Silyl enol ether Prins cyclization: Diastereoselective formation of substituted tetrahydropyran-4-ones

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Open Access on 09/09/2015

Silyl Enol Ether Prins Cyclization: Diastereoselective Formation of

Substituted Tetrahydropyran-4-ones

Gidget C. Tay, Chloe Y. Huang, and Scott D. Rychnovsky*

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

S

* Supporting Information

ABSTRACT: A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this

methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether

and an aldehyde to aﬀord substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the

modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up

to 97% yield and >95:5 dr. The cyclization step forms new carbon−carbon and carbon−oxygen bonds, as well as a quaternary

center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans.

INTRODUCTION

■

Substituted tetrahydropyrans and tetrahydropyranones are a

common motif in numerous biologically active natural products

(Figure 1).¹Synthesis of tetrahydropyran-4-ones (THPOs),

Figure 2. Common methods for forming tetrahydropyran-4-ones and

the silyl enol ether Prins cyclization method discussed in this paper.

For example, the hetero-Diels−Alder cycloaddition requires

electronic matching of the diene and dienophile.⁴The Petasis−

Ferrier rearrangement precursor is often obtained through

Figure 1. Biologically active natural products containing highly

substituted tetrahydropyran rings, such as pederin,¹⁰psymberin,¹¹

kendomycin,¹²and lasonolide A.¹³

oleﬁnation of an ester; this route would be incompatible with

other unprotected carbonyl groups in the substrate. Because

tetrahydropyrans are prevalent in natural products, the

development of ﬂexible new routes for their synthesis is an

important goal. We present a full account of the silyl enol ether

Prins cyclization for the synthesis of tetrahydropyranones.⁹

Synthetic methods focused on the preparation of tetrahy-

dropyran-4-ones with an enol ether and oxocarbenium ion have

followed by reduction of the ketone, has been used to form 4-

hydroxytetrahydropyran rings.²Tetrahydropyranones are com-

monly prepared with carbon−carbon or carbon−oxygen bond

forming reactions by aldol-type cyclization,³hetero-Diels−

Alder cycloaddition,⁴Japp−Maitland reaction,⁵oxa-Michael

condensation,⁶and Petasis−Ferrier rearrangement⁷(Figure

2).⁸These various methods have their strengths and limitations.

Received: July 15, 2014

Published: September 9, 2014

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been reported.^14,15Recently, we reported the diastereoselective

synthesis of 2,6-cis-tetrahydropyran-4-ones through cyclization

between a hydroxy silyl enol ether and an aldehyde.⁹This

method was used in the total synthesis of cyanolide A.¹⁶

Intrigued by the diastereoselectivity and functional group

tolerance of this silyl enol ether Prins cyclization,¹⁷we decided

to develop the method further by exploring the scope with

diﬀerent substitution patterns. An overview of the tetrahy-

dropyran-4-one synthesis is shown in Scheme 1. The synthesis

THPO 5 with high diastereoselectivity. The thermodynamically

favored cyclization is very eﬀective for introducing quaternary

centers at the C-3 position of the THPO. This method allows

for the formation of highly functionalized tetrahydropyran-4-

ones with substituents at each carbon atom of the THPO core.

RESULTS

■

The syntheses of a variety of Weinreb amides are presented in

Table 1. The formation of ester 7 occurred in satisfactory yields

by reacting the ketene, prepared in situ by deprotonation of the

acid chloride, with silyl ketene acetal 6.²¹Dimethyl ketene

(entry 2), which comes from the least acidic acid chloride, was

prepared by zinc reduction of 2-bromo-2-methylpropionyl

bromide.²²In entry 3, no desired ester was observed due to the

instability of the unsubstituted silyl enol ether product. The

acid chloride precursors from entries 5 and 6 were prepared

from the nonsteroidal anti-inﬂammatory drugs, ibuprofen and

naproxen, respectively, demonstrating that motifs present in

biologically active molecules can be incorporated into the

THPO using this method. Acid chlorides with an aryl group for

R²and a proton for R³generally led to low yields of ester 7

(entry 7); these esters were not taken further in the sequence.

The transformation to ester 7 was highly diastereoselective;

ketene acetal 6 underwent nucleophilic addition at the less

hindered face of the ketene. Only a single alkene isomer of

Weinreb amide 8 was isolated. The conﬁguration with the

larger R²substituent cis to the −OTBS group was favored in

each case.

Scheme 1. General Overview of This Method for

Diastereoselective THPO Synthesis²⁰

began with deprotonation of an acid chloride using triethyl-

amine to form a ketene in situ that, when reacted with silyl

ketene acetal 1,¹⁸produced ester 2. Ester 2 was transformed to

Weinreb amide 3.¹⁹Addition of a nucleophilic organometallic

reagent and subsequent reduction of the resulting ketone

aﬀorded alcohol 4. Silyl enol ether Prins cyclization of alcohol 4

with a Lewis acid activated aldehyde produced the desired

Weinreb amide 10 underwent nucleophilic addition with a

variety of Grignard and organolithium reagents to yield ketone

14 (Table 2). Direct reduction of the crude allylic ketone

Table 1. Preparation of Weinreb Amides 9−13

a

The dimethylketene reagent was prepared in situ by zinc reduction of 2-bromo-2-methylpropionyl bromide.

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Table 2. Preparation of Hydroxy Silyl Enol Ether from

Amide 10

Table 3. Preparation of the Hydroxy Silyl Enol Ether with

Varying R²and R³Substituents

a

Crude ketone was directly reduced with DIBAL-H. The alcohol was

b

c

obtained through a: NaBH₄reduction, NaBH₄reduction with

d

e

Et₂B(OMe) additive, double addition to ester 7, Luche reduction,

a

NaBH₄reduction.

f

CBS reduction.

(entry 1) was necessary to prevent isomerization of the double

bond into conjugation with the ketone. Reduction of a vinyl

ketone (entry 6) could be achieved in high yields with a Luche

reduction or enantioselectively with a CBS reduction.²³The β-

oxy-alkyllithium reagent²⁴from entry 4 was enantioenriched

and syn-selective reduction²⁵of the ketone resulted in diol 19 as

a single diastereomer. Tertiary alcohol 20 was obtained by

double addition of methylmagnesium bromide into ester 7 (R²

and R³= Me). Modest yields were observed with smaller

nucleophiles (entry 7), possibly due to deprotection of the

product by nucleophilic attack on the silyl group.²⁶A wide

variety of hydroxy silyl enol ethers were prepared by this

sequence.

acetonitrile (MeCN) as the solvent resulted in similar yields,

66% and 65%, respectively, after 4 h. Dichloromethane was

selected as the solvent of choice due to its ease of removal after

the cyclization. Reaction concentrations were also examined,

with concentrations of 0.1, 0.4, and 1.0 M of alcohol 17

evaluated (entries 4−6). It was found that the most

concentrated mixture, 1.0 M, gave the highest yield of 69%.

Optimization of temperature, equivalents of the aldehyde, and

equivalents of Lewis acid were conducted using design of

experiments (DoE).²⁷Yields were improved at lower temper-

atures: reactions at −95 °C gave the slightly higher yields but

were much slower. Cyclization reactions shown herein were

conducted at −78 °C for ease of operation. Excess BF₃·OEt₂

relative to the aldehyde lowered yields (entry 10), and a 1:1

molar ratio was found to be optimal. It was found that a large

excess of both BF₃·OEt₂and aldehyde minimally aﬀected the

yields (entry 9). Dropwise addition of hydroxyl silyl enol ether

17 to a solution of aldehyde and Lewis acid lowered yields

(entry 16). In the optimized conditions for the cyclization

reaction, it was run at −78 °C in 1.0 M dichloromethane with

1.5 equiv of both the Lewis acid and the aldehyde relative to the

alcohol.

Transformation of Weinreb amides with varying R²and R³

substituents to the corresponding alcohols is shown in Table 3.

Addition of Grignard or organolithium reagents to Weinreb

amide 8 gave the desired ketone 23. When treated with

organolithium reagents, isomerization of less substituted silyl

enol ether 9 to form the conjugated silyl enol ether was

observed as a side reaction. Reduction of ketone 23 with

sodium borohydride occurred in good yield to give racemic

hydroxyl silyl enol ethers 25−32.

In our previous publication, cyclization of hydroxyl silyl enol

ethers with aromatic and conjugated aldehydes was shown to

be most eﬀective with BF₃·OEt₂, while TMSOTf was necessary

for aliphatic aldehydes.⁹A new optimization of the THPO

cyclization reaction was performed with hydroxyl silyl enol

ether 17, benzaldehyde, and BF₃·OEt₂(Table 4). It was

determined that a polar solvent was necessary for reactivity

(entries 1−3). No product was observed when the reaction was

run in toluene (entry 2). Dichloromethane (DCM) or

The tetrahydropyran-4-one synthesis with aromatic alde-

hydes is shown in Table 5. Electron-rich aldehydes gave higher

yields than electron-poor aldehydes (entries 1−4), possibly due

to enhanced stabilization of oxocarbenium ion intermediate 33.

This cyclization reaction is compatible with heterocycles such

as furans (entry 6) and benzothiophenes (entry 7), but no

reaction occurred with sulfonate-protected indole carboxalde-

hyde²⁸(entry 5). Indole carboxaldehyde²⁹and 2-pyridine-

carboxaldehyde were also tested as the aldehyde partner in the

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Table 4. Optimization of the THPO Cyclization Reaction

a

entry

temp (°C)

equiv of PhCHO

equiv of BF₃·OEt₂

solvent

conc (M)

% yield

1

2

−78

−95

−40

−78

3.0

4.5

1.5

4.5

1.5

4.5

1.5

4.5

1.5

3.0

2.0

1.5

4.5

1.5

4.5

1.5

DCM

toluene

MeCN

DCM

0.4

1.0

0.5

0.1

0.4

1.0

0.5

66

no rxn

65

3

4

69

5

46

6

48

7

71

8

71

9

74

10

11

12

13

14

15

63

51

49

50

62

69

b

16

−78

DCM

b

48

a

1

Yields were determined by H NMR spectroscopy with respect to mesitylene internal standard. A diluted solution of silyl enol ether was added

dropwise to a solution of aldehyde and BF₃·OEt₂at −78 °C.

cyclization, but only starting material was recovered. Irrever-

sible binding of the Lewis acid to the nitrogen atom may cause

the lack of reactivity. The reaction conditions are tolerant of

free aliphatic and aromatic alcohols (entries 8 and 9), esters

(entry 4), and aryl halides (entry 3). Only the THPO 2,6-cis

diastereomer was observed when starting with hydroxyl silyl

enol ether 15.

The scalability of the cyclization reaction was explored with

alcohol 17 (eq 1). Reacting crotonaldehyde with 1.9 g (6.7

mmol) of alcohol 17 produced THPO 46 in 73% yield as a

single diastereomer. The reaction was completed after 4 h at

−78 °C. This result indicates that no signiﬁcant loss in yield

was observed at a scale useful in multistep syntheses.

The cyclization reaction also was compatible with aliphatic

and conjugated aldehydes (Table 6). Conjugated aldehydes are

especially good substrates and generated clean products in high

yields (entries 3 and 6). These aldehydes are expected to form

resonance stabilized oxocarbenium ion intermediates, which

appear to facilitate the cyclization. The diﬀerence between

aliphatic and conjugated aldehydes is especially apparent when

comparing entries 5 and 6. The reaction is tolerant of Boc-

protected amines (entry 2). Tertiary alcohol 20 resulted in

THPO 50 with two tetrasubstituted carbons (entry 8). A silyl-

protected alcohol (entry 1) was partially deprotected under the

cyclization reaction conditions. Optimized procedures were

found to allow for deprotection or retention of the silyl-

protected alcohols. Full deprotection of the silyl group was

achieved by removing the reaction mixture from its −78 °C

bath and stirring for a few minutes before quenching with

sodium bicarbonate. Retention of the silyl group was achieved

by adding a bulky base additive, 2,6-di-tert-butyl-4-methyl-

pyridine, to neutralize the triﬂic acid formed during the

reaction. Cyclization of hydroxy silyl enol ether 22 with

crotonaldehyde led to a 4.1:1.0 ratio of the 2,6-cis and 2,6-trans

THPO product. Cyclizations with a variety of aldehydes and

alcohols 16−21 resulted in only a single diastereomer. The

origin of the diastereoselectivity in the cyclization with hydroxy

silyl enol ether 22 will be considered in the Discussion section.

Enantiomerically enriched THPOs can be synthesized using

this route (Scheme 2).⁹THPO 48 was synthesized from

enantiomerically enriched alcohol precursor 19. The enantio-

meric ratio of thioether 53, obtained from epoxide opening

with thiophenol, was 98.0:2.0. The enantiomeric ratio of

THPO 48 was 97.9:2.1, and the enantiospeciﬁcity of the

reaction was >99%, demonstrating that essentially no optical

activity was lost during the cyclization reaction.³⁰

The tetrahydropyran-4-ones described to this point have

been dimethyl substituted at the C-3 position. Table 7 shows

examples with a variety of diﬀerent substituents on the silyl

enol ether. These silyl enol ethers often resulted in a mixture of

2,6-cis and 2,6-trans diastereomers; when the C-3 was dimethyl

substituted, usually only a single diastereomer was observed by

¹H NMR. The cyclization reactions with unsymmetric silyl enol

ethers form two new stereocenters during the cyclizations, one

of them at a quaternary carbon. Substituents R³= methyl and

R²= hydrogen (entries 1−4) were examined because many

THP(O) natural products contain a single methyl group at the

C-3 position.¹Lower THPO yields were obtained with hydroxy

silyl enol ether 25 because this monosubstituted silyl enol ether

underwent the competitive intermolecular Mukaiyama aldol

addition, presumably because 25 is less sterically hindered at

the enol ether moiety than other hydroxy silyl enol ether

cyclization partners. The cyclization was compatible with ester

groups (entry 3). Alkene geometries were unchanged under the

cyclization reaction conditions even though a conjugated

oxocarbenium ion was formed. THPO 62 was synthesized

with a 5:1 Z:E mixture of the aldehyde,³¹and the same Z:E

ratio was obtained after the reaction. Similar to THPO 52

(Table 6, entry 10), the small alkyne substituent on the alcohol

led to a loss of cis/trans diastereoselectivity (Table 7, entry 9).

Hydroxy silyl enol ethers with substituted aromatic rings

underwent cyclization successfully (entries 10 and 11).

The stereoselective outcome of the THPO cyclization

reaction was further examined with substitution at C-5. The

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Table 5. Scope of the Tetrahydropyran-4-one Synthesis with

Hydroxyl Silyl Enol Ether 15 and Aromatic Aldehydes²⁰

Table 6. Scope of the Tetrahydropyran-4-one Synthesis with

Hydroxy Silyl Enol Ether 15 and Conjugated and Aliphatic

Aldehydes²⁰

a

TMSOTf was used as the Lewis acid instead of BF₃·OEt₂.

hydroxy silyl enol ether synthesis is shown in Scheme 3. The

synthesis began with zinc reduction of 2-bromo-2-methylpro-

pionyl bromide to form dimethyl ketene in situ.²²Dimethyl

ketene added to silyl ketene acetal 66 to aﬀord ester 67, which

was transformed to Weinreb amide 68. Addition of n-

butyllithium resulted in ketone 69, and diastereoselective

reduction of 69 with L-selectride produced a mixture of anti-

alcohol 70 (major) and syn-alcohol 71 (minor). The two

diastereomers were isolated and used in separate THPO

forming reactions.

Scheme 2. Enantiomeric Ratio Is Retained Throughout the

Cyclization

Alcohol 70 underwent cyclization with crotonaldehyde to

aﬀord THPO 72 as a single diastereomer in 50% yield. All four

substituents on the six-membered ring occupied pseudo-

equatorial positions in THPO 72 (Scheme 4). Cyclization of

cis-alcohol 71 with crotonaldehyde resulted in a mixture of

diastereomers, THPO 73c and 73t. This cyclization was the

ﬁrst in which the 2,6-trans THPO was the major product and

the 2,6-cis THPO was the minor product. An explanation for

this reversal of selectivity is presented in the Discussion section.

