The stereochemical course of intramolecular michael reactions

Article

pubs.acs.org/joc

The Stereochemical Course of Intramolecular Michael Reactions

Eugene E. Kwan,^†Jonathan R. Scheerer,^‡and David A. Evans*^,†

^†Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United

States

^‡Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States

S

* Supporting Information

ABSTRACT: We present a general model for understanding the stereochemical

course of intramolecular Michael reactions. We show that the addition of β-

ketoester enolates to α,β-unsaturated esters and imides bearing adjacent

stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction.

Reinforcing and nonreinforcing stereochemical relationships are evaluated from

the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic,

and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair

transition-state model.

revealed that Michael acceptors bearing adjacent stereocenters

can engage pendant β-carboxyester enolates in highly diastereo-

selective bond formations (Scheme 1). Interestingly, the

observed facial selectivity was independent of whether the

reaction was conducted in a transannular (eq 1) or intra-

molecular (eq 2) format. To disentangle the local perturbations

introduced by the substituents adjacent to the acceptor from the

global conformational demands of macrocycle 1, we decided to

consider the behavior of intramolecular Michael additions in

more detail.

INTRODUCTION

■

In 1887, Arthur Michael showed that the intermolecular

conjugate addition of stabilized carbanions to electron-deﬁcient

oleﬁns is an eﬃcient method for the mild formation of C−C

bonds.¹⁻³Since then, intramolecular Michael reactions have

seen extensive use in the construction of polycyclic natural

products.⁴⁻⁸For example, en route to a synthesis of adreno-

sterone, Stork and co-workers formed the requisite trans-

hydrindane systems by adding aldehyde and β-ketoester enolates

to α,β-unsaturated ketones and esters.⁹⁻¹¹In this paper, we

demonstrate that high levels of diastereoselection can be

achieved in the intramolecular addition of β-ketoester enolates

to α,β-unsaturated carbonyl groups bearing allylic and

homoallylic stereocenters.

RESULTS AND DISCUSSION

■

If the reactions proceed via chair transition states, then two

plausible scenarios can be envisioned. With a dipole-minimized

enolate (eq 3), avoidance of a 1,3-diaxial interaction and an open

In certain cases, the sense of asymmetric induction is

signiﬁcantly inﬂuenced by counterion structure and solvent. In

others, reinforcing and non-reinforcing stereochemical relation-

ships between the allylic and homoallylic centers are clearly

present. Based on synthetic, spectroscopic, and computational

studies, we propose a dipole-minimized chair transition-state

model that accounts for the bulk of our observations.

transition state would lead to β,γ-anti selectivity. Alternatively, a

more chelating metal might enforce a closed transition state in

which the acceptor occupies an axial position, leading to β,γ-syn

selectivity (eq 4).

Our interest in this area arose during the course of our total

syntheses of clavolonine¹²and salvinorin A.¹³These eﬀorts

Scheme 1. Transannular vs. intramolecular Michael additions

Special Issue: Robert Ireland Memorial Issue

Received: October 26, 2012

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a

Table 1. Alkyl Substituents (E-Conﬁgured Acceptors)¹⁹

Table 2. Alkoxy Substituents (E-Conﬁgured Acceptors)

a

Conditions: base (equiv), −78 °C to rt, 18 h; dr refers to anti/syn.

Remainder was recovered starting material.

b

a

Conditions: base (equiv), −78 °C to rt, 18 h; dr refers to anti/syn

Scheme 2. Minimization of 1,3-Allylic Strain for Z-Acceptors

ratio.

In accordance with this hypothesis, Table 1 demonstrates that

alkyl-substituted substrates can lead to either diastereomer,

depending on the conditions.¹⁴These ﬁndings echo the results of

our previous studies¹²and those of Keck¹⁵and Gung.^16,17In

contrast, β,γ-anti products predominate for alkoxy-substituted

substrates (Table 2). Changing the enolization conditions

generally allowed us to perturb the level, but not overall sense,

of diastereoselection. Although one provocative explanation for

this marked β,γ-anti preference might be that it is stereo-

electronically favorable to position the forming bond anti to the

C−O σ* orbital, in analogy to the polar Felkin−Anh model for

carbonyl additions,¹⁸we will suggest below that more mundane

steric and electrostatic factors are responsible.

Although keto−enol tautomerism ultimately erases any

memory of the reactive conﬁguration at the enolate, it is clear

that enolate geometry plays an important role in determining

stereoselectivity. In general, β-ketoester enolates can exist as

chelated (Z) or dipole-minimized (E) forms:²¹⁻²⁵

We hypothesized that an alternative means of enforcing β,γ-

anti selectivity might be to use the 1,3-allylic strain induced by a

combination of Z-acceptors and γ-substituents. In such arrange-

ments, there are two conformations that place the acceptor and

its allylic hydrogen in the same plane (Scheme 2). For a reaction

to occur, there must be suﬃcient orbital overlap between the π-

system of the enolate and the π*-system of the acceptor.

Therefore, only 23^⧧should be reactive and β,γ-anti selectivity

should be observed.

An examination of Table 3 shows that Z-acceptors are indeed

uniformly β,γ-anti selective, regardless of γ-alkyl or γ-alkoxy

substitution. Similar to the results of Table 2, changing the

enolization conditions sometimes decreased the magnitude of

selectivity, but never overturned it completely. Notably, the use

of β,β-disubstituted acceptors allowed the formation of

quaternary stereocenters. However, this required the increased

electrophilicity of imide acceptors.²⁰

1

Variable-temperature H and ¹³C NMR studies show that

when methyl 3-oxodecanoate (37) is treated with 1 equiv of

LiHMDS in THF-d₈, it is converted to Z enolate 38:

(The Z,Z and Z,E forms were not distinguishable.) Similar

behavior was observed in THF-d₈with LiOMe (with and without

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Table 3. Alkyl and Alkoxy Substituents (Z Acceptors)

Figure 1. Selective inversion data for the tetrabutylammonium enolate

of 39 (0.12 M in THF at 318 K). The unequal asymptotes reﬂect the ca.

2:1 equilibrium ratio of enolate isomers.

Fitting the data to a two-site model and subsequent Eyring

analysis places the activation enthalpy of enolate isomerization at

ca. 14 kcal/mol (see the Supporting Information). This is

signiﬁcantly lower than the >20 kcal/mol barriers that would be

expected for these Michael reactions, which are unimolecular

reactions with half-lives of hours. Similar experiments with

Cs₂CO₃/MeOH gave broad signals also indicative of rapid

enolate geometry equilibration.

a

Base (equiv); −78 °C to rt; β,γ-anti/β,γ-syn.

This behavior contrasts with that of more conventional ester

enolates, which do not easily isomerize. This can be readily

explained. In ethereal solutions, enolate isomerization must

occur through a high barrier CC π-bond rotation process. In

hydroxylic solutions, the acidity of the solvent allows small

amounts of β-ketoester to exist and undergo facile C−C σ-bond

rotation. Additionally, these Michael reactions are irreversible:

re-exposure of diastereomeric mixtures of Michael products to

the reaction conditions gave no change in the product ratio.

Together, these observations suggest that the sensitivity of the

diastereoselectivity to the enolization conditions results from

diﬀerentially selective E and Z enolate pathways that can

compete via a Curtin−Hammett scenario in hydroxylic solvents.

How is stereochemical information relayed in these reactions?

Although modeling the subtle eﬀects of ion-pairing with metals

like cesium is still challenging,³⁰we have previously shown that

the stereochemical outcomes of Michael additions can be

successfully predicted by treating lithium enolates as explicitly

ether-solvated contact ion pairs.³¹Such an analysis of simpliﬁed

system 40 at M05-2X/6-311+g(d,p)//M05-2X/6-31g(d) re-

produces the irreversibility noted above (Scheme 3): the forward

free energy barrier is somewhat underestimated (18.6 kcal/mol)

but signiﬁcantly smaller than the reverse barrier (33.8 kcal/

mol).³²This diﬀerence largely reﬂects the favorability of

replacing a less stable CC bond with a more stable C−C

bond. While this is initially countered by the conversion of a

more stable β-ketoester enolate (40, pK_ain DMSO ∼ 14) into a

less stable ester enolate (45, pK_a∼ 30), eventual proton transfer

to form a new β-ketoester enolate (46) compensates for this.

A search for transition structures revealed that chair

conformations (41^⧧and 42^⧧) are considerably favored over

LiClO₄), NaHMDS, and NaH. No evidence of the E enolate was

found and the lineshapes were unchanged with temperature. In

MeOH-d₄, deuterium exchange with solvent complicates NMR

observations.²⁶Instead, the enolates of [3-¹³C]-tert-butyl 3-

oxodecanoate (39) were directly observed in standard protio-

solvents via ¹³C NMR with inverse-gated decoupling.

Upon the addition of 1 equiv of LiHMDS to 39 in THF, the

carbonyl resonance shifted from 201.6 ppm to 188.6 ppm,

indicating enolization. Similar experiments in methanol with

NaHMDS, KHMDS, and Cs₂CO₃revealed two singlets at ca. 190

ppm (Z isomer) and 182 ppm (E isomer) in ratios of 5:1, 1:1, 1:2,

and 1:3, respectively. These assignments were conﬁrmed by the

addition of one equivalent of LiOMe to the cesium enolate; the

ratio was reversed from 1:3 to 3:1.

The possibility that these enolate isomers are in rapid

equilibrium was conﬁrmed by selective inversion experi-

ments.²⁷⁻²⁹We made the unusual choice of performing the

experiments in the ¹³C domain not only to avoid the interference

of water, but also to take advantage of the relatively long T₁

relaxation times of carbonyl carbons. An equimolar mixture of 39

and Bu₄NOH·30H₂O gave a ca. 2:1 ratio of isomers (no

assignments made). When one of the resulting singlets was

selectively inverted, the magnetization of its counterpart

experienced a transient decrease (Figure 1). This observation

is a classic hallmark of a chemical exchange process.

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Scheme 3. Energetics of Intramolecular Michael Additions

Figure 3. Diaxial preference in transition states.

(15 vs 17). Additionally, the axial orientation of the γ-silyloxy

substituent minimizes its dipole interactions with the enolate and

acceptor carbonyl groups.

This 1,2-diaxial model also accounts for the increase in β,γ-anti

selectivity (17 vs 21) observed when an equatorial δ-methyl

group is added (Scheme 4, eq 6).³³Reinforcing stereocontrol

results from the unfavorable 1,3-interactions that would be

incurred by placing the δ-methyl group in a pseudoaxial position.

In contrast, adding an axial δ-methyl completely reverses the

selectivity to β,γ-syn (17 vs 19). The normally favored diaxial

geometry now suﬀers from a destabilizing 1,3-interaction (eq 7).

As a consequence, the substituents adopt a more stable 1,2-

diequatorial conformation, while the acceptor remains axial to

facilitate lithium ion transfer.

boat ones (43^⧧and 44^⧧). Interestingly, the acceptor prefers to

occupy an axial orientation (by 1 kcal/mol). Although this may

be somewhat surprising, the disfavored equatorial orientation

incurs a steric interaction between the enolate and the acceptor

(Figure 2). This is reﬂected in the elongated distance for the

CONCLUSIONS

■

Intramolecular Michael reactions are kinetically controlled

transformations whose product distributions reﬂect a complex

interplay between the intrinsic stereochemical preferences of the

substituents present and the enolate geometry. If the lithium

enolates are treated as geometrically pure contact ion pairs, the

predicted dipole-minimized chair transition states are in

qualitative agreement with experiment. This analysis should

provide a basis for greater sophistication in the design of future

Michael additions.

Figure 2. Preferred acceptor orientation.

forming C−C bond (1.96 Å for 42^⧧vs 1.92 Å for 41^⧧). In turn,

this appears to decrease the favorability of lithium ion transfer;

for example, the distance from the lithium ion to the acceptor

carbonyl oxygen increases from 1.98 Å in 41^⧧to 2.15 Å for 42^⧧).

For a truncated version of γ-silyloxy-substituted substrate 15,

the lowest energy chair transition state also orients its

substituents in a trans-1,2-diaxial fashion (47^⧧, Scheme 4). In

this case, 47^⧧avoids both an analogous enolate−acceptor

interaction and a new acceptor−substituent interaction (Figure

3). The minimization of the acceptor−substituent interaction

accounts for the increase in selectivity with protecting group size

EXPERIMENTAL SECTION

■

Computations. All structures were optimized at M05-2X/6-31g(d)

in the gas phase using the ultraﬁne grid. Single point energies were

obtained at M05-2X/6-311+g(d,p) and the free energy corrections from

M05-2X/6-31g(d) were added to obtain the ﬁnal energies. Frequency

analyses were performed to verify that each structure actually

corresponds to a local minimum or ﬁrst-order saddle point.

Computations were performed using Gaussian 09, Revision A.02.

Selective Inversion Analysis. Selective 180° inversions were

achieved with shaped IBURP2 pulses and used in a standard selective-

inversion recovery experiment as described by Bain and co-workers.²⁷A

delay of 60 s was used in between delay time increments.

General Experimental Details. All reactions were carried out

under an atmosphere of nitrogen in ﬂame-dried or oven-dried glassware

with magnetic stirring. Flash chromatography was carried out with 230−

400 mesh silica gel. Analytical thin-layer chromatography was performed

with 0.25 mm silica gel plates. Visualization was accomplished with UV

light, aqueous ceric ammonium molybdate (CAM) solution, anisalde-

hyde, potassium permanganate, or potassium iodoplatinate (PIP)

staining followed by heating. Melting points are uncorrected. Optical

rotations were measured on a digital polarimeter with a sodium lamp.

Infrared spectra were recorded on an FT-IR spectrometer. NMR spectra

are reported in ppm using residual solvent as the internal standard.

High-resolution mass spectrometry data were obtained generally

obtained via electrospray ionizartion with a quadrupole detector.

Semipreparative HPLC was performed using an a 21.2 mm normal

Scheme 4. Inﬂuence of the δ-Stereocenter

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phase silica column. Unless otherwise noted, the synthesized

compounds were judged to be >95% pure.

°C over 1 h while stirring. The reaction was quenched with 5 mL of 2-

propanol and 25 mL of saturated aqueous ammonium chloride. The

mixture was extracted with 100 mL of diethyl ether three times, diluted

with hexanes, dried over sodium sulfate, and concentrated to yield a

brown oil. The oil was puriﬁed by silica gel chromatography (5, 10% 2-

propanol/hexanes) to aﬀord the desired alkylated lactone as a clear

yellow oil (8.98 g, 87%): TLC R_f= 0.60 (20% 2-propanol/hexanes,

KMnO₄stain); IR (CHCl₃ﬁlm) 3028, 2950, 2874, 1956, 1747, 1604,

1496, 1454, 1392, 1344, 1248, 1150, 1072, 977, 747, 702 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 1.75−1.83 (1 H, m), 1.84−1.95 (2 H, m), 2.66−

2.78 (2 H, m), 3.36 (2 H, dd, J = 18.56, 8.79 Hz), 4.21−4.33 (2 H, m),

7.18−7.24 (3 H, m), 7.25−7.32 (2 H, m); ¹³C NMR (100 MHz, CDCl₃)

δ 22.0, 24.2, 37.3, 41.6, 68.6, 126.6, 129.3, 139.1, 174.2; HRMS (CI)

calcd for C₁₂H₁₈O₂N [M + NH₄]⁺208.1338, found 208.1328.

Tetrahydrofuran, dichloromethane, ethyl ether, and toluene were

puriﬁed by ﬁltration through a column of activated alumina under an

argon atmosphere. Triethylamine, diisopropylethylamine, and diisopro-

pylamine were distilled from calcium hydride immediately before use.

Benzyl bromide and allyl bromide were puriﬁed by passage through a

column of basic alumina before use.

General Procedure for Michael Additions. A solution of

substrate (ca. 20 mg) in 1 mL of solvent was prepared under an argon

atmosphere and chilled to −78 °C. A solution of base in 1 mL of solvent

was prepared at room temperature and added dropwise. The clear and

colorless or slightly yellow solution generally became vivid yellow in

color. The reaction was allowed to proceed at −78 °C for 1 h and

allowed to warm to room temperature slowly over several hours. After

18 h, the mixture was diluted with 30 mL of dichloromethane and

extracted with 30 mL of 0.1 M HCl. The layers were separated and the

aqueous layer was back-extracted four times with 10 mL portions of

dichloromethane. The combined organic layers were washed with 10

mL of brine, dried over sodium sulfate, ﬁltered, and concentrated. The

crude Michael adduct was puriﬁed by silica gel chromatography to yield

a yellow oil. Typically, the ¹H NMR spectra of these adducts were very

complex due to the presence of keto−enol tautomers and diastereomers.

As a result, only characterization data for their decarboxylated

counterparts are given (see the Supporting Information; diastereomer

ratios were assessed on the crude material). These cyclohexanones were

typically isolated as yellow oils and were further puriﬁed by

semipreparative HPLC to separate any diastereomers for detailed

stereochemical analysis.

Decarboxylation Procedures. A. Krapcho Method. A solution of

Michael adduct (10 mg) in 1 mL of DMSO was prepared in a sealed

tube. Lithium chloride (approximately 10 mg) and water (approx-

imately 0.1 mL) were added. The mixture was heated at 135 °C for 3.5 h.

B. TFA Method. A solution of tert-butyl β-ketoester (10 mg) was

dissolved in 0.8 mL of CDCl₃at room temperature. Triﬂuoroacetic acid

(0.2 mL) was added. The yellow solution was allowed to stand at room

temperature for 2 h. The solvent was removed by passing a gentle stream

of nitrogen over the solution. The oil was then thoroughly evacuated

under high vacuum for 5 min. The oil was suspended in 1 mL of CDCl₃

and heated at 80 °C for 1 h. The ratio of diastereomers was assessed by

¹H NMR analysis. The crude cyclohexanone was puriﬁed by silica gel

2-Benzyl-5-(tert-butyldimethylsilanyloxy)pentanoic Acid Methox-

ymethylamide (S-018). To a solution of N,O-dimethylhydroxylamine

hydrochloride (dried azeotropically with benzene immediately prior to

use) (3.07 g, 31.5 mmol) in dichloromethane (17.5 mL, to make a 1.8 M

solution) at 0 °C was added trimethylaluminum (3.02 mL, 31.5 mmol)

dropwise over 5 min. The solution was stirred for 45 min. Valerolactone

(2.00 g, 10.5 mmol in 20 mL of dichloromethane) was added dropwise

over 5 min. The solution was stirred for 3 h. The reaction was quenched

with a solution of Rochelle’s salt (3.60 g, 12.6 mmol) in water (5.0 mL,

280 mmol). The mixture was ﬁltered over a Celite plug and rinsed with

10 mL of dichloromethane. The mixture was concentrated to yield the

desired Weinreb amide as a clear oil (2.61 g, 99%). The oil was dissolved

in 20 mL of DMF, and tert-butyldimethylsilyl chloride (1.58 g, 10.5

mmol) and imidazole (1.70 g, 25.0 mmol) were added. The mixture was

stirred overnight. The mixture was diluted with 100 mL 3:1 hexanes/

ethyl acetate and 100 mL of 1 M HCl. The layers were separated, and the

aqueous layer was washed three times with 20 mL portions of 3:1

hexanes/ethyl acetate. The combined organic layers were washed with

50 mL of water and 50 mL of brine, dried over sodium sulfate,

concentrated, and puriﬁed by silica gel chromatography (3, 5, 7% 2-

propanol/hexanes) to yield the desired protected alcohol as a clear oil

(3.26 g, 85%): TLC R_f= 0.30 (30% 2-propanol/hexanes, KMnO₄stain);

IR (CHCl₃ﬁlm) 2930, 2857, 1662, 1468, 1387, 1255, 1175, 1101, 992,

836, 776, 700, 668 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.02 (6 H, s),

0.83−0.94 (9 H, s), 1.39−1.75 (5 H, m), 2.67 (1 H, dd, J = 12.9, 5.6 Hz),

2.97 (1 H, dd, J = 13.2, 8.8 Hz), 3.10 (3 H, s), 3.30 (3 H, s), 3.48−3.66 (2

H, m), 7.07−7.33 (5 H, m); ¹³C NMR (100 MHz, CDCl₃) δ −5.3, 18.3,

25.9, 28.8, 30.6, 38.9, 43.1, 61.1, 62.9, 126.1, 128.2, 129.1, 140.2; HRMS

(ESI) calcd for C₂₀H₃₆NO₃Si [M + H]⁺366.2464, found 366.2459.

chromatography.

C. Pd Method. A solution of allyl β-ketoester (10 mg) was dissolved

in 5 mL of CH₂Cl₂at room temperature under an argon atmosphere.

Morpholine (20 equivalents) was added, followed by palladium

tetrakis(triphenylphosphine) (10 mol %). The yellow solution was

allowed to stand at room temperature for 1 h. The mixture was diluted

with 50 mL of 3:1 hexanes/ethyl acetate and 50 mL of 0.1 M HCl. The

layers were separated, and the aqueous layer was back-extracted four

times with 10 mL portions of 3:1 hexanes/ethyl acetate. The combined

organic layers were washed with 50 mL of water and 10 mL of brine,

dried over sodium sulfate, and concentrated. The crude cyclohexanone

was puriﬁed by silica gel chromatography. The ratio of diastereomers

was assessed by ¹H NMR analysis.

