Total Synthesis of the Marine Phosphomacrolide, (-)-Enigmazole A, Exploiting Multicomponent Type i Anion Relay Chemistry (ARC) in Conjunction with a Late-Stage Petasis-Ferrier Union/Rearrangement

Article

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Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Total Synthesis of the Marine Phosphomacrolide, (−)-Enigmazole A,

Exploiting Multicomponent Type I Anion Relay Chemistry (ARC) in

Conjunction with a Late-Stage Petasis−Ferrier Union/Rearrangement

Yanran Ai, Mariya V. Kozytska, Yike Zou, Anton S. Khartulyari, William A. Maio,

and Amos B. Smith, III*

Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of

Pennsylvania, Philadelphia, Pennsylvania 19104, United States

S

* Supporting Information

ABSTRACT: An eﬀective late-stage large-fragment union/

rearrangement exploiting the Petasis−Ferrier protocol, in

conjunction with multicomponent Type I Anion Relay

Chemistry (ARC) to access advanced intermediates, permits

completion of a convergent, stereocontrolled total synthesis of

the architecturally complex phosphomacrolide (−)-enigmazole

A (1).

INTRODUCTION

■

The Petasis−Ferrier rearrangement¹comprises a versatile

protocol for the construction of multisubstituted tetrahydro-

pyrans that comprise diverse structural components widely

found in bioactive natural products.^2,3Modiﬁcation of this

reaction sequence early on in our laboratory led to a three-stage

protocol for the construction of polyketides⁴that possess cis-

disubstituted tetrahydropyran rings (Scheme 1).⁵

Scheme 1. Petasis−Ferrier Union/Rearrangement Protocol

Figure 1. Enigmazole family of molecules.

structural features of (−)-enigmazole A (1), including the

unprecedented phosphate substituent on the macrolide ring,

(−)-enigmazole B (2) was found to possess a trisubstituted

Partnering the Petasis−Ferrier union/rearrangement proto-

col with Anion Relay Chemistry (ARC),⁶also developed in our

dihydropyran moiety with a methyl dienoate moiety attached to

the dihydropyran core, which may well represent the

laboratory, extends considerably this construction paradigm.

distinguishing structural feature that contributes to the

With these tactics in hand, we initiated a synthetic program to

diﬀerential selective C-Kit activity.

access members of the novel polyketide phosphomacrolide

family of marine toxins, known as the enigmazoles. The ﬁrst

member of this family, (−)-enigmazole A (1, Figure 1),

Synthetic as well as additional structural interests in the

enigmazole family of phosphomacrolides ﬁrst appeared with

back to back publications⁸in 2010 on the total synthesis of

disclosed by Gustafson et al. at the National Cancer Institute in

(−)-enigmazole A (1) by the Molinski group and a full

2010, exhibited potent activity across the NCI 60-cell line assay

with a mean GI50 value of 1.7 μm.⁷Pure enigmazole A (1)

structural account by Gustafson et al. More recently, total

syntheses were reported in 2015 by our group,⁹by the Furstner

̈

group in 2016,¹⁰and by the Fuwa group in 2018.¹¹Herein, we

provide a full account on the development and execution of the

Penn total synthesis of (−)-enigmazole A (1) that exploits the

however did not display the selective inhibition of cells

expressing mutant C-Kit as originally observed for the crude

extract of the marine sponge, Cinachyrella enigmatica.⁷

Subsequent extensive chemical investigations of the crude

sponge extract by Gustafson et al. suggested that a structurally

related metabolite, (−)-enigmazole B (2), was responsible for

the selective C-Kit inhibition.^7b,cWhile sharing the common

Received: April 10, 2018

A

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eﬀective combination of a late-stage large fragment Petasis−

Ferrier union/rearrangement in conjunction with construction

of the requisite advanced acyclic intermediate exploiting Type I

Anion Relay Chemistry (ARC).

Scheme 3. Synthesis of (+)-Oxazole 6

RESULTS AND DISCUSSION

■

From the retrosynthetic perspective, our intent for the

(−)-enigmazole A (1) program was to establish a general

strategy leading to the construction of a common enigmazole

macrocyclic precursor not only for (−)-enigmazole A (1), but

also for potential analogues (Scheme 2). Ideal here appeared to

Scheme 2. Retrosynthetic Analysis of (−)-Enigmazole A

carbonate in methanol then furnished the β-hydroxyl epoxide

(+)-18, which was protected as the TBS silyl ether to yield the

oxazole component (+)-6 in near quantitative yield.

With the oxazole component (+)-6 in hand, we next

explored the three-component Type I ARC union of

commercially available dithiane 7 with enantiomeric enriched

epoxide (−)-8¹⁵(Scheme 4). Crucial factors that often dictate

Scheme 4. Initial Study of the Three-Component Type I

ARC Union

be use of the Petasis−Ferrier union/rearrangement tactic

comprising an unprecedented late-stage coupling of large

fragments to construct the requisite substituted pyran

functionality, that would not only lead to (−)-enigmazole A

(1) after macrolactonization and further elaboration, but to

potential analogues. Toward this end, the requisite advanced

pyran intermediate 3 was envisioned to be constructed from a

western hemisphere aldehyde (4) that would arise from

commercially available (R)-(−)-Roche ester, and a carboxylic

acid eastern hemisphere (5), comprising the C9−C24 fragment

of the (−)-enigmazole A skeleton, which would be constructed

via a three-component Type I ARC tactic. The oxazole-

containing component 6 in turn would be elaborated via a

Negishi cross-coupling¹²employing vinyl iodide 9 and

commercially available chloride 10.

We initiated the synthesis with construction of oxazole 6 for

the eastern hemisphere (Scheme 3). Commercially available

(R)-3-butyn-2-ol [(+)-11] was ﬁrst subjected to a copper-

catalyzed carbometalation/iodination reaction¹³followed by

methylation to generate Z-oleﬁn (+)-12. Subsequential Negishi

coupling was then achieved via exploiting a ﬁnely tuned solvent

system that permitted union of an in situ generated zincate with

aryl chloride 10 to deliver the desired product (+)-13 in 80%

yield. Following a chelation controlled DIBAL reduction, the

derived aldehyde (+)-14 was subjected to Brown allylation to

furnish homoallylic alcohol (+)-15 with high diastereoselectiv-

ity (>20:1). Subsequent carbamation provided (+)-16 that was

submitted to a modiﬁed Bartlett iodocarbonate cyclization, via a

protocol developed earlier in our laboratory,¹⁴to furnish

iodocarbonate (+)-17. Treatment of the latter with potassium

the success of ARC transformations,⁶such as the solvent

system (i.e., Et₂O, Et₂O/HMPA, THF, THF/HMPA, etc.),

bases (n-BuLi, t-BuLi, t-BuLi/KOt-Bu, etc.), as well as various

temperature regimes (−78 °C to rt), were extensively screened.

The desired union product 19 however was not observed.

In the event, our typical ARC conditions (e.g., n-BuLi,

HMPA, Et₂O, −78 °C to rt) resulted in an 80−90% recovery of

epoxide (−)-8, in conjunction with a complex mixture of

products that derive from vinyl oxazole (+)-6, presumably due

to the acidic protons at C-23 and C-25. We therefore took

advantage of one of the signiﬁcant attributes of the ARC

protocol, the ability to reverse the reactivity of the nucleophile

and electrophile, recognizing that the oxazole ring might

stabilize the requisite negative charge at C-17 and thus lead to

the desired alkylation product (Scheme 5). This revision

required a revised synthetic plan for the eastern hemisphere 5

to accommodate the acidic protons at the allylic positions.

To this end, disconnection at the C-16/17 junction of 5

would permit construction from the previously available

aldehyde (+)-14 upon conversion to the corresponding dithane

20 and epoxide 21, again exploiting a three-component Type I

ARC tactic with epoxides (−)-22 and (−)-23 as electrophiles

and dithiane 7 as the nucleophile.

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fragment (−)-21 (Scheme 6, route B) had resulted in a mixture

of diastereomers.¹⁷

Scheme 5. Revised Retrosynthetic Analysis for the Eastern

Hemisphere Intermediate 5

We next turned to construct oxazole 20 (Scheme 7).

Aldehyde (+)-14 was condensed with 1,3-propanedithiol to

a

Scheme 7. Installation of the Oxazole-Containing Fragment

We began with construction of epoxide (−)-21 (Scheme 6,

route A). Deprotonation of dithiane 7 with n-BuLi in diethyl

ether at 0 °C generated the dithiane anion, which upon

addition of epoxide (−)-22 followed by 1,4-Brook rearrange-

ment triggered by increasing the temperature to −30 °C and

addition of the second electrophile epoxide (−)-23 in DMPU

furnished the desired tricomponent adduct (−)-24 in 90% yield

as a single diastereomer. Importantly, this transformation could

be carried out on up to the 10 g scale! The dithiane was then

removed via Raney nickel hydrogenolysis to deliver (−)-25.

Scheme 6. Synthesis of the Epoxide Fragment 21

a

Reactions shown in the table were carried out on ca. 1 mmol scale.

provide dithiane (+)-20 for the proposed alkylation with

epoxide (−)-21. Initial attempts (entries 1−5) however only

provided moderate yields of the desired union product (+)-29,

accompanied by the C-23 allylic epimer (+)-30, along with the

double-alkylated product (+)-31. We reasoned that the amount

of n-BuLi was critical; excess would lead to deprotonation at

the C-23 allylic proton and thus a second alkylation with the

unreacted epoxide to give (+)-31 as well as the undesired

epimer (+)-30. Not surprisingly in our initial synthetic route

(Scheme 3), more basic nucleophiles such as alkyl dithiane

anions generated via a 1,4-Brook rearrangement had induced

decomposition of the vinyl oxazole electrophile (+)-6.

Pleasingly optimal reaction conditions were obtained upon

screening such variables as the electrophile and n-BuLi

stoichiometry, solvent, and reaction temperature regimes, to

furnish the desired union product (+)-29 in 77% yield (entry

9).

Continuing with the synthesis, application of the recently

developed iron-mediated oxidative hydrolysis protocol¹⁸on

dithiane (+)-29 led to ketone (+)-32 (Scheme 8), which in

turn was submitted to the Narasaka−Prasad reduction¹⁹to

provide diol (+)-33 with high diastereoselectivity (single

diastereomer, dr >20:1).

Next, upon formation of the PMP acetal (−)-34 employing

p-anisaldehyde dimethyl acetal and CSA, we were pleased to

discover that DIBAL reduction led to the secondary alcohol

(+)-35 as a single isomer. Although more sterically hindered,

the observed regioselectivity is likely the result of strong

chelation of the α-oxygenated oxazole with the aluminum of the

DIBAL, thereby permitting delivery of the hydride to the

desired site. Following chemoselective formation of the primary

TBS ether alcohol (+)-36 with HF·Py, TEMPO-mediated

Interestingly, the 4-methoxybenzyl ether (PMB) protection

remained intact. However, after puriﬁcation, the same hydro-

genolysis conditions permitted conversion to diol (−)-26.

Possibly in the ﬁrst hydrogenolysis the Raney nickel was

poisoned by the sulfur from the dithiane. Epoxidation

exploiting the one-step Fraser−Reid protocol¹⁶then furnished

fragment (−)-21 in high yield as a single diastereomer.

As demonstrated above, a major advantage of the ARC

strategy is the eﬃcient construction of multiple stereocenters in

a fully stereocontrolled manner from simple enantiomeric

enriched linchpins. In fact, an earlier devised route to epoxide

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Scheme 8. Elaboration toward the Synthesis of the Eastern

Hemisphere (5)

Scheme 10. Synthesis of the Western Hemisphere Fragment

(4)

dimethyl alcohol (−)-42 in near quantitative yield. The

diastereoselectivity proved excellent (single diastereomer, dr

>20:1). Following in turn a Parikh−Doering oxidation and a

Brown allylation, oleﬁn (−)-43 was produced as a single

diastereomer, which was then protected as the TIPS ether to

give (−)-44. Osmium promoted dihydroxylation in conjugation

with oxidative cleavage of the oleﬁn (NaIO₄) completed

construction of the requisite western hemisphere (−)-4.

oxidation²⁰provided carboxylic acid (+)-37, albeit with

inconsistent eﬃciency likely due to competitive oxidation at

the C-17 position.

To avoid this inconsistency/chemoselectivity issue, we

adjusted the synthetic sequence (Scheme 9). Diol (+)-33 was

With both late-stage intermediates (−)-4 and (+)-5 secure

and readily available, we began exploring the critical strategic

level transformation: a three-stage Petasis−Ferrier union/

rearrangement to construct the entire carbon skeleton of

(−)-engimazole A (1). At the outset, union of (−)-4 and (+)-5

(i.e., stage 1) employing our standard conditions of HMDS and

TMSOTf⁵resulted in only a trace amount of the desired

product (entry 1, Scheme 11), along with recovered starting

material (−)-4 and a mixture of silylated (+)-5. Increasing the

reactivity by elevating the temperature proved detrimental

(entries 2−5). However, during these trials, we occasionally

obtained a dramatic increase in the yield (ca. 40−80%). This

occurred when a frequently employed older sample of the

Scheme 9. Adjusted Synthetic Sequence to the Eastern

Hemisphere (5)

a

Scheme 11. Study on the Union Stage

ﬁrst converted to the PMP acetal with removal of the TBS

group in single ﬂask operation to deliver alcohol (−)-38 in 88%

yield. Subsequent TEMPO-mediated oxidation now consis-

tently led to carboxylic acid (+)-39 in nearly quantitative yield.

A chelation controlled regioselective reduction with DIBAL

then permitted access to alcohol (+)-37 with the carboxylic acid

group intact, the latter due to the strength of the chelation of

the α-oxygenated oxazole with aluminum hydride. Final

deprotection then aﬀorded the desired eastern hemisphere

carboxylic acid (+)-5. The overall yield for this 12-step

sequence was 27%.

We next initiated construction of the western hemisphere 4

(Scheme 10) with commercially available (−)-R-Roche ester,

employing a three-step protection/reduction/iodination se-

quence²¹to produce iodide (−)-40, which in turn was

employed in a two-step Myers alkylation/reduction protocol²²

exploiting pseudoephedrine amide (−)-41 to furnish the 1,3-

a

Reactions were carried out on ca. 0.1 mmol scale.

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a

reagent TMSOTf was use. We reasoned that a trace amount of

triﬂic acid in the TMSOTf reagent might facilitate the key

union transformation. Such an observation had in fact occurred

in our earlier (+)-zampanolide synthesis, where addition of a

catalytic amount of TfOH signiﬁcantly increased the yield,

particularly for reactions on a larger scale.²³In the current case,

however, addition of a catalytic amount of TfOH was not

proﬁtable (0−16%, entries 6 and 7) with no starting material

recovered! Careful NMR analysis of the reaction mixture (entry

6) suggested that the desired dioxanone moiety of (−)-45 was

in fact generated, albeit with removal of both the TMS and the

PMB groups presumably due to the strong acidic character of

TfOH. Eventually we discovered that introduction of a trace

amount of water into the reaction mixture to mimic a

frequently used source of TMSOTf dramatically increased the

yield (ca. 95%) of (−)-45 (entries 9 and 10), now in a

controlled manner (see Experimental Section).²⁴

Scheme 13. Study on the Rearrangement Stage

With dioxanone (−)-45 now available, we moved to stage 2

of our Petasis−Ferrier union/rearrangement (i.e., oleﬁnation;

Scheme 12). Initial attempts utilizing 0.05 M Petasis reagent²⁵

a

Reactions were carried out on ca. 0.05 mmol scale.

union product (−)-47 in 69% overall yield with complete

stereochemical control for (−)-enigmazole A (1).

a

Scheme 12. Study on the Oleﬁnation Stage

With all eight stereocenters embedded in (−)-47, we

advanced to the elaboration of (+)-48 requiring removal of

both the TBDPS and the TMS groups, and then macro-

cyclization (Scheme 14). Use of KOH/18-crown-6 in water

Scheme 14. Late-Stage Elaboration I of (−)-Enigmazole A

a

Reactions were carried out on ca. 0.15 mmol scale.

led to enol acetal (−)-46 in 40−50% yield (entry 1, Scheme

12). Further investigation indicated that the concentration of

the Petasis reagent and precise heating (i.e., microwave

irradiation) proved critical (entry 6), and as such furnished

(−)-46 in 87% yield.

