricyclic tetrahy-

drofuran 4 was seen arising from α-methylene cis-hydrindan-

dione 5 by conjugate addition of a two-carbon fragment,

followed by oxidation of the resulting enolate or silyl derivative

from the less-hindered convex face.

Figure 1. Structure of (−)-huperizine A, (+)-sieboldine A, and

(+)-alopecuridine and X-ray model⁴of (+)-sieboldine A.

In 2003, Kobayashi and co-workers reported the isolation of

(+)-sieboldine A (2) as a minor alkaloid of the Japanese club

moss Lycopodium sieboldii together with the known alkaloid

(+)-alopecuridine (3).⁴Extensive NMR and single-crystal X-ray

analysis secured the unprecedented structure of sieboldine A.

This structurally unique Lycopodium alkaloid was reported to

inhibit electric eel acetylcholinesterase with an IC₅₀value of 2.0

μM, which is comparable to that reported for ( )-huperzine A

Because of the many previous syntheses of Lycopodium

alkaloids of the fawcettimine class,⁸a variety of approaches for

Special Issue: Robert Ireland Memorial Issue

Received: May 3, 2012

A

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Scheme 1. Initial Retrosynthetic Analysis of Sieboldine A

Scheme 2. Synthesis of Vinyl Iodide 13

low temperatures (−100 °C → −78 °C), provided a 1:1 ratio

of adduct 15 to the cis-alkene resulting from protodeiondina-

tion of 13 (Scheme 3).¹⁶To suppress competitive enolization,

Scheme 3. Nucleophilic Addition to Cyclopentanone 14

forming the cis-hydrindanone portion of sieboldine A were

conceivable. In earlier work from our laboratory, we had used a

pinacol-terminated Prins cyclization to assemble this fragment

in total syntheses of (−)-magellanine and (+)-magellani-

none.^9,10We were attracted again to this strategy in the

present context, envisaging cis-hydrindandione 6 as the direct

precursor of α-methylene dione 5. If the alkoxymethyl side

chain of the cyclopentane ring of 6 were to be introduced in a

pinacol-terminated cyclization, the progenitor of cis-hydrindan-

dione 6 would be an intermediate such as 7. This projected

cascade sequence would examine for the ﬁrst time whether an

alkene π nucleophile containing two inductively deactivating

allylic oxygen substituents would be viable in a Prins−pinacol

transformation. As indicated in intermediates 7−9, the C15

methyl group could be incorporated at the outset, or potentially

introduced after forming the cis-hydrindanone ring. Although

several steps would be involved in introducing the C15 methyl

group at the cis-hydrindanone stage, this strategy would allow

the pivotal Prins−pinacol reaction (8 → 7) to be quickly

examined. Our initial investigations pursued this strategy.

Prins−Pinacol Rearrangement to Assemble the cis-

Hydrindanone Core in the C15 Demethyl Series. As

precursor 8 (R¹= H) should be readily available from the

reaction of vinyl organometallic 10 and cyclopentanone 9 (R¹=

H), synthesis of an appropriate vinyl iodide fragment 13 began

with readily available 6-(tert-butyldiphenylsiloxy)-2-hexynoate

(11).¹¹Stannylcupration of this ynoate, followed by quenching

with MeOH at −78 °C, aﬀorded vinylstannane 12 (>20:1 E/Z)

in high yield (Scheme 2).¹²Reduction of the methyl ester of

12, etheriﬁcation of the resulting primary alcohol with phenol

under Mitsunobu conditions,¹³and stereospeciﬁc tin−halogen

exchange gave (E)-vinyl iodide 13 in 68% overall yield from 11.

This series of reactions could be carried out eﬃciently to access

13 on scales up to 60 g.

(E)-vinyl iodide 13 was converted to the corresponding lithium

reagent with 1.65 equiv of s-BuLi and added to a slurry of

CeCl₃in THF at −78 °C. After formation of the vinylcerium

species, ketone 14 was added at −78 °C to give tertiary allylic

alcohol 15 in 81% yield. Addition of anhydrous LiCl to the

cerium slurry, a procedure initially reported by Knochel,¹⁷

improved the yield of allylic alcohol 15 to 96% (>10:1

diastereoselectivity).¹⁸Silylation of tertiary allylic alcohol 15

with TMS-imidazole and a catalytic amount of tetrabutylam-

monium ﬂuoride (TBAF) provided the Prins−pinacol

precursor 16 in 76% yield.¹⁹

The pivotal Prins−pinacol reaction of alkenyl acetal 16 was

studied in detail (Scheme 4). Exposure of alkenyl acetal 16 to

0.9 equiv of BCl₃, BF₃·OEt₂, or TMSOTf in CH₂Cl₂at −78 °C

and quenching the reaction at low temperature gave either a

complex mixture of products or largely bicyclic acetal 17

resulting from desilylation of 16. However, in the presence of

0.9 equiv of SnCl₄(in CH₂Cl₂at −78 °C → 0 °C), precursor

16 provided cis-hydrindanone 19, a 5.6:1 mixture of α:β

methoxy epimers, in 51% yield together with 25% of a less-

polar byproduct. Upon isolation, this byproduct was shown to

be the Prins cyclization product 18; particularly diagnostic were

signals for the allylic methine and methylene hydrogens

between 4.20 and 4.63 ppm.

Hydrindene 18 would arise from deprotonation of the axial

β-hydrogen of tertiary carbocation intermediate B prior to the

desired semipinacol shift to give Prins−pinacol product 19. The

formation of Prins cyclization byproducts similar to hydrindene

Coupling of vinyl iodide 13 with cyclopentanone 14¹⁴

initially proved challenging. Using s-BuLi in the iodide−lithium

exchange of iodide 13,¹⁵followed by addition of ketone 14 at

B

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Scheme 4. Prins−Pinacol Rearrangement To Form the cis-

Hydrindanone Core

Table 1. Lewis Acid Activation of Dimethyl Acetal 16

a

b

c

entry

1

conditions

18/19

yield

complex

mixture

17 major

83% 17

BCl₃, CH₂Cl₂, −78 °C

nd

2

3

4

5

BF₃·OEt₂, CH₂Cl₂, −78 °C

TMSOTf, CH₂Cl₂, −78 °C

SnCl₄, CH₂Cl₂, −78 °C → −20 °C

SnCl₄, MeNO₂, 0 °C

nd

1.0:2.0 51% 19

nd

complex

mixture

6

7

SnCl₄, i-PrNO₂, −78 °C → −20 °C

1.0:2.8 54% 19

<1:8 70% 19

TiCl₄, CH₂Cl₂, −78 °C → −20 °C

a

b

0.9 equiv of Lewis acid was used. Ratios determined by integration

c

1

of H NMR spectra of unpuriﬁed reaction mixtures. Isolated yields;

nd = not determined.

intermediates that incorporated the C15 methyl group, because

an equatorial methyl substituent at C15 should not inﬂuence

the conformation of intermediates containing a cis-hydrinda-

nane ring system. The mixture of cis-hydrindanone epimers

undoubtedly could be processed further; however, for the sake

of convenience, the readily separated major epimer α-19 was

typically employed in subsequent transformations. Oxidation of

the methoxy group of the α-19 directly to the ketone using

catalytic RuO₄was low yielding, as oxidative decomposition of

the phenyl ether was observed.^23,24Because the methyl ether

could not be directly converted into a ketone, two-step

procedures were investigated.²⁵Attempted demethylation of 19

with a variety of reagents (e.g., BBr₃, chlorocatacholborane,

bromocatacholborane, Me₂BBr, AlBr₃/EtSH) were unpromis-

ing, with side products resulting from the partial cleavage of the

TBDPS group being observed. Trimethylsilyl iodide (5−10

equiv) rapidly converted the silyl ether of α-19 to the

corresponding iodide and subsequently cleaved the methyl

ether (Scheme 5).²⁶However, yields in this transformation

18 had not been observed in appreciable yields in other closely

related Prins−pinacol cascades studied in our laboratory.¹⁰The

intervention of this pathway in the present case is attributed to

enhanced acidity of the axial methine hydrogen resulting from

the presence of the inductively electron-withdrawing phenox-

ymethyl substituent.

Scheme 5. Elaboration of cis-Hydrindanone 19 in the

Demethyl Series

Numerous attempts were made to minimize this undesired

Prins cyclization pathway (16 → A → B → 18). Variation of

the reaction temperature had little eﬀect. For example, allowing

the reaction to warm slightly to −60 °C and maintaining it at

this temperature for 14 h resulted in full consumption of

dimethyl acetal 16;²⁰however, the ratio of Prins−pinacol

product 19 to the elimination product 18 was not improved.

Initiating the reaction at higher temperatures resulted in

substantial decomposition of the starting alkenyl acetal. The use

of polar solvents, such as MeNO₂or i-PrNO₂, led to little or no

improvement in the yield of 19 (entries 5 and 6, Table 1).²¹

Conversely, employing TiCl₄instead of SnCl₄resulted in an

enhanced 70% yield of Prins−pinacol product 19 (a 4.3:1

mixture of α:β methoxy epimers) with decreased formation of

byproduct 18 (Table 1, entry 7). We attribute this improve-

ment to the increased strength of the Ti−Cl bond relative to

the Sn−Cl bond and the resulting decreased basicity of the

conjugate anion.²²

were found to be variable and sensitive to the water content of

the reaction mixture. Addition of 5 equiv of H₂O to the

reaction mixture and heating to 50 °C reproducibly provided

20 in 68% yield,²⁷thereby implicating HI in the reaction. Our

singular attempt to cleave methyl ether 19 by reaction with HI

(5 equiv, 50% aqueous HI in MeCN at room temperature)

resulted only in decomposition.

Elaboration of the N-Hydroxyazacyclononane Ring in

the Demethyl Series. With cis-hydrindanone 19 in hand, we

chose to utilize this intermediate to investigate strategies for

forming the N-hydroxyazacyclononane ring. We anticipated

that what we learned in this series would be applicable to

C

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As a prelude to incorporating the remaining two carbons of

the tetrahydrofuran ring, the alcohol substituent of intermediate

20 was oxidized with Dess−Martin periodianane,²⁸and the

resulting β-phenoxyketone was exposed to 1.2 equiv of 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) in THF at 0 °C to give

α-methylene ketone 21 in 71% yield over two steps (Scheme

5). Initial attempts to append the ﬁnal two carbons by

Mukaiyama−Michael reaction of enedione 21 with the ketene

silyl acetals (TMS or TBS) generated from phenylthioacetate

were unpromising.²⁹Cyclocondensation of ethyl vinyl ether

with enedione 21 at 100 °C in a sealed tube provided

dihydropyran 22, albeit in low yield. However, europium(III)-

catalyzed cyclocondensation was highly eﬃcient,³⁰providing

oxatricyclic product 22 in 86% yield. The primary alkyl iodide

was unaﬀected during this series of transformations, which

allowed for straightforward incorporation of various N- and O-

protected hydroxylamines to furnish intermediates 23−27. This

late-stage diversiﬁcation was valuable, as determining how the

hydroxylamine fragment should be functionalized proved

challenging (see below).

Boc groups and concurrently form the N-hydroxyazacyclono-

nane ring, this mixture was exposed at room temperature to an

excess of TFA in CH₂Cl₂. Instead of forming the nine-

membered ring, condensation of the N-3-(hydroxyamino)-

propyl chain with the C13 carbonyl gave rise to tetracyclic

nitrone 28 as the major product in 28% yield over the two

steps.

We next investigated the formation of the N-hydroxyazacy-

clononane ring independently from the oxidation−rearrange-

ment step. Oxidation of tricyclic dihydropyrans 24−27 with m-

CPBA in CH₂Cl₂, followed by hydrolysis of the resulting

mixture of tricyclic acetal epimers in TFA/H₂O/THF (1:1:3)

at room temperature, provided spirotricyclic lactols 29−32 as

an ∼1:1 mixture of epimers. To our surprise, attempts to

remove the Boc group from the hydroxylamine side chains of

intermediates 29 or 30 with TFA at room temperature in

CH₂Cl₂resulted in substantial cleavage of the N−O bond, with

an aldehyde being identiﬁed by ¹H NMR analysis as a

substantial byproduct. One potential mechanism for this

apparently unknown fragmentation is suggested in eq 1.

Other acidic conditions (AcOH, HCl, AcCl/MeOH), as well

as thermal conditions, also resulted in substantial N−O bond

fragmentation.

As a prelude to investigating the formation of the N-

hydroxyazacyclononane ring,³¹elaboration of tricyclic dihy-

dropyrans 23−27 to the corresponding spirocyclic tetrahy-

drofuran lactols was investigated (Scheme 6). Epoxidation of

dihydropyran precursor 23 occurred cleanly from the convex

face to give a putative epoxide intermediate C that transformed

in situ to tricyclic tetrahydrofuran D (a mixture of ethoxy

epimers by ¹H NMR analysis).³²In an attempt to remove both

Scheme 6. Initial Attempts To Form the Tetrahydrofuran

and N-Hydroxycyclononane Rings

Protecting groups for the hydroxylamine that might be

removed under nonacidic conditions were also investigated.

Attempts to remove the allyl carbamate from 31 by standard

palladium(0) catalysis conditions (Pd(PPh₃)₄; Et₃SiH, dime-

done, or morpholine) or the nosyl group from 32 with

thiophenol and K₂CO₃³³resulted in complex reaction mixtures

(Scheme 6). Immediately after removal of the nosyl group from

32, the IR absorption of the cyclohexanone carbonyl (1696

cm⁻¹) was signiﬁcantly weaker than that of the cyclopentanone

carbonyl (1744 cm⁻¹); if left standing, the intensity of the

cyclohexanone band continued to decrease. These observations

suggest that, after deprotection, the hydroxylamine side chain

eventually cyclizes with the C13 carbonyl to form tetracyclic

carbinolamine E. Such an outcome has considerable precedent

dating from Heathcock’s inaugural total synthesis of the

Lycopodium alkaloid fawcettimine.³⁴

To prevent formation of the six-membered nitrone upon

unveiling the tethered hydroxylamine, we explored masking the

C13 carbonyl by reduction. Reduction of tricyclic dihydropyran

ketone 23 with 1.0 equiv of NaBH₄in MeOH at 0 °C took

place largely from the convex face. Without puriﬁcation, this

crude alcohol intermediate was directly epoxidized with 1.2

equiv of m-CPBA (Scheme 7). Exposure of the resulting

mixture of products to TFA in CH₂Cl₂(1:3) in the presence of

MgSO₄at room temperature gave rise to one major product 33,

which was isolated in 25% overall yield from 23. Single-crystal

X-ray analysis established that cyclization had taken place, not

on nitrogen, but on the hydroxylamine oxygen, to give

D

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Scheme 7. Formation of 1,2-Oxazacyclodecane 33

Scheme 9. Unsuccessful Attempts To Form the N-

Hydroxyazacyclononane Ring

pentacyclic product 33 having a rare 1,2-oxazacyclodecane ring.

In the oﬀ chance that 1,2-oxazacyclodecane 33 was less stable

than the corresponding bicyclo[5.2.1]decane-N,O-acetal, it was

exposed at room temperature to 1.1 equiv of camphorsulfonic

acid (CSA) in CDCl₃. Monitoring this reaction by ¹H NMR for

24 h provided no evidence for isomerization to form the

desired N-hydroxyazacyclononane ring. We concluded that the

hydroxyl group of the N-3-(hydroxyamino)propyl chain would

require masking during the cyclization event.

We turned to investigate the elaboration of tricyclic

dihydropryan 27 in which the hydroxylamine side chain is

masked on oxygen with a p-methoxybenzyl (PMB) group.

Reduction of 27 with NaBH₄in MeOH at 0 °C, followed by

oxidation and acidic hydrolysis, provided a ca. 1:3 mixture of

the equatorial alcohol product 34 and the tetracyclic dilactol 35

resulting from cyclization of the axial alcohol epimer (Scheme

8). It was later discovered that the use of 2 equiv of DIBALH in

fragmentation. Eﬀorts to induce dehydrative condensation by

subjecting amino lactol 36 to MgSO₄, or a combination of

MgSO₄and ZnCl₂, also were unrewarded. Moreover, attempted

activation of lactol 36 with Lewis acids or under Mitsunobu³⁷

conditions did not promote azacyclononane ring formation.

Our inability to detect formation of the azacyclononane ring

under Brønsted acidic, Lewis acidic, thermal, or dehydrative

reaction conditions suggested that the conditions investigated

were likely incompatible with the fragile bicyclo[5.2.1]decane-

N,O-acetal. With this in mind, our focus shifted to investigating

milder cyclization conditions by utilizing more activated

derivatives of the ﬁve-membered lactol.

Schmidt-type glycosylation conditions proved more success-

ful.³⁸Thus, exposure of amino lactol 36 to 1.8 equiv of

Cl₃CCN and 10 mol % DBU in CH₂Cl₂(0.09 M) led directly

to the formation of pentacyclic product 37 in 26% yield

(Scheme 10).³⁹Formation of the bicyclo[5.2.1]decane-N,O-

Scheme 8. Protection of the C13 Carbonyl and Oxidation

Scheme 10. Formation of the N-Alkoxyazacyclononane Ring

CH₂Cl₂at −78 °C in the reduction step of this sequence

strongly favored hydride addition from the equatorial vector to

provide ultimately tetracyclic intermediate 35 in 63% overall

yield from 27.^35,36

acetal was conﬁrmed by 2D NMR experiments that showed a

10 Hz HMBC coupling between a hydrogen at C9 and the

anomeric carbon (C1). When the equatorial C13 alcohol 38

lacking the cyclic (C13−O−C5−OH) hemiacetal was sub-

jected to identical cyclization conditions, cyclization was not

observed. Eﬀorts to improve the ring closure were made by

evaluating a variety of bases, solvents, and reagent concen-

trations (DBU, K₂CO₃, CH₂Cl₂, CH₃CN), but no improve-

ment in yield was realized. Although formation of a

trichloroacetimidate in the presence of a basic secondary

amine has been reported,⁴⁰trichloroacetonitrile is known to

readily react with primary and secondary amines in the absence

We turned to explore forming the N-hydroxyazacyclononane

ring from intermediate 35 (Scheme 9). Removal of the nosyl

group from 35 by reaction with thiophenol and K₂CO₃gave

intermediate 36 in good yield. Attempts to eﬀect the cyclization

of the N-3-(alkoxyamino)propyl chain by exposing 36 to

dichloroacetic acid (10 mol % in CH₂Cl₂) or pyridinium p-

toluenesulfonic acid (PPTS) in pyridine resulted in complex

reaction mixtures. Condensation to form the azacyclononane

ring was attempted by heating amino lactol 36 to 80 °C in

benzene; however, this treatment resulted largely in N−O bond

E

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of base to form amidines.⁴¹Competitive formation of an

amidine by reaction of the secondary hydroxylamine and

trichloroacetonitrile might well be occurring; however, this

presumption was not conﬁrmed by the isolation of amidine

products.

aqueous HF in acetonitrile at 70 °C provided trace amounts of

the free hydroxylamine 40. Allowing N,O-acetal 39 to react

with 1.0 equiv of ZrCl₄in acetonitrile at 70 °C aﬀorded crude

40 (∼30% yield by ¹H NMR analysis);⁴³however, this product

could not be isolated cleanly from the reaction mixture.

With a method established to form the bicyclo[5.2.1]decane-

N,O-acetal, we examined restoring the C13 ketone (Scheme

11). Exposure of cyclic hemiacetal 37 to a catalytic amount of

The diﬃculties encountered in removing the PMB group led

us to seek alternate protecting groups for the hydroxylamine

oxygen that would be cleaved under milder conditions. Because

the protected hydroxylamine fragment could not be introduced

at a late stage,⁴⁴several silyl O-protected hydroxylamines were

appended to alkyl iodide 22. TBS-protected 41 was elaborated

by the previously described three-step sequence, but the TBS

group was cleaved under the aqueous TFA conditions, resulting

in low and variable yields of lactol 44 (0−20%, Scheme 12).⁴⁵

The TIPS-protected substrate 42 was somewhat better,

providing 45 in 36% yield for the three steps. Removal of the

Ns group from silyl-protected hydroxylamine 44 or 45,

followed by exposure to CCl₃CN and DBU in CH₂Cl₂, did

not result in azacyclononane ring formation. The lack of

observed cyclization of the TBS- or TIPS-protected hydroxyl-

amines was attributed to the steric bulk of these silyl groups.

The stability of the 2-trimethylsilylethyl (TMSE) group along

with its minimal steric bulk suggested that it might provide a

solution to the demanding protecting group requirements.

TMSE analogue 43 was elaborated to 46 in 54% overall yield.

Removal of the Ns group from 46 aﬀorded amino lactol 49,

which cyclized under the trichloroacetimidate conditions to

form tetracyclic product 50 in 23% yield as a major product. To

examine removal of the TMSE group, hemiacetal 50 was ﬁrst

oxidized with TPAP to furnish diketone 51. However, a variety

of ﬂuoride conditions (TBAF, CsF, KF, TASF, LiBF₄,

HF·pyridine, aqueous HF, NH₄F) at room temperature were

unsuccessful in removing the TMSE group from tetracyclic

intermediate 51, providing recovered starting material.

Subjecting 51 to ﬂuoride conditions at 100 °C for a prolonged

period of time resulted in substantial decomposition.

Scheme 11. Oxidation of 37 to the Dione and Attempted

Removal of the PMB Group

Pr₄N⁺RuO₄(TPAP)⁴²and 4-methylmorpholine N-oxide

−

(NMO) in CH₂Cl₂uneventfully provided crystalline diketone

39, whose structure was veriﬁed by X-ray crystallographic

analysis.

Removal of the p-methoxybenzyl group from intermediate 39

would yield 15-demethylsieboldine A (40). Oxidative (CAN,

DDQ) and hydrogenolytic (Pd/C or Pd(OH)₂with H₂or

NH₄CO₂H) conditions were evaluated initially without success.

The N,O-acetal of tetracyclic 39 was found to be stable upon

exposure to 1−10 equiv of bromocatecholborane, BBr₃, or

TMSI (buﬀered with 2,6-di-tert-butyl-4-methylpyridine,

DTBMP) in CH₂Cl₂even after extended periods at room

temperature; although higher temperatures did eventually result

in decomposition of the starting material. Subjecting 39 to 48%

At this point, we decided to evaluate the suitability of other

oxygen protecting groups in a simple model system. In

choosing potential O-protected hydroxylamines to examine,

several factors were considered. First, the facile oxidation of

hydroxylamines to nitrones⁴⁶under oxidative conditions

eliminated protecting groups removed under conventional

oxidative conditions. Second, we eliminated groups requiring

reductive or hydrogenolysis conditions, because of concerns

with the potential N−O bond reduction of the hydroxyl-

Scheme 12. Evaluation of Alternative O-Protecting Groups

F

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amine.⁴⁷Third, to favor formation of the N-hydroxyazonane

ring, we wanted to minimize the steric bulk in the vicinity of the

hydroxylamine nitrogen. The nine protecting groups depicted

in eq 2 were evaluated. Of these, the methoxymethyl ether

Scheme 13. Introduction of the C15 Methyl into an Enone

Precursor

(MOM) group captured our attention, as it was smoothly

removed to give N,N-bis(3-phenyl)hydroxylamine when

exposed to bromocatecholborane or BBr₃in CH₂Cl₂at −78 °C.

Introduction of the C15 Methyl Group by Conjugate

Addition. Prior to incorporating what we had learned about

constructing the bicyclo[5.2.1]decane-N,O-acetal moiety of

sieboldine A in a ﬁnal synthesis sequence, we brieﬂy examined

whether the C15 methyl group could be incorporated

eﬃciently after formation of the cis-hydrindanone ring. The

obvious possibility was to dehydrogenate an intermediate, such

as cis-hydrindanone 19, to the corresponding conjugated enone

and introduce the C15 methyl group by conjugate addition of a

methyl nucleophile. We expected that this latter functionaliza-

tion would occur preferentially from the convex faceby axial

addition to conformer G^48,49ato give hydrindanone 53

(Figure 2). Although we were aware of no close precedent at

methyl epimers β-52 and β-53 in a 1.4:1 ratio and 74%

combined yield.^53,54

After these studies were completed, two examples of

conjugate additions to structurally related enones were reported

from the groups of Hiroya (eq 3)⁵⁵and Elliott (eq 4).⁵⁶

Consistent with our original expectations, in both cases the

methyl nucleophile added preferentially from the convex face.

We speculate that the unexpected stereochemical outcome in

the conjugate addition to enones 54 is a result of the large 3-

(tert-butyldiphenylsiloxy)propyl substituent being oriented

toward the cyclohexenone ring to avoid interactions with the

vicinal phenoxymethyl substituent, which itself is thrust toward

the angular substituent to minimize interactions with the

adjacent methoxy group. This situation is illustrated in the

molecular mechanics model of cis-hydrindenone α-54 (Figure

3).⁵⁷Consistent with this analysis, methylcuprate addition to β-

methoxy enone 55, which lacks the bulky tert-butyldimethylsi-

loxy group, took place preferentially from the convex face to

give product 56 and its methyl epimer in a ratio of 1.6:1 (eq 5).

Figure 2. Products arising by axial addition of methyl to the two

conformers of a cis-hydrindenone intermediate.

the time, this expectation was in accord with the well-

established preference of 5-substituted-2-cyclohexen-1-ones to

undergo conjugate addition from the face opposite the 5-

substituent.⁴⁹

Salient results of our exploration of this approach for

incorporating the C15 methyl group are summarized in Scheme

13. After evaluating several methods to introduce the double

bond (selenoxide elimination, o-iodoxybenzoic acid (IBX)

oxidation, DDQ or CAN oxidation, and N-tert-butylbenzene-

sulfonimidoyl chloride dehydrogenation),⁵⁰Saegusa oxidation

was found most reliable and scalable.⁵¹In this way, cis-

hydrindenones α-54 and β-54 were formed in 85% and 61%

yields from their respective ketone precursors.⁵²Reaction of α-

54 with the homocuprate generated from MeLi and CuBr·SMe₂

in Et₂O at 0 °C gave a single product in 94% yield (eventually

determined to be hydrindanone α-52), in which methyl

addition had taken place from the concave face. Subjecting

the β-methoxy epimer, β-54, to identical conditions gave

Rigorous proof that methyl addition to enones α- and β-54

had taken place preferentially from the concave face was not

obtained until the α-epimer was elaborated further (Scheme

14). Thus, cis-hydrindanone α-52 was transformed to tricyclic

G

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ate having a trans-2-carbon side chain at C2 (e.g., intermediate

9 with R¹= Me, Scheme 1) were explored. The route initiating

from known tetrahydrocyclopenta[b]furan-2-one 60 proved to

be the most practical and was especially attractive as convenient

access to the 3aS,6aR enantiomer had been described (see

Scheme 15).^58,59Organocopper-promoted S_N2′ anti opening of

Scheme 15. Synthesis of 2,4-trans-Disubstituted

Cyclopentanone 63

Figure 3. Low-energy conformer of cis-hydrindenone α-54 showing

shielding of the proximal face of the enone by the 3-(tert-

butyldiphenylsiloxy)propyl side chain.⁵⁷

Scheme 14. X-ray Conﬁrmation of the Unnatural Relative

Conﬁguration of the C15 Methyl Substituent

allylic lactone (3aS,6aR)-60,⁶⁰followed by iodolactonization of

the carboxylic acid product, a sequence developed by Curran et

al., provided iodolactone 61 in 93% yield.⁶¹Slow addition of

iodolactone 61 to a reﬂuxing slurry of LiAlH₄in THF gave diol

62,⁶²which was selectively silylated⁶³and the secondary

alcohol oxidized with Dess−Martin periodinane²⁸to give trans-

substituted cyclopentanone 63 in 73% overall yield from

lactone 60.