(E)-Methyl 4-Benzyl-7-((tert-butyldimethylsilyl)oxy)hept-2-enoate

(18a). To a solution of Weinreb amide (210 mg, 0.574 mmol) in 5 mL of

toluene at −78 °C was added a solution of DIBAL-H (1.72 mL, 1.72

mmol, 1.0 M in toluene) dropwise. The solution was stirred for 4 h at

−78 °C and quenched by the addition of ethyl acetate followed by water.

The solution was diluted with 100 mL of dichloromethane and 100 mL

of 1 M HCl. The emulsion was stirred vigorously for 20 min. The layers

were separated, and the aqueous layer was washed three times with 20

mL of dichloromethane. The combined organic layers were washed with

50 mL of brine and concentrated to yield a clear oil. The oil was puriﬁed

by silica gel chromatography (3% EtOAc/hexanes) to yield the desired

alcohol as a clear oil (114 mg, 70%). n-BuLi in hexanes (0.15 mL, 0.42

mmol, 2.89 M) and trimethyl phosphonoacetate (70 uL, 0.43 mmol)

were added in sequence to a solution of 1,1,1,3,3,3-hexaﬂuoro-2-

propanol (47 uL, 0.44 mmol) in 3 mL of DME at −15 °C. Aldehyde

(100 mg, 0.36 mmol) was added, and the reaction was stirred for 4 h.

The reaction was allowed to warm to room temperature and was stirred

Substrate Preparation and Compound Characterization

Data.

3-Benzyltetrahydropyran-2-one (S-017). To a solution of diisopropyl-

amine (8.7 mL, 62.1 mmol) in 50 mL of THF at −10 °C was added

freshly titrated n-butyllithium (22.2 mL of a 2.68 M solution in hexane,

59.4 mmol). The solution was stirred for 30 min and cooled to −78 °C.

A solution of recently distilled δ-valerolactone (5.0 mL, 54 mmol) in 50

mL of THF was added dropwise over 1.5 h, followed by a solution of

benzyl bromide (12.8 mL in 25 mL THF, 108 mmol). The benzyl

bromide was ﬁltered through a neutral alumina plug before use. The

solution was stirred at −78 °C for 3 h. The solution was warmed to −40

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for an additional 20 h. The mixture was diluted with 50 mL of

dichloromethane and quenched with 10 mL of saturated aqueous

ammonium chloride and 50 mL of water. The aqueous layer was

separated and extracted three times with dichloromethane. The

combined organic layers were washed with sodium sulfate and

concentrated to yield a white suspension. The mixture was puriﬁed by

silica gel chromatography (5% EtOAc/hexanes) to yield the desired

protected oleﬁn as a clear oil (99 mg, 70%, 34:1 E:Z).

(E)-9-tert-Butyl 1-Methyl 4-benzyl-7-oxonon-2-enedioate Ester

(5). To a dry vial were added tin(II) chloride (76 mg, 0.4 mmol) and

dichloromethane (3 mL). tert-Butyl diazoacetate (1.12 mL, 8.12 mmol)

was added dropwise to the vial with vigorous stirring. After gas evolution

ceased, aldehyde (1.00 g, 4.06 mmol) was added, and the yellow solution

was stirred overnight. The solution was diluted with 100 mL of

dichloromethane and 100 mL of saturated sodium bicarbonate solution.

The layers were separated, and the aqueous layer was back-extracted

three times with 10 mL portions of dichloromethane. The combined

organic layers were washed with 50 mL of water and 50 mL of brine,

dried over sodium sulfate, and concentrated to yield a yellow oil. The oil

was puriﬁed by silica gel chromatography (5% 2-propanol/hexanes).

The remaining tert-butyl diazoacetate was removed by high vacuum

evaporation to yield the desired ketoester as a yellow oil (1.32 g, 91%):

TLC R_f0.65 (20% 2-propanol/hexanes, red, anisaldehyde stain); IR

(CHCl₃ﬁlm) 3429, 2963, 2932, 1720, 1654, 1496, 1456, 1436, 1369,

1317, 1272, 1215, 1160, 985, 851, 749, 701, 668 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 1.34−1.36 (9 H, s), 1.43−1.56 (1 H, m), 1.71−1.83 (1

H, m), 2.30−2.48 (3 H, m), 2.56−2.67 (2 H, m), 3.18 (2 H, s), 3.60 (3

H, s), 5.59 (1 H, d, J = 16.5 Hz), 6.64 (1 H, dd, J = 15.6, 9.2 Hz), 7.01 (2

H, d, J = 6.9 Hz), 7.09 (1 H, t, J = 7.3 Hz), 7.16 (2 H, t, J = 7.3 Hz); ¹³C

NMR (100 MHz, CDCl₃) δ 27.0, 27.9, 40.3, 41.1, 43.5, 50.6, 51.4, 81.9,

121.8, 126.2, 128.3, 128.1, 129.0, 138.8, 151.3, 166.2, 166.5, 202.4;

HRMS (ESI) calcd for C₂₁H₃₂O₅N [M + NH₄]⁺378.2280, found

378.2282.

(E)-Methyl 4-Benzyl-7-hydroxyhept-2-enoate (S-019). The oleﬁn

(99 mg) was dissolved in 5 mL of methanol, and 10-camphorsulfonic

acid (63 mg, 0.27 mmol) was added. The solution was stirred at room

temperature for 30 min, after which TLC analysis indicated full

consumption of starting material. Ten milliliters of sodium bicarbonate

solution was added, and the bulk of the methanol was removed by rotary

evaporation. The mixture was resuspended in 50 mL of dichloro-

methane and 50 mL of sodium bicarbonate. The layers were separated,

and the aqueous layer was back-extracted three times with 10 mL

portions of dichloromethane. The combined organic layers were washed

with 20 mL of brine, dried over sodium sulfate, concentrated, and

puriﬁed by silica gel chromatography (30, 60% EtOAc/hexanes) to yield

the desired oleﬁn−alcohol as a clear oil (54 mg, 73%): TLC R_f0.3 (50%

EtOAc/hexanes); IR (CHCl₃ﬁlm) 3422 (br), 3026, 2931, 2358, 1718,

1

1654, 1496, 1436, 1271, 1210, 1157, 1053, 983, 699 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ ppm 1.36−1.44 (1H, m), 1.44−1.53 (1H, m),

1.54−1.65 (2H, m), 2.44−2.54 (1H, m), 2.65−2.76 (2H, m), 3.55−3.64

(2H, m), 3.71 (3H, s), 5.70 (1H, dd, J = 15.6, 1.0 Hz), 6.80 (1H, dd, J =

15.6, 9.3 Hz), 7.12 (2H, d, J = 6.8 Hz), 7.19 (1H, t, J = 7.3 Hz), 7.27 (2H,

dd, J = 10.3, 7.3 Hz); ¹³C NMR (125 MHz, CDCl₃, and via spectrally

edited gHSQC, 500 MHz in CDCl₃, 4 transients per increment, 2 × 128

increments with linear prediction to 1024, ¹H spectral window of 4015

Hz, ¹³C spectral window of 21384 Hz) δ 167.1 (C), 152.5 (6.81, CH),

139.5 (C), 129.3 (7.28, CH), 128.6 (7.21, CH), 126.4 (7.12, CH), 121.6

(5.70, CH), 62.9 (3.59, CH₂), 51.7 (3.71, CH₃), 44.5 (2.49, CH), 41.3

(2.71, CH₂), 30.6 (1.48, 1.58, CH₂), 30.1 (1.41, 1.58, CH₂); HRMS

(ESI) calcd for C₁₅H₂₁O₃[M + H]⁺249.1491, found 249.1481.

1,2-trans-(2-Benzyl-5-oxocyclohexyl)acetic acid methyl ester (S-

021-anti): TLC R_f0.30 (30% EtOAc/hexanes, CAM stain); HRMS

(ESI) calcd for C₁₆H₂₁O₃[M + H]⁺261.1491, found 261.1486. The

compound was characterized by extensive NMR analysis (Table 4).

While data are given in CDCl₃, good separation of peaks was observed in

1:1 C₆D₆/CDCl₃.

4-Benzyl-7-oxo-hept-2-enoic Acid Methyl Ester (S-020). To a

stirring solution of alcohol (36 mg, 0.145 mmol) in 4 mL of CH₂Cl₂at 0

°C was added freshly distilled N,N-diisopropylethylamine (0.18 mL,

1.01 mmol) dropwise via syringe. After 10 min, dimethyl sulfoxide (0.10

mL, 1.45 mmol) was added to the reaction mixture via syringe and the

solution was allowed to stir for an additional 10 min. Sulfur trioxide

pyridine complex (0.122 g, 11.7 mmol) was then added in one portion.

The reaction was allowed to proceed for 4 h at 0 °C, after which TLC

analysis indicated complete consumption of starting material. The

reaction was quenched by transfer into an 125 mL Erlenmeyer ﬂask that

contained a stirring saturated aqueous NaHCO₃solution. The aqueous

layer was back-extracted three times with 3:1 hexanes/ethyl acetate. The

organic layers were combined, washed with brine, dried over sodium

sulfate, and concentrated. The yellow oil was puriﬁed by silica gel

chromatography (5% 2-propanol/hexanes) to yield the desired

aldehyde as a clear, colorless oil (33 mg, 92%): TLC R_f0.5 (20% 2-

propanol/hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 2341, 1722, 1654,

1,2-cis-(2-Benzyl-5-oxocyclohexyl)acetic acid methyl ester (S-021-

syn): TLC R_f= 0.30 (30% EtOAc/hexanes, CAM stain); ¹H NMR (500

MHz, CDCl₃) δ 1.63 (1 H, m, J = 14.1, 8.8 × 2, 5.5), 1.80, 1 H, ddd, J =

13.7, 6.9, 3.8), 2.33 (1 H, m), 2.26 (1 H, m), 2.34 (1 H, m), 2.52 (1 H,

m), 2.62 (1 H, m), 2.65 (1 H, m), 2.77 (dd, J = 13.5, 5.5), 3.70 (3 H, s),

7.17 (2 H, m), 7.23 (1 H, m), 7.32 (2 H, m); ¹³C NMR (125 MHz,

CDCl₃, obtained by HSQC/HMBC) δ 27.3, 34.6, 36.2, 37.6, 40.1, 51.9,

126.5, 128.8, 129.1, 140.3, 172.0, 211.0; HRMS (ESI) calcd for

C₁₆H₂₁O₃[M + H]⁺261.1491, found 261.1500.

1

1457, 1435, 1362, 1317, 1273, 1213, 1161, 1031, 986, 857 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 1.55−1.69 (1H, m), 1.82−1.95 (1H, m),

2.31−2.45 (2H, m), 2.44−2.57 (1H, m), 2.72 (2 H, d, J = 7.0 Hz), 3.71

(3H, s), 5.70 (1H, dd, J = 15.7, 0.7 Hz), 6.74 (1H, dd, J = 15.7, 9.3 Hz),

7.10−7.13 (2H, m), 7.16−7.23 (1H, m), 7.23−7.31 (2H, m), 9.71 (1H,

s); ¹³C NMR (100 MHz, CDCl₃) δ 25.7, 41.1, 41.5, 43.7, 51.5, 122.0,

126.4, 128.3, 129.1, 138.7, 151.1, 166.6, 201.5; HRMS (CI) calcd for

C₁₅H₁₈O₃[M + H⁺] 246.1256, found 246.1271.

F

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The Journal of Organic Chemistry

Article

1.46 (1 H, td, J = 13.4, 6.3 Hz), 1.52−1.61 (1 H, m, J = 13.2, 13.2, 6.3

Hz), 2.25 (1 H, ddd, J = 18.1, 7.8, 2.9 Hz), 2.42−2.49 (1 H, m, J = 12.0,

8.5, 6.0, 2.0 Hz), 3.59−3.72 (4 H, m), 9.75 (1 H, t, J = 2.2 Hz).

To a suspension of lithium chloride (4.56 g, 108 mmol) in 30 mL of

acetonitrile was added trimethyl phosphonoacetate (5.2 mL, 32.3

mmol) followed by diisopropylethylamine (11.2 mL, 64.5 mmol). A

solution of aldehyde (4.95 g, 21.5 mmol) in 30 mL of acetonitrile as

added, and the solution was heated at 60 C for 2 h. The solution was

cooled, and the bulk of the lithium chloride was removed by decanting.

The solution was concentrated, and transferred to a separatory funnel

with successive washes with diethyl ether and water. 100 mL 1 M HCl

was added, and the layers were separated. The aqueous layer was back-

extracted three times with 50 mL portion of diethyl ether. The combined

organic layers were washed with 50 mL of water and 50 mL of brine,

diluted with 100 mL of hexanes, and dried over sodium sulfate. The

solution was ﬁltered through a combined Celite (2 × 15 cm) and silica

plug (5 × 15 cm). 250 mL of 30% v/v ethyl acetate in hexanes was

poured through the plug. The combined solution was concentrated to

yield the desired enoate as a yellow oil (5.3 g, 86%): TLC R_f= 0.8 (30%

EtOAc/hexanes, KMnO₄); IR (CHCl₃ﬁlm) 2929, 1726, 1657, 1437,

1323, 1272, 1204, 1171, 1093, 1045, 983, 837, 777 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ ppm −0.04−0.08 (6 H, m), 0.78−0.98 (12 H, m),

1.28−1.47 (1 H, m), 1.47−1.69 (1 H, m), 1.72−1.86 (1 H, m), 1.89−

2.13 (2 H, m), 2.15−2.28 (1 H, m), 3.55−3.75 (5 H, m), 5.74−5.87 (1

H, m), 6.92 (1 H, ddd, J = 15.4, 7.7, 7.6 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ −5.4, −3.6, −3.0, 17.9, 18.0, 18.2, 19.4, 25.5, 25.6, 25.8, 29.1,

39.1, 39.3, 39.6, 51.3, 51.3, 60.5, 60.9, 122.0, 122.2, 147.9, 148.3, 166.9;

HRMS (ESI) calcd for [C₁₅H₃₁O₃Si]⁺287.2042, found 287.2046.

Table 4. NMR Data for S-021-anti (500 MHz, CDCl₃)

ID

δ ¹H

δ

¹³C

Hs

type

couplings (Hz)

1

7.31

7.23

7.17

3.70

3.06

2.62

2.50

2.41

2.34

2.33

2.27

2.21

2.19

1.90

1.89

1.42

128.7

126.5

129.3

51.9

39.0

38.8

45.9

38.8

39.0

40.2

45.9

40.2

39.6

29.6

41.3

29.6

2

1

2

3

1

m

2

m

3

m

4

s

5

dd

td

m

13.6, 4.1

15.3, 4.8

8.7, 3.2

6

7

8

9

m

10

11

12

13

14

15

16

m

dddd

14.8, 11.2, 10.4, 4.5

quaternary carbons: 170.0, 140.3, 211.0

3-((tert-Butyldimethylsilyl)oxy)-2-methylpropan-1-ol (S-022). n-

BuLi (2.74 M in hexane, 36.5 mL, 100 mmol) was added dropwise to

a solution of 3-methyl-1,5-pentanediol (12.1 mL, 100 mmol, dried

azeotropically with benzene immediately prior to use) in 250 mL of

THF at 0 °C. The solution was stirred for 30 min and warmed to room

temperature. The solution was stirred for another 1 h, after which tert-

butyldimethylsilyl chloride (15.1 g, 100 mmol) was added in one

portion. The mixture was stirred at room temperature overnight. The

cloudy yellow solution was concentrated and resuspended in 200 mL of

ether and 200 mL of 1 M HCl. The layers were separated, and the

aqueous layer was back-extracted three times with 30 mL portions of

ether. The combined organic extracts were washed with 100 mL of water

and 100 mL of brine, diluted with 300 mL hexanes, dried over sodium

sulfate, and concentrated to give a yellow oil. The oil was puriﬁed by dry

column vacuum chromatography (0, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30%

EtOAc/hexanes) to yield the desired monoprotected diol as a clear oil

(12 g, 52%): TLC R_f0.5 (30% EtOAc/hexanes); IR 3339, 2929, 2859,

1463, 1388, 1362, 1256, 1097, 1006, 898, 836, 775, 663 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 0.04 (6 H, s), 0.83−0.93 (12 H, m), 1.32−1.47 (2

H, m), 1.52−1.64 (2 H, m), 1.66−1.75 (1 H, m), 1.82 (1 H, br s), 3.55−

3.77 (4 H, m); ¹³C NMR (500 MHz, CDCl₃) δ −5.3, 18.2, 19.9, 25.9,

26.4, 39.6, 39.8, 60.9, 61.3; HRMS (ESI) calcd for [C₁₂H₂₉O₂Si]⁺

233.1937, found 233.1935.

7-Hydroxy-5-methyl-hept-2-enoic Acid Methyl Ester (S-024). 10-

Camphorsulfonic acid (4.23 g, 18.2 mmol) was added to a room-

temperature solution of enoate (5.22 g, 18.2 mmol) in 30 mL of

anhydrous methanol. The solution was stirred vigorously for 20 min.

Dichloromethane (50 mL) followed by 50 mL of saturated sodium

bicarbonate solution was added slowly. The suspension was stirred

vigorously for 5 min, after which the bulk of the organic solvent was

evaporated. Dichloromethane (100 mL) and 50 mL of sodium

bicarbonate solution were added, and the layers were separated. The

aqueous layer was back-extracted ﬁve times with 20 mL portions of

dichloromethane. The combined organic extracts were washed with 50

mL of brine and dried over sodium sulfate. Two thirds of the solvent was

evaporated, and roughly 25 g of Celite were added. The suspension was

evaporated to dryness and puriﬁed by dry column ﬂash chromatography

(5 × 15 cm) using a gradient elution: 0, 5, 10, 15, 20, 30, 40% EtOAc/

hexanes to yield the desired alcohol as a yellow oil (3.04 g, 97%): TLC R_f

= 0.4 (30% EtOAc/hexanes, CAM stain); IR (CHCl₃ﬁlm) 3436, 2929,

1727, 1656, 1437, 1324, 1274, 1203, 1168, 1046, 984, 851, 720 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ ppm 0.88 (3 H, d, J = 6.4 Hz), 1.36 (1 H, td,

J = 14.0, 6.4 Hz), 1.56 (1 H, td, J = 13.2, 7.1 Hz), 1.76 (1 H, app td, J =

13.3, 6.9 Hz), 2.00−2.07 (1 H, m, J = 15.1, 7.3, 7.3, 1.4 Hz), 2.14−2.23

(1 H, m, J = 14.2, 7.2, 5.8, 1.6 Hz), 2.28 (1 H, br s), 3.53−3.70 (5 H, m),

5.78 (1 H, d, J = 15.6 Hz), 6.89 (1 H, ddd, J = 15.5, 7.7, 7.6 Hz); ¹³C

NMR (125 MHz, CDCl₃) δ 19.3, 29.0, 39.1, 39.5, 51.2, 60.3, 122.0,

148.0, 166.9; HRMS (ESI) calcd for [C₉H₁₇O₃]⁺173.1177, found

173.1171.

7-(tert-Butyldimethylsilanyloxy)-5-methylhept-2-enoic Acid

Methyl Ester (S-023). To a solution of distilled oxalyl chloride (2.58

mL, 30.1 mmol) in 40 mL of dichloromethane at −78 °C was added

DMSO (4.28 mL, 60.2 mmol) dropwise via syringe. After the solution

was stirred at −78 °C for 0.5 h, a precooled (−78 °C) solution of alcohol

(5.0 g, 21.5 mmol) in 40 mL of dichloromethane was added dropwise via

cannula. The resulting solution was stirred for 0.5 h at −78 °C. Freshly

distilled triethylamine (13.2 mL, 94.6 mmol) was added over 5 min. The

reaction was allowed to proceed at −78 °C for 30 min and then at 0 °C

1

for 1.5 h, after which H NMR indicated complete consumption of

starting material. The reaction was quenched with 20 mL pH 7

phosphate buﬀer and stirred for 5 min while warming to room

temperature. HCl (1 M, 100 mL) was added, and the layers were

separated. The aqueous layer was back-extracted three times with 50 mL

portions of dichloromethane. The combined organic extracts were

washed with 50 mL of water followed by 50 mL of brine. The solution

was dried over sodium sulfate and concentrated to yield the desired

aldehyde as a yellow oil (5.1 g, 100%): TLC R_f= 0.7 (30% EtOAc/

hexanes, CAM stain); ¹H NMR (500 MHz, CDCl₃) δ 0.03−0.06 (6 H,

m), 0.87−0.90 (9 H, m), 0.98 (6 H, d, J = 6.3 Hz), 1.05−1.19 (1 H, m),

(E)-9-tert-Butyl 1-Methyl 4-Methyl-7-oxonon-2-enedioate (7). To

a stirring solution of alcohol (1.72 g, 10 mmol) in 50 mL of CH₂Cl₂at 0

°C was added freshly distilled N,N-diisopropylethylamine (12.2 mL, 70

mmol) followed by dimethyl sulfoxide (7.1 mL, 100 mmol). Sulfur

G

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The Journal of Organic Chemistry

Article

trioxide pyridine complex (8.41 g, 40 mmol) was then added in one

portion. The reaction was allowed to proceed for 3 h at 0 °C, after which

time TLC indicated consumption of starting material. A 100 mL

saturated sodium bicarbonate solution was added, and the solution was

stirred vigorously. Dichloromethane (50 mL) was added, and the layers

were separated. The aqueous layer was washed three times with 20 mL

portions of dichloromethane. The combined organic extracts were

washed with 50 mL of 1 M HCl and 50 mL of brine. The organic extract

was dried over sodium sulfate and puriﬁed by ﬂash chromatography (10,

20, 30% EtOAc/hexanes) to yield the desired aldehyde as a clear oil

Table 5. NMR Data for S-05-anti (500 MHz, C₆D₆)

ID

δ ¹H

δ

¹³C

Hs

type

couplings (Hz)

1

2

3

4

3.24

2.30

2.08

1.98

1.87

1.78

1.63

1.62

1.10

0.58

51.0

31.3

46.4

48.5

38.7

46.4

48.5

29.3

36.6

20.8

3

1

2

1

2

3

s

dddddd

dddd

ddd

dd

4.3, 5.2, 7.5 × 4

0.9, 1.3, 5.2, 13.8

8.6, 1.6, 0.9

5/6

1.7, 7.3

7

dddd

m

13.8, 7.7, 1.6, 0.8

1

8

(1.27 g, 75%): TLC R_f= 0.7 (30% EtOAc/hexanes, CAM stain); H

9

m

NMR (400 MHz, CDCl₃) δ 1.00 (3 H, d, J = 5.5 Hz), 2.09−2.52 (5 H,

m), 3.73 (3 H, s), 5.85 (1 H, d, J = 15.7 Hz), 6.91 (1 H, ddd, J = 15.2, 7.5,

7.3 Hz), 9.76 (1 H, s). To a dry vial were added tin(II) chloride (80 mg,

0.80 mmol) and dichloromethane (5 mL). tert-Butyl diazoacetate (2.06

mL, 14.9 mmol) was added dropwise to the vial with vigorous stirring.