Turning to stage 3 of the Petasis−Ferrier union/rearrange-

ment protocol, we explored the use of Me₂AlCl, well-known in

this venue⁵(Scheme 13, entries 1−7); unfortunately, only

decomposition resulted presumably via a retro-Michael

fragmentation.²⁶Extensive experimentation proved uneventful;

we were not able to isolate the desired, standard ketone

product. We concluded however that the reaction sequence

might proceed to advanced oleﬁn (−)-47, via in situ capture of

the rearranged/generated ketone with methylene ylide (PPh₃

CH).

Pleasingly under these conditions, an 84% yield of (−)-47

was obtained for the third stage with complete stereocontrol.⁵

The requisite three-stage Petasis−Ferrier union/rearrangement

protocol had thus been demonstrated by utilizing highly

functionalized late-stage synthetic intermediates (−)-4 and

(+)-5, in conjunction with the methyl ylide to deliver advanced

proved highly selective for the latter. The primary hydroxyl

group was next oxidized chemoselectively to the carboxylic acid

under TEMPO-mediated oxidation conditions to furnish seco-

acid (+)-3. From initial trials with the Keck macrolactonization

condition,²⁷although providing the macrolactone (+)-49, the

yield was only moderate (40−50%). Pleasingly the macro-

cyclization could be improved to 89% by applying the

Yamaguchi protocol.²⁸

The next critical issue was selective removal of the TIPS

group to install the requisite phosphate group. Initial attempts

with various deprotection conditions proved challenging

(Scheme 15). Conditions such as HF/acetonitrile, TBAF,

TASF, or TBAT in various solvents led to total decomposition,

or to δ-lactone (−)-50 obtained via intramolecular trans-

esteriﬁcation. The latter unfortunately could not be converted

to the desired macrolactone 51 via treatment with various acids

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a

(−)-54, (−)-55, (−)-56, and (−)-enigmazole A (1)].

Eventually, we were able to determine that the monosodium

phosphate of (−)-56 displayed excellent agreement (¹H, ¹³C,

³¹P NMR spectra) with the previous reports from both

Gustafson^8aand Molinski.^8bThus, the total synthesis of

(−)-enigmazole A (1) as well as a series of salts had been

achieved.

Scheme 15. Late-Stage Elaboration II of (−)-Enigmazole A

SUMMARY

■

The total synthesis of the marine phosphomacrolide

(−)-enigmazole A (1), along with the mono- and disodium

phosphate salts, is reported. The overall yield was 4.4%,

proceeding in a longest linear sequence of 22 steps from

commercially available (R)-3-butyn-2-ol. Application of a late-

stage Petasis−Ferrier union/rearrangement in conjunction with

construction of advanced intermediates via multicomponent

Type I Anion Relay Chemistry (ARC) proved highly eﬀective

for the total synthesis of (−)-enigmazole A (1). Further

exploitation of the Petasis−Ferrier union/rearrangement and

various ARC tactics continue in our laboratory.

a

(a) Reactions were carried out on ca. 0.01 mmol scale. (b) Results

were determined by NMR and isolation yields.

EXPERIMENTAL SECTION

■

such as triﬂuoroacetic acid, but instead provided diol (−)-52

upon removal of the PMB group. Eventually however we

discovered that HF buﬀered with pyridine (entry 8) led to the

successful selective removal of the TIPS group to generate

(+)-51 in 70% yield accompanied by only a small amount of

(−)-50 (<5%).

Materials and Methods. All chemicals were purchased from

Sigma-Aldrich, Acros, or TCI America, unless otherwise referenced.

Anhydrous tetrahydrofuran (THF), diethyl ether (Et₂O), dichloro-

methane (CH₂Cl₂), and toluene were acquired from a Pure Solve PS-

400 system. Triethylamine, diisopropylamine, diisopropylethylamine,

and DMPU were freshly distilled from calcium hydride under a

nitrogen atmosphere. Commercial n-butyllithium (n-BuLi) and tert-

butyllithium (t-BuLi) solutions were titrated by using diphenylacetic

acid. All reactions that require anhydrous conditions were performed

in oven- or ﬂame-dried glassware under N₂or Ar atmosphere. High

vacuum (0.05 Torr) was created by using an oil pump (Nandor model

1400N). All reactions were stirred magnetically unless otherwise

mentioned. Ice/water bath created 0 °C reaction temperature; dry ice/

acetonitrile bath created −40 °C reaction temperature; dry ice/

acetone bath created −78 °C reaction temperature. All yields refer to

spectroscopically pure compounds unless otherwise mentioned.

Microwave reactions were carried out in a Biotage Initiator microwave

reactor with employed vials and septa caps purchased from Biotage

(Microwave Reaction Kits), and the temperature was monitored with

external surface sensor. Reactions were monitored by thin layer

chromatography (TLC) with 250 mm precoated silica gel plates

purchased from Silicycle Technology, and C18 silica gel thin layer

chromatography (C18 TLC) with 100 mm precoated C18 silica gel

plates purchased from Sorbent Technologies. Flash chromatography

was conducted by using ACS grade solvents and silica gel, which was

purchased from Silicycle Technology. Preparative thin layer

chromatography (PTLC) was done with 500 or 1000 mm precoated

silica gel plates purchased from Silicycle Technology. High-perform-

ance liquid chromatography (HPLC) was conducted by using Gilson

333/334 pumps equipped with a UV−vis dual wavelength detector

and a C18 column (Vydac 5 μm C18, 250 × 10 mm). All melting

points were obtained on a Thomas−Hoover apparatus and were

uncorrected. All infrared spectra were recorded on a Jasco model FT/

IR-480 Plus spectrometer. All optical rotations were measured on a

Turning to installation of the phosphate substituent, we

employed the conditions of i-Pr₂NP(OFm)₂/1H-tetrazole on

(+)-51 (Scheme 16),²⁹followed by DDQ removal of the PMB

Scheme 16. End Game of (−)-Enigmazole A

group to deliver the desired tertiary alcohol (−)-53. Final

deprotection applying potassium carbonate then furnished the

dipotassium phosphate of (−)-enigmazole A (−)-54. Surpris-

ingly, multiple inconsistencies in the proton resonances were

observed upon comparing the NMR spectrum of synthetic

(−)-54 with the natural product (e.g., H2 and H5, diﬀerence

>0.11 ppm; see the Supporting Information). We reasoned that

diﬀerent ionic forms (i.e., sodium, potassium, mono- and bis-

salt forms) of (−)-enigmazole A may result in diﬀerent sets of

¹H NMR data. We thereby conducted ion exchange experi-

ments in addition to acidiﬁcation to furnish a series of salts [i.e.,

1

Jasco P-2000 polarimeter. H NMR, ¹³C NMR, and ³¹P NMR spectra

were recorded on Bruker Avance III 500 MHz spectrometer equipped

with either an Oxford cryomagnet or a Spectrospin/Bruker

cryomagnet (500 MHz/52 mm) with a 5 mm dual cryo probe by

using either 5 or 3 mm NMR tubes. All chemical shifts (δ, in ppm)

reported were referred to chloroform (δ 7.26), benzene (δ 7.16), or

methanol (δ 3.30) for ¹H NMR and chloroform (δ 77.23), benzene (δ

128.39), or methanol (δ 49.00) for ¹³C NMR. High-resolution mass

spectra (HRMS) were acquired either on a Waters LC-TOF mass

spectrometer (model LCT-XE Premier) or on a waters GCT Premier

spectrometer at the University of Pennsylvania.

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Preparation of All New Compounds. Compound (+)-12. To a

stirred solution of (R)-3-butyn-2-ol (+)-11 (12.4 g, 177 mmol, 1.0

equiv) in dry toluene (330 mL) at room temperature under a nitrogen

atmosphere was added CuI (17.4 g, 88.8 mmol, 0.5 equiv)

portionwise. After complete addition, the temperature was decreased

to −78 °C before the dropwise addition of MeMgBr solution (1.4 M

in THF/toluene, 1:3, 456 mL, 638 mmol, 3.6 equiv) over 2 h. The

reaction mixture then was warmed gradually to room temperature and

stirred overnight. The reaction was quenched with the dropwise

addition of I₂solution (162 g of I₂in 250 mL of THF, 638 mmol, 3.6

equiv) at −40 °C. The resulting mixture was washed with a saturated

aqueous solution of Na₂S₂O₃(250 mL). The organic layer was

removed, and the aqueous layer was extracted with diethyl ether (50

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

mL), dried over MgSO₄, ﬁltered and concentrated carefully (volatile!),

and the resulting oil was puriﬁed using a column chromatography

(pentane/Et₂O, 5:1) to aﬀord a hydroxyl vinyl iodide in a mixture with

toluene (50 g). The mixture was moved to the next step without

further puriﬁcation. To a stirred suspension of NaH (24.0 g, 600

mmol, 60% in mineral oil, 3.4 equiv) in 250 mL of Et₂O at 0 °C under

a nitrogen atmosphere was added slowly a solution of the hydroxyl

vinyl iodide [50 g, mixture with toluene made from 177 mmol of

(+)-11] in 100 mL of Et₂O. After complete addition, the temperature

was increased to room temperature, and the reaction mixture was

allowed to stir for 20 min before it was recooled to 0 °C. Methyl

iodide (96.4 mL, 679 mmol, 3.8 equiv) was added dropwise, followed

by very slow addition (over 40 min) of 15-crown-5 (30.5 g, 141 mmol,

0.8 equiv) at 0 °C. The resulted mixture was stirred overnight at room

temperature and quenched at 0 °C by very careful addition of

saturated aqueous NH₄Cl (100 mL over 1 h). The organic layer was

removed, and the aqueous layer was extracted with diethyl ether (50

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

mL), dried over MgSO₄, ﬁltered and concentrated carefully (volatile!),

and the resulting oil was puriﬁed by reduced pressure distillation (80

°C at 5 mmHg) to give iodide (+)-12 (30.7 g, 136 mmol, 76.8%, two

steps) as a colorless liquid. [α]²_D⁰= +9.5 (c 2.2, CHCl₃); IR (ﬁlm)

2979, 2927, 2900, 2819, 1654, 1443, 1370, 1338, 1281, 1206, 1145,

56.5, 19.4, 17.9, 14.4; high-resolution mass spectrum (ESI) m/z

262.1051 [(M + Na)⁺calcd for C₁₂H₁₇NO₄Na, 262.1055].

Compound (+)-14. A solution of ester (+)-13 (9.00 g, 37.6 mmol, 1

equiv) in 200 mL of CH₂Cl₂was treated with DIBAL-H (1 M in

hexanes, 75.2 mL, 75.2 mmol, 2.0 equiv) at −78 °C under nitrogen

atmosphere, followed by stirring at that temperature for 30 min. The

resulted mixture was quenched with MeOH (20 mL) at −78 °C before

it was warmed to room temperature. Saturated aqueous Rochelle’s salt

(80 mL) was then added, and the mixture was stirred vigorously for 1

h. The resulting mixture was diluted with 100 mL of diethyl ether. The

organic layer was removed, and the aqueous layer was extracted with

diethyl ether (50 mL) twice. The combined organic layers were

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

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 10:90, 15:85, 20:80)

to furnish aldehyde (+)-14 (6.35 g, 32.7 mmol, 87.0%) as a white

solid. mp 55.0−57.0 °C; [α]_D²⁰= +25.2 (c 1.0, CHCl₃); IR (ﬁlm) 2978,

2924, 1699, 1651, 1562, 1114 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ =

9.95 (s, 1H), 8.18 (s, 1H), 6.23 (s, 1H), 5.24 (q, J = 6.5 Hz, 1H), 3.24

(s, 3H), 1.94 (d, J = 1.5 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ = 184.8, 161.5, 154.8, 143.0, 141.7, 112.2, 75.0,

56.8, 19.4, 18.1; high-resolution mass spectrum (ESI) m/z 196.0971

[(M + H)⁺calcd for C₁₀H₁₄NO₃, 196.0974].

Compound (+)-15. To a solution of (−)-B-methoxydiisopinocam-

pheylborane (0.78 g, 2.47 mmol, 3.2 equiv) in Et₂O (10 mL) under

argon atmosphere at −5 °C was added allylmagnesium bromide

solution (2.1 mL, 1.0 M in Et₂O) dropwise via syringe over 10 min.

The resulting mixture was allowed to warm to room temperature and

was stirred for 1 h. This mixture was cooled to −78 °C, and a solution

of aldehyde (+)-14 (0.150 g, 0.77 mmol, 1.0 equiv) in Et₂O (3 mL)

was added over 15 min. The reaction mixture was stirred at the same

temperature for 3 h, and then MeOH (5 mL) was added. The mixture

was allowed to warm to room temperature and treated with 0.2 N

NaOH (1 mL) and 30% H₂O₂(2 mL) (exothermic, use water bath).

The mixture was stirred for 10 h, and the organic phase was separated.

The aqueous part was extracted with diethyl ether (3 × 20 mL), and

the combined organic extracts were washed with brine, dried

(MgSO₄), and the solvent was removed under reduced pressure.

Puriﬁcation using column chromatography (SiO₂, hexanes/EtOAc,

1

1115, 1098, 1031, 968, 866, 774, 655 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 6.03 (d, J = 1.0 Hz, 1H), 4.27 (q, J = 6.5 Hz, 1H), 3.23 (s,

3H), 1.80 (d, J = 1.0 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ = 147.5, 80.9, 75.7, 56.5, 18.6, 18.0; high-

resolution mass spectrum (CI) m/z 225.9852 [(M)⁺calcd for

C₆H₁₁IO, 225.9855].

5:1) gave pure alcohol (+)-15 (0.164 g, 0.69 mmol, 90.0%). [α]_D²⁰

=

+27.3 (c 1.0, CHCl₃); IR (ﬁlm) 3407 (br), 3052, 2978, 2931, 2821,

1

1656, 1541, 1446, 1381, 1206, 1153, 1095, 973, 915, 861 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ = 7.44 (d, J = 0.6 Hz, 1H), 6.16 (dq, J =

1.4, 0.6 Hz, 1H), 5.81 (dddd, J = 17.0, 10.1, 7.1, 7.1 Hz, 1H), 5.14

(dddd, J = 17.0, 2.0, 1.4, 1.4 Hz, 1H), 5.12 (dq, J = 6.5, 0.6 Hz, 1H),

5.10 (dddd, J = 10.1, 2.0, 1.2, 1.2 Hz, 1H), 4.71−4.67 (m, 1H), 3.18 (s,

3H), 2.99 (d, J = 3.8 Hz, 1H), 2.62 (ddddd, J = 14.3, 7.1, 7.1, 1.4, 1.2

Hz, 1H), 2.53 (ddddd, J = 14.3, 7.1, 7.1, 1.4, 1.2 Hz, 1H), 1.88 (d, J =

1.4 Hz, 3H), 1.28 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

= 160.4, 150.7, 143.8, 133.9, 133.1, 118.3, 113.3, 74.7, 66.4, 56.4, 40.8,

19.1, 17.5; high-resolution mass spectrum (ESI) m/z 260.1258 [(M +

Na)⁺calcd for C₁₃H₁₉NO₃Na, 260.1263].