Coupling vinyl iodide 13 to cyclopentanone 63 required

minor modiﬁcations of the previously developed conditions.

Eﬃcient addition of the vinylcerium reagent generated from 13

to ketone 63 necessitated slowly warming the reaction mixture

to room temperature overnight (Scheme 16). Silylation of

Scheme 16. Formation of Prins−Pinacol Precursor 66

dihydropyran 57 by the ﬁve-step sequence shown in Scheme 5.

Sequential reaction of intermediate 57 with DIBALH at low

temperature, m-CPBA, and aqueous TFA provided as the major

product spirotricyclic tetrahydrofuran 58. Our ﬁrst hint that

methyl introduction into the cyclohexane ring had taken place

from the concave face was provided by the NMR and IR

spectra of tricyclic intermediate 58, which clearly showedin

contrast to the related intermediate 35 in the demethyl series

that 58 did not exist as a tetracyclic (C13−O−C5−OH)

hemiacetal. Rigorous proof that the relative conﬁguration of the

C15 methyl substituent was opposite to that of sieboldine A

was obtained from single-crystal X-ray analysis of the minor

product, tetracyclic acetal 59. Moreover, the relative conﬁg-

uration of 59 at C4 was opposite to that of major product 58,

consistent with it arising from epoxidation of the alcohol

intermediate generated from α-57 from the concave face.

Early Incorporation of the C15 Methyl Group and

Optimization of the Synthesis of the cis-Hydrindanone

Intermediate. As it appeared unlikely that the C15 methyl

group could be introduced eﬃciently after constructing a cis-

hydrindenone intermediate, we turned to examine installing the

methyl group prior to the Prins−pinacol reaction. Several

sequences for preparing a 4-methylcyclopentanone intermedi-

tertiary allylic alcohol product 64, followed by Swern oxidation

of the primary TES ether,^64,65aﬀorded aldehyde 65 in 77%

yield over two steps. Exposure of aldehyde 65 to

trimethylorthoformate and a catalytic amount of pyridinium

p-toluenesulfonate (PPTS) provided the requisite alkenyl acetal

Prins−pinacol precursor 66 bearing the C15 methyl group.⁶⁶

Examination of the Prins−pinacol cascade with alkenyl acetal

66 was facilitated by our earlier investigations in the model

H

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series lacking the C15 methyl substituent. Using the previously

optimized Prins−pinacol conditions, a solution of dimethyl

acetal 66 in CH₂Cl₂was exposed to 0.9 equiv of TiCl₄

(CH₂Cl₂, −78 °C → −20 °C) to give hydrindanones 53 in

40% yield as a 2.2:1 mixture of α:β methoxy epimers (Table 2).

Scheme 17. Attempted Pinacol-Terminated Keteneiminium

Ion Cyclization

Table 2. Prins−Pinacol Rearrangement with the C15 Methyl

Group Incorporated

R

conditions

yield

TMS

TES

0.9 equiv TiCl₄

0.5 equiv TiCl₄

0.9 equiv TiCl₄

29%

13%

42%

40%

Varying the stoichiometry of TiCl₄or the silyl protecting group

of the precursor resulted in no signiﬁcant improvements in

yield.⁶⁷The unsatisfactory yield obtained in the Prins−pinacol

reaction of 66 forced us to explore other methods to initiate the

desired cationic cyclization event.

We had previously described several alternate methods for

initiating cationic cyclization−pinacol cascade reactions.^10b,68

Of these methods, use of a keteneiminium ion-initiated

cyclization−pinacol rearrangement was enticing, as it would

directly aﬀord dione product 70 (Scheme 17). The requisite

ketoamide 68 was readily synthesized from iodolactone 61 in

69% yield over three steps. Cerium-mediated addition of the

lithium reagent derived from 13 to cyclopentanone 68 and

subsequent silylation provided precursor 69. Exposure of amide

69 to 1.1−1.3 equiv of Tf₂O and 1.5 equiv of 2,6-di-tert-butyl-4-

methylpyridine (DTBMP) in 1,2-dichloroethane at −20 °C

resulted in formation of a colorless precipitate and loss of 17

mass units as determined by low-resolution mass spectrometry,

thus suggesting the formation of keteneiminium intermediate

H.⁶⁹However, warming the reaction mixture to room

temperature and eventually to reﬂux did not provide any

evidence that the desired transformation to iminium

intermediate I had occurred.⁷⁰

and byproduct 73 were formed in a >10:1 ratio (Table 3, entry

8). Computational studies by Toste, Goddard, et al. have

suggested that the steric size of the 2-(di-tert-butylphosphino)-

biphenyl ligand inhibits back-bonding stabilization between the

metal center and the alkyne, eﬀectively increasing the

carbocationic nature of the gold alkyne species.^75,76In the

present case, the reduced Au-dπ to C-pπ orbital overlap likely

favors cationic oleﬁn cyclization over the heterocyclization

pathway.⁷⁷The Au(I)-initiated cascade 71 → 72 was readily

scalable to a gram-scale reaction providing cis-hydrindanone 72

in 84% yield (Table 3, entry 9).

Completion of the Total Synthesis of (+)-Sieboldine

A. With access to gram quantities of enantioenriched cis-

hydrindanone 72 in hand, we turned to see if the chemistry

deﬁned in the C15 demethyl series would allow (+)-sieboldine

A to be prepared in a straightforward fashion. Fortunately, that

proved to be the case with one important modiﬁcation

(Scheme 19). The ﬁnal elaboration to sieboldine A began by

oxidative cleavage of the exomethylene group of 72 by

ozonolysis, a transformation that required careful monitoring

to prevent the formation of overoxidation products. After

quenching the ozonide with dimethyl sulﬁde at −78 °C and

allowing the reaction to warm to room temperature overnight, a

solvent swap from CH₂Cl₂to acetonitrile, followed by addition

of 1.2 equiv of DBU at 0 °C to the crude diketone, delivered

methylene enone 74 in 75% yield from 72. Cyclocondensation

of enone 74 with ethyl vinyl ether aﬀorded dihydropyran 75 in

86% yield.³⁰Selective reduction of the C13 carbonyl of tricyclic

intermediate 75 with DIBALH in CH₂Cl₂at −78 °C, followed

by epoxidation of the dihydropyran with 1.2 equiv of

dimethyldioxirane (DMDO) in CH₂Cl₂at 0 °C, gave rise to

Lack of success with the Prins or keteneiminium ion-initiated

cyclizations to form the cis-hydrindane core of sieboldine A

directed our attention to the related pinacol-terminated 1,6-

enyne cyclization reported by Kirsch, Rhee, et al. in 2008.⁷¹

The requisite alkyne precursor 71 was synthesized in 90% yield

by homologation of aldehyde 65 with 1.6 equiv of the Ohira−

Bestmann reagent (Scheme 18).⁷²Exposure of 1,6-enyne 71 to

−

10 mol % PPh₃Au⁺SbF₆and 1.1 equiv of i-PrOH in CH₂Cl₂

(Table 3, entry 2) yielded a 1:1 ratio of the desired pinacol-

terminated cyclization product 72 and byproduct 73⁷³resulting

from a Claisen-terminated heterocyclization pathway (J → L →

73). Homogenous gold catalysis is known to be sensitive to

ligand eﬀects, and altering the electronic nature of the ligand on

the cationic gold complex resulted in a signiﬁcant change in the

product distribution of this reaction (Table 3).⁷⁴A trend

similar to that reported by Kirsch and Rhee was observed

wherein electron-rich gold(I) complexes improved the

selectivity for the pinacol-terminated cyclization.^71aUsing [(t-

Bu)₂P(o-biphenyl)]AuSbF₆, the pinacol-terminated product 72

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Scheme 18. Au(I)-Catalyzed Pinacol-Terminated 1,6-Enyne

Cyclization

Scheme 19. Elaboration of cis-Hydrindanone 72 to

Thioglycoside Intermediate 77

intermediate 35, Scheme 8) with TFA/H₂O/THF (1:1:3)

were low yielding and plagued by partial cleavage of the

TBDPS group.

Thioglycosides are commonly utilized in carbohydrate

chemistry to form bonds at the anomeric carbon and are

activated under a variety of mild reaction conditions.⁷⁸With

this in mind, the mixture of ethoxy epimers formed from

DMDO oxidation of 75 was redissolved in CH₂Cl₂containing 5

equiv of EtSH, cooled to −78 °C, and exposed to 1.1 equiv of

BF₃·OEt₂to give thioglycoside 76 in 53% yield (Scheme 19).⁷⁹

Removal of the TBDPS group of 76 with 3 equiv of TBAF in

THF, coupling with N-(methoxymethoxy)-2-nitrobenzenesul-

fonamide under Mitsunobu conditions,⁸⁰and removal of the

nosyl group provided intermediate 77.

Several conditions were examined for forming the ﬁnal

azacyclononane ring from thioglycoside precursor 77 (Table 4).

Exposure of 77 to mercury or silver salts, tris(4-bromophenyl)-

ammoniumyl hexachloroantimonate (TBPA),⁸¹or p-nitro-

benzenesulfenyl triﬂate (NO₂PhSOTf)⁸²provided product 78

harboring the desired N-alkoxyazacyclononane ring in low

a tricyclic dihydropyran intermediate as a 1:1 mixture of ethoxy

epimers. Initial attempts to convert this intermediate to the

corresponding dilactol (i.e., the C15 methyl analogue of

Table 3. Au(I) Catalysts and Selectivity for Pinacol-

Terminated 1,6-Enyne Cyclization

Table 4. Activation Conditions for Formation of the N-

Alkoxyazacyclononane Ring

a

entry

conditions

yield (72/73)

a

1

2

3

4

5

6

7

8

9

10 mol % [Au(PPh₃)]₃OBF₄

NR

entry

conditions

yield

b

10 mol % PPh₃AuCl

94% (1:1)

90% (1.5:1)

91% (2:1)

85% (2:1)

88% (2.5:1)

89% (3:1)

95% (10:1)

84% (13:1)

1

2

3

4

5

6

7

NO₂PhSOTf, DTBMP, 4 Å MS, CH₂Cl₂, −78 °C

HgCl₂, CaCO₃, 4 Å MS, CH₂Cl_2,rt

10%

16%

18%

28%

37%

42%

51%

b

10 mol % Me₃PAuCl

b

10 mol % Et₃PAuCl

TBPA, 4 Å MS, CH₃CN

c

10 mol % μ-(Ph₂P)₂CH₂Au₂Cl₂

AgPF₆, DTBMP, 4 Å MS, CH₂Cl₂, 0 °C

DMTST, DTBMP, 4 Å MS, CH₂Cl₂, 0 °C

DMTST, DTBMP, 4 Å MS, CH₂Cl₂, 0 °C, inverse addition

b

10 mol % t-Bu₃PAuCl

b

10 mol % (NHC)AuCl

b

10 mol % [(t-Bu)₂P(o-biphenyl)]AuCl

DMTST, DTBMP, 4 Å MS, CH₃CN, −20 °C, inverse

bd

,

addition

a

All reactions were carried out on a 0.03 mmol scale at 0.05 M in

DTBMP = 2,6-di-tert-butyl-4-methylpyridine. TBPA = tris(4-

bromophenyl)ammoniumyl hexachloroantimonate. DMTST =

dimethyl(metylthio)sulfonium triﬂate.

b

c

CH₂Cl₂with 1.1 equiv of i-PrOH at rt. 5 mol % AgSbF₆. 9 mol %

AgSbF₆. Conducted on 3.2 mmol scale; NR = no reaction.

d

J

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yields, 10−28% (Table 4, entries 1−4). Activation of

thioglycoside 77 with 5 equiv of dimethyl(methylthio)-

sulfonium triﬂate (DMTST)^83,84in CH₂Cl₂(0.009 M) at 0

°C was somewhat better, giving 78 in 37% yield (Table 4, entry

5). The cyclization was further improved by slow addition of

thioglycoside 77 to a solution of 5 equiv of DMTST in MeCN

(0.009 M) at −20 °C, which delivered pentacyclic intermediate

78 in a notable 51% yield (Table 4, entry 7).

EXPERIMENTAL SECTION

■

Experimental procedures and characterization data for the preparation

of vinyl iodide 13, N-(methoxymethoxy)-2-nitrobenzenesulfonamide,

and compounds 60−65, 71−79, and 2 have been reported previously.⁵

General Procedure for Adding Vinylcerium Reagents to

Cyclopentanone Intermeiates. Preparation of (1*S,2S*)-1-((E)-

6-(tert-Butyldiphenylsilyloxy)-1-phenoxyhex-2-en-3-yl)-2-(2,2-

dimethoxyethyl)cyclopentanol (15). A cyclohexane solution of s-

BuLi (13.3 mL, 12.9 mmol, 0.97 M, 1.65 equiv)⁸⁷was added dropwise

to THF (26 mL) at −78 °C, forming a clear bright yellow solution. A

solution of vinyl iodide 13⁵(6.50 g, 11.7 mmol, 1.50 equiv) and THF

(8.5 mL) was added dropwise; the internal temperature was

monitored during the addition to ensure that the temperature did

not exceed −50 °C. After the addition, the solution was stirred at −78

°C for 15 min. In a separate ﬂask, a previously prepared slurry of

anhydrous CeCl₃(4.41 g, 17.9 mmol, 1.70 equiv),⁸⁸anhydrous LiCl

(1.12 g, 26.5 mmol, 3.40 equiv), and THF (39 mL) was cooled to −78

°C and a cyclohexane solution of s-BuLi was added dropwise until a

pale yellow color persisted (ca. 1.0 mL). The vinyllithium species was

cannulated to the CeCl₃·2LiCl slurry, producing an orange suspension,

which was stirred at −78 °C for 30 min. A solution of cyclopentanone

14¹⁴(1.34 g, 7.79 mmol, 1.00 equiv) and THF (8.5 mL) was then

added dropwise, resulting in the disappearance of the orange color.

The suspension was allowed to slowly warm to rt over 12 h. The

solution was then partitioned between Et₂O (100 mL) and 10% aq.

AcOH (100 mL). The layers were separated, and the aqueous phase

was extracted with Et₂O (2 × 100 mL). The combined organic layers

were washed with sat. aq. NaHCO₃(50 mL), followed by a wash with

brine (30 mL). The organic phase was dried over MgSO₄, ﬁltered

through a plug of cotton, and concentrated under reduced pressure.

Puriﬁcation by ﬂash column chromatography (24:75:1 EtOAc/

hexanes/Et₃N) aﬀorded a 14:1 ratio of tertiary alcohol 15 and its

The total synthesis of (+)-sieboldine A was completed in two

additional steps (Scheme 20). Oxidation of the cyclic

Scheme 20. Completion of the Total Synthesis of Sieboldine

A

1

(1S*,2R*) diasteromer (4.50 g, 96% yield) as a clear colorless oil: H

NMR (500 MHz, CDCl₃) δ 7.65 (dd, J = 8.0, 1.4 Hz, 4H), 7.41 (t, J =

7.3 Hz, 2H), 7.36 (t, J = 7.5 Hz, 4H), 7.25 (t, J = 8.6 Hz, 2H), 6.93 (t,

J = 7.3 Hz, 1H), 6.87 (d, J = 7.8 Hz, 2H), 5.90 (t, J = 6.3 Hz, 1H), 4.60

(d, J = 6.3 Hz, 2H), 4.38 (dd, J = 7.2, 4.2 Hz, 1H), 3.67 (t, J = 5.1 Hz,

2H), 3.28 (s, 3H), 3.25 (s, 3H), 2.26−2.20 (m, 1H), 2.17−2.11 (m,

1H), 2.05−1.99 (m, 1H), 1.95−1.91 (m, 2H), 1.87−1.83 (m, 1H),

1.76−1.69 (m, 2H), 1.67−1.57 (m, 4H), 1.52−1.47 (m, 1H), 1.05 (s,

9H); ¹³C NMR (125 MHz, CDCl₃) δ 158.8, 147.1, 135.6, 133.8,

129.7, 129.5, 127.7, 120.7, 120.5, 114.7, 104.0, 85.1, 65.0, 63.8, 52.8,

52.7, 42.7, 39.9, 33.6, 31.7, 30.1, 26.9, 25.1, 22.1, 19.3; IR (thin ﬁlm)

3437, 2955, 2930, 1496, 1240, 1112 cm⁻¹; HRMS-ESI (m/z) [M +

Na]⁺calcd for C₃₇H₅₀O₅SiNa, 625.3325; found, 625.3318.

tert-Butyl((E)-4-((1S*,2S*)-2-(2,2-dimethoxyethyl)-1-

(trimethylsilyloxy)cyclopentyl)-6-phenoxyhex-4-enyloxy)-

diphenylsilane (16). A solution of tetra-n-butylammonium ﬂuoride

in THF (0.17 mL, 0.17 mmol, 1.0 M, 0.01 equiv) was added dropwise

to a solution of tertiary alcohol 15 (10.0 g, 17.0 mmol, 1.00 equiv),

TMS-imidazole (5.1 mL, 35 mmol, 2.0 equiv), and DMF (44 mL) at

rt. After 3 h, the solution was partitioned between water (500 mL) and

Et₂O (250 mL), the layers were separated, and the aqueous phase was

extracted with Et₂O (3 × 200 mL). The combined organic layers were

washed with water (500 mL) and then brine (500 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography (1:10:89

Et₃N/EtOAc/hexanes) aﬀorded silyl ether 16 as a colorless oil (9.0 g,

76% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.65 (dd, J = 7.9, 1.3 Hz,

4H), 7.42 (tt, J = 7.3, 2.0 Hz, 2H), 7.36 (t, J = 6.8 Hz, 4H), 7.24 (t, J =

7.9 Hz, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.87 (dd, J = 8.8, 1.0 Hz, 2H),

5.83 (t, J = 6.4 Hz, 1H), 4.59 (dd, J = 6.4, 2.9 Hz, 2H), 4.37 (dd, J =

7.6, 4.4 Hz, 1H), 3.69−3.64 (m, 2H), 3.29 (s, 3H), 3.21 (s, 3H), 2.26−

2.20 (m, 1H), 2.04−2.00 (m, 1H), 1.97−1.91 (m, 1H), 1.88−1.84 (m,

1H), 1.83−1.78 (m, 1H), 1.77−1.71 (m, 2H), 1.69−1.62 (m, 3H),

1.61−1.60 (m, 1H), 1.49−1.43 (m, 1H), 1.42−1.36 (m, 1H), 1.05 (s,

9H), 0.07 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 158.9, 145.6,

135.6, 133.8, 129.7, 129.4, 127.7, 121.9, 120.5, 114.8, 104.2, 88.1, 64.9,

63.8, 53.2, 51.7, 44.5, 36.4, 33.6, 30.9, 29.6, 26.9, 25.2, 22.1, 19.3, 2.0;

hemiacetal unit of 78 with TPAP provided diketone 79 in

88% yield. The MOM ether of 79 could be removed to give

(+)-sieboldine A, albeit in low yield (<40%), by reaction with a

large excess (5−20 equiv) of bromocatecholborane, BBr₃,

TMSBr, or BCl₃at room temperature, Fortunately, we

discovered that deprotection with 2 equiv of bromodimethyl-

borane⁸⁵(0 °C in CH₂Cl₂) was more eﬃcient, delivering

(+)-sieboldine A (2) in 67% yield. Synthetic (+)-sieboldine A

1

(2) exhibited H and ¹³C NMR spectra and optical rotation

{[α]²_D³+141 (c 0.4, MeOH); lit.⁴[α]_D+139 (c 0.3, MeOH)}

indistinguishable from those reported for the natural sample.^4,86

CONCLUSION

■

The ﬁrst total synthesis of the Lycopodium alkaloid

(+)-sieboldine A has been accomplished in 20 steps from

(3aS,6aR)-tetrahydrocyclopenta-[b]-furan-2-one (60). The syn-

thesis features the formation of the unique N-hydroxyazacy-

clononane ring by cyclization of a thioglycoside precursor. Our

success in constructing sieboldine A in this way required that

the hydroxy group of the tethered hydroxylamine be masked

with a protecting group (methoxymethyl) that did not decrease

the reactivity of the nitrogen and could be removed in the

presence of the delicate the bicyclo[5.2.1]decane-N,O-acetal

moiety. The synthesis also illustrates the use of Au(I)-catalyzed

activation of an alkyne to promote a cyclization−pinacol

sequence, ﬁrst introduced by Rhee and Kirsch,⁷¹which in

demanding contexts can be superior to Lewis acid-activation of

an acetal.

K

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IR (thin ﬁlm) 2975, 2956, 1251 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₄₀H₅₈O₅Si₂Na, 697.3721; found, 697.3737.

(thin ﬁlm) 2951, 1495, 1106 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₃₉H₅₄O₄Si₂Na, 665.3458; found, 665.3451.

tert-Butyl((E)-4-((3aS*,6aS*)-2-methoxyhexahydro-2H-

cyclopenta[b]furan-6a-yl)-6-phenoxyhex-4-enyloxy)-

diphenylsilane (17). A 1 M solution of TMSOTf in CH₂Cl₂(0.015

mL, 0.081 mmol, 0.98 equiv) was added dropwise to a solution of

acetal 16 (0.050 g, 0.083 mmol, 1.00 equiv), 2,6-di-tert-butyl-4-

methylpyridine (34 mg, 0.17 mmol, 2.0 equiv), and CH₂Cl₂(1.5 mL)

at −78 °C. The solution was allowed to warm to −20 °C. After 20

min, the solution was quenched at −20 °C by adding triethylamine

(93 μL, 0.66 mmol) and then partitioned between sat. aq. NaHCO₃

(10 mL) and CH₂Cl₂(5 mL). The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂(3 × 5 mL). The combined

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

ﬁltered through a plug of cotton, and concentrated under reduced

pressure. Puriﬁcation by column chromatography (1:9 EtOAc/

hexanes) aﬀorded cyclic acetal 17 (39 mg, 83% yield) as a colorless

oil and a mixture of methoxy epimers: ¹H NMR (500 MHz, CDCl₃) δ

7.67 (d, J = 7.0 Hz, 2H), 7.45−7.42 (m, 2H), 7.40−7.36 (m, 4H),

7.29−7.25 (m, 4H), 6.94 (q, J = 7.0 Hz, 1H), 6.89 (dd, J = 2.0, 8.0 Hz,

2H), 5.92 (t, J = 6.0 Hz, 0.5H), 5.84 (t, J = 6.5 Hz, 0.5H), 5.07 (dd, J =

2.5, 5.5 Hz, 0.5H), 5.04 (d, J = 5.5 Hz, 0.5H), 4.60 (d, J = 6.0 Hz, 1H),

4.57 (t, J = 5.5 Hz, 1H), 3.70−3.68 (m, 2H), 3.37 (s, 1.5H), 3,34 (s,

1.5H), 2.78 (q, J = 6.0 Hz, 0.5H), 2.43 (dt, J = 0.5, 8.0 Hz, 0.5H),

2.30−2.19 (m, 2H), 2.17−2.09 (m, 1H), 2.08−1.97 (m, 1H), 1.88−

1.79 (m, 2H), 1.77−1.71 (m, 1H), 1.70−1.60 (m, 4H), 1.53 (dd, J =

0.5, 11.5 Hz, 1H), 1.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ

158.94 (C), 158.90 (C), 147.2 (C), 146.1 (C), 135.8 (CH), 133.9 (C),

129.9 (CH), 129.6 (CH), 127.9 (CH), 120.7 (CH), 119.3 (CH),

119.1 (CH), 114.8 (CH), 106.9 (CH), 106.5 (CH), 99.6 (C), 98.4

(C), 65.1 (CH₂), 64.0 (CH₂), 63.9 (CH₂), 55.9 (CH₃), 55.3 (CH₃),

45.4 (CH), 44.9 (CH), 41.1 (CH₂), 40.9 (CH₂), 39.7 (CH₂), 38.8

(CH₂), 34.5 (CH₂), 33.9 (CH₂), 29.9 (C), 27.1 (CH₃), 25.6 (CH₂),

24.8 (CH₂), 24.3 (CH₂), 19.4 (C); IR (thin ﬁlm) 2951, 2858, 1598,

1495, 1239, 1108 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₃₆H₄₆O₄SiNa, 593.3063; found, 593.3057.

General Procedure for the Prins−Pinacol Reactions of

Acetal Precursors. Preparation of 18, α-19, and β-19. A solution

of TiCl₄and CH₂Cl₂(10.4 mL, 10.4 mmol, 1.0 M, 0.900 equiv) was

added dropwise to a solution of dimethyl acetal 16 (7.84 g, 11.6 mmol,

1.00 equiv) and CH₂Cl₂(230 mL) at −78 °C, resulting immediately in

a bright orange solution. The solution was then placed in a −20 °C

(ice−acetone) bath and maintained for 20 min. The orange solution

then was treated with Et₃N (12.9 mL, 92.8 mmol, 8.00 equiv), then

MeOH (3.75 mL, 92.8 mmol, 8.00 equiv), resulting in the loss of

color. The cold mixture was partitioned between sat. aq. NaHCO₃

(200 mL) and CH₂Cl₂(100 mL), resulting in the formation of a

colorless precipitate. The triphasic mixture was then passed through a

pad of Celite. The liquid phases were separated, and the aqueous

phase was extracted with CH₂Cl₂(2 × 200 mL). The combined

organic layers were washed with brine (500 mL), dried over MgSO₄,

ﬁltered through a plug of cotton, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography (1:9

EtOAc/hexanes → 2:3 EtOAc/hexanes) to aﬀord the following three

products.

