Total synthesis of (-)-goniotrionin

Article

pubs.acs.org/joc

Total Synthesis of (−)-Goniotrionin

Luiz C. Dias* and Marco A. B. Ferreira

Chemistry Institute, State University of Campinas, UNICAMP, 13083-970, C.P. 6154, Campinas, SP, Brazil

S

* Supporting Information

ABSTRACT: A stereoselective total synthesis of the reported

structure of goniotrionin (4) has been accomplished. The key

steps involved the opening of a chiral epoxide, a highly

diastereoselective Mukaiyama aerobic oxidative cyclization, a

selective 1,2-syn Mukaiyama aldol reaction, and a Noyori

reduction.

10⁵times more potent than adriamycin against the breast cancer

cell line MCF-7. The skeletal structure of goniotrionin (4) was

assigned based on NMR, 2D-NMR and EIMS analysis, and the

relative stereochemistry of the C10−C16 fragment was estab-

lished by comparing the ¹H and ¹³C NMR spectra to the corre-

sponding Fujimoto’s⁹model and 1,3-diol¹⁰systems.

We describe herein our efforts toward the total synthesis of

the assigned enantiomer of goniotrionin (4) for the purposes of

checking McLaughlin’s structural assignment, obtaining material

for further biological evaluation and gaining access to novel

analogues.

1. INTRODUCTION

Natural products derived from terrestrial plants play a significant

role in the search for new molecules with potential pharmaco-

logical activity, particularly in the battle against cancer.¹Plants of

the Annonaceous family have been investigated over the last two

decades due to a number of antifungal and cytotoxic constituents

found in their leaves and bark.²Annonaceous acetogenins (AGEs)

are a series of polyketides that were initially isolated from various

Annonaceous plant species.³They are typically constituted as

long-chain fatty acids derivatives (32 or 34 carbons) containing

hydroxyl groups, one or more tetrahydrofuran (THF) or

tetrahydropyran units, and a γ-lactone (Scheme 1). Since the

antitumor activity of uvaricin (1) was first described in 1982,⁴

there has been a great deal of interest in this family of natural

products. Further interest was generated by the discovery of other

biological activities, such as immunosuppressive, pesticidal and

antimalarial effects. More than 500 AGEs have been isolated, and

more than 60 total syntheses have been published.²Some

examples of AGEs are shown in Scheme 1.⁵

Acetogenins have emerged as excellent leads for the

development of the next generation of antitumor drugs. Their

mechanism of action is attributed to the blocking of oxidative

pathways in the mitochondrial complex I (CMI) and the

inhibition of NADH oxidases, inducing the apoptosis of tumor

cells even in multidrug-resistant (MDR) tumors.^6,7

Although Annonaceae species are relatively abundant, the

AGEs within these plants are present in very small amounts and

are found as complex mixtures of similar isomers. Due to the

difficulty of crystallizing aliphatic AGEs, the assignment of their

absolute stereochemistries remains a major challenge. The use

of Mosher ester or acetonide derivatives and the total synthesis

of analogs are currently the most suitable methods for the

determination of AGE configurations.⁸

2. RETROSYNTHETIC ANALYSIS OF GONIOTRIONIN (4)

Goniotrionin (4) has a number of unique structural features

that make it a challenging synthetic target (Scheme 2). Our

disconnection approach began with the installation of the C14

stereogenic center through a late-stage chelation-controlled

1,2-syn Mukaiyama aldol reaction between aldehyde 6 and either

alkynyl silyl enol ether 5 or the Z-alkenyl silyl enol ether 5′.¹¹

The subsequent steps required to construct the Z-allylic

alcohol unit of goniotrionin (4) will depend on the choice of

enol silyl ether. If 5 is used, the obvious path forward would

involve a selective carbonyl reduction followed by a partial

alkyne reduction, whereas if 5′ is used, a selective carbonyl

reduction would be sufficient because the Z-alkene would

already be installed. The terminal butenolide portion of

aldehyde 6 would be assembled by an alkylation reaction

involving the lithium enolate of White’s lactone 8 and the

proper electrophile, which could be obtained from intermediate

7 following the removal of the PMB group. To access the THF

unit of intermediate 7, a Sonogashira cross-coupling reaction

between fragments 9 and 10 was considered. We planned to

establish the trans-THF configuration in vinyl iodide 10 by a

Mukaiyama oxidative cyclization catalyzed by 13.¹²This

convergent synthetic plan therefore divided goniotrionin (4)

into the chiral fragments 8, 9 and 10, which could all be easily

prepared from commercially available enantiomerically pure

Goniotrionin (4) was isolated in 1998 by Alali, McLaughlin

and co-workers in small quantities (1.5 mg as a whitish wax)

from Goniothalamus giganteus, a tree native to Thailand

(Scheme 1).^5jGoniotrionin (4) exhibited a high cytotoxicity

against the A-549, MCF-7, A-498 and PACA-2 cancer cell lines,

resulting in ED50 values of 7.7, 5.3 × 10⁻³, 2.0 and 5.4 ng/mL,

respectively. In particular, goniotrionin was found to be

Received: February 26, 2012

Published: March 23, 2012

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Scheme 1. Representative Examples of AGEs

Scheme 2. Synthetic Route to Goniotrionin (4)

epoxides 11 and 12. Alternatively, epoxides 11 and 12 can be

obtained by hydrolytic kinetic resolution using Jacobsen’s

methodology.¹³

protocol,¹²providing 2,5-trans-THF 17 as a single diastereoisomer

in 73% yield (dr > 95:05) on a multigram scale. This methodology

has proven to be a very useful synthetic tool for accessing 2,5-

trans-THF rings in natural product syntheses.^12b,5g,h,15The H

1

NMR, ¹³C NMR and [α]_Dof trans-THF 17 matched the reported

values for this compound, which was obtained previously by a

different synthetic route.¹⁶Next, a Swern oxidation of primary

alcohol 17 followed by a Wittig olefination using phosphonium

salt 19¹⁷afforded Z-vinyl iodide 10 as the only isolated product

(77% yield for the 2-step sequence).

3. RESULTS AND DISCUSSION

3.1. Preparation of Aldehyde 6. Our synthesis began with

the preparation of vinyl iodide 10 (Scheme 3). The protection of

the primary hydroxyl group of glycidol (R)-12 with the TBDPS

group (62%) followed by the opening of epoxide 14 with

allylmagnesium bromide (15) led to hydroxyalkene 16 in 90%

yield.¹⁴The subsequent aerobic oxidative cyclization of 16 was

mediated by a Co(modp)₂(13) catalyst according to Mukaiyama’s

Our efforts to prepare the Co(modp)₂(13) catalyst were

based on the previously reported procedure by Pagenkopf and

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Scheme 3. Preparation of Vinyl Iodide 10

Scheme 4. Preparation of the Co(modp)₂Catalyst (13)

Scheme 5. Preparation of Alcohol 24 and Electrophiles 25 and 26

co-workers¹⁸but with a slight modification in the preparation

of intermediate 20, in which we used solvent-free conditions

(Scheme 4).

The next step involved the protection of glycidol (S)-12 with

a PMB group (Scheme 5).¹⁹The subsequent opening of

epoxide 22 with a lithium acetylide ethylenediamine complex

followed by protection of the resulting hydroxyl group with

TBDPS led to alkyne 9 (89% yield for two steps). Sonogashira

cross-coupling between 9 and 10 led to compound 23 in 82%

yield.²⁰A two-step enyne reduction and PMB deprotection was

performed on 23 under neutral conditions to prevent silyl

migration in diol 24.²¹Enyne reduction with H₂/Pd−C

followed by the removal of the PMB protecting group with

DDQ in a phosphate buffer (pH 7) led to primary alcohol 24 in

73% yield for the two-step sequence. With alcohol 24 in hand,

we turned our attention to the alkylation step in which the

butenolide portion of goniotrionin would be installed by

alkylating White’s lactone 8.²²For this purpose, we investigated

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Table 1. Alkylation Reaction Involving White’s Lactone 8 and Electrophiles 25 and 26

a

b

c

entry

electrophile

base

LDA

equiv of 8

additive (equiv)

T (°C)

time (h)

yield

d

1

2

3

4

5

6

7

25

26

1.3

4

rt

16

2

NR

d

HMPA (4)

rt

NR

e

LiHMDS

NaHMDS

LiHMDS

4

50

ND

d

4

rt

NR

d

3

rt

NR

3

HMPA (2)

rt

trace

LiHMDS

3

HMPA (10)

0 to rt

62%

a

b

c

d

Base:8 (1:1.4), 1.0 M solution of the base. Excess 8 was recovered by silica gel column chromatography. Yield of the isolated product. Only

e

starting material was recovered. Complex mixture by TLC.

Scheme 6. Preparation of the Aldehyde 6

Scheme 7. Preparation of Enol Silane 5′

both iodide 25 and triflate 26 as electrophiles. First, alcohol 24

was subjected to the Appel reaction conditions,^23a,bproviding

iodide 25 in 71% yield (Scheme 5). The triflate 26 was formed

in 94% yield by employing Tf₂O^23cand pyridine.

91% yield over 2 steps (Scheme 6). Selective removal of the

primary TBDPS group using an HF·py complex provided

alcohol 29 in 95% yield.²⁵Alcohol 29 was then subjected to the

Parikh-Doering oxidation procedure to prepare the desired

aldehyde 6.

3.2. Preparation of Enol Silanes 5 and 5′. Silyl enol

ether 5′ was prepared as outlined in Scheme 7. Oxidative

cleavage of terminal alkene 30 with NaIO₄in the presence of

catalytic amounts of OsO₄lead to aldehyde 31 in 89% yield.

Next, HWE coupling using Ando’s phosphonate reagent 32²⁶

and aldehyde 31 provided the Z-ester 33 (79% yield, Z:E >

95:5). The conversion of ester 33 to the Weinreb amide 34²⁷

followed by reaction with methyl magnesium iodide gave

exclusively the Z-α,β-unsaturated methyl ketone Z-35 in

75% yield. Next, the treatment of methyl ketone Z-35 with

LDA and TMSCl gave the silyl enol ether 5′ in quantitative

yield.²⁸We assigned the Z configuration to silyl enol ether 5′

Table 1 summarizes the conditions that we investigated for

the alkylation reaction. We were unable to obtain satisfactory

results with iodide 25 and metal enolate 8′ (Table 1, entries 1−4),

probably due to the close proximity of the bulky OTBDPS

group to the electrophilic carbon C3. In contrast, we were

pleased to find that the more reactive triflate 26 is a competent

substrate for the alkylation of 8′, leading to intermediate 27 as a

mixture of diastereoisomers, and in an acceptable yield (62%

yield), although 10 equivalents of HMPA are required (Table 1,

entry 7). We were unable to devise conditions that provided

higher yields.²⁴

Next, m-CPBA oxidation of sulfide 27 to the sulfoxide

derivative and thermal elimination led to intermediate 28 in

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Scheme 8. Preparation of Enol Silane 5

Scheme 9. Expected Stereochemical Outcome for a Chelation-controlled Mukaiyama Aldol Reaction

1

by examining the coupling constant in the H NMR spectrum

(J_H17/H18= 11.9 Hz).

The diastereoselectivity of the key Mukaiyama aldol reaction

was first investigated using the simpler aldehydes 18 and 41 as

model substrates before exposing the advanced aldehyde 6 to

the aldol coupling (Table 2). Our first choice was to use silyl

enol ether 5′ because the aldol adduct would already contain

the necessary Z double bond geometry. Previous reports have

shown that B- and Li-enolates of Z-unsaturated ketones can be

used without losing the Z double bond geometry.^27,33However,

we were unable to obtain acceptable results with enol silane 5′.

The exposure of aldehyde 41 to enol silane 5′ in the presence of

MgBr₂·Et₂O at −30 °C led to aldol adduct Z-42, but the

presence of E-42 confirmed that some double bond isomer-

ization had occurred (Table 2, entry 2). An increase in the

temperature led to exclusive formation of the E-43 aldol adduct

(Table 2, entry 4). SnCl₄and TiCl₄have been found to be the

best Lewis acids for many chelation-controlled Mukaiyama

aldol reactions,³⁰but the use of these catalysts on our system

showed only decomposition of the enol silane, leading to the

double-bond isomerization product, methyl ketone E-34 (Table 2,

entries 5−6). The same behavior was observed for Sn(OTf)₂

and Me₂AlCl (Table 6, entries 7−8). LiClO₄has also been used

as a Lewis acid in chelation-controlled Mukaiyama aldol

reactions, either at high concentrations (homogeneous system

in ethyl ether, entry 9)^34aor in catalytic amounts (heteroge-

neous system in CH₂Cl₂, entry 10).^34bHowever, even under

these conditions, we did not observe any formation of the

desired aldol adduct.

The construction of enol silane 5 started with a Seyferth-

Gilbert homologation from aldehyde 31 using the Ohira-

Bestmann reagent 36.²⁹Further treatment with n-BuLi and

Weinreb amide 38 produced methyl ketone 39 in 73% yield

(Scheme 8). Finally, treatment of methyl ketone 39 with

LiHMDS and TMSCl gave enol silane 5 in quantitative yield.

3.3.1. Installation of the C14 Stereocenter and Com-

pletion of the Synthesis of Goniotrionin (4). Studies on

the Mukaiyama Aldol Reaction and the 1,3-Carbonyl Reduction.

Our goal at this point was to develop conditions favoring

the nucleophilic attack of an enol silane from the si face

of α−alkoxy aldehyde 6 to produce the required C14 stereo-

center of goniotrionin (4). We hypothesized that a chelation-

controlled Mukaiyama aldol reaction might achieve the desired

C14 stereocenter as depicted in Scheme 9 (eq 1).³⁰The co-

ordination between the Lewis acid and the THF oxygen atom

keeps the substrate in a rigid conformation, allowing the enol

silane to attack from the less sterically hindered side of the

aldehyde through a Cram-chelate transition state (TS-A), thus

leading to the 1,2-syn aldol adducts.³¹A Mukaiyama aldol

reaction involving activation of the α−alkoxy aldehyde by

a monodentate Lewis acid or an aldol reaction involving a

preformed metal enolate cannot be used in this case be-

cause they would produce the undesired 1,2-anti aldol adduct

(eq 2).³²

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a

Table 2. Model Studies of the Mukaiyama Aldol Reaction between Enol Silane 5′ and Aldehyde 18 or 41

entry

P

solvent

T (°C)

LA (equiv)

time (h)

yield

1

2

3

4

5

6

7

8

9

10

TBS

CH₂Cl₂

PhMe

−78

−30

0

MgBr₂·OEt₂(3)

MgBr₂.OEt₂(3)

SnCl₄(1)

4.5

1

6.3% [Z-42], 55% [E-34]

TBS

38% [Z-42], 22% [E-42], 28% [E-34]

b

TBS

only E-34

TBDPS

CH₂Cl₂

Et₂O

20% [E-43], 21% [E-34]

b

−78

rt

only E-34

b

TiCl₄(1)

1

only E-34

b

Sn(OTf)₂(1)

Me₂AlCl (1)

1

only E-34

b

1

only E-34

b

LiClO₄(5 M)

LiClO₄(3 mol %)

18

4

only E-34

b

CH₂Cl₂

rt

only E-34

a

Conditions: A 0.2 M solution of 5′ (1.5 equiv) was added to a 0.2 M solution of aldehyde (1 equiv) that had been preactivated with the Lewis acid

b

for 5 min. Yield not determined.

Scheme 10. Model Study of the Mukaiyama Aldol Reaction between Aldehyde 18 and Enol Silane 5

In contrast, to our delight, we found that the chelation-

controlled Mukaiyama aldol reaction between aldehyde 18 and

silyl enol ether 5 using MgBr₂·OEt₂provided the aldol adduct

44 in 68% yield as the only diastereoisomer measured by NMR

spectra (Scheme 10).