After gas evolution ceased, aldehyde (1.27 g, 7.46 mmol) was added and

the yellow solution was stirred overnight. The solution was diluted with

100 mL of dichloromethane and 100 mL of saturated sodium

bicarbonate solution. The layers were separated, and the aqueous

layer was back-extracted three times with 10 mL portions of

dichloromethane. The combined organic layers were washed with 50

mL of water and 50 mL of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil. The oil was puriﬁed by silica gel

chromatography (5% 2-propanol/hexanes). The remaining tert-butyl

diazoacetate was removed by high vacuum evaporation to yield the

desired ketoester as a yellow oil (1.71 g, 80%): TLC R_f= 0.40 (30%

EtOAc/hexanes, CAM stain); IR (CHCl₃ﬁlm) 2957, 1726, 1657, 1437,

1369, 1323, 1273, 1154, 1042, 985, 844, 720 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 1.45−1.51 (12 H, m), 2.07−2.16 (1 H, m), 2.18−2.29 (2 H,

m), 2.37−2.44 (1 H, app dd, J = 17.1, 7.3 Hz), 2.52 (1 H, app dd, J =

17.1, 5.4 Hz), 3.32 (2 H, s), 3.73 (3 H, s), 5.74−5.92 (1 H, m), 6.82−

6.96 (1 H, m); ¹³C NMR (125 MHz, CDCl₃) δ 19.6, 27.8, 27.9, 28.0,

28.1, 28.2, 38.9, 49.1, 51.0, 51.3, 81.9, 122.7, 146.9, 166.2, 166.6, 202.1;

HRMS (ESI) calcd for [C₁₅H₂₈O₅N]⁺302.1967, found 302.1955.

10/11

12

m

d

6.6

quaternary carbons: 208.0, 171.8

3,4-Dimethyl-5-oxo-5-pyrrolidin-1-ylpentanoic Acid Methyl Ester

(S-026). Propionyl chloride (20.8 mL, 240 mmol) was added dropwise

to a solution of pyrrolidine (20.0 mL, 240 mmol) and triethylamine

(83.6 mL, 600 mmol) in 500 mL of dichloromethane at 0 °C. The large

amount of evolved HCl gas was carefully purged during the addition

with a stream of nitrogen gas. The solution became viscous. The cooling

bath was removed, and the less viscous yellow suspension was allowed to

stir overnight. The mixture was diluted with 200 mL of dichloromethane

and washed with 250 mL of 1 M HCl. The aqueous layer was separated

and back-extracted three times with 50 mL portions of dichloromethane.

The combined organic layers were washed with 250 mL of 1 M NaOH

and 50 mL of brine. The organic extracts were ﬁltered through a

combined pad of Celite (5 × 10 cm) and silica (10 × 10 cm). The pad

was washed with 150 mL of ethyl acetate. The yellow solution was

concentrated to yield N-propionoylpyrrolidine as a yellow oil (26.6 g,

87%). This amide was surprisingly unstable, proving unsuitable for the

subsequent Michael addition if not prepared immediately before use.

Old samples of amide were suitable if puriﬁed by the above aqueous

workup immediately before use.

The following procedure is adapted from that of Yamaguchi.³⁴To a

solution of freshly distilled diispropylamine (12.2 mL, 87 mmol) in 250

mL of THF at 0 °C was added n-butyllithium (29.3 mL, 78.6 mmol, 2.68

M in hexane) dropwise. The solution was stirred for 30 min and cooled

to −78 °C. N-Propionylpyrrolidine (10.0 g, 78.6 mmol) was added

dropwise, after which the solution turned yellow. The solution was

stirred for 30 min. Methyl crotonate (8.34 mL, 78.6 mmol) was added

dropwise. The solution became a vivid yellow color. The solution was

The compound was formed as a mixture of diastereomers. Separation

via silica gel chromatography (gradient elution: 10, 20, 30, 50% EtOAc/

hexanes) yielded a yellow oil. The mixture was further puriﬁed by

semipreparative HPLC (Zorbax RX-SIL column, 0.5% 2-propanol/

hexanes, 215 nm, 20 mL/min) to yield the 1,3-cis (26.2 min) and 1,3-

trans (34.3 min) adducts.

1,3-trans-(3-Methyl-5-oxocyclohexyl)acetic acid methyl ester (S-

025-anti): TLC R_f= 0.35 (30% EtOAc/hexanes, CAM stain); IR (ﬁlm)

2938, 2874, 1734, 1713, 1440, 1370, 1323, 1259, 1226, 1164, 1105,

1063, 1014 cm⁻¹; HRMS (ESI) calcd for C₁₀H₁₇O₃[M + H]⁺: 185.1177,

found 185.1178; NMR data, see Table 5.

1

stirred at −78 °C for 1.5 h, after which H NMR analysis indicated

complete consumption of starting materials. Methanol (5 mL) was

added, and the solution was warmed to room temperature (the addition

of 2-propanol causes immediate transesteriﬁcation). The solution was

washed with 300 mL of 1 M HCl. The aqueous layer was back-extracted

three times with diethyl ether. The combined organic layers were

washed twice with 50 mL portions of 1 M HCl and 200 mL of 1 M

NaOH and 100 mL of brine. The combined organic extracts were

diluted with 100 mL hexanes and dried over sodium sulfate. The dried

extract was ﬁltered through a pad of Celite (5 × 10 cm) and silica (10 ×

10 cm). The pad was washed with 200 mL of ethyl acetate. The

combined organic extracts were concentrated to yield the desired

Michael adduct as a yellow oil (15.02 g, 84%, >20:1 syn:anti): TLC R_f=

0.4 (20% i-PrOH/hexanes, PIP stain); IR (CHCl₃ﬁlm) 2971, 2877,

1734, 1635, 1435, 1372, 1343, 1313, 1254, 1193, 1089, 1005 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 0.93 (3 H, d, J = 6.9 Hz), 1.04 (3 H, d, J = 6.9

Hz), 1.80 (2 H, ddd, J = 13.6, 6.8, 6.6 Hz), 1.85−1.95 (2 H, m), 2.13−

2.19 (1 H, m, J = 15.1, 7.8 Hz), 2.20−2.27 (1 H, m, J = 7.3 Hz), 2.32−

2.40 (1 H, m, J = 14.6, 5.0 Hz), 2.49 (1 H, ddd, J = 14.1, 7.0, 6.9 Hz),

3.34−3.47 (3 H, m), 3.50 (1 H, ddd, J = 9.8, 7.1, 6.9 Hz), 3.58−3.63 (3

H, m); ¹³C NMR (100 MHz, CDCl₃) δ 13.6, 16.1, 24.2, 26.1, 32.4, 39.1,

41.8, 45.6, 46.4, 51.3, 173.2, 174.1; HRMS (ESI) calcd for C₁₂H₂₂NO₃

[M + H]⁺228.1599, found 228.1596.

1,3-cis-(3-Methyl-5-oxocyclohexyl)acetic acid methyl ester (S-

025-syn): TLC R_f= 0.35 (30% EtOAc/hexanes, CAM stain); IR

(CHCl₃ﬁlm) 2939, 2848, 1734, 1715, 1652, 1558, 1436, 1235, 1168,

1110, 1021 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 0.38−0.45 (2 H, m),

0.53 (3 H, d, J = 6.3 Hz), 1.20−1.32 (1 H, m), 1.31−1.51 (3 H, m),

1.74−1.91 (3 H, m), 2.13 (1 H, ddd, J = 13.4, 2.0, 1.7 Hz), 2.26 (1 H, dt, J

= 13.2, 1.5 Hz), 3.26 (3 H, s); HRMS (ESI) calcd for C₁₀H₁₇O₃[M +

H]⁺185.1177, found 185.1185.

H

dx.doi.org/10.1021/jo302138z | J. Org. Chem. XXXX, XXX, XXX−XXX

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5-Hydroxy-2,3-dimethyl-1-pyrrolidin-1-ylpentan-1-one (S-027).

Dry THF (225 mL) was carefully and slowly added to lithium

aluminum hydride (2.23 g, 58.8 mmol) (caution! gas evolution!). The

gray suspension was cooled to −40 °C and stirred for 10 min. A solution

of ester (5.34 g, 23.5 mmol) in 10 mL of THF was added slowly to the

rapidly stirring suspension of lithium aluminum hydride. The solution

was allowed to warm to −30 °C over 45 min. A 1:1 by weight mixture of

sodium sulfate decahydrate and Celite was added portionwise until gas

evolution ceased. The suspension was warmed to room temperature and

ﬁltered. The gray cake was washed with 250 mL 10% 2-propanol/ethyl

acetate. The solution was concentrated to yield the desired alcohol as a

yellow oil (4.38 g, 94%): TLC R_f= 0.1 (30% i-PrOH/hexanes, PIP

stain); IR (CHCl₃ﬁlm) 3407, 2968, 2875, 1620, 1436, 1378, 1341, 1228,

1191, 1060, 916, 854 cm⁻¹; 1H NMR (500 MHz, CDCl₃) δ ppm 0.91 (3

H, d, J = 6.9 Hz), 1.06 (3 H, d, J = 6.9 Hz), 1.33−1.44 (1 H, m), 1.45−

1.57 (1 H, m), 1.77−1.87 (2 H, m), 1.88−2.04 (3 H, m), 2.23−2.37 (1

H, m), 3.38−3.51 (4 H, m), 3.58 (2 H, t, J = 6.4 Hz); ¹³C NMR (125

MHz, CDCl₃) 14.5, 16.7, 24.2, 26.0, 31.7, 38.8, 43.6, 45.6, 45.7, 46.5,

60.5, 175.5; HRMS (ESI) calcd for [C₁₁H₂₂NO₂]⁺200.1650, found

200.1643.

mmol) and tert-butyl-dimethylsilyl chloride (1.43 g, 9.51 mmol). The

reaction was stirred overnight. The mixture was diluted with 100 mL of

3:1 hexanes/EtOAc and 100 mL of 1 M HCl. The layers were separated,

and the aqueous layer was back-extracted three times with 20 mL

portions of 3:1 hexanes/EtOAc. The combined organic layers were

washed with 100 mL of water and 50 mL of brine, dried over sodium

sulfate, and concentrated to yield the desired silyl ether as a clear oil

(2.78 g, 97%): TLC R_f= 0.4 (30% EtOAc/hexanes, PIP stain); IR

(CHCl₃ﬁlm) 2932, 2858, 1668, 1463, 1385, 1256, 1095, 996, 901, 836,

776, 662; ¹H NMR (500 MHz, CDCl₃) δ 0.03 (6 H, s), 0.82−0.94 (12

H, m), 1.04 (3 H, t, J = 6.6 Hz), 1.07−1.13 (1 H, m), 1.30−1.41 (1 H,

m), 1.59 (1 H, ddd, J = 20.6, 7.6, 4.3 Hz), 1.82−1.98 (1 H, m), 2.70−2.83

(1 H, m), 3.17 (3 H, s), 3.57−3.69 (2 H, m), 3.67 (3 H, s); 13C NMR

(100 MHz, CDCl₃) δ −5.3, 13.2, 15.8, 18.3, 25.9, 32.0, 38.2, 40.0, 61.3,

61.6; HRMS (ESI) calcd for C₉H₂₀NO₃[M + H]⁺190.1443, found

190.1434.

3,4-Dimethyltetrahydropyran-2-one (S-028). To a solution of

amide (4.1 g, 20.6 mmol) in 25 mL of chloroform was added p-

toluenesulfonic acid monohydrate (4.32 g, 22.7 mmol). The solution

was heated at 40 °C for 1.5 h. The solution was diluted with 50 mL of

dichloromethane and extracted with 75 mL of 1 M HCl. The layers were

separated, and the aqueous layer was back-extracted three times with 20

mL portions of dichloromethane. The combined organic layers were

washed with 75 mL of 1 M NaOH and 50 mL of brine. The solution was

ﬁltered through a pad of silica (5 × 5 cm), and the pad was washed with

100 mL of 20% 2-propanol/hexanes. The solution was concentrated to

yield the desired valerolactone as a clear oil (1.87 g, 71%): TLC R_f= 0.50

(30% EtOAc/hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 2967, 2891,

1732, 1458, 1401, 1315, 1258, 1228, 1193, 1137, 1106, 1044, 992 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 1.10 (3 H, d, J = 6.3 Hz), 1.28 (3 H, d, J =

7.3 Hz), 1.53−1.63 (2 H, m), 1.66−1.76 (1 H, m), 1.91−1.99 (2 H, m),

2.08−2.16 (1 H, m), 4.21−4.29 (1 H, m), 4.30−4.40 (1 H, m); ¹³C

NMR (125 MHz, CDCl₃) δ 14.5, 16.7, 24.2, 26.0, 31.7, 38.8, 43.6, 45.6,

45.7, 46.5, 60.5, 175.5; HRMS (ESI) calcd for [C₇H₁₂O₂+ MeCN + H]⁺

170.1181, found 170.1187.

(4,5-erythro,E)-Methyl 7-((tert-Butyldimethylsilyl)oxy)-4,5-dime-

thylhept-2-enoate (S-030). To a solution of Weinreb amide (2.42 g,

7.97 mmol) in 100 mL of toluene at −78 °C was added

diisobutylaluminum hydride (2.5 mL, 19.9 mmol) dropwise over 5

min. The solution was stirred for 2 h and then quenched cold with 2 mL

of 2-propanol. The solution was diluted with 200 mL of dichloro-

methane and stirred with 200 mL of 1 M HCl. The organic layer was

washed with 100 mL of 1 M NaOH. The combined aqueous layers were

back-extracted three times with 20 mL portions of dichloromethane.

The combined organic layers were diluted with 100 mL hexanes, dried

over sodium sulfate, and ﬁltered through a Celite plug (10 × 10 cm).

The cloudy white solution was concentrated to yield the desired

aldehyde as a cloudy white oil (1.89 g, 97%): TLC R_f= 0.8 (30% EtOAc/

hexanes, CAM stain); ¹H NMR (500 MHz, CDCl₃) δ 0.00−0.05 (6 H,

m), 0.82−0.91 (12 H, m), 1.00 (3 H, d, J = 6.8 Hz), 1.40−1.51 (1 H, m, J

= 13.8, 8.2, 5.9, 5.9 Hz), 1.60 (1 H, td, J = 13.2, 6.3 Hz), 2.18−2.29 (1 H,

m), 2.32−2.43 (1 H, m), 3.59−3.74 (2 H, m), 9.65 (1 H, s).

To 20 mL of freshly distilled acetonitrile were added lithium chloride

(1.64 g, 38.7 mmol), freshly distilled diisopropylethylamine (4.02 mL,

23.1 mmol), and trimethyl phosphonoacetate (1.48 mL, 9.2 mmol).

Aldehyde (1.89 g, 7.73 mmol) was then added. The yellow suspension

was heated at 60 °C for 1 h. The suspension was cooled and poured into

a separatory funnel. One hundred milliliters of 25% EtOAc/hexanes

followed by 200 mL of 1 M HCl were carefully poured in. The triphasic

mixture became biphasic upon gentle agitation. The layers were

separated, and the aqueous layer was back-extracted ﬁve times with 30

mL portions of 25% EtOAc/hexanes. The combined organic layers were

washed twice with 75 mL portions of 1 M NaOH, followed by 100 mL of

brine. The combined organic extracts were dried over sodium sulfate

and ﬁltered through a silica plug (5 × 10 cm). The plug was washed with

250 mL 40% EtOAc/hexanes. The solution was concentrated to yield

the desired a yellow oil. The oil was puriﬁed by silica gel chromatography

(10, 20% EtOAc/hexanes) to give the desired enoate (1.44 g, 62%,

>20:1 E/Z): TLC R_f= 0.8 (30% EtOAc/hexanes); IR (CHCl₃ﬁlm)

2943, 2858, 1728, 1654, 1472, 1436, 1386, 1256, 1177, 1098, 988, 899,

836, 776, 728, 667 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.03−0.05 (6

H, m), 0.85 (6 H, d, J = 6.9 Hz), 0.89 (9 H, t), 0.99 (3 H, t, J = 7.6 Hz),

1.23−1.32 (1 H, m), 1.59−1.75 (2 H, m), 2.23−2.34 (1 H, m), 3.56−

3.70 (2 H, m), 3.73 (3 H, s), 5.78 (1 H, d, J = 16.9 Hz), 6.93 (1 H, dd, J =

15.8, 7.6 Hz); ¹³C NMR (125 MHz, CDCl₃) δ −5.39, −5.35, 14.7, 15.9,

18.2, 25.8, 33.8, 36.9, 41.1, 51.3, 61.2, 119.9, 153.9, 167.1; HRMS (ESI)

calcd for C₁₆H₃₃O₃Si [M + H]⁺301.2199, found 301.2190.

(2,3-erythro)-5-((tert-Butyldimethylsilyl)oxy)-N-methoxy-N,2,3-tri-

methylpentanamide (S-029). To a solution of N,O-dimethylhydroxyl-

amine hydrochloride (4.01 g, 41.1 mmol, freshly dried by iterative

azeotropic drying with benzene) in dichloromethane (22.8 mL, to make

a 1.8 M solution) at 0 °C was added trimethylaluminum (3.94 mL, 41.1

mmol) dropwise over 15 min under vigorous purging with argon. The

solution was stirred for 1 h. A solution of valerolactone (1.76 g, 13.7

mmol) in 25 mL of dichloromethane was added dropwise over 5 min.

The solution was stirred for 3 h. The reaction was carefully quenched

dropwise with a solution of Rochelle’s salt (4.64 g, 16.4 mmol) in water

(6.86 mL, 381 mmol). The evolved methane was carefully removed

during quenching with a continuous stream of argon. The mixture was

ﬁltered over a Celite plug (2 × 10 cm) and rinsed with 50 mL of

dichloromethane. The mixture was concentrated to yield the desired

alcohol as a yellow oil (1.89 g, 73%): TLC R_f0.1 (30% EtOAc/hexanes,

PIP stain); ¹H NMR (500 MHz, CDCl₃) δ 0.92 (3 H, t, J = 6.1 Hz), 1.08

(3 H, d, J = 6.8 Hz), 1.43 (1 H, td, J = 14.2, 6.3 Hz), 1.53 (1 H, td, J =

12.9, 6.8 Hz), 1.58−1.64 (1 H, m), 1.72 (1 H, s), 1.81−1.88 (1 H, m),

1.89−2.01 (1 H, m), 2.70 (1 H, s), 3.18 (3 H, s), 3.46 (1 H, td, J = 6.6, 2.9

Hz), 3.58−3.66 (2 H, m), 3.66−3.70 (3 H, m). To a solution of alcohol

(1.8 g, 9.51 mmol) in 10 mL of DMF were added imidazole (1.63 g, 24

I

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NMR (500 MHz, CDCl₃) δ 0.93 (3 H, d, J = 6.4 Hz), 1.41−1.50 (12 H,

m), 2.01−2.15 (1 H, m), 2.17−2.27 (1 H, m), 2.34−2.43 (1 H, m, J =

17.4, 7.3 Hz), 2.46−2.55 (1 H, m, J = 17.4, 5.5 Hz), 3.29 (2 H, s), 3.63−

3.76 (3 H, m), 5.81 (1 H, d, J = 15.6 Hz), 6.81−6.97 (1 H, m); ¹³C NMR

(125 MHz, CDCl₃) δ 19.6, 27.9, 28.0, 28.1, 28.2, 38.9, 49.1, 51.0, 51.3,

81.9, 122.7, 146.9, 166.2, 166.6, 202.1; HRMS (ESI) calcd For

C₁₆H₃₀O₅N [M + NH₄]⁺316.2124, found 316.2125.