(2S*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)propyl)-2-

methoxy-3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-one (α-

19). The major hydrindanone diastereomer α-19 eluted next as a

clear colorless oil (3.44 g, 52% yield): ¹H NMR (500 MHz, CDCl₃) δ

7.56 (d, J = 7.6 Hz, 4H), 7.42−7.40 (m, 2H), 7.38−7.35 (m, 4H),

7.27−7.23 (m, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.88−6.86 (dd, J = 8.7,

1.0 Hz, 2H), 4.16 (t, J = 8.7 Hz, 1H), 3.99 (dd, J = 9.3, 4.7 Hz, 1H),

3.89 (dd, J = 10.3, 6.3 Hz, 1H), 3.69−3.64 (m, 1H), 3.58−3.53 (m,

1H), 3.26 (s, 3H), 2.77 (dd, J = 13.3, 5.5 Hz, 1H), 2.53 (quintet, J =

7.3 Hz, 1H), 2.41 (dt, J = 16.1, 5.6 Hz, 1H), 2.32−2.26 (m, 1H),

1.99−1.93 (m, 1H), 1.85−1.78 (m, 2H), 1.76−1.69 (m, 5H), 1.47−

1.40 (m, 1H), 1.39−1.33 (m, 1H), 1.04 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 214.9, 158.9, 135.7, 135.6, 134.1, 134.0, 129.6, 129.4, 127.6,

120.5, 114.6, 80.6, 64.1, 63.5, 59.0, 57.5, 47.8, 43.4, 39.3, 36.4, 29.1,

28.6, 28.0, 26.9, 22.0, 19.2; IR (thin ﬁlm) 3071, 2927, 2856, 1697,

1472, 1242 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₃₆H₄₆O₄SiNa, 593.3063; found, 593.3055.

(2R*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)propyl)-2-

methoxy-3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-one (β-19).

The minor hydrindanone diastereomer β-19 eluted last as a clear

colorless oil (0.861 g, 13% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.62

(dd, J = 8.0, 1.3 Hz, 4H), 7.41 (t, J = 7.2 Hz, 2H), 7.37−7.33 (m, 4H),

7.23 (d, J = 7.7 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.8 Hz,

2H), 4.02 (dd, J = 9.6, 5.0 Hz, 1H), 3.84 (dd, J = 9.5, 6.4 Hz, 1H), 3.80

(quint., J = 3.6 Hz, 1H), 3.61−3.55 (m, 2H), 3.29 (s, 3H), 3.13 (q, J =

4.8 Hz, 1H), 2.43−2.39 (m, 2H), 2.34−2.28 (m, 1H), 2.19 (dt, J =

13.9, 7.8 Hz, 1H), 1.99−1.96 (m, 1H), 1.91−1.86 (m, 1H), 1.77−1.63

(m, 4H), 1.54−1.44 (m, 2H), 1.34−1.29 (m, 1H), 1.01 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃) δ 212.7, 158.8, 135.6, 133.9, 129.7, 129.6,

129.5, 127.7, 120.8, 114.5, 83.8, 66.7, 64.0, 59.6, 56.8, 47.5, 44.8, 38.7,

36.1, 28.6, 28.2, 26.9, 26.0, 22.5, 19.2; IR (thin ﬁlm) 3071, 2859, 1703,

1429, 1242 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₃₆H₄₆O₄SiNa, 593.3063; found, 593.3061.

An additional 0.330 g (5.0%) of the desired hydrindanone products

α-19 and β-19 was obtained from the mixed fractions of this column.

(2S*,3S*,3aS*,7aS*)-2-Hydroxy-3a-(3-iodopropyl)-3-

(phenoxymethyl)hexahydro-1H-inden-4(2H)-one (20). TMSCl

(7.5 mL, 59 mmol, 10 equiv)⁸⁹was added dropwise to a solution of

NaI (8.9 g, 59 mmol, 10 equiv)⁹⁰and dry MeCN (49 mL) at rt with

vigorous stirring for 20 min, which resulted in formation of a colorless

precipitate. The freshly prepared solution of TMSI was decanted from

the precipitate via syringe and added dropwise to a solution of methyl

ether α-19 (3.4 g, 5.9 mmol, 1.0 equiv), H₂O (0.53 mL, 30 mmol, 5.0

equiv), and MeCN (17 mL). The solution was then heated to 50 °C

for 2 h. The resulting brown solution was cooled to rt, diluted with

Et₂O (100 mL), and treated with 1:1:1 H₂O/sat. aq. NaHCO₃/sat. aq.

Na₂S₂O₃(100 mL) and stirred for 15 min, resulting in the

disappearance of the brown color. The layers were separated, and

the aqueous phase was extracted with Et₂O (3 × 50 mL). The

combined organic layers were washed with brine (150 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography (2:3 EtOAc/

hexanes) provided iodoalcohol 20 (1.7 g, 68% yield) as a pale yellow

oil: ¹H NMR (500 MHz, C₆D₆) δ 7.14 (t, J = 8.0 Hz, 2H), 6.90 (d, J =

8.0 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 4.27−4.23 (m, 1H), 4.21 (t, J =

9.1 Hz, 1H), 4.06 (dd, J = 9.4, 4.8 Hz, 1H), 2.79−2.74 (m, 1H), 2.66−

2.61 (m, 1H), 2.57−2.53 (m, 1H), 2.14−2.11 (m, 1H), 2.07−2.02 (m,

1H), 1.99−1.95 (m, 1H), 1.77 (td, J = 12.5, 3.8 Hz, 1H), 1.69−1.61

(m, 2H), 1.57−1.46 (m, 2H), 1.43−1.37 (m, 1H), 1.34−1.13 (m, 3H),

0.98−0.92 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ 212.1, 158.9,

129.5, 120.9, 114.5, 71.3, 63.8, 58.6, 48.4, 43.1, 39.5, 38.3, 32.9, 29.8,

27.5, 21.9, 6.4; IR (thin ﬁlm) 3456, 2935, 1694, 1600, 1497, 1243

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₉H₂₆IO₃, 429.0927;

found, 429.0935.

tert-Butyl(3-((3aS*,7aS*)-6-methoxy-5-(phenoxymethyl)-3a-(tri-

methylsilyloxy)-2,3,3a,6,7,7a-hexahydro-1H-inden-4-yl)propoxy)-

diphenylsilane (18). First eluting was elimination product 18 (0.107 g,

1.4% yield) as a clear colorless oil composed of an unassigned mixture

of methoxy epimers. The major diastereomer was characterized as

follows: ¹H NMR (500 MHz, CDCl₃) δ 7.75 (dd, J = 7.9, 1.4 Hz, 4H),

7.50−7.43 (m, 6H), 7.31 (t, J = 8.0 Hz, 2H), 6.96−6.94 (m, 3H), 4.62

(dd, J = 5.3, 3.0 Hz, 1H), 4.41−4.39 (m, 1H), 4.31 (dd, J = 8.6, 3.7 Hz,

1H), 4.20 (dd, J = 11.0, 8.6 Hz, 1H), 3.71 (dd, J = 9.9, 6.2 Hz, 1H),

3.68 (dd, J = 9.9, 6.3 Hz, 1H), 3.48 (s, 3H), 2.50−2.44 (m, 1H), 2.21

(dt, J = 11.0, 4.0 Hz, 1H), 2.09−2.03 (m, 2H), 1.83 (td, J = 11.9, 4.0

Hz, 1H), 1.71−1.52 (m, 6H), 1.44−1.41 (m, 1H), 1.11 (s, 9H), 0.06

(s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 160.8, 159.3, 135.7, 134.4,

134.3, 129.5, 129.3, 127.61, 127.60, 119.9, 114.4, 92.5, 71.9, 65.1, 64.7,

54.4, 53.9, 46.9, 42.5, 39.1, 30.5, 28.7, 27.0, 25.9, 20.4, 19.3, 0.1; IR

(3aS*,7aS*)-3a-(3-Iodopropyl)-3-methylenetetrahydro-1H-

indene-2,4(5H,6H)-dione (21). Dess−Martin periodinane (1.45 g,

3.42 mmol, 1.50 equiv)²⁸was added in one portion to a stirring

suspension of iodoalcohol 20 (0.975 g, 2.28 mmol) and NaHCO₃

L

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(1.92 g, 22.8 mmol, 10.0 equiv) in CH₂Cl₂(12.7 mL) and stirred

vigorously for 20 min. The suspension was treated with 10% aq.

Na₂S₂O₃(10.0 mL) and stirred for 15 min. The layers were separated,

and the aqueous phase was extracted with CH₂Cl₂(3 × 20 mL). The

combined organic layers were washed with brine (20 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure to provide the dione (0.917 g, 94%). A solution of

1,8-diazabicyclo[5.4.0]undec-7-ene and THF (4.74 mL, 2.37 mmol,

0.50 M, 1.10 equiv) was added dropwise to a solution of dione (0.917

g, 2.15 mmol, 1.00 equiv) and THF (43 mL) at 0 °C. The cooling bath

was removed, and the pale brown solution was stirred for 20 min. The

solution was then partitioned between sat. aq. NH₄Cl (75 mL) and

Et₂O (50 mL), the layers were separated, and the aqueous phase was

extracted with Et₂O (2 × 50 mL). The combined organic layers were

washed with brine (100 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography (15:85 EtOAc/hexanes) provided endione

dropwise to a solution of 2-(4-methoxybenzyloxy)isoindoline-1,3-

dione (5.00 g, 18.6 mmol, 1.00 equiv) in THF (60 mL) at rt. After

completion of the addition, a colorless precipitate appeared and the

solution was stirred at rt for 1 h. Pyridine (3.00 mL, 37.1 mmol, 2.00

equiv) was then added by syringe, followed by addition of 2-

nitrobenzenesulfonyl chloride (4.12 g, 18.6 mmol, 1.00 equiv) in one

portion to the suspension. The resulting cloudy orange solution was

stirred at rt for 2 h. The solution was then partitioned between Et₂O

(100 mL) and sat. aq. NH₄Cl (75 mL). The aqueous phase was

extracted with Et₂O (3 × 100 mL), and the combined organic layers

were washed with brine, dried over MgSO₄, ﬁltered through a plug of

cotton, and concentrated under reduced pressure. The residue was

triturated with i-PrOH (100 mL), resulting in the formation of a

colorless solid. The solid was ﬁltered and washed with i-PrOH (100

mL) and recrystallized by dissolving in hot acetone (100 mL),

followed by addition of an equal volume of hexanes (100 mL) and

cooling to −4 °C overnight. The solid was ﬁltered and washed with

hexanes to give N-(4-methoxybenzyloxy)-2-nitrobenzenesulfonamide

1

21 (0.543 g, 76% yield) as a pale yellow oil: H NMR (500 MHz,

1

CDCl₃) δ 6.13 (s, 1H), 5.21 (s, 1H), 3.22 (dt, J = 9.6, 6.3 Hz, 1H),

3.09 (dt, J = 9.6, 7.3 Hz, 1H), 2.64 (dd, J = 18.2, 7.6 Hz, 1H), 2.59−

2.54 (m, 1H), 2.41 (dtd, J = 15.7, 4.5, 1.7 Hz, 1H), 2.33 (td, J = 11.9,

5.4 Hz, 1H), 2.21 (dd, J = 18.2, 2.0 Hz, 1H), 1.98−1.90 (m, 3H), 1.82

(dt, J = 15.3, 6.9 Hz, 2H), 1.74−1.59 (m, 2H), 1.42−1.33 (m, 1H);

¹³C NMR (125 MHz, CDCl₃) δ 209.6, 204.0, 146.8, 120.3, 60.3, 42.6,

38.6, 38.5, 37.2, 29.62, 29.60, 22.8, 6.6; IR (thin ﬁlm) 2925, 1727,

1636, 1447, 1231 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₃H₁₇IO₂Na, 355.0171; found, 355.0168.

(2.39 g, 38% yield) as colorless crystals: mp 165−167 °C; H NMR

(500 MHz, CDCl₃) δ 8.25 (t, J = 4.7 Hz, 1H), 8.08 (s, 1H), 7.88 (t, J =

4.3 Hz, 1H), 7.80−7.77 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 6.90 (d, J =

8.3 Hz, 2H), 5.01 (s, 2H), 3.82 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 160.4 (C), 148.7 (C), 134.9 (CH), 133.9 (CH), 133.1 (CH), 131.5

(CH), 130.7 (C), 127.2 (C), 125.8 (CH), 114.2 (CH), 79.8 (CH₂),

55.6 (CH₃); IR (thin ﬁlm) 3267, 2902, 1612, 1536, 1514, 1247, 1175

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₄H₁₄O₆N₂SNa,

361.0470; found, 361.0460.

Allyl 4-methoxybenzyloxycarbamate. Hydrazine hydrate (0.12

mL, 2.0 mmol, 1.0 equiv) was added dropwise to a solution of 2-(4-

methoxybenzyloxy)isoindoline-1,3-dione (0.556 g, 1.96 mmol, 1.00

equiv) in EtOH (57 mL) and stirred at rt for 14 h, during which time a

colorless precipitate formed. The precipitate was ﬁltered and washed

with EtOH (20 mL). The washes were combined and concentrated

under reduced pressure. The residue was diluted in a solution of THF

(3.9 mL), 1N NaOH (3 mL), and Et₃N (0.41 mL) and cooled to 0 °C.

Allylchloroformate (0.23 mL, 2.2 mmol, 1.1 equiv) was added

dropwise and stirred for 10 min; the cold bath was removed and

stirred for 14 h at rt. The solution was then partitioned between

EtOAc (50 mL) and H₂O (50 mL), and the aqueous phase was

extracted with EtOAc (3 × 30 mL). The combined organic layers were

washed with brine (30 mL), dried over MgSO₄, ﬁltered through a plug

of cotton, and concentrated under reduced pressure. Puriﬁcation by

ﬂash chromatography (3:7 EtOAc/hexanes) provided allyl 4-

(4bS*,8aS*)-2-Ethoxy-4b-(3-iodopropyl)-3,4,4b,6,7,8,8a,9-

octahydro-2H-1-oxaﬂuoren-5-one (22). In one portion, Eu(fod)₃

(228 mg, 0.220 mmol, 0.100 equiv) was added to a stirred solution of

endione 21 (0.731 g, 2.20 mmol, 1.00 equiv) in ethyl vinyl ether (4.3

mL, 46 mmol, 21 equiv), and the reaction was maintained at rt for 18

h. The solution was concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography (1:15:84 Et₃N/EtOAc/hexanes) provided

dihydropyran 22 as an approximately 1:1 mixture of ethoxy epimers

(0.766 g, 86% yield) as a clear oil. The product was stored in a

benzene matrix at −20 °C in a base-washed vial. ¹H NMR (500 MHz,

C₆D₆) δ 4.88 (s, 1H, single diastereomer), 4.85 (s, 1H, single

diastereomer), 3.82−3.74 (m, 1H), 3.41−3.34 (m, 1H), 2.91−2.81 (m,

3H), 2.62−2.52 (m, 2H), 2.18−2.12 (m, 3H), 2.04−1.85 (m, 2H),

1.78−1.72 (m, 4H), 1.62−1.59 (m, 1H), 1.53−1.40 (m, 3H), 1.37−

1.31 (m, 1H), 1.11 (t, J = 7.1 Hz, 3H, single diastereomer), 1.04 (t, J =

7.1 Hz, 3H, single diastereomer); ¹³C NMR (125 MHz, CDCl₃) δ

214.6, 214.0, 150.7, 150.5, 109.5, 109.3, 98.4, 98.3, 63.9, 62.30, 62.28,

39.3, 38.6, 38.3, 37.2, 36.9, 35.9, 35.6, 29.48, 29.46, 28.9, 28.8, 26.81,

26.78, 19.7, 19.4, 16.0, 15.9, 15.44, 15.38, 7.3, 7.0; IR (thin ﬁlm) 2931,

1692, 1627, 1227, 1064 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₇H₂₅O₃INa, 427.0746; found, 427.0737.

1

methoxybenzyloxycarbamate (189 mg, 41% yield) as a clear oil: H

NMR (500 MHz, CDCl₃) δ 7.43 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H),

6.89 (d, J = 8.5 Hz, 2H), 5.95−5.89 (m, 1H), 5.32 (dd, J = 1.0, 17.0

Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 4.81 (s, 2H), 4.64 (d, J = 6.0 Hz,

2H), 3.81 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 160.1 (C), 157.4

(C), 132.2 (CH), 131.1 (CH), 127.6 (C), 118.8 (CH), 114.1 (CH),

78.5 (CH₂), 66.6 (CH₂), 55.5 (CH₃); IR (thin ﬁlm) 3284, 2938, 2838,

1727, 1612, 1514, 1250 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₂H₁₅NO₄Na, 260.0899; found, 260.0895.

2-(2-Nitrobenzyloxy)isoindoline-1,3-dione. 2-(2-

Nitrobenzyloxy)isoindoline-1,3-dione was synthesized as reported by

Sebesta and co-workers.⁹¹Sodium acetate (1.90 g, 23.2 mmol) was

added to a solution of N-hydroxyphthalimide (3.78 g, 23.2 mmol) in

DMF (230 mL) at rt, causing the appearance of a deep red color. 2-

Nitrobenzyl bromide (5.01 g, 23.2 mmol) was then added to the

solution, followed by heating to 80 °C under a cold water condenser.

After 14 h, the solution became a clear yellow solution and was cooled

to rt and partitioned between EtOAc (200 mL) and water (1 L). The

aqueous phase was extracted with EtOAc (3 × 200 mL). The

combined organic layers were washed with brine (200 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure to aﬀord 2-(2-nitrobenzyloxy)isoindoline-1,3-dione

as a crystalline yellow solid (6.91 g, 99% yield). The product was

carried on without further puriﬁcation. ¹H NMR spectra matched

those reported by Sebasta.⁹⁰

2-(4-Methoxybenzyloxy)isoindoline-1,3-dione. Diisopropyl

azodicarboxylate (21.7 mL, 0.110 mol, 1.10 equiv) was slowly added

dropwise to a solution of N-hydroxyphthalimide (15.0 g, 92.0 mmol,

1.00 equiv), triphenylphosphine (26.5 g, 101 mmol, 1.10 equiv), 4-

methoxybenzyl alcohol (11.5 mL, 92.0 mmol, 1.00 equiv), and CH₂Cl₂

(600 mL) at 0 °C. After completion of the addition, the cold bath was

removed and the solution was stirred at rt for 16 h. The solution was

then concentrated under reduced pressure and recrystallized in hot

EtOH (700 mL). The solution was slowly cooled to rt and left

standing overnight. Crystals were ﬁltered and washed with cold EtOH

(2 × 100 mL). The crystals were recrystallized a second time with

EtOH (600 mL) to aﬀord 2-(4-methoxybenzyloxy)isoindoline-1,3-

1

dione (20.2 g, 82% yield) as colorless crystals: mp 141−142 °C; H

NMR (500 MHz, CDCl₃) δ 7.81−7.79 (m, 2H), 7.74−7.72 (m, 2H),

7.45 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.15 (s, 2H), 3.80

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 163.8 (C), 160.7 (C), 134.6

(CH), 131.9 (CH), 129.1 (C), 126.1 (C), 123.7 (CH), 114.1 (CH),

79.7 (CH₂), 55.5 (CH₃); IR (thin ﬁlm) 2963, 1727 cm⁻¹; HRMS-ESI

(m/z) [M + Na]⁺calcd for C₁₆H₁₃O₄NNa, 306.0742; found,

306.0746.

N-(4-Methoxybenzyloxy)-2-nitrobenzenesulfonamide. Hy-

drazine hydrate (1.17 mL, 20.4 mmol, 51%, 1.10 equiv) was added

tert-Butyl 2-nitrobenzyloxycarbamate. Hydrazine hydrate

(0.640 mL, 10 mmol, 1.0 equiv) was added dropwise to a solution

M

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

of 2-(2-nitrobenzyloxy)isoindoline-1,3-dione (3.00 g, 10.0 mmol, 1.00

equiv) in EtOH (100 mL) at rt and stirred for 16 h, during which time

a colorless precipitate formed. The precipitate was ﬁltered and washed

with EtOH. The washes were combined and concentrated under

reduced pressure to provide a yellow solid. The yellow residue was

combined with (Boc)₂O (2.29 g, 10.5 mmol, 1.05 equiv) and

suspended in a mixture of THF (50 mL), H₂O (50 mL), and Et₃N

(1.53 mL). The biphasic mixture was stirred vigorously for 5 h at rt.

The mixture was partitioned between Et₂O (100 mL) and H₂O (100

mL), and the aqueous phase was extracted with Et₂O (3 × 100 mL).

The combined organic layers were washed with brine (75 mL), dried

over MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. The residue was recrystallized with acetone/hexanes

to aﬀord tert-butyl 2-nitrobenzyloxycarbamate (0.59 g, 22% yield) as

3251, 2949, 1538 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₅H₂₆O₅N₂SSiNa, 397.1230; found, 397.1223.

2-(2-(Trimethylsilyl)ethoxy)isoindoline-1,3-dione. 2-(2-

(Trimethylsilyl)ethoxy)isoindoline-1,3-dione was prepared as de-

scribed by Kikugawa and co-workers⁹³with minor modiﬁcations.

Diisopropyl azodicarboxylate (5.80 mL, 24.9 mmol, 1.02 equiv) was

slowly added dropwise to a solution of N-hydroxyphthalimide (4.00 g,

24.5 mmol, 1.00 equiv), 2-trimethylsilyl ethanol (3.51 mL, 24.5 mmol,

1.00 equiv), triphenylphosphine (7.07 g, 26.8 mmol, 1.1 equiv), and

anhydrous chloroform (41 mL) at 0 °C. After completion of the

addition, the cold bath was removed and the mixture was allowed to

stir at rt for 14 h. The solution was then partitioned between CH₂Cl₂

(200 mL) and H₂O (300 mL), and the aqueous phase was extracted

with CH₂Cl₂(3 × 100 mL). The combined organic layers were

washed with brine (100 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography (1:1 EtOAc/benzene) aﬀorded 2-(2-

(trimethylsilyl)ethoxy)isoindoline-1,3-dione (4.58 g, 71% yield) as a

1

pale yellow crystals: mp 98−99 °C; H NMR (500 MHz, CDCl₃) δ

8.06 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 8.0 Hz,

1H), 7.49 (t, J = 8.0 Hz, 1H), 7.30 (br s, 1H), 5.29 (s, 2H), 1.48 (s,

9H); ¹³C NMR (125 MHz, CDCl₃) δ 156.9 (C), 148.2 (C), 133.8

(CH), 132.5 (C), 130.2 (CH), 129.0 (CH), 125.1 (CH), 82.5 (C),

75.2 (CH₂), 28.4 (CH₃); IR (thin ﬁlm) 3271, 2980, 1719, 1527 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₂H₁₆N₂O₅Na, 291.0957;

found, 291.0958.

1

gray solid: mp 95−96 °C; H NMR (500 MHz, CDCl₃) δ 7.83−7.85

(m, 2H), 7.74−7.76 (m, 2H), 4.26−4.30 (m, 2H), 1.20−1.23 (m, 2H),

0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 164.0 (C), 134.6 (CH),

129.2 (C), 123.7 (CH), 76.7 (CH₂), 17.2 (CH₂), −1.2 (CH₃); IR

(thin ﬁlm) 2953, 1790, 1733 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₁₃H₁₇NO₃SiNa, 286.0876; found, 286.0885.

N-(tert-Butyldimethylsilyloxy)-2-nitrobenzenesulfonamide.

Pyridine (2.19 mL, 27.2 mmol, 2.00 equiv), followed by 2-

nitrobenzenesulfonyl chloride (3.01 g, 13.6 mmol, 1.00 equiv), was

added in one portion to a solution of O-(tert-butyldimethylsilyl)-

hydroxylamine⁹²(2.00 g, 13.6 mmol, 1.00 equiv) in THF (45 mL).

The solution was stirred at rt for 14 h and then partitioned between

sat. aq. NH₄Cl (300 mL) and Et₂O (150 mL). The layers were

separated, and the aqueous phase was extracted with Et₂O (3 × 100

mL). The combined organic layers were washed with brine (75 mL),

dried over MgSO₄, ﬁltered through a plug of cotton, and concentrated

under reduced pressure. Puriﬁcation by ﬂash chromatography (1:4

EtOAc/hexanes) provided N-(tert-butyldimethylsilyloxy)-2-nitroben-

zenesulfonamide (2.14 g, 47% yield) as a pale orange solid: mp 73−75

2-Nitro-N-(2-(trimethylsilyl)ethoxy)benzenesulfonamide.

Hydrazine hydrate (2.19 mL, 19.2 mmol, 51%, 1.10 equiv) was added

dropwise to a solution of 2-(2-(trimethylsilyl)ethoxy)isoindoline-1,3-

dione (4.58 g, 17.4 mmol, 1.00 equiv) in CH₂Cl₂(60 mL). A colorless

precipitate formed, and the solution was stirred at rt for 1 h. Pyridine

(2.81 mL, 34.8 mmol, 2.00 equiv), followed by 2-nitrobenzenesulfonyl

chloride (3.85 g, 17.4 mmol, 1.00 equiv), was added in one portion to

the suspension, and the mixture became a dark yellow. The suspension

was allowed to stir at rt for 14 h. The suspension was then partitioned

between sat. aq. NH₄Cl (300 mL) and CH₂Cl₂(150 mL), and the

aqueous phase was extracted with CH₂Cl₂(3 × 100 mL). The

combined organic layers were washed with brine (75 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography (3:7 EtOAc/

hexanes) aﬀorded 2-nitro-N-(2-(trimethylsilyl)ethoxy)-

benzenesulfonamide (1.90 g, 49% yield) as a tan amorphous solid:

¹H NMR (500 MHz, CDCl₃) δ 8.24−8.22 (m, 1H), 8.05 (s, 1H),

7.91−7.90 (m, 1H), 7.86−7.75 (m, 2H), 4.15 (m, 2H), 0.97 (m, 2H),

0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 148.8 (C), 134.7 (CH),

134.0 (CH), 133.0 (CH), 130.8 (CH), 125.8 (C), 76.0 (CH₂), 17.2

(CH₂), −1.2 (CH₃); IR (thin ﬁlm) 3245, 2955, 1733, 1543, 1362

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₁H₁₈N₂O₅SSiNa,

341.0603; found, 341.0604.