DISCUSSION

■

The proposed mechanism for the silyl enol ether cyclization is

outlined in Scheme 5. The reaction begins with formation of

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Table 7. Scope of the Tetrahydropyran-4-one Synthesis with

Diﬀerent Aldehydes and Alcohols, with Varying Substituents

at the C-3 Position

Scheme 3. Formation of the Hydroxy Silyl Enol Ether with

R¹= Methyl for Substitution at C-5 in the Resulting

Tetrahydropyran-4-one

Scheme 4. Tetrahydropyran-4-one Synthesis with

Substitution at C-5

Scheme 5. Proposed Mechanism for the Silyl Enol Ether

Prins Cyclization

favors one of the two possible chairlike transitions states. The

quaternary stereocenter at C-3 arises from the Z-conﬁguration

of the enol ether in the chairlike transition state. The sterically

biased ketene addition (Table 3) results in the less bulky

substituent at R³in enol ether 24; the cyclization reactions

place this substituent in the axial position at C-3 in the new

tetrahydropyran-4-one ring. The stereochemical outcome of the

silyl enol ether Prins cyclization is consistent with the expected

chairlike transition state.

Silyl enol ether 22 (Table 6, entry 10) leads to a large

amount of the 2,6-trans THPO product in the cyclization with

crotonaldehyde. The diastereoselectivity of the major product

in the cyclization results from the alkyne and crotonaldehyde

alkene being placed in the lower energy pseudo-equatorial

a

TMSOTf was used as the Lewis acid instead of BF₃·OEt₂.

Abbreviation: PMP = p-methoxyphenyl.

the hemiacetal 74 from the alcohol and the aldehyde, followed

by expulsion of the leaving group, to generate the key

oxocarbenium ion intermediate 76. These steps are presumably

promoted by the Lewis acid. Irreversible³²nucleophilic attack

of the silyl enol ether onto the oxocarbenium ion forms the

desired THPO 54. A chairlike conformation with E-

conﬁguration at the oxocarbenium³³is expected in the

cyclization transition state. The conﬁguration of the major

product is consistent with this transition state geometry.

Placement of the R⁴groups in the pseudo-equatorial position

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position in the chairlike reactive conformer 77 (Scheme 6).

was observed as a single diastereomer with a 2,6-cis

conﬁguration. When there was a methyl group and proton on

C-3, a 7.0:1.0 cis:trans diastereomeric ratio was obtained. With

aryl and methyl substitution on C-3, diastereoselectivity further

diminished to about a 3:1 ratio of cis:trans diastereomers. Note

that, in all of these examples, the larger group occupied the

equatorial position at C-3 in the 2,6-cis product. Interestingly,

the minor diastereomer in this cyclization reaction is not the

same one reported for similar cyclizations, an oxonia-cope Prins

reaction.³⁵Dalgard and Rychnovsky reported¹⁴the C-3 epimer

of the 2,6-cis product as the minor diastereomer in their

systems and suggest that the minor product could arise from E/

Z isomerization of the starting silyl enol ether³⁶or a competing

chair−boat cyclization.^1aOur minor diastereomer had a

diﬀerent relative stereochemical relationship between C-2 and

C-6 and retained relative stereochemistry between C-2 and C-

3; we proposed that the minor diastereomer would arise

through the diastereomeric chairlike transition state 80 (Figure

3). One would expect that, as the size of the R²group increases,

the steric interactions between the R²substituent and the

−OTBS and crotyl groups in TS 79 would increase. TS 80

places the R²substituent axial, relieving steric interactions

between the crotyl group, and becomes more favorable as the

size of the R²substituent relative to the R³substituent

increases. Thus, increasing the diﬀerence in size between the

large R²and small R³subsitutents would lead to more of the

2,6-trans diastereomer, which is the observed outcome in this

series.

When the R⁴substituent is sterically small, in this case an

Scheme 6. Small R⁴Groups Resulted in Diminished

Diastereoselectivity during Cyclization

alkyne, the energetic cost for it to occupy a pseudo-axial

position in the reactive conformation 78 is modest, and the

cyclization results in a signiﬁcant amount of the 2,6-trans

diastereomer 52t. For relative size comparison, an alkyne group

has an A value of 0.41 kcal/mol and a methyl group has an A

value of 1.7 kcal/mol in a cyclohexane ring.³⁴The 2,6-trans

diastereomer was obtained when the small alkyne substituent

occupied a pseudo-axial position in the chairlike transition state.

The 2,6-cis/trans selectivity was inﬂuenced by the sub-

stituents on the C-3 position. The data are summarized in

Figure 3. When the substituents on C-3 are identical, THPO 46

Introducing a new stereogenic center at C-5 inﬂuenced the

selectivity of the cyclization (Scheme 4 and Figure 4). When

Figure 4. Proposed chairlike transition states to explain the

diastereoselectivity of THPO 72, 73c, and 73t. Full reaction conditions

are shown in Scheme 4.

alcohol 70 reacted with crotonaldehyde, it likely proceeded

through chairlike transition state 81 where all possible

substituents adopted pseudo-equatorial positions (Figure 4).

In contrast, the cyclization geometry from the reaction of

alcohol 71 and crotonaldehyde must have at least one

substituent axial. Disfavored transition state 82 has the C-5

methyl group in an axial conﬁguration with a 1,3-diaxial

orientation to a C-3 methyl group. In the preferred transition

state 83, the n-butyl group at C-6 occupies an axial position.

Both of these transition states have destabilizing interactions,

and the result is modest selectivity in the cyclization for 73t.

Apparently, placing the n-butyl group axial is preferable to the

Figure 3. Diastereoselective trend caused by varying the substituents

at C-3 is shown with the major 2,6-cis isomer drawn. The minor

diastereomer has a 2,6-trans relationship. The relative stereochemistry

between C-2 and C-3 remained the same for both diastereomers.

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chromatography (5:1:94 Et₂O:Et₃N:hexanes) of the crude residue

diaxial interaction between the methyl groups in the transition

state, leading to 73c. The lowest energy chair conformer for

each is product shown in Figure 4.³⁷

aﬀorded 105 as a clear colorless oil (2.5 g, 77%): R_f= 0.49 (10% Et₂O/

1

hexanes); H NMR (500 MHz, CDCl₃) δ 4.66 (q, J = 6.6 Hz, 1H),

4.15 (q, J = 7.1 Hz, 2H), 3.02 (s 1H), 1.56 (d, J = 6.7 Hz, 3H), 1.26 (t,

J = 7.1 Hz, 3H), 0.94 (s, 9H), 0.14 (s, 6H); ¹³C NMR (126 MHz,

CDCl₃) δ 170.8, 144.4, 106.4, 60.9, 43.0, 25.9, 18.4, 14.3, 11.19, −3.9;

IR (thin ﬁlm) 2958, 2931, 2859, 1742, 1682 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₁₃H₂₆O₃SiNa [M + Na]⁺281.1549, found

281.1542

CONCLUSION

■

The silyl enol ether Prins reaction is highly diastereoselective

with most substrates, and the major products are consistent

with cyclizations through chairlike transition states. The

reaction is tolerant of a variety of functional groups and can

form a quaternary center on the THPO with good

diastereoselectivity. This method allows for the synthesis of

substituted THPOs with substitution demonstrated at every

carbon atom in the ring. The ﬂexibility of this silyl enol ether

Prins method makes it a useful tool for synthesizing diverse

THPO cores found in natural products or medicinal chemistry

targets.

(Z)-Ethyl 3-(tert-Butyldimethylsilyloxy)-4-phenylpent-3-

enoate (106). A sample of silyl ketene acetal 6 (300 mg, 1.48

mmol) and 2-phenylpropanoyl (424 mg, 2.52 mmol) was converted to

106 following the general procedures for ester 7 formation.

Puriﬁcation by column chromatography (5:1:94 Et₂O:Et₃N:hexanes)

of the crude residue aﬀorded 106 as a clear colorless oil (400 mg,

1

81%): R_f= 0.43 (5% Et₂O/hexanes); H NMR (500 MHz, CDCl₃) δ

EXPERIMENTAL SECTION

■

7.31−7.25 (m, 4H), 7.15 (t, J = 7.5 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H),

3.29 (s, 2H), 1.96 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.73 (s, 9H), −0.25

(s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 170.5, 141.9, 139.8, 129.4,

127.9, 126.1, 118.1, 60.9, 39.8, 25.7, 19.6, 18.1, 14.4, −4.5; IR (thin

ﬁlm) 2956, 2930, 2896, 2858, 1738, 1660 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₁₉H₃₀O₃SiNa [M + Na]⁺357.1862, found 357.1863.

General Information. All air- and moisture-sensitive reactions

were carried out in ﬂame- or oven-dried ﬂasks equipped with a

magnetic stir bar under an argon atmosphere. All commercially

available reagents were used as received unless stated otherwise. Zinc

dust was activated by sequential washing with 1 M HCl, water, and

ethanol and was then dried under reduced pressure. BF₃·OEt₂was

distilled neat under an argon atmosphere. TMSOTf was distilled over

CaH₂under reduced pressure. Thin-layer chromatography (TLC) was

performed on 250 μm layer silica gel plates, and developed plates were

visualized by UV light, p-anisaldehyde, potassium permanganate, or

vanillin.

(Z)-Ethyl 3-(tert-Butyldimethylsilyloxy)-4-(4-isobutylphenyl)-

pent-3-enoate (107). A sample of silyl ketene acetal 6 (267 mg, 1.32

mmol) and 2-(4-isobutylphenyl)propanoyl chloride (504 mg, 2.24

mmol) was converted to 107 following the general procedures for

ester 7 formation. Puriﬁcation by column chromatography (15:1:84

EtOAc:Et₃N:hexanes) of the crude residue aﬀorded 107 as a clear

¹H NMR spectra were recorded at 500 MHz, and ¹³C NMR spectra

were recorded at 126 MHz. Chemical shifts (δ) were referenced to

either TMS or the residual solvent peak. The ¹H NMR spectra data are

presented as follows: chemical shift, multiplicity (s = singlet, d =

doublet, t = triplet, q = quartet, m = multiplet, app. = apparent, br. =

broad), coupling constant(s) in hertz (Hz), and integration. Infrared

spectra were recorded on NaCl plates. High-resolution mass

spectrometry was performed using ESI-TOF. Structures not numbered

in the article were numbered consecutively starting with 101.

Compounds 101−104, 10, 16−20, 35−39, 41, 44, 47, 48, 50, and

53 were formed using known procedures.⁹

1

colorless oil (362 mg, 70%): R_f= 0.67 (15% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.20 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 10.5

Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.28 (s, 2H), 2.44 (d, J = 7.5 Hz,

2H), 1.95 (s, 3H), 1.84 (app. septet, J = 6.8 Hz, 1H), 1.30 (t, J = 7.2

Hz, 3H), 0.89 (d, J = 7.0 Hz, 6H), 0.73 (s, 9H), −0.25 (s, 6H); ¹³C

NMR (126 MHz, CDCl₃) δ 170.9, 139.8, 139.7, 139.4, 129.3, 128.9,

118.3, 61.1, 45.6, 40.1, 30.7, 26.0, 22.7, 19.9, 18.4, 14.6, −4.2; IR (thin

ﬁlm) 2955, 2929, 2093, 2858, 1741, 1658 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₂₃H₃₈O₃SiNa [M + Na]⁺413.2488, found 413.2486.

(Z)-Ethyl 3-(tert-Butyldimethylsilyloxy)-4-(6-methoxynaph-

thalen-2-yl)pent-3-enoate (108). Triethylamine (0.31 mL, 2.22

mmol, 1.70 equiv) was added dropwise to a solution of 2-(6-

methoxynaphthalen-2-yl)propanoyl chloride (552 mg, 2.22 mmol, 1.70

equiv) in dry THF (0.6 M relative to 6) at 0 °C. The mixture turned

into a white sludge due to the formation of Et₃N·HCl salt. Silyl ketene

acetal 6 (264 mg, 1.30 mmol, 1.00 equiv) was added to the mixture,

and the solution was stirred overnight slowly, warming from 0 °C to

room temperature. A second portion of triethylamine (0.31 mL, 2.22

mmol, 1.70 equiv) was added dropwise to the solution at rt. The

reaction was monitored by TLC, and once starting material was

consumed, the reaction was quenched with saturated aqueous

NaHCO₃(10 mL). The mixture was extracted with Et₂O (3 × 10

mL). The organic layers were combined, dried over anhydrous

MgSO₄, and ﬁltered, and the resulting solution was concentrated in

vacuo. Puriﬁcation by column chromatography (10:1:89 EtOA-

c:Et₃N:hexanes) of the crude residue aﬀorded 108 as a clear colorless

General Procedures to Form Ester 7. Triethylamine (1.7 equiv)

was added dropwise to a solution of acid chloride (1.7 equiv) in dry

THF (0.6 M relative to 6) at 0 °C. The mixture turned into a white

sludge due to the formation of Et₃NCl salt. Silyl ketene acetal 6 (1.0

equiv) was added to the mixture, and the solution was stirred

overnight, slowly warming from 0 °C to room temperature. The

reaction was quenched with saturated aqueous NaHCO₃, and the

mixture was extracted with Et₂O (3×). The organic layer was dried

over anhydrous MgSO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by column chromatography of the crude residue produced

ethyl ester 7.

(Z)-Ethyl 3-(tert-Butyldimethylsilyloxy)pent-3-enoate (105).

A sample of silyl ketene acetal 6 (2.50 g, 12.4 mmol) and propanoyl

chloride (1.95 g, 21.1 mmol) was converted to 105 following the

general procedures for ester 7 formation. Puriﬁcation by column

1

oil (471 mg. 87%): R_f= 0.7 (10% EtOAc/hexanes); H NMR (500

MHz, CDCl₃) δ 7.70 (br. s, 1H), 7.65 (dd, J = 9.0, 7.0 Hz, 2H), 7.44

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Article

(dd, J = 8.5, 1.5 Hz, 1H), 7.11−7.09 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H),

3.92 (s, 3H), 3.34 (s, 2H), 2.04 (s, 3H), 1.32 (t, J = 7.25 Hz, 3H), 0.71

(s, 9H), −0.30 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 170.8, 157.7,

140.3, 137.3, 133.4, 129.7, 129.1, 128.8, 127.9, 126.3, 118.8, 118.1,

105.9, 61.2, 55.6, 40.2, 26.0, 19.8, 18.3, 14.7, −4.2; IR (thin ﬁlm) 2931,

2956, 2897, 2857, 1739, 1605 cm⁻¹; HRMS (ES/MeOH) m/z calcd

for C₂₄H₃₄O₄SiNa [M + Na]⁺437.2124, found 437.2112.

mixture was stirred for 6 h at rt. Four portions of 2.0 M i-PrMgCl

(each portion: 0.30 mL, 0.60 mmol, 2.0 equiv) in dry THF and

Me(MeO)NH·HCl (each portion: 29 mg, 0.30 mmol, 1.0 equiv) were

added to the solution at rt in 6 h intervals. The reaction was monitored

by TLC, and once starting material was consumed, the reaction was

quenched with saturated aqueous NH₄Cl (3 mL). The mixture was

extracted with Et₂O (3 × 5 mL). The organic layers were combined,

dried over anhydrous MgSO₄, and ﬁltered, and the resulting solution

was concentrated in vacuo. Puriﬁcation by column chromatography

(15:1:84 EtOAc:Et₃N:hexanes) of the crude residue aﬀorded Weinreb

amide 12 as a clear colorless oil (92 mg. 76%): R_f= 0.17 (15% EtOAc/

1

(Z)-Ethyl 3-(tert-Butyldimethylsilyloxy)-4-phenylbut-3-

enoate (109). A sample of silyl ketene acetal 6 (200 mg, 1.00

mmol) and phenylacetyl chloride (260 mg, 1.68 mmol) was converted

to 109 following the general procedures for ester 7 formation.