3.3.2. Mukaiyama Aldol Reaction between Silyl Enol Ether

5 and Aldehyde 6 and the Conclusion of the Synthesis of

Goniotrionin (4). At this point, the advanced fragments 5

(C15−C32) and 6 (C1−C14) were coupled by a chelation-

controlled Mukaiyama aldol reaction using the optimized

conditions, which employ MgBr₂·OEt₂as a Lewis acid,

providing aldol adduct 49 in 59% yield (for two steps) as a

single diastereoisomer (Scheme 12). With the desired aldol

adduct 49 available, construction of the stereogenic center at

C16 was performed using Noyori hydrogenation.³⁸When 49

was exposed to (S,S)-Noyori’s catalyst (50) (5 mol %), a clean

reduction of the carbonyl occurred, providing diol 51 as a single

diastereoisomer in 71% isolated yield.

Again, the preparation of acetonide 52 allowed us to confirm

the relative stereochemistry for diol 51 via Rychnovsky

acetonide ¹³C NMR analysis (Scheme 13).³⁷At this point,

we attempted to determine the absolute stereochemistry of the

newly created stereogenic centers at C14 and C16. Efforts to

reach the Mosher ester derivatives 53a−b from aldol adduct 49

proved to be unfruitful because the decomposition of the

starting material was observed under the various conditions

tested. Furthermore, the modified Mosher’s method using di-

MTPA is not useful in the case of acyclic anti-1,3-diols because

the Δδ values are irregularly arranged.³⁹As an alternative to the

direct use of Mosher’s method, the aldol adduct 49 was

protected with a TBS group, and a subsequent Noyori

reduction produced the monoprotected diol 55,⁴⁰as depicted

in Scheme 13. The monodesilylation⁴¹of 1,3-diol 55 produced

compound 51 (Scheme 13), which had identical spectroscopic

With the aldol adduct 44 in hand, we continued our model

studies, investigating the best way to establish the anti-diol

relationship between the C14 and C16 stereocenters present in

goniotrionin (4). Using Me₄NBH(OAc)₃in AcOH and MeCN

produced the inseparable diols 45 and 46 in excellent yields but

with low diastereoselectivity (7:3) in favor of anti-diol 45

(Scheme 11). Previous reports have also shown low 1,3-anti

selectivity for alkynyl ketone substrates.³⁵In general, a large

preference for 1,3-anti reduction is observed when employing

this methodology, but we strongly believe that the presence of

the triple bond in ketone 44 attenuates the 1,3-diaxial

repulsions in the cyclic transition state TS-B′ that are

responsible for the diastereoselectivity of this transformation.³⁶

Acetonide formation permitted the confirmation of the

stereochemistry in diols 45 and 46 via Rychnovsky acetonide

¹³C NMR analysis of compounds 47 and 48 (which were

separable by chromatography).³⁷Acetonides 47 and 48

matched with the anti class 3 and syn class acetonides proposed

by Rychnovsky,³⁷respectively.

In light of these disappointing results, we envisaged the

possibility of using the asymmetric Noyori carbonyl reduction

of α,β-acetylenic ketones³⁸to construct the 1,3-anti diol

relationship found in goniotrionin (4).

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Scheme 11. 1,3-Reduction of Aldol Adduct 44

reported in the literature for the natural product (Table 3).^5j

However, the optical rotation value for natural goniotrionin (4)

was not reported, and because a sample of the authentic natural

product was not available for comparison, the absolute

stereochemistry of goniotrionin (4) is still subject to

conjecture. Our synthetic sample showed low specific rotation

values that were dependent on the concentration: [α]_D²³= −7

(c = 1.2/CHCl₃), [α]_D²³= −3 (c = 0.12/CHCl₃), [α]_D²³= 0 (c =

0.012/CHCl₃). In a discussion with Prof. Alali,^5jhe suggested

that the originally isolated goniotrionin (4) may not have

exhibited an optical rotation due to the very low isolated mass

(1.5 mg). The optical rotation values for our synthetic sample

corroborate this hypothesis. We believe that this result might

represent a complex equilibrium of self-aggregating species. It is

known that the formation of dimers or trimers can result in a

nonlinear concentration dependence for self-aggregating

species in solution. This may help to explain the differences

in optical rotation at different concentrations of goniotrionin

(4) because the positive and negative contributions from

equilibrating species to [α]_Dmay cancel out at low

concentrations.⁴⁴In this case, the solution becomes cryptochiral

despite the presence of a single diastereoisomer.⁴⁵

Scheme 12. Synthesis of Intermediate 51 (C1−C32)

However, the not reported specific rotation data for the

natural sample of goniotrionin prevented the assignment of the

absolute configuration, and the diastereomeric relationship

between the remote C4/C34 and trans-THF associated

data and physical properties when compared to the same

compound prepared directly from aldol adduct 49 (Scheme 12;

in the Supporting Information, see Figures S80, S81, S97, and

S98), ensuring that both diols had the same absolute stereo-

chemistry. Finally, the preparation of Mosher ester derivatives

56a−b and the subsequent NMR analysis (δS − δR)⁴²directly

confirmed the absolute configuration at C16 and indirectly

confirmed the configuration at C14 (from acetonide 52).

Finally, a highly cis-selective zinc-mediated partial reduction

of alkyne 51 was performed, producing Z-allylic alcohol 57 in

86% yield (Scheme 14).⁴³Deprotection of the silyl group at C4

provided goniotrionin (4) in 95% yield.

1

stereocenters. Consequently, it is possible that the H and

¹³C NMR chemical shifts of the proposed structure for

goniotrionin (4) and one of the diastereoisomers are nearly

identical simply by coincidence.

CONCLUSION

■

In conclusion, we have accomplished the first total synthesis of

the reported structure of goniotrionin (4) in 4% overall yield

over a longest-linear sequence of 17 steps from comercial

epoxide (R)-12. Our synthetic route employed an epoxide-

opening strategy, using chiral epoxides as building blocks. Key

Spectral data (¹H and ¹³C NMR, IR, and HRMS) from the

synthetic sample were in complete agreement with those

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Scheme 13. Confirming the Stereochemistry at C14 and C16

employs highly flexible key couplings that allow for the

preparation of analogs, including other diastereoisomers of

goniotrionin (4). To get more insights about the remote

relative configuration of natural goniotrionin (4), efforts to

synthesize others diastereoisomers are currently in progress and

will be reported in due course.

Scheme 14. Completion of the Synthesis of Goniotrionin (4)

EXPERIMENTAL SECTION

■

Materials and Methods. Unless otherwise noted, all reactions

were performed under an argon atmosphere in flame-dried glassware

with magnetic stirring. Dichloromethane (CH₂Cl₂), triethylamine

(Et₃N), 2,6-lutidine, diisopropylethylamine (DIPEA), dimethylforma-

mide (DMF), benzene, pyridine (py), and diisopropylamine (DIPA)

were distilled from CaH₂. Dimethyl sulfoxide (DMSO) and HMPA

were distilled under reduced pressure from CaH₂and stored over

molecular sieves. Tetrahydrofuran (THF) and diethyl ether (Et₂O)

were distilled from sodium/benzophenone. SnCl₄and TiCl₄were

distilled over CaH₂before use. LiClO₄was activated under high

vacuum at 120 °C for 24 h before use. Oxalyl chloride was distilled

immediately prior to use. The reaction products were purified by flash

column chromatography using silica gel (230−400 mesh). Analytical

thin-layer chromatography was performed on silica-gel 60 and GF (5−

40 μm thickness) plates. The TLC plates were visualized with UV light

and phosphomolybdic acid followed by heating. Optical rotations were

measured with a sodium lamp and are reported as follows: [α]_D°^c(c =

g/100 mL, solvent). For the infrared spectra, wavelengths of maximum

absorbance (max) are quoted in wavenumbers (cm⁻¹). ¹H and proton-

decoupled ¹³C NMR spectra were taken in C₆D₆, CDCl₃or DMSO-d₆

steps included a Mukaiyama aerobic oxidative cyclization and a

1,2-syn selective Mukaiyama aldol reaction. This synthesis

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1

Table 3. H and ¹³C NMR Chemical Shifts for Natural and Synthetic Goniotrionin (4)

isolated natural product

synthetic product

a

position

δ (H)

δ (C)

174.6

multiplicity H (J in Hz)

δ (H)

δ (C)

multiplicity H (J in Hz)

1

174.6

131.1

33.4

2

131.1

33.4

3a

2.54

ddt (15.5, 3.5, and 1.0)

2.52

2.38

3.85

1.48

ddt (15.1, 3.2, and 1.5)

3b

4

2.40

ddt (15.0, 8.0, and 1.0)

ddt (15.1, 8.3, and 1.2)

3.85

69.9

m

69.9

m

5

1.48

37.2

m

37.3

m

b

6−8

9

1.18−1.65

1.53−1.64

3.89

25.5−37.2

35.4

m

1.18−1.65

1.57−1.69

3.89

25.5−29.7

35.4

m

10

11

12

13

14

15

16

17

18

19

20−29

30

31

32

33

34

35

OH

79.3

m

79.3

m

2.03 and 1.54

1.96 and 1.60

3.85

32.4

m

2.03 and 1.54

1.95 and 1.60

3.85

32.4

m

28.2

m

28.2

m

81.8

m

81.8

m

3.73

71.5

dt (11.5 and 3.5)

3.73

71.5

td (7.8 and 3.9)

1.58

39.6

m

1.59

39.7

m

4.78

65.0

dt (8.0 and 4.0)

4.77

65.0

dt (7.81 and 4.15)

5.48

131.6

132.2

25.5−37.2

31.9

m

5.47

131.6

132.2

27.7

m

5.44

m

5.46

m

b

2.10 and 2.05

1.18−1.65

1.30

m

2.10 and 2.05

1.18−1.65

0.87

m

25.5−29.7

31.9

m

22.7

m

22.7

m

0.88

14.1

t (7.0)

14.1

t (6.8)

7.19

151.9

78.0

q (1.5)

7.18

151.8

78.0

m

5.07

qq (7.0 and 1.5)

d (7.0)

5.05

qq (6.8 and 1.5)

d (6.7)

1.44

19.1

1.43

19.1

c

nr

2.80, 2.63, and 2.36

bs

a

b

c

Assignment based on COSY, HMBC and HMQC experiments. The value 37.2 is a typo because this value was attributed to the C5 carbon. Not

reported.

at 250 MHz (¹H) and 62.9 MHz (¹³C), 400 MHz (¹H) and 100 MHz

(¹³C) or 500 MHz (¹H) and 125 MHz (¹³C). The chemical shifts (δ)

are reported in ppm using the solvent peak as an internal standard

(C₆D₆at 7.16 ppm, CDCl₃at 7.26 ppm and DMSO-d₆at 2.49 ppm for

¹H NMR spectra and C₆D₆at 128.0 ppm, CDCl₃at 77.0 ppm and

DMSO-d₆at 39.50 ppm for ¹³C NMR spectra). Data are reported as

the following: s = singlet, bs = broad singlet, d = doublet, t = triplet,

q = quartet, quint = quintuplet, sext = sextet, dd = doublet of doublets,

dt = doublet of triplets, dq = doublet of quartets, ddd = doublet of

doublet of doublets, td = triplet of doublets, tt = triplet of triplets, qd =

quartet of doublets, m = multiplet, ad = apparent doublet, aquint =

apparent quintuplet; coupling constant(s) in Hz; integration. The

signals from the minor isomers are listed in brackets. High-resolution

mass spectrometry (HRMS) was performed using either electrospray

ionization (ESI) or electron ionization (EI). The parent ions ([M + H]⁺,

[M + Na]⁺, [M + K]⁺, [M − OH]⁺, and [M − C₆H₅]⁺) are listed.

Preparation of Aldehyde 6: (2S)-1-(tert-Butyldiphenylsilyloxy)-

with Et₂O (2 × 50 mL). The combined organic phases were dried

(Na₂SO₄) and filtered, and the solvent was removed in vacuo.

Purification by flash column chromatography using Et₂O/hexane (1:4)

as the eluent gave the known secondary alcohol 16 (12.3 g, 34.6

mmol) in 90% yield as a colorless oil. R_f0.58 (20% Et₂O in hexane).

[α]_D²³= −7.2 (c = 2.1/CH₂Cl₂). Lit.¹³: [α]_D²⁹= −7.8 (c = 1.8/CH₂Cl₂).

¹H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H), 1.38−1.66 (m, 2H),

2.00−2.30 (m, 2H), 2.38 (s, 1H), 3.51 (dd, J = 9.9 and 7.5 Hz, 1H),

3.68 (dd, J = 9.9 and 3.5 Hz, 1H), 3.71−3.81 (m, 1H), 4.90−5.08 (m,

2H), 5.81 (ddt, J = 17.1, 10.3, and 5.8 Hz, 1H), 7.33−7.50 (m, 6H),

7.60−7.76 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) δ 19.2 (C), 26.8

(CH₃), 29.7 (CH₂), 31.9 (CH₂), 67.9 (CH₂), 71.3 (CH), 114.74

(CH₂), 127.76 (CH), 129.8 (CH), 133.1 (C), 135.5 (CH), 138.3

(CH). IR ν_max(film) 3577, 3436, 3072, 2929, 2858, 1959, 1890, 1824,

1739, 1641, 1589, 1473, 1427, 1261, 1112, 912, 823, 740, 702.

((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-

2-yl)methanol (17). Co(modp)₂(13) (2.71 g, 5.03 mmol) was added

to a solution of i-PrOH (500 mL), 16 (11.3 g, 33.4 mmol) and

t-BuOOH (6.1 mL, 33.4 mmol, 5−6 M in nonane). The mixture was

kept under an O₂atmosphere (1 atm) and stirred vigorously at 60 °C.

After stirring for 24 h, the reaction mixture was cooled to rt. A

saturated aqueous solution of Na₂S₂O₃(5 mL) was then added, the

organic solvent was removed in vacuo and the residual dark green oil

was partitioned between EtOAc (150 mL) and a saturated aqueous

solution of NH₄Cl (50 mL). The aqueous phase was then extracted

with EtOAc (3 × 70 mL), the organic solvent was removed in vacuo

and the residue was purified by flash column chromatography using

Et₂O/hexane (1:9 to 3:7) as an eluent to afford the known com-

pound 17 as a light green oil (8.98 g, 24.2 mmol) in 73% yield. R_f0.46

prop-2-enoxide (14).¹⁴R_f0.58 (10% EtOAc in hexane). [α]_D²³

=

13

−2.3 (c = 10.0/CH₂Cl₂). Lit. : [α]_D²⁹= −2.1 (c = 1.8/CH₂Cl₂). H

NMR (250 MHz, CDCl₃) δ 1.08 (s, 9H), 2.63 (dd, J = 5.2 and 2.7 Hz,

1H), 2.66 (dd, J = 5.2 and 4.1 Hz, 1H), 3.10−3.19 (m, 1H), 3.72 (dd,

J = 11.8 and 4.8 Hz, 1H), 3.88 (dd, J = 11.8 and 3.2 Hz, 1H), 7.33−

7.50 (m, 6H), 7.65−7.77 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃)

δ 19.3 (C), 26.7 (CH₃), 44.4 (CH₂), 52.3 (CH), 64.3 (CH₂), 127.7

(CH), 129.7 (CH), 133.2 (CH), 135.54 (C), 135.59 (CH).