General Procedure for the S_N2 Addition of Protected

Hydroxylamines. Iodide 22 (771 mg, 1.91 mmol, 1.00 equiv),

K₂CO₃(396 mg, 2.86 mmol, 1.50 equiv), and protected hydroxyl-

amine (0.700 g, 2.00 mmol, 1.05 equiv) were suspended in DMF (3.2

mL) and stirred at rt for 16 h. The mixture was partitioned between

Et₂O (50 mL) and H₂O (200 mL). The aqueous phase was extracted

with Et₂O (3 × 70 mL). The combined organic layers were washed

with brine, dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure. Isolated dihydropyrans were

approximately 1:1 mixtures of ethoxy epimers. The tricyclic

dihydropyrans products were stored in a benzene matrix at −20 °C

in base-washed vials.⁹⁴

1

°C; H NMR (500 MHz, CDCl₃) δ 8.16 (dd, J = 1.4, 7.4 Hz, 1H),

7.90 (dd, J = 1.4, 7.8 Hz, 1H), 7.81 (doublet of quintets, J = 1.6, 7.6

Hz, 2H), 7.66 (s, 1H), 0.89 (s, 9H), 0.26 (s, 6H); ¹³C NMR (125

MHz, CDCl₃) δ 148.9 (C), 134.9 (CH), 134.4 (CH), 132.8 (CH),

130.3 (C), 125.7 (CH), 20.1 (CH₃), 18.3 (C), −5.0 (CH₃); IR (thin

ﬁlm) 3266, 2932, 1541, 1396, 1362, 1181 cm⁻¹; HRMS-ESI (m/z) [M

+ H]⁺calcd for C₁₂H₂₁N₂O₅SSi, 333.0941; found, 333.0948.

2-Nitro-N-(triisopropylsilyloxy)benzenesulfonamide. Hy-

droxylamine hydrochloride (695 mg, 10.0 mmol, 1.00 equiv) was

added to a solution of ethylenediamine (540 μL, 10.0 mmol, 1.0

equiv) in CH₂Cl₂(4.3 mL) and stirred at rt for 24 h. To the resulting

biphasic mixture was added a solution of TIPSCl (2.14 mL, 10.0

mmol, 1.00 equiv) in CH₂Cl₂(1 mL) in ﬁve portions via syringe. The

mixture was stirred for 36 h and ﬁltered. The precipitate was washed

with CH₂Cl₂(2 × 5 mL). The combined washes were evaporated

under reduced pressure, and the residue was puriﬁed by Kugelrohr

distillation to aﬀord O-(triisopropylsilyl)hydroxylamine as a clear oil

(1.20 g, 63% yield). Pyridine (1.03 mL, 12.7 mmol, 2.00 equiv),

followed by 2-nitrobenzenesulfonyl chloride (1.41 g, 6.34 mmol, 1.00

equiv), was added in one portion to a solution of O-(triisopropylsilyl)-

hydroxylamine (1.20 g, 6.34 mmol, 1.00 equiv) in CH₂Cl₂(16 mL).

The solution was stirred at rt for 14 h in which a colorless precipitate

appeared. The mixture was partitioned between H₂O (50 mL) and

CH₂Cl₂(50 mL), and the aqueous phase was extracted with CH₂Cl₂

(3 × 50 mL). The combined organic layers were washed with brine

(50 mL), dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure. Puriﬁcation by ﬂash chromatog-

raphy (3:7 EtOAc/hexanes) aﬀorded N-(diisopropylsilyloxy)-2-nitro-

benzenesulfonamide (0.87 g, 37% yield) as a yellow orange solid: mp

(4bS*,8aS*)-2-Ethoxy-4b-(3-bis(tert-butoxycarbonyl)-

hydroxyaminopropyl)-3,4,4b,6,7,8,8a,9-octahydro-2H-1-oxa-

ﬂuoren-5-one (23). Following the general procedure, iodide 22

(0.038 g, 0.094 mmol) was converted to an approximately 1:1 mixture

of ethoxy epimers 23. Puriﬁcation by ﬂash chromatography (3:1:96

EtOAc/Et₃N/benzene) provided 23 (0.042 g, 88% yield) as a colorless

1

94−96 °C; H NMR (500 MHz, CDCl₃) δ 8.21 (dd, J = 1.8, 7.4 Hz,

foam: H NMR (500 MHz, C₆D₆) δ 4.83 (dd, J = 3.9, 2.4 Hz, 1H),

1H), 7.91 (dd, J = 1.6, 7.5 Hz, 1H), 7.83−7.79 (m, 2H), 7.64 (s, 1H),

1.27 (septet, J = 7.3 Hz, 3H), 1.09 (d, J = 7.4 Hz, 18H); ¹³C NMR

(125 MHz, CDCl₃) δ 148.9 (C), 134.8 (CH), 134.5 (CH), 132.7

(CH), 130.3 (C), 125.6 (CH), 17.9 (CH₃), 12.1 (CH); IR (thin ﬁlm)

4.81 (dd, J = 3.7, 2.4 Hz, 1H), 3.83−3.73 (m, 1H), 3.70 (br s, 2H),

3.38−3.32 (m, 1H), 2.55−2.50 (m, 1H), 2.48−2.44 (m, 1H), 2.14−

1.94 (m, 5H), 1.86−1.50 (m, 8H), 1.43 (s, 9H), 1.42 (s, 9H), 1.33 (s,

9H), 1.32 (s, 9H), 1.31−1.26 (m, 2H), 1.20−1.12 (m, 1H), 1.09 (t, J =

N

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆) δ

212.1, 211.5, 154.9, 154.8, 152.8, 152.7, 150.1, 149.8, 109.9, 109.6,

98.21, 98.20, 83.6, 83.5, 81.3, 81.2, 63.4, 62.0, 50.72, 50.68, 39.2, 39.0,

38.4, 38.1, 36.83, 36.79, 32.3, 32.0, 29.0, 28.7, 27.8, 27.2, 26.9, 26.8,

22.41, 22.38, 19.8, 19.4, 16.3, 15.9, 15.2, 15.1; IR (thin ﬁlm) 2935,

1785, 1692, 1370, 1150 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₇H₄₃NO₈Na, 532.2886; found, 532.2880.

(4bS*,8aS*)-2-Ethoxy-4b-(3-(tert-butyoxycarbonyl-2-

nitrobenzyloxy)aminopropyl)-3,4,4b,6,7,8,8a,9-octahydro-2H-

1-oxaﬂuoren-5-one (24). Following the general procedure, iodide

22 (0.047 g, 0.12 mmol) and tert-butyl 2-nitrobenzyloxycarbamate

were converted to an approximately 5:1 mixture of ethoxy epimers 24.

Puriﬁcation by ﬂash chromatography (3:1:96 EtOAc/Et₃N/benzene)

provided 24 (0.063 g, 99% yield) as a colorless oil. Data for major

diastereomer: ¹H NMR (500 MHz, C₆D₆) δ 7.53−7.51 (m, 2H),

6.93−6.89 (m, 1H), 6.65 (t, J = 7.5 Hz, 1H), 5.26 (s, 2H), 4.85−4.83

(m, 1H), 3.80−3.74 (m, 1H), 3.53−3.47 (m, 2H), 3.39−3.33 (m, 1H),

2.58 (ddt, J = 15.8, 8.9, 2.8 Hz, 1H), 2.21−1.97 (m, 5H), 1.88−1.81

(m, 1H), 1.76−1.70 (m, 1H), 1.66−1.51 (m, 5H), 1.42 (s, 9H), 1.35−

1.22 (m, 4H), 1.04 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆) δ

211.6, 156.4, 150.2, 148.4, 132.5, 131.7, 130.5, 128.2, 124.1, 109.7,

98.2, 80.7, 72.7, 63.5, 62.1, 50.2, 39.1, 38.1, 36.8, 32.1, 29.0, 27.9, 26.9,

22.2, 19.4, 16.0, 15.1; IR (thin ﬁlm) 2933, 1698, 1530, 1368, 1162

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₉H₄₀N₂O₈Na,

567.2682; found, 567.2670.

2933, 1694 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₉H₃₉NO₇Na, 536.2625; found, 536.2634.

(4bS*,8aS*)-2-Ethoxy-4b-(3-(4-methoxybenzyloxy-2-

nitrobenzenesulfonyl)aminopropyl)-3,4,4b,6,7,8,8a,9-octahy-

dro-2H-1-oxaﬂuoren-5-one (27). Following the general procedure,

iodide 22 (0.281 g, 0.695 mmol) and N-(4-methoxybenzyloxy)-2-

nitrobenzenesulfonamide were converted to an approximately 1:1

mixture of ethoxy epimers 27. Puriﬁcation by ﬂash chromatography

(10:1:89 EtOAc/Et₃N/benzene) provided 27 (0.376 g, 88% yield) as a

colorless foam: ¹H NMR (500 MHz, C₆D₆) δ 7.89 (d, J = 7.7 Hz, 1H,

single diastereomer), 7.86 (d, J = 7.7 Hz, 1H, single diastereomer),

7.39−7.37 (m, 2H), 6.78 (t, J = 8.9 Hz, 2H), 6.68−6.59 (m, 3H),

5.25−5.18 (m, 2H), 4.83 (br s, 1H), 3.80−3.76 (m, 1H), 3.39−3.34

(m, 1H), 3.30 (s, 3H, single diastereomer), 3.29 (s, 3H, single

diastereomer), 3.15 (br s, 2H), 2.55−2.50 (m, 1H), 2.18−2.11 (m,

1H), 2.05−1.86 (m, 4H), 1.77−1.67 (m, 2H), 1.58−1.22 (m, 8H),

1.05 (t, J = 7.1 Hz, 3H), 0.91−0.89 (m, 1H); ¹³C NMR (125 MHz,

C₆D₆) δ 212.0, 211.6, 160.30, 160.27, 150.3, 150.1, 149.9, 149.8, 134.1,

134.0, 132.40, 132.36, 131.8, 131.7, 130.01, 129.99, 127.4, 127.3,

125.9, 125.8, 123.0, 113.94, 113.91, 109.7, 109.6, 98.4, 98.2, 79.84,

79.80, 63.7, 63.5, 62.02, 62.00, 54.44, 54.43, 54.1, 54.0, 39.3, 39.1, 38.5,

38.2, 36.8, 36.7, 32.6, 32.4, 29.3, 28.8, 26.9, 26.8, 22.2, 22.0, 19.8, 19.5,

16.3, 15.8, 15.2; IR (thin ﬁlm) 2933, 2856, 1686, 1547 cm⁻¹; HRMS-

ESI (m/z) [M + Na]⁺calcd for C₃₁H₃₈N₂O₉SNa, 637.2195; found,

637.2193.

(4bS*,8aS*)-2-Ethoxy-4b-(3-tert-butyldimethylsilyoxy-2-

nitrobenzenesulfonyl)aminopropyl)-3,4,4b,6,7,8,8a,9-octahy-

dro-2H-1-oxaﬂuoren-5-one (41). Following the general procedure,

iodide 22 (723 mg, 1.79 mmol) and N-(tert-butyldimethylsilyloxy)-2-

nitrobenzenesulfonamide (625 mg, 1.88 mmol) were converted to

tricycle 41 as an approximately 1:1 mixture of ethoxy epimers.

Puriﬁcation by ﬂash chromatography (5:1:94 EtOAc/Et₃N/benzene)

provided tricyclic dihydropyran 41 (698 mg, 69% yield) as a clear oil:

¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 7.8 Hz, 1H), 7.68 (t, J =

7.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 4.93

(m, 1H), 3.76−3.72 (m, 1H), 3.51−3.46 (m, 1H), 3.12−3.01 (m, 2H),

2.51−2.47 (m, 1H), 2.35−2.19 (m, 2H), 2.10−1.98 (m, 1H), 1.81

(quintet, J = 3.8 Hz, 1H), 1.79−1.71 (m, 1H), 1.66−1.64 (m, 1H),

1.60−1.58 (m, 4H), 1.56−1.47 (m, 2H), 1.37−1.33 (m, 3H), 1.23

(sextet, J = 7.5 Hz, 1H), 1.12 (q, J = 3.4 Hz, 3H), 1.05 (d, J = 7.4 Hz,

4H), 0.95 (s, 1H), 0.85 (s, 6H), 0.17 (s, 2H), 0.15 (s, 2H); ¹³C NMR

(125 MHz, CDCl₃) complex spectra due to mixture of epimers peaks

observed are listed δ 214.6, 150.9, 150.6, 134.9, 134.7, 133.3, 130.9,

128.6, 123.6, 123.5, 109.6, 109.4, 98.7, 98.5, 64.1, 64.0, 62.7, 62.6, 56.2,

56.1, 39.5, 39.4, 38.9, 37.2, 37.0, 32.4, 31.9, 29.7, 29.4, 27.1, 27.0, 26.2,

22.4, 22.2, 20.0, 19.6, 18.4, 17.9, 16.4, 16.1, 15.5, 12.9, 12.8, −4.18,

−4.23; IR (thin ﬁlm) 2931, 2859, 1691, 1549, 1375, 1179 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₉H₄₄N₂O₈SSiNa, 631.2485;

found, 631.2480.

(4bS*,8aS*)-2-Ethoxy-4b-(3-(4-methoxybenzyloxy-tert-

butyoxycarbonyl)aminopropyl)-3,4,4b,6,7,8,8a,9-octahydro-

2H-1-oxaﬂuoren-5-one (25). Following the general procedure,

iodide 22 (0.100 g, 0.247 mmol) and O-(tert-butoxycarbonyl)-N-(4-

methoxybenzyl) hydroxylamine⁹⁵were converted to an approximately

1:1 mixture of ethoxy epimers 25. Puriﬁcation by ﬂash chromatog-

raphy (3:1:96 EtOAc/Et₃N/benzene) provided 25 as a colorless ﬁlm

1

(0.088 g, 67% yield): H NMR (500 MHz, CDCl₃) δ 7.32 (d, J = 8.6

Hz, 2H, single diastereomer), 7.31 (d, J = 8.7 Hz, 2H, single

diastereomer), 6.87 (d, J = 8.6 Hz, 2H), 5.00 (br s, 1H), 4.75 (s, 2H),

3.84−3.81 (m, 1H), 3.80 (s, 3H), 3.58−3.56 (m, 1H), 3.36−3.34 (m,

2H), 2.66−2.56 (m, 1H), 2.41 (septet, J = 4.7 Hz, 1H), 2.34−2.28 (m,

1H), 2.25−2.16 (m, 1H), 2.08 (t, J = 15 Hz, 1H), 1.97−1.54 (m, 9H),

1.49 (s, 9H), 1.46−1.44 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H, single

diastereomer), 1.17 (t, J = 7.1 Hz, 3H, single diastereomer); ¹³C NMR

(125 MHz, CDCl₃) δ 214.6, 214.3, 159.9, 159.8, 156.59, 156.56, 150.4,

150.1, 131.1, 131.0, 128.0, 127.9, 113.8, 109.7, 109.4, 98.5, 98.4, 81.2,

81.1, 76.5, 63.9, 63.8, 62.5, 62.4, 55.3, 50.2, 39.20, 39.17, 38.7, 38.3,

36.9, 32.2, 31.7, 29.3, 29.1, 28.4, 26.9, 26.8, 22.1, 22.0, 19.8, 19.4, 16.3,

16.0, 15.4, 15.3; IR (thin ﬁlm) 2933, 2854, 1694, 1248 cm⁻¹; HRMS-

ESI (m/z) [M + Na]⁺calcd for C₃₀H₄₃NO₇Na, 552.2937; found,

552.2936.

(4bS*,8aS*)-2-Ethoxy-4b-(3-(allyloxycarbonyl-4-

methoxybenzyloxy)aminopropyl)-3,4,4b,6,7,8,8a,9-octahydro-

2H-1-oxaﬂuoren-5-one (26). Following the general procedure,

iodide 22 (0.105 g, 0.260 mmol) and allyl 4-methoxybenzyloxycarba-

mate were converted to an approximately 1:1 mixture of ethoxy

epimers 26. Puriﬁcation by ﬂash chromatography (3:1:96 EtOAc/

Et₃N/benzene) provided 26 (0.104 g, 78% yield) as a colorless foam:

¹H NMR (500 MHz, C₆D₆) δ 7.33 (d, J = 7.7 Hz, 2H), 6.76 (d, J = 8.7

Hz, 2H, single diastereomer), 6.75 (d, J = 8.6 Hz, 2H, single

diastereomer), 5.83−5.76 (m, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.00 (d,

J = 10.5 Hz, 1H), 4.86 (d, J = 11.1 Hz, 2H), 4.82 (d, J = 11.7 Hz, 1H),

4.59 (br s, 2H), 3.77 (sextet, J = 8.0 Hz, 1H), 3.52 (t, J = 6.5 Hz, 1H,

single diastereomer), 3.47 (t, J = 6.8 Hz, 1H, single diastereomer),

3.37−3.33 (m, 1H), 3.27 (s, 3H, single diastereomer), 3.26 (s, 3H,

single diastereomer), 2.52−2.47 (m, 1H), 2.18−2.01 (m, 4H), 1.96−

1.93 (m, 1H), 1.83−1.69 (m, 3H), 1.63−1.49 (m, 5H), 1.27−1.24 (m,

2H), 1.19−1.16 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H, single diastereomer),

1.03 (t, J = 7.1 Hz, 3H, single diastereomer); ¹³C NMR (125 MHz,

C₆D₆) δ 212.1, 211.6, 160.03, 160.01, 157.1, 157.0, 150.1, 149.8,

132.85, 132.83, 131.0, 128.24, 128.19, 117.22, 117.19, 113.76, 113.75,

109.9, 109.7, 98.22, 98.20, 76.60, 76.56, 66.1, 66.0, 63.50, 63.48, 62.1,

54.4, 50.6, 50.5, 39.1, 39.0, 38.4, 38.1, 36.83, 36.78, 32.4, 32.1, 29.0,

28.7, 26.9, 26.8, 22.2, 22.1, 19.7, 19.4, 16.2, 16.0, 15.1; IR (thin ﬁlm)

(4bS*,8aS*)-2-Ethoxy-4b-(3-triisopropylsilyoxy-2-

nitrobenzenesulfonyl)aminopropyl)-3,4,4b,6,7,8,8a,9-octahy-

dro-2H-1-oxaﬂuoren-5-one (42). Following the general procedure,

iodide 22 (0.900 g, 2.23 mmol) and 2-nitro-N-(triisopropylsilyloxy)-

benzenesulfonamide (876 mg, 2.34 mmol) were coverted to tricycle

42 as an approximately 1:1 mixture of ethoxy epimers. Puriﬁcation by

ﬂash chromatography (5:1:94 EtOAc/Et₃N/benzene) provided

tricyclic dihydropyran 42 (1.32 g, 91% yield) as a clear oil: ¹H

NMR (500 MHz, C₆D₆) δ 8.04 (t, J = 7.8 Hz, 1H), 6.82 (t, J = 7.6 Hz,

1H), 6.74−6.70 (m, 2H), 4.85−4.82 (m, 1H), 3.76−3.74 (m, 1H),

3.39−3.26 (m, 3H), 2.55−2.45 (m, 1H), 2.17−2.01 (m, 5H), 1.72−

1.66 (m, 1H), 1.57−1.52 (m, 3H), 1.37−1.29 (m, 4H), 1.37−1.29 (m,

4H), 1.15 (d, J = 4.3 Hz, 9H), 1.07 (d, J = 9.3 Hz, 9H), 1.02−0.91 (m,

5H); ¹³C NMR (125 MHz, C₆D₆) complex spectra due to mixture of

epimers peaks observed are listed δ 213.0, 212.5, 170.6, 151.1, 150.9,

150.1, 134.7, 132.9, 130.6, 128.9, 127.4, 123.6, 110.1, 109.8, 98.9, 98.7,

64.3, 62.8, 60.5, 56.9, 39.9, 38.8, 37.6, 33.1, 32.7, 29.9, 29.4, 27.5, 22.3,

20.4, 19.9, 18.4, 16.4, 15.8, 13.2; IR (thin ﬁlm) 2944, 1693, 1549, 1464,

1179 cm⁻¹

; HRMS-ESI (m/z) [M +

Na]⁺calcd for

C₃₂H₅₀O₈N₂SSiNa, 673.2955; found, 673.2941.

O

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(4bS*,8aS*)-2-Ethoxy-4b-(3-(2-(trimethylsilyl)ethyloxy-2-

nitrobenzenesulfonyl)aminopropyl)-3,4,4b,6,7,8,8a,9-octahy-

dro-2H-1-oxaﬂuoren-5-one (43). Following the general procedure

described above, iodide 22 (0.900 g, 2.23 mmol) and 2-nitro-N-(2-

(trimethylsilyl)ethoxy)benzenesulfonamide were converted to tricyclic

dihydropyran 43 as an approximately 1:1 mixture of ethoxy epimers.

Puriﬁcation by ﬂash chromatography (5:1:94 EtOAc/Et₃N/benzene)

aﬀorded tricyclic dihydropyran 43 (1.29 g, 97% yield) as a brown oil:

¹H NMR (500 MHz, C₆D₆) δ 7.88 (dd, J = 14.8, 7.4 Hz, 1H), 6.73 (q,

J = 6.8 Hz, 1H), 6.65−6.58 (m, 2H), 4.82 (m, 1H), 4.47−4.33 (m,

2H), 3.78 (m, 1H), 3.36 (m, 1H), 3.17 (br s, 1H), 2.60−2.48 (m, 1H),

2.13 (m, 1H), 2.07−1.88 (m, 4H), 1.72−1.67 (m, 2H), 1.59−1.37 (m,

4H), 1.32−1.13 (m, 4H), 1.13−1.03 (m, 6H), 0.91 (t, J = 7.2 Hz, 1H),

−0.02 (s, 9H); ¹³C NMR (125 MHz, C₆D₆) δ 211.9 (C), 150.7 (C),

134.6 (CH), 133.0 (CH), 130.5 (CH), 126.9 (C), 123.8 (CH), 110.3

(CH₂), 98.9 (CH), 76.7 (CH₂), 64.2 (CH₂), 62.7 (C), 60.4 (C), 54.5

(C), 39.9 (CH₂), 39.0 (CH₂), 37.6 (CH₂), 33.3 (CH₂), 29.7 (CH₂),

27.6 (CH₂), 23.0 (CH₂), 20.9 (CH₂), 20.2 (CH₂), 17.8 (CH₂), 16.5

(CH₂), 15.9 (CH₂), 14.5 (CH₃), −1.2 (CH₃); IR (thin ﬁlm) 2948,

1692, 1549, 1375, 1179 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₈H₄₂O₈N₂SSiNa, 617.2329; found, 617.2339.

Tetracyclic Nitrone 28. Solid m-CPBA (0.013 g, 0.059 mmol, 1.5

equiv) was added in one portion to a solution of dihydropyran 23

(0.020 g, 0.039 mmol, 1.0 equiv) in CH₂Cl₂(1.2 mL) at −78 °C. After

addition, the mixture was placed in a −20 °C ice−acetone bath and

maintained for 30 min. The solution was poured into a 1:1:1 solution

of H₂O/sat. aq. Na₂S₂O₃/sat. aq. NaHCO₃(1 mL) and stirred

vigorously at rt for 30 min. The layers were separated, and the aqueous

phase was extracted with CH₂Cl₂(2 × 5 mL). The combined organic

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

through a plug of cotton, and concentrated under reduced pressure.

The residue was dissolved in CH₂Cl₂(0.3 mL), and CF₃CO₂H (0.3

mL) was added. The solution was maintained at rt for 8 h. The

solution was then transferred carefully into a stirred biphasic mixture

of CH₂Cl₂(10 mL) and sat. aq. NaHCO₃(10 mL), resulting in a

vigorous evolution of gas. The layers were separated, and the aqueous

phase was extracted with CH₂Cl₂(2 × 10 mL). The combined organic

layers were washed with brine (20 mL), dried over MgSO₄, ﬁltered

through a plug of cotton, and concentrated under reduced pressure.

Puriﬁcation by preparatory thin-layer chromatography (1:9 MeOH/

CHCl₃) aﬀorded nitrone 28 (0.003 g, 28% yield) as a pale yellow oil:

¹H NMR (500 MHz, CD₃OD) δ 5.08−5.07 (m, 1H), 3.89−3.87 (m,

and sat. aq. NaHCO₃(10 mL), resulting in a vigorous evolution of gas.

The layers were separated, and the aqueous layer was extracted with

Et₂O (2 × 10 mL). The combined organic layers were washed with

brine (20 mL), dried over MgSO₄, ﬁltered through a plug of cotton,

and concentrated under reduced pressure. Puriﬁcation by ﬂash

chromatography (2:3 EtOAc/hexanes) aﬀorded lactol 29 (0.036 g,

1

58% yield) as a pale yellow oil: H NMR (500 MHz, CDCl₃) δ 8.01

(d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H),

7.50 (t, J = 7.7 Hz, 1H), 5.35 (br s, 1H), 5.20 (s, 2H), 3.46−3.41 (m,

1H), 3.39−3.33 (m, 1H), 2.56−2.43 (m, 3H), 2.40−2.32 (m, 1H),

2.23−2.19 (m, 1H), 2.13−1.80 (m, 7H), 1.64−1.62 (m, 2H), 1.52−

1.44 (m, 1H), 1.48 (s, 9H), 1.39−1.37 (m, 1H), 0.92−0.85 (m, 1H);

¹³C NMR (125 MHz, CDCl₃) δ 217.4, 213.8, 211.6, 156.3, 148.4,

133.4, 131.2, 130.9, 129.2, 124.7, 100.7, 99.9, 92.4, 91.7, 81.9, 72.9,

58.8, 58.2, 49.7, 42.2, 42.1, 40.4, 39.9, 37.4, 37.3, 34.4, 34.0, 30.4, 30.2,

29.9, 29.4, 28.3, 25.1, 24.2, 22.9, 22.8, 22.6, 22.5; IR (thin ﬁlm) 2939,

1748, 1698, 1368, 1162 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₇H₃₆N₂O₉Na, 555.2319; found, 555.2327.

tert-Butyl 3-((1′R*,3a′S*,7a′S*)-5-Hydroxy-2′,7′-dioxodeca-

hydro-3H-spiro[furan-2,1′-indene]-7a′-yl)propyl(4-

methoxybenzyloxy)carbamate (30). Following the general

procedure, dihydropyran 25 (0.044 g, 0.083 mmol) was converted

to an approximately 1:1 mixture of lactol epimers. Puriﬁcation by ﬂash

chromatography (2:3 EtOAc/hexanes) aﬀorded lactol 30 (0.016 g,

1

37% yield) as a pale yellow oil: H NMR (500 MHz, CDCl₃) δ 7.31

(d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.35 (br s, 1H), 4.75 (s,

2H), 3.82 (s, 3H), 3.39−3.28 (m, 2H), 2.55−2.41 (m, 4H), 2.39−2.30

(m, 1H), 2.24−2.16 (m, 1H), 2.13−1.80 (m, 7H), 1.53−1.50 (m, 2H),

1.51 (s, 9H), 1.39−1.34 (m, 1H), 0.84 (qd, J = 12.5, 4.3 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 217.3, 213.8, 213.7, 211.6, 159.9, 156.5,

131.2, 131.1, 127.8, 113.90, 113.86, 100.7, 99.9, 92.4, 91.7, 81.4, 76.5,

76.4, 58.8, 58.2, 55.3, 49.8, 42.2, 42.1, 40.4, 39.9, 37.4, 37.3, 34.4, 34.0,

30.4, 30.2, 30.0, 29.5, 28.4, 25.0, 24.2, 22.95, 22.93, 22.6, 22.5; IR (thin

ﬁlm) 3379, 2925, 1748, 1698, 1250 cm⁻¹; HRMS-ESI (m/z) [M +

Na]⁺calcd for C₂₈H₃₉NO₈Na, 540.2573; found, 540.2572.