Puriﬁcation by column chromatography (20:1:79 EtOA-

c:Et₃N:hexanes) of the crude residue aﬀorded 109 as a clear colorless

hexanes); H NMR (500 MHz, CDCl₃) δ 7.23 (d, J = 8.0 Hz, 2H),

7.04 (d, J = 8.0 Hz, 2H), 3.74 (s, 3H), 3.43 (s, 2H), 3.22 (s, 3H), 2.43

(d, J = 7.2 Hz, 2H), 1.94 (s, 3H), 1.83 (app. septet, J = 6.7 Hz, 1H),

0.89 (d, J = 6.6 Hz, 6H), 0.73 (s, 9H), −0.24 (s, 6H); ¹³C NMR (126

MHz, CDCl₃) δ 171.5, 140.0, 139.4 (2), 129.1, 128.6, 117.7, 61.4, 45.3,

38.3, 32.6, 30.4, 25.9, 22.4, 19.5, 18.1, −4.4; IR (thin ﬁlm) 2954, 2930,

2857, 1677 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₂₃H₃₉NO₃SiNa

[M + Na]⁺428.2597, found 428.2599.

1

oil (98 mg, 31%): R_f= 0.65 (20% EtOAc/hexanes); H NMR (500

MHz, CDCl₃) δ 7.48 (d, J = 7.5 Hz, 2H), 7.25 (app. t, J = 7.8 Hz, 2H),

7.13 (app. t, J = 7.5 Hz, 1H), 5.58 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.2

(s, 2H), 1.29 (t, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.06 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 170.2, 145.5, 136.0, 128.7, 127.9, 126.0, 111.6,

61.0, 43.8, 25.8, 18.3, 14.3, −3.8; IR (thin ﬁlm) 2931, 2858, 1740, 1654

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₈H₂₈O₃SiNa [M + Na]⁺

343.1705, found 343.1712.

(Z)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-4-(6-methoxy-

naphthalen-2-yl)-N-methylpent-3-enamide (13). A solution of

2.0 M i-PrMgCl (0.48 mL, 0.96 mmol, 2.0 equiv) in dry THF was

added dropwise to a two-neck ﬂask containing ethyl ester 108 (200

mg, 0.48 mmol, 1.0 equiv) and Me(MeO)NH·HCl (47 mg, 0.48

mmol, 1.0 equiv) in dry THF (2 mL) and dry toluene (2 mL) at 0 °C.

The mixture was stirred for 7 h, slowly warming to rt. A second

portion of 2.0 M i-PrMgCl (0.48 mL, 0.96 mmol, 2.0 equiv) in dry

THF and Me(MeO)NH·HCl (47 mg, 0.48 mmol, 1.0 equiv) was

added to the solution and stirred overnight at rt. A third portion of 2.0

M i-PrMgCl (0.48 mL, 0.96 mmol, 2.0 equiv) in dry THF and

Me(MeO)NH·HCl (47 mg, 0.48 mmol, 1.0 equiv) was added to the

solution. The reaction was monitored by TLC, and once starting

material was consumed, the reaction was quenched with saturated

aqueous NH₄Cl (20 mL). The mixture was extracted with EtOAc (5 ×

20 mL). The organic layers were combined, dried over anhydrous

MgSO₄, and ﬁltered, and the resulting solution was concentrated in

vacuo. Puriﬁcation by column chromatography (20:1:79 EtOA-

c:Et₃N:hexanes) of the crude residue aﬀorded Weinreb amide 13 as

a clear colorless oil (183 mg. 90%): R_f= 0.55 (20% EtOAc/hexanes);

¹H NMR (500 MHz, CDCl₃) δ 7.74 (br. s, 1H), 7.65 (app. dd, J = 8.8,

General Procedures To Form Weinreb Amide 8.¹⁹A solution

of 2.0 M i-PrMgCl (2.4 equiv) in dry THF was added dropwise to a

solution of ethyl ester 7 (1.0 equiv) and Me(MeO)NH·HCl (1.2

equiv) in dry THF (0.12 M relative to 7) at −20 °C. The mixture was

stirred at −20 °C for 2 h, and the reaction was then quenched with

saturated aqueous NH₄Cl. The mixture was extracted with Et₂O (3×).

The organic layers were combined, dried over anhydrous MgSO₄, and

ﬁltered, and the resulting solution was concentrated in vacuo.

Puriﬁcation by column chromatography of the crude residue aﬀorded

Weinreb amide 8.

(Z)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methylpent-

3-enamide (9). A sample of 258 mg of ester 105 (1.0 mmol) was

converted to 9 following the general procedures for Weinreb amide 8

formation; the combined organic layers were dried over anhydrous

Na₂SO₄instead of MgSO₄. Puriﬁcation by column chromatography

(20:1:79 EtOAc:Et₃N:hexanes) of the crude residue aﬀorded 9 as a

clear colorless oil (230 mg, 84%): R_f= 0.47 (20% EtOAc/hexanes); ¹H

NMR (500 MHz, CDCl₃) δ 4.52 (q, J = 6.8 Hz, 1H), 3.61 (s, 3H),

3.11 (app. s, 5H), 1.49 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H);

¹³C NMR (126 MHz, CDCl₃) δ 171.2, 144.7, 105.0, 61.2, 40.3, 32.2,

6.1 Hz, 2H), 7.5 (app. d, J = 8.5 Hz, 1H), 7.12−7.07 (m, 2H), 3.91 (s,

3H), 3.77 (s, 3H), 3.49 (s, 2H), 3.24 (s, 3H), 2.04 (s, 3H), 0.72 (s,

9H), 0.29 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 171.1, 157.3,

140.5, 137.2, 133.0, 129.4, 128.8, 128.6, 127.7, 126.0, 118.5, 117.6,

105.6, 77.4, 61.4, 55.3, 38.2, 25.8, 19.4, 18.1, −4.3; IR (thin ﬁlm) 2954,

2932, 2856, 2896, 1674, 1604 cm⁻¹; HRMS (ES/MeOH) m/z calcd

for C₂₄H₃₅NO₄SiNa [M + Na]⁺452.2233, found 452.2219.

25.7, 18.18, 10.9, −4.1; IR (thin ﬁlm) 2957, 2931, 2896, 2858, 1682

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₃H₂₇NO₃SiNa [M + Na]⁺

296.1658, found 296.1663.

General Procedures to Form Ketone 14/23 with an

Organolithium Reagent. To a ﬂask containing Weinreb amide 8/

10 (1.0 equiv) and dry THF (0.3 M) was added an organolithium

reagent (1.5 equiv) dropwise at −78 °C. The mixture was stirred for 5

h at −78 °C, and the reaction was quenched with saturated aqueous

NH₄Cl. The solution was extracted with DCM (4×). The organic

layers were combined, dried with anhydrous MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by column chromatography of the

crude residue aﬀorded ketone 14/23.

(Z)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methyl-4-

phenylpent-3-enamide (11). A sample of 843 mg of ester 106 (2.50

mmol) was converted to 11 following the general procedures for

Weinreb amide 8 formation. The amount of the 2.0 M i-PrMgCl

solution added was increased from 2.4 equiv to 3.0 equiv. The amount

of Me(MeO)NH·HCl added was increased from 1.2 equiv to 1.5

equiv. Puriﬁcation by column chromatography (20:1:79 EtOA-

c:Et₃N:hexanes) of the crude residue aﬀorded 11 as a clear colorless

1

oil (733 mg, 83%): R_f= 0.42 (20% EtOAc/hexanes); H NMR (500

General Procedures to Form Ketone 14/23 with a Grignard

Reagent. A Grignard reagent (1.5 equiv) was added dropwise to a

solution of Weinreb amide 8/10 (1.0 equiv) in dry THF (0.3 M) at 0

°C. The mixture was stirred overnight, slowly warming to room

temperature. The reaction was quenched with saturated aqueous

NH₄Cl. The mixture was extracted with EtOAc (4×). The organic

layers were combined and dried over anhydrous Na₂SO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by column chromatography of the

crude residue aﬀorded ketone 14/23.

MHz, CDCl₃) δ 7.33 (d, J = 7.3 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.14

(t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 3.44 (s, 2H), 3.22 (s, 3H), 1.96 (s,

3H), 0.73 (s, 9H), −0.24 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ

171.4, 142.1, 140.3, 129.4, 127.8, 126.0, 117.8, 61.4, 38.2, 32.6, 25.8,

19.4, 18.1, −4.4; IR (thin ﬁlm) 2955, 2930, 2895, 2857, 1682 cm⁻¹;

HRMS (ES/MeOH) m/z calcd for C₁₉H₃₁NO₃SiNa [M + Na]⁺

372.1971, found 372.1963.

(Z)-3-(tert-Butyldimethylsilyloxy)-4-(4-isobutylphenyl)-N-

methoxy-N-methylpent-3-enamide (12). A solution of 2.0 M i-

PrMgCl (0.30 mL, 0.60 mmol, 2.0 equiv) in dry THF was added

dropwise to a two-neck ﬂask containing ethyl ester 107 (116 mg, 0.30

mmol, 1.0 equiv) and Me(MeO)NH·HCl (29 mg, 0.30 mmol, 1.0

equiv) in dry THF (1.25 mL) and dry toluene (1.25 mL) at rt. The

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Article

5-(tert-Butyldimethylsilyloxy)-6-methylhepta-1,5-dien-3-

one (110). Vinylmagnesium bromide (0.87 M in THF, 1.7 mL) and

Weinreb amide 10 (100 mg, 0.348 mmol) were converted to ketone

110 following the general procedures for ketone 14 formation with a

Grignard reagent. The solution was stirred for 3 h, slowly warming to

room temperature. The mixture was extracted with DCM (3 × 5 mL)

instead of EtOAc. Puriﬁcation by column chromatography (100%

hexanes on ﬂorisil instead of Si₂O) of the crude residue aﬀorded

ketone 110 as a yellow oil (60 mg, 67%): R_f= 0.43 (100% hexanes);

¹H NMR (500 MHz, CDCl₃) δ 6.48 (dd, J = 17.5, 10.5 Hz, 1H), 6.27

of the crude residue aﬀorded ketone 113 as a clear colorless oil (129

mg, 59%): R_f= 0.44 (10% EtOAc:hexanes); H NMR (500 MHz,

1

CDCl₃) δ 4.71 (q, J = 6.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.54 (s,

2H), 3.18 (s, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H),

0.93 (s, 9H), 0.13 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 201.0,

167.6, 144.4, 108.3, 61.4, 51.8, 47.5, 25.8, 18.3, 14.2, 11.3, −3.9; IR

(thin ﬁlm) 2932, 2957, 2859, 2897, 1748, 1721, 1676 cm⁻¹; HRMS

(ES/MeOH) m/z calcd for C₁₅H₂₈O₄SiNa [M + Na]⁺323.1655,

found 323.1652.

(dd, J = 17.5, 1.4 Hz, 1H), 5.73 (dd, J = 10.6, 1.4 Hz, 1H), 3.34, (s,

2H), 1.65 (s, 3H), 1.60 (s, 3H), 0.91 (s, 9H), 0.10 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 197.1, 137.6, 135.0, 128.3, 114.2, 45.8, 25.9,

19.2, 18.3, 18.2, −3.8; IR (thin ﬁlm) 2957, 2930, 2858, 1698, 1678,

1617 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₄H₂₆O₂SiNa [M +

Na]⁺277.1600, found 277.1607.

(2Z,8Z)-3-(tert-Butyldimethylsilyloxy)undeca-2,8-dien-5-one

(114). Freshly formed (Z)-hex-3-enylmagnesium bromide (1.0 M in

THF, 2.0 mL) was added dropwise to a solution of amide 9 (365 mg,

1.30 mmol) in dry THF (4.3 mL) at 0 °C. The mixture was stirred for

6 h at 0 °C, and the reaction was quenched with saturated aqueous

NH₄Cl (10 mL). The mixture was extracted with EtOAc (3 × 10 mL).

The organic layers were combined, dried over anhydrous MgSO₄, and

ﬁltered, and the resulting solution was concentrated in vacuo.

Puriﬁcation by column chromatography (10:1:89 EtOA-

c:Et₃N:hexanes) of the crude residue aﬀorded ketone 114 as a

5-(tert-Butyldimethylsilyloxy)-6-methyl-1-phenylhept-5-en-

1-yn-3-one (111). n-BuLi (2.27 M in hexanes, 0.22 mL) was added

to a solution of phenyl acetylene (57 μL, 0.52 mmol) in dry THF (1.2

mL) at −78 °C. The mixture was stirred for 1 h; then Weinreb amide

10 (100 mg, 0.35 mmol) was added. The solution was stirred for 4 h,

slowly warming to rt. The reaction was quenched with saturated

aqueous NH₄Cl (2 mL), and the mixture was extracted with EtOAc (3

× 5 mL). The organic layers were combined, dried with anhydrous

MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by column

chromatography (5% EtOAc/hexanes) of the crude residue aﬀorded

ketone 111 as a yellow oil (45 mg, 39%): R_f= 0.62 (10% EtOAc/

1

colorless oil (289 mg, 75%): R_f= 0.68 (10% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 5.40−5.36 (m, 1H), 5.30−5.25 (m, 1H),

4.65 (q, J = 6.7 Hz, 1H), 3.04 (s, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.28 (q,

J = 7.4 Hz, 2H), 2.04 (quintet, J = 7.3 Hz, 2H), 1.57 (d, J = 6.7 Hz,

3H), 0.95 (t, J = 1.0 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 208.2, 145.2, 132.8, 127.5, 107.2, 51.8, 41.2,

25.9, 21.6, 20.6, 18.3, 14.4, 11.2, −3.8; IR (thin ﬁlm) 3007, 2988, 2959,

2859, 2896, 1718, 1675 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₁₇H₃₂O₂SiNa [M + Na]⁺319.2069, found 319.2063.

1

hexanes); H NMR (500 MHz, CDCl₃) δ 7.56−7.54 (m, 2H), 7.45−

7.43 (m, 1H), 7.40−7.36 (m, 2H), 3.46 (s, 2H), 1.72 (s, 3H), 1.71 (s,

3H), 0.94 (s, 9H), 0.14 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ

184.8, 137.1, 133.3, 130.8, 128.7, 120.3, 115.0, 91.2, 88.0, 49.5, 30.0,

19.6, 18.4, 18.3, −3.7; IR (thin ﬁlm) 2957, 2929, 2858, 1667 cm⁻¹;

HRMS (ES/MeOH) m/z calcd for C₂₀H₂₈O₂SiNa [M + Na]⁺

351.1756, found 351.1754.

(Z)-3-(tert-Butyldimethylsilyloxy)-1-(furan-2-yl)-4-phenyl-

pent-3-en-1-one (115). n-BuLi (2.27 M in hexanes, 0.18 mL) was

added to a solution of furan (30 μL, 0.40 mmol) and TMEDA (60 μL,

0.40 mmol) in dry THF (0.95 mL) at 0 °C. The mixture was stirred

for 1 h, followed by addition of Weinreb amide 11 (100 mg, 0.29

mmol). The solution was stirred for 1 h, and then the reaction was

quenched with saturated aqueous NaHCO₃(3 mL). The mixture was

extracted with EtOAc (3 × 10 mL). The organic layers were

combined, dried with anhydrous MgSO₄, ﬁltered, and concentrated in

vacuo. Puriﬁcation by column chromatography (15% EtOAc/hexanes)

of the crude residue aﬀorded ketone 115 as a yellow oil (89 mg, 87%):

R_f= 0.52 (15% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.61

(dd, J = 1.65, 0.69 Hz, 1H), 7.33 (dd, J = 3.5, 0.7 Hz, 1H), 7.31−7.24

(m, 4H), 7.15 (tt, J = 7.1, 2.2 Hz, 1H), 6.56 (dd, J = 3.6, 1.7 Hz, 1H),

3.78 (s, 2H), 1.99 (s, 3H), 0.70 (s, 9H), −0.26 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 185.3, 152.6, 146.4, 141.8, 140.0, 129.4, 127.9,

126.2, 118.7, 117.4, 112.4, 44.7, 25.8, 19.6, 18.1, −4.4; IR (thin ﬁlm)

3022, 2954, 2928, 2894, 2856, 1682 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₁H₂₈O₃SiNa [M + Na]⁺379.1705, found 379.1696.