1

(S)-1-((tert-Butyldiphenylsilyl)oxy)hex-5-en-2-ol (16).¹⁴Allyl

magnesium bromide (2.1 equiv, 80.0 mL, 80.0 mmol, 1.0 M in Et₂O)

was added to a flame-dried flask under an Ar atmosphere at −20 °C,

and a solution of 14 (12.0 g, 38.4 mmol) in anhydrous Et₂O (10 mL)

was added dropwise while stirring the reaction vigorously. After

10 min at −20 °C and 1 h at rt, a saturated aqueous solution of

ammonium chloride (60 mL) and H₂O (7 mL) were added. The

suspension was warmed to rt, and the reaction mixture was extracted

(30% EtOAc in hexane). [α]_D²³= +9.0 (c = 1.4/CHCl₃). Lit.¹⁵: [α]_D²⁰

=

+5.9 (c = 1.7/CHCl₃). ¹H NMR (250 MHz, CDCl₃) δ 1.07 (s, 9H), 1.61−

2.10 (m, 4H), 2.23 (bs, 1H), 3.49 (dd, J = 11.5 and 6.1 Hz, 1H), 3.60−3.76

(m, 3H), 4.05−4.21 (m, 2H), 7.32−7.49 (m, 6H), 7.64−7.75 (m, 4H).

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Article

¹³C NMR (62.9 MHz, CDCl₃) δ 19.2 (C), 26.8 (CH₃), 27.4 (CH₂),

filtered, and the solids were washed with CH₂Cl₂. The combined

organic phases were washed with a saturated aqueous solution of

NaHCO₃and brine, dried with Na₂SO₄, and filtered, and the organic

solvent was removed under vacuum to give the known compound 21

(2.07 g, 8.58 mmol) as an orange solid in 80% yield, which was used

28.1 (CH₂), 64.9 (CH₂), 66.4 (CH₂), 79.6 (CH), 79.7 (CH), 127.6 (CH),

129.6 (CH), 133.54 (C), 135.59 (CH). IR ν_max(film) 3456, 3070, 3049,

2948, 2856, 1961, 1892, 1824, 1739, 1589, 1473, 1427, 1242, 1109,

823, 740, 700.

1

without further purification. R_f0.51 (50% Et₂O in hexane). H NMR

tert-Butyl(((2S,5S)-5-((Z)-2-iodovinyl)tetrahydrofuran-2-yl)-

methoxy)diphenylsilane (10). A solution of oxalyl chloride (5.84 mL,

68.0 mmol) in anhydrous CH₂Cl₂(390 mL) was stirred vigorously under

an argon atmosphere at −78 °C, and DMSO was added dropwise

(6.90 mL, 97.1 mmol). After 30 min, a solution of alcohol 17 (7.20 g,

19.4 mmol) in anhydrous CH₂Cl₂(52 mL) was added, and the solution

was stirred for an additional 30 min. Then, Et₃N (17.7 mL, 126 mmol)

was added dropwise, and the resulting suspension was vigorously stirred

for another 30 min. The reaction was quenched by the addition of a

saturated aqueous solution of NH₄Cl (30 mL) followed by H₂O (20 mL).

The aqueous phase was then extracted with EtOAc (3 × 70 mL). The

combined organic phases were washed with H₂O (2 × 70 mL) and a

saturated aqueous solution of NaCl (70 mL) and then dried with Na₂SO₄.

The organic solvent was removed in vacuo to afford the crude aldehyde

18 (7.2 g), which was used in the next step without further purification.

R_f0.65 (30% EtOAc in hexane).

(250 MHz, CDCl₃) δ 1.12 (s, 9H), 3.50−3.72 (m, 8H), 5.95 (s, 1H).

¹³C NMR (125.7 MHz, CDCl₃) δ 27.0, 42.04, 42.07, 46.5, 66.4, 66.7,

95.3, 163.7, 184.5, 201.0.

Co(modp)₂(13). To a solution of ligand 21 (1 equiv, 14.7 g, 60.9

mmol) in benzene (30 mL) was added Co(ethylhexanoate)₂(0.5

equiv, 16.2 mL, 30.4 mmol, 1.88 M in mineral spirits). After 15 min,

water (2 equiv, 2.2 mL, 120 mmol) was added, and stirring was

continued for 16 h. Hexanes (1200 mL) were added, and the brown

solids were separated by filtration, washed with hexane, and dried to

afford the known Co(modp)₂catalyst (13) (12.5 g, 23.1 mmol) as a

beige solid in 76% yield.

(R)-2-(((4-Methoxybenzyl)oxy)methyl)oxirane (22).¹⁹R_f0.55

(30% EtOAc in hexane). [α]_D²³= +3.9 (c = 1.6/CHCl₃). Lit.¹⁹: [α]_D¹⁹

=

1

+3.5 (c = 1.0/CHCl₃). H NMR (250 MHz, CDCl₃) δ 2.60 (dd, J =

5.0 and 2.9 Hz, 1H), 2.79 (dd, J = 5.0 and 4.2 Hz, 1H), 3.17 (ddt, J =

5.8, 4.1, and 2.9 Hz, 1H), 3.40 (dd, J = 11.4 and 5.8 Hz, 1H), 3.73 (dd,

J = 11.4 and 2.9 Hz, 1H), 3.80 (s, 3H), 4.48 (d, J = 11.5 Hz, 1H), 4.54

(d, J = 11.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz,

2H). ¹³C NMR (62.9 MHz, CDCl₃) δ 44.2 (CH₂), 50.9 (CH), 55.2

(CH₃), 70.4 (CH₂), 72.9 (CH₂), 113.7 (CH), 129.4 (CH), 129.9 (C),

159.2 (C).

A flame-dried round-bottomed flask was charged with a suspension

of the phosphonium salt 19 (1.6 equiv, 7.0 g, 13.0 mmol) in anhydrous

THF (240 mL) at 0 °C, and NaHMDS (1.5 equiv, 6.1 mL, 12.2 mmol,

2.0 M in THF) was added dropwise. The solution was stirred

vigorously for 10 min at rt and then cooled to −78 °C. A solution of

crude aldehyde 18 (3.01 g, 8.12 mmol) in anhydrous THF (60 mL)

was added dropwise, and the reaction mixture was stirred for an

additional 30 min. The reaction was quenched by the addition of a

saturated aqueous solution of NH₄Cl (50 mL), and the aqueous phase

was extracted with Et₂O (2 × 30 mL). The combined organic phases

were dried with Na₂SO₄, filtered, and concentrated under vacuum.

The residue was then purified by flash column chromatography,

eluting with EtOAc/hexane (1:9) to produce vinyl iodide 10 (3.10 g,

6.29 mmol) as a colorless oil in 77% yield over two steps. [α]_D²³= +60

(R)-tert-Butyl((1-((4-methoxybenzyl)oxy)pent-4-yn-2-yl)-

oxy)diphenylsilane (9). A solution of lithium acetylide ethylenedi-

amine complex (2 equiv, 1.70 g, 15.8 mmol) was stirred in anhydrous

DMSO (9 mL) under an argon atmosphere at rt. A solution of glycidol

22 (1.5 g, 7.9 mmol) in THF (2.6 mL) was then added slowly over

30 min. The reaction mixture was stirred for 2 h and then cooled to

0 °C. The reaction was cautiously quenched by the addition of a

saturated aqueous solution of NH₄Cl (6 mL) followed by H₂O

(2 mL). The THF was removed under vacuum, and the aqueous phase

was extracted with Et₂O (3 × 10 mL). The combined organic phases

were washed with brine, dried with Na₂SO₄, and filtered, and the

organic solvent was removed under vacuum to give a known

homopropargylic alcohol¹⁹(1.78 g), which was used in the next step

without further purification. An analytically pure sample was obtained

by flash column chromatography using EtOAc/hexane (1:1) as the

eluent. R_f0.73 (20% EtOAc in hexane). [α]_D²³= +4.5 (c = 1.94/

CHCl₃). Lit.¹⁹: ent-compound [α]_D= −4.4 (c = 1.0/CHCl₃). ¹H NMR

(250 MHz, CDCl₃) δ 2.02 (t, J = 2.7 Hz, 1H), 2.43 (dd, J = 6.3 and 2.7

Hz, 2H), 2.51 (s, 1H), 3.47 (dd, J = 9.6 and 6.6 Hz, 1H), 3.58 (dd, J =

9.6 and 4.0 Hz, 1H), 3.80 (s, 3H), 3.95 (m, 1H), 4.49 (s, 2H), 6.88 (d,

J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H).

The previously obtained homopropargylic alcohol (1.78 g) was

dissolved in anhydrous DMF (3 mL) under an argon atmosphere at rt.

Imidazole (2.64 g, 38.7 mmol) and TBDPSCl (2.11 mL, 8.13 mmol)

were then added to this solution, and the reaction was stirred for 18 h.

The reaction mixture was then diluted with EtOAc (60 mL), and the

organic phase was washed with H₂O (3 × 10 mL), a saturated aqueous

solution of NH₄Cl (10 mL), and brine (10 mL). The organic phase

was dried with Na₂SO₄and filtered, the organic solvent was removed

under vacuum, and the residue was purified by flash column

chromatography using EtOAc/hexane (1:4) as the eluent, affording

9 (2.68 g, 5.85 mmol) as a colorless oil in 74% yield. R_f0.50 (10%

EtOAc in hexane). [α]_D²³= +6 (c = 1.2/CH₂Cl₂). ¹H NMR (250 MHz,

CDCl₃) δ 1.06 (s, 9H), 1.92 (t, J = 2.6 Hz, 1H), 2.24−2.50 (m, 2H),

3.46 (dd, J = 9.7 and 5.2 Hz, 1H), 3.52 (dd, J = 9.7 and 5.4 Hz, 1H),

3.78 (s, 3H), 3.98 (aquint, J = 5.3 Hz, 1H), 4.27−4.39 (m, 2H), 6.82

(d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.28−7.45 (m, 6H),

7.64−7.73 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) δ 19.3 (C), 24.1

(CH₂), 26.9 (CH₃), 55.2 (CH₃), 70.0 (C), 70.36 (CH), 72.43 (CH₂),

72.8 (CH₂), 81.0 (C), 113.6 (CH), 127.46 (CH), 127.53 (CH), 129.1

(CH), 129.6 (C), 129.7 (C), 130.4 (C), 133.7 (C), 133.9 (C), 135.8

(CH), 135.9 (CH), 159.0 (C). IR ν_max(film) 3306, 3072, 3051, 2958,

2931, 2858, 1612, 1514, 1463, 1427, 1265, 1248, 1111, 1036, 821, 739,

1

(c = 0.33/CH₂Cl₂). H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H),

1.54−2.36 (m, 4H), 3.62−3.76 (m, 2H), 4.14−4.27 (m, 1H), 4.69 (dt,

J = 8.2 and 6.0 Hz, 1H), 6.27−6.39 (m, 2H), 7.32−7.49 (m, 6H),

7.64−7.75 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) δ 19.3, 26.9, 28.0,

31.7, 66.4, 79.8, 81.4, 81.8, 127.7, 129.6, 133.54, 133.57, 135.63, 142.3.

IR ν_max(film) 3070, 3051, 2958, 2931, 2858, 1471, 1427, 1265, 1112,

1072, 1006, 999, 738, 703. HRMS (ESI-TOF) m/z [M + K]⁺for

C₂₃H₂₉O₂SiKI calcd 531.0619, found 531.0645.

(Iodomethyl)triphenylphosphonium Iodide (19).¹⁷A solu-

tion of PPh₃(12.02 g, 45.8 mmol) and CH₂I₂(4.92 mL, 61.1 mmol)

in toluene (40 mL) was made under an argon atmosphere in a flask

equipped with a reflux condenser and protected from the light by

aluminum foil. The solution was heated at 100 °C for 20 h and then

cooled to 0 °C. The resulting white crystals were filtered, washed with

cold toluene, and dried under vacuum, giving the known phosphonium

1

salt 19 (22.1 g, 41.7 mmol) as a white solid in 91% yield. H NMR

(250 MHz, DMSO-d₆) δ 4.93−5.10 (m, 2H), 7.65−8.00 (m, 15H).

1

¹³C NMR (62.9 MHz, DMSO-d₆) δ −15.2 (d, J

= 52 Hz, CH₂),

P/C

118.4 (d, ¹J _P/C= 88 Hz, C), 130.2 (d, ²J _P/C= 13 Hz, CH), 133.8 (d,

³J

= 10 Hz, CH), 135.1 (CH).

P/C

Ethyl 2-Morpholino-2-oxoethaneperoxoate (20). A 100 mL

round-bottomed flask was charged with diethyl oxalate (6.33 g, 43.3

mmol), and morpholine (1.3 equiv, 5.0 mL, 65 mmol) was added over

5 min. The reaction was stirred for 10 h at rt. The organic solvent was

then removed under vacuum to give the known compound 20 (8.11 g,

43.3 mmol) in >99% yield as a colorless oil, which was used without

1

further purification. R_f0.39 (50% Et₂O in hexane). H NMR (250

MHz, CDCl₃) δ 0.88 (t, J = 7.1 Hz, 3H), 2.82−3.23 (m, 8H), 3.90 (q,

J = 7.1 Hz).

(Z)-2-Hydroxy-5,5-dimethyl-1-morpholinohex-2-ene-1,4-

dione (21).^18aA solution of t-BuOK (2.1 equiv, 2.50 g, 22.5 mmol)

in THF (19.6 mL) was added via cannula over 40 min to a solution of

pinacolone (1 equiv, 1.07 g, 1.34 mL, 10.7 mmol) and 20 (1 equiv,

2.00 g, 10.7 mmol) in THF (4.5 mL) at rt. After 3 h, AcOH (3.6 equiv,

2.20 mL, 38.5 mmol) was added over 5 min, the resulting mixture was

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The Journal of Organic Chemistry

Article

704. HRMS (ESI-TOF) m/z [M + Na]⁺for C₂₉H₃₄O₃SiNa calcd

481.2175, found 481.2161.

1427, 1265, 1111, 897, 824, 739, 706. HRMS (ESI-TOF) m/z [M + K]⁺

for C₄₄H₆₀O₄Si₂K calcd 747.3667, found 747.3649.

tert-Butyl(((2S,5R)-5-((R)-6-((tert-butyldiphenylsilyl)oxy)-7-

iodoheptyl) tetrahydrofuran-2-yl)methoxy)diphenylsilane

(25). To a solution of alcohol 24 (0.133 g, 0.192 mmol) in THF

(7 mL) were added I₂(0.17 g, 0.653 mmol) and PPh₃(0.076 g, 0.288

mmol). The reaction mixture was stirred for 1 h at rt. Additional

equivalents of I₂(0.17 g, 0.653 mmol) and PPh₃(0.076 g, 0.288

mmol) were added, and the reaction mixture was stirred for another

1 h at 80 °C for 30 min. The reaction was quenched with saturated

aqueous Na₂S₂O₃and stirred for 5 min before it was extracted with

EtOAc (3 × 30 mL). The combined organic phases were dried with

Na₂SO₄and filtered, and the organic solvent was removed under

vacuum. The residue was purified by flash column chromatography,

eluting with EtOAc/hexane (1:9) to give the desired iodide 25 (0.111 g,

0.136 mmol) as a colorless oil in 71% yield. R_f0.63 (10% EtOAc in

hexane). [α]_D²³= +2 (c = 0.69/CH₂Cl₂). ¹H NMR (250 MHz, CDCl₃)

δ 1.07 (s, 9H), 1.09 (s, 9H), 1.14−2.10 (m, 14H), 3.10−3.18 (m, 2H),

3.39−3.50 (m, 1H), 3.63 (dd, J = 10.4 and 5.2 Hz, 1H), 3.69 (dd, J =

10.4 and 4.8 Hz, 1H), 3.82−3.97 (m, 1H), 4.07−4.20 (m, 1H), 7.30−

7.56 (m, 12H), 7.62−7.86 (m, 8H). ¹³C NMR (62.9 MHz, CDCl₃)

δ 14.5 (CH₂), 19.3 (C), 19.4 (C), 24.6 (CH₂), 26.2 (CH₂), 26.9

(CH₃), 27.0 (CH₃), 28.2 (CH₂), 29.5 (CH₂), 32.0 (CH₂), 35.8 (CH₂),

36.7 (CH₂), 66.6 (CH₂), 71.4 (CH), 78.8 (CH), 79.5 (CH), 127.6

(CH), 129.5 (CH), 129.7 (CH), 129.8 (CH), 133.8 (C), 133.9 (C),

135.6 (CH), 135.85 (CH), 135.89 (CH). IR ν_max(film) 3072, 3051,

2959, 2932, 2858, 1962, 1902, 1827, 1776, 1589, 1472, 1463, 1427,

1391, 1361, 1265, 1188, 1113, 1084, 1007, 939, 895, 824, 739, 704.