Allyl 3-((1′R*,3a′S*,7a′S*)-5-Hydroxy-2′,7′-dioxodecahydro

3 H - s p i r o [ f u r a n - 2 , 1 ′ - i n d e n e ] - 7 a ′ - y l ) p r o p y l ( 4 -

methoxybenzyloxy)carbamate (31). Following the general

procedure, dihydropyran 26 (0.040 g, 0.078 mmol) was converted

to an approximately 1:1 mixture of lactol epimers. Puriﬁcation by ﬂash

chromatography (2:3 EtOAc/hexanes) aﬀorded lactol 31 (0.020 g,

1

50% yield) as a pale yellow oil: H NMR (500 MHz, CDCl₃) δ 7.31

(d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.95 (ddt, J = 17.0, 10.6,

5.6 Hz, 1H), 5.36−5.33 (m, 2H), 5.26 (d, J = 10.4 Hz, 1H), 4.78 (s,

2H), 4.65 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.37−3.33 (m, 2H), 2.48−

2.40 (m, 3H), 2.37−2.30 (m, 2H), 2.20−2.15 (m, 1H), 2.09−1.81 (m,

7H), 1.54−1.50 (m, 2H), 1.41−1.35 (m, 1H), 0.85−0.83 (m, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 217.3, 213.77, 213.68, 211.6, 160.0, 157.1,

132.3, 131.1, 127.6, 118.3, 113.9, 100.5, 99.9, 92.4, 91.7, 66.7, 58.7,

58.2, 55.3, 50.0, 42.2, 42.1, 40.4, 39.9, 37.4, 37.3, 34.4, 34.0, 30.4, 30.1,

29.9, 29.5, 25.1, 24.2, 22.9, 22.6, 22.5; IR (thin ﬁlm) 3464, 2954, 1748,

1698, 1250 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₇H₃₅NO₈Na, 524.2260; found, 524.2258.

2H), 3.70 (m, 1H), 2.75 (dd, J = 19.6, 10.0 Hz, 1H, single

diastereomer), 2.63 (dd, J = 19.7, 8.7 Hz, 1H, single diastereomer),

2.43−2.38 (m, 1H, single diastereomer), 2.34−2.18 (m, 4H), 2.15−

1.82 (m, 8H), 1.78 −1.50 (m, 3H); ¹³C NMR (125 MHz, CD₃OD) δ

214.4, 212.5, 156.6, 155.9, 106.7, 106.0, 93.3, 92.8, 57.7, 57.2, 44.4,

42.4, 39.0, 37.3, 31.5, 31.0, 30.4, 29.1, 28.6, 27.2, 26.8, 26.5, 26.0, 23.8,

23.7, 21.09, 21.06, 19.4, 18.3; IR (thin ﬁlm) 3448, 2933, 1748, 1580,

1185 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₅H₂₁NO₄Na,

302.1368; found, 302.1373.

General Procedure for Epoxidation−Acidic Rearrangement.

Preparation of tert-Butyl 3-((1′R*,3a′S*,7a′S*)-5-Hydroxy-

2′,7′-dioxodecahydro-3H-spiro[furan-2,1′-indene]-7a′-yl)-

propyl(2-nitrobenzyloxy)carbamate (29). Solid m-CPBA (0.053

g, 0.23 mmol, 1.9 equiv) was added in one portion to a solution of

dihydropyran (0.063 g, 0.12 mmol, 1.0 equiv) in CH₂Cl₂(0.6 mL) at

−78 °C. After addition, the mixture was placed in a −20 °C ice−

acetone bath and maintained for 30 min. The solution was then

poured into a 1:1:1 solution of H₂O/sat. aq. Na₂S₂O₃/sat. aq.

NaHCO₃(1 mL) and stirred vigorously at rt for 30 min. The layers

were separated, and the aqueous phase was extracted with CH₂Cl₂(2

× 5 mL). The combined organic layers were washed with brine (10

mL), dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure. The residue was dissolved in

THF (0.6 mL) and H₂O (0.2 mL). The biphasic mixture was cooled to

0 °C, and CF₃CO₂H (0.2 mL) was added dropwise, resulting in a

single-phase solution. The solution was allowed to warm to rt over 2 h

and maintained at rt for an additional 8 h. The solution was then

transferred carefully into a stirred biphasic mixture of Et₂O (10 mL)

N-(3-((1′R*,3a′S*,7a′S*)-5-Hydroxy-2′,7′-dioxodecahydro-

3H-spiro[furan-2,1′-indene]-7a′-yl)propyl)-N-(4-methoxyben-

zyloxy)-2-nitrobenzenesulfonamide (32). Following the general

procedure, dihydropyran 27 (0.017 g, 0.027 mmol) was converted to

an approximately 1:1 mixture of lactol epimers. Puriﬁcation by ﬂash

chromatography (2:3 EtOAc/hexanes) aﬀorded lactol 27 (0.006 g,

1

38% yield) as a pale yellow oil: H NMR (500 MHz, CDCl₃) δ 8.00

(d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H),

7.55 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.0 Hz,

2H), 5.36−5.33 (m, 1H), 5.03−5.01 (m, 2H), 3.82 (s, 3H), 3.08−2.87

(m, 2H), 2.52−2.30 (m, 5H), 2.24−1.79 (m, 8H), 1.56−1.51 (m, 1H),

1.42−1.36 (m, 1H), 1.32−1.23 (m, 1H), 0.80 (q, J = 13.0 Hz, 1H,

single diastereomer), 0.79 (q, J = 13.3 Hz, 1H, single diastereomer);

¹³C NMR (125 MHz, CDCl₃) δ 216.9, 213.4, 213.2, 211.3, 160.1,

149.7, 134.8, 132.6, 131.6, 131.0, 127.01, 126.99, 125.7, 123.6, 113.9,

100.7, 99.8, 92.2, 91.5, 79.58, 79.55, 58.5, 58.0, 55.2, 53.4, 42.2, 42.1,

40.3, 39.7, 37.4, 37.3, 34.2, 33.8, 30.3, 30.0, 29.7, 29.3, 25.1, 24.1, 22.6,

P

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

22.55, 22.46; IR (thin ﬁlm) 3464, 2981, 1748, 1696, 1547, 1376 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₉H₃₄N₂O₁₀SNa, 625.1832;

found, 625.1838.

CF₃CO₂H (2.0 mL) was added dropwise, resulting in a single-phase

solution. The solution was allowed to warm to rt over 2 h and

maintained at rt for an additional 8 h. The solution was then

transferred carefully into a stirred biphasic mixture of Et₂O (50 mL)

and sat. aq. NaHCO₃(50 mL), resulting in a vigorous evolution of gas.

The layers were separated, and the aqueous layer was extracted with

Et₂O (2 × 30 mL). The combined organic layers were washed with

brine (50 mL), dried over MgSO₄, ﬁltered through a plug of cotton,

and concentrated under reduced pressure to give an approximate 1:3

mixture of alcohol 34 and hemiacetal 35, which were separated by

ﬂash chromatography (3:2 EtOAc/hexanes). First eluting was alcohol

34 (0.051 g, 16% yield over three steps) as a colorless foam. This

sample was not pure, as NMR spectra showed the presence of an

additional minor component that was inseparable by preparatory TLC,

ﬂash chromatography, or HPLC chromatography; this impurity could

be the oxepane resulting from closure of C1 onto the C13 hydroxyl:

¹H NMR (500 MHz, CDCl₃) δ 8.02−8.00 (m, 1H), 7.76−7.74 (m,

1H), 7.68−7.65 (m, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.39−7.35 (m, 2H),

6.91−6.89 (m, 2H), 5.34−5.32 (m, 1H, single constitutional isomer),

5.25 (br s, 1H, single constitutional isomer), 5.08−4.94 (m, 2H), 3.81

(s, 3H), 3.23 (br s, 1H, single constitutional isomer), 3.21 (br s, 1H,

single constitutional isomer), 3.03 (br s, 2H, single constitutional

isomer), 2.90 (br s, 2H, single constitutional isomer), 2.69 (br s, 1H),

2.58−2.00 (m, 6H), 1.93−1.81 (m, 2H), 1.66−1.63 (m, 1H), 1.53−

1.42 (m, 6H), 1.06−1.05 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ

218.3, 214.8, 160.3, 160.2, 149.8, 134.9, 134.8, 132.7, 132.4, 131.9,

131.7, 131.1, 131.0, 127.1, 127.0, 126.2, 126.1, 123.8, 123.6, 114.04,

113.96, 99.7, 98.0, 96.3, 96.2, 94.8, 80.0, 79.9, 70.0, 69.7, 55.4, 55.3,

54.6, 53.5, 48.7, 48.2, 36.5, 36.0, 35.5, 35.3, 34.6, 34.2, 32.2, 32.1, 24.6,

24.2, 23.7, 23.5, 23.4, 23.30, 23.26, 22.3, 18.9, 18.8; IR (thin ﬁlm)

3481, 2927, 1746, 1374, 1177 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₂₉H₃₆N₂O₁₀SNa, 627.1989; found, 627.1981. Next,

hemiacetal 35 (0.157 g, 50% yield over three steps) was obtained as

a colorless foam. Compound 35 was not a single set of lactol epimers.

One possible explanation involves ring-opening the hemiacetal at C5:

¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 7.8 Hz, 1H), 7.74 (t, J =

7.3 Hz, 1H), 7.66−7.64 (m, 1H), 7.55−7.53 (m, 1H), 7.33 (d, J = 8.5

Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.38−5.37 (m, 1H), 4.99 (br s, 2H),

3.82 (s, 3H), 3.77 (s, 1H), 3.00 (br s, 2H), 2.41−2.34 (m, 1H), 2.27−

2.16 (m, 1H), 2.01−1.99 (m, 2H), 1.89−1.64 (m, 6H), 1.53−1.51 (m,

2H), 1.38−1.18 (m, 4H), 0.88−0.86 (m, 1H); ¹³C NMR (125 MHz,

CDCl₃) δ 160.3, 149.7, 134.8, 132.8, 131.6, 131.0, 126.9, 126.0, 123.6,

114.1, 105.3, 98.7, 95.4, 80.1, 78.9, 55.4, 54.3, 45.9, 36.3, 34.0, 32.1,

29.8, 25.2, 23.1, 23.0, 21.7, 20.6, 14.4; IR (thin ﬁlm) 3421, 2937, 1374,

1175 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₉H₃₆N₂O₁₀SNa,

627.1989; found, 627.1985.

General Procedure for Reduction with DIBALH−Oxidation−

Acidic Rearrangement. A solution of diisobutylaluminum hydride

(2.74 mL, 2.74 mmol, 1 M in CH₂Cl₂, 2.00 equiv) was added to a

solution of tricyclic dihydropyran (0.862 g, 1.37 mmol, 1.00 equiv) in

THF (4.6 mL) at −78 °C. The solution was maintained at −78 °C for

1 h and then warmed to 0 °C, quenched with a solution of sat. aq.

Rochelle’s salt (10 mL), and stirred for 1 h at rt. The mixture was then

partitioned between CH₂Cl₂(40 mL) and H₂O (50 mL). The layers

were separated, and the aqueous phase was extracted with CH₂Cl₂(3

× 40 mL). The combined organic layers were washed with brine (50

mL), dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure. The residue (0.863 g, 1.37

mmol) was dissolved in CH₂Cl₂(6.9 mL) and cooled to −78 °C. Solid

m-CPBA (0.405 g, 1.64 mmol, 1.20 equiv) was added in one portion,

and the mixture was placed in a −20 °C ice−acetone bath and

maintained for 30 min. The solution was then poured into a 1:1:1

solution of H₂O/sat. aq. Na₂S₂O₃/sat. aq. NaHCO₃(15 mL) and

stirred vigorously at rt for 30 min. The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂(3 × 20 mL). The

combined organic layers were washed with brine (20 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. The residue was dissolved in THF (4.0 mL), and

H₂O (2.0 mL) was added. Triﬂuoroacetic acid (2.0 mL) was then

added, resulting in a single-phase solution. The solution was stirred at

1,2-Oxazacyclodecane 33. Solid NaBH₄(0.005 g, 0.1 mmol) was

added in one portion to a solution of dihydropyran 23 (0.065 g, 0.13

mmol) in MeOH (0.6 mL) at 0 °C. After the addition, the cooling

bath was removed and the reaction was stirred at rt for 3 h. The

mixture was partitioned between CH₂Cl₂(10 mL) and sat. aq.

NaHCO₃(10 mL). The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(2 × 10 mL). The combined organic layers

were washed with brine (20 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure. The residue

was dissolved in CH₂Cl₂(0.8 mL) and cooled to −78 °C. A solution

of m-CPBA (0.035 g, 0.15 mmol) and CH₂Cl₂(0.4 mL) was added

dropwise. The mixture was placed in a −20 °C ice−acetone bath and

maintained for 30 min. The solution was then poured into a 1:1:1

solution of H₂O/sat. aq. Na₂S₂O₃/sat. aq. NaHCO₃(1 mL) and

stirred vigorously at rt for 30 min. The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂(2 × 5 mL). The combined

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

ﬁltered through a plug of cotton, and concentrated under reduced

pressure. The residue was dissolved in CH₂Cl₂(0.6 mL), and MgSO₄

(0.030 g) was added. CF₃CO₂H (0.2 mL) was added to the biphasic

mixture. The suspension was maintained at rt for 1 h. The solution was

then decanted carefully into a stirred biphasic mixture of CH₂Cl₂(5

mL) and sat. aq. NaHCO₃(5 mL), resulting in a vigorous evolution of

gas. The layers were separated, and the aqueous phase was extracted

with CH₂Cl₂(2 × 5 mL). The combined organic layers were washed

with brine (20 mL), dried over MgSO₄, ﬁltered through a plug of

cotton, and concentrated under reduced pressure. The residue was

puriﬁed by preparatory thin-layer chromatography (0.25 mm SiO₂

plate, 1:4 acetone/CH₂Cl₂) to aﬀord 1,2-oxaazacyclodecane 33 (0.009

g, 25% yield over three steps) as a pale yellow oil that solidiﬁed upon

standing at rt. Crystallization by slow evaporation from CHCl₃

aﬀorded an X-ray quality crystal: ¹H NMR (500 MHz, CDCl₃) δ

5.54 (s, 1H, NH), 5.47 (d, J = 5.9 Hz, 1H), 3.75 (s, 1H), 3.18 (d, J =

12.9 Hz, 1H), 2.69 (d, J = 11.0 Hz, 1H), 2.61 (t, J = 12.0 Hz, 1H),

2.55−2.48 (m, 2H), 2.30 (t, J = 11.6 Hz, 1H), 2.25−2.18 (m, 2H),

2.15−2.07 (m, 1H), 1.97 (t, J = 11.1 Hz, 1H), 1.93−1.87 (m, 1H),

1.80−1.72 (m, 3H), 1.57−1.51 (m, 1H), 1.48−1.38 (m, 4H); ¹³C

NMR (125 MHz, CDCl₃) δ 105.5 (CH), 105.1 (C), 96.0 (C), 78.3

(CH), 53.2 (CH₂), 46.7 (C), 35.4 (CH₂), 32.2 (CH), 31.3 (CH₂),

25.2 (CH₂), 23.33 (CH₂), 23.31 (CH₂), 21.0 (CH₂), 18.5 (CH₂), 14.7

(CH₂); IR (thin ﬁlm) 3284, 2929, 1457, 1322 cm⁻¹; HRMS-ESI (m/

z) [M + Na]⁺calcd for C₁₅H₂₃NO₄Na, 304.1525; found, 304.1524.

General Procedure for NaBH₄Reduction−Oxidation−Acidic

Rearrangement Sequence. Preparation of N-(3-

((1′R*,3a′S*,7a′R*)-5,7′-Dihydroxy-2′-oxodecahydro-3H-spiro-

[furan-2,1′-indene]-7a′-yl)propyl)-N-(4-methoxybenzyloxy)-2-

nitrobenzenesulfonamide (34) and N-2-Nitrobenzenesulfonyl-

O-(4-methoxybenzyl) Hemiacetal 35. Solid NaBH₄(0.020 g, 0.52

mmol) was added in one portion to a solution of dihydropyran (0.320

g, 0.52 mmol) in MeOH (5.2 mL) at 0 °C. After the addition, the

cooling bath was removed and the solution was warmed to rt. After 1.5

h, the mixture was partitioned between CH₂Cl₂(50 mL) and sat. aq.

NaHCO₃(50 mL). The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(2 × 50 mL). The combined organic layers

were washed with brine (100 mL), dried over MgSO₄, ﬁltered through

a plug of cotton, and concentrated under reduced pressure. Solid m-

CPBA (0.99 mmol, 1.9 equiv) was added in one portion to a solution

of dihydropyran residue in CH₂Cl₂(4.0 mL) at −78 °C. After

addition, the mixture was placed in a −20 °C ice−acetone bath and

maintained for 30 min. The solution was then poured into a 1:1:1

solution of H₂O/sat. aq. Na₂S₂O₃/sat. aq. NaHCO₃(3 mL) and

stirred vigorously at rt for 30 min. The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂(2 × 15 mL). The

combined organic layers were washed with brine (20 mL), dried over

MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. The residue was dissolved in THF (6.0 mL) and

H₂O (2.0 mL). The biphasic mixture was cooled to 0 °C, and

Q

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

rt for 12 h and then partitioned between Et₂O (40 mL) and sat. aq.

NaHCO₃(50 mL), resulting in the vigorous evolution of gas. The

layers were separated, and the aqueous phase was extracted with Et₂O

(3 × 30 mL). The combined organic layers were washed with brine

(50 mL), dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure.

through a plug of cotton, and concentrated under reduced pressure.

Puriﬁcation by ﬂash chromatography (pH 7 buﬀered SiO₂,⁹⁸2:3

acetone/hexanes) provided amino lactol 36 (0.211 g, 84% yield) as a

1

colorless foam: H NMR (500 MHz, CDCl₃) δ 7.28 (d, J = 8.6 Hz,

2H), 6.87 (d, J = 8.5 Hz, 2H), 5.53−5.52 (m, 1H), 5.42−5.41 (m,

1H), 4.64 (s, 2H), 4.62 (s, 2H), 3.82−3.79 (m, 4H), 2.85 (t, J = 7.0

Hz, 2H), 2.50−2.44 (m, 1H), 2.24−2.10 (m, 2H), 2.08−1.93 (m, 3H),

1.84−1.72 (m, 4H), 1.67−1.18 (m, 6H), 0.97−0.84 (m, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 159.7, 130.5, 130.2, 114.1, 105.4, 98.8,

95.7, 79.2, 76.0, 55.6, 53.3, 46.3, 36.7, 34.3, 32.5, 25.6, 23.9, 23.4, 22.3,

20.6, 14.7; IR (thin ﬁlm) 3253, 2937, 1462, 1249 cm⁻¹; HRMS-ESI

(m/z) [M + H]⁺calcd for C₂₃H₃₄NO₆, 420.2386; found, 420.2393.

O-Triisopropylsilyl Hydroxylamine 48. Following the general

procedure for Ns removal, N-Ns hydroxylamine 45 (350 mg, 0.547

mmol) was converted to amino lactol 48. Puriﬁcation by ﬂash

chromatography (pH 7 buﬀered SiO₂,⁹⁷1:1 EtOAc/hexanes) provided

N-2-Nitrobenzenesulfonyl-O-(tert-butyldimethylsilyl) Tetra-

cyclic Hemiacetal 44. Following the general procedure, dihydropyr-

an 41 (251 mg, 0.411 mmol) was converted to tetracyclic hemiacetal

44. Puriﬁcation by ﬂash chromatography (3:2 EtOAc/hexanes)

provided tetracyclic hemiacetal 44 (53 mg, 21% yield) as a clear

colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J = 7.3 Hz, 1H),

7.79 (t, J = 7.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.8 Hz,

1H), 5.37 (d, J = 4.6 Hz, 1H), 3.79 (s, 1H), 3.18−3.08 (m, 2H), 2.41−

2.35 (m, 1H), 2.20 (t, J = 11.5 Hz, 2H), 2.06−1.97 (m, 2H), 1.83−

1.59 (m, 5H), 1.59−1.45 (m, 4H), 1.40−1.26 (m, 4H), 1.16 (dt, J =

4.6, 14.2 Hz, 1H), 0.95 (s, 9H), 0.27 (s, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 149.6 (C), 134.6 (CH), 133.5 (CH), 131.0 (CH), 126.5

(C), 123.5 (CH), 105.5 (C), 98.8 (CH), 95.6 (C), 79.2 (CH), 56.4

(CH₂), 46.1 (C), 36.5 (CH₂), 34.1 (CH₂), 32.4 (CH₂), 29.9 (CH₂),

27.1 (CH₃), 26.2 (CH₂), 25.4 (CH₂), 23.4 (CH₂), 23.3 (C), 21.8

(CH₂), 20.6 (CH₂), 18.4 (CH₂), 14.7 (CH₂), −4.2 (CH₃); IR (thin

ﬁlm) 3353, 2930, 2252, 1747, 1548 cm⁻¹; HRMS-ESI (m/z) [M +

Na]⁺calcd for C₂₇H₄₂N₂O₉SSiNa, 621.2278; found, 621.2291.

N-2-Nitrobenzenesulfonyl-O-(triisopropylsilyl) Tetracyclic

Hemiacetal 45. Following the general procedure, dihydropyran 42

(1.3 g, 2.0 mmol) was converted to tetracyclic hemiacetal 45.

Puriﬁcation by ﬂash chromatography (3:2 EtOAc/hexanes) provided

1

amino lactol 48 (0.211 g, 84% yield) as a colorless foam: H NMR

(500 MHz, CDCl₃) δ 5.39 (d, J = 3.2 Hz, 1H), 3.80 (s, 1H), 2.94−

2.83 (m, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.46 (d, J = 10.8 Hz, 1H),

2.21−2.10 (m, 2H), 2.00−1.95 (m, 2H), 1.85−1.79 (m, 2H), 1.73 (dt,

J = 3.5, 11.8 Hz, 2H), 1.64−1.57 (m, 2H), 1.50−1.45 (m, 2H), 1.45−

1.41 (m, 2H), 1.37−1.35 (m, 3H), 1.16−1.09 (m, 3H), 1.06 (m, 18H);

¹³C NMR (125 MHz, CDCl₃) δ 105.4, 98.6, 95.6, 79.1, 55.5, 46.1,

36.5, 34.2, 32.4, 25.5, 23.8, 23.3, 21.7, 20.5, 18.4, 14.7, 12.0; IR (thin

ﬁlm) 3355, 2944, 1464, 1200 cm⁻¹; HRMS-ESI (m/z) [M + H]⁺calcd

for C₂₄H₄₆NO₅Si, 456.3145; found, 456.3140.

O-2-(Trimethylsilyl)ethyl Hydroxylamine 49. Following the

general procedure, N-Ns hydroxylamine 46 (301 mg, 0.524 mmol)

was converted to amino lactol 49. Puriﬁcation by ﬂash chromatog-

raphy (pH 7 buﬀered SiO₂,⁹⁷2:3 acetone/hexanes) aﬀorded amino

1

tetracyclic hemiacetal 45 (0.46 g, 36% yield) as a clear oil: H NMR

(500 MHz, C₆D₆) δ 8.05 (d, J = 7.7 Hz, 1H), 6.73−6.71 (m, 1H), 6.61

(br s, 2H), 5.30 (br s, 1H), 3.61 (br s, 1H), 3.33−3.26 (m, 2H), 2.42−

2.40 (m, 1H), 2.34 (t, J = 11.0 Hz, 1H), 2.22−2.18 (m, 1H), 1.93−

1.88 (m, 3H), 1.77−1.72 (m, 3H), 1.69−1.63 (m, 2H), 1.36−1.28 (m,

7H), 1.16 (d, J = 7.0 Hz, 18H), 1.05−0.95 (m, 2H); ¹³C NMR (125

MHz, CDCl₃) δ 149.9 (C), 134.7 (CH), 132.9 (CH), 130.7 (CH),

128.9 (C), 123.5 (CH), 106.0 (C), 99.3 (CH), 95.8 (C), 79.3 (CH),

56.9 (CH₂), 46.3 (C), 36.9 (CH₂), 34.8 (CH₂), 32.8 (CH₂), 30.6

(CH₂), 25.9 (CH), 23.7 (CH₂), 21.2 (CH), 20.9 (CH), 18.5 (CH₃),

15.3 (C), 13.2 (CH₂); IR (thin ﬁlm) 3361, 2943, 1741, 1549, 1374,

1

lactol 49 (188 mg, 89% yield) as a colorless foam: H NMR (500

MHz, CDCl₃) δ 5.58−5.42 (m, 1H), 3.83 (s, 1H), 3.72 (t, J = 8.4 Hz,

2H), 2.85 (q, J = 6.8 Hz, 2H), 2.50−2.43 (m, 2H), 2.31−2.14 (m,

2H), 2.11−1.98 (m, 2H), 1.88−1.72 (m, 5H), 1.66−1.20 (m, 9H),

0.89 (t, J = 8.1 Hz, 2H), 0.01 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ

105.4 (C), 98.7 (CH), 95.7 (C), 95.5 (CH₂), 79.2 (CH), 71.4 (CH₂),

53.3 (CH₂), 46.2 (C), 36.5 (CH₂), 35.9 (CH₂), 34.3 (CH₂), 32.5

(CH), 25.5 (CH₂), 23.9 (CH₂), 23.4 (CH₂), 22.2 (CH₂), 20.6 (CH₂),

17.5 (CH₂), 14.7 (CH₂), −1.1 (CH₃); IR (thin ﬁlm) 3379, 2947,

1745, 1249 cm⁻¹; HRMS-ESI (m/z) [M + H]⁺calcd for

C₂₀H₃₇O₅NSiH, 400.2519; found, 400.2515.

1178 cm⁻¹

; HRMS-ESI (m/z) [M +

Na]⁺calcd for

C₃₀H₄₈O₉N₂SSiNa, 663.2748; found, 663.2751.