Compound (+)-16. To an ice-cold solution of alcohol (+)-15 (3.04

g, 12.8 mmol, 1.0 equiv) in dry toluene (60 mL) was dropwise added

n-BuLi (5.2 mL, 2.5 M in hexanes). After being stirred for 15 min,

Boc₂O (3.10 g, 14.2 mmol, 1.1 equiv) was added, and stirring was

continued for 2 h at room temperature. The reaction mixture was

quenched with saturated aqueous NH₄Cl solution, and the organic

phase was separated. The aqueous part was extracted with Et₂O (2 ×

100 mL), and the combined organic extracts were dried and

concentrated under reduced pressure. Flash chromatography of the

residue on silica (hexanes/EtOAc, 20:1) gave 3.89 g (11.53 mmol,

90.1%) of the desired product as yellow oil. [α]²_D⁰= +2.5 (c 0.85,

CHCl₃); IR (neat) 3052, 2979, 2932, 2819, 1741, 1644, 1546, 1449,

1369, 1280, 1254, 1163, 1095, 972, 919, 845, 791, 759 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ = 7.45 (d, J = 0.8 Hz, 1H), 6.18 (dq, J = 1.4, 0.6

Hz, 1H), 5.76 (dddd, J = 17.0, 10.3, 7.1, 7.1 Hz, 1H), 5.62 (ddd, J =

7.1, 6.3, 0.8 Hz, 1H), 5.23 (dq, J = 6.5, 0.6 Hz, 1H), 5.16 (dddd, J =

17.0, 2.0, 1.4, 1.4 Hz, 1H), 5.07 (dddd, J = 10.3, 2.0, 1.0, 1.0 Hz, 1H),

3.21 (s, 3H), 2.78 (ddddd, J = 14.3, 6.3, 6.3, 1.4, 1.2 Hz, 1H), 2.71

Compound (+)-13. To a solution of iodide (+)-12 (19.0 g, 84.1

mmol, 1.0 equiv) in Et₂O (70 mL) under a nitrogen atmosphere at

−78 °C was added t-BuLi (99 mL, 1.7 M in pentane, 168.0 mmol, 2.0

equiv) dropwise over 30 min. The resulting heterogeneous mixture

was stirred for 1 h at the same temperature, then ZnCl₂solution (100

mL, freshly prepared from solid ﬂame-dried ZnCl₂, 1 M in THF, 100.0

mmol, 1.19 equiv) was added dropwise, and the reaction mixture was

allowed to warm to room temperature over a 30 min period. At this

point, pentane and diethyl ether were removed from the reaction

under reduced pressure and nitrogen atmosphere. A solution of

oxazolyl chloride 8 (14.9 g, 84.1 mmol, 1.0 equiv) and Pd(PPh₃)₄(2.0

g, 1.73 mmol, 0.02 equiv) was separately prepared in THF (80 mL)

and was added dropwise. The resulting mixture was vigorously stirred

at reﬂux for 2 h, then cooled to room temperature and quenched by

the addition of a saturated aqueous NH₄Cl solution (50 mL). The

mixture was diluted with diethyl ether. The organic layer was removed,

and the aqueous layer was extracted with diethyl ether (30 mL) twice.

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

over MgSO₄, ﬁltered, and concentrated. The resulting oil was puriﬁed

by column chromatography (SiO_2,ethyl acetate/hexanes 10:90, 15:85,

20:80) to furnish ester (+)-13 (16.1 g, 67.3 mmol, 80.0%) as a

colorless oil. [α]²_D⁰= +43.9 (c 0.5, CHCl₃); IR (ﬁlm) 2980, 1743, 1722,

1

1654, 1576, 1448, 1370, 1316, 1178, 1113, 1025, 839, 770 cm⁻¹; H

NMR (500 MHz, CDCl3) δ = 8.11 (s, 1H), 6.26 (s, 1H), 5.14 (q, J =

6.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.23 (s, 3H), 1.93 (d, J = 1.0 Hz,

3H), 1.38 (t, J = 7.1 Hz, 3H), 1.32 (d, J = 6.5 Hz, 3H); ¹³C NMR (125

MHz, CDCl3) δ = 161.4, 161.0, 153.2, 142.8, 134.2, 112.7, 74.8, 61.2,

G

DOI: 10.1021/acs.joc.8b00899

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The Journal of Organic Chemistry

Article

(ddddd, J = 14.3, 7.1, 7.1, 1.4, 1.2 Hz, 1H), 1.88 (d, J = 1.4 Hz, 3H),

1.47 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

= 160.3, 152.9, 151.0 139.9, 134.8, 132.8, 118.2, 113.2, 82.3, 74.7, 71.0,

56.3, 37.6, 27.8, 19.1, 17.6; high-resolution mass spectrum (ESI) m/z

338.1956 [(M + H)⁺calcd for C₁₈H₂₈NO₅, 338.1967].

mL) was treated dropwise with n-BuLi (7.70 mL, 19.3 mmol, 2.5 M in

hexanes, 1.3 equiv) at 0 °C under a nitrogen atmosphere. The mixture

was kept at 0 °C for 15 min, warmed to room temperature, and then

stirred for 18 min before it was cooled to −78 °C. Epoxide (−)-22

(4.00 g, 19.8 mmol, 1.35 equiv) in 40 mL of diethyl ether was added to

the reaction mixture dropwise via a syringe followed by warming to

−30 °C and stirring at that temperature for 2 h. The reaction mixture

was cooled back to −78 °C, and the epoxide (−)-24 (2.85 g, 14.7

mmol, 1.0 equiv) in 25 mL of diethyl ether and 5 mL of DMPU was

added dropwise via a syringe. The reaction mixture was kept at −78 °C

for 30 min and then slowly warmed to room temperature overnight

without removing the bath. The resulting mixture was quenched with

the addition of saturated aqueous NH₄Cl (20 mL) and diluted with

diethyl ether (30 mL). The organic layer was removed, and the

aqueous layer was extracted with diethyl ether (15 mL) twice. The

combined organic layers were washed with brine, dried over MgSO₄,

ﬁltered and concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 10:90, 15:85, 20:80) to

furnish dithiane (−)-24 (8.30 g, 13.2 mmol, 89.8%) as a light yellow

oil. [α]²_D⁰= −3.8 (c 4.0, CHCl₃); IR (ﬁlm) 3466, 2954, 2928, 2856,

Compound (+)-17. Iodine monobromide (20 mL, 10.0 equiv, 1.0

M in CH₂Cl₂) was slowly added dropwise to a solution of tert-

butylcarbonate (+)-16 (0.68 g, 2.0 mmol, 1.0 equiv) in dry toluene (20

mL) at −85 °C. After 24 h, the mixture was diluted with Et₂O and

poured into a mixture of NaHCO₃/Na₂S₂O₃aqueous solutions (1:1).

After being stirred for 15 min, the organic phase was separated, and

the inorganic part was extracted with Et₂O (2 × 50 mL). The

combined organic extracts were washed with brine, dried with MgSO₄,

and concentrated. The crude material was puriﬁed using column

chromatography on silica (hexanes/EtOAc, 1:1, R_f= 0.5) to give 0.45

g (1.11 mmol, 55.3%) of iodocarbonate (+)-17. [α]²_D⁰= +28.5 (c 1.2,

CHCl₃); IR (ﬁlm) 3052, 2977, 2930, 2819, 1749, 1653, 1540, 1447,

1

1383, 1241, 1186, 1112, 971, 856, 760 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ = 7.65 (s, 1H), 6.17 (s, 1H), 5.49 (dd, J = 11.7, 3.0 Hz, 1H),

5.14 (q, J = 6.3 Hz, 1H), 4.60 (dddd, J = 11.7, 7.3, 4.0, 4.0 Hz, 1H),

3.44 (dd, J = 10.7, 4.4 Hz, 1H), 3.32 (dd, J = 10.7, 7.3 Hz, 1H), 3.21

(s, 3H), 2.75 (ddd, J = 14.5, 3.0, 3.0 Hz, 1H), 2.15 (ddd, J = 14.5, 11.7,

11.7 Hz, 1H), 1.90 (s, 3H), 1.3 (d, J = 6.3 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ = 160.9, 152.3, 147.6, 138.1, 134.7, 112.6, 77.2, 74.6,

73.0, 56.4, 32.5, 19.1, 17.6, 5.0; high-resolution mass spectrum (ESI)

m/z 408.0302 [(M + H)⁺calcd for C₁₄H₁₉INO₅, 408.0308].

Compound (+)-18. A solution of iodocarbonate (+)-17 (0.45 g, 1.1

mmol, 1.0 equiv) in dry methanol (7.5 mL) at room temperature was

treated with potassium carbonate (0.51 g, 3.7 mmol, 3.4 equiv) and

stirred for 2 h. The mixture was diluted with ether and quenched with

saturated aqueous NH₄Cl. The aqueous layer was then extracted with

Et₂O (3 × 50 mL), and the combined extracts were washed with brine,

dried with MgSO₄, and concentrated under reduced pressure. Column

chromatography (hexanes/EtOAc, 1:1, R_f= 0.35) provided the desired

epoxy alcohol (+)-18 (0.24 g, 84%). [α]²_D⁰= +45.0 (c 0.5, CHCl₃); IR

(ﬁlm) 3433 (br), 3052, 2978, 2925, 2820, 1656, 1590, 1543, 1447,

1369, 1205, 1153, 1093, 971, 855 cm⁻¹; ¹H NMR (500 MHz, CDCl₃)

δ = 7.53 (d, J = 0.8 Hz, 1H), 6.18 (dq, J = 1.6, 0.8 Hz, 1H), 5.16 (dq, J

= 6.5, 0.8 Hz, 1H), 4.95−4.88 (m, 1H), 3.19 (s, 3H), 3.1 (br s, 1H),

3.09 (dddd, J = 6.9, 4.2, 4.2, 2.8 Hz, 1H), 2.76 (dd, J = 5.0, 4.2 Hz,

1H), 2.55 (dd, J = 5.0, 2.8 Hz, 1H), 2.22 (ddd, J = 14.5, 4.6, 4.6 Hz,

1H), 1.93 (ddd, J = 14.5, 7.5, 6.9 Hz, 1H), 1.88 (d, J = 1.6, 3H), 1.31

(d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.6, 151.0,

143.7, 133.2, 113.2, 74.7, 65.7, 56.4, 49.9, 46.7, 39.0, 19.1, 17.6; high-

resolution mass spectrum (ESI) m/z 276.1216 [(M + H)⁺calcd for

C₁₃H₁₉NO₄Na, 276.1212].

Compound (+)-6. To an ice-cold solution of alcohol (+)-18 (0.24

g, 0.95 mmol, 1.0 equiv) and triethylamine (0.58 mL, 0.42 g, 4.1

mmol) in DMF (10 mL) were added TBSCl (0.58 g, 3.85 mmol, 4.1

equiv) followed by DMAP (10 mg). The resulted mixture was stirred

at room temperature overnight and then was poured into ice-cold

saturated aqueous NH₄Cl, and extracted with Et₂O (3 × 20 mL). The

combined organic extracts were washed with brine, dried with MgSO₄,

concentrated under reduced pressure, and the residue was puriﬁed

using ﬂash chromatography on silica (hexanes/EtOAc, 5:1, R_f= 0.5) to

give 0.34 g (0.93 mmol, 98%) of product (+)-6. [α]²_D⁰= +13.3 (c 1.35,

CHCl₃); IR (ﬁlm) 3052, 2953, 2929, 2888, 2857, 2820, 1654, 1592,

1541, 1472, 1447, 1362, 1255, 1206, 1153, 1097, 969, 872, 836, 778

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 7.44 (d, J = 1.0 Hz, 1H), 6.17

(dq, J = 1.4, 0.6 Hz, 1H), 5.19 (dq, J = 6.5, 0.6 Hz, 1H), 4.90 (ddd, J =

5.8, 5.8, 1.0 Hz, 1H), 3.22 (s, 3H), 3.03 (dddd, J = 6.0, 6.0, 4.0, 2.8 Hz,

1H), 2.74 (dd, J = 5.0, 4.0, 1H), 2.49 (dd, J = 5.0, 2.8 Hz, 1H), 2.10

(ddd, J = 14.1, 6.0, 6.0 Hz, 1H), 1.91 (ddd, J = 14.1, 5.8, 5.8 Hz, 1H),

1.68 (d, J = 1.4 Hz, 3H), 1.28 (d, J = 6.5 Hz, 3H), 0.90 (s, 9H), 0.09

(s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.2, 150.5,

144.9, 133.5, 113.4, 74.8, 66.9, 56.4, 49.3, 46.9, 40.5, 25.7, 19.5, 18.1,

17.6, −4.8, −5.0; high-resolution mass spectrum (ESI) m/z 368.2249

[(M + H)⁺calcd for C₁₉H₃₄NO₄Si, 368.2257].

1

1613, 1514, 1471, 1250, 1097, 1038, 836, 775, 664 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ = 7.27 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz,

2H), 4.50 (s, 2H), 4.28−4.20 (m, 2H), 3.80 (s, 3H), 3.75−3.67 (m,

2H), 3.43 (dd, J = 4.5 Hz, 9.0 Hz, 1H), 3.39 (dd, J = 6.5 Hz, 9.0 Hz,

1H), 3.15 (s, 1H), 2.97−2.91 (m, 1H), 2.89−2.75 (m, 3H), 2.31 (m,

2H), 2.10 (m, 2H), 1.98 (m, 2H), 1.92 (m, 1H), 1.76 (m, 1H), 0.91 (s,

9H), 0.89 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.07 (s, 6H); ¹³C NMR

(125 MHz, CDCl₃) δ = 159.4, 130.4, 129.5, 112.9, 74.4, 73.0, 68.0,

67.6, 59.8, 55.4, 51.6, 47.1, 43.1, 42.2, 26.7, 26.3, 26.2, 26.1, 24.9, 18.3,

18.2, −3.6, −4.0, −5.1, −5.14; high-resolution mass spectrum (ESI)

m/z 653.3168 [(M + Na)⁺calcd for C₃₁H₅₈O₅S₂Si₂Na, 653.3162].

Compound (−)-25. Commercially available Raney nickel (19.0 g

with water, grade: Raney 2800 nickel from Aldrich) as a slurry in water

was weighed into the 200 mL round-bottomed ﬂask and washed with

anhydrous ethanol (20 mL) three times under a nitrogen atmosphere.

Dithane (−)-24 (1.00 g, 1.59 mmol, 1.0 equiv) in 35 mL of ethanol

was added via syringe to the slurry mixture before hydrogen gas was

bubbled through for 20 min. The mixture was heated to 80 °C and

kept at that temperature for 2.5 h with stirring under a hydrogen

atmosphere before it was brought to room temperature. The liquid

phase then was carefully transferred using a pipet to separate the

desired product from residual ﬂammable Raney nickel and washed

with ethanol (15 mL) four times. The combined liquid was

concentrated and puriﬁed by column chromatography (SiO₂, ethyl

acetate/hexanes 10:90, 15:85, 20:80) to furnish alcohol (−)-25 (0.79

g, 1.50 mmol, 94.5%) as a colorless oil. [α]²_D⁰= −4.1 (c 5.0, CHCl₃);

IR (ﬁlm) 3466, 2953, 2929, 2857, 1613, 1514, 1463, 1388, 1361, 1302,

1251, 1093, 1039, 836, 775, 664 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ

= 7.25 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.48 (s, 2H), 3.80

(s, 3H), 3.80−3.75 (m, 2H), 3.64 (m, 2H), 3.47 (dd, J = 9.8 Hz, 2.8

Hz, 1H), 3.28 (t, J = 8.8 Hz, 1H), 2.31 (brs, 1H), 1.63 (q, J = 6.5 Hz,

2H) 1.55−1.30 (m, 6H), 0.88 (s, 9H), 0.87 (s, 9H), 0.04 (s, 9H),

0.03(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 159.4, 130.2, 129.4,

113.9, 74.4, 73.0, 70.3, 69.2, 60.0, 55.2, 40.1, 37.5, 33.4, 26.1, 26.0,

21.2, 18.3, 18.2, −4.3, −4.5, −5.2; high-resolution mass spectrum

(ESI) m/z 549.3394 [(M + Na)⁺calcd for C₂₈H₅₄O₅Si₂Na, 549.3407].

Compound (−)-26. Commercially available Raney nickel (9.0 g

with water, grade: Raney 2800 nickel from Aldrich) as a slurry in water

was weighed out into a 100 mL round-bottomed ﬂask and washed with

anhydrous ethanol (10 mL) three times under a nitrogen atmosphere.