(Z)-3-(tert-Butyldimethylsilyloxy)non-2-en-5-one (112).

Weinreb amide 9 (200 mg, 0.82 mmol) and n-BuLi (2.27 M in

hexanes, 0.38 mL) were converted to ketone 112 following the general

procedures for ketone 23 formation with an organolithium reagent.

Puriﬁcation by column chromatography (10% EtOAc/hexanes) of the

crude residue aﬀorded ketone 112 as a clear colorless oil (130 mg,

66%): R_f= 0.66 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 4.64 (q, J = 6.7 Hz, 1H), 3.03 (s, 2H), 2.50 (t, J = 7.4 Hz, 2H), 1.56

(d, J = 6.7 Hz, 3H), 1.56−1.51 (m, 2H), 1.26 (app. sextet, J = 7.4 Hz,

2H), 0.93 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H), 0.12 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 208.8, 145.3, 107.0, 51.7, 40.9, 25.89, 25.86,

22.4, 18.3, 14.0, 11.2, −3.9; IR (thin ﬁlm) 2958, 2932, 2860, 1716,

1674 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₅H₃₀O₂SiNa [M +

Na]⁺293.1913, found 293.1909.

(Z)-3-(tert-Butyldimethylsilyloxy)-2-phenylnon-2-en-5-one

(116). Weinreb amide 11 (438 mg, 1.25 mmol) and n-BuLi (2.27 M in

hexanes, 0.83 mL) were converted to ketone 116 following the general

procedures for ketone 23 formation with an organolithium reagent.

Puriﬁcation by column chromatography (10% EtOAc/hexanes) of the

crude residue aﬀorded ketone 116 as a light yellow oil (337 mg, 78%):

(Z)-Ethyl 5-(tert-Butyldimethylsilyloxy)-3-oxohept-5-enoate

(113). Ethyl acetate (0.09 mL, 0.88 mmol) was added dropwise to a

freshly made solution of LDA (0.5 M in THF, 1.8 mL) over 5 min at

−78 °C. The mixture was stirred for 1 h. DMPU (0.13 mL, 1.10

mmol) and Weinreb amide 9 (200 mg, 0.82 mmol) were added to the

solution, and the mixture was stirred for 28 h at −78 °C. The reaction

was quenched with saturated aqueous NH₄Cl (2 mL), and the mixture

was extracted with EtOAc (3 × 10 mL). The organic layers were

combined, dried with anhydrous MgSO₄, ﬁltered, and concentrated in

vacuo. Puriﬁcation by column chromatography (10% EtOAc:hexanes)

1

R_f= 0.68 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ

7.30−7.25 (m, 4H), 7.19−7.15 (m, 1H), 3.29 (s, 2H), 2.61 (t, J = 7.4

Hz, 2H), 1.96 (s, 3H), 1.64−1.58 (m, 2H), 1.39−1.32 (m, 2H), 0.93

(t, J = 7.4 Hz, 3H), 0.72 (s, 9H), −0.27 (s, 6H); ¹³C NMR (126 MHz,

8742

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CDCl₃) δ 208.0, 141.8, 140.6, 129.2, 128.0, 126.2, 118.5, 48.8, 40.9,

25.9, 25.7, 22.5, 19.6, 18.0, 14.0, −4.4; IR (thin ﬁlm) 2956, 2930, 2858,

1716, 1652 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₂₁H₃₄O₂SiNa

[M + Na]⁺369.2226, found 369.2233.

Hz, 2H), 1.39 (app. sextet, J = 7.4 Hz, 2H), 0.96 (t, J = 3H), 0.70 (s,

9H), −0.32 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 207.9, 157.5,

140.8, 136.9, 133.2, 129.4, 128.9, 128.4, 127.6, 126.2, 118.7, 118.3,

105.7, 55.4, 49.0, 41.0, 26.0, 25.8, 22.6, 19.7, 18.0, 14.0, −4.3; IR (thin

ﬁlm) 2956, 2931, 2858, 1717, 1633, 1605 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₂₆H₃₈O₃SiNa [M + Na]⁺449.2488, found 449.2477.

General Procedures to Form Alcohol 15/24. Sodium

borohydride (1.1 equiv) was added to a vial containing ketone 14/

23 (1.0 equiv) in MeOH (0.2 M relative to the ketone) at −20 °C.

The reaction was monitored by TLC, and when starting material was

consumed, the reaction was quenched with saturated aqueous NH₄Cl.

The solution was extracted with EtOAc (3×), and the organic layers

were combined, dried with anhydrous MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by column chromatography of

the crude residue aﬀorded alcohol 15/24.

(Z)-5-(tert-Butyldimethylsilyloxy)-1,6-diphenylhept-5-en-1-

yn-3-one (117). n-BuLi (2.27 M in hexanes, 0.28 mL) was added to a

solution of phenyl acetylene (70 μL, 0.63 mmol) in dry THF (1.9 mL)

at −78 °C. The mixture was stirred for 1.5 h; then Weinreb amide 11

(200 mg, 0.57 mmol) was added. The solution was stirred for 2.5 h at

−78 °C, warmed to 0 °C, and stirred for an additional 2 h. The

reaction was quenched with saturated aqueous NaHCO₃(3 mL), and

the mixture was extracted with EtOAc (3 × 10 mL). The organic

layers were combined, dried with anhydrous MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by column chromatography (15%

EtOAc/hexanes) of the crude residue aﬀorded ketone 117 as a yellow

(S)-5-(tert-Butyldimethylsilyloxy)-6-methylhepta-1,5-dien-3-

ol (21). Enantioselective Reduction. A solution of BH₃·SMe₂(1.0

M in DCM, 0.23 mL), (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0 M

in toluene, 0.04 mL) and 3.6 mL of dry toluene was stirred for 10 min

at rt, cooled to −40 °C, and stirred for an additional 10 min. A

solution of enone 110 (91 mg, 0.36 mmol) in 0.8 mL dry toluene was

added dropwise over 5 min. The mixture was stirred overnight,

warming to 0 °C. The solution was cooled back down to −40 °C, and

an additional portion of BH₃·SMe₂(1.0 M in DCM, 0.23 mL) was

added. The mixture was stirred for 4.5 h, slowly warming to −20 °C.

The reaction was quenched with H₂O (1 mL), and the solution was

extracted with EtOAc (3 × 2 mL). The combined organic layers were

washed with saturated aqueous NaCl (2 mL), dried with anhydrous

MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation of the crude

residue by column chromatography (10% EtOAc:hexanes) aﬀorded

enantioenriched alcohol 21 (9.0:1.0 e.r.) as a clear colorless oil (50 mg,

60%). Racemic reduction: CeCl₃·7H₂O (160 mg, 0.43 mmol) was

added to a vial containing enone 110 (100 mg, 0.39 mmol) and

MeOH (1.95 mL) at −78 °C. The mixture was stirred for 10 min.

Then NaBH₄(16 mg, 0.43 mmol) was added, and the solution was

stirred for an additional 20 min. The reaction was quenched with

saturated aqueous NH₄Cl (10 mL) and diluted with 10 mL of

saturated aqueous NaCl. The solution was extracted with EtOAc (3 ×

15 mL), and the organic layers were combined, dried with anhydrous

Na₂SO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by column

chromatography (10% EtOAc:hexanes) of the crude residue aﬀorded

racemic alcohol 21 as a clear colorless oil (94 mg, 94%): R_f= 0.46

1

oil (130 mg, 58%): R_f= 0.76 (15% EtOAc/hexanes); H NMR (500

MHz, CDCl₃) δ 7.58 (dd, J = 8.2, 1.1 Hz, 2H), 7.47−7.44 (m, 1H),

7.39−7.34 (m, 4H), 7.28 (app. t, J = 8.3 Hz, 2H), 7.19−7.16 (m, 1H),

3.56 (s, 2H), 2.07 (s, 3H), 0.73 (s, 9H), −0.23 (s, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 184.4, 141.8, 139.5, 133.3, 130.9, 129.3, 128.8,

128.0, 126.3, 120.2, 120.0, 91.4, 87.9, 50.3, 25.7, 19.9, 18.1, −4.4; IR

(thin ﬁlm) 2954, 2928, 2856, 1673 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₅H₃₀O₂SiNa [M + Na]⁺413.1913, found 413.1923.

(Z)-3-(tert-Butyldimethylsilyloxy)-2-(4-isobutylphenyl)non-

2-en-5-one (118). Weinreb amide 12 (176 mg, 0.43 mmol) and n-

BuLi (2.49 M in hexanes, 0.36 mL) were converted to ketone 118

following the general procedures for ketone 23 formation with an

organolithium reagent. The mixture was stirred overnight, slowly

warming from −78 to 0 °C. The solution was extracted with EtOAc

instead of DCM. Puriﬁcation by column chromatography (20%

EtOAc/hexanes) of the crude residue aﬀorded ketone 118 as a clear

1

colorless oil (126 mg, 73%): R_f= 0.86 (20% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.20 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0

Hz, 2H), 3.28 (s, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.44 (d, J = 7.1 Hz,

2H), 1.96 (s, 3H), 1.84 (app. septet, J = 6.9 Hz, 1H), 1.61 (app.

quintet, J = 7.4 Hz, 2H), 1.35 (app. sextet, J = 7.4 Hz, 2H), 0.93 (t, J =

7.4 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6 H), 0.72 (s, 9H), 0.27 (s, 6H); ¹³C

NMR (126 MHz, CDCl₃) δ 208.2, 140.3, 139.6, 139.0, 128.9, 128.7,

118.4, 48.8, 45.3, 40.8, 30.4, 25.9, 25.8, 22.5, 22.4, 19.7, 18.0, 14.0,

−4.4; IR (thin ﬁlm) 2957, 2930, 2859, 1717, 1653 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₂₅H₄₂O₂SiNa [M + Na]⁺425.2852, found

425.2842.

(10% EtOAc/hexanes); [α]²_D⁴= 7.5 (c 1.97, acetone); H NMR (500

1

MHz, CDCl₃) δ 5.89 (ddd, J = 17.0, 10.7, 6.0 Hz, 1H), 5.26 (d, J =

17.2 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 4.35−4.31 (m, 1H), 2.41 (dd,

J = 14.1, 8.8 Hz, 1H), 2.27 (dd, J = 14.1, 4.1 Hz, 1H), 1.64 (app. s,

6H), 0.95 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 140.8, 140.5, 114.4, 113.6, 71.3, 40.1, 26.0, 19.3, 18.4, 18.3,

−3.67, −3.74; IR (thin ﬁlm) 3417, 2958, 2930, 2859, 1681 cm⁻¹;

HRMS (ES/MeOH) m/z calcd for C₁₄H₂₈O₂SiNa [M + Na]⁺

279.1756, found 279.1762.

5-(tert-Butyldimethylsilyloxy)-6-methyl-1-phenylhept-5-en-

1-yn-3-ol (22). Ketone 111 (207 mg, 0.63 mmol) was converted to

alcohol 22 following the general procedures for alcohol 15 formation.

The mixture was stirred for 1.5 h at −20 °C and extracted with DCM

instead of EtOAc. Puriﬁcation by column chromatography (20%

EtOAc/hexanes) of the crude residue aﬀorded alcohol 22 as a clear

1

(Z)-3-(tert-Butyldimethylsilyloxy)-2-(6-methoxynaphthalen-

2-yl)non-2-en-5-one (119). Weinreb amide 13 (50 mg, 0.12 mmol)

and n-BuLi (2.37 M in hexanes, 0.16 mL) were converted to ketone

119 following the general procedures for ketone 23 formation with an

organolithium reagent. n-BuLi was added in two equal portions; the

second portion was added after 5 h. The mixture was stirred for an

additional 1 h. The solution was extracted with EtOAc instead of

DCM. Puriﬁcation by column chromatography (10% EtOAc/hexanes)

of the crude residue aﬀorded ketone 119 as a clear colorless oil (30

light yellow oil (182 mg, 87%): R_f= 0.55 (20% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.44−7.42 (m, 2H), 7.30−7.29 (m, 3H),

4.82 (dd, J = 7.7, 5.2 Hz, 1H), 2.73 (dd, J = 14.1, 7.7 Hz, 1H), 2.62

(dd, J = 14.0, 5.1 Hz, 1H), 2.55 (br. s, 1H), 1.72 (s, 3H), 1.67 (s, 3H),

0.97 (s, 9H), 0.15 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 140.0,

131.8, 128.34, 128.30, 122.9, 114.5, 89.9, 84.6, 61.6, 40.5, 26.0, 19.4,

18.4, 18.3, −3.7, −3.8; IR (thin ﬁlm) 3390, 2956, 2929, 2858, 1682

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₂₀H₃₀O₂SiNa [M + Na]⁺

353.1913, found 353.1920.

(Z)-3-(tert-Butyldimethylsilyloxy)non-2-en-5-ol (25). Ketone

112 (120 mg, 0.44 mmol) was converted to alcohol 25 following the

general procedures for alcohol 24 formation. The mixture was stirred

for 1 h at −20 °C. The reaction was quenched with H₂O instead of

1

mg, 60%): R_f= 0.63 (10% EtOAc/hexanes); H NMR (500 MHz,

CDCl₃) δ 7.69 (d, J = 7.4 Hz, 1H), 7.66 (dd, J = 9.0, 2.7 Hz, 2H), 7.44

(dd, J = 8.5, 1.7 Hz, 1H), 7.13−7.09 (m, 2H), 3.92 (s, 3H), 3.35 (s,

2H), 2.65 (t, J = 7.4 Hz, 2H), 2.04 (s, 3H), 1.65 (app. quintet, J = 7.5

8743

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saturated aqueous NH₄Cl and dried with Na₂SO₄instead of MgSO₄.

Puriﬁcation by column chromatography (10% EtOAc/hexanes) of the

crude residue aﬀorded alcohol 25 as a clear colorless oil (109 mg,

91%): R_f= 0.44 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 4.61 (q, J = 6.7 Hz, 1H), 3.80−3.73 (m, 1H), 2.19−2.18 (m, 1H),

2.03 (d, J = 2.5 Hz, 1H), 2.00 (dd, J = 13.8, 8.8 Hz, 1H), 1.54 (dd, J =

6.7, 0.5 Hz, 3H), 1.43−1.32 (m, 6H), 0.96 (s, 9H), 0.90 (t, J = 7.2 Hz,

3H), 0.15 (s, 3H), 0.13 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

148.5, 105.6, 69.2, 45.0, 36.6, 28.0, 25.9, 22.9, 18.4, 14.2, 11.1, −3.8; IR

(thin ﬁlm) 3340, 2957, 2931, 2860, 1678 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₁₅H₃₂O₂SiNa [M + Na]⁺295.2069, found 295.2075.

(Z)-Ethyl 5-(tert-Butyldimethylsilyloxy)-3-hydroxyhept-5-

enoate (26). Ketone 113 (50 mg, 0.17 mmol) was converted to

alcohol 26 following the general procedures for alcohol 24 formation.

EtOH was used as the solvent instead of MeOH, in case

transesteriﬁcation occurred. The mixture was stirred for 2 h at −40

°C. Puriﬁcation by column chromatography (10% EtOAc/hexanes) of

the crude residue aﬀorded alcohol 26 as a clear yellow oil (47 mg,

96%): R_f= 0.32 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 4.60 (q, J = 6.9 Hz, 1H), 4.24−4.18 (m, 1H), 4.16 (q, J = 7.2 Hz,

2H), 2.88 (d, J = 2.9 Hz, 1H), 2.53 (dd, J = 16.2, 3.9 Hz, 1H), 2.42

(dd, J = 16.2, 8.4 Hz, 1H), 2.25 (dd, J = 14.0, 7.2 Hz, 1H), 2.16 (dd, J

= 14.0, 6.0 Hz, 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H),

0.95 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 172.7, 147.5, 105.9, 66.1, 60.7, 44.0, 40.9, 25.9, 18.4, 14.3, 11.1, −3.8,

−3.9; IR (thin ﬁlm) 3461, 2956, 2931, 2859, 1736, 1677 cm⁻¹; HRMS

(ES/MeOH) m/z calcd for C₁₅H₃₀O₄SiNa [M + Na]⁺325.1811,

found 325.1803.