N-2-Nitrobenzenesulfonyl-O-2-(trimethylsilyl)ethyl Tetracy-

clic Hemiacetal 46. Following the general procedure, tricyclic

dihydropyran 43 (401 mg, 0.673 mmol) was converted to tetracyclic

hemiacetal 46. Puriﬁcation by ﬂash chromatography (3:2 EtOAc/

hexanes) provided hemiacetal 46 (211 mg, 54%) as a colorless foam:

¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.79 (t, J =

6.8 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 5.58−

5.34 (m, 1H), 4.97 (br s, 1H), 4.10 (m, 2H), 3.78 (m, 1H), 3.05 (br s,

2H), 2.48−2.39 (m, 1H), 2.21 (t, J = 12.1 Hz, 2H), 2.11−1.94 (m,

2H), 1.93−1.33 (m, 13H), 0.96 (t, J = 8.7 Hz, 2H), 0.02 (s, 9H); ¹³C

NMR (125 MHz, CDCl₃) δ 149.9 (C), 135.0 (CH), 132.9 (CH),

131.1 (CH), 126.3 (C), 123.8 (CH), 105.5 (C), 98.8 (CH), 95.6 (C),

79.3 (CH), 76.5 (CH₂), 64.0 (CH₂), 54.2 (CH₂), 46.0 (C), 36.4

(CH₂), 34.3 (CH₂), 32.3 (CH), 29.9 (CH₂), 25.4 (CH₂), 23.5 (CH₂),

23.4 (CH₂), 21.9 (CH₂), 20.6 (CH₂), 17.4 (CH₂), 14.6 (CH₂), −1.2

(CH₃); IR (thin ﬁlm) 3369, 2949, 2251, 1734, 1549, 1375, 1178 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₆H₄₀O₉N₂SSiNa, 607.2122;

found, 607.2125.

O-4-Methoxybenzyl Octahydroazonine 37. A solution of DBU

and CH₂Cl₂(0.10 mL, 0.060 mmol, 0.60 M in DBU) was added

dropwise to a solution of amino lactol 36 (0.211 g, 0.504 mmol) and

CH₂Cl₂(5.9 mL). Trichloroacetonitrile (0.09 mL, 0.9 mmol) was

added to the solution and maintained at rt for 18 h. The solution was

concentrated under reduced pressure, and the residue was puriﬁed by

ﬂash chromatography (1:30:69 aq. NH₄OH/acetone/hexanes) to give

octahydroazonine 37 (0.061 g, 26% yield) as a colorless ﬁlm: ¹H NMR

(500 MHz, CDCl₃) δ 7.27 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz,

2H), 5.25 (br s, 1H), 4.58 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.5 Hz,

1H), 3.80 (s, 3H), 3.66 (s, 1H), 3.35 (dd, J = 9.5, 15.6 Hz, 1H), 2.65−

2.54 (m, 2H), 2.24 (t, J = 11.6 Hz, 2H), 2.18−2.12 (m, 1H), 2.03−

1.97 (m, 1H), 1.87−1.72 (m, 4H), 1.65 (dd, J = 3.6, 11.9 Hz, 2H),

1.54−1.25 (m, 5H), 1.15−1.07 (m, 1H); ¹³C NMR (125 MHz,

CDCl₃) δ 159.3 (C), 130.4 (CH), 130.3 (C), 113.6 (CH), 105.3 (C),

94.9 (CH), 93.2 (C), 79.0 (CH), 73.7 (CH₂), 55.3 (CH₃), 50.6

(CH₂), 46.0 (C), 35.7 (CH₂), 31.6 (CH), 28.7 (CH₂), 25.5 (CH₂),

25.4 (CH₂), 23.2 (CH₂), 21.6 (CH₂), 18.0 (CH₂), 14.7 (CH₂); IR

(thin ﬁlm) cm⁻¹; HRMS-ESI (m/z) [M + H]⁺calcd for C₂₃H₃₂NO₅,

402.2281; found, 402.2276.

General Procedure for Removal of the Nosyl Group.³³

Preparation of O-4-Methoxybenzyl Hydroxylamine 36. A

solution of PhSH⁹⁶and DMF⁹⁷(3.28 mL, 0.656 mmol, 0.200 M in

PhSH, 1.10 equiv) was added to a vial containing N-Ns hydroxyamine

35 (0.360 g, 0.596 mmol, 1.00 equiv) (0.360 g, 0.596 mmol, 1.00

equiv) and solid K₂CO₃(0.164 g, 1.19 mmol, 2.00 equiv). The

heterogeneous mixture was stirred vigorously under an Ar atmosphere

at rt for 2.5 h. The mixture was then partitioned between CH₂Cl₂(20

mL) and H₂O (30 mL). The layers were separated, and the aqueous

phase was extracted with CH₂Cl₂(2 × 30 mL). The combined organic

layers were washed with brine (80 mL), dried over MgSO₄, ﬁltered

O-2-(Trimethylsilyl)ethyl Octahydroazonine 50. A 0.471 M

solution of DBU (100.0 μL, 0.0471 mmol, 0.10 equiv) in CH₂Cl₂was

added to a solution of amino lactol 49 (188 mg, 0.471 mmol, 1.00

equiv) in CH₂Cl₂(4.70 mL). Trichloroacetonitrile (50.0 μL, 0.707

mmol, 1.50 equiv) was then added dropwise, and after the addition,

the solution was capped and stirred for 14 h at rt. The solution was

concentrated and puriﬁed by ﬂash chromatography (1:20:79 aq.

NH₄OH/acetone/chloroform) to aﬀord octahydroazonine 50 (0.042

1

g, 23% yield) as a clear colorless ﬁlm: H NMR (500 MHz, C₆D₆) δ

R

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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5.50 (br s, 1H), 3.80 (dt, J = 2.6, 8.0 Hz, 2H), 3.55 (s, 1H), 3.46 (dd, J

= 9.9, 14.9 Hz, 1H), 2.62 (m, 1H), 2.59 (m, 2H), 2.24−2.08 (m, 2H),

1.99−1.86 (m, 2H), 1.79−1.72 (m, 3H), 1.59 (m, 1H), 1.40−1.10 (m,

5H), 1.11−0.98 (m, 2H), 0.93 (t, J = 7.8 Hz, 2H), 0.74 (t, J = 12.9 Hz,

1H), 0.00 (s, 9H); ¹³C NMR (125 MHz, C₆D₆) δ 106.4 (C), 95.1

(CH), 93.9 (C), 79.3 (CH), 69.0 (CH₂), 51.3 (CH₂), 46.5 (C), 36.7

(CH₂), 32.4 (CH), 29.5 (CH₂), 26.2 (CH₂), 23.9 (CH₂), 22.2 (CH₂),

19.0 (CH₂), 18.0 (CH₂), 17.8 (CH₂), 15.6 (CH₂), −0.9 (CH₃);

HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₀H₃₅O₄NSiNa, 404.2233;

found, 404.2228.

(1.33 g, 5.94 mmol) was added in one portion to a solution of enol

silane (3.47 g, 5.40 mmol) in anhydrous DMSO (22 mL). A balloon of

oxygen with a cannula needle was inserted to slowly bubble O₂

through the suspension, and the mixture was slowly warmed to 55 °C

and maintained for 12 h. After consumption of the starting material,

the ﬂask was cooled to rt and the suspension was partitioned between

1N HCl (250 mL) and ether (100 mL). The aqueous phase was

extracted with ether (3 × 100 mL). The combined organic layers were

washed with sat. aq. NaHCO₃(100 mL), followed by brine (100 mL).

The organic phase was dried over MgSO₄, ﬁltered through a plug of

cotton, and concentrated under reduced pressure. Puriﬁcation by

column chromatography (1:4 EtOAc/hexanes) provided hydrinde-

General Procedure for TPAP Oxidation.⁴²Preparation of

Diketooctahydroazonine 39. Solid N-methylmorpholine-N-oxide

(0.028 g, 0.24 mmol, 1.5 equiv), octahydroazonine 37 (0.064 g, 0.16

mmol, 1.0 equiv), and oven-dried powdered 4 Å mol. sieves (0.027 g)

were suspended in CH₂Cl₂(0.9 mL) and stirred at rt for 10 min. A

solution of (n-Pr)₄NRuO₄(TPAP) and CH₂Cl₂(1.6 mL, 0.016 mmol,

0.010 M in TPAP, 0.10 equiv) was added, resulting in a dark green

liquid phase. The mixture was maintained at rt for 1 h, then ﬁltered

through a plug of Celite, and concentrated under reduced pressure.

Puriﬁcation by ﬂash chromatography (1:20:79 aq. NH₄OH/acetone/

hexanes) provided diketooctahydroazonine 39 (0.055 g, 86% yield) as

a colorless crystalline solid. Slow evaporation from MeOH provided

single crystals suitable for X-ray analysis: ¹H NMR (500 MHz, CDCl₃)

δ 7.31 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.04 (d, J = 7.0

Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 3.86 (s,

3H), 3.33−3.28 (m, 2H), 2.79−2.69 (m, 2H), 2.64−2.44 (m, 4H),

2.30−2.22 (m, 1H), 2.18−2.15 (m, 1H), 2.14−1.85 (m, 6H), 1.78−

1.71 (m, 2H), 1.66−1.64 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ

214.9 (C), 210.4 (C), 159.4 (C), 130.5 (CH), 129.8 (C), 113.6 (CH),

95.7 (CH), 91.2 (C), 74.1 (CH₂), 61.7 (C), 55.3 (CH₃), 51.0 (CH₂),

38.6 (CH₂), 38.1 (CH), 35.5 (CH₂), 30.7 (CH₂), 28.0 (CH₂), 25.3

(CH₂), 23.4 (CH₂), 21.9 (CH₂), 19.0 (CH₂); IR (thin ﬁlm) 2925,

2854, 1756, 1698, 1515, 1248 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₂₃H₂₉NO₅Na, 422.1943; found, 422.1941; mp (dec) 145−

148 °C.

O-2-(Trimethylsilyl)ethyl Diketooctahydroazonine 51. Fol-

lowing the general TPAP oxidation procedure, octahydroazonine 50

(42 mg, 0.11 mmol) was converted to diketooctahydroazonine 51.

Puriﬁcation by ﬁltration through a plug of SiO₂(100% EtOAc)

provided diketooctahydroazonine 51 (38 mg, 91% yield) as a clear

colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 5.07 (d, J = 7.4 Hz, 1H),

3.66 (t, J = 8.7 Hz, 2H), 3.37−3.34 (m, 2H), 2.77−2.65 (m, 2H),

2.57−2.40 (m, 4H), 2.31−2.17 (m, 1H), 2.12−1.81 (m, 7H), 1.80−

1.57 (m, 3H), 0.95−0.83 (m, 2H), 0.00 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 215.2 (C), 210.5 (C), 95.8 (CH), 91.4 (C), 69.3 (CH₂),

61.9 (C), 51.2 (CH₂), 38.9 (CH₂), 38.3 (CH), 35.7 (CH₂), 30.8

(CH₂), 28.4 (CH₂), 25.5 (CH₂), 23.6 (CH₂), 22.1 (CH₂), 19.1 (CH₂),

17.5 (CH₂), −1.13 (CH₃); IR (thin ﬁlm) 2945, 1760, 1705, 1424,

1242, 834 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₂₀H₃₃O₄NSiNa, 402.2077; found, 402.2081.

G e n e r al P r oc e d u r e f or S a e g u s a O x i d a t i o n .

(2S*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)propyl)-

2-methoxy-3-(phenoxymethyl)-3,3a,7,7a-tetrahydro-1H-

inden-4(2H)-one (α-54). Freshly titrated n-BuLi (3.33 mL, 8.24

mmol, 1.45 equiv) was added dropwise to a solution of diisopropyl-

amine (1.20 mL, 8.52 mmol, 1.50 equiv) in THF (26 mL) at 0 °C.

After addition, the pale yellow solution was stirred for 15 min. The

solution of lithium diisopropylamine was cooled to −78 °C, and

chlorotrimethylsilane⁸⁸(3.60 mL, 28.4 mmol, 5.00 equiv) was added

and stirred for 5 min, followed by dropwise addition of a solution of

ketone 19 (3.24 g, 5.68 mmol, 1.00 equiv) in THF (12 mL) at −78

°C. The solution was maintained at −78 °C for 20 min, and then

anhydrous Et₃N (12 mL) was added and allowed to stir for 30 min.

The reaction was warmed to 0 °C and quenched with 2 M pH 7 buﬀer.

The layers were separated, and the aqueous phase was extracted with

ether (3 × 100 mL). The combined organic phases were washed with

brine (100 mL), dried over MgSO₄, ﬁltered through a plug of cotton,

and concentrated under reduced pressure. The resulting oil was left on

a high-vacuum line (1 mmHg) overnight, and the enol silane was of

suﬃcient purity to carry on without further puriﬁcation. Pd(OAc)₂

1

none α-54 (2.75 g, 85% yield) as a clear colorless oil: H NMR (500

MHz, CDCl₃) δ 7.63 (d, J = 7.3 Hz, 4H), 7.41 (td, J = 7.4, 1.3 Hz,

2H), 7.35 (td, J = 7.3, 1.5 Hz, 4H), 7.25 (t, J = 8.0 Hz, 2H), 6.91 (t, J =

7.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 2H), 6.80 (dt, J = 8.5, 4.7 Hz, 1H),

6.03 (d, J = 10.2 Hz, 1H), 4.21 (t, J = 9.0 Hz, 1H), 4.11 (dd, J = 9.3,

4.4 Hz, 1H), 3.88−3.85 (m, 1H), 3.66−3.61 (m, 1H), 3.57−3.53 (m,

1H), 3.26 (s, 3H), 2.67−2.64 (m, 1H), 2.63−2.59 (m, 1H), 2.55−2.50

(m, 1H), 2.24 (d, J = 19.6 Hz, 1H), 2.03 (ddd, J = 13.5, 8.1, 3.4 Hz,

1H), 1.82 (td, J = 12.6, 4.5 Hz, 1H), 1.71−1.63 (m, 2H), 1.50−1.40

(m, 2H), 1.03 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 201.9, 159.0,

147.5, 135.7, 135.6, 134.1, 134.0, 129.6, 129.4, 129.2, 127.6, 120.5,

114.7, 80.2, 64.1, 63.4, 57.6, 55.0, 49.1, 39.6, 37.8, 29.6, 28.6, 28.2,

26.9, 19.2; IR (thin ﬁlm) 2960, 2858, 1661, 1600, 1497, 1243 cm⁻¹;

HRMS-ESI (m/z) [M + H]⁺calcd for C₃₆H₄₅O₄Si, 569.3087; found,

569.3099.

(2R*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)-

propyl)-2-methoxy-3-(phenoxymethyl)-3,3a,7,7a-tetrahydro-

1H-inden-4(2H)-one (β-54). Following the general procedure,

hydrindanone β-19 (1.29 g, 2.26 mmol) was converted into

hydrindenone β-54. Puriﬁcation by column chromatography (1:4

EtOAc/hexanes) provided hydrindenone β-54 (786 mg, 61% yield) as

a clear colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.51(d, J = 6.8 Hz,

4H), 7.30 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.1 Hz, 4H), 7.14 (t, J = 8.4

Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 7.9 Hz, 2H), 6.63−6.60

(m, 1H), 5.91 (d, J = 10.1 Hz, 1H), 4.01 (dd, J = 4.1, 9.5 Hz, 1H),

3.80−3.76 (m, 2H), 3.49−3.44 (m, 2H), 3.17 (s, 3H), 3.00 (m, 1H),

2.49−2.44 (m, 2H), 2.30 (dd, J = 4.3, 17.9 Hz, 1H), 2.24 (pentet, 1H),

1.61 (dt, J = 4.0, 13.5 Hz, 1H), 1.55−1.37 (m, 3H), 1.36−1.28 (m,

1H), 0.89 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 200.8 (C), 159.1

(C), 145.7 (CH), 135.8 (CH), 134.1 (C), 129.8 (CH), 129.7 (CH),

128.6 (CH), 127.81 (CH), 121.1 (CH), 114.8 (CH), 83.9 (CH), 67.2

(CH₂), 64.3 (CH₂), 56.9 (C), 56.4 (CH₃), 47.8 (CH), 41.5 (CH),

37.8 (CH₂), 28.5 (CH₂), 28.4 (CH₂), 27.3 (CH₂), 27.0 (CH₃), 19.4

(C); IR (thin ﬁlm) 1669, 1600, 1497, 1242 cm⁻¹; HRMS-ESI (m/z)

[M + Na]⁺calcd for C₃₆H₄₄O₄SiNa, 591.2906; found, 591.2905.

General Procedure for Methyl Cuprate Addition. Prepara-

tion of (2S*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)-

propyl)-2-methoxy-6-methyl-3-(phenoxymethyl)hexahydro-

1H-inden-4(2H)-one (α-52). A solution of MeLi (21.7 mL, 29.8

mmol, 1.37 M in Et₂O, 6.20 equiv) was added dropwise to a

suspension of CuBr·Me₂S⁹⁹(3.01 g, 14.6 mmol, 3.05 equiv) in Et₂O

(96 mL) at −78 °C, producing a bright yellow precipitate. The mixture

was warmed to 0 °C, resulting in a clear colorless solution. A solution

of hydrindenone 54 (2.73 g, 4.80 mmol, 1.00 equiv) in Et₂O (7 mL)

was then added dropwise. The solution was maintained for 10 min and

then treated with a 9:1 solution of sat. aq. NH₄Cl/NH₄OH (50 mL).

The mixture was partitioned between water (100 mL) and Et₂O (100

mL). The layers were separated, and the aqueous phase was extracted

with Et₂O (3 × 100 mL). The combined organic layers were washed

with brine (75 mL), dried over MgSO₄, ﬁltered through a plug of

cotton, and concentrated under reduced pressure. Puriﬁcation by ﬂash

chromatography (1:9 EtOAc/hexanes) provided β-methyl ketone α-52

1

(2.63 g, 94% yield) as a clear oil: H NMR (500 MHz, CDCl₃) δ

7.68−7.65 (m, 4H), 7.43−7.35 (m, 6H), 7.25 (td, J = 7.0, 1.6 Hz, 2H),

6.91 (t, J = 7.3 Hz, 1H), 6.86 (dd, J = 8.7, 1.0 Hz, 2H), 4.18 (t, J = 9.2

Hz, 1H), 4.00 (td, J = 7.0, 3.7 Hz, 1H), 3.88 (dd, J = 9.2, 4.4 Hz, 1H),

3.71−3.70 (m, 1H), 3.59−3.54 (m, 1H), 3.22 (s, 3H), 2.71−2.67 (m,

1H), 2.44−2.41 (m, 1H), 2.32 (ddd, J = 14.6, 3.0, 2.2 Hz, 1H), 2.10

S

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(dd, J = 16.0, 12.8 Hz, 1H), 2.00 (ddd, J = 14.2, 8.0, 3.7 Hz, 1H), 1.88

(ddd, J = 14.2, 7.0, 2.3 Hz, 1H), 1.82−1.72 (m, 3H), 1.61 (td, J = 12.7,

4.6 Hz, 1H), 1.58 (s, 9H), 1.42−1.33 (m, 2H), 1.10 (q, J = 12.7 Hz,

1H), 0.96 (d, J = 6.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 213.6

(C), 158.8 (C), 135.6 (CH), 134.1 (C), 129.5 (CH), 129.3 (CH),

127.6 (CH), 120.4 (CH), 114.6 (CH), 80.2 (CH), 64.2 (CH₂), 63.2

(CH₂), 58.7 (C), 57.6 (CH₃), 48.8 (CH), 46.3 (CH), 42.8 (CH), 39.1

(CH₂), 38.6 (CH₂), 31.0 (CH₂), 28.6 (CH₂), 26.9 (CH₃), 25.8 (CH₂),

22.1 (CH₃), 19.2 (C); IR (thin ﬁlm) 2958, 1694, 1600, 1497, 1243

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₃₇H₄₈O₄SiNa,

607.3220; found, 607.3200.

(2R*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)-

propyl)-2-methoxy-6-methyl-3-(phenoxymethyl)hexahydro-

1H-inden-4(2H)-one (β-52 and β-53). Following the general

procedure for methyl cuprate addition, hydrindenone β-54 was

converted to hydrindanones β-52 and β-53. Puriﬁcation by ﬂash

chromatography (1:9 EtOAc/hexanes) provided β-methyl ketones β-

52 and β-53. Eluting ﬁrst was β-53 (247 mg, 30% yield) as a clear oil:

¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J = 6.8 Hz, 4H), 7.41 (t, J =

ﬁlm) 3426, 2931, 1769, 1666, 1594, 1496, 1242 cm⁻¹; HRMS-ESI (m/

z) [M + Na]⁺calcd for C₂₀H₂₆O₄Na, 353.1729; found, 353.1721.

(2R*,3S*,3aS*,6R*,7aS*)-3a-(3-Hydroxypropyl)-2-methoxy-

6-methyl-3-(phenoxymethyl)hexahydro-1H-indene-4(2H)-one

(56). Following the general procedure for methyl cuprate addition,

hydrindenone 55 (10.0 mg, 0.03 mmol) was converted into a 1.6:1

1

mixture of methyl epimers as determined by H NMR (9.8 mg, 94%)

with β-methyl ketone 56 as the major diastereomer. For chemical

comparison and to assign the major and minor diastereomeric

products, the crude residue above was converted as follows into β-52

and β-53. The crude product was dissolved in pyridine (0.3 mL).

DMAP (single crystal) was added, followed by addition of TBDPSCl

(15 μL, 0.05 mmol). The reaction mixture was stirred at rt for 18 h

and then concentrated under reduced pressure. Puriﬁcation by ﬂash

c h r o m a t o g r a p h y ( 1 : 9 E t O A c / h e x a n e s ) p r o v i d e d

(2R*,3S*,3aS*,7aS*)-3a-(3-(tert-butyldiphenylsilyloxy)propyl)-2-me-

thoxy-6-methyl-3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-one

15 mg (86% over two steps) in a 1.6:1 ratio (β-53/β-52) as

1

determined by H NMR.

(2S*,3S*,3aS*,7aS*)-2-Hydroxy-3a-(3-iodopropyl)-6-methyl-

3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-one. TMSCl⁸⁸

(11.2 mL, 87.9 mmol, 10.0 equiv) was added dropwise to a solution

of NaI⁸⁹(13.2 g, 87.9 mmol, 10.0 equiv) and dry MeCN (73 mL) at rt

and vigorously stirred for 20 min, which resulted in formation of a

colorless precipitate. The freshly prepared solution of TMSI was

decanted from the precipitate via syringe and added dropwise to a

solution of methyl ether α-52 (5.14 g, 8.79 mmol, 1.0 equiv), H₂O

(0.791 mL, 44.0 mmol, 5.00 equiv), and MeCN (17 mL). The solution

was then heated to 50 °C for 2 h. The resulting brown solution was

cooled to rt, diluted with Et₂O (200 mL), and treated with 1:1:1 H₂O/

sat. aq. NaHCO₃/sat. aq. Na₂S₂O₃(200 mL) and stirred for 15 min,

resulting in the disappearance of the brown color. The layers were

separated, and the aqueous phase was extracted with Et₂O (3 × 100

mL). The combined organic layers were washed with brine (150 mL),

dried over MgSO₄, ﬁltered through a plug of cotton, and concentrated

under reduced pressure. Puriﬁcation by ﬂash chromatography (1:4

EtOAc/hexanes) provided (2S*,3S*,3aS*,7aS*)-2-Hydroxy-3a-(3-io-

dopropyl)-6-methyl-3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-

one (2.35 g, 61%) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ

7.29 (d, J = 8.6 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 7.8 Hz,

2H), 4.71 (m, 1H), 4.23 (t, J = 9.3 Hz, 1H), 3.90 (dd, J = 4.4, 9.1 Hz,

1H), 3.22 (m, 1H), 3.09 (q, J = 9.3 Hz, 1H), 2.65 (m, 1H), 2.45 (m,

1H), 2.32 (d, J = 16.2 Hz, 1H), 2.02 (m, 2H), 1.92−1.96 (m, 3H),

1.58−1.78 (m, 5H), 1.16 (q, J = 12.9 Hz, 1H), 0.98 (d, J = 6.4 Hz,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 213.3, 158.5, 129.8, 121.4,

114.7, 71.5, 63.7, 58.9, 48.7, 46.2, 43.0, 40.7, 38.6, 31.5, 30.3, 30.2,

22.3, 6.9; IR (thin ﬁlm) 3465, 2950, 1692, 1598, 1496, 1242 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₀H₂₇IO₃Na, 465.0903;

found, 465.0899.

7.3 Hz, 2H), 7.35 (t, J = 7.3 Hz, 4H), 7.25 (t, J = 7.6 Hz, 2H), 6.94 (t,

J = 7.3 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 4.02 (dd, J = 4.5, 9.5 Hz,

1H), 3.82 (dd, J = 6.0, 8.9 Hz, 2H), 3.56 (t, J = 6.1 Hz, 2H), 3.26 (s,

3H), 2.43 (m, 1H), 2.38−2.35 (m, 1H), 2.25−2.19 (m, 2H), 2.05 (t, J

= 7.8 Hz, 1H), 1.85 (dt, J = 8.8, 13.5 Hz, 1H), 1.76 (d, J = 12.3 Hz,

1H), 1.66−1.58 (m, 2H), 1.56 (m, 1H), 1.47−1.40 (m, 3H), 1.01 (s,

9H), 0.99 (d, overlapping signal, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

212.6 (C), 159.1 (C), 135.8 (CH), 134.0 (C), 129.89 (CH), 129.87

(CH), 127.9 (CH), 121.0 (CH), 114.7 (CH), 83.8 (CH), 67.3 (CH₂),

64.1 (CH₂), 58.7 (C), 56.6 (CH₃), 47.3 (CH₂), 46.0 (CH), 44.8

(CH), 36.8 (CH₂), 33.6 (CH₂), 29.4 (CH₂), 28.8 (CH₂), 28.7 (CH),

27.1 (CH₃), 22.4 (CH₃), 19.4 (C); IR (thin ﬁlm) 3070, 2954, 1703,

1600 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₃₇H₄₈O₄SiNa,

607.3220; found, 607.3226. Eluting second was β-52 (316 mg, 38%

1

yield) as a clear oil: H NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 7.1

Hz, 4H), 7.41 (m, 2H), 7.37 (t, J = 6.0 Hz, 4H), 7.25 (t, J = 8.1 Hz,

2H), 6.92 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 2H), 3.97 (dd, J =

6.3, 9.5 Hz, 1H), 3.92 (dd, J = 6.7, 9.5 Hz, 1H), 3.75−3.68 (m, 2H),

3.60−3.55 (m, 1H), 3.36 (s, 3H), 2.33 (m, 1H), 2.26 (d, J = 9.8 Hz,

2H), 2.22−2.16 (m, 1H), 1.91 (m, 1H), 1.74 (m, 2H), 1.65−1.60 (m,

2H), 1.56 (m, 1H), 2.38 (pentet, J = 7.8 Hz, 2H), 1.13−1.08 (m, 1H),

1.05 (s, 9H), 1.00 (d, J = 6.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

212.8 (C), 158.9 (C), 135.9 (CH), 134.3 (C), 129.8 (CH), 129.6

(CH), 127.9 (CH), 121.0 (CH), 114.8 (CH), 85.0 (CH), 66.2 (CH₂),

64.5 (CH₂), 59.1 (C), 58.0 (CH₃), 52.2 (CH), 46.2 (CH), 43.4 (CH),

38.5 (CH₂), 36.8 (CH₂), 32.5 (CH₂), 28.5 (CH₂), 27.2 (CH₃), 25.4

(CH₂), 22.3 (CH₃), 19.5 (C); IR (thin ﬁlm) 3070, 2936, 2859, 1701,

1600 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₃₇H₄₈O₄SiNa,

607.3220; found, 607.3216. Additionally, a small amount of mixed

fractions was recovered (54 mg, 6% yield).