Alcohol (−)-25 (0.50 g, 0.95 mmol, 1.0 equiv) in 25 mL of ethanol

was added via syringe to the slurry mixture before hydrogen gas was

bubbled through over 20 min. The mixture was heated to 80 °C and

kept at that temperature for 15 h with stirring under a hydrogen

atmosphere before it was allowed to attain room temperature. The

liquid phase was transferred carefully using a pipet to separate it from

residual ﬂammable Raney nickel and washed with ethanol (8 mL) four

times. The combined liquid was concentrated and puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes, 20:80, 30:70, 40:60) to

furnish diol (−)-26 (337 mg, 0.83 mmol, 87.3%) as a colorless oil.

Compound (−)-24. A solution of tert-butyl(1,3-dithian-2-yl)-

dimethylsilane (4.12 g, 17.6 mmol, 1.2 equiv) in diethyl ether (30

H

DOI: 10.1021/acs.joc.8b00899

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The Journal of Organic Chemistry

Article

[α]²_D⁰= −7.5 (c 5.0, CHCl₃); IR (ﬁlm) 3379, 2953, 2929, 2857, 1472,

high-resolution mass spectrum (ESI) m/z 259.2088 [(M + H)⁺calcd

for C₁₄H₃₁O₂Si, 259.2093].

1

1361, 1255, 1094, 938, 836, 774, 664 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ = 3.81 (m, 1H), 3.71 (m, 1H), 3.70−3.63 (m, 3H), 3.43

(dd, J = 8.0 Hz, 11.0 Hz, 1H), 1.95−1.75 (brs, 2H), 1.65 (ddd, J = 2.3

Hz, 6.5 Hz, 11 Hz, 2H), 1.58−1.42 (m, 5H), 1.42−1.35 (m, 1H), 0.89

(s, 9H), 0.88 (s, 9H), 0.04 (s, 6H), 0.04 (s, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ = 72.4, 69.3, 66.9, 60.2, 40.2, 37.5, 33.5, 26.2 (3C), 26.1

(3C), 21.3, 18.5, 18.3, −4.2, −4.4, −5.1; high-resolution mass

spectrum (ESI) m/z 429.2844 [(M + Na)⁺calcd for C₂₀H₄₆O₄Si₂Na,

429.2832].

Alternative Route for Compound (−)-26 (Synthesis via Scheme 2,

Route B). To a solution of oleﬁn (−)-28 (4.70 g, 12.62 mmol, 1.0

equiv) in 80 mL of t-BuOH and 80 mL of water was added a mixture

of (DHQ)₂PHAL (500 mg, 0.642 mmol, 5 mol %), K₂CO₄(5.23 g,

37.86 mmol, 3.0 equiv), K₃Fe(CN)₆(12.50 g, 37.86 mmol, 3.0 equiv),

and potassium osmate(VI) dehydrate (100 mg, 0.271 mmol, 2 mol %)

at 0 °C. The reaction mixture was stirred for 10 h at 0 °C before it was

diluted with ethyl acetate (200 mL). The organic layer was removed,

and the aqueous layer was extracted with ethyl acetate (50 mL) twice.

The combined organic layers were washed with brine (10 mL), dried

over MgSO₄, ﬁltered and concentrated, and the resulting oil was

puriﬁed by column chromatography (SiO₂, ethyl acetate:hexanes

20:90, 30:70) to furnish diol (−)-26 with its diastereomer (4.66 g, 11.5

mmol, 91.0%) as a colorless oil. The product exists as a mixture of

inseparable diastereomers with the same ¹H NMR spectra and slightly

diﬀerent ¹³C NMR spectra.

Compound (−)-28. To a solution of alcohol (+)-27 (3.70 g, 14.3

mmol, 1.0 equiv) in 80 mL of dichloromethane at 0 °C under a

nitrogen atmosphere were added 2,6-lutidine (3.5 mL, 30.1 mmol, 2.1

equiv) followed by TBSOTf (4.0 g, 15.15 mmol, 1.06 equiv). The

reaction mixture was stirred for 2 h at 0 °C before it was quenched by

addition of saturated aqueous NaHCO₃(20 mL). The organic layer

was removed, and the aqueous layer was extracted with dichloro-

methane (20 mL) twice. The combined organic layers were washed

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

the resulting oil was puriﬁed by column chromatography (SiO₂, ethyl

acetate:hexanes 2:98, 5:95, 10:90) to furnish oleﬁn (−)-28 (4.93 g,

13.2 mmol, 92.4%) as a colorless oil. [α]²_D⁰= −9.45 (c 3.00, CHCl₃);

IR (ﬁlm) 2956, 2928, 2858, 1472, 1256, 1094, 839, 833, 775 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ = 5.80 (m, 1H), 5.00 (d, J = 17.0 Hz, 1H),

4.94 (d, J = 10.5 Hz, 1H), 3.81 (brs, 1H), 3.66 (m, 2H), 2.04 (d, J =

6.5 Hz, 2H), 1.65 (q, J = 6.0 Hz, 2H), 1.48−1.52 (m, 4H), 0.89 (s,

18H), 0.04 (s, 12H); ¹³C NMR (125 MHz, CDCl₃) δ = 139.1, 114.6,

69.4, 60.2, 40.3, 37.1, 34.1, 26.18, 26.15, 24.7, 18.5, 18.3, −4.2, −4.4,

−5.1; high-resolution mass spectrum (ES) m/z 373.2955 [(M + H)⁺

calcd for C₂₀H₄₅O₂Si₂, 373.2958]

Compound (+)-20. A solution of aldehyde (+)-14 (2.30 g, 11.7

mmol, 1.0 equiv) in 60 mL of CH₂Cl₂was treated with 1,3-

propanedithiol (1.75 mL 17.51 mmol, 1.5 equiv) and BF₃·OEt₂(0.55

mL, 4.08 mmol, 0.35 equiv), respectively, at 0 °C under a nitrogen

atmosphere, followed by stirring at that temperature for 2 h. The

resulting mixture was quenched by the addition of a 2 M NaOH

aqueous solution (20 mL), and diluted with 30 mL of Et₂O. The

organic layer was removed, and the aqueous layer was extracted with

Et₂O (30 mL) twice. The combined organic layers were washed with

the 2 M aqueous NaOH (15 mL) three times, saturated aqueous

NaHCO₃(20 mL), and brine (20 mL), dried over MgSO₄, ﬁltered and

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 10:90, 15:85, 20:80)

to furnish dithiane (+)-14 (3.21 g, 11.2 mmol, 96.1%) as an

amorphous white solid. [α]_D²⁰= +43.7 (c 4.75, CHCl₃); IR (ﬁlm) 2977,

2931, 2900, 2819, 1654, 1542, 1446, 1422, 1368, 1273, 1204, 1149,

Compound (−)-21. To a solution of diol (−)-26 (1.57 g, 3.87

mmol, 1.0 equiv) in 40 mL of THF was added 223 mg of NaH (95 wt

%, 8.83 mmol, 2.28 equiv) at 0 °C in nitrogen atmosphere, followed by

stirring at room temperature for 20 min. The reaction mixture was

then cooled to 0 °C, and solid TrisIm (1.54 g, 4.62 mmol, 1.2 equiv)

was added in one portion. The resulting mixture was stirred for 1 h

before it was quenched with the addition of 10 mL of saturated

aqueous NH₄Cl and diluted with diethyl ether. The organic layer was

removed, and the aqueous layer was extracted with diethyl ether (15

mL) twice. The combined organic layers were washed with saturated

aqueous NaHCO₃(10 mL) and brine (10 mL), dried over MgSO₄,

ﬁltered, and concentrated. The resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 5:95, 10:90) to furnish

epoxide (−)-21 (1.50 g, 3.86 mmol, quantitative) as a colorless oil.

[α]²_D⁰= −10.3 (c 4.4, CHCl₃); IR (ﬁlm) 2954, 2929, 2857, 1472, 1388,

1

1112, 1095, 971.0, 875, 760 cm⁻¹; H NMR (500 MHz, CDCl₃) δ =

7.60 (s, 1H), 6.21 (s, 1H), 5.16 (q, J = 6.5 Hz, 1H), 5.13 (s, 1H), 3.23

(s, 3H), 3.06−2.95 (m, 4H), 2.17 (m, 1H), 2.01 (m, 1H), 1.89 (d, J =

1.5 Hz, 3H) 1.31 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

= 160.2, 151.1, 140.6, 134.4, 113.2, 74.7, 56.4, 41.3, 30.3, 25.3, 19.2,

17.6; high-resolution mass spectrum (ESI) m/z 286.0940 [(M + H)⁺

calcd for C₁₃H₂₀NO₂S₂, 286.0935].

1

1361, 1255, 1095, 1006, 938, 836, 774, 664 cm⁻¹; H NMR (500

MHz, CDCl₃) δ = 3.83 (m, 1H), 3.71 (td, J = 6 Hz, 3.5 Hz, 2H), 2.90

(m, 1H), 2.75 (t, J = 4.5 Hz, 1H), 2.46 (dd, J = 5.2 Hz, 2.8 Hz, 1H),

1.65 (ddd, J = 11.0 Hz, 6.5 Hz, 2.3 Hz, 2H), 1.58−1.42 (m, 6H), 0.89

(s, 9H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ = 69.1, 59.9, 52.3, 47.0, 40.1, 37.3, 32.8, 26.1, 26.0, 21.7,

18.4, 18.2, −4.3, −4.4, −5.2; high-resolution mass spectrum (ESI) m/z

411.2729 [(M + Na)⁺calcd for C₂₀H₄₄O₃Si₂Na, 411.2727].

Compound (+)-29. To a solution of dithiane (+)-20 (3.30 g, 11.6

mmol, 1.0 equiv) in 40 mL of Et₂O at −78 °C under a nitrogen

atmosphere was added a solution of n-BuLi (2.30 M in hexanes, 5.79

mL, 13.3 mmol, 1.15 equiv) over a 5 min period. After complete

addition, the reaction mixture was stirred for 20 min at −78 °C.

Epoxide (−)-21 (4.50 g, 11.57 mmol, 1.0 equiv) in 20 mL of Et₂O was

added to the reaction mixture dropwise at the same temperature over

5 min. The resulting mixture was gradually allowed to come to 0 °C

over 2 h before it was quenched by addition of saturated aqueous

NH₄Cl (20 mL). The organic layer was removed, and the aqueous

layer was extracted with Et₂O (30 mL) twice. The combined organic

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

and concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 15:85, 20:80, 30:70) to

furnish dithiane (+)-29 (6.01 g, 8.92 mmol, 77.0%) as a colorless oil.

[α]²_D⁰= +16.0 (c 1.7, CHCl₃); IR (ﬁlm) 2928, 2856, 1468, 1255, 1096,

836, 774 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 7.71 (s, 1H), 6.21 (s,

1H), 5.11 (q, J = 6.5 Hz, 1H), 3.89 (brs, 1H), 3.78 (m, 1H), 3.64, (dd,

J = 10.5 Hz, 6.5 Hz, 2H), 3.49 (s, 1H), 3.23 (s, 3H), 2.78−2.92 (m,

4H), 2.22−2.35 (m, 2H), 2.01 (m, 2H), 1.90 (s, 3H), 1.45 (m, 2H),

1.47−1.52 (m, 6H), 1.31 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.87 (s,

9H), 0.03 (s, 12H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.9, 152.1,

143.9, 136.5, 113.3, 75.1, 69.4, 68.5, 60.2, 56.8, 49.5, 40.2, 37.9, 37.7,

27.8, 27.6, 26.2, 26.1, 25.0, 21.4, 19.4, 18.5, 18.3, 17.9, −4.2, −4.4,

−5.09, −5.10; high-resolution mass spectrum (ESI) m/z 674.3765

Compound (+)-27. To a solution of epoxide (−)-22 (1.80 g, 8.90

mmol, 1.0 equiv) and copper(I) iodide (0.70 g, 3.67 mmol, 0.41

equiv) in 30 mL of Et₂O at −78 °C under a nitrogen atmosphere was

added a solution of but-3-en-1-ylmagnesium bromide (1 M in Et₂O,

26.7 mL, 26.7 mmol, 3.0 equiv) dropwise. After complete addition, the

temperature was increased to room temperature, and the reaction

mixture was continued to stir for 4 h before it was recooled to 0 °C.

The resulting mixture was quenched at 0 °C by addition of saturated

aqueous NH₄Cl (20 mL). The organic layer was removed, and the

aqueous layer was extracted with diethyl ether (30 mL) twice. The

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

MgSO₄, ﬁltered and concentrated, and the resulting oil was puriﬁed by

column chromatography (SiO₂, ethyl acetate:hexanes 10:90, 15:85,

20:80) to furnish alcohol (+)-27 (2.14 g, 8.28 mmol, 93.0%) as a

colorless oil. [α]²_D⁰= +14.40 (c 1.40, CHCl₃); IR (ﬁlm) 3443, 3077

2928, 2858, 1641, 1472, 1463, 1256, 1090, 1005, 910, 837, 777 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ = 5.77 (m, 1H), 4.97 (d, J = 17.0 Hz,

1H), 4.91 (d, J = 10.0 Hz, 1H), 3.86 (m, 1H), 3.78 (m, 2H), 3.44 (s,

1H), 2.04 (m, 2H), 1.61 (m, 2H), 1.48−1.60 (m, 2H), 1.39−1.48 (m,

2H), 0.87 (s, 9H), 0.05 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ =

139.0, 114.6, 72.1, 63.0, 38.5, 37.1, 33.9, 26.0, 25.0, 18.3, −5.39, −5.41;

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The Journal of Organic Chemistry

Article

[(M + H)⁺calcd for C₃₃H₆₄NO₅S₂Si₂, 674.3764]. In an earlier

condition screening, side product (+)-30 was inseparable from the

desired product (+)-29. The approximate yield shown in Scheme 7

was calculated on the basis of crude NMR spectra. Side product

(+)-31 exists as a mixture of two inseparable diastereomers with

multiple other minor side products. The structure was proposed on

the basis of the absence of C-23 proton (5.1−5.2 ppm, q) in ¹H NMR

spectra as well as high resolution mass spectra (ESI) m/z 1062.6581

[(M + H)⁺calcd for C₅₃H₁₀₈NO₈S₂Si₄, 1062.6593].

stirred for 20 min at the same temperature before it was quenched by

saturated aqueous NaHCO₃(10 mL). The organic layer was separated,

and the aqueous phase was extracted with dichloromethane (10 mL)

twice. The combined organic layers were washed with brine (10 mL),

dried over MgSO₄, ﬁltered and concentrated, and the resulting oil was

puriﬁed by column chromatography (SiO₂, ethyl acetate:hexanes 5:95,

10:90, 20:80) to furnish PMP acetal (−)-34 (585 mg, 0.83 mmol,

80.0%) as a colorless oil. [α]²_D⁰= −1.62 (c 0.77, CHCl₃); IR (ﬁlm)

2929, 2856, 1616, 1518, 1463, 1362, 1251, 1097, 1037, 835, 774 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ = 7.54 (s, 1H), 7.46 (d, J = 7.8 Hz,

2H), 6.88 (d, J = 7.8 Hz, 2H), 6.21 (s, 1H), 5.65 (s, 1H), 5.17 (q, J =

6.5 Hz, 1H), 4.92 (d, J = 11.0 Hz, 1H), 3.93 (brs, 1H), 3.81 (brs, 1H),

3.80 (s, 3H), 3.66 (d, J = 3.5 Hz, 2H), 3.23 (s, 3H), 2.00 (d, J = 12.5

Hz, 1H), 1.89 (s, 3H), 1.73 (m, 2H), 1.65 (q, J = 6.0 Hz, 2H), 1.39−

1.61 (m, 5H), 1.31 (d, J = 6.5 Hz, 3H), 0.89 (s, 18H), 0.04 (s, 12H);

¹³C NMR (125 MHz, CDCl₃) δ = 160.5, 160.1, 150.7, 142.5, 134.0,

131.4, 127.7, 113.8, 113.7, 101.1, 75.0, 73.1, 69.4, 60.2, 56.7, 55.5, 40.3,

37.6, 36.6, 36.3, 26.2, 26.1, 20.9, 19.5, 18.5, 18.3, 17.8, −4.2, −4.3,

−5.1; high-resolution mass spectrum (ESI) m/z 704.4380 [(M + H)⁺

calcd for C₃₈H₆₆NO₇Si₂, 704.4378].