7-Hydroxy-4,5-dimethylhept-2-enoic Acid Methyl Ester (S-031).

The oleﬁn (1.44 g, 4.79 mmol) was dissolved in 10 mL of methanol, and

10-camphorsulfonic acid (1.11 g, 4.79 mmol) was added. The solution

was stirred at room temperature for 30 min, after which TLC analysis

indicated full consumption of starting material. Ten mL of sodium

bicarbonate solution was added, and the bulk of the methanol was

removed by rotary evaporation. The mixture was resuspended in 50 mL

of dichloromethane and 50 mL of sodium bicarbonate. The layers were

separated, and the aqueous layer was back-extracted three times with 10

mL portions of dichloromethane. The combined organic layers were

washed with 20 mL of brine, dried over sodium sulfate, concentrated,

and puriﬁed by silica gel chromatography (30% EtOAc/hexanes) to

yield the desired oleﬁn−alcohol as a clear oil (0.90 g, 100%): TLC R_f=

0.3 (30% EtOAc/hexanes, CAM stain); IR (CHCl₃ﬁlm) 3435, 2943,

2878, 1724, 1653, 1436, 1272, 1178, 1047, 988, 864 cm⁻¹; 1H NMR

(500 MHz, CDCl₃) δ ppm 0.87 (3 H, d, J = 6.9 Hz), 1.01 (3 H, d, J = 6.9

Hz), 1.28−1.37 (1 H, m), 1.42−1.49 (1 H, br s), 1.63−1.73 (2 H, m),

2.21−2.32 (1 H, m, J = 13.2, 13.2, 6.8, 1.1 Hz), 3.59−3.72 (2 H, m), 3.72

(3 H, s), 5.78 (1 H, d, J = 16.9 Hz), 6.91 (1 H, dd, J = 15.8, 7.6 Hz); ¹³C

NMR (125 MHz, CDCl₃) d 15.00, 16.00, 33.87, 36.91, 41.30, 51.38,

61.00, 120.13, 153.60, 167.17; HRMS (ESI) calcd for C₁₀H₁₉O₃[M +

H]⁺187.1334, found 187.1339.

Methyl 2-((1,2-syn)-(2,3-anti)-2,3-dimethyl-5-oxocyclohexyl)-

acetate (S-032-syn): TLC R_f= 0.4 (30% EtOAc/hexanes, CAM

stain); IR (CHCl₃ﬁlm) 2956, 2882, 1731, 1714, 1698, 1434, 1381, 1270,

1240, 1166, 1112, 1072, 1015, 894 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ

= 3.26 (s, 3 H), 2.26 (dt, J = 1.5, 13.2 Hz, 1 H), 2.13 (ddd, J = 1.7, 2.0,

13.4 Hz, 1 H), 1.91−1.74 (m, 3 H), 1.51−1.31 (m, 3 H), 1.32−1.20 (m,

1 H), 0.53 (d, J = 6.3 Hz, 3 H), 0.45−0.38 (m, 2 H); HRMS (ESI) calcd

for C₁₁H₁₉O₃[M + H]⁺199.1334, found 199.1325.

Methyl 2-((1,2-anti)-(2,3-anti)-2,3-dimethyl-5-oxocyclohexyl)-

acetate (S-032-anti): TLC R_f= 0.4 (30% EtOAc/hexanes, CAM

stain); IR (CHCl₃ﬁlm) 2956, 2882, 1738, 1716, 1434, 1373, 1328, 1284,

1

1260, 1240, 1169, 1147 cm⁻¹; H NMR (500 MHz, ca. 10% C₆D₆in

CDCl₃) (¹³C NMR, 125 MHz, via gHSQC/gHMBC correlations) δ

0.82−16.1 (3 H, d, J = 6.3 Hz), 0.85 (3 H, d, J = 6.3 Hz), 1.02−1.10 −

41.5 (1 H, m), 1.29−1.39 − 38.3 (1 H, m), 1.68−1.78 − 40.9 (1 H, m),

1.88−49.4 (1 H, t, J = 13.4 × 2 Hz), 2.01−2.05 − 39.3 (1 H, m), 2.06−

2.09 − 47.1 (1 H, m), 2.18−49.4 (1 H, ddd, J = 14.0, 4.3, 2.2 Hz), 2.26−

47.1 (1 H, ddd, J = 13.9, 4.2, 2.4 Hz), 2.39−39.3 (1 H, dd, J = 15.1, 4.4

Hz), 3.48−51.6 (3 H, s), quaternary carbons: 172.4, 209.6; HRMS (ESI)

calcd for C₁₁H₁₉O₃[M + H]⁺199.1334, found 199.1340.

(4,5-erythro,E)-9-tert-Butyl 1-Methyl 4,5-Dimethyl-7-oxonon-2-

enedioate (9). To a stirring solution of alcohol (0.88 g, 4.72 mmol)

in 20 mL of CH₂Cl₂at −5 °C was added freshly distilled N,N-

diisopropylethylamine (5.75 mL, 33 mmol) dropwise via syringe. After

10 min at −5 °C, dimethyl sulfoxide (3.34 mL, 47 mmol) was added to

the reaction mixture via syringe, and the solution was allowed to stir for

an additional 10 min. Sulfur trioxide pyridine complex (3.98 g, 18.9

mmol) was then added in one portion. The reaction was allowed to

proceed for 4 h at −5 °C, after which time TLC analysis indicated

complete consumption of starting material. The reaction was quenched

by transfer into a 125 mL Erlenmeyer ﬂask that contained 50 mL of

saturated aqueous NaHCO₃solution. The mixture was stirred for 5 min.

The layers were separated, and the aqueous phase was back-extracted

three times with 20 mL portions of dichloromethane. The reaction

mixture was then concentrated under reduced pressure to yield a yellow

oil which was immediately puriﬁed by silica gel chromatography (15,

30% EtOAc/hexanes) to yield the aldehyde as a clear yellow oil (0.67 g,

76%): TLC R_f= 0.65 (30% EtOAc/hexanes, KMnO₄stain); ¹H NMR

(500 MHz, CDCl₃) δ 0.95 (3 H, d, J = 6.8 Hz), 1.05 (3 H, d, J = 6.8 Hz),

2.13−2.21 (1 H, m), 2.21−2.27 (1 H, m), 2.26−2.34 (1 H, m), 2.49 (1

H, dd, J = 16.4, 4.2 Hz), 3.74 (3 H, s), 5.82 (1 H, d, J = 16.1 Hz), 6.87 (1

H, dd, J = 15.6, 8.3 Hz), 9.75 (1 H, s).

(2,3-erythro)-Methyl 2-Methyl-3-phenylpent-4-enoate (S-033).

This sequence commences with a carboxylic acid, which was obtained

in racemic form using a known procedure.³⁵To a stirring solution of acid

(3.11 g, 16.3 mmol) in 32 mL of acetone at room temperature was added

potassium carbonate (2.71 g, 19.6 mmol). The white suspension was

stirred vigorously for 30 min. Methyl iodide (1.22 mL, 19.6 mmol) was

added, and the suspension was stirred overnight. The bulk of the acetone

was removed by rotary evaporation at 20 °C and 200 Torr. The white

slurry was dissolved in 100 mL of saturated sodium bicarbonate and 50

mL of diethyl ether. The layers were separated, and the aqueous layer

was back-extracted ﬁve times with 20 mL portions of ether. Pentane was

added, and the yellow solution was dried over sodium sulfate, ﬁltered,

and concentrated at 20 °C and 200 Torr to yield the desired methyl ester

as a yellow oil (3.29 g, 99%). TLC R_f0.7 (30% EtOAc/hexanes,

anisaldehyde stain, yellow). The properties of this compound matched

those known in the literature.³⁵

To a dry vial were added tin(II) chloride (66 mg, 0.35 mmol) and

dichloromethane (2 mL). tert-Butyl diazoacetate (0.99 mL, 7.2 mmol)

was added dropwise to the vial with vigorous stirring. After gas evolution

ceased, aldehyde (0.66 g, 3.58 mmol) was added, and the yellow solution

was stirred overnight. The solution was diluted with 100 mL of

dichloromethane and 100 mL of saturated sodium bicarbonate solution.

The layers were separated, and the aqueous layer was back-extracted

three times with 10 mL portions of dichloromethane. The combined

organic layers were washed with 50 mL of water and 50 mL of brine,

dried over sodium sulfate, and concentrated to yield a yellow oil. The oil

was puriﬁed by silica gel chromatography (15% EtOAc/hexanes). The

remaining tert-butyl diazoacetate was removed by high vacuum

evaporation to yield the desired ketoester as a yellow oil (0.80 g,

75%): TLC R_f0.6 (30% EtOAc/hexanes, CAM stain); IR (CHCl₃ﬁlm)

tert-Butyldimethyl(((2,3-threo)-2-methyl-3-phenylpent-4-en-1-

yl)oxy)silane (S-034). To a solution of methyl ester (5.08 g, 24.9 mmol)

in 100 mL of tetrahydrofuran at −20 °C was added lithium aluminum

hydride (4.06 g, 107 mmol) in several portions over 5 min. Some gas

evolution was observed. The gray suspension was allowed to stir for 30

min at −20 °C, after which TLC analysis indicated complete

consumption of starting material. Celite and sodium sulfate decahydrate

1

2976, 1720, 1654, 1457, 1436, 1369, 1319, 1275, 1151, 846 cm⁻¹; H

J

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were added slowly. After the cessation of gas evolution, a small amount

of water was added to completely quench any remaining lithium

aluminum hydride. The gray suspension was ﬁltered over Celite, and the

ﬁlter cake was washed with 250 mL of ether. Hexanes (100 mL) was

added, and the clear and colorless solution was dried over sodium

sulfate, ﬁltered over paper, and concentrated to yield the desired alcohol

as a clear and colorless oil (2.84 g, 65%): TLC R_f0.5 (30% EtOAc/

(6,7-threo)-2,2,3,3,6,12,12-Heptamethyl-7,11,11-triphenyl-4,10-

dioxa-3,11-disilatridecane (S-036). To a solution of alcohol (3.04 g,

9.85 mmol) in 10 mL of DMF were added imidazole (1.68 g, 24.6

mmol) and tert-butyldiphenylsilyl chloride (2.65 mL, 10.3 mmol). The

reaction was stirred overnight. The reaction was diluted with 50 mL 3:1

hexanes/ethyl acetate and 100 mL of 1 M HCl. The layers were

separated, and the aqueous layer was back-extracted three times with 20

mL portions of 3:1 hexanes/ethyl acetate. The combined organic layers

were washed with 50 mL of water and 50 mL of brine, dried over sodium

sulfate, and concentrated to yield a clear oil. The oil was puriﬁed by silica

gel chromatography (5, 10% EtOAc/hexaners) to yield the desired

protected alcohol as a clear and colorless oil (4.01 g, 94%): TLC R_f0.8

(30% EtOAc/hexanes, CAM stain); IR (ATR) 3071, 3028, 2955, 2929,

2856, 1589, 1492, 1472, 1427, 1389, 1361, 1251, 1188, 1105, 1085,

1

hexanes, anisaldehyde stain, blue); H NMR (500 MHz, CDCl₃) δ =

7.36−7.29 (m, 2 H), 7.26−7.16 (m, 3 H), 6.10−5.97 (m, 1 H), 5.13−

5.05 (m, 2 H), 3.76 (s, 1 H), 3.53−3.44 (m, 1 H), 3.39−3.30 (m, 1 H),

3.24 (t, J = 9.0 Hz, 1 H), 2.09−1.98 (m, 1 H), 1.87 (s, 1 H), 1.17 (t, J =

5.9 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3 H).

To a solution of primary alcohol (2.84 g, 16.1 mmol) in 20 mL of

DMF at room temperature was added imidazole (2.74 g, 40.3 mmol)

followed by tert-butyldiphenylsilyl chloride (2.67 g, 17.7 mmol). After

30 min, TLC indicated complete consumption of starting material.

Methanol (5 mL) was added, and the clear and colorless solution was

stirred for 10 min. The mixture was diluted with 50 mL of 0.1 M HCl and

50 mL of 1:1 hexanes/ether. The layers were separated, and the aqueous

layer was back-extracted three times with 15 mL portions of 1:1

hexanes/ether. The combined organic extracts were washed twice with

50 mL portions of water and once with 10 mL of brine. The clear and

colorless solution was dried over sodium sulfate, ﬁltered over paper, and

concentrated to yield the desired silyl ether as a clear and colorless oil

(4.30 g, 92%): TLC R_f0.7 (30% EtOAc/hexanes, anisaldehyde stain,

green); IR (ATR) 3078, 3029, 2956, 2929, 2857, 1684, 1601, 1472,

1389, 1361, 1331, 1089, 1023, 913, 837, 776, 671 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ = 7.38−7.29 (m, 2 H), 7.26−7.19 (m, 3 H), 6.11−6.01

(m, 1 H), 5.16−5.05 (m, 2 H), 3.47−3.38 (m, 1 H), 3.32 (s, 2 H), 2.06−

1.96 (m, 1 H), 1.06−0.98 (m, 3 H), 0.95−0.89 (m, 9 H), 0.01 (d, J = 6.9

Hz, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ = 144.0, 139.9, 128.3, 127.9,

126.0, 115.6, 65.8, 52.4, 40.4, 25.9, 18.3, 14.6, −5.5, −5.5; HRMS (ESI)

calcd for C₁₈H₃₁OSi [M + H]⁺: 291.2139, found 291.2140.

1

1056, 1027, 1006, 938, 833, 774, 761, 738, 699, 668; H NMR (500

MHz, CDCl₃) δ = 7.71−7.63 (m, 2 H), 7.62−7.54 (m, 2 H), 7.48−7.31

(m, 6 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.24−7.15 (m, 1 H), 7.16−7.06 (m, 2

H), 3.58−3.50 (m, 1 H), 3.49−3.36 (m, 2 H), 3.27−3.17 (m, 1 H),

2.90−2.80 (m, 1 H), 2.17−2.07 (m, 1 H), 1.87−1.71 (m, 2 H), 1.07 (s,

12 H), 0.95−0.86 (m, 12 H), 0.00 (d, J = 6.8 Hz, 6 H); ¹³C NMR (126

MHz, CDCl₃) δ = 143.9, 135.5, 135.5, 134.8, 134.0, 134.0, 129.4, 129.3,

128.4, 128.0, 127.7, 127.5, 127.5, 125.8, 66.3, 62.1, 43.7, 41.4, 34.7, 26.8,

26.5, 25.9, 19.1, 18.2, 14.9, −5.5, −5.5; HRMS (ESI) calcd for

C₃₄H₅₀O₂Si₂Na [M + Na]⁺569.3242, found 569.3237.

5-(tert-Butyldiphenylsilanyloxy)-2-methyl-3-phenylpentan-1-ol

(S-037). To a solution of disilyl ether (1.12 g, 2.05 mmol) in 5 mL of

methanol and 5 mL of dichloromethane at 0 °C was added 10-

camphorsulfonic acid (72 mg, 0.31 mmol). The clear and colorless

solution was stirred for 1 h at 0 °C. The mixture was poured into 50 mL

of saturated sodium bicarbonate solution and 50 mL of dichloro-

methane. The layers were separated, and the aqueous layer was back-

extracted four times with 10 mL portions of dichloromethane. The

combined organic extracts were washed once with 10 mL of brine, dried

over sodium sulfate, ﬁltered, and concentrated to yield a yellow oil. The

oil was puriﬁed by silica gel chromatography (gradient elution: 5, 10, 20,

25% EtOAc/hexanes) to yield the desired alcohol as a clear and colorless

oil (0.72 g, 81%): TLC R_f0.65 (30% EtOAc/hexanes, CAM stain); IR

(ATR) 3341, 3070, 3027, 2956, 2930, 2857, 1589, 1492, 1472, 1453,

1427, 1389, 1361, 1189, 1107, 1028, 982, 938, 822, 782, 72, 739, 629

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 7.74 (d, J = 6.9 Hz, 2 H), 7.67

(d, J = 6.9 Hz, 2 H), 7.54−7.38 (m, 6 H), 7.33 (d, J = 7.6 Hz, 2 H), 7.27

(s, 1 H), 7.19 (d, J = 7.3 Hz, 2 H), 3.67−3.59 (m, 1 H), 3.58−3.47 (m, 2

H), 3.37−3.26 (m, 1 H), 2.91−2.80 (m, 1 H), 2.28−2.14 (m, 1 H),

2.01−1.82 (m, 2 H), 1.80−1.67 (m, 1 H), 1.16 (s, 9 H), 1.11 (d, J = 6.6

Hz, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ = 143.4, 135.4, 135.4, 133.8,

133.8, 129.4, 129.4, 128.2, 128.2, 127.5, 127.4, 126.0, 66.4, 61.9, 44.3,

41.2, 34.8, 26.8, 19.1, 14.8; HRMS (ESI) calcd for C₂₈H₃₇O₂Si [M + H]⁺

433.2563, found 433.2563.

(3,4-threo)-5-((tert-Butyldimethylsilyl)oxy)-4-methyl-3-phenyl-

pentan-1-ol (S-035). 9-BBN dimer (2.58 g, 10.6 mmol, carefully

prepared³⁶and stored at −20 °C in a nitrogen glovebox; commercial

material gave poor results) was dissolved in 120 mL of THF at room

temperature. The clear and colorless solution was stirred for 1 h. A

solution of oleﬁn (4.1 g, 14.1 mmol) in 20 mL of THF was added

dropwise via cannula over 20 min. The clear and colorless solution was

stirred for 3 h at room temperature. At this point, TLC analysis indicated

complete consumption of starting material. The solution was cooled to 0

°C, and water (120 mL) was added (gas evolution!), followed by sodium

perborate tetrahydrate (10.8 g, 70.5 mmol). The white suspension was

allowed to warm to room temperature and stirred overnight. The white

suspension was diluted with 100 mL of ether and decanted into a

separatory funnel. The remaining white particulates were alternately

washed three times with 50 mL portions of 1:1 ether/water. The layers

were separated, and the aqueous phase was back-extracted three times

with 50 mL portions of ether. The combined organic phases were

washed twice with 50 mL of water and once with 25 mL of brine. The

clear and colorless solution was diluted with 200 mL of hexanes, dried

thoroughly over sodium sulfate, and concentrated to yield a clear and

colorless oil. The oil was puriﬁed by silica gel chromatography (gradient

elution 5, 10, 20% EtOAc/hexanes) to yield the desired alcohol as a clear

and colorless oil (4.20 g, 96%): TLC R_f0.4 (borane)/0.5 (alcohol) (30%

EtOAc/hexanes, CAM stain; a number of other spots visible above and

below); IR (ATR) 3343, 2954, 2929, 2857, 1471, 1388, 1361, 1220,

1070, 1029, 833, 773, 735, 667 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ =

7.28 (d, J = 7.6 Hz, 2 H), 7.23−7.15 (m, 3 H), 3.50−3.44 (m, 1 H),

3.41−3.33 (m, 2 H), 3.23−3.16 (m, 1 H), 2.75−2.66 (m, 1 H), 2.12−

2.02 (m, 1 H), 1.92−1.79 (m, 2 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.90−0.85

(m, 9 H), −0.04 (d, J = 5.7 Hz, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ =

143.8, 128.2, 128.2, 126.1, 66.1, 61.5, 44.3, 41.3, 34.8, 25.9, 18.2, 14.7,

−5.5, −5.6; HRMS (ESI) calcd for C₁₈H₃₂O₂SiNa [M + Na]⁺331.2064,

found 331.2060.

(2,3-erythro)-5-((tert-Butyldiphenylsilyl)oxy)-2-methyl-3-phenyl-

pentanal (S-038a). To a suspension of Dess−Martin periodinane (1.96

g, 4.62 mmol) in 6 mL of dichloromethane at room temperature was

added sodium bicarbonate (0.78 g, 9.24 mmol). A solution of alcohol

(1.00 g, 2.31 mmol) in 6 mL of dichloromethane was added. The white

suspension was stirred for 2.5 h. Twelve mL of 1:1 hexanes/ether was

added, followed by 12 mL of saturated sodium thiosulfate solution and 6

mL of saturated sodium bicarbonate solution. The mixture was stirred

vigorously for 10 min. At this point, the solution became mostly clear,

with a few remaining particulates. The mixture was poured into 20 mL of

saturated sodium bicarbonate solution, 20 mL of saturated sodium

K

dx.doi.org/10.1021/jo302138z | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

thiosulfate solution, and 50 mL of 1:1 hexanes/ether. The layers were

separated, and the aqueous layer was back-extracted four times with 10

mL portions of 1:1 hexanes/ether. The clear and colorless solution was

washed with 10 mL of brine, dried over sodium sulfate, ﬁltered, and

concentrated to yield a yellow oil. The oil was puriﬁed by silica gel

chromatography (gradient elution: 4, 8% EtOAc/hexanes) to yield the

desired aldehyde as a clear and colorless oil (0.78 g, 78%): TLC R_f0.7

(30% EtOAc/hexanes, CAM stain); ¹H NMR (500 MHz, CDCl₃) δ =

9.61−9.53 (m, 1 H), 7.66−7.59 (m, 2 H), 7.57−7.48 (m, 2 H), 7.28 (s, 3

H), 3.63−3.52 (m, 1 H), 3.52−3.38 (m, 1 H), 3.30−3.23 (m, 1 H),

2.65−2.57 (m, 1 H), 2.05−1.96 (m, 1 H), 1.91−1.81 (m, 1 H), 1.04 (s, 9

H).

syringe, and the solution was allowed to stir for an additional 10 min.