(2Z,8Z)-3-(tert-Butyldimethylsilyloxy)undeca-2,8-dien-5-ol

(27). Ketone 114 (50 mg, 0.17 mmol) was converted to alcohol 27

following the general procedures for alcohol 24 formation. The

mixture was stirred for 1 h at −20 °C. Puriﬁcation by column

chromatography (10:1:89 EtOAc:Et₃N,hexanes) of the crude residue

aﬀorded alcohol 28 (43 mg, 85%): R_f= 0.48 (10% EtOAc/hexanes);

¹H NMR (500 MHz, CDCl₃) δ 5.41−5.31 (m, 2H), 4.61 (q, J = 6.5

Hz, 1H), 3.86−3.76 (m, 1H), 2.20−2.01 (m, 3H), 2.09−2.01 (m, 4H),

1.54 (d, J = 6.6 Hz, 3H), 1.53−1.43 (m, 2H), 0.97−0.92 (m, 3H), 0.95

(s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

148.4, 132.4, 128.7, 105.6, 68.8, 45.0, 36.9, 26.0, 23.6, 20.7, 18.4, 14.5,

11.1, −3.8; IR (thin ﬁlm) 3375, 3006, 2961, 2932, 2859, 1676 cm⁻¹;

HRMS (ES/MeOH) m/z calcd for C₁₇H₃₄O₂SiNa [M + Na]⁺

321.2226, found 321.2223.

MeOH) m/z calcd for C₂₁H₃₆O₂SiNa [M + Na]⁺371.2382, found

371.2379.

(Z)-5-(tert-Butyldimethylsilyloxy)-1,6-diphenylhept-5-en-1-

yn-3-ol (30). Ketone 117 (130 mg, 0.33 mmol) was converted to

alcohol 30 following the general procedures for alcohol 24 formation.

The mixture was stirred for 2 h at −20 °C. Puriﬁcation by column

chromatography (15% EtOAc/hexanes) of the crude residue aﬀorded

alcohol 30 as a clear yellow oil (82 mg, 63%): R_f= 0.44 (15% EtOAc/

1

hexanes); H NMR (500 MHz, CDCl₃) δ 7.44−7.41 (m, 2H), 7.31−

7.24 (m, 7H), 7.18−7.14 (m, 1H), 4.98−4.94 (m, 1H), 2.83 (dd, J =

13.7, 6.9 Hz, 1H), 2.76 (dd, J = 13.7, 5.9 Hz, 1H), 2.62 (br. s, 1H),

2.06 (s, 3H), 0.75 (s, 9H), −0.22 (s, 3H), −0.27 (s, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 142.3, 142.1, 131.8, 129.4, 128.45, 128.38, 128.0,

126.2, 122.8, 119.3, 89.6, 85.0, 62.1, 41.1, 25.8, 19.9, 18.1, −4.4, −4.5;

IR (thin ﬁlm) 3350, 2954, 2928, 2894, 2857, 1655 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₂₅H₃₂O₂SiNa [M + Na]⁺415.2069, found

415.2067.

(Z)-3-(tert-Butyldimethylsilyloxy)-2-(4-isobutylphenyl)non-

2-en-5-ol (31). Ketone 118 (126 mg, 0.31 mmol) was converted to

alcohol 31 following the general procedures for alcohol 24 formation.

The mixture was stirred for 4 h at −20 °C and extracted with DCM

instead of EtOAc. Puriﬁcation by column chromatography (10%

EtOAc/hexanes) of the crude residue aﬀorded alcohol 31 as a clear

1

light yellow oil (122 mg, 97%): R_f= 0.46 (10% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.18 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.0

Hz, 2H), 4.00−3.95 (m, 1H), 2.44 (d, J = 7.2 Hz, 2H), 2.42−2.36 (m,

2H), 2.32 (br. s, 1H), 1.98 (s, 3H), 1.84 (app. septet, J = 6.7 Hz, 1H),

1.60−1.36 (m, 6H), 0.94 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H),

0.75 (s, 9H), −0.24 (s, 3H), −0.28 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 143.8, 139.5, 139.4, 129.1, 128.7, 118.0, 70.8, 45.3, 40.8,

36.8, 30.4, 28.1, 25.9, 22.9, 22.4, 19.6, 18.1, 14.2, −4.3, −4.4; IR (thin

ﬁlm) 3400, 2955, 2929, 2859, 1652 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₅H₄₄O₂SiNa [M + Na]⁺427.3008, found 427.3010.

(Z)-3-(tert-Butyldimethylsilyloxy)-2-(6-methoxynaphthalen-

2-yl)non-2-en-5-ol (32). Ketone 119 (51 mg, 0.12 mmol) was

converted to alcohol 32 following the general procedures for alcohol

24 formation. The mixture was stirred for 4 h at −20 °C and extracted

with DCM instead of EtOAc. Puriﬁcation by column chromatography

(10% EtOAc/hexanes) of the crude residue aﬀorded alcohol 32 as a

clear light yellow oil (40 mg, 79%): R_f= 0.30 (10% EtOAc/hexanes);

¹H NMR (500 MHz, CDCl₃) δ 7.67−7.64 (m, 3H), 7.41 (dd, J = 8.5,

1.5 Hz, 1H), 7.12−7.10 (m, 2H), 4.05−3.99 (m, 1H), 3.92 (s, 3H),

2.50−2.42 (m, 2H), 2.32 (br. s, 1H), 2.07 (s, 3H), 1.63−1.36 (m, 6H),

0.95 (t, J = 7.1 Hz, 3H), 0.72 (s, 9H), −0.29 (s, 3H), −0.35 (s, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 157.4, 144.4, 137.4, 133.1, 129.4,

128.9, 128.6, 127.7, 126.1, 118.6, 117.8, 105.6, 70.9, 55.4, 40.9, 36.9,

28.1, 25.9, 22.9, 19.6, 18.1, 14.2, −4.2, −4.3; IR (thin ﬁlm) 3444, 2956,

2929, 2858, 1604 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₂₆H₄₀O₃SiNa [M + Na]⁺451.2644, found 451.2645.

(Z)-3-(tert-Butyldimethylsilyloxy)-1-(furan-2-yl)-4-phenyl-

pent-3-en-1-ol (28). Ketone 115 (58 mg, 0.16 mmol) was converted

to alcohol 28 following the general procedures for alcohol 24

formation. The mixture was stirred for 3 h at −20 °C. Puriﬁcation by

column chromatography (15% EtOAc/hexanes) of the crude residue

aﬀorded alcohol 28 as a clear colorless oil (58 mg, quant.): R_f= 0.40

1

(15% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ 7.46−7.45

(m, 1H), 7.34−7.28 (m, 4H), 7.26−7.20 (m, 1H), 6.42−6.38 (m, 2H),

5.15 (dd, J = 7.4, 5.7 Hz, 1H), 2.92 (dd, J = 13.8, 8.0 Hz, 1H), 2.82

(dd, J = 13.9, 5.3 Hz, 1H), 2.70 (br. s, 1H), 1.97 (s, 3H), 0.82 (s, 9H),

−0.17 (s, 3H), −0.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 156.0,

142.5, 142.1, 142.0, 129.4, 127.9, 126.1, 118.9, 110.4, 106.2, 66.9, 39.4,

25.8, 19.4, 18.1, −4.4, −4.5; IR (thin ﬁlm) 3396, 2954, 2928, 2857,

1659, 1600 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₂₁H₃₀O₃SiNa

[M + Na]⁺381.1862, found 381.1870.

General Procedures for THPO Formation. BF₃·OEt₂(1.5

equiv) was added dropwise to a solution of aldehyde (1.5 equiv)

and hydroxy silyl enol ether (1.0 equiv) in DCM (1.0 M relative to the

silyl enol ether) at −78 °C. The mixture was stirred for 4 h, and the

reaction was quenched with saturated aqueous NaHCO₃. The solution

was extracted with DCM (3×), and the organic layers were combined,

dried with anhydrous MgSO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by column chromatography of the crude residue aﬀorded

the desired THP.

(2R,6S)-2-(Benzo[b]thiophen-2-yl)-3,3-dimethyl-6-phenyl-

dihydro-2H-pyran-4(3H)-one (40). Alcohol 18 (50 mg, 0.16 mmol)

and 1-(1-benzothien-3-yl)ethanone (41 mg, 0.25 mmol) were

converted to 40 following the general procedures for THPO

formation. Puriﬁcation by column chromatography (10% EtOAc/

hexanes) of the crude residue aﬀorded THPO 40 as a clear colorless

oil (21 mg, 38%) and recovered alcohol 18 (34 mg): R_f= 0.36 (10%

EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.90−7.86 (m, 2H),

7.57 (s, 1H), 7.48−7.46 (m, 2H), 7.41−7.38 (m, 3H), 7.36−7.31 (m,

2H), 5.06 (s, 1H), 4.87 (dd, J = 12.0, 2.8 Hz, 1H), 3.08 (dd, J = 14.5,

12.1 Hz, 1H), 2.71 (dd, J = 14.4, 2.9 Hz, 1H), 1.31 (s, 3H), 1.03 (s,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 211.1, 141.0, 140.1, 138.3,

(Z)-3-(tert-Butyldimethylsilyloxy)-2-phenylnon-2-en-5-ol

(29). Ketone 116 (325 mg, 0.94 mmol) was converted to alcohol 29

following the general procedures for alcohol 24 formation. The

mixture was stirred for 1 h at −20 °C. Puriﬁcation by column

chromatography (10% EtOAc/hexanes) of the crude residue aﬀorded

alcohol 29 as a clear yellow oil (277 mg, 84%): R_f= 0.56 (10% EtOAc/

1

hexanes); H NMR (500 MHz, CDCl₃) δ 7.30−7.22 (m, 4H), 7.15

(app. sextet, J = 4.3 Hz, 1H), 4.00−3.94 (m, 1H), 2.45−2.36 (m, 2H),

1.98 (s, 3H), 1.58−1.52 (m, 2H), 1.50−1.45 (m, 1H), 1.43−1.33 (m,

3H), 0.93 (t, J = 7.0 Hz, 3H), 0.74 (s, 9H), −0.25 (s, 3H), −0.30 (s,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 144.1, 142.2, 129.4, 127.9,

126.1, 118.0, 70.8, 40.7, 36.8, 28.1, 25.8, 22.9, 19.6, 18.1, 14.2, −4.3,

−4.4; IR (thin ﬁlm) 3388, 2930, 2856, 2858, 1651 cm⁻¹; HRMS (ES/

8744

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The Journal of Organic Chemistry

Article

132.5, 128.8, 128.3, 125.7, 124.4, 124.2, 122.93, 122.88, 81.9, 79.8,

51.3, 46.3, 20.7, 19.9; IR (thin ﬁlm) 2972, 1710 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₂₁H₂₄O₂SN [M + NH₄]⁺354.1528, found

354.1535.

(m, 1H), 2.53 (dd, J = 14.2, 11.8 Hz, 1H), 2.26 (dd, J = 14.2, 2.6 Hz,

1H), 1.75−1.74 (m, 3H), 1.73−1.66 (m, 1H), 1.58−1.50 (m, 1H),

1.44−1.37 (m, 1H), 1.36−1.28 (m, 3H), 1.11 (s, 3H), 0.94 (s, 3H),

0.90 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 212.4, 130.7,

126.1, 85.3, 77.5, 49.5, 44.6, 36.3, 27.4, 22.8, 19.8, 19.2, 18.2, 14.1; IR

(thin ﬁlm) 2961, 2933, 2860, 1713 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₁₄H₂₅O₂[M + H]⁺225.1855, found 225.1857.

(2S,6R)-6-((R)-2-Hydroxybutyl)-3,3-dimethyl-2-((E)-prop-1-

enyl)dihydro-2H-pyran-4(3H)-one (49). Alcohol 19 (50 mg, 0.17

mmol) and crotonaldehyde (18 mg, 0.26 mmol) were converted to 49

following the general procedures for THPO formation. Puriﬁcation by

column chromatography (30% EtOAc/hexanes) of the crude residue

aﬀorded THPO 49 as a clear colorless oil (26 mg, 65%): R_f= 0.42

(30% EtOAc/hexanes); [α]²_D⁴= −24.5 (c 1.30, CHCl₃), ¹H NMR (500

MHz, CDCl₃) δ 5.76−5.67 (m, 1H), 5.49 (ddq, J = 15.4, 7.1, 1.8 Hz,

1H), 3.89 (ddt, J = 12.1, 9.4, 4.7 Hz, 1H), 3.79−3.72 (m, 2H), 3.52

(br. s, 1H), 2.61 (dd, J = 14.4, 11.9 Hz, 1H), 2.28 (dd, J = 14.4, 2.7 Hz,

1H), 1.73−1.71 (m, 3H), 1.66−1.62 (m, 2H), 1.54−1.43 (m, 2H),

1.11 (s, 3H), 0.95 (s, 3H), 0.94 (t, J = 7.4 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 211.0, 131.1, 125.4, 85.4, 78.5, 72.9, 49.6, 44.9, 42.6,

30.4, 19.7, 19.1, 18.1, 9.9; IR (thin ﬁlm) 3468, 2967, 2936, 2875, 1712

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₄H₂₅O₃[M + H]⁺

241.1804, found 241.1812.

(2S,6S)-2-(4-Hydroxy-3-methoxyphenyl)-3,3-dimethyl-6-

vinyldihydro-2H-pyran-4(3H)-one (42). Alcohol 21 (43 mg, 0.16

mmol) and vanillin (38 mg, 0.25 mmol) were converted to 42

following the general procedures for THPO formation. Puriﬁcation by

column chromatography (gradient: 10% to 50% EtOAc/hexanes) of

the crude residue aﬀorded THPO 42 as a clear colorless oil (13 mg,

30%): R_f= 0.78 (50% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 6.88 (dd, J = 5.0, 3.2 Hz, 2H), 6.81 (dd, J = 8.2, 1.8 Hz, 1H), 6.00

(ddd, J = 17.3, 10.6, 5.4 Hz, 1H), 5.59 (s, 1H), 5.35 (app. dt, J = 9.3,

5.8 Hz, 1H), 5.22 (app. dt, J = 5.9, 3.5 Hz, 1H), 4.34 (s, 1H), 4.28−

4.24 (m, 1H), 3.91 (s, 3H), 2.79 (dd, J = 14.3, 12.0 Hz, 1H), 2.44 (dd,

J = 14.3, 2.9 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 211.4, 146.0, 145.5, 137.4, 129.1, 121.3, 116.2, 113.7, 110.7,

86.1, 78.1, 56.2, 50.7, 44.2, 20.0, 19.6; IR (thin ﬁlm) 3418, 2970, 2934,

1712, 1604 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₆H₂₁O₄[M +

H]⁺277.1440, found 277.1450.

THPO 43. Alcohol 16 (49 mg, 0.18 mmol) and 3-(tert-

butyldimethylsilyloxy)propanal (53 mg, 0.28 mmol) were converted

to 43 following the general procedures for THPO formation.