Note: Similar yield (75%−77%) was achieved when the reaction

was carried out on ca. 1 mmol scale.

Compound (+)-32. To a solution of dithiane (+)-29 (2.55 g, 3.77

mmol, 1.0 equiv) in ethyl acetate (40 mL) and water (40 mL) were

added Fe(acac)₃(271 mg, 0.757 mmol, 0.2 equiv), sodium iodide (848

mg, 5.66 mmol, 1.5 equiv), and 30% hydrogen peroxide (1.3 mL

aqueous solution, 11.31 mmol, 3.0 equiv) sequentially at 0 °C under

an air atmosphere. The reaction mixture was stirred for 30 min at the

same temperature before it was quenched by the addition of saturated

aqueous Na₂S₂O₃. The organic layer was separated, and the aqueous

phase was extracted with ethyl acetate (20 mL) three times. The

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

MgSO₄, ﬁltered and concentrated, and the resulting oil was puriﬁed by

column chromatography (SiO₂, ethyl acetate:hexanes 15:85, 20:80,

30:70) to furnish ketone (+)-32 (1.65 g, 2.83 mmol, 75.0%) as a

colorless oil. [α]²_D⁰= +24.6 (c 1.4, CHCl₃); IR (ﬁlm) 3465, 2928, 2856,

Compound (+)-35. To a solution of PMP acetal (−)-34 (250 mg,

0.355 mmol, 1.0 equiv) in 10 mL of dichloromethane was added a

DIBAL-H solution (1 M in hexanes, 1.24 mL, 1.24 mmol, 3.5 equiv)

dropwise at −78 °C under a nitrogen atmosphere. The resulting

mixture was stirred for 100 min at the same temperature before it was

quenched with MeOH at −78 °C. The temperature was then allowed

to increase to 0 °C, at which point a saturated aqueous Rochelle’s salt

solution (10 mL) was added. The resulting mixture was stirred at

room temperature for 30 min before it was diluted with ethyl acetate

(20 mL). The organic layer was separated, and the aqueous phase was

extracted with ethyl acetate (10 mL) twice. The combined organic

layers were washed with brine (5 mL), dried over MgSO₄, ﬁltered and

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate: hexanes 10:90, 30:70) to furnish

1

1686, 1562, 1463, 1386, 1255, 1096, 968, 836, 774, 664 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ = 8.15 (d, J = 1.5 Hz, 1H), 6.24 (s, 1H),

5.19 (q, J = 6.5 Hz, 1H), 4.19 (brs, 1H), 3.83 (brs, 1H), 3.67 (brs,

2H), 3.25 (s, 3H), 3.13 (d, J = 17.5 Hz, 2H), 3.01 (d, J = 17.5 Hz, 9.0

Hz, 1H), 1.95 (s, 3H), 1.66 (q, J = 6.0 Hz, 2H), 1.35−1.68 (m, 6H),

1.34 (dd, J = 6.5 Hz, 1.0 Hz, 3H), 0.891 (s, 9H), 0.887 (s, 9H), 0.05 (s,

12H); ¹³C NMR (125 MHz, CDCl₃) δ = 196.1, 160.7, 154.2, 141.4,

141.2, 112.4, 75.1, 69.4, 67.9, 60.2, 56.8, 46.9, 40.2, 37.5, 37.2, 26.2,

26.1, 21.3, 19.4, 18.5, 18.3, 18.1, −4.2, −4.4, −5.1; high-resolution

mass spectrum (ESI) m/z 584.3802 [(M + H)⁺calcd for

C₃₀H₅₈NO₆Si₂, 584.3803].

acid (+)-35 (230 mg, 0.327 mmol, 92.0%) as a colorless oil. [α]_D²⁰

=

+27.72 (c 1.00, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ = 7.44 (d, J =

1.0 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.19 (s,

1H), 5.16 (q, J = 6.5 Hz, 1H), 4.84 (d, J = 9.5 Hz, 1H), 4.61 (d, J =

11.0 Hz, 1H), 4.39 (d, J = 9.0 Hz, 1H), 3.95 (s, 1H), 3.85−3.74 (m,

2H), 3.82 (s, 3H), 3.67 (m, 2H), 3.22 (s, 3H), 2.07 (dt, J = 11.0 Hz,

3.5 Hz, 1H), 1.93−1.89 (m, 1H), 1.89 (s, 3H), 1.65 (m, 4H), 1.51−

1.37 (m, 3H), 1.30 (d, J = 6.5 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H) 0.06

(s, 6H), 0.05 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.5, 159.6,

150.3, 144.9, 133.3, 130.2, 129.8, 114.2, 113.7, 79.5, 74.9, 70.6, 69.3,

68.3, 60.1, 56.6, 55.4, 41.1, 40.2, 37.9, 33.9, 26.11, 26.07, 20.3, 19.4,

18.4, 18.3 17.7, −4.2, −4.4, −5.1; high-resolution mass spectrum (ESI)

m/z 706.4501 [(M + H)⁺calcd for C₃₈H₆₈NO₇Si₂, 706.4534].

Compound (+)-33. To a solution of ketone (+)-32 (1.70 g, 2.91

mmol, 1.0 equiv) in 30 mL of THF/MeOH (4:1) was added a

solution of Et₂BOMe (1 M in THF, 6.11 mL, 6.11 mmol, 2.1 equiv)

dropwise at −78 °C under a nitrogen atmosphere. After the reaction

mixture was stirred for 15 min at the same temperature, NaBH₄(250

mg, 6.58 mmol, 2.25 equiv) was added in one portion. The resulting

mixture was stirred for 2 h before it was diluted by MeOH (20 mL).

The temperature was then allowed to increase to 0 °C followed by the

addition of saturated aqueous Rochelle’s salt solution (30 mL). The

resulting mixture was stirred at room temperature for 30 min before it

was diluted by ethyl acetate (50 mL). The organic layer was separated,

and the aqueous phase was extracted with ethyl acetate (20 mL) three

times. The combined organic layers were washed with 2 M aqueous

NaOH (20 mL) three times, saturated aqueous NH₄Cl (20 mL), and

brine (20 mL), then dried over MgSO₄, ﬁltered, and concentrated.

The resulting oil was puriﬁed by column chromatography (SiO₂, ethyl

acetate/hexanes 20:80, 30:70, 50:50) to furnish diol (+)-33 (1.62 g,

2.76 mmol, 95.0%) as a colorless oil. [α]²_D⁰= +12.8 (c 1.0, CHCl₃); IR

(ﬁlm) 3388, 2929, 2857, 1655, 1472, 1363, 1255, 1095, 836, 775 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ = 7.48 (s, 1H), 6.18 (s, 1H), 5.13 (q, J

= 6.5 Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 3.95 (brs, 1H), 3.81 (brs, 2H),

3.66 (brs, 2H), 3.21 (s, 3H), 3.13 (brs, 1H), 1.98 (d, J = 14.5 Hz, 1H),

1.88 (s, 3H), 1.86 (m, 1H), 1.64 (q, J = 6.0 Hz, 2H), 1.32−1.58 (m,

6H), 1.29 (dd, J = 6.5 Hz, 3H), 0.874 (s, 9H), 0.868 (s, 9H), 0.03 (s,

12H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.7, 151.1, 144.7, 133.1,

113.5, 75.0, 72.4, 69.4, 68.5, 60.2, 56.7, 43.0, 40.2, 38.5, 37.5, 26.2,

26.1, 21.0, 19.5, 18.5, 18.3, 17.9, −4.2, −4.4, −5.1; high-resolution

mass spectrum (ESI) m/z 586.3953 [(M + H)⁺calcd for

C₃₀H₆₀NO₆Si₂, 586.3959].

Compound (+)-36. To a solution of alcohol (+)-35 (227 mg, 0.322

mmol, 1.0 equiv) in 5 mL of THF in a 50 mL plastic container was

added 4.7 mL of the mixture of HF-pyridine complex/pyridine/THF

(1:1.5:2.5) dropwise at 0 °C. The reaction mixture was allowed to stir

at the same temperature for 45 min before it was slowly quenched by

saturated aqueous NaHCO₃. After dilution with ethyl acetate (20 mL),

the organic layer was separated, and the aqueous phase was extracted

with ethyl acetate (20 mL) twice. The combined organic layers were

washed with brine (5 mL), dried over MgSO₄, ﬁltered, and

concentrated. The resulting oil was puriﬁed by column chromatog-

raphy (SiO₂, ethyl acetate:hexanes 20:80, 30:70, 40:60) to furnish diol

(+)-36 (152 mg, 0.258 mmol, 80.0%) as a colorless oil. [α]²_D⁰= +21.11

(c 1.33, CHCl₃); IR (ﬁlm) 3407, 2929, 2856, 1613, 1514, 1250, 1095,

1

1036, 856, 775 cm⁻¹; H NMR (500 MHz, CDCl₃) δ = 7.44 (s, 1H),

7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.19 (s, 1H), 5.16

(q, J = 6.5 Hz, 1H), 4.83 (dd, J = 8.9 Hz, 2.9 Hz, 1H), 4.58 (d, J = 11.0

Hz, 1H), 4.40 (d, J = 11.0 Hz, 1H), 4.02−3.92 (m, 2H), 3.79 (s, 3H),

3.78 (m, 2H), 3.72 (m, 1H), 3.21 (s, 3H), 2.07 (dt, J = 11.0 Hz, 3.5

Hz, 1H), 1.92 (m, 1H), 1.88 (s, 3H), 1.77 (m, 1H), 1.55 (m, 2H), 1.63

(m, 4H), 1.38 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.09 (s,

3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.5, 159.6,

150.4, 144.8, 133.3, 130.2, 129.7, 114.2, 113.7, 79.0, 74.9, 71.5, 70.6,

67.9, 60.2, 56.6, 55.4, 41.0, 38.1, 37.3, 33.8, 26.0, 20.5, 19.4, 18.1, 17.7,

Compound (−)-34. To a solution of diol (+)-33 (610 mg, 1.04

mmol, 1.0 equiv) in 20 mL of dichloromethane was added CSA (20

mg, 0.086 mmol, 0.083 equiv) as one portion followed by addition of

p-methoxybenzaldehyde dimethyl acetate (304 mg, 1.67 mmol, 1.60

equiv) at 0 °C under an air atmosphere. The resulting mixture was

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Article

−4.2, −4.5; high-resolution mass spectrum (ES) m/z 592.3652 [(M +

H)⁺calcd for C₃₂H₅₄NO₇Si, 592.3670].

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

concentrated. The resulting oil was puriﬁed by column chromatog-

raphy (SiO₂, ethyl acetate/hexanes 20:80, 30:70, 50:50, 80:20) to

furnish carboxylic acid (+)-37 (1.17 g, 1.93 mmol, 93.0%) as a

colorless oil. [α]²_D⁰= +32.4 (c 1.0, CHCl₃); IR (ﬁlm) 2930, 1712, 1514,

1245, 1096, 836 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 7.43 (s, 1H),

7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.19 (s, 1H), 5.11

(q, J = 6.5 Hz, 1H), 4.83 (dd, J = 9.5 Hz, 2.9 Hz, 1H), 4.57 (d, J = 11.0

Hz, 1H), 4.39 (d, J = 11.0 Hz, 1H), 4.12 (m, 1H), 3.79 (s, 3H), 3.75

(m, 1H), 3.21 (s, 3H), 2.28 (d, J = 6.1 Hz, 2H), 2.05 (dt, J = 11.0 Hz,

3.5 Hz, 1H), 1.95 (m, 1H), 1.88 (s, 3H), 1.73 (m, 2H), 1.67 (m, 2H),

1.42 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 175.9, 160.7, 159.6, 150.8,

144.6, 133.5, 130.2, 129.8, 114.2, 113.6, 78.8, 75.0, 70.7, 69.4, 67.6,

56.6, 55.5, 42.2, 40.8, 37.7, 33.6, 26.0, 20.3, 19.5, 18.2, 17.8, −4.3,

−4.6; high-resolution mass spectrum (ESI) m/z 606.3466 [(M + H)⁺

calcd for C₃₂H₅₂NO₈Si, 606.3462].

Compound (−)-38. To a solution of diol (+)-33 (790 mg, 1.35

mmol, 1.0 equiv) in 20 mL of dichloromethane was added CSA (30

mg, 0.13 mmol, 0.096 equiv) in one portion followed by addition of p-

methoxybenzaldehyde dimethyl acetate (345 mg, 1.89 mmol, 1.4

equiv) at 0 °C under an air atmosphere. The resulting mixture was

stirred for 10 min at the same temperature before addition of TBAF

(1.0 M in THF, 10.80 mL, 10.80 mmol, 8.0 equiv) and acetic acid

(473 mg, 6.75 mmol, 5.0 equiv). The resulting mixture was allowed to

increase to room temperature and was allowed to stir for 16 h before it

was quenched with brine. The organic layer was separated, and the

aqueous phase was extracted with ethyl acetate (20 mL) twice. The

combined organic layers were dried over MgSO₄, ﬁltered and

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 5:95, 10:90, 20:80) to

furnish alcohol (−)-38 (700 mg, 1.19 mmol, 88.0%) as a colorless oil.

[α]²_D⁰= −3.4 (c 1.6, CHCl₃); IR (ﬁlm) 3435, 2929, 2856, 1615, 1518,

Alternative Route for Compound (+)-37 (Scheme 5). To a

solution of diol (+)-36 (58 mg, 0.098 mmol, 1.0 equiv) in 0.775 mL of

t-BuOH and 0.5 mL of pH 7 buﬀer solution was added a TEMPO

solution (0.025 M in CH₃CN, 1.18 mL, 0.029 mmol, 0.3 equiv) at

room temperature. The resulting mixture was stirred for 20 min at the

same temperature before the subsequent addition of NaClO₂(1 M in

water, 0.196 mL, 0.196 mmol, 2.0 equiv) and NaClO (0.025 M in

water, 4.0 mL, 0.1 mmol, 1.0 equiv). The reaction was stirred at room

temperature for 3 h before it was quenched with saturated aqueous

Na₂SO₃solution (5 mL). After dilution with ethyl acetate (10 mL),

the organic layer was separated, and the aqueous phase was extracted

with ethyl acetate (10 mL) twice. The combined organic layers were

washed with brine (5 mL), dried over MgSO₄, ﬁltered and

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate:hexanes 20:80, 30:70, 50:50,

80:20) to furnish acid (+)-37 (36 mg, 0.059 mmol, 60.0%) as a

colorless oil. (Note: The yield for this TEMPO oxidation is not always

reproducible due to competitive oxidation at the C-17 position.)

Compound (+)-5. To a solution of carboxylic acid (+)-37 (800 mg,

1.32 mmol, 1.0 equiv) in 30 mL of THF was added TBAF (1.0 M in

THF, 9.24 mL, 9.24 mmol, 7.0 equiv) dropwise followed by acetic acid

(400 mg, 6.60 mmol, 5.0 equiv) at room temperature. The resulting

mixture was stirred for 8 h before it was quenched with brine. The

organic layer was separated, and the aqueous phase was extracted with

ethyl acetate (20 mL) six times. The combined organic layers were

dried over MgSO₄, ﬁltered and concentrated, and the resulting oil was

puriﬁed by column chromatography (SiO₂, ethyl acetate/hexanes

50:50, 80:20 then ethyl acetate:acetic acid 99:1) to furnish β-hydroxy

1

1463, 1368, 1336, 1250, 1171, 1112, 1035, 835, 775 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ = 7.54 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 6.88 (d,

J = 7.8 Hz, 2H), 6.20 (s, 1H), 5.64 (s, 1H), 5.17 (q, J = 6.5 Hz, 1H),

4.92 (d, J = 11.0 Hz, 1H), 3.93 (brs, 2H), 3.81 (brs, 1H), 3.80 (s, 3H),

3.72 (brs, 1H), 3.22 (d, J = 1.0 Hz, 3H), 2.34 (brs, 1H), 2.00 (d, J =

12.8 Hz, 1H), 1.89 (s, 3H), 1.81 (m, 1H), 1.75 (m, 1H), 1.68 (m, 2H),

1.58 (m, 4H), 1.42 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H),

0.09 (s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.5,

160.1, 150.6, 142.4, 133.9, 131.2, 127.6, 113.7, 113.6, 101.1, 76.8, 74.8,

72.9, 71.6, 60.3, 56.6, 55.4, 38.0, 36.9, 36.5, 36.1, 26.0, 21.0, 19.4, 18.1,

17.7, −4.3, −4.5; high-resolution mass spectrum (ESI) m/z 590.3506

[(M + H)⁺calcd for C₃₂H₅₂NO₇Si, 590.3513].