HRMS (ESI-TOF) m/z [M + Na]⁺for C₄₄H₅₉IO₃Si₂Na calcd

841.2945, found 841.2958.

tert-Butyl(((2S,5S)-5-((R,Z)-6-((tert-butyldiphenylsilyl)oxy)-7-

((4-methoxybenzyl) oxy)hept-1-en-3-yn-1-yl)tetrahydrofuran-

2-yl)methoxy)diphenylsilane (23).²⁰To a solution of vinyl iodide

10 (3.01 g, 6.11 mmol) in Et₃N (50 mL), CuI (0.11 g, 0.61 mmol) and

PdCl₂(PPh₃)₂(0.21 g, 0.31 mmol) were added in one portion under

an argon atmosphere. The resulting suspension was stirred at rt for

30 min. To this solution was added alkyne 9 (2.80 g, 6.11 mmol) in

Et₃N (30 mL), and stirring was continued for an additional 2 h. The

reaction was quenched by adding a saturated aqueous solution of

NH₄Cl (50 mL). The Et₃N was removed under vacuum, the aqueous

phase was extracted with EtOAc (3 × 50 mL), and the combined

organic phases were washed with brine and dried with Na₂SO₄. The

organic solvent was removed under vacuum and the residue was

purified by flash column chromatography, eluting with EtOAc/hexane

(1:5) to give 23 (4.12 g, 5.00 mmol) as a colorless oil in 82% yield.

R_f0.52 (15% EtOAc in hexane). [α]_D²³= +34 (c = 0.25/CH₂Cl₂). H

1

NMR (250 MHz, CDCl₃) δ 1.08 (s, 9H), 1.09 (s, 9H), 1.52−2.31 (m,

4H), 2.44−2.67 (m, 2H), 3.42−3.57 (m, 2H), 3.64 (dd, J = 10.4 and

5.4 Hz, 1H), 3.74 (dd, J = 10.4 and 4.7 Hz, 1H), 3.81 (s, 3H), 4.00

(aquint, J = 5.5 Hz, 1H), 4.14−4.26 (m, 1H), 4.28−4.41 (m, 2H),

4.87−4.99 (m, 1H), 5.44−5.53 (m, 1H), 5.88 (dd, J = 10.9 and 8.1 Hz,

1H), 6.84 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.30−7.50 (m,

12H), 7.65−7.79 (m, 8H). ¹³C NMR (62.9 MHz, CDCl₃) δ 19.2 (C),

19.3 (C), 25.3 (CH₂), 26.8 (CH₃), 26.9 (CH₃), 28.7 (CH₂), 32.5

(CH₂), 55.2 (CH₃), 66.5 (CH₂), 70.68 (CH), 72.72 (CH₂), 72.8

(CH₂), 77.20 (C), 77.25 (CH), 78.2 (C), 79.5 (CH), 92.3 (C), 110.2

(CH), 113.6 (CH), 127.47 (CH), 127.53 (CH), 127.6 (CH), 129.1

(CH), 129.56 (CH), 129.63 (CH), 130.4 (C), 133.6 (C), 133.7 (C),

134.0 (C), 135.6 (CH), 135.8 (CH), 135.9 (CH), 142.8 (CH), 159.0

(CH). IR ν_max(film) 3583, 3070, 3049, 2957, 2932, 2858, 1612, 1587,

1514, 1472, 1463, 1427, 1390, 1361, 1302, 1248, 1173, 1113, 1038,

1007, 824, 739, 702. HRMS (ESI-TOF) m/z [M + H]⁺for C₅₂H₆₃-

O₅Si₂calcd 823.4214, found 823.4245.

(2RS,5S)-5-Methyl-3-(phenylthio)dihydrofuran-2(3H)-one

(8).²²R_f0.34 (20% EtOAc in hexane). ¹H NMR (250 MHz, CDCl₃) δ

1.29−1.39 (m, 6H), 1.75−1.90 (m, 1H), 2.17−2.42 (m, 2H), 2.66−

2.79 (m, 1H), 3.86−4.02 (m, 2H), 4.44−4.61 (m, 2H), 7.27−7.37 (m,

6H), 7.48−7.57 (m, 4H).

(3RS,5S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-

(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-

heptyl)-5-methyl-3-(phenylthio) dihydrofuran-2(3H)-one (27).

To a solution of anhydrous pyridine (0.20 mL) and CH₂Cl₂(7 mL),

Tf₂O²³(0.36 mL, 2.14 mmol) was added dropwise at −78 °C under

an argon atmosphere. The reaction mixture was stirred for 15 min.

Next, a solution of alcohol 24 (0.68 g, 0.96 mmol) in CH₂Cl₂(7 mL)

was added dropwise to the reaction mixture and stirred for 20 min at

−78 °C. The reaction mixture was warmed to −30 °C and stirred

for an additional 20 min. The reaction was then diluted with CH₂Cl₂

(25 mL) and washed with a 0.1 M aqueous solution of HCl (2 ×

10 mL). The organic solvent was removed under vacuum, providing

triflate 26 (0.76 g, 0.90 mmol) as a light brown oil in 94% yield, which

was used in the next step without further purification.

(R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-(((tert-butyl-

diphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)heptan-1-ol

(24). To a solution of enyne 23 (2.91 g, 3.53 mmol) in EtOH (60 mL)

(compound 23 was dissolved in EtOH by heating with a heat-gun

under continuous shaking) was added 5% Pd/C (0.30 g, 10% w/w).

The resulting suspension was vigorously stirred at rt under a H₂

atmosphere (1 atm) after three vacuum/H₂cycles were performed to

remove any air from the reaction flask. The reaction mixture was

stirred for 60 h before it was filtered (silica flash), and the filtrate was

concentrated to give 2.41 g of a reduced compound that was used in

the next step without further purification. R_f0.50 (10% EtOAc in

hexane).

To a solution of the previously obtained reduced compound (2.41 g)

in a mixture of CH₂Cl₂(32 mL) and pH 7 phosphate buffer (4 mL),

DDQ (1.29 g, 5.42 mmol) was added at 0 °C. After 10 min, the reaction

mixture was warmed to room temperature and stirred for an additional

35 min before it was diluted with Et₂O (100 mL) and quenched with

water (30 mL). The resulting heterogeneous mixture was filtered, and the

organic phase was separated, washed with saturated aqueous NaHCO₃

(20 mL), dried with Na₂SO₄, and filtered. The organic solvent was

removed under vacuum, and the residue was purified by flash column

chromatography, eluting with EtOAc/hexane (1:4) to afford the pure

alcohol 24 (1.82 g, 2.57 mmol) as a colorless oil in 73% yield over two

steps. R_f0.59 (20% EtOAc in hexane). [α]_D²³= −14 (c = 0.55/CH₂Cl₂).

¹H NMR (500 MHz, C₆D₆) δ 1.17 (s, 9H), 1.20 (s, 9H), 1.08−1.79 (m,

To a solution of lactone 8 (0.540 g, 2.88 mmol) in THF (5 mL), a

solution of LiHMDS (2.11 mL, 2.11 mmol, 1 M in THF) was added

dropwise at −78 °C. The resulting mixture was stirred for 5 min and

warmed to 0 °C. After an additional 30 min at 0 °C, HMPA (1.7 mL)

was added dropwise. Next, a solution of triflate 26 (0.76 g, 0.90 mmol)

in THF (7 mL) was added dropwise, and the resulting solution was

stirred for 30 min at 0 °C. The reaction was quenched with saturated

aqueous NH₄Cl (15 mL) and diluted with EtOAc (25 mL), and the

aqueous phase was extracted with EtOAc (3 × 15 mL). The combined

organic phases were dried with Na₂SO₄and filtered, and the organic

solvents were removed under vacuum. The residue was purified by

flash column chromatography, eluting with EtOAc/hexane (1.5:8.5) to

afford 27 (0.49 g, 0.55 mmol) as a colorless oil in 62% yield, and as a

mixture of diastereoisomers. Some lactone 8 was also recovered (0.33 g).

14H), 3.45 (dd, J = 11.0 and 5.2 Hz, 1H), 3.50 (dd, J = 11.0 and 3.8 Hz,

1H), 3.68 (dd, J = 10.5 and 4.8 Hz, 1H), 3.72 (dd, J = 10.5 and 4.5 Hz,

1H), 3.79−3.88 (m, 2H), 4.14 (dt, J = 7.0 and 4.7 Hz, 1H), 7.19−7.30

(m, 12H), 7.76−7.91 (m, 8H). ¹³C NMR (125.7 MHz, C₆D₆) δ 19.5

(C), 19.6 (C), 25.4 (CH₂), 26.7 (CH₂), 27.1 (CH₃), 27.3 (CH₃), 28.4

(CH₂), 30.1 (CH₂), 32.4 (CH₂), 34.0 (CH₂), 36.3 (CH₂), 66.2 (CH₂),

67.2 (CH₂), 74.7 (CH), 79.1 (CH), 79.5 (CH), 128.3 (C), 129.9 (CH),

130.0 (CH), 134.2 (C), 134.3 (C), 134.5 (C), 134.7 (C), 136.10 (CH),

136.14 (CH), 136.31 (CH). IR ν_max(film) 3584, 3053, 2934, 2860, 1474,

1

R_f0.55 (15% EtOAc and hexane). Major diastereoisomer: H NMR

(250 MHz, CDCl₃) δ 1.05 (s, 9H), 1.06 (s, 9H), 1.16 (d, J = 6.1 Hz, 3H),

0.33−1.53 (m, 12H), 1.69−2.18 (m, 5H), 2.93 (dd, J = 13.7 and 7.2 Hz,

1H), 3.56−3.72 (m, 2H), 3.74−3.91 (m, 1H), 4.03−4.19 (m, 1H), 4.20−

4.33 (m, 1H), 4.40 (sext, J = 6.8 Hz, 1H), 7.21−7.54 (m, 17H), 7.60−

7.83 (m, 8H). ¹³C NMR (125 MHz, CDCl₃) δ 19.25 (C), 19.31 (C),

21.1 (CH₃), 24.7 (CH₂), 26.1 (CH₂), 26.8 (CH₃), 27.0 (CH₃), 28.2 (CH₂),

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29.3 (CH₂), 31.9 (CH₂), 35.6 (CH₂), 38.1 (CH₂), 39.5 (CH₂), 41.4 (CH₂),

55.5 (C), 66.6 (CH₂), 71.3 (CH), 73.2 (CH), 78.8 (CH), 79.5 (CH),

127.5 (CH), 127.7 (CH), 129.0 (CH), 129.5 (C), 135.6 (CH), 135.86

(CH), 135.88 (CH), 136.6 (CH), 177.5 (C).

organic solvents were removed under vacuum. The residue was then

loaded onto a silica gel flash plug and eluted with EtOAc/hexane

(0.5:9.5) to give the known compound pentadecanal (31)⁴⁶(3.92 g,

17.2 mmol) as a brown oil in 89% yield, which was used in the next

step without further purification. An analytical sample was purified by

flash column chromatography, eluting with EtOAc/hexane (0.5:9.5).

(S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-(((tert-

butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)heptyl)-5-

methylfuran-2(5H)-one (28). To a solution of 27 (0.300 g, 0.355

mmol) in CH₂Cl₂(8 mL) at 0 °C was added m-CPBA (0.090 g, 0.37

mmol, 77% w/w), and the reaction was stirred for 30 min. The

reaction was quenched with a saturated aqueous solution of NaHCO₃/

Na₂S₂O₃(1:1, 10 mL), warmed to room temperature and stirred for

an additional 30 min. The aqueous phase was extracted with CH₂Cl₂

(20 mL), the combined organic phases were dried with Na₂SO₄, and

the organic solvents were removed under vacuum. The residue was

then dissolved in benzene (20 mL), and the solution was refluxed for

30 min. The organic solvent was removed under vacuum, and the

residue was purified by flash column chromatography, eluting with

EtOAc/hexane (1:4) to provide the desired α,β-unsaturated lactone

28 (0.254 g, 0.322 mmol) as a colorless oil in 91% yield over two

steps. R_f0.54 (20% EtOAc in hexane). [α]_D²³= −7 (c = 1.7/CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃) δ 1.03 (s, 9H), 1.05 (s, 9H), 1.30 (d, J =

6.8 Hz, 3H), 1.03−1.52 (m, 11H), 1.74−2.06 (m, 3H), 2.37−2.48 (m,

2H), 3.61 (dd, J = 10.5 and 5.2 Hz, 1H), 3.66 (dd, J = 10.5 and 4.6 Hz,

1H), 3.81−3.90 (m, 1H), 4.02 (quint, J = 5.6 Hz, 1H), 4.11 (tt, J = 6.9

and 4.9 Hz, 1H), 4.82−4.90 (m, 1H), 6.90 (d, J = 1.3 Hz, 1H), 7.32−

7.45 (m, 12H), 7.61−7.73 (m, 8H). ¹³C NMR (100.6 MHz, CDCl₃)

18.9 (CH₃), 19.3 (C), 19.4 (C), 24.9 (CH₂), 26.2 (CH₂), 26.8 (CH₃),

27.0 (CH₃), 28.2 (CH₂), 29.6 (CH₂), 31.8 (CH₂), 32.0 (CH₂), 35.8

(CH₂), 36.3 (CH₂), 66.6 (CH₂), 71.7 (CH), 77.4 (CH), 78.8 (CH),

79.5 (CH), 127.55 (CH), 127.58 (CH), 129.5 (CH), 129.6 (CH),

130.6 (C), 133.74 (C), 133.76 (C), 134.05 (C), 134.09 (C), 135.6

(CH), 135.8 (CH), 135.9 (CH), 151.2 (CH), 174.0 (C). IR ν_max

(film) 3071, 3049, 2932, 2858, 1757, 1589, 1472, 1461, 1427, 1388,

1362, 1319, 1265, 1194, 1113, 1080, 1029, 1007, 824, 739, 702, 613.

HRMS (ESI-TOF) m/z [M + K]⁺for C₄₉H₆₄O₅Si₂K calcd 827.3929,

found 827.3940.

(S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-

(hydroxymethyl)tetrahydrofuran-2-yl)heptyl)-5-methylfuran-

2(5H)-one (29):.²⁵To a solution of silyl ether 28 (0.124 g, 0.157

mmol) in anhydrous THF (4 mL) and pyridine (4 mL), HF·py

complex (1 mL) was added dropwise at 0 °C. The reaction mixture

was warmed to room temperature and stirred for 18 h. The reaction

was quenched with saturated aqueous NaHCO₃(20 mL), and solid

NaHCO₃was added until gas evolution ceased. The aqueous phase

was extracted with Et₂O (3 × 30 mL), the combined organic solvents

were removed under vacuum, and the residue was purified by flash

column chromatography, eluting with EtOAc/hexane (1:4) to give the

desired primary alcohol 29 (0.0818 g, 0.149 mmol) in 95% yield as a

colorless oil. R_f0.73 (15% EtOAc in hexane). [α]_D²³= −8 (c = 2.0/

CH₂Cl₂). ¹H NMR (250 MHz, CDCl₃) δ 1.03 (s, 9H), 1.31 (d, J = 6.8

Hz, 3H), 1.10−1.80 (m, 11H), 1.85−2.13 (m, 3H), 2.36−2.50 (m,

2H), 3.40−3.54 (m, 1H), 3.56−3.68 (m, 1H), 3.78−3.93 (m, 1H),

3.94−4.17 (m, 2H), 4.82−4.94 (m, 1H), 6.91 (s, 1H), 7.29−7.48 (m,

6H), 7.58−7.75 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) 18.9 (CH₃),

19.3 (C), 24.8 (CH₂), 26.0 (CH₂), 27.0 (CH₃), 27.5 (CH₂), 29.5

(CH₂), 31.7 (CH₂), 32.0 (CH₂), 35.5 (CH₂), 36.3 (CH₂), 65.0 (CH₂),

71.7 (CH), 77.4 (CH), 78.8 (CH), 79.3 (CH), 127.5 (CH), 129.6

(CH), 130.6 (C), 134.0 (C), 134.1 (C), 135.8 (CH), 135.8 (CH),

151.3 (CH), 174.0 (C). IR ν_max(film) 3447, 3071, 3051, 2932, 2858,

1755, 1463, 1427, 1375, 1319, 1267, 1198, 1105, 1078, 1027, 822, 739,

704, 611. HRMS (ESI-TOF) m/z [M + H]⁺for C₃₃H₄₇O₅Si calcd

551.3193, found 551.3176.