TMSOTf was used as the Lewis acid instead of BF₃·OEt₂. Puriﬁcation

by column chromatography (gradient: 10% EtOAc/hexanes to 100%

EtOAc) of the crude residue aﬀorded THPO 43 as a clear colorless oil

(Overall: 35 mg, 76%): For R = H: Isolated 18.2 mg, 48%, R_f= 0.51

(2S,6S)-3,3-Dimethyl-2-styryl-6-vinyldihydro-2H-pyran-

4(3H)-one (51). Alcohol 21 (47 mg, 0.18 mmol) and cinnamaldehyde

(36 mg, 0.27 mmol) were converted to 51 following the general

procedures for THPO formation. Puriﬁcation by column chromatog-

raphy (10% EtOAc/hexanes) of the crude residue aﬀorded THPO 51

as a clear colorless oil (29 mg, 62%): R_f= 0.43 (10% EtOAc/hexanes);

1

(10% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ 5.85−5.76

(m, 1H), 5.16−5.12 (m, 2H), 3.82−3.78 (m, 2H), 3.75−3.70 (m, 1H),

3.48 (dd, J = 10.7, 2.1 Hz, 1H), 2.65 (t, J = 5.5 Hz, 1H), 2.56 (dd, J =

14.4, 11.9 Hz, 1H), 2.40−2.33 (m, 2H), 2.29 (dd, J = 14.4, 2.7 Hz,

1H), 1.85−1.93 (m, 1H), 1.67−1.62 (m, 1H), 1.13 (s, 3H), 1.00 (s,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 211.1, 133.5, 118.6, 84.9, 77.1,

62.0, 49.2, 44.1, 40.8, 31.1, 19.5, 18.9; IR (thin ﬁlm) 3416, 3078, 2969,

2934, 2875, 1712, 1642 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₁₂H₂₁O₃[M + H]⁺213.1491, found 213.1490. For R = TBS: Isolated

16.5 mg, 28%, R_f= 0.46 (50% EtOAc/hexanes); ¹H NMR (500 MHz,

CDCl₃) δ 5.89 (tdd, J = 17.1, 10.2, 7.0 Hz, 1H), 5.18−5.14 (m, 2H),

3.84−3.78 (m, 2H), 3.69−3.63 (m, 1H), 3.46 (dd, J = 6.8, 5.3 Hz,

1H), 2.58 (dd, J = 14.4, 11.8 Hz, 1H), 2.48−2.43 (m, 1H), 2.38−2.32

(m, 1H), 2.32 (dd, J = 14.3, 2.7 Hz, 1H), 1.76−1.72 (m, 2H), 1.15 (s,

3H), 1.05 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H); ¹³C NMR (126 MHz,

CDCl₃) δ 212.3, 133.7, 117.8, 80.2, 76.8, 59.9, 49.0, 44.2, 40.7, 32.7,

26.1, 19.4, 18.9, 18.4, −5.2, −5.3; IR (thin ﬁlm) 2958, 2930, 2857,

1714, 1643 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₈H₃₄O₃SiNa

[M + Na]⁺349.2175, found 349.2173.

[α]²_D⁴= −24.7 (c 0.28, CHCl₃); H NMR (500 MHz, CDCl₃) δ 7.41

1

(d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.26 (app. t, J = 7.3 Hz,

1H), 6.68 (d, J = 15.9 Hz, 1H), 6.24 (dd, J = 16.0, 6.7 Hz, 1H), 5.98

(ddd, J = 17.2, 10.6, 5.6 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 5.24 (d, J

= 10.6 Hz, 1H), 4.24−4.20 (m, 1H), 4.00 (dd, J = 6.7, 0.6 Hz, 1H),

2.72 (dd, J = 14.3, 12.0 Hz, 1H), 2.40 (dd, J = 14.4, 2.8 Hz, 1H), 1.19

(s, 3H), 1.06 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 211.0, 137.3,

136.6, 133.8, 128.7, 128.0, 126.7, 124.1, 116.5, 85.0, 76.9, 49.9, 44.2,

19.9, 19.2; IR (thin ﬁlm) 3026, 2972, 2933, 2843, 1713 cm⁻¹; HRMS

(ES/MeOH) m/z calcd for C₁₇H₂₄O₂N [M + NH₄]⁺274.1807, found

274.1821.

3,3-Dimethyl-6-(phenylethynyl)-2-((E)-prop-1-enyl)dihydro-

2H-pyran-4(3H)-one (52). Alcohol 22 (90 mg, 0.27 mmol) and

crotonaldehyde (29 mg, 0.41 mmol) were converted to 52 following

the general procedures for THPO formation. Puriﬁcation by column

chromatography (10% EtOAc/hexanes) of the crude residue aﬀorded

THPO 52 as a clear colorless oil (51 mg, 71%) in a 4.1:1.0 cis:trans

ratio. A small amount of THPO 52c and THPO 52t was separated for

characterization, but most of it was recovered as a mixture of the two

diastereomers: THPO 52c: R_f= 0.57 (10% EtOAc/hexanes); ¹H

NMR (500 MHz, CDCl₃) δ 7.46 (dd, J = 7.6, 1.8 Hz, 2H), 7.33−7.26

(m, 3H), 5.84−5.77 (m, 1H), 5.59 (app. ddq, J = 15.4, 7.6, 1.6 Hz,

1H), 4.63 (dd, J = 12.2, 3.0 Hz, 1H), 3.77 (d, J = 7.6 Hz, 1H), 3.06

(dd, J = 14.6, 12.2 Hz, 1H), 2.59 (dd, J = 14.7, 3.0 Hz, 1H), 1.76 (dd, J

= 15.7, 8.7 Hz, 3H), 1.20 (s, 3H), 0.98 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 209.9, 132.0, 131.9, 128.9, 128.4, 125.3, 122.2, 86.3, 86.2,

85.6, 67.8, 49.7, 44.8, 19.7, 19.1, 18.1; IR (thin ﬁlm) 2971, 2934, 2854,

2232, 1715 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₈H₂₄O₂N [M

+ NH₄]⁺286.1807, found 286.1796. THPO 52t: R_f= 0.46 (10%

EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.42−7.40 (m, 2H),

7.33−7.26 (m, 3H), 5.83 (dq, J = 15.3, 3.0 Hz, 1H), 5.56 (ddq, J =

15.3, 7.4, 1.8 Hz, 1H), 5.29 (dd, J = 7.2, 1.8 Hz, 1H), 4.42 (d, J = 7.4

Hz, 1H), 3.14 (dd, J = 14.3, 7.2 Hz, 1H), 2.52 (dd, J = 14.2, 1.8 Hz,

1H), 1.76 (dd, J = 6.5, 1.1 Hz, 3H), 1.15 (s, 3H), 1.04 (s, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 209.9, 132.0, 131.7. 128.9, 128.4, 125.6,

122.1, 88.6, 85.6, 80.7, 65.8, 50.1, 43.7, 19.9, 19.7, 18.2; IR (thin ﬁlm)

2970, 2932, 2872, 1714 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₁₈H₂₄O₂N [M + NH₄]⁺286.1807, found 286.1793.

(2S,6R)-6-Allyl-3,3-dimethyl-2-styryldihydro-2H-pyran-

4(3H)-one (45). Alcohol 16 (49 mg, 0.18 mmol) and cinnamaldehyde

(37 mg, 0.28 mmol) were converted to 45 following the general

procedures for THPO formation. Puriﬁcation by column chromatog-

raphy (10% EtOAc/hexanes) of the crude residue aﬀorded THPO 45

as a clear colorless oil (44 mg, 91%): R_f= 0.50 (10% EtOAc/hexanes);

¹H NMR (500 MHz, CDCl₃) δ 7.47 (d, J = 7.3 Hz, 2H), 7.40 (t, J =

7.6 Hz, 2H), 7.32 (app. t, J = 7.3 Hz, 1H), 6.73 (d, J = 15.9 Hz, 1H),

6.29 (dd, J = 16.0, 6.6 Hz, 1H), 5.94 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H),

5.23−5.19 (m, 2H), 4.00 (d, J = 6.6 Hz, 1H), 3.83 (dtd, J = 11.8, 9.2,

4.3 Hz, 1H), 2.70 (dd, J = 14.4, 11.9 Hz, 1H), 2.58−2.43 (m, 2H),

2.38 (dd, J = 14.4, 2.7 Hz, 1H), 1.23 (s, 3H), 1.11 (s, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 211.7, 136.7, 133.6, 133.4, 128.7, 128.0, 126.7,

124.3, 118.3, 85.0, 76.8, 49.7, 43.9, 40.7, 19.9, 19.2; IR (thin ﬁlm)

3080, 3026, 2976, 2933, 2850, 1713 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₁₈H₂₃O₂[M + H]⁺271.1698, found 271.1690.

(2S,6R)-6-Butyl-3,3-dimethyl-2-((E)-prop-1-enyl)dihydro-2H-

pyran-4(3H)-one (46). Alcohol 17 (1.92 g, 6.70 mmol) and

crotonaldehyde (0.70 g, 10 mmol) were converted to 46 following

the general procedures for THPO formation. Puriﬁcation by column

chromatography (10% EtOAc/hexanes) of the crude residue aﬀorded

THPO 46 as a clear light yellow oil (1.09 g, 73%): R_f= 0.51 (10%

EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ 5.78−5.72 (m, 1H),

5.53 (dq, J = 15.3, 2.9 Hz, 1H), 3.67 (d, J = 7.2 Hz, 1H), 3.61−3.58

(2S,3S,6R)-6-Butyl-3-methyl-2-styryldihydro-2H-pyran-

4(3H)-one (55c). Alcohol 25 (40 mg, 0.15 mmol) and cinnamalde-

hyde (29 mg, 0.22 mmol) were converted to 55c following the general

8745

dx.doi.org/10.1021/jo501580p | J. Org. Chem. 2014, 79, 8733−8749

The Journal of Organic Chemistry

Article

procedures for THPO formation. Puriﬁcation by column chromatog-

raphy (10% EtOAc/hexanes) of the crude residue aﬀorded THPO 55

as a clear colorless oil in a 8.3:1.0 cis:trans ratio (16 mg, 40%): R_f=

154.3, 153.2, 132.8, 127.9, 116.1, 114.7, 81.5, 77.0, 70.0, 55.9, 48.0,

46.5, 36.2, 23.0, 20.6, 14.5, 9.3; IR (thin ﬁlm) 3000, 2960, 2932, 2873,

2852, 1716, 1508 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₂₀H₂₈O₄Na [M + Na]⁺355.1885, found 355.1884.

1

0.43 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ 7.42−

7.40 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.28−7.25 (m, 1H), 6.64 (d, J =

15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.4 Hz, 1H), 3.83 (dd, J = 10.0, 7.6

Hz, 1H), 3.71−3.66 (m, 1H), 2.49−2.37 (m, 3H), 1.75−1.72 (m 1H),

1.59−1.54 (m, 1H), 1.46−1.32 (m, 4H), 1.01 (d, J = 6.7 Hz, 3H), 0.91

(t, J = 3H); ¹³C NMR (126 MHz, CDCl₃) δ 208.5, 136.4, 133.5, 128.7,

128.2, 127.7, 126.8, 84.4, 76.9, 50.3, 48.2, 36.3, 27.5, 22.7, 14.1, 9.6; IR

(thin ﬁlm) 3026, 2957, 2932, 2860, 1715 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₁₈H₂₅O₂[M + H]⁺273.1855, found 273.1857.

(2S,3S,6R)-6-Butyl-3-methyl-2-((E)-prop-1-enyl)dihydro-2H-

pyran-4(3H)-one (56c). Alcohol 25 (69 mg, 0.25 mmol) and

crotonaldehyde (26 mg, 0.37 mmol) were converted to 56c following

the general procedures for THPO formation. Puriﬁcation by column

chromatography (10% EtOAc/hexanes) of the crude residue aﬀorded

THPO 56 as a clear colorless oil in a 7.0:1.0 cis:trans ratio (16 mg,

30%): R_f= 0.51 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 5.75 (dq, J = 17.4, 6.5 Hz, 1H), 5.51 (app. dqd, J = 15.2, 7.8, 1.8 Hz,

1H), 3.63−3.58 (m, 2H), 2.41 (dd, J = 13.6, 2.4 Hz, 1H), 2.37−2.28

(m, 2H), 1.74 (dd, J = 6.5, 1.6 Hz, 3H), 1.73−1.66 (m, 1H), 1.56−

1.49 (m, 1H), 1.44−1.37 (m, 1H), 1.36−1.28 (m, 3H), 0.93 (d, J = 6.7

Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

209.0, 130.6, 130.0, 84.5, 77.6, 50.1, 48.2, 36.3, 27.5, 22.7, 18.0, 14.1,

9.6; IR (thin ﬁlm) 2959, 2934, 2860, 1717 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₁₃H₂₆O₂N [M + NH₄]⁺228.1964, found 228.1964.

Ethyl 2-((2S,5S,6S)-5-Methyl-4-oxo-6-((E)-prop-1-enyl)tetra-

hydro-2H-pyran-2-yl)acetate (57c). Alcohol 26 (46 mg, 0.15

mmol) and crotonaldehyde (16 mg, 0.23 mmol) were converted to

57c following the general procedures for THPO formation. TMSOTf

was used as the Lewis acid instead of BF₃·OEt₂. Puriﬁcation by column

chromatography (20% EtOAc/hexanes) of the crude residue aﬀorded

THPO 57 as a clear colorless oil in a 5.6:1.0 cis:trans ratio (18 mg,

49%): R_f= 0.45 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃)

δ 5.78−5.68 (m, 1H), 5.48 (app. ddq, J = 14.8, 7.3, 1.8 Hz, 1H), 4.17−

4.06 (m, 3H), 3.66 (dd, J = 10.2, 7.8 Hz, 1H), 2.72 (dd, J = 15.4, 6.8

Hz, 1H), 2.53−2.48 (m, 2H), 2.42 (dd, J = 11.6, 1.1 Hz, 1H), 2.33−

2.26 (m, 1H), 1.73 (dd, J = 6.5, 1.6 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H),

0.94 (d, J = 6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 207.5, 170.2,

131.0, 129.6, 84.3, 73.6, 60.9, 49.8, 47.4, 41.4, 17.9, 14.3, 9.6; IR (thin

ﬁlm) 2977, 2935, 2877, 1736, 1717 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₁₃H₂₀O₄Na [M + Na]⁺263.1259, found 263.1258.

(2S,3S,6S)-6-(Furan-2-yl)-3-methyl-3-phenyl-2-((E)-prop-1-

enyl)dihydro-2H-pyran-4(3H)-one (59c). Alcohol 28 (58 mg, 0.16

mmol) and crotonaldehyde (17 mg, 0.24 mmol) were converted to

59c following the general procedures for THPO formation.

Puriﬁcation of the crude residue on a preparative TLC plate (10%

EtOAc/hexanes) aﬀorded THPO 59 as a white ﬁlm in a 6.0:1.0

1

cis:trans ratio (29 mg, 62%): R_f= 0.44 (10% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 7.46 (app. d, J = 1.0 Hz, 1H), 7.37−7.32

(m, 2H), 7.31−7.27 (m, 1H), 7.20−7.18 (m, 2H), 6.40−6.39 (m, 2H),

5.50−5.43 (m, 1H), 5.17 (ddt, J = 15.4, 5.6, 4.9 Hz, 1H), 5.02 (dd, J =

12.4, 3.0 Hz, 1H), 4.59 (d, J = 5.5 Hz, 1H), 3.28 (dd, J = 15.8, 12.4 Hz,

1H), 2.71 (dd, J = 15.8, 3.1 Hz, 1H), 1.62 (s, 3H), 1.53 (dd, J = 6.5,

1.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 209.8, 152.7, 143.1,

139.5, 130.0, 128.4, 128.3, 127.3, 124.8, 110.5, 108.0, 84.4, 72.0, 58.8,

42.0, 18.0, 16.7; IR (thin ﬁlm) 3031, 2989, 2916, 2854, 1714 cm⁻¹;

HRMS (ES/MeOH) m/z calcd for C₁₉H₂₀O₃Na [M + Na]⁺319.1310,

found 319.1305.