Compound (+)-39. To a solution of alcohol (−)-38 (184 mg, 0.312

mmol, 1.0 equiv) in 2.5 mL of t-BuOH and 0.25 mL of pH 7 buﬀer

solution was added TEMPO solution (0.025 M in CH₃CN, 5 mL,

0.125 mmol, 0.4 equiv) at room temperature under an air atmosphere.

The resulting mixture was stirred for 20 min at the same temperature

before the subsequent addition of NaClO₂(1 M in water, 0.624 mL,

0.624 mmol, 2.0 equiv) and NaClO (0.025 M in water, 12.5 mL, 0.312

mmol, 1.0 equiv) solution. The reaction was stirred at room

temperature for 3 h before it was quenched by saturated aqueous

Na₂SO₃(10 mL). After dilution with ethyl acetate (20 mL), the

organic layer was separated, and the aqueous phase was extracted with

ethyl acetate (20 mL) twice. The combined organic layers were

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

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 5:95, 10:90, 20:80,

30:70) to furnish carboxylic acid (+)-39 (184 mg, 0.296 mmol, 95.0%)

as a colorless oil. [α]²_D⁰= +4.8 (c 1.0, CHCl₃); IR (ﬁlm) 2930, 1711,

acid (+)-5 (569 mg, 1.16 mmol, 87.7%) as a colorless oil. [α]_D²⁰

=

+56.2 (c 1.47, CHCl₃); IR (ﬁlm) 3421, 2934, 1719, 1612, 1514, 1443,

1

1518, 1250, 1114, 834, 776 cm⁻¹; H NMR (500 MHz, CDCl₃) δ =

1

1249, 1177, 1094, 1035, 822 cm⁻¹; H NMR (500 MHz, CDCl₃) δ =

7.55 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.23

(s, 1H), 5.64 (s, 1H), 5.15 (q, J = 6.5 Hz, 1H), 4.93 (d, J = 10.5 Hz,

1H), 4.14 (t, J = 5.4 Hz, 1H), 3.93 (brs, 1H), 3.80 (s, 3H), 3.23 (s,

3H), 2.50 (d, J = 6.1 Hz, 2H), 2.00 (d, J = 12.8 Hz, 1H), 1.89 (d, J =

1.5 Hz, 3H), 1.72 (m, 1H), 1.70 (m, 1H), 1.59 (m, 4H), 1.45 (brs,

1H), 1.30 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ = 176.4, 160.5, 160.0, 150.8, 142.3,

134.0, 131.2, 127.6, 113.7, 113.6, 101.1, 76.7, 75.0, 72.8, 69.4, 56.6,

55.4, 42.1, 37.4, 36.4, 36.0, 25.9, 20.8, 19.4, 18.1, 17.7, −4.4, −4.7;

high-resolution mass spectrum (ESI) m/z 626.3118 [(M + Na)⁺calcd

for C₃₂H₄₉NO₈SiNa, 626.3125].

Compound (+)-37. To a solution of PMP acetal (+)-39 (1.25 g,

2.07 mmol, 1.0 equiv) in 50 mL of dichloromethane was added a

DIBAL-H solution (1 M in hexanes, 9.93 mL, 9.93 mmol, 4.8 equiv)

dropwise at −78 °C under nitrogen atmosphere. The resulting mixture

was stirred for 100 min at the same temperature before it was

quenched with MeOH at −78 °C. The temperature was then allowed

to increase to 0 °C followed by the addition of saturated aqueous

Rochelle’s salt (30 mL). The resulting mixture was stirred at room

temperature for 30 min before it was diluted by ethyl acetate (50 mL).

The organic layer was separated, and the aqueous phase was extracted

with ethyl acetate (30 mL) six times. The combined organic layers

7.46 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.21

(s, 1H), 5.03 (q, J = 6.5 Hz, 1H), 4.86 (dd, J = 9.3 Hz, 2.6 Hz, 1H),

4.58 (d, J = 11.0 Hz, 1H), 4.39 (d, J = 11.0 Hz, 1H), 4.04 (brs, 1H),

3.80 (s, 3H), 3.75 (brs, 1H), 3.21 (s, 3H), 2.50 (m, 2H), 2.13 (d, J =

14.3 Hz, 1H), 1.89 (m, 1H), 1.89 (s, 3H), 1.72 (m, 1H), 1.63 (m, 1H),

1.38−1.58 (m, 4H), 1.29 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ = 176.1, 160.9, 159.5, 151.5, 144.2, 133.8, 130.2, 129.7,

114.1, 113.2, 79.1, 75.1, 70.5, 68.0, 67.4, 56.6, 55.4, 41.4, 40.7, 36.8,

33.3, 21.0, 19.5, 17.8; high-resolution mass spectrum (ESI) m/z

490.2440 [(M − H)⁻calcd for C₂₆H₃₆NO₈, 490.2441].

Compound (−)-42. To a suspended solution of diisopropylamine

(7.81 g, 77.2 mmol, 4.3 equiv) and ﬂame-dried LiCl (9.59 g, 226

mmol, 12.6 equiv) in 80 mL of THF was added a n-BuLi solution

(2.33 M in hexanes, 30.8 mL, 71.8 mmol, 4.0 equiv) dropwise over 15

min at 0 °C under a nitrogen atmosphere. The resulting mixture was

stirred for 10 min at the same temperature before it was cooled to −78

°C. To the resulting mixture was then added amide (−)-41 (8.35 g,

37.7 mmol, 2.1 equiv) in 80 mL of THF dropwise at −78 °C over 30

min. The reaction mixture was then warmed to room temperature

before the addition of iodide (−)-40 (7.87g, 18.0 mmol, 1.0 equiv) in

30 mL of THF over 20 min. The resulting mixture was stirred

overnight at room temperature before it was quenched by saturated

K

DOI: 10.1021/acs.joc.8b00899

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The Journal of Organic Chemistry

Article

aqueous NH₄Cl (30 mL) and diluted by EtOAc (200 mL). The

organic layer was separated, and the aqueous phase was extracted with

EtOAc (50 mL) twice. The combined organic layers were washed with

saturated aqueous NaHCO₃(30 mL) and brine (20 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting oil was puriﬁed by

column chromatography (SiO₂, ethyl acetate:hexanes 90:10, 80:20,

60:40) to furnish the amide with a small amount of (−)-41 derived

impurity as an amorphous solid. The mixture was moved to the next

step without further puriﬁcation. To a solution of diisopropylamine

(10.6 mL, 75.4 mmol, 4.2 equiv) in 60 mL of THF was added a n-BuLi

solution (2.33 M in hexanes, 30 mL, 70.0 mmol, 3.9 equiv) dropwise

over 10 min at 0 °C under a nitrogen atmosphere. The resulting

mixture was stirred for 15 min at the same temperature before the

addition of ammonium-borane solid (2.22 g, 71.8 mmol, 4.0 equiv) in

one portion at 0 °C. The temperature was increased to room

temperature, and the reaction mixture was stirred for 30 min before it

was recooled to 0 °C. A solution of the amide [made from 18.0 mmol

of iodide (−)-40] in 90 mL of THF was then added dropwise, and the

temperature was allowed to increase to room temperature after the

addition. The resulting mixture was stirred at the same temperature for

2 h before it was slowly quenched with 100 mL of 3 N HCl aqueous

solution over 20 min at 0 °C. The resulting mixture was stirred at 0 °C

for a further 30 min before the dilution with Et₂O (200 mL). The

organic layer was separated, and the aqueous phase was extracted with

Et₂O (50 mL) twice. The combined organic layers were washed with

saturated aqueous NaHCO₃(50 mL) and brine (30 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting oil was puriﬁed by

column chromatography (SiO₂, ethyl acetate/hexanes 90:10, 80:20,

60:40) to furnish alcohol (−)-42 (6.60 g, 17.81 mmol, 99.2% over two

steps) as a colorless oil. [α]_D²⁰= −15.7 (c 3.2, CHCl₃); IR (ﬁlm) 3342,

2929, 2857, 1417, 1427, 1389, 1112, 1036, 824, 740, 701, 613.3 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ = 7.72−7.65 (m, 4H), 7.45−7.35 (m,

6H), 3.52−3.47 (m, 3H), 3.40 (m, 1H), 1.79 (m, 1H), 1.70 (m, 1H),

1.22 (ddd, J = 13.5 Hz, 9.0 Hz, 4.0 Hz, 1H), 1.14 (ddd, J = 13.5 Hz,

9.0 Hz, 4.5 Hz, 1.0H), 1.08 (s, 9H), 0.90 (d, J = 7.0 Hz, 3H), 0.89 (d, J

= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 135.8, 134.3, 134.2,

129.7, 127.8, 68.8, 69.2, 37.0, 33.31, 33.26, 27.1, 19.5, 16.8, 16.6; high-

resolution mass spectrum (ESI) m/z 371.2390 [(M + H)⁺calcd for

C₂₃H₃₅O₂Si, 371.2406].

Compound (−)-43. To a solution of alcohol (−)-42 (6.50 g, 17.5

mmol, 1.0 equiv) in 70 mL of dichloromethane were added

diisopropylethylamine (9.15 mL, 52.5 mmol, 3.0 equiv) and DMSO

(6.21 mL, 87.5 mmol, 5.0 equiv) followed by portionwise addition of

SO₃·pyridine (8.36 g, 52.5 mmol, 3.0 equiv) at 0 °C under an air

atmosphere. The resulting mixture was stirred for 1 h at the same

temperature before it was quenched by 2 M NaHSO₄aqueous solution

(30 mL). The organic layer was separated, and the aqueous phase was

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

washed with saturated aqueous NaHCO₃(50 mL) and brine (30 mL),

dried over MgSO₄, ﬁltered and concentrated, and the resulting

aldehyde was moved to the next step as a colorless oil without further

puriﬁcation. To a solution of (−)-B-methoxydiisopinocampheylborane

(9.41 g, 29.8 mmol, 1.7 equiv) in 50 mL of Et₂O was added

allylmagnesium bromide solution (1.0 M in Et₂O, 21.87 mL, 21.87

mmol, 1.25 equiv) dropwise over 20 min at −78 °C under a nitrogen

atmosphere. The resulting mixture was stirred for 1 h at the same

temperature. The temperature was allowed to increase to room

temperature, and the reaction mixture was stirred for 1 h before it was

recooled to −78 °C. A solution of corresponding aldehyde of alcohol

(−)-42 (17.5 mmol, 1.0 equiv, crude) in 35 mL of Et₂O was then

added dropwise to the reaction mixture at −78 °C over 20 min. The

resulting mixture was stirred at the same temperature for 1 h before

the temperature was allowed to increase to 0 °C. A pH 7 buﬀer

solution (30 mL) was then added followed by the careful addition of

30% aqueous H₂O₂(7 mL) over 20 min at 0 °C. The resulting mixture

was then stirred at room temperature overnight before it was diluted

by Et₂O. The organic layer was separated, and the aqueous phase was

extracted with Et₂O (60 mL) twice. The combined organic layers were

washed with saturated aqueous NaS₂O₃(30 mL) and brine (30 mL),

dried over MgSO₄, ﬁltered and concentrated, and the resulting oil was

puriﬁed by column chromatography (SiO₂, ethyl acetate/hexanes

10:90, 20:80, 30:70) to furnish oleﬁn (−)-43 (6.53 g, 15.93 mmol,

91.0% over two steps) as a colorless oil. [α]²_D⁰= −13.4 (c 2.86,

CHCl₃); IR (ﬁlm) 3325, 3071, 2959, 2930, 2858, 1709, 1640, 1589,

1

1471, 1428, 1389, 1112, 914, 824, 702 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ = 7.68−7.62 (m, 4H), 7.41−7.31 (m, 6H), 5.81 (dddd, J =

17.5 Hz, 9.7 Hz. 7.2 Hz, 6.5 Hz, 1H), 5.18−5.08 (m, 2H), 3.53−3.48

(m, 3H), 2.31−2.25 (m, 1H), 2.15 (m, 1H), 1.76 (brs, 1H), 1.62 (brs,

1H), 1.35−1.25 (m, 1H), 1.21−1.11 (m, 1H), 1.07 (s, 9H), 0.91 (d, J

= 6.8 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ = 135.9, 135.7, 134.29, 134.27, 129.7, 127.8, 118.0, 74.7, 69.8, 39.2,

36.8, 35.3, 33.4, 27.1, 19.5, 16.7, 14.1; high-resolution mass spectrum

(ESI) m/z 411.2717 [(M + H)⁺calcd for C₂₆H₃₉O₂Si, 411.2719].

Compound (−)-44. To a solution of oleﬁn (−)-43 (1.03 g, 2.51

mmol, 1.0 equiv) in 20 mL of dichloromethane at 0 °C under a

nitrogen atmosphere was added 2,6-lutidine (0.7 mL, 6.02 mmol, 2.4

equiv), followed by the dropwise addition of TIPSOTf (0.80 g, 3.01

mmol, 1.2 equiv). The reaction mixture was stirred for 2 h at 0 °C

before it was quenched by addition of saturated aqueous NaHCO₃(10

mL). The organic layer was removed, and the aqueous layer was

extracted with dichloromethane (10 mL) twice. The combined organic

layers were washed with brine (5 mL), dried over MgSO₄, ﬁltered and

concentrated, and the resulting oil was puriﬁed by column

chromatography (SiO₂, ethyl acetate/hexanes 2:98, 5:95, 10:90) to

furnish oleﬁn (−)-44 (1.29 g, 2.28 mmol, 90.7%) as a colorless oil.

[α]²_D⁰= −10.0 (c 2.22, CHCl₃); IR (ﬁlm) 3072, 2942, 2865, 1463,

1

1428, 1388, 1112, 882, 824, 784, 701, 678, 613 cm⁻¹; H NMR (500

MHz, CDCl₃) δ = 7.71−7.68 (m, 4H), 7.43−7.36 (m, 6H), 5.78

(dddd, J = 17.2 Hz, 9.8 Hz, 7.2 Hz, 6.5 Hz, 1H), 5.04 (dd, J = 17.2 Hz,

1.8 Hz, 1H), 4.99 (dt, J = 9.8 Hz, 1.0 Hz, 1H), 3.79 (m,1H), 3.49 (m,

2H), 2.28 (m, 2H), 1.80−1.68 (m, 2H), 1.41 (td, J = 9.8 Hz, 4.0 Hz,

1H), 1.37 (td, J = 9.8 Hz, 4.0 Hz, 1H), 1.12−1.02 (m, 30H), 0.89 (d, J

= 6.8 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ = 136.1 135.87, 135.86, 134.39, 134.37, 129.7, 127.8, 116.6, 76.7,

70.0, 39.3, 36.4, 34.9, 33.5, 27.1, 19.5, 18.6, 18.5, 16.6, 13.9, 13.2; high-

resolution mass spectrum (ESI) m/z 589.3871 [(M + Na)⁺calcd for

C₃₅H₅₈O₂Si₂Na, 589.3873].