(3aS*,7aS*)-3a-(3-Iodopropyl)-6-methyl-3-methylenetetra-

hydro-1H-indene-2,4(5H,6H)-dione. Dess−Martin periodinane²⁸

(2.37 g, 5.59 mmol, 1.5 equiv) was added in one portion to a stirring

solution of (2S*,3S*,3aS*,7aS*)-2-hydroxy-3a-(3-iodopropyl)-6-meth-

yl-3-(phenoxymethyl)hexahydro-1H-inden-4(2H)-one (2.35 g, 5.31

mmol, 1.00 equiv), solid NaHCO₃(4.46 g, 53.1 mmol, 10.0 equiv),

and CH₂Cl₂(30 mL). The mixture was stirred vigorously for 15 min,

then treated with 10% aq. Na₂S₂O₃(15 mL) and stirred for an

additional 15 min. The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 20 mL). The combined organic layers

were washed with brine (40 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure to aﬀord the

dione (3.04 g, 90% yield) as a pale yellow oil. Because of the

propensity to eliminate PhOH, the dione was carried on without

puriﬁcation. 1,8-Diazabicyclo[5.4.0]undec-7-ene¹⁰⁰(1.14 mL, 7.63

mmol, 1.1 equiv) was added dropwise to a solution of dione (3.04 g,

6.93 mmol, 1.00 equiv) and THF (150 mL) at 0 °C. The cooling bath

was removed, and the pale brown solution was stirred for 30 min. The

solution was then partitioned between sat. aq. NH₄Cl (100 mL) and

EtOAc (150 mL). The layers were separated, and the aqueous phase

was extracted with EtOAc (3 × 100 mL). The combined organic layers

(2R*,3S*,3aS*,7aS*)-3a(3-Hydroxypropyl)-2-methoxy-3-

(phenoxymethyl)-3,3a,7,7a-tetrahydro-1H-inden-4(2H)-one

(55). A solution of TBAF in THF (1.1 mL, 1M) was added dropwise

to a stirring solution of β-54 (0.20 g, 0.35 mmol) in THF (3.5 mL).

The solution was maintained at rt for 2 h before quenching with sat.

aq. NaHCO₃. The mixture was extracted with Et₂O (3 × 20 mL), and

the combined organic layers were washed with brine (25 mL), dried

over MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash column

chromatography (3:2 EtOAc/hexanes) to aﬀord 55 (42 mg, 36%) as

1

a clear oil. H NMR (500 MHz, CDCl₃) δ 7.29 (t, J = 7.9 Hz, 2H),

6.95 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 8.1 Hz, 2H), 6.76−6.74 (m, 1H),

6.03 (d, J = 10.1 Hz, 1H), 4.14 (dd, J = 4.2, 9.5 Hz, 1H), 3.95 (dd, J =

6.5, 9.4 Hz, 1H), 3.89−3.87 (m, 1H), 3.52 (t, J = 6.2 Hz, 2H), 3.27 (s,

3H), 3.07 (br s, 1H), 2.60−2.57 (m, 1H), 2.43 (dd, J = 4.3, 17.0 Hz,

1H), 2.36−2.31 (m, 1H), 1.78−1.71 (m, 2H), 1.64−1.54 (m, 2H),

1.51−1.44 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 200.9 (C), 159.0

(C), 146.2 (CH), 129.8 (CH), 128.6 (CH), 121.2 (CH), 114.9 (CH),

83.9 (CH), 67.2 (CH₂), 63.1 (CH), 56.9 (CH₃), 56.1 (C), 48.3 (CH),

41.3 (CH), 37.7 (CH₂), 28.5 (C), 28.1 (CH₂), 27.5 (CH₂); IR (thin

T

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were washed with aq. NaOH (2 M, 100 mL) and then brine (100 mL),

dried over MgSO₄, ﬁltered through a plug of cotton, and concentrated

under reduced pressure to aﬀord (3aS*,7aS*)-3a-(3-iodopropyl)-6-

methyl-3-methylenetetrahydro-1H-indene-2,4(5H,6H)-dione (2.39 g,

6.90 mmol) as a colorless oil. Because of the sensitivity of

(3aS*,7aS*)-3a-(3-iodopropyl)-6-methyl-3-methylenetetrahydro-1H-

indene-2,4(5H,6H)-dione, it was carried on without further

puriﬁcation.

(CH), 102.9 (CH₂), 98.7 (CH₂), 88.2 (C), 71.7 (CH), 57.8 (CH₃),

54.2 (CH₂), 43.2 (CH), 42.9 (CH), 37.2 (CH₂), 36.8 (CH₂), 35.7

(CH₂), 33.2 (CH₂), 29.5 (CH₂), 27.1 (CH), 24.5 (CH₃), 22.6 (CH₂),

21.3 (C); IR (thin ﬁlm) 2953, 2917, 2254, 1751, 1547, 1374, 1178

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₂₄H₃₂O₉N₂SNa,

547.1726; found, 547.1722. Eluting second was tricycle 58 (0.773 g,

1

68% yield) as a colorless foam: H NMR (500 MHz, CDCl₃) δ 8.02

(d, J = 7.9 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H),

7.60 (d, J = 7.9 Hz, 1H), 5.57 (dd, J = 2.4, 4.6 Hz, 1H), 5.03−4.95 (m,

2H), 4.11 (dq, J = 1.7, 7.1 Hz, 1H), 3.88−3.85 (m, 1H), 3.46 (s, 3H),

3.21−3.09 (m, 2H), 2.59−2.52 (m, 1H), 2.41 (dd, J = 19.3, 8.0 Hz,

1H), 2.30−2.23 (m, 1H), 2.12−1.91 (m, 4H), 1.90−1.84 (m, 2H),

1.80−1.73 (m, 2H), 1.68−1.61 (m, 1H), 1.55−1.51 (m, 1H), 1.43−

1.38 (m, 1H), 1.33 (dt, J = 3.3, 9.5 Hz, 1H), 1.26 (dt, J = 1.6, 7.1 Hz,

1H), 1.05 (dt, J = 4.6, 13.6 Hz, 1H), 0.95 (dd, J = 2.4, 6.3 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 219.4 (C), 150.1 (C), 135.4 (CH), 132.7

(CH), 131.4 (CH), 126.2 (C), 124.1 (CH), 102.9 (CH₂), 100.9 (CH),

92.2 (C), 72.4 (CH), 57.9 (CH₃), 53.9 (CH₂), 49.2 (CH₂), 41.2

(CH₂), 40.7 (CH₂), 39.4 (CH₂), 36.4 (CH), 34.6 (CH₂), 30.5 (CH),

28.9 (CH₂), 28.3 (CH₂), 22.2 (CH₃), 21.5 (C); IR (thin ﬁlm) 3354,

2953, 1743, 1548, 1374, 1179 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₂₄H₃₄N₂O₁₀SNa, 565.1832; found, 565.1837.

3-Propyl N-(methoxymethoxy)-2-nitrobenzenesulfonamide

Dihydropyran 57. Eu(fod)₃(0.72 g, 0.690 mmol, 0.10 equiv) was

added in one portion to a solution of endione (2.39 g, 6.90 mmol, 1.00

equiv) in ethyl vinyl ether (11.0 mL, 145 mmol, 21.0 equiv), and the

mixture was stirred at rt for 18 h. The homogeneous solution was

concentrated under reduced pressure. Puriﬁcation by ﬂash chromatog-

raphy (10:89:1 EtOAc/hexanes/Et₃N) provided the 3-iodopropyl

dihydropyran as an approximately 1:1 mixture of ethoxy epimers (2.55

1

g, 89% yield over three steps) as a pale yellow oil: H NMR (500

MHz, C₆D₆) δ 4.81 (t, J = 3.6 Hz, 1H, single diastereomer), 3.74−3.83

(m, 1H), 3.28−3.40 (m, 1H), 2.67−2.84 (m, 2H), 2.54−2.61 (m, 1H),

2.23 (t, J = 3.7 Hz, 2H, single diastereomer), 2.02−2.11 (m, 1H), 1.85

(dq, J = 5.2, 13.0 Hz, 3H), 1.67−1.76 (m, 3H), 1.54−1.64 (m, 2H),

1.40−1.49 (m, 1H), 1.32−1.37 (m, 1H), 1.25 (dt, J = 4.0, 12.2 Hz,

1H), 1.07 (t, J = 5.0 Hz, 3H, single diastereomer), 0.89 (s, J = 12.2 Hz,

1H), 0.60 (d, J = 6.5 Hz, 3H, single diastereomer); ¹³C NMR (125

MHz, C₆D₆) δ 211.3 (C), 150.3 (C), 110.4 (CH₂), 99.1 (CH), 64.3

(CH₂), 61.8 (C), 48.4 (CH₂), 40.6 (CH₂), 40.1 (CH), 38.9 (CH₂),

37.1 (CH₂), 30.3 (CH₂), 29.4 (C), 27.6 (CH), 22.4 (CH₃), 16.4

(CH₂), 15.9 (CH₂), 7.8 (CH₂); IR (thin ﬁlm) 2924, 1684, 1380, 1285

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₈H₂₇IO₃Na, 441.0903;

found, 441.0903. Following the general procedure for the S_N2 reaction

with protected hydroxylamines, N-(methoxymethoxy)-2-nitrobenze-

nesulfonamide (0.614 g, 2.34 mmol) and 3-iodopropyl dihydropyran

(0.611 g, 2.13 mmol) were converted to 57. Puriﬁcation by ﬂash

chromatography (10:1:89 EtOAc/Et₃N/benzene) aﬀorded 57 (1.13 g,

95% yield) as a colorless foam. Product 57 was isolated as a 1:1

mixture of ethoxy epimers: ¹H NMR (500 MHz, C₆D₆) δ 7.78 (d, J =

7.5 Hz, 0.5H), 7.75 (d, J = 8.5 Hz, 0.5H), 6.63 (q, J = 6.4 Hz, 1H),

6.56 (d, J = 13.2 Hz, 1H), 6.53 (m, 1H), 5.07 (d, J = 5.1 Hz, 0.5H),

5.04 (d, J = 5.0 Hz, 0.5H), 4.97 (d, J = 5.0 Hz, 0.5H), 4.94 (d, J = 4.9

Hz, 0.5H), 4.81 (m, 1H), 3.78 (m, 1H), 3.36 (m, 1H), 3.10 (br s, 1H),

3.15 (s, 3H), 3.14 (m, 1H), 2.65 (m, 1H), 2.27−2.23 (m, 2H), 1.87

(m, 1H), 1.95−1.57 (m, 8H), 1.48−1.32 (m, 3H), 1.08−1.03 (m, 3H),

0.99−0.88 (m, 1H), 0.66 (d, J = 6.5 Hz, 1.5H), 0.63 (d, J = 6.5 Hz,

1.5H); ¹³C NMR (125 MHz, C₆D₆) δ 211.8 (C), 150.4 (C), 135.0

(CH), 132.5 (CH), 130.8 (CH), 128.9 (C), 126.7 (C), 123.9 (CH),

110.3 (CH₂), 103.2 (CH₂), 98.8 (CH), 64.2 (CH₂), 61.8 (C), 57.7

(CH₃), 54.8 (C), 48.5 (CH₂), 40.5 (CH₂), 40.0 (C), 38.5 (CH), 33.2

(CH₂), 29.5 (CH₂), 27.6 (CH), 23.4 (CH₂), 22.4 (CH₃), 16.4 (CH₂),

15.8 (CH₃); IR (thin ﬁlm) 2927, 2360, 1685, 1548 cm⁻¹; HRMS-ESI

(m/z) [M + Na]⁺calcd for C₂₆H₃₆N₂O₉SNa, 575.2039; found,

575.2031.

tert-Butyl(2-((1S*,2S*,4R*)-2-(tert-butyldimethylsilyloxy)-4-

methylcyclopentyl)ethoxy)dimethylsilane. TBSCl (10.6 g, 77.2

mmol, 3.10 equiv) was added in one portion to a solution of diol 62

(3.26 g, 22.7 mmol, 1.00 equiv), imidazole (4.94 g, 72.5 mmol, 3.20

equiv), and DMF (150 mL) at rt and stirred for 15 h. The solution was

then partitioned between H₂O (500 mL) and EtOAc (100 mL). The

layers were separated, and the aqueous phase was extracted with

EtOAc (3 × 150 mL). The combined organic layers were washed with

H₂O (150 mL) and then brine (100 mL), dried over MgSO₄, ﬁltered

through a plug of cotton, and concentrated under reduced pressure.

Puriﬁcation by ﬂash chromatography (100% hexanes) aﬀorded tert-

butyl(2-((1S*,2S*,4R*)-2-(tert-butyldimethylsilyloxy)-4-

methylcyclopentyl)ethoxy)dimethylsilane (7.44 g, 88% yield) as a clear

1

colorless oil: H NMR (500 MHz, CDCl₃) δ 4.09 (s, 1H), 3.66−2.57

(m, 2H), 2.32−2.22 (m, 1H), 1.98−1.91 (m, 1H), 1.79 (dd, J = 8.0,

12.0 Hz, 1H), 1.70 (sextet, J = 7.0 Hz, 1H), 1.64 (dq, J = 3.0, 9.5 Hz,

1H), 1.51−1.44 (m, 1H), 1.29−1.26 (m, 2H), 0.97 (d, J = 7.0 Hz,

3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 76.5 (CH), 62.8 (CH₂), 44.7

(CH₂), 41.4 (CH), 37.5 (CH₂), 33.4 (CH₂), 30.2 (CH), 26.2 (CH₃),

20.0 (CH₃), 22.6 (CH₃), 18.7 (C), 18.4 (C), −4.1 (CH₃), −4.6

(CH₃), −4.9 (CH₃); IR (thin ﬁlm) 2951, 1462, 1253, 1099, 1051

cm⁻¹; HRMS-ESI (m/z) [M + H]⁺calcd for C₂₀H₄₅O₂Si₂, 373.2958;

found, 373.2950.

2-((1S*,2S*,4R*)-2-(tert-Butyldimethylsilyloxy)-4-

methylcyclopentyl)ethanol. A solution of HF·pyridine (8.4 mL)

(CAUTION! HF is extremely dangerous and caustic; the reaction was

carried out in a Nalgene bottle.) was added dropwise to a solution of

tert-butyl(2-((1S*,2S*,4R*)-2-(tert-butyldimethylsilyloxy)-4-

methylcyclopentyl)ethoxy)dimethylsilane (4.78 g, 11.2 mmol, 1.0

equiv), THF (110 mL), and pyridine (11 mL) at 0 °C. After stirring

for 10 min, the solution was warmed to rt and stirred for 1.5 h. The

reaction was quenched with sat. aq. NaHCO₃(100 mL), and the

solution was extracted with EtOAc (3 × 100 mL). The combined

organic layers were washed with sat. aq. CuSO₄(50 mL) followed by

H₂O (2 × 100 mL) and brine (100 mL). The organic phase was dried

over MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography (1:9 EtOAc/

hexanes) provided 2-((1S*,2S*,4R*)-2-(tert-butyldimethylsilyloxy)-4-

methylcyclopentyl)ethanol (2.12 g, 73% yield) as a pale yellow oil: ¹H

NMR (500 MHz, CDCl₃) δ 4.15−1.13 (m, 1H), 3.70−3.60 (m, 2H),

2.26 (sextet, J = 7.0 Hz, 1H), 2.02−1.95 (m, 1H), 1.83 (dd, J = 2.0, 8.0

Hz, 1H), 1.81−1.74 (m, 1H), 1.69−1.63 (m, 1H), 1.56 (sextet, J = 6.5

Hz, 1H), 1.52 (br s, 1H), 1.34−1.25 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H),

0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 76.4 (CH), 62.6 (CH₂), 44.3 (CH₂), 41.8 (CH), 37.7 (CH₂), 33.5

(CH₂), 30.1 (CH), 26.1 (CH₃), 22.6 (CH₃), 18.4 (C), −4.1 (CH₃),

−4.7 (CH₃); IR (thin ﬁlm) 3342, 2952, 2858, 1253, 1051 cm⁻¹;

N-(3-((1′R*,3a′S*,7a′R*)-5,7′-Dihydroxy-5′-methyl-2′-oxode-

cahydro-3H-spiro[furan-2,1′-indene]-7a′-yl)propyl)-N-(me-

thoxymethoxy)-2-nitrobenzenesulfonamide (58) and Tetracy-

clic Acetal 59. Following the general procedure for the DIBALH

reduction−oxidation−acidic rearrangement sequence, dihydropyran

57 (1.13 g, 2.04 mmol) was converted into tetracyclic acetal 59 and

tricycle 58. Puriﬁcation by column chromatography (1:1 EtOAc/

hexanes) aﬀorded the following. Eluting ﬁrst was tetracyclic acetal 59

(127 mg, 11% yield) as a colorless crystalline solid. Slow evaporation

from MeOH aﬀorded single crystals for X-ray analysis: mp 144−145

1

°C; H NMR (500 MHz, CDCl₃) δ 8.00 (dd, J = 1.1, 8.0 Hz, 1H),

7.81 (dt, J = 1.2, 7.7 Hz, 1H), 7.73 (dt, J = 1.1, 7.8 Hz, 1H), 7.59 (dd, J

= 0.9, 7.9 Hz, 1H), 5.53 (d, J = 4.8 Hz, 1H), 4.97 (dd, J = 7.9, 12.4 Hz,

2H), 3.81 (t, J = 4.2 Hz, 1H), 3.44 (s, 3H), 3.10 (br m, 2H), 2.55 (dd,

J = 9.0, 19.3 Hz, 1H), 2.32 (dd, J = 3.1, 19.4 Hz, 1H), 2.17−2.00 (m,

2H), 1.95−1.81 (m, 4H), 1.77−1.71 (m, 1H), 1.69−1.63 (m, 2H),

1.50 (td, J = 4.1, 14.7 Hz, 1H), 1.43 (br m, 3H), 1.34−1.27 (m, 1H),

1.06 (d, J = 6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 213.3 (C),

156.2 (C), 135.4 (CH), 132.7 (CH), 131.3 (CH), 126.4 (C), 124.0

U

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

HRMS-ESI (m/z) [M + H]⁺calcd for C₁₄H₃₁O₂Si, 259.2093; found,

259.2090.

with CH₂Cl₂(3 × 20 mL). The combined organic layers were washed

with brine (30 mL), dried over MgSO₄, ﬁltered through a plug of

cotton, and concentrated under reduced pressure. Puriﬁcation by ﬂash

chromatography (3:7 EtOAc/hexanes) provided (2S*,4R*)-2-(2,2-

dimethoxyethyl)-4-methylcyclopentanone (0.398 g, 87% yield) as a

clear colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 4.47 (t, J = 5.5 Hz,

1H), 3.29 (s, 3H), 3.28 (s, 3H), 2.34−2.29 (m, 3H), 1.98 (td, J = 5.0,

14.0 Hz, 1H), 1.90 (dd, J = 0.5, 14.0 Hz, 1H), 1.88−1.77 (m, 2H),

1.51 (m, 1H), 1.05 (d, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 221.2 (C), 103.1 (CH), 53.4 (CH₃), 52.7 (CH₃), 46.4 (CH₂), 42.9

(CH), 37.3 (CH₂), 33.4 (CH₂), 28.3 (CH), 20.9 (CH₃); IR (thin ﬁlm)

2955, 1738, 1455 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₀H₁₈O₃Na, 209.1154; found, 209.1159.

tert-Butyl((1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-

methylcyclopentyloxy)dimethylsilane. A solution of DMSO

(0.89 mL, 12.5 mmol, 2.7 equiv) in CH₂Cl₂(3 mL) was slowly

added dropwise (keeping the internal temperature below −60 °C) to a

solution of oxalyl chloride (0.50 mL, 6.0 mmol, 1.3 equiv) in CH₂Cl₂

(23 mL) at −78 °C. The resulting solution was stirred for 15 min at

−78 °C. A solution of 2-((1S*,2S*,4R*)-2-(tert-butyldimethylsily-

loxy)-4-methylcyclopentyl)ethanol (1.2 g, 4.6 mmol, 1.0 equiv) was

then added dropwise, and the solution was stirred for 40 min. Et₃N

(3.3 mL, 23.0 mmol, 5.0 equiv) was added at −78 °C and stirred for

10 min before warming to 0 °C. The solution was stirred at 0 °C for 1

h and then partitioned between sat. aq. NaHCO₃(75 mL) and

CH₂Cl₂(100 mL). The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 100 mL). The combined organic

layers were washed with brine (75 mL), dried over MgSO₄, ﬁltered

through a plug of cotton, and concentrated under reduced pressure to

aﬀord the corresponding aldehyde (1.93 g, 92% yield). Pyridinium p-

toluenesulfonate (11 mg, 0.044 mmol, 0.005 equiv) was added to a

solution of the aldehyde (2.27 g, 8.85 mmol, 1.00 equiv),

trimethylorthoformate (14.5 mL, 133 mmol, 15.0 equiv), and

CH₂Cl₂(30 mL) and stirred at rt for 7 h. The solution was ﬁltered

through a plug of Florisil and eluted with Et₂O. The eluent was

concentrated under reduced pressure to aﬀord tert-butyl-

((1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-methylcyclopentyloxy)-

(1S*,2S*,4R*)-1-((E)-6-(tert-Butyldiphenylsilyloxy)-1-phenox-

yhex-2-en-3-yl)-2-(2,2-dimethoxyethyl)-4-methylcyclopenta-

nol. Following the general vinylcerium addition procedure, vinyl

iodide 13⁵(1.79 g, 3.21 mmol, 1.50 equiv) was added to (2S*,4R*)-2-

(2,2-dimethoxyethyl)-4-methylcyclopentanone (398 mg, 2.14 mmol,

1.00 equiv) to provide (1S*,2S*,4R*)-1-((E)-6-(tert-butyldiphenylsi-

lyloxy)-1-phenoxyhex-2-en-3-yl)-2-(2,2-dimethoxyethyl)-4-methylcy-

clopentanol. Puriﬁcation by column chromatography (24:1:75 EtOAc/

Et₃N/hexanes) provided (1S*,2S*,4R*)-1-((E)-6-(tert-butyldiphenyl-

silyloxy)-1-phenoxyhex-2-en-3-yl)-2-(2,2-dimethoxyethyl)-4-methylcy-

1

clopentanol (887 mg, 67% yield) as a clear colorless oil: H NMR

(500 MHz, CDCl₃) δ 7.70 (d, J = 6.8 Hz, 4H), 7.45 (t, J = 7.4 Hz,

2H), 7.40 (t, J = 7.4 Hz, 4H), 7.28 (t, J = 7.4 Hz, 2H), 6.95 (t, J = 7.3

Hz, 1H), 6.91 (d, J = 7.7 Hz, 2H), 5.94 (dt, J = 2.5, 6.2 Hz, 1H), 4.63

(d, J = 6.3 Hz, 2H), 4.40−4.38 (m, 1H), 3.72 (t, J = 5.6 Hz, 2H), 3.31

(s, 3H), 3.28 (s, 3H), 2.43−2.38 (m, 1H), 2.33−2.15 (m, 3H), 1.85−

1.75 (m, 4H), 1.73−1.68 (m, 2H), 1.59−1.50 (m, 3H), 1.10 (s, 9H),

1.04 (d, J = 6.9 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 159.0 (C),

147.1 (C), 135.8 (CH), 134.0 (C), 129.9 (CH), 129.7 (CH), 127.9

(CH), 120.9 (CH), 114.9 (CH), 104.2 (CH), 86.1 (C), 77.5 (CH),

65.2 (CH₂), 64.1 (CH₂), 53.0 (CH₃), 52.9 (CH₃), 49.1 (CH₂), 41.5

(CH), 38.9 (CH₂), 33.9 (CH₂), 32.4 (CH₂), 30.4 (CH), 27.1 (CH₃),

25.3 (CH₂), 22.1 (CH₃), 19.5 (C); IR (thin ﬁlm) 3462, 3070, 2950,

1599, 1239, 1111 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₃₈H₅₂O₅SiNa, 639.3481; found, 639.3486.

tert-Butyl((E)-4-((1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-

methyl-1-(trimethylsilyloxy)cyclopentyl)-6-phenoxyhex-4-

enyloxy)diphenylsilane (66a). A solution of tetra-n-butylammo-

nium ﬂuoride in THF (13 μL, 0.013 mmol, 1.0 M, 0.01 equiv) was

added dropwise to a solution of (1S*,2S*,4R*)-1-((E)-6-(tert-

butyldiphenylsilyloxy)-1-phenoxyhex-2-en-3-yl)-2-(2,2-dimethoxyeth-

yl)-4-methylcyclopentanol (874 mg, 1.42 mmol, 1.0 equiv), TMS-

imidazole (420 μL, 2.8 mmol, 2.0 equiv), and DMF (3.6 mL) and

stirred at rt for 3 h. The solution was partitioned between water (50

mL) and Et₂O (25 mL). The layers were separated, and the aqueous

phase was extracted with Et₂O (3 × 20 mL). The combined organic

layers were washed with water (50 mL) and then brine (50 mL), dried

over MgSO₄, ﬁltered through a plug of cotton, and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography (1:5:94 Et₃N/

EtOAc/hexanes) aﬀorded alkene acetal 66a (759 mg, 77% yield) as a

clear colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J = 7.8 Hz,

4H), 7.44−7.41 (m, 2H), 7.38 (t, J = 6.9 Hz, 4H), 7.26 (t, J = 8.2 Hz,

2H), 6.92 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 7.9 Hz, 2H), 5.83 (t, J = 6.4

Hz, 1H), 4.63−4.56 (m, 3H), 4.37 (dd, J = 4.2, 6.8 Hz, 1H), 3.68 (t, J

= 5.7 Hz, 3H), 2.32−2.26 (m, 3H), 1.98−1.90 (m, 2H), 1.82 (dt, J =

3.2, 9.9 Hz, 1H), 1.76−1.64 (m, 4H), 1.59−1.51 (m, 2H), 1.48−1.35

(m, 2H), 1.22 (t, J = 7.0 Hz, 2H), 1.09 (s, 9H), 1.01 (d, J = 6.9 Hz,

3H), 0.09 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 159.1 (C), 145.6

(C), 135.8 (CH), 134.1 (C), 129.9 (CH), 129.8 (CH), 127.9 (CH),

122.6 (CH), 120.9 (CH), 115.1 (CH), 104.4 (CH), 89.3 (C), 77.2

(CH), 65.2 (CH₂), 64.1 (CH₂), 53.5 (CH₃), 51.8 (CH₃), 45.7 (CH₂),

43.3 (CH), 38.2 (CH₂), 33.1 (CH₂), 30.1 (CH), 27.2 (CH₃), 25.6

(CH₂), 23.7 (CH₃), 19.5 (C), 2.6 (CH₃); IR (thin ﬁlm) 3071, 2954,

2860, 1599, 1250, 1112, 1078 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₄₁H₆₀O₅Si₂Na, 711.3877; found, 711.3867.