Sulfur trioxide−pyridine complex (0.48 g, 2.3 mmol) was then added in

one portion. The reaction was allowed to proceed for 1 h at 0 °C, after

which TLC analysis indicated complete consumption of starting

material. The reaction was diluted with 50 mL of dichloromethane

and 50 mL of 0.1 M HCl. The layers were separated, and the aqueous

phase was back-extracted four times with 15 mL portions of

dichloromethane. The combined organic layers were washed with 25

mL of saturated sodium bicarbonate solution followed by 25 mL of

brine. The clear and colorless solution was washed with brine, dried over

sodium sulfate, and concentrated to yield a yellow oil. The oil was

puriﬁed by silica gel chromatography to yield the desired aldehyde as a

clear, colorless oil (115 mg, 89%): TLC R_f0.5 (30% EtOAc/hexanes,

KMnO₄stain); ¹H NMR (500 MHz, CDCl₃) δ = 9.66 (t, J = 1.7 Hz, 1

H), 7.43−7.09 (m, 5 H), 6.81 (dd, J = 8.3, 15.6 Hz, 1 H), 5.74 (dd, J =

1.2, 15.9 Hz, 1 H), 3.72 (s, 3 H), 3.37−3.30 (m, 1 H), 2.93−2.74 (m, 3

H), 2.71−2.61 (m, 1 H), 1.05 (d, J = 6.3 Hz, 3 H).

(4,5-erythro,E)-Methyl 7-(tert-Butyldiphenylsilyloxy)-4-methyl-5-

phenylhept-2-enoate (S-038b). To a solution of aldehyde (0.6 g,

1.39 mmol) in 10 mL of acetonitrile were added lithium chloride (0.12 g,

2.8 mmol) and trimethylphosphonoacetate (0.27 mL, 1.67 mmol).

Diisopropylethylamine (0.24 mL, 1.39 mmol) was added. The clear

white suspension became brown within minutes. The mixture was

stirred overnight at room temperature. The brown solution was poured

into 50 mL of dichloromethane and 50 mL of 0.1 M HCl. The layers

were separated, and the aqueous phase was back-extracted three times

with 10 mL portions of dichloromethane. The combined organic

extracts were washed with 10 mL of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil (>20:1 E/Z). The oil was puriﬁed by

silica gel chromatography (gradient elution: 2, 4, 10% EtOAc/hexanes)

to yield the desired E-ester (0.04 g, 18%) as a clear and colorless oil:

(4S,5R,E)-9-tert-Butyl 1-Methyl 4-Methyl-7-oxo-5-phenylnon-2-

enedioate (11). To a dry vial were added tin(II) chloride (4.7 mg,

0.03 mmol) and 1 mL of deuterochloroform. tert-Butyl diazoacetate

(0.12 mL, 0.9 mmol) was added dropwise to the vial with vigorous

stirring. After gas evolution ceased, aldehyde (115 mg, 0.47 mmol) was

added, and the yellow solution was stirred overnight. The solution was

diluted with 50 mL of dichloromethane and 50 mL of saturated sodium

bicarbonate solution. The layers were separated, and the aqueous layer

was back-extracted four times with 10 mL portions of dichloromethane.

The combined organic layers were washed consecutively with 50 mL of

water and 50 mL of brine, dried over sodium sulfate, and concentrated to

yield a yellow oil. The oil was puriﬁed by silica gel chromatography

(gradient elution: 10, 20% EtOAc/hexanes) to yield the desired

ketoester as a yellow oil (150 mg, 90%): TLC R_f0.5 (30% EtOAc/

hexanes, anisaldehyde stain, brown); IR (ATR) 2977, 1717, 1653, 1495,

1455, 1435, 1394, 1368, 1316, 11258, 1145, 1071, 1032, 984, 845, 757,

729, 702 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 7.33−7.08 (m, 5 H),

6.79 (dd, J = 8.4, 15.7 Hz, 1 H), 5.73 (dd, J = 1.1, 15.8 Hz, 1 H), 3.71 (s, 2

H), 3.36−3.27 (m, 1 H), 3.23 (s, 2 H), 2.98−2.92 (m, 1 H), 1.44 (s, 9

H), 1.02 (d, J = 6.6 Hz, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ = 201.5,

166.7, 166.1, 151.2, 140.6, 128.6, 128.4, 128.4, 128.3, 128.1, 127.9, 126.9,

126.8, 121.2, 82.0, 77.2, 77.0, 76.7, 51.4, 51.1, 45.9, 45.1, 45.1, 43.1, 41.1,

28.3, 27.9, 17.3; HRMS (ESI) calcd for C₂₁H₂₈O₅Na [M + Na]⁺

383.1829, found 383.1827.

1

TLC R_f= 0.75 (30% EtOAc/hexanes, KMnO₄stain); H NMR (500

MHz, CDCl₃) δ = 7.66−7.57 (m, 2 H), 7.58−7.48 (m, 2 H), 7.28 (s, 10

H), 7.08−7.00 (m, 1 H), 6.90−6.78 (m, 1 H), 5.73−5.63 (m, 1 H), 3.71

(s, 3 H), 3.61−3.52 (m, 1 H), 3.52−3.43 (m, 1 H), 2.95−2.88 (m, 1 H),

2.65−2.52 (m, 1 H), 2.05−1.96 (m, 1 H), 1.92−1.81 (m, 1 H), 1.05−

1.00 (m, 15 H); ¹³C NMR (126 MHz, CDCl₃) δ = 167.1, 152.9, 135.5,

133.9, 129.5, 127.6, 120.4, 120.0, 77.2, 77.0, 76.7, 62.1, 61.9, 51.3, 41.0,

36.7, 34.1, 33.8, 26.8, 19.2, 16.5, 16.1, 14.8.

(4,5-erythro,E)-Methyl 7-Hydroxy-4-methyl-5-phenylhept-2-

enoate (S-039a). To a solution of silyl ether (0.48 g, 0.99 mmol) in

10 mL of methanol at room temperature was added 10-camphorsulfonic

acid (0.46 g, 1.97 mmol). The mixture was stirred for 1 h, after which

TLC analysis indicated complete consumption of starting material. The

mixture was diluted with 50 mL of saturated sodium bicarbonate

solution and 50 mL of dichloromethane. The layers were separated, and

the aqueous layer was back-extracted three times with 15 mL portions of

dichloromethane. The combined organic layers were washed with 20

mL of brine, dried over sodium sulfate, ﬁltered, and concentrated to

yield a yellow oil. The oil was puriﬁed by silica gel chromatography

(gradient elution: 15, 40% EtOAc/hexanes) to yield the desired alcohol

as a clear and colorless oil (0.14 g, 58%): TLC R_f= 0.2 (30% EtOAc/

3,4-Bis(tert-butyldimethylsilanyloxy)but-1-ene (S-040). To a sol-

ution of 3,4-dihydroxy-1-butene (1.68 mL, 20 mmol) in 20 mL of DMF

were added imidazole (8.17 g) and tert-butyldimethylsilyl chloride (9.04

g, 60 mmol). The reaction was stirred overnight. The reaction was

diluted with 100 mL of diethyl ether and 100 mL of saturated

ammonium chloride solution. The layers were separated, and the

aqueous phase was back-extracted three times with 20 mL portions of

ether. The combined organic extracts were washed with 50 mL of brine,

diluted with 100 mL of hexanes, dried over sodium sulfate, and

concentrated under reduced pressure to aﬀord the crude product as a

yellow oil. The oil was puriﬁed by silica gel chromatography (5%

EtOAc/hexanes) to give the desired bis-silyl ether as a clear and

colorless oil (5.87 g, 92%): TLC R_f0.9 (30% EtOAc/hexanes, KMnO₄

stain); IR (CHCl₃ﬁlm) 2945, 2858, 1472, 1256, 1123, 1095, 836, 776

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.04−0.07 (12 H, m), 0.91 (18 H,

d, J = 4.6 Hz), 3.46 (1 H, dd, J = 10.1, 6.0 Hz), 3.55 (1 H, dd, J = 10.1, 6.4

Hz), 4.13−4.19 (1 H, m), 5.25 (1 H, t, J = 1.6 Hz), 5.29 (1 H, t, J = 1.8

Hz), 5.87 (1 H, ddd, J = 17.2, 10.5, 5.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ −5.3, −5.2, −4.6, −2.9, 18.3, 18.4, 25.7, 25.9, 26.0, 68.0, 74.5,

114.8, 138.8; HRMS (ESI) calcd for [C₁₆H₃₇O₂Si₂]⁺317.2332, found

317.2322.

1

hexanes, KMnO₄stain); H NMR (500 MHz, CDCl₃) δ = 7.34−7.09

(m, 15 H), 6.85 (dd, J = 8.3, 15.6 Hz, 1 H), 5.70 (dd, J = 1.2, 15.9 Hz, 1

H), 4.13 (s, 1 H), 3.71 (s, 3 H), 3.59−3.51 (m, 1 H), 3.46 (s, 1 H), 2.87−

2.77 (m, 1 H), 2.65−2.58 (m, 1 H), 2.05−1.85 (m, 2 H), 1.32−1.23 (m,

2 H), 1.06 (d, J = 6.8 Hz, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ = 167.2,

167.1, 153.7, 152.6, 120.4, 120.0, 60.8, 60.7, 51.3, 41.2, 41.1, 36.8, 36.8,

34.0, 33.8, 16.3, 15.9, 15.9, 14.9.

(4,5-erythro,E)-Methyl 4-Methyl-7-oxo-5-phenylhept-2-enoate (S-

039b). To a stirring solution of alcohol (130 mg, 0.52 mmol) in 5 mL of

CH₂Cl₂at 0 °C was added freshly distilled N,N-diisopropylethylamine

(0.69 mL, 4.0 mmol) dropwise via syringe. After 10 min, dimethyl

sulfoxide (0.40 mL, 5.6 mmol) was added to the reaction mixture via

L

dx.doi.org/10.1021/jo302138z | J. Org. Chem. XXXX, XXX, XXX−XXX

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(E)-Allyl (2-((tert-Butyldimethylsilyl)oxy)-5-methoxy-5-oxopent-3-

en-1-yl) Malonate (13). To a solution of alcohol (350 mg, 1.34 mmol)

in 10 mL of dichloromethane were added 3-dimethylaminopropylcar-

bodiimide hydrochloride (0.51 g, 2.7 mmol) and 4-dimethylaminopyr-

idine (82 mg, 0.67 mmol) followed by allyl malonic half acid (0.39 g, 2.7

mmol). The white suspension became a clear dark yellow solution. After

4 h, TLC analysis indicated the complete consumption of starting

material. The solution was diluted with 50 mL of dichloromethane and

50 mL of 1 M HCl, and the layers were separated. The aqueous phase

was back-extracted three times with 20 mL portions of dichloromethane.

The combined organic layers were washed with 30 mL of sodium

bicarbonate solution followed by 30 mL of brine. The mixture was

concentrated under reduced pressure to yield a yellow oil. The oil was

passed through a silica gel plug (10 × 10 cm) with 200 mL of 30%

EtOAc/hexanes) to yield the desired allyl malonate as a yellow oil (450

mg, 87%): TLC R_f= 0.8 (50% EtOAc/hexanes, KMnO4 stain); IR

(CHCl₃ﬁlm) 2955, 2942, 2858, 1735, 1664, 1437, 1275, 1146, 1026,

981, 838, 780 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 6.96−6.84 (m, 1

H), 6.15−6.05 (m, 1 H), 5.98−5.82 (m, 1 H), 5.39−5.29 (m, 1 H),

5.29−5.19 (m, 1 H), 4.69−4.58 (m, 2 H), 4.58−4.47 (m, 1 H), 4.16−

4.03 (m, 2 H), 3.74 (d, J = 1.4 Hz, 3 H), 3.41 (d, J = 0.9 Hz, 2 H), 0.90 (d,

J = 0.9 Hz, 9 H), 0.06 (d, J = 10.1 Hz, 6 H); ¹³C NMR (126 MHz,

CDCl₃) δ = 166.5, 166.0, 165.8, 146.3, 131.4, 121.8, 118.8, 69.5, 67.9,

66.1, 51.6, 41.3, 25.6, 18.1, −4.9, −5.0; HRMS (ESI) calcd for

C₁₈H₃₀O₇SiNa [M + Na]⁺409.1658, found 409.1660.

4-(tert-Butyldimethylsilanyloxy)-5-hydroxypent-2-enoic Acid

Methyl Ester (S-041). To a solution of bis-silyl ether (1.58 g, 5.0

mmol) in 40 mL of 3:1 THF/pH 7 buﬀer were added 2,6-lutidine (1.16

mL, 10.0 mmol), osmium tetraoxide (1.0 mL, 0.1 mmol, as a 2.5% by

weight solution in t-BuOH), and sodium periodate (4.28 g, 20 mmol).

The reaction was stirred at room temperature for 3 h. The reaction was

diluted with 150 mL of diethyl ether and 100 mL of saturated

ammonium chloride solution. The layers were separated, and the

aqueous phase was back-extracted three times with 20 mL portions of

ether. The combined organic extracts were washed with 100 mL of

brine, diluted with 100 mL of hexanes, dried over sodium sulfate, and

concentrated under reduced pressure to aﬀord the crude product as a

yellow oil. The oil was puriﬁed by silica gel chromatography (5%

EtOAc/hexanes) to give the desired aldehyde as a clear and colorless oil

(5.87 g, 92%): TLC R_f0.2 (20% EtOAc/hexanes, CAM stain); ¹H NMR

(500 MHz, CDCl₃) d −0.01−0.16 (12 H, m), 0.79−0.97 (18 H, m),

3.81 (3 H, d, J = 4.9 Hz), 4.06 (1 H, t, J = 4.6 Hz), 9.66 (1 H, s).

A solution of n-butyllithium (3.89 mL, 9.81 mmol, 2.52 M in hexane)

and trimethyl phosphonoacetate (1.61 mL, 9.98 mmol) were added in

sequence to a solution of 1,1,1,2,2,2-hexaﬂuoro2-propanol (1.08 mL,

10.3 mmol) in 25 mL of DME at −15 °C. The aldehyde (2.65 g, 8.32

mmol) was then added. The white suspension was stirred for 2 h, after

which the reaction was diluted with 100 mL of dichloromethane and 100

mL of saturated ammonium chloride solution. The layers were

separated, and the aqueous phase was back-extracted three times with

20 mL portions of dichloromethane. The combined organic extracts

were washed with 75 mL of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil. The oil was puriﬁed by silica gel

chromatography (5% EtOAc/hexanes) to yield the desired oleﬁn as a

yellow oil (2.5 g, 80%, 10:1 E:Z): TLC R_f0.8 (30% EtOAc/hexanes,

KMnO₄stain); ¹H NMR (500 MHz, CDCl₃) δ 0.03−0.11 (12 H, m),

0.84−0.97 (18 H, m), 3.44−3.53 (1 H, m), 3.55−3.61 (1 H, m), 3.74 (3

H, s), 4.26−4.40 (1 H, m), 6.07 (1 H, d, J = 15.6 Hz), 7.03 (1 H, dd, J =

15.6, 4.4 Hz); LRMS (CI) calcd for C₁₈H₃₉O₄Si₂[M + H]⁺375.2, found

375.4.

The oleﬁn (1.66 g, 4.43 mmol) was dissolved in 25 mL of methanol

and 25 mL of dichloromethane at 0 °C. 10-Camphorsulfonic acid (1.03

g, 4.43 mmol) was added slowly over 2 min, and the reaction was

allowed to proceed at 0 °C for 1 h and 50 min. The reaction was

quenched by the addition of 50 mL of saturated sodium bicarbonate

solution. The mixture was partially evaporated to remove the bulk of the

organic solvent. The mixture was resuspended in 100 mL of

dichloromethane, and the layers were separated. The aqueous phase

was back-extracted three times with 20 mL portions of dichloromethane.

The combined organic layers were washed with 50 mL of brine, dried

over sodium sulfate, and concentrated to yield a clear oil. The oil was

puriﬁed by silica gel chromatography (15% EtOAc/hexanes) to aﬀord

the desired alcohol (1.06 g, 93%): TLC R_f= 0.5 (30% EtOAc/hexanes,

KMnO₄stain); IR (CHCl₃ﬁlm) 3468, 2943, 2858, 1729, 1662, 1468,

1437, 1362, 1294, 1259, 1167, 1135, 1062, 1135, 1062, 978, 837, 779,

669 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.09 (6 H, d, J = 10.1 Hz),

0.92 (9 H, s), 1.65 (1 H, s), 1.90−2.00 (1 H, m), 3.44−3.56 (1 H, m),

3.63 (1 H, ddd, J = 11.2, 7.1, 4.1 Hz), 3.74 (3 H, s), 4.34−4.46 (1 H, m),

6.06 (1 H, dd, J = 15.6, 1.8 Hz), 6.92 (1 H, dd, J = 15.6, 5.0 Hz); ¹³C

NMR (125 MHz, CDCl₃) δ −4.9, −4.6, 18.1, 25.7, 51.6, 66.1, 72.5,

121.5, 147.3, 166.5; HRMS (ESI) calcd for C₁₂H₂₅O₄Si [M + H]⁺

261.1522, found 261.1520.

3-Hydroxytetrahydro-2H-pyran-2-yl 3-chlorobenzoate (S-042).

m-Chloroperoxybenzoic acid (mCPBA) (15.0 g, 86 mmol) was

dissolved in 300 mL of dichloromethane at 0 °C and stirred for 5

min. 3,4-Dihydro-2H-pyran (6.82 mL, 74.8 mmol) was added over 5

min. The mixture was stirred at 0 °C for 1 h. The mixture was washed

three times with 50 mL of portions of 1 M NaOH. The combined

organic extracts were washed with brine, dried over sodium sulfate, and

concentrated to yield the desired cis-pyran benzoate as a white solid

(21.0 g, 100%): TLC R_f0.60 (20% 2-propanol/hexanes); IR (CHCl₃

ﬁlm) 3437, 2949, 2881, 1734, 1576, 1427, 1288, 1256, 1209, 1131, 1068,

1031, 991, 930, 748 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.57−1.68 (1

H, m), 1.76−1.84 (1 H, m), 1.90−2.01 (1 H, m), 2.10−2.21 (1 H, m),

3.67−3.85 (2 H, m), 3.93−4.03 (1 H, m), 5.93 (1 H, d, J = 4.4 Hz), 7.26

(1 H, s), 7.41 (1 H, dd, J = 8.1 Hz), 7.56 (1 H, d, J = 5.9 Hz), 7.89−8.13

(1 H, m); ¹³C NMR (125 MHz, CDCl₃) δ 21.2, 27.3, 63.9, 66.5, 95.6,

128.0, 129.8, 131.3, 133.4, 133.6, 134.6, 163.8; HRMS (ESI) calcd for

+

C₁₂H₁₇O₄ClN [M + NH₄] 274.0846, found 274.0837.

3-((tert-Butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl 3-Chlor-

obenzoate (S-043). To a solution of lactol benzoate (17.5 g, 68.2

mmol) in 70 mL of DMF were added imidazole (13.6 g, 200 mmol) and

tert-butyldimethylsilyl chloride (15.1 g, 100 mmol). The solution was

stirred overnight. The mixture was diluted with 200 mL of ether and 200

mL of 1 M HCl. The layers were separated, and the aqueous layer was

washed three times with 20 mL portions of ether. The combined organic

extracts were washed with 100 mL of brine, diluted with 200 mL of

hexanes, dried over sodium sulfate, and concentrated to yield the crude

silyl ether as a yellow oil. The oil was puriﬁed by silica gel

chromatography (10, 15, 30% EtOAc/hexanes) to yield the desired

cis-silyl ether as a clear oil (24.5 g, 97%): TLC R_f0.70 (30% EtOAc/

hexanes); IR (CHCl₃ﬁlm) 2942, 2857, 1736, 1576, 1472, 1427, 1361,

1286, 1256, 1212, 1133, 1078, 928, 835, 778, 748, 673 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ ppm 0.09 (6 H, d), 0.76−0.97 (9 H, m), 1.51−

1.60 (1 H, m), 1.66−1.75 (1 H, m), 1.92−2.10 (2 H, m), 3.68−3.81 (2

H, m), 3.91−4.01 (1 H, m), 5.85 (1 H, t, J = 4.2 Hz), 7.40 (1 H, t, J = 7.8

Hz), 7.55 (1 H, d, J = 6.8 Hz), 7.94−7.99 (1 H, m), 8.05 (1 H, s); ¹³C

M

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NMR (125 MHz, CDCl₃) −4.8, −4.7, 17.9, 21.5, 25.6, 28.98, 64.2, 67.1,

96.2, 127.9, 129.7, 129.8, 131.6, 133.2, 134.5, 163.8; HRMS (ESI) calcd

for C₁₈H₃₁O₄SiClN [M + NH₄]⁺388.1711, found 388.1713.

1.78−1.86 (1 H, m), 1.95 (1 H, td, J = 13.7, 6.8 Hz), 2.37−2.57 (2 H, m),

3.73 (3 H, s), 4.35−4.51 (1 H, m), 5.99 (1 H, dd, J = 15.6, 2.0 Hz), 6.86

(1 H, dd, J = 15.6, 4.4 Hz), 9.76 (1 H, s).