1

R_f0.50 (5% EtOAc in hexane). H NMR (250 MHz, CDCl₃) δ 0.86

(t, J = 6.8 Hz, 3H), 1.17−1.36 (m, 22H), 1.61 (q, J = 7.2 Hz, 2H), 2.40

(dt, J = 7.2 and 1.7 Hz, 2H), 9.74 (t, J = 1.7 Hz, 1H). ¹³C NMR (62.9

MHz, CDCl₃) δ 14.1, 22.1, 22.7, 29.2, 29.3, 29.4, 29.57, 29.63, 29.66,

203.0.

(Z)-Ethyl heptadec-2-enoate (33). To a suspension of NaH

(0.960 g, 24.1 mmol, 60% in mineral oil) in THF (51 mL), a solution

of phosphonate 32²⁶(6.00 g, 17.2 mmol) in THF (20 mL) was added

dropwise at 0 °C under an argon atmosphere. After 15 min, the reaction

mixture was cooled to −40 °C, and a solution of 31 (3.90 g) in THF (18

mL) was added dropwise. The reaction mixture was vigorously stirred at

−40 °C for 3 h. The reaction was quenched with a saturated aqueous

solution of NH₄Cl (5 mL), the organic phase was dried with MgSO₄, and

the organic solvent was removed under vacuum. The residue was then

purified by flash column chromatography, eluting with EtOAc/hexane

(5:95) to afford the Z-α,β-unsaturated ester 33 (4.03 g, 13.6 mmol) in

79% yield as a colorless oil (Z:E > 95:5). R_f0.62 (5% EtOAc in hexane).

¹H NMR (250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz, 3H), 0.97 (t, J = 7.1 Hz,

3H), 1.21−1.43 (m, 24H), 2.79 (q, J = 7.0 Hz, 2H), 4.00 (q, J = 7.1 Hz,

2H), 5.83 (d, J = 11.7 Hz, 1H), 5.92 (dt, J = 11.7 and 7.0 Hz, 1H). ¹³C

NMR (62.9 MHz, C₆D₆) δ 14.26, 14.34, 23.1, 29.2, 29.4, 29.7, 29.81,

29.84, 30.0, 30.08, 30.11, 30.14, 32.3, 59.6, 120.1, 150.6, 166.0. HRMS

(ESI-TOF) m/z [M + H]⁺for C₁₉H₃₇O₂calcd 297.2794, found 297.2776.

(Z)-N-Methoxy-N-methylheptadec-2-enamide (34). To a

solution of Z-α,β-unsaturated ester 33 (1.00 g, 3.37 mL) and N,O-

dimethylhydroxylamine hydrochloride (0.654 g, 6.74 mmol) in THF

(7.5 mL), a solution of i-PrMgCl (8.70 mL, 14.8 mmol, 1.7 M in

THF) was slowly added at −10 °C under an argon atmosphere. The

reaction mixture was stirred at 0 °C for 30 min and quenched with a

saturated aqueous solution of NH₄Cl (10 mL). The aqueous phase

was then extracted with Et₂O (3 × 15 mL), and the combined organic

phases were dried with MgSO₄. The organic solvents were removed

under vacuum, and the residue was purified by flash column chromato-

graphy, eluting with EtOAc/hexane (1:9) to give the Z-Weinreb amide

34 (0.745 g, 2.39 mmol) in 71% yield (Z:E > 95:5). R_f0.19 (5%

1

EtOAc in hexane). H NMR (250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz,

3H), 1.20−1.52 (m, 24H), 2.91 (qd, J = 7.7 and 1.6 Hz, 2H), 2.91 (s,

3H), 3.08 (s, 3H), 5.99 (dt, J = 11.5 and 7.7 Hz, 1H), 6.30 (dt, J = 11.5

and 1.6 Hz, 1H). ¹³C NMR (62.9 MHz, C₆D₆) δ 14.3, 23.1, 29.4,

29.75, 29.77, 29.79, 29.92, 30.05, 30.10, 30.14, 31.9, 32.3, 60.8, 118.7,

147.6, 167.5. IR ν_max(film) 2957, 2926, 2854, 1659, 1634, 1464, 1441,

1348, 1265, 1178, 1097, 1001, 795, 739, 704. HRMS (ESI-TOF) m/z

[M + H]⁺for C₁₉H₃₈NO₂calcd 312.2903, found 312.2928.

(Z)-Octadec-3-en-2-one (Z-35). To a solution of the Z-Weinreb

amide 34 (0.500 g, 1.61 mmol) in THF (7 mL) was added a solution

of MeMgI (3.22 mL, 3.22 mmol, 1 M in Et₂O) at −30 °C. The

reaction mixture was warmed to 0 °C and stirred for 30 min. The

reaction was then quenched with a saturated aqueous solution of

NH₄Cl (2 mL), and the aqueous phase was extracted with Et₂O/

EtOAc (1:1, 3 × 8 mL). The combined organic phases were dried with

MgSO₄, the solvent was removed under vacuum, and the residue was

purified by flash column chromatography, eluting with EtOAc/hexane

(1:9) to give methyl ketone Z-35 (0.320 g, 1.20 mmol) in 75% yield as

a colorless oil (Z:E > 95:5). R_f0.71 (10% EtOAc in hexane). ¹H NMR

(250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz, 3H), 1.21−1.42 (m, 24H),

1.80 (s, 3H), 2.71 (q, J = 6.3 Hz, 2H), 5.68−5.83 (m, 2H). ¹³C NMR

(62.9 MHz, C₆D₆) δ 14.3, 23.1, 29.6, 29.7, 29.8, 29.9, 30.0, 30.10,

30.14, 31.18, 32.3, 127.2, 147.8, 197.5. IR ν_max(film) 2926, 2854, 1691,

1612, 1465, 1421, 1356, 1265, 1180, 741, 706. HRMS (ESI-TOF) m/z

[M + H]⁺for C₁₈H₃₅O calcd 267.2688, found 267.2666.

Preparation of Enol Silanes 5 and 5′: Pentadecanal (31). To a

vigorously stirred solution of hexadec-1-ene (30) (4.35 g, 19.3 mmol)

in 1:1 H₂O/Et₂O (90 mL) was added a solution of OsO₄(2 mol %,

2.00 mL, 0.400 mmol, 0.2 M in t-BuOH) at room temperature. After

30 min, NaIO₄(16.0 g, 75.3 mmol) was added in small portions, and

the reaction mixture was stirred for 6 h. The phases were separated,

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

combined organic phases were dried with MgSO₄and filtered, and the

(Z)-Trimethyl(octadeca-1,3-dien-2-yloxy)silane (5′). To a

solution of diisopropylamine (2.0 equiv, 0.32 mL, 2.2 mmol) in THF

(5.7 mL), n-BuLi (2.5 equiv, 2.0 mL, 2.8 mmol, 1.4 M in hexane) was

added dropwise at −78 °C under an argon atmosphere. The reaction

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Article

mixture was stirred for 10 min at −78 °C, and a solution of methyl ketone

Z-35 (0.300 g, 1.12 mmol) in THF (4 mL) was then added. After 20 min,

TMSCl (3.0 equiv, 0.43 mL, 3.4 mmol) was added dropwise, and the

reaction mixture was stirred for another 5 min and warmed to −20 °C.

After 1 h, the reaction was diluted with hexane (5 mL), and the organic

phase was washed with saturated aqueous solutions of NaHCO₃(3 ×

5 mL) and NaCl (5 mL). The combined organic phases were dried with

MgSO₄, and the organic solvent was removed under vacuum, producing

enol silyl ether 5′ (0.39 g) in >99% yield as a slightly yellow oil that was

0.63 mL, 8.95 mmol) and DIPEA (5 equiv, 0.73 mL, 4.5 mmol) at

0 °C under an argon atmosphere. The reaction mixture was stirred

for 5 min, SO₃·py (3 equiv, 0.43 g, 2.7 mmol) was added in one

portion, and the reaction mixture was then stirred for 1 h at 0 °C.

The reaction was quenched with a saturated aqueous solution of

NaHCO₃(5 mL), warmed to rt and extracted with CH₂Cl₂(3 ×

10 mL). The combined organic phases were washed with H₂O

(10 mL) and a saturated aqueous solution of NaCl (10 mL) and

dried with Na₂SO₄. The organic solvent was then removed under

vacuum to produce the corresponding aldehyde (quantitative

yield) as a slightly yellow oil that was submitted to azeotropic

distillation with benzene (2 × 3 mL) and used in the next step

without further purification.

1

used in the next step without further purification. H NMR (250 MHz,

C₆D₆) δ 0.21 (s, 9H), 0.92 (t, J = 6.8 Hz, 3H), 1.26−1.35 (m, 24H), 2.58

(dt, J = 7.5 and 1.6 Hz, 2H), 4.34 (s, 1H), 4.37 (s, 1H), 5.44 (dt, J = 11.9

and 7.5 Hz, 1H), 5.84 (dt, J = 11.9 and 1.6 Hz, 1H).

Hexadec-1-yne (37). To a solution of aldehyde 31 (1.71 g, 7.57

mmol) and the Bestmann-Ohira phosphonate 36²⁹(1.89 g, 9.84 mmol)

in MeOH (177 mL) was added K₂CO₃(1.77 g) in one portion. The

reaction mixture was vigorously stirred at room temperature for 18 h

before it was quenched with a saturated aqueous solution of NH₄Cl

(20 mL). The organic solvent was removed under vacuum, and the

aqueous phase was extracted with EtOAc (3 × 50 mL). The combined

organic phases were dried with Na₂SO₄, the organic solvent was removed

under vacuum, and the residue was purified by flash column

chromatography, eluting with EtOAc/hexane (1:19) to give the known

alkyne 37⁴⁷(1.52 g, 6.83 mmol) in 90% yield. R_f0.93 (5% EtOAc in

hexane). ¹H NMR (250 MHz, CDCl₃) δ 0.87 (t, J = 6.8 Hz, 3H), 1.18−

1.44 (m, 22H), 1.45−1.60 (m, 2H), 1.91 (t, J = 2.7 Hz, 1H), 2.17 (td, J =

7.1 and 2.7 Hz, 2H). ¹³C NMR (62.9 MHz, CDCl₃) δ 14.1 (CH₃), 18.4

(CH₂), 22.7 (CH₂), 28.5 (CH₂), 28.8 (CH₂), 29.1 (CH₂), 29.4 (CH₂),

29.5 (CH₂), 29.7 (CH₂), 68.0 (CH), 84.8 (CH).

General Procedure for the Chelated Mukaiyama Aldol Reaction

between Enol Silane 5′ and Aldehyde 41 or 18. To a solution of

aldehyde 41 or 18 (1 equiv, 0.409 mmol) in CH₂Cl₂(2 mL), a

solution of enol silane 5′ (2 equiv) in CH₂Cl₂(2 mL) was added

dropwise under an argon atmosphere at the temperature and with the

Lewis acid indicated in Table 2. The reaction mixture was monitored

by TLC and quenched with a saturated aqueous solution of NaHCO₃

(5 mL) after the length of time indicated in Table 2. The reaction

mixture was then warmed to rt, the aqueous phase was extracted with

Et₂O (3 × 5 mL), and the combined organic phases were dried with

Na₂SO₄. The organic solvent was removed under vacuum, and the

residue was purified by flash column chromatography, eluting with

EtOAc/hexane (1:9).

(S,Z)-1-((2S,5S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)-1-hydroxynonadec-4-en-3-one (Z-42): R_f0.36 (15%

EtOAc in hexane). [α]_D²³= −8 (c = 1.1/CH₂Cl₂). H NMR (250

1

MHz, C₆D₆) δ 0.07 (s, 6H), 0.92 (t, J = 6.8 Hz, 3H), 0.98 (s, 9H),

1.22−1.43 (m, 24H), 1.51−1.80 (m, 4H), 2.36 (dd, J = 16.3 and 4.0

Hz, 1H), 2.68 (dd, J = 16.3 and 8.4 Hz, 1H), 2.68−2.85 (m, 3H),

3.41−3.53 (m, 2H), 3.81 (td, J = 6.8 and 4.4 Hz, 1H), 3.91−4.06 (m,

2H), 5.79 (dt, J = 11.4 and 7.3 Hz, 1H), 5.95 (dt, J = 11.4 and 1.4 Hz,

1H). ¹³C NMR (62.9 MHz, C₆D₆) δ −5.2, 14.3, 18.5, 23.1, 26.1, 27.8,

28.5, 29.5, 29.7, 29.8, 29.9, 30.0, 30.10, 30.14, 32.3, 48.1, 66.1, 70.4,

80.3, 82.1, 127.4, 148.6, 200.1. IR ν_max(film) 3449, 3053, 2955, 2928,

2856, 1734, 1688, 1614, 1464, 1444, 1420, 1388, 1362, 1265, 1082,

1005, 939, 837, 777, 740, 704. HRMS (ESI-TOF) m/z [M + H]⁺for

C₃₀H₅₉O₄Si calcd 511.4183, found 511.4159.

Octadec-3-yn-2-one (39). To a solution of alkyne 37 (1.4 g, 6.3

mmol) in THF (46 mL), n-BuLi (3.9 mL, 6.3 mmol, 1.6 M in hexane)

was added dropwise at −78 °C. The solution was stirred for 20 min,

warmed to −20 °C and stirred for an additional 10 min. Next, the

solution was cooled to −50 °C, and amide 38 (0.61 mL, 6.3 mmol)

was added dropwise. The reaction mixture was then warmed to 0 °C

and stirred for 1 h. The reaction was quenched with a saturated

aqueous solution of NH₄Cl (10 mL), the aqueous phase was extracted

with Et₂O (3 × 40 mL), and the combined organic phases were dried

with Na₂SO₄. The organic solvent was removed under vacuum, and

the residue was purified by flash column chromatography, eluting with

EtOAc/hexane (1:19) to give α,β-unsaturated alkynyl ketone 39

(1.20 g, 4.61 mmol) in 73% yield as a colorless oil. R_f0.44 (5% EtOAc

(S,E)-1-((2S,5S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)-1-hydroxynonadec-4-en-3-one (E-42): [α]_D²³= −25 (c =

1.5/CH₂Cl₂). ¹H NMR (250 MHz, C₆D₆) δ 0.07 (s, 6H), 0.94 (t, J =

6.2 Hz, 3H), 0.98 (s, 9H), 1.10−1.38 (m, 24H), 1.60−1.91 (m, 6H),

2.48 (dd, J = 16.3 and 3.8 Hz, 1H), 2.85 (dd, J = 16.3 and 8.5 Hz, 1H),

2.96 (d, J = 3.0 Hz, 1H), 3.50−3.55 (m, 2H), 3.96 (td, J = 6.3 and 4.3

Hz, 1H), 4.04−4.14 (m, 2H), 6.06 (dt, J = 16.0 and 1.4 Hz, 1H), 6.70

(dt, J = 16.0 and 6.8 Hz, 1H). HRMS (ESI-TOF) m/z [M + H]⁺for

C₃₀H₅₉O₄Si calcd 511.4183, found 511.4171.