6-Butyl-3-methyl-3-phenyl-2-styryldihydro-2H-pyran-4(3H)-

one (60). Alcohol 29 (36 mg, 0.10 mmol) and cinnamaldehyde (20

mg, 0.15 mmol) were converted to 60 following the general

procedures for THPO formation. Puriﬁcation by column chromatog-

raphy (10% EtOAc/hexanes) of the crude residue aﬀorded THPO 60

as a clear colorless oil in a 8.2:1.0 cis:trans ratio (24 mg, 69%). A small

amount of THPO 60c and THPO 60t was separated for character-

ization, but most of it was recovered as a mixture of the two

diastereomers; R_f= 0.28 (10% EtOAc/hexanes): THPO 60c: ¹H

NMR (500 MHz, CDCl₃) δ 7.37 (app. t, J = 7.5 Hz, 2H), 7.31−7.17

(m, 8H), 6.46 (dd, J = 16.1, 1.4 Hz, 1H), 5.74 (dd, J = 16.1, 4.4 Hz,

1H), 4.64 (dd, J = 4.4, 1.6 Hz, 1H), 3.99−3.93 (m, 1H), 2.71 (dd, J =

15.6, 11.9 Hz, 1H), 2.52 (dd, J = 15.6, 2.9 Hz, 1H), 1.87−1.81 (m,

1H), 1.69−1.63 (m, 1H), 1.58−1.55 (m, 1H), 1.56 (s, 3H), 1.48−1.37

(m, 3H), 0.96 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

210.9, 139.6, 136.9, 131.9, 128.6, 128.43, 128.41, 127.7, 127.4, 126.5,

124.4, 83.9, 76.9, 58.7, 44.4, 36.3, 27.6, 22.8, 16.8, 14.2; IR (thin ﬁlm)

3057, 3026, 2956, 2930, 2859, 1714 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₄H₂₈O₂Na [M + Na]⁺371.1987, found 371.1986. THPO

60t: ¹H NMR (500 MHz, CDCl₃) δ 7.39−7.37 (m, 6H), 7.33 (app. t, J

= 7.4 Hz, 2H), 7.29−7.26 (m, 2H), 6.76 (d, J = 15.6 Hz, 1H), 6.27

(dd, J = 15.6, 8.4 Hz, 1H), 5.22 (d, J = 8.4 Hz, 1H), 4.16 (quintet, J =

6.5 Hz, 1H), 2.41−2.39 (m, 2H), 1.61−1.53 (m, 1H), 1.46−1.37 (m,

1H), 1.30−1.17 (m, 7H), 0.84 (t, J = 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 210.4, 142.4, 136.4, 136.2, 129.0, 128.8, 128.4, 127.1, 127.0,

126.9, 124.3, 80.7, 72.7, 58.2, 45.1, 35.9, 27.2, 22.7, 22.2, 14.1; IR (thin

ﬁlm) 3058, 3026, 2956, 2928, 2860, 1711 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₂₄H₂₈O₂Na [M + Na]⁺371.1987, found 371.1995.

6-Butyl-3-methyl-3-phenyl-2-((E)-prop-1-enyl)dihydro-2H-

pyran-4(3H)-one (61). Alcohol 29 (79 mg, 0.23 mmol) and

crotonaldehyde (30 mg, 0.43 mmol) were converted to 61 following

the general procedures for THPO formation. Puriﬁcation by column

chromatography (10% EtOAc/hexanes) of the crude residue aﬀorded

THPO 61c (39 mg, 60%) and 61t (14 mg, 22%) as a clear colorless

oil. THPO 61c: R_f= 0.35 (10% EtOAc/hexanes); ¹H NMR (500

MHz, CDCl₃) δ 7.26 (app. t, J = 7.5 Hz, 1H), 7.20−7.17 (m, 2H),

7.09 (dd, J = 8.3, 1.1 Hz, 2H), 5.44 (dqd, J = 15.4, 6.6, 1.4 Hz, 1H),

5.03 (dd, J = 15.5, 2.2 Hz, 1H), 4.34 (dd, J = 3.7, 1.2 Hz, 1H), 3.81

(ddq, J = 12.6, 6.6, 1.8 Hz, 1H), 2.58 (dd, J = 15.6, 11.9 Hz, 1H), 2.39

(dd, J = 15.5, 2.9 Hz, 1H), 1.73−1.67 (m, 1H), 1.57−1.51 (m, 1H),

1.49 (app. dt, J = 6.6, 1.4 Hz, 3H), 1.46 (s, 3H), 1.44−1.41 (m, 1H),

1.37−1.27 (m, 3H), 0.87 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 211.2, 139.8, 129.0, 128.4, 128.2, 127.1, 125.4, 84.0, 76.9,

58.6, 44.4, 36.3, 27.5, 22.8, 18.0, 16.6, 14.2; IR (thin ﬁlm) 3031, 2957,

2932, 2859, 1714 cm⁻¹; HRMS (ES/MeOH) m/z calcd for

C₁₉H₂₆O₂Na [M + Na]⁺309.1830, found 309.1820. THPO 61t: R_f

= 0.35 (10% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.35−

7.32 (m, 4H), 7.25−7.22 (m, 1H), 5.88 (dq, J = 17.2, 5.0 Hz, 1H),

5.60 (ddq, J = 14.9, 8.9, 1.9 Hz, 1H), 5.02 (d, J = 8.9 Hz, 1H), 4.09−

6-((Z)-Hex-3-enyl)-2-((4-methoxyphenoxy)methyl)-3-

methyldihydro-2H-pyran-4(3H)-one (58). Alcohol 27 (46 mg,

0.15 mmol) and 2-(4-methoxyphenoxy)acetaldehyde (38 mg, 0.23

mmol) were converted to 58 following the general procedures for

THPO formation using TMSOTf instead of BF₃·OEt₂. Puriﬁcation by

column chromatography (20% EtOAc/hexanes) of the crude residue

aﬀorded THPO 58c (28 mg, 55%) and 58t (8 mg, 17%) as a clear

1

colorless oil: THPO 58c: R_f= 0.42 (20% EtOAc/hexanes); H NMR

(500 MHz, CDCl₃) δ 6.83−6.78 (m, 4H), 5.54−5.47 (m, 1H), 5.22

(ddd, J = 15.3, 8.7, 1.5 Hz, 1H), 4.02 (dd, J = 10.4, 2.0 Hz, 1H), 3.85

(dd, J = 10.4, 6.1 Hz, 1H), 3.82−3.77 (m, 1H), 3.76 (s, 3H), 3.42

(ddd, J = 10.2, 6.1, 2.0 Hz, 1H), 2.75 (dd, J = 15.5, 7.3 Hz, 1H), 2.54−

2.40 (m, 3H), 2.19−2.12 (m, 1H), 1.82 (dq, J = 13.2, 3.5 Hz, 1H),

1.69 (dq, J = 12.7, 4.3 Hz, 1H), 1.62 (dd, J = 6.4, 1.5 Hz, 3H), 1.46 (m,

1H), 1.37−1.29 (m, 1H), 1.02 (t, J = 7.3 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 210.3, 153.9, 153.5, 131.6, 127.2, 116.0, 114.6, 80.2,

74.4, 70.8, 55.8, 49.0, 41.0, 37.2, 31.2, 30.8, 18.2, 7.7; IR (thin ﬁlm)

2935, 2918, 2876, 2854, 1714, 1508 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₀H₂₈O₄Na [M + Na]⁺355.1885, found 355.1878. THPO

58t: R_f= 0.53 (20% EtOAc/hexanes); ¹H NMR (500 MHz, CDCl₃) δ

6.91−6.89 (m, 2H), 6.84−82 (m, 2H), 5.42−5.37 (m, 1H), 5.31−5.26

(m, 1H), 4.22 (ddd, J = 10.6, 2.0 Hz, 1H), 4.06 (ddd, J = 10.6, 4.4 Hz,

1H), 3.77 (s, 3H), 3.66−3.61 (m, 1H), 3.53 (ddd, J = 10.5, 4.3, 2.0 Hz,

1H), 2.78−2.72 (m, 1H), 2.50−2.36 (m, 2H), 2.22 (app. sextet, J = 7.7

Hz, 1H), 2.14 (app. sextet, J = 7.2 Hz, 1H), 2.06 (quintet, J = 7.8 Hz,

2H), 1.84−1.76 (m, 1H), 1.56−1.50 (m, 1H), 1.05 (d, J = 6.6 Hz,

3H), 0.95 (t, J = 7.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 208.8,

8746

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Article

4.04 (m, 1H), 2.33 (dd, J = 13.7, 9.8 Hz, 1H), 2.28 (dd, J = 13.7, 4.2

Hz, 1H), 1.75 (dd, J = 6.5, 1.6 Hz, 3H), 1.54−1.49 (m, 1H), 1.41−

1.33 (m, 1H), 1.28−1.21 (m, 4H), 1.19 (s, 3H), 0.85 (t, J = 7.0 Hz,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 210.5, 142.8, 133.2, 128.9,

126.98, 126.95, 126.2, 81.0, 72.3, 58.0, 45.2, 36.0, 27.1, 22.7, 22.6, 18.2,

14.1; IR (thin ﬁlm) 2956, 2930, 2860, 1713 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₁₉H₂₆O₂Na [M + Na]⁺309.1830, found

309.1826.

84.1, 76.9, 58.3, 45.2, 44.5, 36.3, 30.2, 27.5, 22.8, 22.6, 22.5, 18.0, 16.7,

14.2; IR (thin ﬁlm) 2955, 2929, 2867, 1714 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₂₃H₃₄O₂Na [M + Na]⁺365.2456, found

1

365.2453. THPO 64t: R_f= 0.70 (10% EtOAc/hexanes); H NMR

(500 MHz, CDCl₃) δ 7.23 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz,

2H), 5.86 (dq, J = 14.0, 4.3 Hz, 1H), 5.59 (app. ddd, J = 15.1, 8.8, 1.1

Hz, 1H), 5.00 (d, J = 8.8 Hz, 1H), 4.08−4.03 (m, 1H), 2.44 (d, J = 7.2

Hz, 2H), 2.35 (dd, J = 13.6, 10.4 Hz, 1H), 2.26 (dd, J = 13.7, 3.5 Hz,

1H), 1.85 (app. septet, J = 6.7 Hz, 1H), 1.74 (d, J = 6.4 Hz, 3H),

1.54−1.49 (m, 1H), 1.41−1.33 (m, 2H), 1.31−1.20 (m, 3H), 1.18 (s,

3H), 0.89 (d, J = 6.6 Hz, 6H), 0.84 (t, J = 6.8 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 210.8, 140.4, 140.1, 133.0, 129.6, 126.6, 126.3, 81.2,

72.2, 57.6, 45.1, 45.0, 36.0, 30.3, 27.1, 22.6. 22.54, 22.52, 18.2, 14.1; IR

(thin ﬁlm) 2955, 2927, 2868, 1713 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₃H₃₄O₂Na [M + Na]⁺365.2456, found 365.2447.

6-Butyl-3-(4-isobutylphenyl)-3-methyl-2-((E)-prop-1-enyl)-

dihydro-2H-pyran-4(3H)-one (65). Alcohol 32 (36 mg, 0.08 mmol)

and crotonaldehyde (9 mg, 0.13 mmol) were converted to 65

following the general procedures for THPO formation. Puriﬁcation by

column chromatography (10% EtOAc/hexanes) of the crude residue

aﬀorded THPO 65c (21 mg, 68%) and THPO 65t (8 mg, 26%) as a

clear light yellow oil: THPO 65c: R_f= 0.28 (10% EtOAc/hexanes); ¹H

NMR (500 MHz, CDCl₃) δ 7.70 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 1.6

Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 7.14−7.12 (m, 2H), 5.53

(dqd, J = 15.6, 6.6, 1.4 Hz, 1H), 5.12 (ddq, J = 15.4, 4.9, 1.7 Hz, 1H),

4.52 (dt, J = 3.1, 1.6 Hz, 1H), 3.96−3.90 (m, 1H), 3.92 (s, 3H), 2.69

(dd, J = 15.5, 11.9 Hz, 1H), 2.50 (dd, J = 15.6, 2.9 Hz, 1H), 1.83−1.77

(m, 1H), 1.67−1.60 (m, 1H), 1.63 (s, 3H), 1.52 (app. dt, J = 6.6, 1.4

Hz, 3H), 1.52−1.36 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 211.4, 157.9, 135.1, 133.7, 129.7, 129.0, 128.9, 127.3,

127.0, 126.5, 125.5, 118.8, 105.6, 83.7, 77.2, 58.5, 55.5, 44.6, 36.3, 27.5,

22.8, 18.0, 16.8, 14.2; IR (thin ﬁlm) 3058, 2956, 2933, 2858, 1710,

1606 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₂₄H₃₀O₃Na [M +

Na]⁺389.2093, found 389.2079. THPO 65t: R_f= 0.45 (10% EtOAc/

hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.80 (s, 1H), 7.72 (app. t, J

= 8.1 Hz, 2H), 7.37 (dd, J = 8.6, 1.2 Hz, 1H), 7.15 (dd, J = 8.8, 2.3 Hz,

1H), 7.11 (d, J = 2.1 Hz, 1H), 5.92 (dq, J = 18.2, 4.3 Hz, 1H), 5.64

(dd, J = 14.9, 8.9 Hz, 1H), 5.14 (d, J = 8.9 Hz, 1H), 4.12−4.07 (m,

1H), 3.92 (s, 3H), 2.38−2.28 (m, 2H), 1.76 (d, J = 6.4 Hz, 3H), 1.55−

1.48 (m, 1H), 1.39−1.30 (m, 1H), 1.26−1.18 (m, 6H), 0.93−0.87 (m,

1H), 0.84−0.81 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 210.7,

157.9, 137.9, 133.5, 133.2, 129.8, 129.2, 127.4, 126.3, 125.7, 125.6,

119.1, 105.5, 81.2, 72.3, 57.9, 55.5, 45.2, 36.0, 27.1, 22.7, 22.6, 18.2,

14.1; IR (thin ﬁlm) 2956, 2930, 2858, 1711, 1605 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₂₄H₃₀O₃Na [M + Na]⁺389.2093, found

389.2086.

Ethyl 3-(tert-Butyldimethylsilyloxy)-2,4-dimethylpent-3-

enoate (67). 2-Bromo-2-methylpropionyl bromide (1.6 g, 6.9

mmol) was added dropwise to a suspension of activated zinc dust

(0.91 g, 13.9 mmol) in dry THF (12 mL) at 0 °C. The reaction

mixture was stirred for 1 h at 0 °C and then transferred via cannula to

a solution of silyl ketene acetal 66 (0.5 g, 2.3 mmol) in dry THF (12

mL) at 0 °C. The gray-green mixture was stirred overnight, slowly

warming to room temperature. The reaction mixture was then diluted

with Et₂O (25 mL) and washed with H₂O (15 mL). The aqueous layer

was extracted with Et₂O (20 mL × 6). The organic layers were

combined, dried over anhydrous MgSO₄, ﬁltered, and concentrated in

vacuo. Puriﬁcation by column chromatography (10:1:89

Et₂O:Et₃N:hexanes) of the crude residue produced ethyl ester 67 as

a colorless oil (0.22 g, 33%): R_f= 0.57 (10% Et₂O/hexanes); ¹H NMR

(500 MHz, CDCl₃) δ 4.15−4.03 (m, 2H), 3.53 (q, J = 7.3 Hz, 1H),

1.59 (s, 3H), 1.57 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz,

3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 173.9, 142.8, 111.3, 60.7, 42.6, 26.2, 19.0, 18.9, 18.8, 14.4,

14.4, −3.5, −3.8; IR (thin ﬁlm) 2956, 2932, 2905, 2859, 1736, 1675

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₅H₃₀O₃SiNa [M + Na]⁺

309.1862, found 309.1864.

(2S,3S,6R)-6-Butyl-3-methyl-2-((Z)-2-methylbut-1-en-3-

ynyl)-3-phenyldihydro-2H-pyran-4(3H)-one (62c). Alcohol 29

(33 mg, 0.10 mmol) and 3-methylpent-2-en-4-ynal (5:1 Z:E ratio,

14 mg, 0.15 mmol) were converted to 62c following the general

procedures for THPO formation. Puriﬁcation by column chromatog-

raphy (10% EtOAc/hexanes) of the crude residue aﬀorded THPO 62c

as a clear colorless oil with a 5:1 Z:E ratio (14 mg, 48%); R_f= 0.35

1

(10% EtOAc/hexanes): H NMR (500 MHz, CDCl₃) δ 7.32−7.28

(m, 2H), 7.26−7.22 (m, 1H), 7.19−7.14 (m, 2H), 5.69 (dd, J = 8.7,

0.6 Hz, 1H), 4.91 (d, J = 8.7 Hz, 1H), 3.97−3.91 (m, 1H), 2.92 (s,

1H), 2.65 (dd, J = 15.8, 11.8 Hz, 1H), 2.50 (dd, J = 15.8, 3.2 Hz, 1H),

1.74 (d, J = 1.4 Hz, 3H), 1.62 (s, 3H), 1.61−1.56 (m, 1H), 1.48−1.46

(m, 1H), 1.41−1.33 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 210.6, 139.0, 132.1, 128.6, 128.1, 127.2, 123.4, 82.1,

81.9, 81.8, 76.9, 58.2, 44.5, 36.3, 27.4, 23.5, 22.8, 17.1, 14.2; IR (thin

ﬁlm) 3286, 2955, 2929, 2862, 1715 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₂₁H₂₆O₂Na [M + Na]⁺333.1830, found 333.1825.