To a dry vial were added tin(II) chloride (53 mg, 0.28 mmol) and

dichloromethane (5 mL). tert-Butyl diazoacetate (0.14 mL, 1.0 mmol)

was added dropwise to the vial with vigorous stirring. After gas evolution

ceased, aldehyde (80 mg, 0.28 mmol) was added, and the yellow

solution was stirred overnight. The solution was diluted with 100 mL of

dichloromethane and 100 mL of saturated sodium bicarbonate solution.

The layers were separated, and the aqueous layer was back-extracted

three times with 10 mL portions of dichloromethane. The combined

organic layers were washed with 50 mL of water and 50 mL of brine,

dried over sodium sulfate, and concentrated to yield a yellow oil. The oil

was puriﬁed by silica gel chromatography (5% 2-propanol/hexanes).

The remaining tert-butyl diazoacetate was removed by high vacuum

evaporation to yield the desired ketoester as a yellow oil (110 mg, 98%):

TLC R_f= 0.70 (30% EtOAc/hexanes, CAM stain); IR (CHCl₃ﬁlm)

2931, 2858, 1727, 1650, 1468, 1436, 1369, 1268, 1165, 983, 838, 778,

668 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.04 (6 H, d, J = 8.8 Hz), 0.90

(9 H, s), 1.45 (9 H, s), 1.53−1.65 (1 H, m), 1.75−1.83 (1 H, m, J = 14.2,

8.9, 5.6, 5.5 Hz), 1.88−1.96 (1 H, m, J = 14.0, 9.3, 5.9, 5.9 Hz), 2.44−

2.68 (2 H, m), 3.33 (2 H, s), 3.74 (3 H, s), 4.38−4.47 (1 H, m), 6.00 (1

H, dd, J = 15.6, 2.0 Hz), 6.87 (1 H, dd, J = 15.1, 4.4 Hz); ¹³C NMR (125

MHz, CDCl₃) −5.0, −4.7, 18.1, 25.7, 27.9, 30.1, 37.2, 50.7, 51.5, 69.9,

81.9, 120.1, 150.2, 166.3, 166.7, 202.7; HRMS (ESI) calcd for

C₂₀H₄₀O₆SiN [M + NH₄]⁺418.2625, found 418.2614.

3-((tert-Butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-ol (S-044).

To a solution of lactol benzoate (1.11 g, 3.0 mmol) in 50 mL of THF at

−20 °C was added methylmagnesium chloride (3.0 mL, 9.0 mmol, 3.0

M in THF) dropwise via syringe. The dark brown solution was stirred

for 5 h. The reaction was quenched with the addition of 5 mL of water.

The mixture was diluted with 100 mL of diethyl ether and 100 mL of

saturated ammonium chloride solution. The layers were separated, and

the aqueous phase was back-extracted three times with 20 mL portions

of ether. The solution was diluted with 200 mL of hexanes, dried over

sodium sulfate, and concentrated under reduced pressure to yield the

crude lactol as a yellow oil. The oil was puriﬁed by silica gel

chromatography (10, 20% EtOAc/hexanes) to yield the desired cis-

lactol as a clear oil (0.52 g, 73%): TLC R_f0.5 (30% EtOAc/hexanes,

CAM stain); IR (CHCl₃ﬁlm) 3475, 2943, 2858, 1464, 1390, 1362, 1255,

1209, 1143, 1082, 1011, 924, 838, 782, 678 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 0.13 (6 H, d, J = 9.3 Hz), 0.92 (9 H, s), 1.53−1.72 (3 H, m),

1.73−1.84 (1 H, m), 3.40−3.49 (1 H, m), 3.50−3.57 (1 H, m), 3.68−

3.78 (1 H, m), 4.99 (1 H, d, J = 2.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ

−5.5, −4.4, 18.0, 23.7, 25.6, 27.2, 59.8, 68.4, 93.6; HRMS (ESI) calcd for

C₁₁H₂₅O₃Si [M + H]⁺233.1573, found 233.1571.

tert-Butyldimethyl-pent-4-enyloxysilane (S-045). To a solution of

4-penten-1-ol (26.1 mL, 0.26 mol) in 200 mL of DMF were added

imidazole (43.7 g, 0.64 mol) and tert-butyldimethylsilyl chloride (39.2 g,

0.26 mol) at 0 °C. The reaction was stirred overnight. The reaction was

diluted with 300 mL of diethyl ether and 300 mL of saturated

ammonium chloride solution. The layers were separated, and the

aqueous phase was back-extracted three times with 50 mL portions of

ether. The combined organic extracts were washed with 150 mL of

brine, diluted with 300 mL of hexanes, dried over sodium sulfate, and

concentrated under reduced pressure to aﬀord the desired silyl ether as a

clear and colorless oil (46.2 g, 90%): TLC R_f= 0.9 (30% EtOAc/

hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 3080, 2931, 2859, 1642, 1468,

(E)-9-tert-Butyl 1-Methyl 4-((tert-Butyldimethylsilyl)oxy)-7-oxo-

non-2-enedioate (15). To a suspension of lithium chloride (0.47 g,

11 mmol) in 20 mL of acetonitrile were added diisopropylethylamine

(1.22 mL, 7.0 mmol) and trimethyl phosphonoacetate (0.81 mL, 5.0

mmol). A solution of lactol (0.52 g, 2.26 mmol) in 2 mL of acetonitrile

was added, and the suspension was heated to reﬂux for 5 h. The mixture

was cooled and diluted with 100 mL of diethyl ether and 100 mL of 1 M

HCl. The layers were separated, and the aqueous layer was back-

extracted three times with 20 mL portions of diethyl ether. The

combined organic extracts were washed with 50 mL of brine, diluted

with 100 mL of hexanes, dried over sodium sulfate, and concentrated to

yield a dark yellow oil. The oil was puriﬁed by silica gel chromatography

(10, 20, 50% EtOAc/hexanes) to yield the desired unstable unsaturated

ester as a yellow oil (0.25 g, 40%): TLC R_f0.1 (30% EtOAc/hexanes,

KMnO₄stain); ¹H NMR (500 MHz, CDCl₃) δ 0.06 (6 H, d, J = 12.2

Hz), 1.21 (9 H, d, J = 5.9 Hz), 1.55−1.70 (2 H, m), 3.59−3.67 (1 H, m),

3.73−3.76 (3 H, m), 3.96−4.10 (2 H, m), 4.40 (1 H, dd, J = 3.4 Hz), 6.00

(1 H, dd, J = 15.6, 2.0 Hz), 6.93 (1 H, dd, J = 15.6, 4.4 Hz).

1

1388, 1256, 1102, 1006, 912, 836, 776 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 0.05 (6 H, s), 0.90 (9 H, s), 1.55−1.67 (2 H, m), 2.02−2.18 (2

H, m), 3.62 (2 H, t, J = 6.4 Hz), 4.89−5.10 (2 H, m), 5.82 (1 H, dd, J =

16.9, 10.5 Hz); ¹³C NMR (125 MHz, CDCl₃) δ −5.3, 18.3, 25.9, 30.0,

32.02, 62.5, 114.4, 138.5; HRMS (ESI) calcd for [C₁₁H₂₅OSi]⁺

201.1675, found 201.1674.

The oleﬁn−alcohol (0.11 g, 0.39 mmol) was immediately dissolved in

10 mL of dichloromethane at 0 °C. Freshly distilled N,N-

diisopropylethylamine (0.47 mL, 2.72 mmol) was added dropwise via

syringe. After 10 min of stirring at 0 °C, dimethyl sulfoxide (0.28 mL, 3.9

mmol) was added to the reaction mixture via syringe, and the solution

was allowed to stir for an additional 10 min. Sulfur trioxide pyridine

complex (0.33 g, 1.56 mmol) was then added in one portion. The

reaction was allowed to proceed for 2 h at −0 °C, after which TLC

analysis indicated complete consumption of starting material. The

reaction was quenched by transfer into an 125 mL Erlenmeyer ﬂask that

contained a stirring solution of saturated sodium bicarbonate solution

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

separated. The aqueous layer was back-extracted three times with three

20 mL portions of dichloromethane. The combined organic extracts

were washed with 50 mL of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil. The oil was puriﬁed by silica gel

chromatography (15% EtOAc/hexanes) to yield the desired unstable

aldehyde as a clear oil (80 mg, 77%): TLC R_f0.5 (30% EtOAc/hexanes);

¹H NMR (500 MHz, CDCl₃) δ 0.02 (6 H, d, J = 9.8 Hz), 0.89 (9 H, s),

6-((tert-Butyldimethylsilyl)oxy)hex-1-en-3-ol (S-046). Ozone was

bubbled through a solution of oleﬁn (20 g, 100 mmol) in 200 mL of

dichloromethane at −78 °C until the solution turned blue. The solution

was sparged with nitrogen for 5 min, after which triphenylphosphine

(26.2 g, 100 mmol) was added in one portion. The solution was stirred

for 15 min, after which the cooling bath was removed. The suspension

was stirred for 6 h, after which NMR analysis indicated complete

consumption of ozonide. The bulk of the solvent was removed by rotary

evaporation. The yellow-brown slurry was resuspended in 200 mL of 5%

EtOAc/hexanes and ﬁltered through a silica plug (10 × 10 cm). The

plug was rinsed with 100 mL of 15% EtOAc/hexanes. The solution was

concentrated to yield the desired aldehyde as a clear oil (20.2 g, 100%):

TLC R_f= 0.8 (30% EtOAc/hexanes, CAM stain); ¹H NMR (500 MHz,

CDCl₃) δ 0.04 (6 H, s), 0.88 (9 H, s), 1.86 (2 H, ddd, J = 12.8, 6.6, 6.5

Hz), 2.50 (2 H, s), 3.65 (2 H, t, J = 6.1 Hz), 9.79 (1 H, s). A solution of

aldehyde (20.2 g, 100 mmol) in 100 mL of THF was added dropwise to

a 1.0 M solution of vinylmagnesium bromide in THF (125 mL, 125

mmol) over 15 min at −78 °C. The solution was stirred for 5 min and

warmed to 0 °C. The solution was stirred for 15 min and warmed to

N

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The Journal of Organic Chemistry

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room temperature. 2-Propanol (5 mL) was added, and the mixture was

diluted with 200 mL of diethyl ether and 200 mL of saturated

ammonium chloride. The layers were separated, and the aqueous layer

was back-extracted three times with 50 mL portions of diethyl ether. The

combined organic extracts were washed with 100 mL of brine, diluted

with 200 mL of hexanes, dried over sodium sulfate, and concentrated to

yield the desired allylic alcohol as a yellow oil (23.1 g, 100%): TLC R_f=

0.6 (30% EtOAc/hexanes); IR (CHCl₃ﬁlm) 3364, 2930, 2858, 1472,

1256, 1100, 992, 920, 835, 776 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ

0.05 (9 H, s), 0.89 (9 H, s), 1.51−1.70 (4 H, m), 3.64 (2 H, t, J = 5.7 Hz),

4.05−4.17 (1 H, m), 5.07 (1 H, d, J = 10.5 Hz), 5.22 (1 H, d, J = 17.4

Hz), 5.79−5.94 (1 H, m); ¹³C NMR (125 MHz, CDCl₃) δ −5.4, 18.2,

25.5, 25.6, 25.8, 28.6, 34.3, 63.3, 67.8, 72.5, 114.2, 128.3, 128.4, 128.4,

128.6, 132.0, 133.5, 133.7, 141.2; HRMS (ESI) calcd for [C₁₂H₂₇O₂Si]⁺

231.1780, found 231.1779.

was back-extracted ﬁve times with 30 mL portions of 25% EtOAc/

hexanes. The combined organic layers were washed twice with 75 mL

portions of 1 M NaOH, followed by 100 mL of brine. The combined

organic extracts were dried over sodium sulfate and ﬁltered through a

silica plug (5 × 10 cm). The plug was washed with 250 mL of 40%

EtOAc/hexanes. The solution was concentrated to yield the desired

enoate as a yellow oil (11.01 g, 78%): TLC R_f= 0.3 (30% EtOAc/

hexanes, KMnO₄stain) ; IR (CHCl₃ﬁlm) 2941, 2857, 1727, 1660, 1467,

1436, 1361, 1257, 1203, 1168, 1096, 1028, 936, 777, 740, 697, 663 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 0.04 (6 H, s), 0.89 (9 H, s), 1.56−1.74 (4

H, m), 3.57−3.75 (2 H, m), 3.77 (3 H, s), 3.99 (1 H, q, J = 6.4 Hz), 4.39

(1 H, d, J = 11.9 Hz), 4.59 (1 H, d, J = 11.9 Hz), 6.04 (2 H, d, J = 16.9

Hz), 6.89 (2 H, dd, J = 16.0, 6.4 Hz), 7.21−7.75 (5 H, m); ¹³C NMR

(125 MHz, CDCl₃) δ −5.3, 18.2, 25.9, 28.2, 31.2, 51.5, 62.7, 70.9, 121.6,

127.4, 127.6, 127.6, 128.2, 128.3, 128.3, 128.4, 128.4, 128.4, 128.6, 132.0,

133.6, 138.0, 148.5, 166.6; HRMS (ESI) calcd for [C₂₁H₃₅O₄Si]⁺

379.2304, found 379.2297.

((4-(Benzyloxy)hex-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (S-

047). To a solution of allylic alcohol (1.38 g, 6.0 mmol) in 10 mL of

DMF at 0 °C was added sodium bis(trimethylsilyl)silazane (1.32 g, 7.2

mmol) in one portion. The solution was stirred vigorously for 10 min.

Benzyl bromide (0.71 mL, 6.0 mmol), freshly prepuriﬁed by passage

over neutral alumina, was added. The solution was stirred for 10 min and

warmed to room temperature. The solution was stirred for 1 h. Water (5

mL) was added, and the solution was diluted with 75 mL of 1 M HCl and

30 mL of diethyl ether. The layers were separated, and the aqueous layer

was back-extracted three times with 20 mL portions of diethyl ether. The

combined organic extracts were washed with 100 mL of water and 50

mL of brine. The solution was diluted with 50 mL of hexanes, dried over

sodium sulfate, and concentrated to yield an orange oil. The oil was

puriﬁed by silica gel chromatography (0,3,10% EtOAc/hexanes) to yield

the desired benzyl ether as a clear yellow oil (1.38 g, 72%): TLC R_f= 0.8

(30% EtOAc/hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 3065, 3016,

2930, 2859, 1721, 1460, 1445, 1389, 1361, 1256, 1096, 993, 926, 836,

776, 735, 698 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.05 (6 H, s), 0.90

(9 H, s), 1.47−1.81 (4 H, m), 3.57−3.87 (3 H, m), 4.37 (1 H, d, J = 11.9

Hz), 4.60 (1 H, d, J = 11.9 Hz), 5.18−5.31 (2 H, m), 5.71−5.80 (1 H,

m), 7.12−8.11 (5 H, m); ¹³C NMR (500 MHz, CDCl₃) δ −5.3, −3.6,

18.2, 25.6, 25.9, 28.6, 31.7, 62.9, 69.9, 70.1, 80.3, 117.0, 117.3, 127.3,

127.6, 128.2, 128.9, 129.6, 129.9, 130.0, 130.1, 131.9, 132.0, 132.1, 134.0,

134.1, 138.5, 138.7, 138.9; HRMS (ESI) calcd for [C₁₉H₃₃O₂Si]⁺

321.2250, found 321.2253.

4-Benzyloxy-7-hydroxy-hept-2-enoic Acid Methyl Ester (S-049).

To a solution of silyl ether (3.03 g, 8 mmol) in 10 mL of methanol was

added 10-camphorsulfonic acid (1.86 g, 8 mmol). The solution was

stirred for 20 min. Dichloromethane (50 mL) and 50 mL of saturated

sodium bicarbonate were added. The solution was gently agitated until

gas evolution stopped. The layers were separated, and the aqueous layer

was back-extracted three times with 20 mL portions of dichloromethane.

The combined aqueous extracts were washed with 50 mL of brine, dried

over sodium sulfate, and concentrated to yield a dark yellow oil. The oil

was puriﬁed by silica gel chromatography (10,20,30,50,[100]% EtOAc/

hexanes) to yield the desired alcohol as a clear yellow oil (1.96 g, 93%):

TLC R_f= 0.2 (30% EtOAc/hexanes); IR (CHCl₃ﬁlm) 3421, 3014,

2950, 2868, 1724, 1659, 1497, 1437, 1275, 1169, 1062, 985, 738, 699

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.58−1.79 (4 H, m), 3.61 (1 H, q,

J = 5.9 Hz), 3.75 (3 H, s), 4.00 (1 H, q, J = 4.9 Hz), 4.11 (2 H, q, J = 7.0

Hz), 4.37 (1 H, d, J = 11.7 Hz), 4.59 (1 H, d, J = 11.7 Hz), 6.03 (1 H, d, J

= 17.1 Hz), 6.87 (1 H, dd, J = 16.1, 6.8 Hz), 7.26−7.38 (5 H, m); ¹³C

NMR (125 MHz, CDCl₃) δ 28.2, 31.2, 31.3, 51.6, 62.4, 71.0, 77.7, 121.8,

127.7, 127.8, 128.3, 128.4, 137.7, 148.1, 166.5; HRMS (ESI) calcd for

[C₁₅H₂₁O₄]⁺265.1440, found 265.1435.

4-Benzyloxy-7-(tert-butyldimethylsilanyloxy)hept-2-enoic Acid

Methyl Ester (S-048). Ozone was bubbled through a solution of oleﬁn

(12.5 g, 38.5 mmol) in 200 mL of dichloromethane at −78 °C until the

solution turned blue. The solution was sparged with nitrogen gas for 2

min. Triphenylphosphine (9.59 g, 36.6 mmol) was added. The cooling

bath was removed after 15 min. The solution was stirred vigorously for 3

h. The bulk of the dichloromethane was removed by rotary evaporation

until approximately 50 mL of solution remained. The solution was

passed through a silica plug (10 × 10 cm). The plug was rinsed with 400

mL of 15% EtOAc/hexanes. The light yellow ﬁltrate was concentrated to

yield the desired aldehyde as a yellow oil (12.1 g, 97%): TLC R_f0.75

(30% EtOAc/hexanes); ¹H NMR (600 MHz, CDCl₃) δ ppm 0.07 (6 H,

s), 0.92 (9 H, s), 1.61−1.97 (4 H, m), 3.57−3.69 (2 H, m), 3.79−3.88 (1

H, m), 4.58 (1 H, d, J = 11.7 Hz), 4.72 (1 H, d, J = 11.7 Hz), 7.26−7.44

(5 H, m), 9.69 (1 H, d, J = 2.0 Hz). To 50 mL of freshly distilled

acetonitrile were added lithium chloride (7.93 g, 187 mmol), freshly

distilled diisopropylethylamine (19.6 mL, 113 mmol), and trimethyl-

phosphonoacetate (7.25 mL, 45 mmol). Aldehyde (12.1 g, 37.5 mmol)

was then added. The yellow suspension was heated at 60 °C for 1 h. The

suspension was cooled and poured into a separatory funnel. One

hundred milliliters of 25% EtOAc/hexanes followed by 200 mL of 1 M

HCl were carefully poured in. The triphasic mixture became biphasic

upon gentle agitation. The layers were separated, and the aqueous layer

(E)-9-tert-Butyl 1-Methyl 4-(benzyloxy)-7-oxonon-2-enedioate

(17). The oleﬁn−alcohol (1.25 g, 4.73 mmol) was dissolved in 50 mL

of dichloromethane at 0 °C. Freshly distilled N,N-diisopropylethylamine

(5.8 mL, 33.1 mmol) was added dropwise via syringe. After 10 min of

stirring at 0 °C, dimethyl sulfoxide (3.34 mL, 47 mmol) was added to the

reaction mixture via syringe, and the solution was allowed to stir for an

additional 10 min. Sulfur trioxide pyridine complex (3.98 g, 18.9 mmol)

was then added in one portion. The reaction was allowed to proceed for

2.5 h at 0 °C, after which TLC analysis indicated complete consumption

of starting material. The reaction was quenched by transfer into an 125

mL Erlenmeyer ﬂask that contained a stirring solution of saturated

sodium bicarbonate solution (50 mL). Dichloromethane (50 mL) was

added, and the layers were separated. The aqueous layer was back-

extracted three times with three 20 mL portions of dichloromethane.