1

dimethylsilane (2.53 g, 94% yield) as a clear colorless oil: H NMR

(500 MHz, CDCl₃) δ 4.40 (t, J = 6.0 Hz, 1H), 4.11 (t, J = 4.0 Hz, 1H),

3.32 (s, 3H), 3.31 (s, 3H), 2.35−2.22 (m, 1H), 1.96−1.91 (m, 1H),

1.82−1.77 (m, 2H), 1.58 (q, J = 5.5 Hz, 1H), 1.55−1.51 (m, 1H),

1.33−1.30 (m, 1H), 1.24−1.21 (m, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.88

(s, 9H), 0.03 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 104.2 (CH),

76.4 (CH), 53.0 (CH₃), 52.5 (CH₃), 44.7 (CH₂), 40.7 (CH), 37.6

(CH₂), 32.9 (CH₂), 30.2 (CH), 26.1 (CH₃), 22.5 (CH₃), 18.3 (C),

−4.1 (CH₃), −4.6 (CH₃); IR (thin ﬁlm) 2953, 1472, 1463, 1253,

1127, 1054 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₁₆H₃₄O₃SiNa, 325.2174; found, 325.2166.

(1S*,2S*,4R*)-2-(2,2-Dimethoxyethyl)-4-methylcyclopenta-

nol. A 1 M solution of TBAF in THF (15 mL, 15 mmol) was added to

neat tert-butyl((1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-

methylcyclopentyloxy)dimethylsilane (0.890 g, 2.94 mmol) and heated

to 50 °C for 2 h. After cooling to room temperature, the solution was

partitioned between Et₂O (30 mL) and brine (30 mL). The layers

were separated, and the aqueous phase was extracted with Et₂O (3 ×

30 mL). The combined organic layers were washed with brine (20

mL), dried over MgSO₄, ﬁltered through a plug of cotton, and

concentrated under reduced pressure. Puriﬁcation by ﬂash chromatog-

raphy (3:7 EtOAc/hexanes) aﬀorded (1S*,2S*,4R*)-2-(2,2-dimethox-

yethyl)-4-methylcyclopentanol (0.462 g, 84% yield) as a clear colorless

oil: ¹H NMR (500 MHz, CDCl₃) δ 4.42 (dd, J = 3.0, 7.0 Hz, 1H), 4.14

(t, J = 4.5 Hz, 1H), 3.39 (s, 3H), 3.32 (s, 3H), 2.45 (br s, 1H), 2.31

(m, 1H), 2.02 (m, 1H), 1.91 (dd, J = 8.0, 14.0 Hz, 1H), 1.81 (dt, J =

7.0, 10.0 Hz, 1H), 1.71−1.68 (m, 1H), 1.62 (q, J = 9.5 Hz, 1H), 1.38−

1.32 (m, 2H), 0.97 (d, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 105.1 (CH), 74.9 (CH), 54.9 (CH₃), 52.2 (CH₃), 43.7 (CH₂), 40.9

(CH), 38.5 (CH₂), 33.2 (CH₃), 30.3 (CH), 22.4 (CH₃); IR (thin ﬁlm)

3436, 2950, 2867, 1656, 1454 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₁₀H₂₀O₃Na, 211.1310; found, 211.1306.

(2S*,4R*)-2-(2,2-Dimethoxyethyl)-4-methylcyclopentanone.

A solution of DMSO (470 μL, 6.6 mmol) in CH₂Cl₂(1.5 mL) was

slowly added dropwise (maintaining an internal temperature below

−50 °C during the addition) to a solution of oxalyl chloride (270 μL,

3.2 mmol) in CH₂Cl₂(12 mL) at −78 °C. After completion of the

addition, the solution was stirred for 15 min at −78 °C, and then a

solution of (1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-methylcyclopen-

tanol (0.462 g, 2.46 mmol) in CH₂Cl₂(10 mL) was added slowly and

stirred for 45 min at −78 °C. EtN(i-Pr)₂(2.14 mL, 12.3 mmol) was

added and stirred at −78 °C for 15 min and then allowed to warm to 0

°C over 1 h. The cold solution was quenched with pH 7 buﬀer (20

mL), and the layers were separated. The aqueous phase was extracted

tert-Butyl((E)-4-((1S*,2S*,4R*)-2-(2,2-dimethoxyethyl)-4-

methyl-1-(triethylsilyloxy)cyclopentyl)-6-phenoxyhex-4-

V

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

enyloxy)diphenylsilane (66). Pyridinium p-toluenesulfonate (1.0

mg) was added to a stirring solution of aldehyde 65⁵(356 mg, 0.510

mmol, 1.00 equiv), trimethylorthoformate (840 μL, 7.6 mmol), and

CH₂Cl₂(1.7 mL) and stirred at rt for 5 h. The solution was eluted

through a plug of silica gel and ﬂushed with CH₂Cl₂. The solution was

concentrated under reduced pressure to provide dimethyl acetal 66

enyloxy)diphenylsilane (25 mg, 83% yield) as a clear colorless oil,

which was isolated as an approximately 1:1 mixture of methoxy

epimers: ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J = 6.7 Hz, 8H), 7.43

(m, 4H), 7.37 (t, J = 7.3 Hz, 8H), 7.24 (m, 4H), 6.95−6.90 (m, 2H),

6.89 (d, J = 8.6 Hz, 4H), 5.89 (t, J = 6.3 Hz, 1H, single diastereomer),

5.83 (t, J = 6.3 Hz, 1H, single diastereomer), 5.06 (dd, J = 2.1, 5.3 Hz,

1H), 5.00 (d, J = 4.5 Hz, 1H), 4.58 (m, 4H), 3.70 (q, J = 4.3 Hz, 4H),

3.37 (s, 3H, single diastereomer), 3.31 (s, 3H, single diastereomer),

2.84 (q, J = 8.5 Hz, 1H), 2.51 (t, J = 7.4 Hz, 1H), 2.31−2.04 (m, 6H),

2.02−1.91 (m, 2H), 1.82−1.61 (m, 6H), 1.46−1.32 (m, 4H), 1.28−

1.23 (m, 4H), 1.08 (s, 9H, single diastereomer), 1.07 (s, 9H, single

diastereomer), 1.00 (d, J = 6.4 Hz, 3H, single diastereomer), 0.99 (d, J

= 6.4 Hz, 3H, single diastereomer); ¹³C NMR (125 MHz, CDCl₃) δ

159.1 (C), 147.5 (C), 146.1 (C), 135.8 (CH), 134.1 (C), 129.9 (CH),

129.6 (CH), 127.9 (CH), 120.9 (CH), 119.6 (CH), 119.3 (CH),

115.0 (CH), 106.9 (CH), 106.5 (CH), 99.7 (C), 98.2 (C), 65.3

(CH₃), 64.2 (CH₃), 55.8 (CH₂), 55.5 (CH₂), 49.9 (CH), 47.2 (CH),

45.6 (CH₂), 44.9 (CH₂), 43.3 (CH), 42.9 (CH), 41.7 (CH), 40.5

(CH), 33.8 (CH), 32.2 (CH₂), 27.1 (CH₂), 25.8 (CH₃), 19.6 (CH₂),

19.0 (CH₂); IR (thin ﬁlm) 3070, 2952, 2858, 1599, 1496, 1240, 1111

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₃₇H₄₈O₄SiNa,

607.3220; found, 607.3220.

1

(272 mg, 73% yield) as a clear colorless oil: H NMR (500 MHz,

CDCl₃) δ 7.67 (d, J = 7.2 Hz, 4H), 7.42 (t, J = 7.3 Hz, 2H), 7.37 (t, J =

7.3 Hz, 4H), 7.25 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 7.0 Hz, 1H), 6.87 (d,

J = 8.2 Hz, 2H), 5.85 (t, J = 6.4 Hz, 1H), 4.59 (t, J = 6.0 Hz, 2H), 4.34

(dd, J = 4.2, 7.7 Hz, 1H), 3.67 (t, J = 5.7 Hz, 2H), 3.28 (s, 3H), 3.21

(s, 3H), 2.30−2.26 (m, 2H), 1.89 (dd, J = 7.6, 13.8 Hz, 1H), 1.85−

1.80 (m, 1H), 1.77−1.71 (m, 1H), 1.70−1.62 (m, 2H), 1.49−1.35 (m,

2H), 1.06 (s, 9H), 1.00 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.9 Hz, 12H),

0.58 (q, J = 7.8 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 159.1 (C),

145.5 (CH), 135.8 (C), 134.1 (CH), 129.9 (CH), 129.6 (CH), 127.9

(CH), 122.3 (CH), 120.7 (CH), 115.0 (CH), 104.3 (CH), 89.0 (C),

65.0 (CH₂), 64.2 (CH₂), 53.4 (CH₃), 51.8 (CH₃), 46.3 (CH₂), 43.6

(CH), 38.4 (CH₂), 33.8 (CH₂), 31.3 (CH₂), 30.1 (CH), 27.2 (CH₃),

25.6 (CH₂), 22.8 (CH₃), 19.5 (c), 7.6 (CH₃), 7.1 (CH₂); IR (thin

ﬁlm) 2953, 2873, 1598, 1110 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺

calcd for C₄₄H₆₆O₅Si₂Na, 753.4346; found, 753.4332.

(3aS*,5R*,6aS*)-5-Methylhexahydro-2H-cyclopenta[b]furan-

2-one (67). Bu₃SnH (3.24 mL, 12.03 mmol, 1.60 equiv) was added

dropwise to a solution of iodolactone 61⁵(2.00 g, 7.52 mmol, 1.00

equiv), AIBN (123 mg, 0.75 mmol, 0.100 equiv), and benzene (25

mL), and the solution was heated to reﬂux for 1 h. After cooling to rt,

NaF (947 mg, 22.56 mmol, 3.00 equiv) was added and stirred for 1 h.

The heterogeneous suspension was loaded directly onto a silica gel

column. Puriﬁcation by ﬂash chromatography (100% hexanes → 1:3

EtOAc/hexanes) aﬀorded lactone 67 (1.02 g, 97% yield) as a clear

colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 5.01 (t, J = 6.4 Hz, 1H),

2.98 (q, J = 8.9 Hz, 1H), 2.83 (dd, J = 10.8, 18.5 Hz, 1H), 2.27 (dd, J =

3.2, 18.5 Hz, 1H), 2.20−2.11 (m, 2H), 1.73−1.65 (m, 1H), 1.49−1.42

(m, 1H), 1.34−1.25 (m, 1H), 1.03 (d, J = 6.1 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 178.2 (C), 86.9 (CH), 42.5 (CH₂), 42.3 (CH₂), 37.9

(CH), 36.7 (CH₂), 31.6 (CH), 18.9 (CH₃); IR (thin ﬁlm) 2955, 1775,

1172 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₈H₁₂O₂Na,

163.0735; found, 163.0733.

2-((1S*,2S*,4R*)-2-Hydroxy-4-methylcyclopentyl)-1-(pyrroli-

din-1-yl)ethanone. Lactone 67 (1.05 g, 7.49 mmol, 1.00 equiv) and

pyrrolidine (6.26 mL, 75.0 mmol, 10.1 equiv) were diluted in toluene

and heated to 110 °C for 16 h. After cooling to rt, the solution was

concentrated under reduced pressure. Puriﬁcation by ﬂash chromatog-

raphy (100% EtOAc) eluted ﬁrst the recovered starting material 67

(259 mg, 14% recovery), followed by 2-((1S*,2S*,4R*)-2-hydroxy-4-

methylcyclopentyl)-1-(pyrrolidin-1-yl)ethanone (1.36 g, 86% yield) as

a clear colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 4.24 (s, 1H), 3.78

(s, 1H), 3.44 (m, 4H), 2.49−2.39 (m, 2H), 2.35−2.27 (m, 2H), 1.93

(pentet, J = 6.7 Hz, 2H), 1.87−1.81 (m, 3H), 1.61 (dt, J = 8.5, 12.8

Hz, 1H), 1.39 (m, 2H), 0.94 (d, J = 7.0 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 172.6 (C), 74.4 (CH), 47.1 (CH₂), 45.7 (CH₂), 43.2

(CH₂), 40.7 (CH), 38.7 (CH₂), 35.3 (CH₂), 30.6 (CH), 26.1 (CH₂),

24.5 (CH₂), 21.7 (CH₃); IR (thin ﬁlm) 3418, 2950, 2868, 1619, 1452

cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₂H₂₁NO₂Na,

234.1470; found, 234.1466.

(2S*,3S*,3aS*,7aS*)-3a-(3-(tert-Butyldiphenylsilyloxy)-

propyl)-2-methoxy-6-methyl-3-(phenoxymethyl)hexahydro-

1H-inden-4(2H)-one (53α). A 1 M solution of TiCl₄in CH₂Cl₂(34

μL, 0.061 mmol, 0.5 equiv) was added to a solution of dimethyl acetal

66 (0.050 g, 0.068 mmol, 1.0 equiv) in CH₂Cl₂(1.4 mL) at −78 °C.

The red solution was allowed to warm to −20 °C and stirred for 20

min. The solution was quenched at −20 °C by addition of

triethylamine (77 μL, 0.55 mmol, 8.0 equiv), followed by MeOH

(23 μL, 0.55 mmol, 8.0 equiv), resulting in the disappearance of color.

The cold solution was partitioned between sat. aq. NaHCO₃(10 mL)

and CH₂Cl₂(5 mL). The phases were separated, and the aqueous

phase was extracted with CH₂Cl₂(3 × 7 mL). The combined organic

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

through a plug of cotton, and concentrated under reduced pressure.

Puriﬁcation by column chromatography (1:4 EtOAc/hexanes)

aﬀorded hydrindanones 53α and 53β (17 mg, 42% yield combined,

1

2.2:1 dr α:β) as a clear colorless oils. 53α: H NMR (500 MHz,

CDCl₃) δ 7.64 (d, J = 7.1 Hz, 4H), 7.43−7.34 (m, 6H), 7.25 (t, J = 8.0

Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 2H), 4.16 (dd, J

= 7.0, 9.4 Hz, 1H), 4.03 (dd, J = 5.5, 9.4 Hz, 1H), 3.80 (q, J = 5.5 Hz,

1H), 3.65 (m, 1H), 3.55 (m, 1H), 3.28 (s, 3H), 2.87 (q, J = 5.9 Hz,

1H), 2.62 (dq, J = 2.7, 5.7 Hz, 1H), 2.40 (q, J = 9.6 Hz, 1H), 2.00 (q, J

= 8.6 Hz, 2H), 1.94 (ddd, J = 5.1, 9.3, 13.6 Hz, 1H), 1.85 (dt, J = 4.0,

13.1 Hz, 1H), 1.71−1.60 (m, 3H), 1.56−1.47 (m, 2H), 1.31 (m, 1H),

1.04 (s, 9H), 1.01 (d, J = 5.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

215.6 (C), 159.2 (C), 135.8 (CH), 134.2 (C), 129.8 (CH), 129.6

(CH), 127.9 (CH), 120.7 (CH), 114.8 (CH), 80.9 (CH), 64.1 (CH₂),

63.8 (CH₂), 58.1 (C), 57.7 (CH₃), 48.2 (CH₂), 46.9 (CH), 42.9

(CH), 36.0 (CH₂), 35.3 (CH₂), 30.6 (CH₂), 28.9 (CH₂), 28.4 (CH),

27.1 (CH₃), 22.3 (CH₃), 19.5 (C); IR (thin ﬁlm) 3070, 2952, 2857,

1699, 1600, 1244, 1111 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₃₇H₄₈O₄SiNa, 607.3220; found, 607.3224.

tert-Butyl((E)-4-((3aS*,5R*,6aS*)-2-methoxy-5-methylhexa-

hydro-2H-cyclopenta[b]furan-6a-yl)-6-phenoxyhex-4-

enyloxy)diphenylsilane. A 1 M solution of TMSOTf in CH₂Cl₂(50

μL, 0.05 mmol, 0.98 equiv) was added to a solution of acetal 66 (35

mg, 0.051 mmol, 1.0 equiv), 2,6-di-tert-butyl-4-methylpyridine (21 mg,

0.10 mmol, 2.0 equiv), and CH₂Cl₂(1.1 mL) at −78 °C. The solution

was allowed to warm to −20 °C and stirred for 20 min. The solution

was quenched at −20 °C by adding triethylamine (42 μL, 0.41 mmol),

and then the cold solution was partitioned between sat. aq. NaHCO₃

(10 mL) and CH₂Cl₂(5 mL). The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂(3 × 5 mL). The combined

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

ﬁltered through a plug of cotton, and concentrated under reduced

pressure. Puriﬁcation by column chromatography (1:9 EtOAc/

hexanes) aﬀorded tert-butyl((E)-4-((3aS*,5R*,6aS*)-2-methoxy-5-

methylhexahydro-2H-cyclopenta[b]furan-6a-yl)-6-phenoxyhex-4-

(2S*,4R*)-4-Methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-

cyclopentanone (68). Dess−Martin periodinane²⁸(1.51 g, 3.56

mmol, 1.50 equiv) was added to a solution of 2-((1S*,2S*,4R*)-2-

hydroxy-4-methylcyclopentyl)-1-(pyrrolidin-1-yl)ethanone (496 mg,

2.37 mmol, 1.0 equiv) in CH₂Cl₂(12 mL). The suspension was

stirred vigorously at room temperature for 30 min, then treated with

10% aq. Na₂S₂O₃(5 mL), and stirred for 15 min. The biphasic

solution was partitioned between sat. aq. NaHCO₃(10 mL) and

CH₂Cl₂(10 mL). The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 10 mL). The combined organic layers

were washed with brine (20 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography (4:1 EtOAc/hexanes) provided cyclo-

1

pentanone 68 (413 mg, 83% yield) as a clear colorless oil: H NMR

W

dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(500 MHz, CDCl₃) δ 3.44 (t, J = 6.9 Hz, 2H), 3.38 (m, 2H), 2.69 (t, J

= 8.8 Hz, 1H), 2.64 (dd, J = 3.4, 15.4 Hz, 1H), 2.53 (dd, J = 8.1, 17.9

Hz, 1H), 2.49−2.41 (m, 2H), 2.01−1.92 (m, 5H), 1.84 (pentet, J = 6.6

Hz, 2H), 1.09 (d, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

221.6 (C), 169.5 (C), 46.8 (CH₂), 46.4 (CH₂), 45.9 (CH₂), 42.9

(CH₃), 36.8 (CH₂), 35.4 (CH₂), 28.1 (CH), 26.4 (CH₂), 24.6 (CH₂),

21.3 (CH₃); IR (thin ﬁlm) 3485, 2955, 2873, 1734, 1634, 1450 cm⁻¹;

HRMS-ESI (m/z) [M + Na]⁺calcd for C₁₂H₁₉NO₂Na, 232.1313;

found, 232.1306.

Institutes of General Medical Sciences (GM-098601). Dr. Joe

Ziller, UC Irvine, is acknowledged for X-ray analyses. Synthetic

assistance from Mr. Brian Leon is gratefully acknowledged.

́

NMR, mass spectra, and X-ray analyses were obtained at UC

Irvine using instrumentation acquired with the assistance of

NSF and NIH Shared Instrumentation grants.

REFERENCES

■

2-((1S*,2S*,4R*)-2-((E)-6-(tert-Butyldiphenylsilyloxy)-1-phe-

noxyhex-2-en-3-yl)-4-methyl-2-(triethylsilyloxy)cyclopentyl)-

1-(pyrrolidin-1-yl)ethanone (69). Following the general procedure

for vinylcerium addition, vinyl iodide 13⁵(1.65 g, 2.96 mmol, 1.50

equiv) was added to cyclopentanone 68 (0.412 g, 1.97 mmol, 1.00

equiv) to provide the tertiary allylic alcohol. Puriﬁcation by ﬂash

chromatography (3:2 EtOAc/hexanes) provided the tertiary alcohol

contaminated with residual cyclopentanone 68. The mixture was

carried forward to the next step. TESOTf (740 μL, 3.3 mmol, 3.0

equiv) was added dropwise to a solution of the tertiary allylic alcohol

(0.70 g, 1.1 mmol, 1.0 equiv) and 2,6-lutidine (765 μL, 6.56 mmol,

6.00 equiv) in CH₂Cl₂(6.1 mL) at 0 °C. The solution was stirred for 1

h and then partitioned between sat. aq. NaHCO₃(20 mL) and

CH₂Cl₂(15 mL). The layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 15 mL). The combined organic layers

were washed with brine (20 mL), dried over MgSO₄, ﬁltered through a

plug of cotton, and concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography (3:7 EtOAc/hexanes) aﬀorded silyl ether 69

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(3) (a) Jiang, H.; Luo, X.; Bai., D. Curr. Med. Chem. 2003, 10, 2231−

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̈

641−650.

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1

(0.36 g, 43% yield over two steps) as a clear colorless oil: H NMR

(500 MHz, CDCl₃) δ 7.67 (d, J = 7.5 Hz, 4H), 7.41 (t, J = 7.2 Hz,

2H), 7.37 (t, J = 7.6 Hz, 4H), 7.24, (t, J = 8.2 Hz, 2H), 6.91 (t, J = 7.3

Hz, 1H), 6.85 (d, J = 7.9 Hz, 2H), 5.77 (t, J = 6.5 Hz, 1H), 4.60 (dq, J

= 6.7, 14.1 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.40 (q, J = 6.0 Hz, 2H),

3.28 (m, 1H), 3.21 (m, 1H), 2.35−2.25 (m, 4H), 2.07 (dd, J = 9.3,

15.8 Hz, 1H), 1.98 (dt, J = 4.2, 12.3 Hz, 1H), 1.92−1.86 (m, 3H), 1.81

(q, J = 6.8 Hz, 2H), 1.71−1.56 (m, 5H), 1.06 (s, 9H), 1.01 (d, J = 6.8

Hz, 3H), 0.94 (t, J = 7.8 Hz, 9H), 0.60 (q, J = 7.6 Hz, 6H); ¹³C NMR

(125 MHz, CDCl₃) δ 172.1 (C), 158.9 (C), 145.7 (C), 135.9 (CH),

134.0 (C), 129.9 (CH), 129.6 (CH), 127.9 (CH), 122.0 (CH), 120.7

(CH), 115.1 (CH), 88.9 (C), 65.1 (CH₂), 64.1 (CH₂), 46.7 (CH₂),

46.1 (CH₂), 45.7 (CH₂), 44.2 (CH), 38.6 (CH₂), 34.0 (CH₂), 33.8

(CH₂), 30.2 (CH₃), 27.2 (CH), 26.4 (CH₂), 25.9 (CH₂), 24.7 (CH₂),

22.6 (CH₃), 19.5 (C), 7.6 (CH₃), 7.0 (CH₂); IR (thin ﬁlm) 3067,

2952, 2872, 1643, 1599 cm⁻¹; HRMS-ESI (m/z) [M + Na]⁺calcd for

C₄₆H₆₇O₄Si₂NNa, 776.4506; found, 776.4487.

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́

(e) Merchan, F. L.; Merino, P.; Tejero, T. Glycoconjugate J. 1997, 14,

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F. D. Angew Chem., Int. Ed. 2007, 46, 7671−7673. (b) Kozak, J. A.;

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C. J. Org. Chem. 2010, 75, 3420−3426. (g) Ramharter, J.; Weinstabl, J.;

Mulzer, J. J. Am. Chem. Soc. 2010, 132, 14338−14339. (h) Yang, Y.-R.;

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3690. (i) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H.

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ASSOCIATED CONTENT

■

S

* Supporting Information

Copies of ¹H and ¹³C NMR spectra of new compounds (PDF)

and CIF ﬁles for compounds 33, 39, and 59. This material is

available free of charge via the Internet at http://pubs.acs.org.

(9) Hirst, G. C.; Johnson, T. O., Jr.; Overman, L. E. J. Am. Chem. Soc.

1993, 115, 2992−2993.

AUTHOR INFORMATION

Corresponding Author

*E-mail: leoverma@uci.edu.

■

(10) For a review of pinacol-terminated cyclizations in natural

product syntheses, see: (a) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem.

Rev. 2011, 111, 7523−7556. (b) Overman, L. E.; Pennington, L. D. J.

Org. Chem. 2003, 68, 7143−7157.

Present Addresses

^†Department of Chemistry, University of California, Berkeley,

California, 94720-1460.

(11) Hall, D. G.; Deslongchamps, P. J. Org. Chem. 1995, 60, 7796−

7814.

^‡WestCHEM School of Chemistry, University of Glasgow,

Glasgow, United Kingdom, G12 8QQ.

(12) (a) Hutzinger, M. W.; Oehlschlager, A. C. J. Org. Chem. 1995,

60, 4595−4601. (b) Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron

Lett. 1981, 22, 4905−4908.

Notes

(13) For reviews, see: (a) Mitsunobu, O. Synthesis 1981, 1−28.

(b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P.

P. Chem. Rev. 2009, 109, 2551−2651.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

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This manuscript is dedicated to Robert Ireland in memory of

his many contributions to organic synthesis and its pedagogy.

This research was supported by the NIH Neurological

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dx.doi.org/10.1021/jo300872y | J. Org. Chem. XXXX, XXX, XXX−XXX

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Total synthesis of (+)-Sieboldine a: Evolution of a pinacol-terminated cyclization strategy

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