1

in hexane). H NMR (250 MHz, CDCl₃) δ 0.86 (t, J = 7.0 Hz, 3H),

1.19−1.45 (m, 22H), 1.48−1.61 (m, 2H), 2.29 (s, 3H), 2.33 (t, J =

7.0 Hz, 2H). ¹³C NMR (62.9 MHz, CDCl₃) δ 14.1, 18.9, 22.7, 27.7,

28.8, 29.0, 29.3, 29.4, 29.55, 29.62, 31.9, 32.7, 81.4, 94.1, 184.9. HRMS

(ESI-TOF) m/z [M + H]⁺for C₁₈H₃₃O calcd 265.2531, found 265.2508.

Trimethyl(octadec-1-en-3-yn-2-yloxy)silane (5). To a solution

of alkynyl ketone 39 (0.40 g, 1.51 mmol) in anhydrous THF (13.3 mL),

a solution of LiHMDS (1.6 equiv, 2.4 mL, 2.4 mmol, 1 M solution in

THF) was added dropwise under an argon atmosphere at −50 °C. After

20 min, TMSCl (0.23 mL) was added dropwise, and the resulting

suspension was warmed to 0 °C and stirred for 30 min. The reaction was

quenched with a saturated aqueous solution of NaHCO₃(5 mL), the

organic volatiles were removed under vacuum, and the aqueous phase was

extracted with pentane (60 mL). The organic phase was washed with

H₂O (20 mL) and a saturated aqueous solution of NaHCO₃(20 mL),

and the combined organic phases were dried with Na₂SO₄. The organic

solvent was removed under vacuum, yielding enol silyl ether 5 (0.50 g,

1.50 mmol) as a slightly yellow oil that was used in the next step without

(S,E)-1-((2S,5S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)-1-hydroxynonadec-4-en-3-one (E-43). R_f0.44 (20%

EtOAc in hexane). [α]_D²³= −3 (c = 1.8/CH₂Cl₂). ¹H NMR (250 MHz,

C₆D₆) δ 0.92 (t, J = 7.0 Hz, 3H), 1.18 (s, 9H), 1.22−1.40 (m, 24H),

1.49−1.91 (m, 6H), 2.47 (dd, J = 16.0 and 3.9 Hz, 1H), 2.84 (dd, J =

16.0 and 8.6 Hz, 1H), 2.86 (d, J = 4.3 Hz, 1H), 3.56−3.70 (m, 2H),

3.85 (td, J = 6.6 and 4.3 Hz, 1H), 4.00−4.14 (m, 2H), 6.07 (ad, J =

16.0 Hz, 1H), 6.72 (dt, J = 16.0 and 6.6 Hz, 1H), 7.20−7.30 (m, 6H),

7.73−7.89 (m, 4H). ¹³C NMR (62.9 MHz, C₆D₆) δ 14.3 (CH₃), 19.5

(C), 23.1 (CH₂), 27.1 (CH₃), 27.9 (CH₂), 28.3 (CH₂), 28.5 (CH₂),

29.5 (CH₂), 29.8 (CH₂), 30.0 (CH₂), 30.10 (CH₂), 30.14 (CH₂), 32.3

(CH₂), 32.6 (CH₂), 44.2 (CH₂), 67.0 (CH₂), 70.3 (CH), 80.3 (CH),

82.1 (CH), 129.9 (CH), 131.2 (CH), 134.1 (C), 134.2 (C), 136.04

(CH), 136.08 (CH), 147.4 (CH), 198.9 (C). IR ν_max(film) 3470,

3071, 3049, 2955, 2926, 2854, 1697, 1668, 1626, 1464, 1427, 1361,

1113, 1082, 1007, 1001, 824, 741, 702, 613. HRMS (ESI-TOF) m/z

[M + Na]⁺for C₄₀H₆₂O₄SiNa calcd 657.4315, found 657.4329.

(E)-Octadec-3-en-2-one (E-34). R_f0.69 (10% EtOAc in hexane).

¹H NMR (250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz, 3H), 1.10−1.41 (m,

1

further purification. R_f0.95 (hexane). H NMR (250 MHz, CDCl₃) δ

0.27 (s, 9H), 0.92 (t, J = 6.8 Hz, 3H), 1.12−1.45 (m, 24H), 2.08 (t, J =

7.0 Hz, 2H), 4.77 (s, 1H), 4.79 (s, 1H). ¹³C NMR (62.9 MHz, CDCl₃) δ

0.3 (CH₃), 14.3 (CH₃), 19.2 (CH₂), 23.1 (CH₂), 28.7 (CH₂), 29.2

(CH₂), 29.5 (CH₂), 29.8 (CH₂), 29.9 (CH₂), 30.0 (CH₂), 30.10 (CH₂),

30.14 (CH₂), 32.3 (CH₂), 79.2 (C), 89.0 (C), 101.2 (CH₂), 140.3 (C).

Studies on the Mukaiyama Aldol Reaction and the 1,3-

Carbonyl Reduction. General Procedure for the Preparation of

Aldehydes 41 and 18. To a solution of alcohol 40 or 17 (1 equiv,

0.895 mmol) in CH₂Cl₂(11 mL) were added DMSO (10 equiv,

24H), 1.84 (qd, J = 6.6 and 1.6 Hz, 2H), 1.89 (s, 3H), 5.96 (dt, J =

16.0 and 1.6 Hz, 1H), 6.47 (dt, J = 16.0 and 6.8 Hz, 1H). ¹³C NMR

4058

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The Journal of Organic Chemistry

Article

(62.9 MHz, C₆D₆) δ 14.3, 23.1, 26.7, 28.4, 29.5, 29.8, 30.0, 30.1, 30.2,

32.3, 32.5, 131.6, 146.9, 196.4. IR ν_max(film) 2955, 2926, 2854, 1697,

1676, 1628, 1466, 1362, 1265, 1256, 980, 741, 704. HRMS (EI-TOF)

m/z [M]⁺for C₁₈H₃₄O calcd 266.2610, found 266.2636.

(m, 1H), 7.32−7.47 (m, 6H), 7.63−7.74 (m, 4H). ¹³C NMR (62.9

MHz, CDCl₃) δ 14.1 (CH₃), 18.7 (CH₂), 19.2 (C), 22.7 (CH₂), 26.8

(CH₃), 28.0 (CH₂), 28.2 (CH₂), 28.6 (CH₂), 28.9 (CH₂), 29.1 (CH₂),

29.3 (CH₂), 29.5 (CH₂), 29.64 (CH₂), 29.66 (CH₂), 31.9 (CH₂), 41.4

(CH₂), 61.8 (CH), 66.3 (CH₂), 73.4 (CH), 79.7 (CH), 80.7 (C),

82.28 (CH), 85.5 (C), 127.6 (CH), 129.6 (CH), 133.5 (C), 133.6

(C), 135.57 (CH), 135.62 (CH).

(S)-1-((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)-1-hydroxynonadec-4-yn-3-one (44). To a solution of

aldehyde 18 (1 equiv, 0.29 g, 0.79 mmol) in CH₂Cl₂(3.6 mL),

MgBr₂·Et₂O (3 equiv, 0.66 g, 2.37 mmol) was added quickly in one

portion under an argon atmosphere at −30 °C. The heterogeneous

mixture was vigorously stirred for 5 min. Next, a solution of enol silane

5 (1.9 equiv, 0.501 g, 1.50 mmol) in CH₂Cl₂(3.6 mL) was added

dropwise. The reaction mixture was stirred for 1.5 h at −30 °C and

was quenched with a 10% aqueous solution of NaHCO₃(5 mL). The

reaction mixture was warmed to rt, the aqueous phase was extracted

with Et₂O (3 × 10 mL), and the combined organic phases were dried

with Na₂SO₄. The organic solvent was removed under vacuum, and

the residue was purified by flash column chromatography, eluting with

EtOAc/hexane (5:95) to afford the desired aldol adduct 44 (0.34 g,

54 mmol) in 68% yield as a colorless oil. R_f0.53 (20% EtOAc in

hexane). [α]_D²³= +1 (c = 0.84/CH₂Cl₂). ¹H NMR (250 MHz, C₆D₆) δ

0.92 (t, J = 6.8 Hz, 3H), 1.16 (s, 9H), 1.16−1.37 (m, 24H), 1.45−1.75

(m, 4H), 1.93 (t, J = 6.8 Hz, 2H), 2.48 (d, J = 5.7 Hz, 1H), 2.54 (dd,

J = 16.3 and 4.1 Hz, 1H), 2.89 (dd, J = 16.3 and 8.7 Hz, 1H), 3.50−

3.66 (m, 2H), 3.67−3.80 (m, 1H), 3.90−4.03 (m, 1H), 4.05−4.19 (m,

1H), 7.20−7.34 (m, 6H), 7.72−7.88 (m, 4H). ¹³C NMR (62.9 MHz,

C₆D₆) δ 14.3 (CH₃), 18.9 (CH₂), 19.5 (C), 23.1 (CH₂), 27.1 (CH₂),

27.9 (CH₂), 28.0 (CH₂), 28.4 (CH₂), 29.1 (CH₂), 29.4 (CH₂), 29.79

(CH₂), 29.81 (CH₂), 30.02 (CH₂), 30.08 (CH₂), 30.13 (CH₂), 32.3

(CH₂), 50.3 (CH₂), 66.8 (CH₂), 69.9 (CH), 80.2 (CH), 81.9 (CH),

82.0 (C), 93.8 (C), 128.0 (CH), 128.5 (CH), 130.0 (CH), 134.05 (C),

134.10 (C), 136.0 (CH), 136.1 (CH), 185.5 (C). IR ν_max(film) 3483,

3070, 3049, 2926, 2854, 2212, 1672, 1466, 1427, 1389, 1362, 1240,

1157, 1113, 1072, 1007, 999, 824, 741, 702, 613. HRMS (ESI-TOF)

m/z [M − C₆H₅]⁺for C₃₄H₅₅O₄Si calcd 555.3870, found 555.3836.

(1S,3S)-1-((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-

tetrahydrofuran-2-yl)nonadec-4-yne-1,3-diol (45) and (1S,3R)-

1-((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)nonadec-4-yne-1,3-diol (46). To a suspension of

Me₄NBH(OAc)₃(0.29 g, 1.1 mmol) in CH₃CN (1 mL) was added

anhydrous acetic acid (1 mL). The reaction mixture was stirred

for 30 min at rt before being cooled to −40 °C, at which point a

solution of aldol adduct 44 (0.068 g, 0.107 mmol) in CH₃CN (1 mL)

was added dropwise to the reaction mixture. CSA (2 mg) was added,

and the reaction mixture was stirred for 36 h at −20 °C. The reaction

was quenched with a saturated aqueous solution of NaHCO₃(10 mL)

and poured into an Erlenmeyer flask containing a saturated aqueous

solution of Na/K tartrate (10 mL) and Et₂O (50 mL). The

heterogeneous mixture was vigorously stirred for 8 h. The organic

phase was dried with Na₂SO₄, the organic solvent was removed under

vacuum, and the residue was purified by flash column chromatography,

eluting with EtOAc/hexane (5:95) to produce an inseparable mixture

of diols 45 and 46 (0.065 g, 0.102 mmol) in 96% yield with a

diastereoselectivity of 7:3 (45:46). R_f0.34 (20% EtOAc in hexane).

(1S,3S)-1-((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)nonadec-4-yne-1,3-diol (45). ¹H NMR (250 MHz, CDCl₃)

δ 0.87 (t, J = 6.8 Hz, 3H), 1.05 (s, 9H), 1.18−1.58 (m, 24H), 1.58−

2.09 (m, 6H), 2.13−2.26 (m, 2H), 2.75 (bs, 1H), 3.31 (bs, 1H), 3.59−

3.72 (m, 2H), 3.78−3.99 (m, 2H), 4.06−4.21 (m, 1H), 4.60−4.74 (m,

1H), 7.32−7.47 (m, 6H), 7.63−7.74 (m, 4H). ¹³C NMR (62.9 MHz,

CDCl₃) δ 14.1 (CH₃), 18.7 (CH₂), 19.2 (C), 22.7 (CH₂), 26.8 (CH₃),

28.1 (CH₂), 28.2 (CH₂), 28.7 (CH₂), 28.9 (CH₂), 29.1 (CH₂), 29.3

(CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.7 (CH₂), 31.9 (CH₂), 40.2 (CH₂),

60.6 (CH), 66.3 (CH₂), 71.7 (CH), 79.7 (CH), 80.8 (C), 82.30 (CH),

85.6 (C), 127.6 (CH), 129.6 (CH), 133.5 (C), 133.6 (C), 135.57

(CH), 135.62 (CH).

tert-Butyl(((2S,5S)-5-((4S,6S)-6-(hexadec-1-yn-1-yl)-2,2-dimethyl-

1,3-dioxan-4-yl)tetrahydrofuran-2-yl)methoxy)diphenylsilane

(47) and tert-Butyl(((2S,5S)-5-((4S,6R)-6-(hexadec-1-yn-1-yl)-

2,2-dimethyl-1,3-dioxan-4-yl)tetrahydrofuran-2-yl)methoxy)

diphenylsilane (48). To a solution of diols 45 and 46 (0.053 g,

0.083 mmol) in 2,2-dimethoxypropane (5 mL), CSA (5 mg) was

added. The solution was stirred overnight at rt, and the reaction was

quenched with a saturated aqueous solution of NaHCO₃(5 mL)

and diluted with Et₂O (15 mL). The organic phase was dried with

Na₂SO₄, the organic solvent was removed under vacuum, and the

residue was purified by flash column chromatography, eluting with

EtOAc/hexane (5:95) to produce acetonides 47 (0.037 g, 0.055 mmol)

and 48 (0.020 g, 0.029 mmol) in >99% yield.

tert-Butyl(((2S,5S)-5-((4S,6S)-6-(hexadec-1-yn-1-yl)-2,2-dimethyl-

1,3-dioxan-4-yl)tetrahydrofuran-2-yl)methoxy)diphenylsilane (47):

R_f0.46 (5% EtOAc in hexanes). [α]_D²³= +2 (c = 0.93/CH₂Cl₂). H

1

NMR (250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz, 3H), 1.18 (s, 9H),

1.19−1.45 (m, 24H), 1.45 (s, 3H), 1.59−1.83 (m, 5H), 1.69 (s, 3H),

2.05−2.21 (m, 3H), 3.60−3.73 (m, 2H), 3.87−3.98 (m, 1H), 4.06−

4.22 (m, 2H), 4.83−4.92 (m, 1H), 7.20−7.32 (m, 6H), 7.77−7.89 (m,

4H). ¹³C NMR (62.9 MHz, C₆D₆) δ 14.3 (CH₃), 19.1 (CH₂), 19.5

(C), 23.1 (CH₂), 23.9 (CH₃), 27.1 (CH₃), 27.5 (CH₂), 28.3 (CH₂),

28.93 (CH₃), 28.94 (CH₂), 29.2 (CH₂), 29.5 (CH₂), 29.8 (CH₂), 29.9

(CH₂), 30.04 (CH₂), 30.08 (CH₂), 30.12 (CH₂), 32.3 (CH₂), 33.9

(CH₂), 60.1 (CH), 67.0 (CH₂), 68.8 (CH), 80.2 (CH), 81.1 (CH),

81.7 (C), 85.9 (CH), 100.2 (C), 128.0 (CH), 128.3 (CH), 129.9

(CH), 134.2 (C), 134.2 (C), 136.1 (CH). IR ν_max(film) 3070, 3049,

2955, 2928, 2854, 1464, 1427, 1379, 1362, 1263, 1246, 1223, 1200,

1178, 1161, 1138, 1113, 1086, 999, 978, 947, 874, 824, 739, 702, 613.