The combined organic extracts were washed with 50 mL of brine, dried

over sodium sulfate, and concentrated to yield a yellow oil. Excess

pyridine was removed azeotropically with heptane. The oil was puriﬁed

by silica gel chromatography (15, 30% EtOAc/hexanes) to yield the

desired aldehyde as a clear oil (0.87 g, 70%): TLC R_f= 0.50 (30%

1

EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl₃) δ 1.17−

1.33 (1 H, m), 1.84−2.00 (2 H, m), 2.49−2.56 (1 H, m, J = 7.3, 6.3, 4.4,

O

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The Journal of Organic Chemistry

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1.5 Hz), 3.73−3.78 (3 H, m), 3.99−4.04 (1 H, m, J = 7.3, 5.9, 4.4, 1.0

Hz), 4.33 (1 H, d, J = 11.7 Hz), 4.56 (1 H, d, J = 11.7 Hz), 6.05 (1 H, d, J

= 17.1 Hz), 6.74−6.89 (1 H, m, J = 15.6, 5.9 Hz), 7.25−7.39 (5 H, m),

9.72 (1 H, s). To a dry vial were added tin(II) chloride (57 mg, 0.3

mmol) and dichloromethane (5 mL). tert-Butyl diazoacetate (0.97 mL,

7.0 mmol) was added dropwise to the vial with vigorous stirring. After

gas evolution ceased, aldehyde (0.86 g, 3.28 mmol) was added, and the

yellow solution was stirred overnight. The solution was diluted with 100

mL of dichloromethane and 100 mL of saturated sodium bicarbonate

solution. The layers were separated, and the aqueous layer was back-

extracted three times with 10 mL portions of dichloromethane. The

combined organic layers were washed with 50 mL of water, 50 mL of

brine, dried over sodium sulfate, and concentrated to yield a yellow oil.

The oil was puriﬁed by silica gel chromatography (2% 2-propanol/

hexanes). The remaining tert-butyl diazoacetate was removed by high

vacuum evaporation to yield the desired ketoester as a yellow oil (1.00 g,

82%): TLC R_f= 0.50 (30% EtOAc/hexanes, purple, anisaldehyde stain);

IR (CHCl₃ﬁlm) 2980, 2886, 1726, 1660, 1456, 1369, 1309, 1275, 1168,

1097, 843, 738, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.40−1.50 (9

H, m), 1.83 (1 H, td, J = 13.9, 7.8 Hz), 1.91−2.01 (1 H, m, J = 14.8, 7.3,

7.2, 4.9 Hz), 2.53−2.67 (2 H, m), 3.28 (2 H, d, J = 4.4 Hz), 3.73−3.78 (3

H, m), 3.97−4.05 (3 H, m, J = 7.6, 6.1, 4.9, 1.0 Hz), 4.33 (1 H, d, J = 11.7

Hz), 4.55 (1 H, d, J = 11.7 Hz), 6.04 (1 H, d, J = 14.6 Hz), 6.77−6.89 (1

H, m, J = 15.6, 6.3 Hz), 7.23−7.37 (5 H, m); ¹³C NMR (125 MHz,

CDCl₃) δ 27.9, 27.9, 28.2, 28.3, 37.9, 50.5, 51.6, 71.0, 76.4, 81.9, 122.0,

127.7, 128.4, 137.7, 147.6, 166.3, 166.4, 202.5; HRMS (ESI) calcd for

[C₂₁H₃₂O₆N]⁺394.2230, found 394.2240.

2.29 (1 H, br s), 3.61−3.69 (1 H, m), 3.70−3.79 (1 H, m), 3.85 (1 H, dd,

J = 8.0, 4.3 Hz), 4.42 (1 H, d, J = 11.9 Hz), 4.68 (1 H, d, J = 11.9 Hz), 6.21

(1 H, dd, J = 16.0, 8.2 Hz), 6.56 (1 H, d, J = 16.0 Hz), 7.25−7.32 (4 H,

m), 7.33−7.39 (4 H, m), 7.43 (2 H, d, J = 7.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ 16.6, 35.7, 35.8, 61.3, 70.3, 84.2, 126.5, 127.5, 127.6, 127.6,

127.7, 128.3, 128.6, 133.8, 136.4, 138.3; [α]²⁵_D+88.8 (c = 3.81, CDCl₃);

HRMS (ESI) calcd for C₂₀H₂₈NO₂[M + H]⁺314.2120, found

314.2131.

(((3S,4R,E)-4-(Benzyloxy)-3-methyl-6-phenylhex-5-en-1-yl)oxy)-

(tert-butyl)dimethylsilane (S-051). To a solution of alcohol (2.25 g,

7.59 mmol) in 10 mL of DMF were added tert-butyldimethylsilyl

chloride (1.20 g, 7.97 mmol) and imidazole (1.09 g, 16.0 mmol). The

reaction was stirred overnight. The reaction was diluted with 100 mL of

diethyl ether and 100 mL of saturated ammonium chloride solution. The

layers were separated, and the aqueous phase was back-extracted three

times with 20 mL portions of ether. The combined organic extracts were

washed with 50 mL of brine, diluted with 100 mL of hexanes, dried over

sodium sulfate, and concentrated under reduced pressure to aﬀord the

desired silyl ether as a clear and colorless oil (2.77 g, 90%): TLC R_f= 0.8

(20% EtOAc/hexanes, KMnO₄); IR (CHCl₃ﬁlm) 3028, 2929, 2857,

1944, 1870, 1801, 1496, 1467, 1388, 1360, 1300, 1255, 1206, 1094,

1038, 979, 970, 899, 836, 775, 746, 694, 665 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ ppm 0.02−0.04 (6 H, m), 0.87−0.90 (9 H, m), 1.01 (3 H, d, J

= 6.9 Hz), 1.35 (1 H, ddd, J = 19.5, 8.7, 6.2 Hz), 1.78−1.85 (3 H, m, J =

13.9, 7.1, 7.1, 4.6 Hz), 1.87−1.97 (1 H, m), 3.57−3.71 (2 H, m), 3.75 (1

H, dd, J = 7.8, 6.0 Hz), 4.39 (1 H, d, J = 11.9 Hz), 4.64 (1 H, d, J = 11.9

Hz), 6.16 (1 H, dd, J = 16.0, 7.8 Hz), 6.53 (1 H, d, J = 16.0 Hz), 7.23−

7.30 (4 H, m), 7.31−7.37 (4 H, m), 7.41 (2 H, d, J = 7.3 Hz); ¹³C NMR

(125 MHz, CDCl₃) δ −5.3, 15.4, 18.3, 25.9, 34.9, 35.8, 61.3, 70.2, 84.0,

126.4, 127.3, 127.6, 128.2, 128.5, 129.1, 132.9, 136.7, 138.9; [α]²⁵

Methyl 2-((1,2-erythro)-2-(Benzyloxy)-5-oxocyclohexyl)acetate (S-

049a). The properties of this compound matched those of a known

compound.³⁷

D

+90.3 (c = 0.64, CDCl₃); HRMS (ESI) calcd for C₂₆H₄₂O₂SiN [M +

NH₄]⁺428.2985, found 428.2999.

(3S,4R,E)-4-(Benzyloxy)-3-methyl-6-phenylhex-5-en-1-ol (S-050).

The starting material was prepared by previously published

procedures.¹²To a solution of cyanide (3.67 g, 12.6 mmol,

azeotropically dried with benzene immediately prior to use) in 50 mL

of dry toluene at −78 °C was added diisobutylaluminum hydride (2.37

mL, 18.9 mmol) dropwise over 10 min. The solution was warmed to

−55 °C over 1 h and then stirred at −55 °C for 24 h. The reaction was

quenched with the careful dropwise addition of 5 mL of 2-propanol. The

solution was diluted with 300 mL of 1 M HCl and 300 mL of

dichloromethane and stirred vigorously for 10 min. The layers were

separated, and the aqueous phase was back-extracted four times with 50

mL portions of dichloromethane. The combined organic layers were

washed with 200 mL of 1 M NaOH and 200 mL of brine. The solution

was dried over sodium sulfate, and concentrated to yield the desired

aldehyde as a clear oil (2.60 g, 70%).

The aldehyde (2.60 g, 8.82 mmol) was immediately dissolved in 30

mL of methanol and cooled to 0 °C. Sodium borohydride (0.95 g, 25

mmol) was added. The solution bubbled vigorously. After 10 min, the

solution was warmed to room temperature and stirred for 50 min. The

mixture was concentrated and resuspended in 100 mL of dichloro-

methane and 100 mL of 1 M HCl. The layers were separated, and the

aqueous phase was back-extracted three times with dichloromethane.

The combined organic extracts were washed with 50 mL of pH 7 buﬀer

and 50 mL of brine. The solution was dried over sodium sulfate and

concentrated to yield a clear oil. The oil was puriﬁed by silica gel

chromatography (10, 30, 50% EtOAc/hexanes) to yield the desired

alcohol as a clear oil (2.25 g, 60%): TLC R_f= 0.1 (20% EtOAc/hexanes,

CAM stain); IR (CHCl₃ﬁlm) 3028, 2931, 2875, 1951, 1878, 1810, 1495,

1453, 1372, 1354, 1204, 1064, 970, 747, 694 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 1.00 (3 H, d, J = 6.9 Hz), 1.42−1.54 (1 H, m, J = 12.8, 12.8, 6.9

Hz), 1.82 (1 H, td, J = 14.0, 6.4 Hz), 2.02 (1 H, ddd, J = 13.7, 6.9, 4.6 Hz),

(4R,5S,E)-Methyl 4-(Benzyloxy)-7-((tert-butyldimethylsilyl)oxy)-5-

methylhept-2-enoate (S-052). To a solution of silyl ether (2.70 g, 6.57

mmol) in 15 mL of dichloromethane at −78 °C was added ozone until

the solution turned blue. The solution was then sparged with nitrogen

for 5 min. Triphenylphosphine (1.72 g, 6.57 mmol) was then added.

The solution was allowed to warm to room temperature. The reaction

was stirred for 3 h. The bulk of the solvent was removed, and the mixture

was dissolved in 50 mL of 30% EtOAc/hexanes. The solution was

ﬁltered through a silica plug (5 × 5 cm). The plug was washed with 50

mL of 30% EtOAc/hexanes. The solution was concentrated to yield a

yellow oil. The oil was puriﬁed by silica gel chromatography (5, 10%

EtOAc/hexanes) to yield the desired aldehyde as a yellow oil (2.21 g,

1

100%): TLC R_f= 0.8 (20% EtOAc/hexanes); H NMR (600 MHz,

CDCl₃) δ 0.04−0.08 (6 H, m), 0.89−0.94 (9 H, m), 0.98−1.05 (3 H,

m), 1.49 (1 H, ddd, J = 19.6, 7.9, 5.9 Hz), 1.75 (1 H, td, J = 13.3, 6.6 Hz),

2.20−2.32 (1 H, m), 4.52 (1 H, d, J = 12.0 Hz), 4.76 (1 H, d, J = 12.0

Hz), 7.30−7.42 (5 H, m), 9.73 (1 H, d, J = 2.1 Hz).

To 50 mL of freshly distilled acetonitrile were added lithium chloride

(2.79 g, 65.7 mmol), freshly distilled diisopropylethylamine (3.43 mL,

19.7 mmol), and trimethyl phosphonoacetate (1.59 mL, 9.86 mmol).

Aldehyde (2.21 g, 6.57 mmol) was then added. The yellow suspension

1

was heated at 60 °C for 1.5 h after which H NMR analysis indicated

complete consumption of starting material. The suspension was cooled

and poured into a separatory funnel. One hundred milliliters of 25%

EtOAc/hexanes followed by 100 mL of 1 M HCl were carefully poured

in. The layers were separated, and the aqueous layer was back-extracted

ﬁve times with 20 mL portions of 25% EtOAc/hexanes. The combined

P

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The Journal of Organic Chemistry

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organic layers were washed twice with 75 mL portions of 1 M NaOH,

followed by 100 mL of brine. The combined organic extracts were dried

over sodium sulfate and concentrated to yield a yellow oil. The oil was

puriﬁed by silica gel chromatography (10% EtOAc/hexanes) to aﬀord

the desired enoate as a yellow oil (2.3 g, 90%, >20:1 E:Z): TLC R_f= 0.7

(20% EtOAc/hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 3060, 2952,

2929, 2857, 1959, 1888, 1810, 1725, 1658, 1638, 1582, 1496, 1472,

1458, 1435, 1388, 1360, 1312, 1273, 1257, 1202, 1170, 1094, 1034, 987,

concentrated to yield a yellow oil. Excess pyridine was removed

azeotropically with heptane. The oil was puriﬁed by silica gel

chromatography (5, 10, 20% EtOAc/hexanes) to yield the desired

aldehyde as a clear oil (0.86 g, 82%): TLC R_f= 0.40 (20% EtOAc/

hexanes, CAM stain); ¹H NMR (500 MHz, CDCl₃) δ ppm 0.98 (3 H, d,

J = 6.8 Hz), 2.19−2.32 (1 H, m), 2.39−2.51 (1 H, m), 2.61 (1 H, dd, J =

17.1, 5.9 Hz), 3.95 (1 H, ddd, J = 6.0, 4.5, 1.2 Hz), 4.33 (2 H, d, J = 11.7

Hz), 4.59 (2 H, d, J = 12.2 Hz), 6.83−6.91 (4 H, m, J = 22.0, 6.3 Hz),

7.20−7.44 (5 H, m), 9.71 (1 H, s).

1

900, 836, 775, 744, 721, 697 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

To a dry vial were added tin(II) chloride (57 mg, 0.3 mmol) and

dichloromethane (5 mL). tert-Butyl diazoacetate (0.46 mL, 3.3 mmol)

was added dropwise to the vial with vigorous stirring. After gas evolution

ceased, aldehyde (0.34 g, 1.22 mmol) was added, and the yellow solution

was stirred overnight. The solution was diluted with 100 mL of

dichloromethane and 100 mL of saturated sodium bicarbonate solution.

The layers were separated, and the aqueous layer was back-extracted

three times with 10 mL portions of dichloromethane. The combined

organic layers were washed with 50 mL of water and 50 mL of brine,

dried over sodium sulfate, and concentrated to yield a yellow oil. The oil

was puriﬁed by silica gel chromatography (0, 10, 20, 50% EtOAc/

hexanes). The remaining tert-butyl diazoacetate was removed by high

vacuum evaporation to yield the desired β-ketoester as a yellow oil (0.42

g, 90%): TLC R_f= 0.3 (20% EtOAc/hexanes, KMnO₄stain); IR (CHCl₃

ﬁlm) 2978, 2879, 1726, 1654, 1456, 1436, 1369, 1307, 1275, 1159, 1070,

987, 843, 738, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ ppm 0.93 (3 H,

d, J = 6.9 Hz), 1.42−1.51 (9 H, m), 2.31−2.38 (1 H, m, J = 16.9, 7.8 Hz),

2.40−2.47 (1 H, m), 2.70 (1 H, dd, J = 17.2, 5.3 Hz), 3.25 (2 H, d, J = 6.4

Hz), 3.77 (3 H, s), 3.94 (1 H, ddd, J = 5.8, 4.2, 1.4 Hz), 4.33 (1 H, d, J =

11.9 Hz), 4.57 (1 H, d, J = 11.9 Hz), 6.06 (1 H, d, J = 14.2 Hz), 6.87 (1 H,

dd, J = 15.6, 6.0 Hz), 7.24−7.37 (5 H, m); ¹³C NMR (125 MHz, CDCl₃)

15.1, 27.9, 32.8, 45.3, 51.0, 51.6, 71.1, 80.2, 81.9, 122.8, 127.7, 127.7,

128.4, 137.9, 146.2, 166.3, 166.4, 202.3; [α]²⁵_D+116 (c = 1.38, CH₂Cl₂);

HRMS (ESI) calcd for C₂₂H₃₄O₆N [M + NH₄]⁺408.2386, found

408.2373.

0.01−0.04 (6 H, m), 0.86−0.91 (9 H, m), 0.94 (3 H, d, J = 6.9 Hz),

1.29−1.39 (1 H, m), 1.68−1.76 (1 H, m), 1.87−1.97 (1 H, m), 3.55−

3.65 (2 H, m), 3.76 (3 H, s), 3.86 (1 H, t, J = 5.0 Hz), 4.35 (1 H, d, J =

11.9 Hz), 4.59 (1 H, d, J = 11.9 Hz), 6.03 (1 H, d, J = 14.6 Hz), 6.90 (1 H,

dd, J = 16.0, 6.4 Hz), 7.22−7.40 (5 H, m); ¹³C NMR (125 MHz, CDCl₃)

δ −5.3, −5.3, 14.8, 18.2, 25.9, 30.9, 34.0, 35.5, 51.5, 60.9, 71.1, 81.5,

122.3, 127.5, 127.6, 128.0, 128.3, 128.4, 128.4, 128.5, 128.6, 128.8, 130.2,

131.9, 132.0, 132.1, 133.6, 133.7, 138.2, 147.5, 167.4; [α]²⁵_D+14.0 (c =

0.64, CDCl₃); HRMS (ESI) calcd for C₂₂H₄₀NO₄Si [M + NH₄]⁺

410.2727, found 410.2722.

(4R,5S,E)-Methyl 4-(Benzyloxy)-7-hydroxy-5-methylhept-2-

enoate (S-053). To a solution of silyl ether (2.30 g, 5.86 mmol) in 20

mL of methanol was added 10-camphorsulfonic acid (1.36 g, 5.86

mmol). The solution was stirred for 45 min. Dichloromethane (50 mL)

and 50 mL of saturated sodium bicarbonate was added. The solution was

gently agitated until gas evolution stopped. The layers were separated,

and the aqueous layer was back-extracted three times with 20 mL

portions of dichloromethane. The combined aqueous extracts were

washed with 50 mL of brine, dried over sodium sulfate, and concentrated

to yield a yellow oil. The oil was puriﬁed by silica gel chromatography

(10, 20, 50% EtOAc/hexanes) to yield the desired alcohol as a clear

yellow oil (1.08 g, 67%): TLC R_f= 0.1 (20% EtOAc/hexanes, CAM

stain); IR (CHCl₃ﬁlm) 3417, 2936, 2876, 1724, 1657, 1436, 1277, 1196,

1171, 1066, 987, 866, 738, 698 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ

0.95 (3 H, d, J = 6.9 Hz), 1.44 (1 H, td, J = 13.7, 6.0 Hz), 1.73 (1 H, td, J =

13.8, 6.2 Hz), 2.00 (1 H, ddd, J = 13.5, 7.1, 4.6 Hz), 3.58−3.64 (1 H, m, J

= 11.0, 7.8, 6.0 Hz), 3.66−3.74 (1 H, m), 3.77 (3 H, s), 3.90 (1 H, ddd, J

= 6.3, 4.7, 1.4 Hz), 4.37 (1 H, d, J = 11.9 Hz), 4.61 (1 H, d, J = 11.9 Hz),

6.05 (1 H, d, J = 16.9 Hz), 6.91 (1 H, dd, J = 16.0, 6.4 Hz), 7.31 (5 H, d);

¹³C NMR (125 MHz, CDCl₃) δ 15.7, 34.7, 35.5, 51.6, 61.0, 71.2, 81.8,

Methyl 2-((1R,2R,3S)-2-(Benzyloxy)-3-methyl-5-oxocyclohexyl)-

acetate (S-054-syn). The crude decarboxylated adduct was puriﬁed

by silica gel chromatography (gradient elution: 5, 10, 15, 25% EtOAc/

hexanes) to yield the desired decarboxylated adduct as a mixture of

diastereomers. The yellow oil was puriﬁed by preparative HPLC

(Zorbax RX-SIL, 0.7% 2-propanol/hexanes, 215 nm, 20 mL/min). This

separated the desired 1,2-cis (S-65, 19 min) and 1,2-trans (S-66, 31 min)

isomers: TLC R_f= 0.20 (20% EtOAc/hexanes, CAM stain); ¹H NMR

(500 MHz, C₆D₆) (¹³C NMR, 125 MHz, via gHSQC/gHMBC

correlations) δ 0.62−17.1 (3 H, d, J = 7.3 Hz), 1.75−43.5 (1 H, dd, J

= 13.5, 5.1), 1.88−1.97 − 32.5 (1 H, m), 1.97−35.6 (1 H, dd, J = 16.0,

7.1 Hz), 2.06−43.2 (1 H, dd, J = 14.0, 4.9 Hz), 2.25−43.2 (1 H, dd, J =

14.0, 10.7 Hz), 2.35−43.5 (1 H, dd, J = 13.5, 4.6 Hz), 2.37−2.43 − 35.6

(1 H, m, J = 16.0, 7.3 Hz), 2.43−2.52 − 34.1 (1 H, m), 3.07−79.8 (1 H,

dd, J = 4.9, 2.9), 3.23−50.9 (3 H, s), 4.11−71.1 (1 H, d, J = 11.4), 4.19−

71.1 (1 H, d, J = 11.4), 7.04−7.21 − 128.03−128.08−128.48, quaternary

carbons: 138.5, 172.2, 207.6; HRMS calcd for C₁₇H₂₃O₄[M + H]⁺

291.1596, found 291.1606.

122.9, 127.6, 127.7, 128.4, 137.8, 146.4, 166.4; [α]²⁵_D+36.1 (c = 0.81,

CDCl₃); HRMS (ESI) calcd for C₁₆H₂₃O₄[M + H]⁺279.1596, found

279.1606.

(4R,5S,E)-9-tert-Butyl 1-Methyl 4-(benzyloxy)-5-methyl-7-oxonon-

2-enedioate (19). The oleﬁn−alcohol (1.05 g, 3.77 mmol) was

dissolved in 10 mL of dichloromethane at 0 °C. Freshly distilled N,N-

diisopropylethylamine (4.88 mL, 28.0 mmol) was added dropwise via

syringe. After 10 min of stirring at 0 °C, dimethyl sulfoxide (2.70 mL,

38.0 mmol) was added to the reaction mixture via syringe, and the

solution was allowed to stir for an additional 10 min. Sulfur trioxide−

pyridine complex (3.36 g, 16.0 mmol) was then added in one portion.