Compound (−)-4. To a solution of oleﬁn (−)-44 (570 mg, 1.01

mmol, 1.0 equiv) in 35 mL of acetone/tert-butanol/water (3:3:1) was

added NMO (357 mg, 3.0 mmol, 3.0 equiv) as one portion followed

by potassium osmate(VI) dihydrate (30 mg, 0.08 mmol, 0.08 equiv) at

0 °C. The resulting mixture was stirred overnight at room temperature

before it was quenched with 10 g of solid Na₂S₂O₃. The resulting

heterogeneous mixture was stirred for a further 30 min before it was

diluted by ethyl acetate (20 mL). The organic layer was separated, and

the aqueous phase was extracted with ethyl acetate (30 mL) three

times. The combined organic layers were washed with saturated

aqueous NH₄Cl (10 mL) and brine (5 mL), dried over MgSO₄,

ﬁltered, and concentrated. The resulting diol was moved to the next

step as a black oil without further puriﬁcation. To a solution of the

corresponding diol of (−)-44 (1.01 mmol, crude) in 25 mL of

acetone/water (4:1) was added NaIO₄(750 mg, 3.50 mmol, 3.50

equiv) as one portion at room temperature under air atmosphere. The

resulting mixture was stirred at the same temperature for 3 h before it

was diluted with ethyl acetate (30 mL). The organic layer was

separated, and the aqueous phase was extracted with ethyl acetate (20

mL). The combined organic layers were washed with brine (10 mL),

dried over MgSO₄, ﬁltered and concentrated, and the resulting oil was

puriﬁed by column chromatography (SiO₂, ethyl acetate/hexanes 2:98,

5:95, 10:90) to furnish aldehyde (−)-4 (436 mg, 0.75 mmol, 75.0%

over two steps) as a colorless oil. [α]²_D⁰= −21.7 (c 1.75, CHCl₃); IR

(ﬁlm) 2943, 2865, 1727, 1463, 1427, 1389, 1112, 882, 824, 740, 702,

667 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ = 9.87 (t, J = 2.2 Hz, 1H),

7.71−7.68 (m, 4H), 7.46−7.39 (m, 6H), 4.34 (m, 1H), 3.51 (d, J = 6.0

Hz, 2H), 2.54 (m, 2H), 1.82 (m, 1H), 1.73 (m, 1H), 1.39 (td, J = 13.0

Hz, 2.5 Hz, 1H), 1.27 (m, 1H), 1.09 (m, 30H), 0.91 (d, J = 6.8 Hz,

3H), 0.85 (d, J = 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ =

202.4, 135.8, 134.17, 134.15, 129.7, 127.3, 72.6, 70.0, 47.7, 36.8, 34.4,

33.3, 27.0, 19.4, 18.4, 18.3, 16.1, 15.2, 12.9; high-resolution mass (ESI)

m/z 591.3664 [(M + Na)⁺calcd for C₃₄H₅₆O₃Si₂Na, 591.3666].

L

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The Journal of Organic Chemistry

Article

Compound (−)-45. To a solution of β-hydroxy acid (+)-5 (58.0

mg, 0.118 mmol, 1.0 equiv) in 0.9 mL of THF was added 0.6 mL of

HMDS as one portion at room temperature under a nitrogen

atmosphere. The resulting mixture was stirred for 22 h at 40−45 °C

before the HMDS/THF was removed under high vacuum (pressure

<5 Torr). The mixture was then azeotropically puriﬁed with toluene to

remove the residual amount of HMDS, applying high vacuum with no

access of air followed by stirring overnight at 40−45 °C under the

same high vacuum conditions. The resulting tris-silylated ester was

dissolved in 2 mL of dichloromethane before the addition of aldehyde

(−)-4 (80.0 mg, 0.138 mmol, 1.17 equiv) solution in 2 mL of

dichloromethane at −78 °C under nitrogen atmosphere. TMSOTf

(50.0 mg, 0.225 mmol, 1.90 equiv of a newly opened bottle purchased

from Sigma-Aldrich) was then added to the reaction mixture at −78

°C. The resulting mixture was stirred for 1 h at −78 °C under a

nitrogen atmosphere before allowing access to air via insertion of a

needle (1.2 mm diameter) at −78 °C for 10 min to introduce a small

amount of moisture (H₂O). The reaction mixture was then stirred at

−78 °C under a nitrogen atmosphere for 50 min before it was slowly

diluted with 5 mL of dichloromethane at the same temperature. The

resulting mixture was then quenched with 100 mg of 2,6-lutidine and

attached to the high vacuum to partially remove solvent at 5−10 °C.

The resulting solution (1 mL) was puriﬁed by column chromatog-

raphy (SiO₂, ethyl acetate/hexanes, 10:90, 20:80) to furnish dioxanone

(−)-45 (125 mg, 0.112 mmol, 95.1%) as a colorless oil. [α]²_D⁰= −3.3

(c 1.15, CHCl₃); IR (ﬁlm) 2930, 2864, 1752, 1513, 1463, 1428, 1388,

1250, 1112, 883, 824, 740, 702 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ =

7.81−7.79 (m, 4H), 7.30 (d, J = 8.6 Hz, 2H), 7.27−7.24 (m, 7H), 6.85

(d, J = 8.6 Hz, 2H), 6.16 (s, 1H), 5.58 (q, J = 6.5 Hz, 1H), 5.29 (q, J =

6.8 Hz, 1H), 5.08 (t, J = 6.4 Hz, 1H), 4.53 (d, J = 11.3 Hz, 1H), 4.42

(d, J = 11.3 Hz, 1H), 4.13 (m, 1H), 3.67 (m, 1H), 3.63−3.53 (m, 2H),

3.34 (s, 3H), 3.30−3.25 (m, 1H), 3.12 (s, 3H), 2.40−2.33 (m, 1H),

2.20−2.10 (m, 2H), 2.06−1.96 (m, 2H), 1.87−1.81 (m, 1H), 1.74 (d, J

= 1.1 Hz, 3H), 1.48−1.25 (m, 6H), 1.39 (d, J = 6.5 Hz, 3H), 1.19 (s,

9H), 1.17−1.13 (m, 21H), 1.12−1.05 (m, 3H), 1.01 (d, J = 6.7 Hz,

3H), 0.92−0.89 (s, 1H), 0.83 (d, J = 6.7 Hz, 3H), 0.14 (s, 9H); ¹³C

NMR (125 MHz, C₆D₆) δ = 166.7, 161.3, 160.4, 152.3, 146.9, 136.7,

135.0, 134.3, 132.3, 130.6, 130.1, 129.2, 114.7, 113.9, 102.0, 76.0, 75.7,

75.1, 73.7, 71.4, 70.9, 66.9, 56.9, 55.4, 43.3, 40.1, 37.1, 36.9, 36.6,

35.22, 35.18, 34.3, 27.8, 21.4, 20.2, 20.0, 19.21, 19.15, 18.2, 16.9, 15.4,

13.0, 0.9; high-resolution mass (ESI) m/z 1114.6652 [(M + H)⁺calcd

for C₆₃H₁₀₀NO₁₀Si_3,1114.6655]. Note: Employing similar reaction

conditions (HMDS, newly purchased/opened bottle of TMSOTf, −78

°C), without introduction of air, gave the desired product in very low

yield (<5%), with most of the starting materials, aldehyde (−)-4 and a

mixture of silylated (+)-5 (mono-, bis-, or tris-) being recovered.

Interestingly, the yield of the union reaction signiﬁcantly increased (ca.

40−80%) through utilizing TMSOTf from frequently used bottles.

This observation suggested that a trace amount of TfOH derived from

TMSOTf facilitated the union. We therefore added a catalytic amount

of either TfOH or H₂O to our reaction mixture at −78 °C.

Unfortunately, the yield of desired product was unsatisfactory (5−

25%); moreover, no starting material could be recovered. The NMR

analysis of multiple major side products suggested that, although the

dioxanone moiety had been generated, an undesired loss of the TMS

group or both the TMS and the PMB groups had also occurred. The

derived alcohol or diol then underwent further reactions with aldehyde

(−)-4 to form multiple complex side products. This result conﬁrmed

that addition of TfOH was necessary, but the substrates were sensitive

under the acidic conditions utilizing a measurable amount of TfOH or

H₂O. Surprisingly, however, slow introduction of moisture (H₂O) via

simple exposure of the −78 °C reaction mixture to room temperature

air via the insertion of a needle (1.2 mm diameter) for 5−10 min

proved successful, and remarkably led to the desired product (−)-45 in

excellent yield (95%) as a single diastereomer, with no side products

observed! The possibilities of the involvement of other components of

the introduced wet air, N₂and O₂gas, had been excluded through

attempts of the union reaction in either dry N₂or dry O₂atmosphere

(yield <5%).

Compound (−)-46. To a solution of dioxanone (−)-45 (200 mg,

0.180 mmol, 1.0 equiv) in 2.3 mL of THF in a glass microwave vial

(2−5 mL) were added 0.08 mL of 2,6-lutidine followed by 2.4 mL of

Petasis reagent (0.25 M in THF/toluene, freshly prepared, 0.60 mmol,

3.35 equiv) at room temperature under an air atmosphere. The

resulting mixture was sealed and stirred for 3 h at 100 °C in microwave

at the “high” level of absorption setting before it was cooled (three

levels of absorption in Biotage microwave reactor: medium, high, very

high). The resulting mixture was diluted with 20 mL of hexanes and

stirred for 10 min before it was ﬁltered and concentrated. The

resulting oil was puriﬁed by column chromatography (SiO₂, ethyl

acetate/hexanes, 5:95, 10:90) to furnish enol acetal (−)-46 (174 mg,

0.157 mmol, 87.2%) as a colorless oil. [α]²_D⁰= −0.9 (c 1.43, CHCl₃);

IR (ﬁlm) 2930, 2864, 1512, 1462, 1428, 1388, 1249, 1112, 883, 738,

1

702, 666 cm⁻¹; H NMR (500 MHz, C₆D₆) δ = 7.81−7.77 (m, 4H),

7.31 (d, J = 8.6 Hz, 2H), 7.26−7.22 (m, 7H), 6.83 (d, J = 8.6 Hz, 2H),

6.15 (s, 1H), 5.59 (q, J = 6.5 Hz, 1H), 5.08 (q, J = 5.4 Hz, 1H), 4.93 (t,

J = 5.9 Hz, 1H), 4.64 (s, 1H), 4.53−4.43 (m, 2H), 4.24 (brs, 1H), 4.10

(s, 1H), 3.72−3.67 (m, 1H), 3.61−3.53 (m, 2H), 3.48−3.44 (m, 1H),

3.31 (s, 3H), 3.12 (s, 3H), 2.40−2.33 (m, 1H), 2.17−2.06 (m, 3H),

1.91−1.85 (m, 2H), 1.74 (s, 3H), 1.64−1.46 (m, 6H), 1.39 (d, J = 6.5

Hz, 3H), 1.21−1.12 (m, 33H), 1.01 (d, J = 6.9 Hz, 3H), 0.98−0.94

(m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.14 (s, 9H); ¹³C NMR (125 MHz,

C₆D₆) δ = 161.2, 160.3, 158.0, 152.1, 146.9, 136.7, 135.0, 134.2, 132.4,

130.5, 130.0, 129.1, 114.6, 113.9, 101.7, 93.6, 77.3, 76.2, 75.7, 74.0,

71.3, 70.8, 66.9, 56.8, 55.3, 43.3, 40.2, 37.1, 36.8, 35.87, 35.83, 35.3,

34.3, 27.8, 21.6, 20.2, 20.0, 19.24, 19.19, 18.2, 17.1, 15.2, 14.0, 0.9;

high-resolution mass (ESI) m/z 1112.6841 [(M + H)⁺calcd for

C₆₄H₁₀₂NO₉Si₃, 1112.6862].

Compound (−)-47. To a solution of methyltriphenylphosphonium

bromide (475 mg, 1.33 mmol) in 8 mL of THF was added 2 mL of

KOt-Bu solution (1.0 M solution in THF, 2.0 mmol) dropwise at 0 °C

under a nitrogen atmosphere. The resulting mixture was stirred for 30

min at the same temperature to give the ylide solution (0.133 M in

THF, 10 mL). To a solution of enol acetal (−)-46 (70 mg, 0.0629

mmol, 1.0 equiv) in 7 mL of THF was added 0.31 mL of

dimethylaluminum chloride solution (1.0 M in hexanes, newly opened,

0.31 mmol, 4.9 equiv) over 3 s at −78 °C under a nitrogen

atmosphere. The resulting mixture was stirred for 30 s at −78 °C

before the addition of freshly prepared ylide solution (0.133 M in

THF, 4.2 mL, 0.559 mmol, 8.9 equiv) at the same temperature. The

resulting mixture was stirred for a further 10 min at −78 °C before it

was quenched by 10 mL of saturated aqueous NH₄Cl solution. The

resulting mixture was diluted with 20 mL of ethyl acetate. The organic

layer was separated, and the aqueous phase was extracted with ethyl

acetate (10 mL) twice. The combined organic layers were washed with

brine (5 mL), dried over MgSO₄, ﬁltered and concentrated, and the

resulting oil was puriﬁed by column chromatography (SiO₂, ethyl

acetate/hexanes 2:98, 5:95, 10:90) to furnish methylene tetrahy-

dropyran (−)-47 (59 mg, 0.0531 mmol, 84.4%) as a colorless oil. [α]_D²⁰

= −4.1 (c 0.83, CHCl₃); IR (ﬁlm) 2930, 2864, 1589, 1513, 1462, 1428,

1

1388, 1249, 1112, 883, 740, 702 cm⁻¹; H NMR (500 MHz, C₆D₆) δ

= 7.83−7.80 (m, 4H), 7.35 (d, J = 8.5 Hz, 2H), 7.28−7.23 (m, 7H),

6.86 (d, J = 8.5 Hz, 2H), 6.16 (s, 1H), 5.63 (q, J = 6.5 Hz, 1H), 5.14 (t,

J = 6.2 Hz, 1H), 4.76 (d, J = 4.3 Hz, 2H), 4.53 (d, J = 5.9 Hz, 2H),

4.28−4.25 (m, 1H), 3.80−3.73 (m, 1H), 3.66−3.56 (m, 3H), 3.32 (s,

3H), 3.32−3.29 (m, 1H), 3.13 (s, 3H), 2.44−2.37 (m, 1H), 2.25−2.19

(m, 1H), 2.14 (d, J = 13.1 Hz, 2H), 2.01 (d, J = 11.7 Hz, 1H), 1.92 (t, J

= 11.7 Hz, 2H), 1.82−1.70 (m, 3H), 1.75 (d, J = 1.2 Hz, 3H), 1.72−

1.62 (m, 2H), 1.60−1.53 (m, 2H), 1.44 (d, J = 6.3 Hz, 3H), 1.25−1.12

(m, 34H), 1.03 (d, J = 6.6 Hz, 3H), 0.95−0.91 (m, 1H), 0.91 (d, J =

7.3 Hz, 3H), 0.17 (s, 9H); ¹³C NMR (125 MHz, C₆D₆) δ = 160.6,

159.7, 151.5, 146.5, 145.6, 136.1, 134.6, 133.7, 132.0, 130.0, 129.5,

128.6, 114.0, 113.4, 108.4, 78.6, 75.8, 75.5, 75.2, 74.5, 70.8, 70.6, 66.4,

56.3, 54.8, 42.9, 42.2, 41.3, 40.4, 37.3 36.8, 35.0, 34.1, 33.8, 27.2, 21.8,

19.6, 19.5, 18.8, 18.7, 17.7, 16.3, 15.5, 13.6, 0.4; high-resolution mass

(ESI) m/z 1110.7103 [(M + H)⁺calcd for C₆₅H₁₀₄NO₈Si₃,

1110.7070].

Compound (+)-48. To a solution of methylene tetrahydropyran

(−)-47 (47.0 mg, 0.0424 mmol, 1.0 equiv) in 16.5 mL of THF/H₂O

M

DOI: 10.1021/acs.joc.8b00899

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(45:1) were added 18-crown-6 (550 mg, 2.08 mmol, 49.0 equiv)

followed by KOH (420 mg, 7.49 mmol, 177 equiv) at room

temperature. The resulting mixture was stirred for 3 h at the same

temperature before it was quenched by the addition of saturated

aqueous NH₄Cl solution (10 mL). The resulting mixture was diluted

with 20 mL of ethyl acetate. The organic layer was separated, and the

aqueous phase was extracted with ethyl acetate (10 mL) twice. The

combined organic layers were washed with brine (5 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting oil was puriﬁed by

column chromatography (SiO₂, ethyl acetate/hexanes 30:70, 40:60,

50:50) to furnish diol (+)-48 (28.4 mg, 0.0355 mmol, 83.7%) as a

colorless oil. [α]²_D⁰= +3.1 (c 1.5, CHCl₃); IR (ﬁlm) 2932, 2864, 1727,

nitrogen atmosphere. The resulting mixture was stirred for a further 12

h at the same temperature before it was cooled to room temperature.