HRMS (ESI-TOF) m/z [M + Na]⁺for C₄₃H₆₆O₄SiNa calcd 697.4628,

found 697.4624.

tert-Butyl(((2S,5S)-5-((4S,6R)-6-(hexadec-1-yn-1-yl)-2,2-dimethyl-

1,3-dioxan-4-yl)tetrahydrofuran-2-yl)methoxy)diphenylsilane (48):

1

R_f0.31 (5% EtOAc in hexane). [α]_D²³= +8 (c = 0.92/CH₂Cl₂). H

NMR (250 MHz, C₆D₆) δ 0.92 (t, J = 6.8 Hz, 3H), 1.18 (s, 9H),

1.16−1.37 (m, 21H), 1.21 (s, 3H), 1.37−1.81 (m, 8H), 1.51 (s, 3H),

1.97−2.18 (m, 3H), 3.52−3.72 (m, 3H), 3.84−3.96 (m, 1H), 4.07−

4.19 (m, 1H), 4.54−4.64 (m, 1H), 7.20−7.32 (m, 6H), 7.77−7.89 (m,

4H). ¹³C NMR (62.9 MHz, C₆D₆) δ 14.3 (CH₃), 19.0 (CH₂), 19.4

(CH₃), 19.5 (C), 23.1 (CH₂), 27.1 (CH₃), 27.3 (CH₂), 28.2 (CH₂),

29.1 (CH₂), 29.2 (CH₂), 29.5 (CH₂), 29.8 (CH₂), 29.9 (CH₂), 30.07

(CH₂), 30.10 (CH₂), 30.14 (CH₂), 30.4 (CH₃), 32.3 (CH₂), 34.0

(CH₂), 60.9 (CH), 67.0 (CH₂), 71.5 (CH), 80.1 (CH), 80.4 (C), 81.1

(CH), 84.8 (C), 99.0 (C), 128.0 (CH), 128.3 (CH), 129.9 (CH),

134.2 (C), 136.1 (CH). IR ν_max(film) 3070, 3049, 2955, 2926, 2854,

1464, 1427, 1379, 1362, 1258, 1199, 1178, 1163, 1113, 1090, 1065,

999, 968, 866, 824, 740, 702, 613. HRMS (ESI-TOF) m/z [M + Na]⁺

for C₄₃H₆₆O₄SiNa calcd 697.4628, found 697.4648.

Mukaiyama Aldol Reaction between Enol Silane 5 and

Aldehyde 6 and the Conclusion of the Synthesis of

Goniotrionin (4). (S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-

((2R,5S)-5-((S)-1-hydroxy-3-oxononadec-4-yn-1-yl)-

tetrahydrofuran-2-yl)heptyl)-5-methylfuran-2(5H)-one (49). To

a solution of alcohol 29 (0.0387 g, 0.0703 mmol) in CH₂Cl₂(2 mL)

were added DMSO (0.05 mL, 0.70 mmol) and DIPEA (0.06 mL, 0.34

mmol) at 0 °C under an argon atmosphere. The reaction mixture was

stirred for 5 min. SO₃·py (0.033 g, 0.21 mmol) was then added in one

portion, and the reaction mixture was stirred for an additional 1 h at

0 °C. The reaction was quenched with a saturated aqueous solution of

NaHCO₃(5 mL), diluted with CH₂Cl₂(10 mL), warmed to rt and

extracted with CH₂Cl₂(1 × 10 mL). The combined organic phases

were washed with H₂O (5 mL) and a saturated aqueous solution of

NaCl (5 mL) and dried with Na₂SO₄. The organic solvent was then

removed under vacuum, yielding aldehyde 6 (0.038 g) as a slightly

(1S,3R)-1-((2S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-

furan-2-yl)nonadec-4-yne-1,3-diol (46). ¹H NMR (250 MHz, CDCl₃)

δ 0.87 (t, J = 6.8 Hz, 3H), 1.05 (s, 9H), 1.18−1.58 (m, 24H), 1.58−

2.09 (m, 6H), 2.13−2.26 (m, 2H), 2.78 (bs, 1H), 3.11 (bs, 1H), 3.59−

3.72 (m, 2H), 3.78−3.99 (m, 2H), 4.06−4.21 (m, 1H), 4.60−4.74

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Article

yellow oil that was submitted to azeotropic distillation with benzene

(2 × 3 mL) and used in the next step without further purification.

To a solution of aldehyde 6 (0.038 g) in CH₂Cl₂(1 mL),

MgBr₂·Et₂O (3 equiv, 0.054 g, 0.21 mmol) was added quickly in one

portion under an argon atmosphere at −30 °C. The heterogeneous

mixture was vigorously stirred for 5 min. Next, a solution of enol silane

5 (4 equiv, 0.094 g, 0.28 mmol) in CH₂Cl₂(1 mL) was added. The

reaction mixture was stirred for 1.5 h at −30 °C before being

quenched with a 10% aqueous solution of NaHCO₃(5 mL). The

reaction mixture was warmed to rt, the aqueous phase was extracted

with CH₂Cl₂(3 × 10 mL), and the combined organic phases were

dried with Na₂SO₄. The organic solvent was removed under vacuum,

and the residue was purified by flash column chromatography, eluting

with EtOAc/hexane (5:95) to produce the desired aldol adduct 49

(0.034 g, 0.041 mmol) in 59% yield as a colorless oil. R_f0.43 (25%

0.90 (d, J = 6.8 Hz, 3H), 1.16 (s, 9H), 1.25−2.75 (m, 40H), 1.45 (s,

3H), 1.70 (s, 3H), 2.09 (td, J = 6.8 and 1.9 Hz, 2H), 2.38−2.59 (m,

2H), 3.83−4.03 (m, 2H), 4.08−4.33 (m, 3H), 4.83−4.94 (m, 1H),

6.29 (s, 1H), 7.19−7.33 (m, 6H), 7.70−7.85 (m, 4H). ¹³C NMR (62.9

MHz, CDCl₃) δ 14.3 (CH₃), 18.8 (CH₃), 19.1 (CH₂), 19.6 (C), 23.1

(CH₂), 23.9 (CH₃), 25.1 (CH₂), 26.4 (CH₂), 27.3 (CH₃), 27.5 (CH₂),

28.96 (CH₂), 29.00 (CH₃), 29.2 (CH₂), 29.5 (CH₂), 29.8 (CH₂), 29.9

(CH₂), 30.05 (CH₂), 30.10 (CH₂), 30.14 (CH₂), 32.3 (CH₂), 32.6

(CH₂), 33.9 (CH₂), 36.2 (CH₂), 36.8 (CH₂), 60.1 (CH), 68.9 (CH),

72.1 (CH), 76.7 (CH), 79.8 (CH), 80.2 (CH), 81.8 (C), 85.9 (C),

100.2 (C), 128.3 (CH), 130.0 (CH), 131.1 (C), 134.5 (C), 134.7 (C),

136.3 (CH), 150.5 (CH), 173.1 (C). IR ν_max(film) 2928, 2854, 1759,

1462, 1427, 1379, 1317, 1200, 1111, 1094, 1078, 1028, 822, 741, 704,

611. HRMS (ESI-TOF) m/z [M + Na]⁺for C₅₄H₈₂O₆SiNa calcd

877.5778, found 877.5747.

EtOAc in hexane). [α]_D²³= −8 (c = 0.30/CH₂Cl₂). H NMR (400

1

(S)-3-((R)-7-((2R,5S)-5-((S)-1-((tert-Butyldimethylsilyl)oxy)-3-

oxononadec-4-yn-1-yl)tetrahydrofuran-2-yl)-2-((tert-

butyldiphenylsilyl)oxy)heptyl)-5-methylfuran-2(5H)-one (54).

To a solution of aldol adduct 49 (0.035 g, 0.043 mmol) in anhydrous

DMF (0.5 mL), imidazole (0.020 g, 0.32 mmol) and TBSCl (0.020 g,

0.073 mmol) were added under an argon atmosphere at rt. The reaction

mixture was stirred for 18 h, at which point the reaction was diluted with

EtOAc (10 mL), and the organic phase was washed with a saturated

aqueous solution of NaHCO₃(5 mL). The organic phase was dried with

Na₂SO₄and filtered, and the organic solvent was removed under vacuum.

The residue was then purified by flash column chromatography, eluting

with EtOAc/hexane (1:4) to afford 54 (0.029 g, 0.031 mmol) as a

colorless oil in 72% yield. R_f0.65 (20% EtOAc in hexane). [α]_D²³= −9 (c =

MHz, C₆D₆) δ 0.83 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H), 1.04−

1.40 (m, 32H), 1.17 (s, 9H), 1.14−1.79 (m, 6H), 1.92 (t, J = 7.0 Hz,

2H), 2.48−2.53 (m, 2H), 2.55 (dd, J = 16.1 and 4.0 Hz, 1H), 2.61 (d,

J = 4.8 Hz, 1H), 2.90 (dd, J = 16.1 and 8.8 Hz, 1H), 3.67−3.76 (m,

2H), 4.14 (dq, J = 8.3 and 4.0 Hz, 1H), 4.20 (quint, J = 5.8 Hz, 1H),

4.24−4.31 (m, 1H), 6.31 (ad, J = 1.3 Hz, 1H), 7.20−7.33 (m, 6H),

7.74−7.86 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) δ 14.3 (CH₃), 18.8

(CH₃), 18.9 (CH₂), 19.6 (C), 23.1 (CH₂), 25.1 (CH₂), 26.4 (CH₂),

27.3 (CH₃), 28.0 (CH₂), 29.1 (CH₂), 29.4 (CH₂), 29.8 (CH₂), 30.01

(CH₂), 30.08 (CH₂), 30.13 (CH₂), 32.3 (CH₂), 32.6 (CH₂), 36.0

(CH₂), 36.7 (CH₂), 50.1 (CH₂), 70.4 (CH), 72.1 (CH), 76.8 (CH),

79.8 (CH), 81.1 (CH), 82.1 (C), 93.8 (C), 128.3 (CH), 130.1 (CH),

131.0 (C), 134.5 (C), 134.7 (C), 136.2 (CH), 150.8 (CH), 173.2 (C),

185.5 (C). HRMS (ESI-TOF) m/z [M + Na]⁺for C₅₁H₇₆O₆SiNa

calcd 835.5309, found 835.5320.

1

2.9/CH₂Cl₂). H NMR (250 MHz, C₆D₆) δ 0.26 (bs, 6H), 0.83 (d, J =

7.1 Hz, 3H), 0.88−0.97 (m, 3H), 1.05 (s, 9H), 1.18 (s, 9H), 1.10−1.74

(m, 38H), 1.96 (t, J = 6.8 Hz, 2H), 2.41−2.60 (m, 2H), 2.69 (dd, J = 15.3

and 4.4 Hz, 1H), 2.79 (dd, J = 15.3 and 7.9 Hz, 1H), 3.68−3.82 (m, 1H),

3.92−4.04 (m, 1H), 4.14−4.39 (m, 2H), 4.50 (ddd, J = 7.7, 6.0, and 4.4

Hz, 1H), 6.31 (s, 1H), 7.20−7.31 (m, 6H), 7.73−7.87 (m, 4H). ¹³C NMR

(62.9 MHz, C₆D₆) δ −4.6, −4.1, 14.3, 18.5, 18.8, 18.9, 19.6, 23.1, 25.1,

26.3, 26.5, 27.3, 27.9, 28.0, 29.1, 29.4, 29.80, 29.84, 29.95, 30.03, 30.10,

30.14, 32.3, 32.5, 32.6, 36.2, 36.8, 49.8, 72.1, 72.2, 76.8, 79.7, 81.4, 82.4,

93.4, 130.0, 131.0, 134.5, 134.7, 136.3, 150.6, 173.1, 184.9. HRMS (ESI-

TOF) m/z [M+H]⁺for C₅₇H₉₁O₆Si₂calcd 927.6354, found 927.6360.

(S)-3-((R)-7-((2R,5S)-5-((1S,3S)-1-((tert-Butyldimethylsilyl)-

oxy)-3-hydroxynonadec-4-yn-1-yl)tetrahydrofuran-2-yl)-2-

((tert-butyldiphenylsilyl)oxy)heptyl)-5-methylfuran-2(5H)-one

(55). To a solution of compound 54 (0.020 g, 0.022 mmol) in i-PrOH

(3 mL) was added (S,S)-Noyori’s catalyst (50)³⁸(10 mol %, 0.0013 g,

0.011 mmol). The reaction mixture was stirred for 18 h, the organic

solvent was removed under vacuum, and the residue was purified by

flash column chromatography, eluting with EtOAc/hexane (1:4) to

produce the desired alcohol 55 (0.012 g, 0.011 mmol) in 53% yield as

a brown oil. R_f0.68 (40% EtOAc in hexane). [α]_D²³= −6 (c = 0.5/

(S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-((1S,3S)-

1,3-dihydroxynonadec-4-yn-1-yl)tetrahydrofuran-2-yl)heptyl)-5-

methylfuran-2(5H)-one (51). To a solution of aldol adduct 49 (0.137 g,

0.170 mmol) in i-PrOH (4 mL) was added (S,S)-Noyori’s catalyst

(50)³⁸(10 mol %, 10 mg, 0.085 mmol). The reaction mixture was

stirred for 18 h, the organic solvent was removed under vacuum, and

the residue was purified by flash column chromatography, eluting with

EtOAc/hexane (1:4) to afford the desired diol 51 (0.10 g, 0.12 mmol)

in 71% yield as a brown oil. R_f0.68 (40% EtOAc in hexane). [α]_D²³

=

1

−17 (c = 0.97/CH₂Cl₂). H NMR (250 MHz, CDCl₃) δ 0.88 (t, J =

6.8 Hz, 3H), 1.03 (s, 9H), 1.32 (d, J = 6.9 Hz, 3H), 1.07−1.57 (m,

36H), 1.72 (ddd, J = 14.5, 6.3, and 2.3 Hz, 1H), 1.84 (ddd, J = 14.5,

9.3, and 3.5 Hz, 1H), 1.90−2.07 (m, 2H), 2.21 (td, J = 6.9 and 1.6 Hz,

2H), 2.39−2.50 (m, 2H), 2.79 (d, J = 3.3 Hz, 1H), 3.32 (d, J = 7.2

Hz), 3.75−3.96 (m, 3H), 4.01 (quint, J = 5.6 Hz, 1H), 4.59−4.73 (m,

1H), 4.82−4.96 (m, 1H), 6.91 (bs, 1H), 7.32−7.48 (m, 6H), 7.58−

7.71 (m, 4H). ¹³C NMR (62.9 MHz, CDCl₃) δ 14.1 (CH₃), 18.7

(CH₂), 18.9 (CH₃), 19.3 (C), 22.7 (CH₂), 24.8 (CH₂), 26.0 (CH₂),

27.0 (CH₃), 28.2 (CH₂), 28.7 (CH₂), 28.9 (CH₂), 29.1 (CH₂), 29.3

(CH₂), 29.45 (CH₂), 29.53 (CH₂), 29.63 (CH₂), 29.66 (CH₂), 31.8

(CH₂), 31.9 (CH₂), 32.3 (CH₂), 35.4 (CH₂), 36.3 (CH₂), 39.8 (CH₂),

60.6 (CH), 71.7 (CH), 71.9 (CH), 77.4 (CH), 79.4 (CH), 80.9 (C),

81.5 (CH), 85.6 (C), 127.6 (CH), 129.7 (CH), 130.6 (C), 134.0 (C),

134.1 (C), 135.80 (CH), 135.84 (CH), 151.3 (CH), 173.9 (C). IR

ν_max(film) 3427, 2928, 2854, 1759, 1464, 1427, 1375, 1319, 1198,

1111, 1072, 1028, 822, 739, 704, 611. HRMS (ESI-TOF) m/z [M + H]⁺

for C₅₁H₇₉O₆Si calcd 815.5646, found 815.5667.