The reaction was allowed to proceed for 2 h at 0 °C, after which TLC

analysis indicated complete consumption of starting material. The

reaction was quenched by transfer into an 125 mL Erlenmeyer ﬂask that

contained a stirring solution of saturated sodium bicarbonate solution

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

separated. The aqueous layer was back-extracted three times with three

20 mL portions of dichloromethane. The combined organic extracts

were washed with 50 mL of brine, dried over sodium sulfate, and

Methyl 2-((1S,2R,3S)-2-(benzyloxy)-3-methyl-5-oxocyclohexyl)-

acetate (S-054-anti): TLC R_f= 0.20 (20% EtOAc/hexanes, CAM

stain); ¹H NMR (500 MHz, CDCl₃) 1.18 (3 H, d, J = 7.0 Hz), 2.05−2.52

Q

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The Journal of Organic Chemistry

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(7 H, m), 2.69 (1 H, dd, J = 5.4, 15.4 Hz), 3.34 (1 H, t, J = 9.6 Hz), 3.62

(3 H, s), 4.63 (2 H, dd, J = 11.4 Hz), 7.26−7.39 (5 H, m); HRMS calcd

for C₁₇H₂₃O₄[M + H]⁺291.1596, found 291.1606.

MHz, CDCl₃) δ 13.7, 40.2, 67.2, 70.2, 85.7, 126.5, 127.7, 127.8, 127.9,

128.3, 128.4, 128.4, 128.6, 134.0, 136.1, 137.9; [α]²⁵_D−84.2° (c = 1.93,

CH₂Cl₂); HRMS (ESI) calcd for [C₁₉H₂₆O₂N]⁺300.1964, found

300.1966.

4-Benzyloxy-3-methyl-6-phenylhex-5-enenitrile (S-057). To a

solution of alcohol (13.8 g, 48.9 mmol) in 63 mL of dichloromethane

were added p-toluenesulfonyl chloride (10.2 g, 53.7 mmol), 4-

dimethylaminopyridine (0.60 mg, 4.89 mmol), and triethylamine (8.5

mL, 91.1 mmol). The reaction was stirred for 6 h and then diluted with

100 mL of 1 M HCl. The layers were separated, and the aqueous layer

was back-extracted with three 25 mL portions of dichloromethane. The

combined organic extracts were washed with 100 mL of brine, dried over

sodium sulfate, and concentrated to yield the desired tosylate as a yellow

oil. TLC R_f= 0.35 (20% EtOAc/hexanes, KMnO₄stain). The oil was

immediately dissolved in 50 mL of DMSO. Potassium cyanide (6.37 g,

48.9 mmol) was added (caution: highly toxic!), and the mixture was

heated at 50 °C for 20 h. The mixture was diluted with 250 mL of 1 M

NaOH. The layers were separated and the aqueous layer was back-

extracted three times with 200 mL portions of diethyl ether. The

combined organic layers were diluted with 400 mL of hexanes, washed

with 200 mL of brine, dried over sodium sulfate, and concentrated to

yield the desired cyanide (13.4 g, 94%) as a yellow oil, which did not

require further puriﬁcation: TLC R_f= 0.5 (20% EtOAc/hexanes,

KMnO₄stain); IR (CHCl₃ﬁlm) 3061, 2968, 2931, 2864, 2245, 1652,

1600, 1578, 1495, 1454, 1420, 1385, 1348, 1206, 1109, 1086, 1028, 971,

748, 694 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.12 (3 H, d, J = 7.0

Hz), 2.04−2.19 (1 H, m), 2.58 (2 H, d, J = 5.5 Hz), 3.76 (1 H, t, J = 8.2

Hz), 4.40 (1 H, d, J = 11.4 Hz), 4.66 (1 H, d, J = 11.7 Hz), 6.08 (1 H, dd, J

= 15.9, 8.2 Hz), 6.64 (1 H, d, J = 16.1 Hz), 7.26−7.48 (10 H, m); ¹³C

NMR (100 MHz, CDCl₃) 16.0, 20.9, 35.3, 70.5, 82.7, 118.8, 126.5,

(2S,4R,5S)-5-Methyl-2-phenyl-4-((E)-styryl)-1,3-dioxane (S-055).

The starting material oxazolidinone was obtained from our previously

reported magnesium-catalyzed antialdol procedures.³⁸To a solution of

oxazolidinone (25.0 g, 68.4 mmol) in 600 mL of diethyl ether at −10 °C

was added lithium borohydride (34.2 mL, 68.4 mmol, as a 2.0 M

solution in THF). The reaction was stirred for 1.5 h and quenched with

150 mL of 1 M NaOH and 200 mL of water. The layers were separated

and the aqueous layer was back-extracted three times with 100 mL

portions of ether. The combined organic extracts were washed with 100

mL of brine, diluted with 300 mL of hexanes, dried over sodium sulfate,

and concentrated to give a yellow oil. The oil was dissolved in

dichloromethane and ﬁltered through a silica plug (5 × 2 cm). The plug

was rinsed with 20% EtOAc/dichloromethane, and the combined

ﬁltrate was concentrated to give the desired diol as a crude yellow oil.

TLC R_f= 0.2 (50% EtOAc/hexanes, CAM stain). The diol was dissolved

in 400 mL of benzene, and dimethoxymethylbenzene (13.3 mL, 88.9

mmol) and p-toluenesulfonic acid monohydrate (17.0 g, 88.9 mmol)

were added. The reaction was stirred overnight. The reaction was

diluted with 500 mL of saturated sodium bicarbonate solution. The

layers were separated, and the aqueous layer was back-extracted with

three 100 mL portions of dichloromethane. The combined organic

layers were washed with 200 mL of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil. The oil was puriﬁed by silica gel

chromatography (10% EtOAc/hexanes) to yield the desired benzyli-

dene acetal (13.0 g, 63%). NOESY measurements (1D PFGSE)

conﬁrmed the proposed all-equatorial stereochemistry at the

benzylidene acetal: TLC R_f= 0.5 (50% EtOAc/hexaenes); IR (CHCl₃

ﬁlm) 3029, 2562, 2896, 2842, 1494, 1451, 1396, 1370, 1300, 1162, 1147,

1107, 1086, 1071, 1026, 974, 926, 747, 697 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 0.84 (3 H, d, J = 7.0 Hz), 1.92−2.11 (1 H, m), 3.61 (1 H, t, J =

11.4 Hz), 4.08 (1 H, dd, J = 9.7, 7.5 Hz), 4.22 (1 H, dd, J = 11.4, 4.8 Hz),

5.61 (1 H, s), 6.27 (1 H, dd, J = 15.9, 7.5 Hz), 6.70 (1 H, d, J = 15.7 Hz),

7.20−7.58 (10 H, m); ¹³C NMR (100 MHz, CDCl₃) δ 12.4, 34.3, 73.0,

84.5, 101.2, 126.1, 126.6, 127.2, 127.8, 128.2, 128.5, 128.8, 133.1, 136.5,

127.3, 127.7, 127.8, 128.1, 128.4, 128.6, 134.9, 135.9, 137.9; [α]²⁵

D

−61.6 (c = 3.05, CH₂Cl₂); HRMS (ESI) calcd for [C₂₀H₂₅ON₂]⁺

309.1967, found 309.1971.

4-Benzyloxy-3-methyl-6-phenylhex-5-en-1-ol (S-058). To a sol-

ution of cyanide (1.40 g, 4.8 mmol, azeotropically dried with benzene

immediately prior to use) in 100 mL of dry toluene at −40 °C was added

diisobutylaluminum hydride (0.90 mL, 7.2 mmol) dropwise over 10

min. The solution was warmed to −20 °C over 1 h and then stirred at

−20 °C for 10 h. The reaction was quenched with the careful dropwise

addition of 2 mL of 2-propanol. The solution was diluted with 200 mL of

1 M HCl and stirred vigorously for 10 min. The layers were separated

and the aqueous phase was back-extracted three times with 20 mL

portions of ethyl acetate. The combined organic layers were washed with

200 mL of pH 7 phosphate buﬀer and 200 mL of brine. The solution was

dried over sodium sulfate and concentrated to yield the desired aldehyde

as a clear oil (1.10 g, 77%): TLC R_f= 0.45 (20% EtOAc/hexanes, CAM

stain); ¹H NMR (500 MHz, CDCl₃) δ 0.98 (3 H, d, J = 6.9 Hz), 2.26−

2.46 (3 H, m), 2.64 (1 H, ddd, J = 16.0, 6.2, 2.5 Hz), 3.65 (1 H, t, J = 8.0

Hz), 4.36 (1 H, d, J = 11.4 Hz), 4.61 (1 H, d, J = 11.4 Hz), 6.09 (1 H, dd, J

= 16.0, 8.2 Hz), 6.56 (1 H, d, J = 15.6 Hz), 7.11−7.49 (10 H, m), 9.76 (1

H, s).

The aldehyde (1.04 g, 3.53 mmol) was immediately dissolved in 10

mL of methanol and cooled to 0 °C. Sodium borohydride (0.40 g, 10.5

mmol) was added. The solution bubbled vigorously. After 10 min, the

solution was warmed to room temperature and stirred for 30 min. The

mixture was concentrated and resuspended in 100 mL of dichloro-

methane and 100 mL of 1 M HCl. The layers were separated, and the

aqueous phase was back-extracted three times with dichloromethane.

The combined organic extracts were washed with 50 mL of pH 7 buﬀer

and 50 mL of brine. The solution was dried over sodium sulfate and

concentrated to yield a clear oil. The oil was puriﬁed by silica gel

chromatography (20, 30, 50% EtOAc/hexanes) to yield the desired

138.4; [α]²⁵+12.5 (c = 2.63, CH₂Cl₂); HRMS (ESI) calcd for

D

[C₁₉H₂₄O₂N]⁺298.1807, found 298.1817.

(2S,3R,E)-3-(Benzyloxy)-2-methyl-5-phenylpent-4-en-1-ol (S-056).

To a solution of benzylidene acetal (19.3 g, 68.8 mmol) in 275 mL of

dichloromethane at −78 °C was added DIBAL-H (36.7 mL, 206 mmol)

dropwise via syringe. The reaction was stirred for 1 h and then warmed

to −10 °C. The reaction was allowed to proceed for 48 h. The reaction

was slowly quenched with methanol and diluted with 500 mL of 1 M

HCl. The mixture was stirred vigorously, and the layers were separated.

The aqueous layer was back-extracted three times with 50 mL portions

of dichloromethane. The combined organic extracts were washed three

times with 100 mL portions of brine, dried over sodium sulfate, and

concentrated to yield a yellow oil. The oil was purifed by silica gel

chromatography (10, 20, 30, 40% EtOAc/hexanes) to yield the desired

alcohol as a clear oil (13.9 g, 72%; also recovered 3% of the incorrect

regioisomer). TLC R_f= 0.2 (20% EtOAc/hexanes); IR (CHCl₃ﬁlm)

3414, 3028, 2962, 2875, 1599, 1494, 1454, 1378, 1660, 1206, 1085,

1066, 1028, 970, 912, 748, 694 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

ppm 0.89 (3 H, dd, J = 7.0, 1.5 Hz), 1.91−2.09 (2 H, m), 3.01 (1 H, dd, J

= 7.0, 3.3 Hz), 3.62−3.75 (2 H, m), 3.86 (1 H, t, J = 8.2 Hz), 4.41 (1 H, d,

J = 11.7 Hz), 4.68 (1 H, d, J = 11.7 Hz), 6.14 (1 H, ddd, J = 15.9, 8.4, 1.6

Hz), 6.57 (1 H, d, J = 15.7 Hz), 7.22−7.50 (10 H, m); ¹³C NMR (100

R

dx.doi.org/10.1021/jo302138z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

alcohol as a clear oil (0.92 g, 88%): TLC R_f= 0.1 (20% EtOAc/hexanes,

CAM stain); IR (CHCl₃ﬁlm) 3349, 3027, 2960, 2927, 2871, 1598, 1494,

followed by 100 mL of 1 M HCl were carefully poured in. The layers

were separated, and the aqueous layer was back-extracted ﬁve times with

20 mL portions of 25% EtOAc/hexanes. The combined organic layers

were washed twice with 75 mL portions of 1 M NaOH, followed by 100

mL of brine. The combined organic extracts were dried over sodium

sulfate and concentrated to yield a yellow oil. The oil was puriﬁed by

silica gel chromatography (10% EtOAc/hexanes) to aﬀord the desired

enoate as a yellow oil (0.87 g, 88%, >20:1 E:Z): TLC R_f= 0.7 (20%

EtOAc/hexanes, KMnO₄stain); IR (CHCl₃ﬁlm) 2942, 2857, 1728,

1658, 1462, 1435, 1388, 1360, 1256, 1169, 1095, 988, 900, 836, 776, 734,

697 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.01−0.05 (6 H, m), 0.87−

0.90 (9 H, m), 0.90−0.93 (3 H, m, J = 6.9 Hz), 1.29−1.37 (1 H, m),

1.70−1.78 (1 H, m, J = 14.0, 7.3, 7.1, 4.6 Hz), 1.93−2.02 (1 H, m), 3.57−

3.72 (2 H, m), 3.76 (3 H, s), 3.82−3.86 (1 H, m, J = 6.4, 6.4, 1.4 Hz),

4.38 (1 H, d, J = 11.9 Hz), 4.57 (1 H, d, J = 11.9 Hz), 6.03 (1 H, d, J =

15.6 Hz), 6.81−6.93 (1 H, m), 7.22−7.41 (5 H, m) ; ¹³C NMR (125

MHz, CDCl₃) δ −5.3, −5.3, 15.2, 18.2, 25.8, 25.9, 34.2, 35.4, 51.5, 61.1,

1

1452, 1380, 1065, 970, 892, 748, 693 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 0.96 (3 H, d, J = 7.3 Hz), 1.79−1.88 (1 H, m), 1.90−1.98 (1 H,

m), 1.99−2.08 (1 H, m), 3.61−3.78 (3 H, m), 4.40 (1 H, d, J = 11.9 Hz),

4.66 (1 H, d, J = 11.9 Hz), 6.14 (1 H, dd, J = 16.0, 8.7 Hz), 6.54 (1 H, d, J

= 16.0 Hz), 7.23−7.47 (10 H, m); ¹³C NMR (125 MHz, CDCl₃) δ 16.5,

30.9, 35.6, 36.3, 61.0, 70.3, 84.6, 126.5, 127.5, 127.8, 127.9, 128.3, 128.6,

128.7, 133.6, 136.4, 138.3; [α]²⁵_D−69.2 (c = 0.48, CDCl₃); HRMS calcd

for C₂₀H₂₈O₂N [M + NH₄]⁺314.2120, found 314.2124.

(4-Benzyloxy-3-methyl-6-phenylhex-5-enyloxy)-tert-butyldime-

thylsilane (S-059). To a solution of alcohol (0.90 g, 3.04 mmol) in 5 mL

of DMF were added tert-butyldimethylsilyl chloride (0.50 g, 3.3 mmol)

and imidazole (0.48 g, 7.0 mmol). The reaction was stirred overnight.

The reaction was diluted with 100 mL of diethyl ether and 100 mL of

saturated ammonium chloride solution. The layers were separated, and

the aqueous phase was back-extracted three times with 20 mL portions

of ether. The combined organic extracts were washed with 50 mL of

brine, diluted with 100 mL of hexanes, dried over sodium sulfate, and

concentrated under reduced pressure to aﬀord the desired silyl ether as a

clear and colorless oil (1.28 g, 94%): TLC R_f= 0.8 (20% EtOAc/

hexanes, KMnO₄); IR (CHCl₃ﬁlm) 3028, 2928, 2856, 1945, 1874,

1806, 1726, 1658, 1600, 1495, 1462, 1388, 1360, 1301, 1255, 1206,

71.0, 82.1, 122.7, 127.5, 128.3, 138.2, 147.0, 166.5; [α]²⁵−7.8° (c =

D

2.03, CDCl₃); HRMS calcd for C₂₂H₄₀O₄SiN [M + NH₄]⁺410.2727,

found 410.2722.

4-Benzyloxy-7-hydroxy-5-methylhept-2-enoic Acid Methyl Ester

(S-061). To a solution of silyl ether (0.70 g, 1.78 mmol) in 10 mL of

methanol was added 10-camphorsulfonic acid (0.47 g, 2.0 mmol). The

solution was stirred for 30 min. Dichloromethane (50 mL) and 50 mL of

saturated sodium bicarbonate were added. The solution was gently

agitated until gas evolution stopped. The layers were separated, and the

aqueous layer was back-extracted three times with 20 mL portions of

dichloromethane. The combined aqueous extracts were washed with 50

mL of brine, dried over sodium sulfate, and concentrated to yield a

yellow oil. The oil was puriﬁed by silica gel chromatography (10, 20, 50%

EtOAc/hexanes) to yield the desired alcohol as a clear yellow oil (0.44 g,

88%): TLC R_f= 0.1 (20% EtOAc/hexanes, CAM stain); IR (CHCl₃

ﬁlm) 3427, 2953, 2876, 1725, 1656, 1455, 1437, 1277, 1196, 1171, 1066,

988, 868, 737, 699 cm⁻¹; ¹³C NMR (500 MHz, CDCl₃) δ 0.93 (3 H, d, J

= 6.9 Hz), 1.44−1.52 (1 H, m), 1.70 (1 H, br s, J = 2.8 Hz), 1.72−1.80 (1

H, m), 1.91−1.98 (1 H, m), 3.58−3.66 (1 H, m), 3.69−3.74 (1 H, m),

3.76−3.83 (4 H, m), 4.36 (1 H, d, J = 11.4 Hz), 4.60 (1 H, d, J = 11.9

Hz), 6.03 (1 H, d, J = 14.6 Hz), 6.87 (1 H, dd, J = 15.8, 6.6 Hz), 7.22−

7.39 (5 H, m); ¹³C NMR (125 MHz, CDCl₃) δ 15.9, 30.9, 34.7, 35.6,

51.6, 60.7, 71.2, 82.3, 110.6, 123.0, 127.8, 128.4, 137.7, 146.8, 166.4;

[α]²⁵_D−32.7 (c = 0.60, CDCl₃); HRMS (ESI) calcd for C₁₆H₂₆O₄N [M

+ NH₄]⁺296.1862, found 296.1868.

1

1094, 1028, 1005, 970, 898, 835, 775, 747, 694 cm⁻¹; H NMR (500

MHz, CDCl₃) δ 0.01−0.07 (6 H, m), 0.86−0.91 (9 H, m), 0.94−0.98 (3

H, m, J = 6.4, 6.4 Hz), 1.32−1.41 (3 H, m, J = 13.7, 8.7, 6.9, 5.5 Hz),

1.82−1.90 (1 H, m), 1.96 (1 H, ddd, J = 12.9, 6.6, 6.5 Hz), 3.63−3.72 (2

H, m), 3.75 (1 H, dd, J = 7.8, 6.0 Hz), 4.37−4.44 (1 H, m, J = 12.4 Hz),

4.64 (1 H, d, J = 11.9 Hz), 6.15 (1 H, dd, J = 15.8, 8.0 Hz), 6.54 (1 H, d, J

= 16.0 Hz), 7.24−7.29 (2 H, m), 7.31−7.37 (6 H, m), 7.40−7.43 (4 H,

m, J = 7.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ −5.28, −5.25, 15.6, 18.3,

25.9, 34.8, 36.0, 61.5, 70.2, 84.3, 126.4, 127.3, 127.6, 128.2, 128.5, 133.2,

136.7, 138.9; [α]²⁵_D−41.3° (c = 1.68, CDCl₃); HRMS (ESI) calcd for

C₂₆H₄₂O₂SiN [M + NH₄]⁺428.2985, found 428.2968.

4-Benzyloxy-7-(tert-butyldimethylsilanyloxy)-5-methylhept-2-

enoic Acid Methyl Ester (S-060). To a solution of silyl ether (1.53 g,

1.22 mmol) in 15 mL of dichloromethane at −78 °C was added ozone

until the solution turned blue. The solution was then sparged with

nitrogen for 5 min. Triphenylphosphine (1.00 g, 3.8 mmol) was then

added. The solution was allowed to warm to room temperature. The

reaction was stirred for 3 h. The bulk of the solvent was removed, and the

mixture was dissolved in 50 mL of 30% EtOAc/hexanes. The solution

was ﬁltered through a silica plug (5 × 5 cm). The plug was washed with

50 mL of 30% EtOAc/hexanes. The solution was concentrated to yield a

yellow oil. The oil was puriﬁed by silica gel chromatography (5, 10%

EtOAc/hexanes) to yield the desired aldehyde as a yellow oil (1.03 g,

(4S,5S,E)-9-tert-Butyl 1-Methyl 4-(Benzyloxy)-5-methyl-7-oxonon-

2-enedioate (21). The oleﬁn−alcohol (0.37 g, 1.33 mmol) was

dissolved in 10 mL of dichloromethane at 0 °C. Freshly distilled N,N-

diisopropylethylamine (1.62 mL, 9.31 mmol) was added dropwise via

syringe. After 10 min of stirring at 0 °C, dimethyl sulfoxide (0.94 mL,

13.3 mmol) was added to the reaction mixture via syringe and the

solution was allowed to stir for an additional 10 min. Sulfur trioxide−

pyridine complex (1.11 g, 5.3 mmol) was then added in one portion.