3-Methyl-3-phenyl-6-(phenylethynyl)-2-((E)-prop-1-enyl)-

dihydro-2H-pyran-4(3H)-one (63). Alcohol 30 (41 mg, 0.10 mmol)

and crotonaldehyde (11 mg, 0.16 mmol) were converted to 63

following the general procedures for THPO formation. Puriﬁcation by

column chromatography (10% EtOAc/hexanes) of the crude residue

aﬀorded THPO 63 as a mixture of diastereomers (1.7:1.0 cis:trans)

that was a clear light yellow oil (31 mg, 94%). Some of THPO 63c and

THPO 63t was separated for characterization, but some of it was

recovered as a mixture of the two diastereomers: THPO 63c: R_f= 0.44

1

(10% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ 7.50−7.48

(m, 2H), 7.37−7.33 (m, 5H), 7.30−7.28 (m, 1H), 7.16 (d, J = 7.3 Hz,

2H), 5.56−5.49 (m, 1H), 5.20 (dq, J = 15.4, 2.4 Hz, 1H), 4.92 (dd, J =

12.1, 3.2 Hz, 1H), 4.49 (d, J = 5.5 Hz, 1H), 3.17 (dd, J = 15.9, 12.1 Hz,

1H), 2.79 (dd, J = 15.9, 3.2 Hz, 1H), 1.56 (s, 3H), 1.56 (d, J = 3H);

¹³C NMR (126 MHz, CDCl₃) δ 209.0, 139.3, 132.1, 130.4, 129.0,

128.4, 128.3, 128.3, 127.4, 124.6, 122.1, 86.5, 86.3, 84.6, 67.6, 58.8,

44.6, 18.0, 16.7; IR (thin ﬁlm) 2915, 1715 cm⁻¹; HRMS (ES/MeOH)

m/z calcd for C₂₃H₂₂O₂Na [M + Na]⁺353.1518, found 353.1519.

1

THPO 63t: R_f= 0.46 (10% EtOAc/hexanes); H NMR (500 MHz,

CDCl₃) δ 7.48−7.46 (m, 2H), 7.36−7.32 (m, 5H), 7.28−7.25 (m,

3H), 5.65−5.58 (m, 1H), 5.36 (dd, J = 6.5, 3.3 Hz, 1H), 5.29 (ddq, J =

14.0, 5.4, 1.4 Hz, 1H), 5.19 (d, J = 6.0 Hz, 1H), 3.14 (dd, J = 15.0, 6.5

Hz, 1H), 2.71 (dd, J = 15.0, 3.4 Hz, 1H), 1.62 (d, J = 6.6 Hz, 3H), 1.50

(s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 209.0, 140.3, 132.0, 130.6,

129.1, 128.6, 128.5, 128.1, 127.2, 125.1, 122.0, 88.9, 86.0, 79.8, 65.2,

58.9, 43.9, 18.1, 18.0; IR (thin ﬁlm) 2927, 2854, 1711 cm⁻¹; HRMS

(ES/MeOH) m/z calcd for C₂₃H₂₂O₂Na [M + Na]⁺353.1518, found

353.1512.

6-Butyl-3-(6-methoxynaphthalen-2-yl)-3-methyl-2-((E)-

prop-1-enyl)dihydro-2H-pyran-4(3H)-one (64). Alcohol 31 (48

mg, 0.12 mmol) and crotonaldehyde (13 mg, 0.18 mmol) were

converted to 64 following the general procedures for THPO

formation. Puriﬁcation by column chromatography (10% EtOAc/

hexanes) of the crude residue aﬀorded THPO 64 as a mixture of

diastereomers (3.0:1.0 cis:trans) that was a clear light yellow oil (20

mg, 50%). Some of THPO 64c and THPO 64t was separated for

characterization, but some of it was recovered as a mixture of the two

diastereomers: THPO 64c: R_f= 0.60 (10% EtOAc/hexanes); ¹H

NMR (500 MHz, CDCl₃) δ 7.10 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.2

Hz, 2H), 5.52−5.45 (m, 1H), 5.12−5.08 (m, 1H), 4.38 (d, J = 4.8 Hz,

1H), 3.90−3.85 (m, 1H), 2.64 (dd, J = 15.5, 11.8 Hz, 1H), 2.48−2.44

(m, 3H), 1.86 (app. septet, J = 6.7 Hz, 1H), 1.81−1.74 (m, 1H), 1.63−

1.57 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.51 (s, 3H), 1.51−1.35 (m,

4H), 0.93 (t, J = 7.1 Hz, 3H), 0.90 (dd, J = 6.6, 1.7 Hz, 6H); ¹³C NMR

(126 MHz, CDCl₃) δ 211.4, 140.4, 137.0, 128.9, 128.8, 128.0, 125.6,

3-(tert-Butyldimethylsilyloxy)-N-methoxy-N,2,4-trimethyl-

pent-3-enamide (68). A solution of 2.0 M i-PrMgCl (0.92 mL, 1.8

mmol) in dry THF was added dropwise to a solution of ethyl ester 67

8747

dx.doi.org/10.1021/jo501580p | J. Org. Chem. 2014, 79, 8733−8749

The Journal of Organic Chemistry

Article

(0.22 g, 0.77 mmol) and Me(MeO)NH·HCl (90 mg, 0.92 mmol) in

dry THF (6.4 mL) at −78 °C. The mixture was stirred for 3.5 h at −78

°C, warmed to 0 °C, and stirred for an additional 2.5 h. A solution of

2.0 M i-PrMgCl (0.92 mL, 1.8 mmol) in dry THF and Me(MeO)NH·

HCl (90 mg, 0.92 mmol) was added to the reaction mixture and

stirred for 2.5 h at 0 °C. The reaction was then quenched with

saturated aqueous NH₄Cl (5 mL). The mixture was extracted with

EtOAc (3 × 10 mL). The organic layers were combined, dried over

anhydrous MgSO₄, and ﬁltered, and the resulting solution was

concentrated in vacuo. Puriﬁcation by column chromatography (15%

EtOAc/hexanes) of the crude residue aﬀorded Weinreb amide 68 as a

aﬀorded THPO 72 as a clear colorless oil (20 mg, 50%): R_f= 0.43 (5%

EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ 5.74 (dq, J = 14.1,

1

4.4 Hz, 1H), 5.53 (app. ddd, J = 15.3, 6.8, 1.4 Hz, 1H), 3.64 (d, J = 7.0

Hz, 1H), 3.23−3.19 (m, 1H), 2.64−2.61 (m, 1H), 1.75 (d, J = 6.5 Hz,

3H), 1.72−1.67 (m, 1H), 1.60−1.52 (m, 1H), 1.43−1.25 (m, 4H),

1.11 (s, 3H), 0.97−0.93 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 213.8, 130.3, 126.3, 85.3, 83.0, 49.3, 45.5, 33.9,

27.1, 22.9, 20.0, 19.7, 18.2, 14.2, 9.9; IR (thin ﬁlm) 2959, 2934, 2859,

1710 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₅H₃₀O₂N [M +

NH₄]⁺256.2277, found 256.2276.

6-Butyl-3,3,5-trimethyl-2-((E)-prop-1-enyl)dihydro-2H-

pyran-4(3H)-one (73). Alcohol 71 (9 mg, 0.03 mmol) and

crotonaldehyde (6 mg, 0.09 mmol) were converted to 73 following

the general procedures for THPO formation using 3.0 equiv of

aldehyde and 3.0 equiv of BF₃·OEt₂instead of 1.5 equiv. The solution

was run at 0.3 M instead of 1.0 M. Puriﬁcation by column

chromatography (5% EtOAc/hexanes) of the crude residue aﬀorded

THPO 73 as a mixture of diastereomers (1.0:1.8 cis:trans) that was a

clear colorless oil (5.2 mg, 72%). Some of the THPO 73t was

separated for characterization, but most of it was recovered as a

mixture of the two diastereomers. THPO 73c: R_f= 0.49 (5% EtOAc/

hexanes); ¹³C NMR (126 MHz, CDCl₃) δ 219.9, 130.4, 126.5, 85.6,

79.0, 49.3, 47.5, 31.6, 27.9, 22.8, 21.1, 21.0, 18.2, 14.2, 12.6; ¹³C

chemical shifts were determined by taking a ¹³C NMR spectra of the

diastereomeric mixture and subtracting peaks that belonged to THPO

73t. THPO 73t: R_f= 0.42 (5% EtOAc/hexanes); ¹H NMR (500 MHz,

CDCl₃) δ 5.72 (dq, J = 18.4, 4.3 Hz, 1H), 5.54 (dd, J = 15.3, 7.5 Hz,

1H), 4.18−4.10 (m, 1H), 3.79 (d, J = 7.4 Hz, 1H), 3.23 (app. quintet, J

= 6.8 Hz, 1H), 1.75 (d, J = 6.4 Hz, 3H), 1.39−1.27 (m, 4H), 1.17 (s,

3H), 0.93 (s, 3H), 0.90 (d, J = 7.5 Hz, 3H), 0.88−0.83 (m, 5H); ¹³C

NMR (126 MHz, CDCl₃) δ 214.0, 130.6, 126.5, 79.2, 78.6, 44.5, 29.8,

27.4, 26.0, 22.6, 20.7, 19.7, 18.1, 14.2, 10.3; IR (thin ﬁlm) 2959, 2932,

2859, 1709 cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₅H₃₀O₂N [M

+ NH₄]⁺256.2277, found 256.2274.

1

colorless oil (183 mg, 79%): R_f= 0.54 (15% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 3.73−3.62 (m, 1H), 3.59 (s, 3H), 3.14 (s,

3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H), 0.93 (s, 9H),

0.14 (s, 3H), 0.12 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.8,

143.7, 109.9, 77.4, 60.7, 41.1, 26.2, 18.9, 18.7, 18.6, 14.8, −3.3, −3.4;

IR (thin ﬁlm) 2956, 2932, 2898, 2858, 1668 cm⁻¹; HRMS (ES/

MeOH) m/z calcd for C₁₅H₃₁NO₃SiNa [M + Na]⁺324.1971, found

324.1979.

3-(tert-Butyldimethylsilyloxy)-2,4-dimethylnon-2-en-5-one

(69). n-BuLi (2.27 M in hexanes, 0.33 mL) was added dropwise to a

solution of amide 68 (150 mg, 0.50 mmol) in dry THF (1.7 mL) at

−78 °C. The mixture was stirred for 2.5 h, and the reaction was

quenched with saturated aqueous NH₄Cl (5 mL). The mixture was

extracted with EtOAc (3 × 5 mL). The organic layers were combined,

dried over anhydrous MgSO₄, and ﬁltered, and the resulting solution

was concentrated in vacuo. Puriﬁcation by column chromatography

(10% EtOAc/hexanes) of the crude residue aﬀorded ketone 69 as a

1

colorless oil (123 mg, 83%): R_f= 0.82 (15% EtOAc/hexanes); H

NMR (500 MHz, CDCl₃) δ 3.34 (q, J = 7.0 Hz, 1H), 2.50 (ddd, J =

16.6, 8.3, 6.9 Hz, 1H), 2.36 (ddd, J = 16.6, 8.3, 6.6 Hz, 1H), 1.61 (s,

3H), 1.58 (s, 3H), 1.56−1.45 (m, 2H), 1.27 (m, 2H), 1.16 (d, J = 7.0

Hz, 3H), 0.90 (s, 9H), 0.86 (t, J = 7.4 Hz, 3H), 0.083 (s, 3H), 0.079 (s,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 210.3, 143.8, 111.7, 50.4, 40.0,

26.3, 26.2, 22.5, 19.1, 18.9, 18.7, 14.0, 13.1, −3.38, −3.42; IR (thin

ﬁlm) 2958, 2932, 2860, 1718, 1670 cm⁻¹; HRMS (ES/MeOH) m/z

calcd for C₁₇H₃₄O₂SiNa [M + Na]⁺321.2226, found 321.2222.

3-(tert-Butyldimethylsilyloxy)-2,4-dimethylnon-2-en-5-ol

(70/71). L-Selectride (1.0 M in THF, 0.53 mL) was added dropwise

to a solution of ketone 69 (106 mg, 0.36 mmol) in dry THF (3.6 mL)

at −78 °C. The mixture was stirred overnight, slowly warming to room

temperature. The reaction was quenched with saturated aqueous

NH₄Cl (10 mL), and the mixture was extracted with EtOAc (3 × 5

mL). The organic layers were combined, dried over anhydrous

MgSO₄, and ﬁltered, and the resulting solution was concentrated in

vacuo. Puriﬁcation by column chromatography (5% EtOAc/hexanes)

of the crude residue aﬀorded a mixture of alcohol 70 as a colorless oil

(50 mg, 46%) and alcohol 71 as a colorless oil (8 mg, 8%): Alcohol

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra of all new compounds, as well as

structure coordinates for the calculation on 72, 73c, and 73t,

and Chiracel AD HPLC traces for 48, 51, and 53. This material

is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: srychnov@uci.edu (S.D.R.).

■

Notes

The authors declare no competing ﬁnancial interest.

1

70: R_f= 0.52 (5% EtOAc/hexanes); H NMR (500 MHz, CDCl₃) δ

3.55−3.52 (m, 1H), 2.62 (app. dt, J = 15.7, 7.1 Hz, 1H), 2.22 (d, J =

2.1 Hz, 1H), 1.633 (s, 3H), 1.628 (s, 3H), 1.56−1.49 (m, 2H), 1.38−

1.29 (m, 4H), 0.98 (d, J = 8.4 Hz, 3H), 0.97 (s, 9H), 0.92−0.89 (m,

3H), 0.16 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 145.7, 111.9, 73.2,

41.7, 34.1, 28.0, 26.5, 23.0, 19.4, 19.2, 19.1, 15.4, 14.3, −2.7, −3.2; IR

(thin ﬁlm) 3567, 3489, 2957, 2932, 2859, 1713, 1668 cm⁻¹; HRMS

(ES/MeOH) m/z calcd for C₁₇H₃₆O₂SiNa [M + Na]⁺323.2382,

found 323.2381. Alcohol 71: R_f= 0.27 (5% EtOAc/hexanes); ¹H

NMR (500 MHz, CDCl₃) δ 3.66−3.62 (m, 1H), 2.58 (app. quintet, J

= 7.0 Hz, 1H), 1.91 (br. s, 1H), 1.62 (s, 3H), 1.59 (s, 3H), 1.38−1.27

(m, 6H), 1.09 (d, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.90 (t, J = 7.0 Hz,

3H), 0.16 (s, 3H), 0.14 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

147.3, 109.2, 75.0, 41.2, 34.8, 28.4, 26.6, 22.9, 19.5, 19.3, 19.1, 14.3,

13.7, −2.4, −3.1; IR (thin ﬁlm) 3340, 2956, 2930, 2858, 1708, 1669

cm⁻¹; HRMS (ES/MeOH) m/z calcd for C₁₇H₃₇O₂Si [M + H]⁺

301.2563, found 301.2576.

ACKNOWLEDGMENTS

■

Support was provided by the National Institute of General

Medicine (GM-43854) and the UC Irvine Undergraduate

Research Opportunities Program (UROP). We acknowledge

Alexander J. Wagner at UC Irvine for assistance with the chiral

HPLC analysis.

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Silyl enol ether Prins cyclization: Diastereoselective formation of substituted tetrahydropyran-4-ones

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