1

CH₂Cl₂). H NMR (250 MHz, C₆D₆) δ 0.24 (s, 3H), 0.27 (s, 3H),

0.82 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 6.9 Hz, 3H), 1.05 (s, 9H), 1.18 (s,

9H), 1.20−1.72 (m, 38H), 1.88 (ddd, J = 14.0, 8.6, and 3.6 Hz, 1H),

2.00 (ddd, J = 14.0, 9.2, and 3.6 Hz, 1H), 2.14 (td, J = 6.9 and 1.7 Hz,

2H), 2.40−2.61 (m, 2H), 3.64−3.78 (m, 1H), 3.85−3.98 (m, 1H),

3.99−4.11 (m, 1H), 4.14−4.32 (m, 2H), 4.80−4.91 (m, 1H), 6.30 (bs,

1H), 7.19−7.32 (m, 6H), 7.71−7.86 (m, 4H). ¹³C NMR (62.9 MHz,

C₆D₆) δ −4.6, −3.8, 14.3, 18.6, 18.8, 19.1, 19.6, 23.1, 25.2, 26.4, 26.6,

27.3, 28.4, 29.2, 29.3, 29.6, 29.8, 30.0, 30.11, 30.14, 32.3, 32.6, 36.2,

36.8, 41.8, 59.6, 72.1, 73.2, 76.8, 79.4, 81.9, 82.9, 84.7, 130.0, 131.0,

134.5, 134.7, 136.3, 150.6, 173.1. HRMS (ESI-TOF) m/z [M − OH]⁺

for C₅₇H₉₁O₅Si₂calcd 911.6405, found 911.6433.

Monodesilylation Procedure: (S)-3-((R)-2-((tert-Butyl-

diphenylsilyl)oxy)-7-((2R,5S)-5-((1S,3S)-1,3-dihydroxynonadec-

4-yn-1-yl)tetrahydrofuran-2-yl)heptyl)-5-methylfuran-2(5H)-

one (51). To a solution of alcohol 55 (0.020 g, 0.022 mmol) in

MeOH (6 mL), p-toluenesulfonic acid monohydrate (0.004 g, 0.002

mmol) was added. The reaction mixture was stirred for 12 h and

neutralized with a saturated aqueous solution of NaHCO₃(1 mL).

The organic solvent was removed under vacuum, and the residue was

purified by flash column chromatography, eluting with EtOAc/hexane

(2:3) to give the desired diol 21 (0.006 g, 0.007 mmol) in 32% yield.

(S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-

((4S,6S)-6-(hexadec-1-yn-1-yl)-2,2-dimethyl-1,3-dioxan-4-yl)-

tetrahydrofuran-2-yl)heptyl)-5-methylfuran-2(5H)-one (52). To

a solution of diol 51 (0.011 g, 0.014 mmol) in 2,2-dimethoxypropane

(1.5 mL), CSA (1 mg) was addeed, and the solution was stirred for 3 h

at rt. The reaction was quenched with a saturated aqueous solution of

NaHCO₃(5 mL) and diluted with Et₂O (15 mL). The organic phase

was dried with Na₂SO₄, the organic solvent was removed under

vacuum, and the residue was purified by flash column chromatography,

eluting with EtOAc/hexane (1:4) to give acetonide 52 (0.010 g, 0.012

mmol) in 87% yield. R_f0.48 (20% EtOAc in hexane). [α]_D²³= −5 (c =

0.9/CH₂Cl₂). ¹H NMR (250 MHz, C₆D₆) δ 0.82 (d, J = 6.9 Hz, 3H),

4060

dx.doi.org/10.1021/jo3004106 | J. Org. Chem. 2012, 77, 4046−4062

The Journal of Organic Chemistry

Article

(R)-(1S,3S)-1-((tert-Butyldimethylsilyl)oxy)-1-((2S,5R)-5-((R)-

6-((tert-butyldiphenylsilyl)oxy)-7-((S)-5-methyl-2-oxo-2,5-dihy-

drofuran-3-yl)heptyl) tetrahydrofuran-2-yl)nonadec-4-yn-3-yl

3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (R-MTPA-56a).

To a solution of alcohol 55 (0.006 g, 0.007 mmol) in CH₂Cl₂(0.3

mL) were added 1 crystal of DMAP, (S)-MTPA chloride (2.2 μL), and

Et₃N (10 μL). After 2 h, the reaction mixture was directly loaded onto

a silica gel flash column, and elution with EtOAc/hexane (1:4) gave

the desired Mosher derivative 56a (0.007 g, 0.007 mmol) in >99%

yield. R_f0.64 (20% EtOAc in hexane). [α]_D²³= +8 (c = 0.45/CH₂Cl₂).

¹H NMR (500 MHz, C₆D₆) δ 0.22 (s, 3H), 0.26 (s, 3H). 0.81 (d, J =

6.8 Hz, 3H), 0.91 (t, J = 6.9 Hz, 3H), 1.04 (s, 9H), 1.17 (s, 9H), 1.10−

1.67 (m, 38H), 1.99 (m, 1H), 2.00 (td, J = 7.0 and 1.9 Hz, 2H), 2.28

(ddd, J = 13.7, 9.7, and 2.2 Hz, 1H), 2.47 (ddt, J = 14.6, 5.9, and 1.5

Hz, 1H), 2.53 (ddt, J = 14.6, 5.6, and 1.3 Hz, 1H), 3.56 (s, 3H), 3.70

(m, 1H), 3.86 (m, 2H), 4.20 (quint, J = 5.7 Hz, 1H), 4.25 (m, 1H),

6.17 (ddt, J = 9.8, 3.6, and 1.9 Hz, 1H), 6.29 (m, 1H), 7.00−7.28 (m,

11H), 7.72−7.83 (m, 4H). IR ν_max(film) 2928, 2856, 1757, 1655,

1572, 1464, 1452, 1362, 1258, 1188, 1170, 1110, 1080, 1018, 837, 779,

719, 704, 611. HRMS (ESI-TOF) m/z [M + Na]⁺for C₆₇H₉₉F₃O₈Si₂Na

calcd 1167.6729, found 1167.6713.

(CH₂), 65.3 (CH), 71.7 (CH), 72.0 (CH), 77.5 (CH), 79.9 (CH),

81.7 (CH), 127.6 (CH), 129.65 (CH), 129.66 (CH), 130.5 (C), 131.6

(CH), 132.1 (CH), 134.0 (C), 134.19 (C), 135.77 (CH), 135.80

(CH), 135.82 (CH), 135.84 (CH), 151.4 (C), 174.1 (C). IR ν_max

(film) 3447, 3015, 2928, 2856, 1751, 1464, 1427, 1375, 1319, 1215,

1111, 1076, 821, 758, 704, 667. HRMS (ESI-TOF) m/z [M + Na]⁺for

C₅₁H₈₀O₆SiNa calcd 839.5622, found 839.5616.

Goniotrionin (4). To a solution of HF·py complex (1.3 mL) in

THF (1.9 mL), a solution of silyl ether 57 (0.023 g, 0.028 mmol) in

THF (1.9 mL) and pyridine (0.5 mL) was added dropwise over 5 min

at 0 °C. The reaction mixture was warmed to room temperature and

stirred for 2 days. The reaction was then cooled to 0 °C and quenched

carefully with MeOTMS (13 mL). The organic solvents were removed

under vacuum, and the residue was purified by flash column

chromatography, eluting with EtOAc/hexane/MeOH (1:1:0.05) to

produce goniotrionin 4 (0.015 g, 0.027 mmol) in 95% yield as a

whitish wax. R_f0.34 (EtOAc/hexane/MeOH 1:1:0.05). [α]_D²³= −7

(c = 1.2/CHCl₃). [α]_D²³= −3 (c = 0.12/CHCl₃). [α]_D²³= 0 (c = 0.012/

1

CHCl₃). H NMR (500 MHz, CDCl₃) δ 0.87 (t, J = 6.8 Hz, 3H),

1.18−1.39 (m, 30H), 1.43 (d, J = 6.7 Hz, 3H), 1.48 (m, 2H), 1.54 (m,

1H), 1.59 (m, 2H), 1.60 (m, 1H), 1.57−1.69 (m, 2H), 1.95 (m, 1H),

2.03 (m, 1H), 2.05 (m, 1H), 2.10 (m, 1H), 2.36 (bs, 1H), 2.38 (ddt,

J = 15.1, 8.3, and 1.2 Hz, 1H), 2.52 (ddt, J = 15.1, 3.2, and 1.5 Hz,

1H), 2.63 (bs, 1H), 3.73 (td, J = 7.8 and 3.9 Hz, 1H), 2.80 (bs, 1H),

3.85 (m, 2H), 3.89 (m, 1H), 4.77 (dt, J = 7.8 and 4.2 Hz, 1H), 5.05

(qq, J = 6.8 and 1.5 Hz, 1H), 5.46 (m, 1H), 5.47 (m, 1H), 7.18 (m,

1H). ¹³C NMR (125 MHz, CDCl₃) δ 14.1 (CH₃), 19.1 (CH₃), 22.7

(CH₂), 25.5 (CH₂), 26.1 (CH₂), 27.7 (CH₂), 28.2 (CH₂), 29.30

(CH₂), 29.34 (CH₂), 29.50 (CH₂), 29.51 (CH₂), 29.60 (CH₂), 29.64

(CH₂), 29.65 (CH₂), 29.66 (CH₂), 29.67 (CH₂), 29.68 (CH₂), 31.9

(CH₂), 32.4 (CH₂), 33.4 (CH₂), 35.4 (CH₂), 37.3 (CH₂), 39.7 (CH₂),

65.0 (CH), 69.9 (CH), 71.5 (CH), 78.0 (CH), 79.3 (CH), 81.8 (CH),

131.1 (C), 131.6 (CH), 132.2 (CH), 151.8 (CH), 174.6 (C). IR ν_max

(film) 3531, 3371, 2955, 2918, 2874, 2851, 1740, 1722, 1499, 1468,

1329, 1205, 1121, 1086, 1059, 1030, 843, 719, 652. HRMS (ESI-TOF)

m/z [M + Na]⁺for C₃₅H₆₂O₆Na calcd 601.4444, found 601.4433.

(S)-(1S,3S)-1-((tert-Butyldimethylsilyl)oxy)-1-((2S,5R)-5-((R)-

6-((tert-butyldiphenylsilyl)oxy)-7-((S)-5-methyl-2-oxo-2,5-dihy-

drofuran-3-yl)heptyl)tetrahydrofuran-2-yl)nonadec-4-yn-3-yl

3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (56b). To a

solution of alcohol 55 (0.005 g, 0.005 mmol) in CH₂Cl₂(0.3 mL)

were added 1 crystal of DMAP, (R)-MTPA chloride (2.2 μL), and

Et₃N (10 μL). After 1 h, the reaction mixture was directly loaded onto

a silica gel flash column, and elution with EtOAc/hexane (1:4) gave

the desired Mosher derivative 56b (0.006 g, 0.005 mmol) in >99%

yield. R_f0.65 (20% EtOAc in hexane). [α]_D²³= −17 (c = 0.55/

1

CH₂Cl₂). H NMR (500 MHz, C₆D₆) δ 0.23 (s, 3H), 0.29 (s, 3H).

0.80 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.9 Hz, 3H), 1.06 (s, 9H), 1.17 (s,

9H), 1.10−1.61 (m, 38H), 1.97 (ddd, J = 14.1, 9.1, and 3.2 Hz, 1H),

2.01 (td, J = 7.1 and 2.0 Hz, 2H), 2.19 (ddd, J = 14.1, 10.0, and 2.5 Hz,

1H), 2.47 (ddt, J = 14.5, 5.9, and 1.5 Hz, 1H), 2.53 (ddt, J = 14.5, 5.7,

and 1.1 Hz, 1H), 3.60 (s, 3H), 3.66 (m, 1H), 3.70 (ddd, J = 9.2, 7.5,

and 2.4 Hz, 1H), 3.79 (m, 1H), 4.19 (quint, J = 5.7 Hz, 1H), 4.25 (m,

1H), 6.20 (m, 1H), 6.29 (m, 1H), 6.95−7.30 (m, 11H), 7.73−7.89 (m,

4H). IR ν_max(film) 2928, 2856, 1759, 1471, 1464, 1452, 1427, 1373,

1254, 1232, 1186, 1171, 1111, 1080, 991, 837, 779, 739, 718, 702, 611.

HRMS (ESI-TOF) m/z [M + Na]⁺for C₆₇H₉₉F₃O₈Si₂Na calcd

1167.6729, found 1167.6731.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H, ¹³C, IR and HRMS spectra for the prepared compounds are

available free of charge via the Internet at http://pubs.acs.org.

(S)-3-((R)-2-((tert-Butyldiphenylsilyl)oxy)-7-((2R,5S)-5-

((1S,3S,Z)-1,3-dihydroxynonadec-4-en-1-yl)tetrahydrofuran-2-

yl)heptyl)-5-methylfuran-2(5H)-one (57). To a suspension of Zn

powder (0.40 g, 6.12 mmol) in EtOH (4 mL) at 80 °C, 1,2-dibromo-

ethane (0.030 mL, 0.34 mmol) was added. After the evolution of

gas ceased, an additional portion of 1,2-dibromoethane (0.030 mL,

0.34 mmol) was added. The reaction mixture was stirred at 80 °C for

an additional 15 min and cooled to 50 °C, at which point a solution of

LiBr (0.15 g, 1.73 mmol) and CuBr (0.10 g, 0.70 mmol) in THF (0.9

mL) was added dropwise with vigorous stirring. A solution of diol 51

(0.035 g, 0.043 mmol) in EtOH (1 mL) and THF (1 mL) was then

added to the mixture. The resulting suspension was heated to 80 °C

and stirred for an additional 8 h. The suspension was then filtered

through a pad of silica gel, eluting with EtOAc. The organic solvent

was removed under vacuum, and the residue was purified by flash

column chromatography, eluting with EtOAc/hexane (2:3) to furnish

the desired allylic alcohol 57 (0.030 g, 0.037 mmol) in 86% yield. R_f

0.52 (40% EtOAc in hexane). [α]_D²³= −17 (c = 2.3/CDCl₃). ¹H NMR

(500 MHz, CDCl₃) δ 0.89 (t, J = 7.1 Hz, 3H), 1.05 (s, 9H), 1.34 (d,

J = 6.9 Hz, 3H), 1.18−1.70 (m, 38H), 1.95−2.17 (m, 4H), 2.40−2.50

(m, 2H), 3.80−3.85 (m, 1H), 3.91−3.99 (m, 2H), 4.03 (quint, J = 5.6

Hz, 1H), 4.81−4.82 (m, 1H), 4.89−4.95 (m, 1H), 5.44−5.55 (m, 2H),

6.90−6.97 (m, 1H), 7.36−7.47 (m, 6H), 7.63−7.71 (m, 4H). ¹³C

NMR (125 MHz, CDCl₃) δ 14.1 (CH₃), 18.9 (CH₃), 19.3 (C), 22.7

(CH₂), 24.7 (CH₂), 25.8 (CH₂), 27.0 (CH₃), 27.7 (CH₂), 28.1 (CH₂),

29.30 (CH₂), 29.33 (CH₂), 29.38 (CH₂), 29.5 (CH₂), 29.59 (CH₂),

29.61 (CH₂), 29.63 (CH₂), 29.64 (CH₂), 29.66 (CH₂), 29.67 (CH₂),

31.72 (CH₂), 31.9 (CH₂), 32.1 (CH₂), 35.2 (CH₂), 36.2 (CH₂), 39.0

AUTHOR INFORMATION

Corresponding Author

*ldias@iqm.unicamp.br

Notes

■

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

■

We are grateful to FAEP-UNICAMP, FAPESP, CNPq and

INCT-INOFAR (Proc. CNPq 573.564/2008-6) for financial

support, and to Prof. Feras Q. Alali (Jordan University of

Science and Technology) for helpful discussions about the

optical rotation of goniotrionin.

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Article Doi

Total synthesis of (-)-goniotrionin

DOI: 10.1021/jo3004106

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