The resulting mixture was ﬁltered and concentrated, and puriﬁed by

column chromatography (SiO₂, ethyl acetate:hexanes 5:95, 10:90,

20:80) to give the crude macrolide, which was then puriﬁed by PTLC

(SiO₂, ethyl acetate:hexanes 10:90) to furnish macrolide (+)-49 (20.8

mg, 0.0261 mmol, 88.5%) as a colorless oil. [α]²_D⁰= +10.3 (c 0.33,

CHCl₃); IR (ﬁlm) 2927, 2856, 1750, 1653, 1613, 1577, 1548, 1513,

1

1464, 1378, 1248, 1160, 1097, 883, 820, 666 cm⁻¹; H NMR (500

MHz, CDCl₃) δ = 7.44 (s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.89 (d, J =

8.6 Hz, 2H), 6.20 (s, 1H), 5.96 (dd, J = 12.6 Hz, 2.6 Hz, 1H), 5.20 (q,

J = 6.5 Hz, 1H), 4.70 (s, 2H), 4.64 (d, J = 10.9 Hz, 1H), 4.43 (d, J =

10.9 Hz, 1H), 4.12 (dd, J = 11.1 Hz, 4.1 Hz, 1H), 3.81 (s, 3H), 3.42 (t,

J = 10.0 Hz, 1H), 3.30 (t, J = 11.1 Hz, 1H), 3.21 (s, 3H), 3.10 (t, J =

9.2 Hz, 1H), 2.73 (td, J = 13.3 Hz, 3.5 Hz, 1H), 2.69−2.63 (m, 1H),

2.13−2.03 (m, 3H), 1.99−1.93 (m, 1H), 1.91 (d, J = 1.3 Hz, 3H),

1.89−1.85 (m, 1H), 1.83−1.70 (m, 4H), 1.66−1.58 (m, 4H), 1.50−

1.55 (m, 1H), 1.48−1.35 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H), 1.30−1.25

(m, 2H), 1.14 (d, J = 6.8 Hz, 3H) 1.12−1.05 (m, 18H), 0.95−0.90 (m,

1H), 0.85 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ =

175.0, 160.7, 159.5, 151.4, 145.0, 141.3, 134.0, 130.9, 129.7, 114.1,

113.4, 108.7, 76.1, 75.9, 75.0, 74.5, 71.8, 71.3, 65.0, 56.7, 55.5, 42.5,

41.8, 41.5, 39.2, 38.6, 37.6, 35.2, 34.5, 31.6, 20.8, 19.4, 18.6, 18.5, 18.1,

17.9, 14.3, 13.4; high-resolution mass (ESI) m/z 796.5194 [(M + H)⁺

calcd for C₄₆H₇₄NO₈Si, 796.5184].

1

1514, 1463, 1249, 1092 cm⁻¹; H NMR (500 MHz, CDCl₃) δ = 7.44

(s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.18 (s,

1H), 5.12 (q, J = 6.5 Hz, 1H), 4.83 (d, J = 8.7 Hz, 1H), 4.68 (s, 2H),

4.60 (d, J = 10.9 Hz, 1H), 4.39 (d, J = 10.9 Hz, 1H), 3.98 (brs, 1H),

3.79 (s, 3H), 3.79−3.77 (brs, 1H), 3.52−3.47 (m, 1H), 3.42−3.39 (m,

1H), 3.34 (t, J = 10.1 Hz, 1H), 3.20 (s, 3H), 3.20−3.17 (m, 1H), 2.18

(d, J = 12.6 Hz, 1H), 2.15−2.03 (m, 2H), 1.99−1.87 (m, 3H), 1.87 (s,

3H), 1.80−1.73 (brs, 1H), 1.70−1.59 (m, 4H), 1.59−1.50 (m, 2H),

1.49−1.40 (m, 3H), 1.32−1.25 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.20

(m, 1H), 1.11−0.99 (m, 21H), 0.87 (d, J = 6.5 Hz, 3H), 0.80 (d, J =

6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 160.6, 159.6, 150.4,

145.2, 144.8, 133.4, 130.2, 129.8, 114.2, 113.8, 108.4, 79.3, 78.3, 75.6,

75.0, 74.1, 70.5, 69.4, 68.3, 56.6, 55.5, 41.9, 41.0, 40.3, 36.9, 36.2, 34.3,

33.7, 33.4, 20.9, 19.5, 18.6, 18.51, 18.48, 17.8, 16.2, 15.0, 13.3; high-

resolution mass (ESI) m/z 800.5486 [(M + H)⁺calcd for

C₄₆H₇₈NO₈Si, 800.5497].

Compound (−)-50. δ-Lactone (−)-50 was isolated as a side

product of TIPS removal reaction of macrolide (+)-49. [α]²_D⁰= −3.5 (c

0.7, CHCl₃); IR (ﬁlm) 2923, 2852, 1738, 1553, 1514, 1463, 1379,

1

Compound (+)-3. To a solution of diol (+)-48 (15.8 mg, 0.0199

mmol, 1.0 equiv) in 0.5 mL of t-BuOH and 0.2 mL of pH 7 buﬀer

solution was added TEMPO solution (0.025 M in CH₃CN, 0.88 mL,

0.022 mmol, 1.1 equiv) at room temperature under an air atmosphere.

The resulting mixture was stirred for 20 min at the same temperature

before the subsequent addition of NaClO₂(1 M in water, 0.068 mL,

0.0677 mmol, 3.4 equiv) and NaClO (0.025 M in water, 1.44 mL,

0.036 mmol, 1.8 equiv) solution. The reaction was stirred at room

temperature for 3 h before it was quenched by saturated aqueous

Na₂S₂O₃solution (3 mL); after dilution with ethyl acetate (5 mL), the

organic layer was separated, and the aqueous phase was extracted with

ethyl acetate (5 mL) twice. The combined organic layers were washed

with brine (2 mL), dried over MgSO₄, ﬁltered and concentrated, and

the resulting oil was puriﬁed by column chromatography (SiO₂, ethyl

acetate/hexanes 20:80, 30:70, 50:50, 80:20) to furnish acid (+)-3 (12.1

mg, 0.0149 mmol, 74.7%) as a colorless oil. [α]²_D⁰= +3.1 (c 0.3,

CHCl₃); IR (ﬁlm) 2926, 2865, 1735, 1707, 1514, 1463, 1381, 1248,

1249, 1174, 1099, 1036, 804 cm⁻¹; H NMR (500 MHz, CDCl₃) δ =

7.45 (s, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.18

(s, 1H), 5.13 (q, J = 6.5 Hz, 1H), 4.83 (d, J = 9.0 Hz, 1H), 4.71 (s,

2H), 4.62 (d, J = 5.5 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 4.41 (d, J =

10.9 Hz, 1H), 3.98 (s, 1H), 3.80 (s, 4H), 3.57 (t, J = 10.4 Hz, 1H),

3.30−3.24 (m, 1H), 3.21 (s, 3H), 2.63−2.57 (m, 1H), 2.22−2.18 (m,

2H), 2.07 (d, J = 14.3 Hz, 1H), 2.06−1.98 (m, 1H), 1.98−1.82 (m,

3H), 1.90 (s, 3H), 1.75−1.52 (m, 5H), 1.51−1.42 (m, 4H), 1.32 (d, J

= 6.4 Hz, 3H), 1.26 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ = 174.8, 160.6, 159.6, 150.5, 144.9, 144.3,

133.4, 130.2, 129.8, 114.2, 113.8, 109.1, 80.3, 79.2, 78.2, 75.0, 74.2,

70.5, 68.2, 56.7, 55.5, 41.5, 41.02, 40.98, 40.0, 36.7, 36.0, 33.5, 31.5,

30.6, 20.7, 19.5, 18.1, 17.8, 11.9; high-resolution mass (ESI) m/z

640.3859 [(M + H)⁺calcd for C₃₇H₅₄NO₈, 640.3849].

Compound (+)-51. To a solution of TIPS ether (+)-49 (9.0 mg,

0.0113 mmol, 1.0 equiv) in 3.5 mL of THF in a plastic container was

added pyridine (3.9 mL) followed by HF/pyridine complex (1.0 mL)

at room temperature in an air atmosphere. The resulting mixture was

stirred for 48 h at 45 °C before it was quenched slowly with saturated

aqueous NaHCO₃(12.0 mL) at room temperature. The resulting

mixture was diluted with ethyl acetate (20 mL). The organic layer was

separated, and the aqueous phase was extracted with ethyl acetate (8

mL) twice. The combined organic layers were washed with brine (5

mL), dried over MgSO₄, ﬁltered and concentrated, and the resulting

mixture was puriﬁed by column chromatography (SiO₂, ethyl acetate/

hexanes, 30:70, 40:60, 50:50) to furnish alcohol (+)-51 (5.1 mg,

0.0080 mmol, 70.5%) as a colorless oil. [α]²_D⁰= +4.9 (c 0.42, CHCl₃);

IR (ﬁlm) 2917.8, 2849.3, 1708.1, 1552.4, 1513.4, 1463.2, 1378.4,

1

883, 821, 666 cm⁻¹; H NMR (500 MHz, CDCl₃) δ = 7.46 (s, 1H),

7.27 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.03

(q, J = 6.5 Hz, 1H), 4.89 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 6.0 Hz, 2H),

4.61 (d, J = 11.2 Hz, 1H), 4.40 (d, J = 11.2 Hz, 1H), 3.98 (m, 1H),

3.80 (s, 3H), 3.80−3.77 (brs, 1H), 3.27−3.20 (m, 1H), 3.21 (s, 3H),

3.20−3.13 (m, 1H), 2.48 (m, 1H), 2.21−2.10 (m, 3H), 2.01−1.97 (m,

1H), 1.89 (s, 3H), 1.89−1.87 (m, 1H), 1.78−1.65 (m, 5H), 1.61−1.50

(m, 5H), 1.48−1.35 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H), 1.30−1.25 (m,

1H), 1.20−1.14 (m, 4H) 1.11−1.03 (m, 19H), 1.02−0.93 (m, 1H),

0.87 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 180.4,

160.9, 159.5, 151.1, 145.0, 144.5, 133.7, 130.1, 129.7, 114.1, 113.4,

108.4, 79.7, 78.6, 75.9, 75.0, 73.3, 70.5, 68.0, 56.6, 55.4, 42.0, 41.2,

41.0, 40.8, 37.9, 36.8, 36.6, 36.3, 33.7, 21.6, 19.5, 18.5, 18.4, 18.0, 17.8,

14.6, 13.3; high-resolution mass (ESI) m/z 814.5298 [(M + H)⁺calcd

for C₄₆H₇₆NO₉Si, 814.5289].

Compound (+)-49. To a solution of carboxylic acid (+)-3 (24 mg,

0.030 mmol, 1.0 equiv) in 0.75 mL of THF were added Hunig’s base

(0.06 mL) followed by 2,4,6-trichlorobenzoyl chloride (54 mg, 0.22

mmol, 7.5 equiv) at room temperature under a nitrogen atmosphere.

The resulting mixture was stirred for 3 h at the same temperature

before it was diluted by toluene (3 mL). This resulting activated

macrolide precursor solution was stored at room temperature for

further use. To a solution of DMAP (120 mg, 0.98 mmol, 33 equiv) in

30 mL of toluene was slowly added the activated macrolide precursor

solution using a syringe pump over 5 h at reﬂux temperature under a

1

1149.9, 1096.8, 807.1, 720.3 cm⁻¹; H NMR (500 MHz, CDCl₃) δ =

7.49 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.20

(s, 1H), 5.84 (dd, J = 12.6 Hz, 2.6 Hz, 1H), 5.16 (q, J = 6.5 Hz, 1H),

4.68 (s, 2H), 4.60 (d, J = 10.9 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 3.80

(s, 4H), 3.47 (t, J = 10.4 Hz, 1H), 3.30 (q, J = 10.4 Hz, 2H), 3.23 (s,

3H), 2.75 (td, J = 12.6 Hz, 3.2 Hz, 1H), 2.70−2.64 (m, 1H), 2.13 (d, J

= 13.5 Hz, 2H), 2.04−1.95 (m, 2H), 1.90 (s, 3H), 1.86−1.76 (m, 3H),

1.76−1.60 (m, 5H), 1.48−1.33 (m, 4H), 1.30 (d, J = 6.4 Hz, 3H), 1.18

(d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ = 175.9, 160.6, 159.4, 151.2, 145.0, 140.6, 134.7, 130.7,

129.7, 114.0, 113.4, 108.5, 76.1, 75.7, 75.03, 74.95, 71.0, 68.9, 65.8,

56.7, 55.4, 41.9, 41.7, 41.5, 38.0, 37.0, 36.5, 35.4, 33.8, 31.6, 21.1, 19.4,

17.8, 16.7, 13.1; high-resolution mass (ESI) m/z 640.3849 [(M + H)⁺

calcd for C₃₇H₅₄NO₈, 640.3849].

N

DOI: 10.1021/acs.joc.8b00899

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The Journal of Organic Chemistry

Article

Compound (−)-52. To a solution of PMB ether (−)-50 (4.0 mg,

0.0063 mmol, 1.0 equiv) in 1.5 mL of dichloromethane was added a

mixture of TFA/H₂O (0.4 mL, TFA:H₂O 1:1) dropwise at room

temperature. The resulting mixture was stirred for 1 h at the same

temperature before it was quenched with saturated aqueous NaHCO₃

(5.0 mL) at room temperature. The resulting mixture was diluted with

ethyl acetate (10 mL). The organic layer was separated, and the

aqueous phase was extracted with ethyl acetate (5 mL) twice. The

combined organic layers were washed with brine (5 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting mixture was

puriﬁed by column chromatography (SiO₂, ethyl acetate:hexanes,

40:60, 50:50, 70:30) to furnish δ-lactone (−)-52 (2.2 mg, 0.00419

mmol, 67.0%) as a colorless oil. [α]²_D⁰= −12.58 (c 0.20, CHCl₃); IR

(ﬁlm) 2920, 1727, 1649, 1551, 1449, 1379, 1323, 1204, 1097 cm⁻¹; ¹H

NMR (500 MHz, CD₃OD) δ = 7.69 (s, 1H), 6.23 (s, 1H), 5.23 (q, J =

6.4 Hz, 1H), 4.82 (m, 1H), 4.73 (d, J = 1.5 Hz, 2H), 4.68 (ddd, J = 9.5,

2.5, 2.5 Hz, 1H), 3.68 (m, 1H), 3.46 (t, J = 10.5 Hz, 1H), 3.24 (m,

1H), 3.21 (s, 3H), 2.64 (m, 1H), 2.24 (s, 1H), 2.22 (s, 1H), 2.10−2.00

(m, 2H), 1.95−1.85 (m, 4H), 1.89 (s, 3H), 1.78−1.72 (m, 2H), 1.65

(m, 1H), 1.60 (m, 1H), 1.52−1.42 (m, 5H), 1.28 (d, J = 6.5 Hz, 3H),

1.24 (d, J = 7.3 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H); ¹³C NMR (125

MHz, CD₃OD) δ = 177.0, 161.5, 151.7, 145.7, 145.6, 135.3, 114.1,

108.8, 81.8, 79.4, 75.9, 75.5, 70.5, 66.2, 56.5, 44.1, 42.0, 41.6, 40.2,

38.3, 37.0, 36.2, 32.3, 31.4, 22.3, 19.3, 17.9, 17.3, 11.8; high-resolution

mass (ES) m/z 520.3254 [(M + H)⁺calcd for C₂₉H₄₆NO₇, 520.3274].

Compound (−)-53. To a solution of alcohol (+)-51 (3.5 mg,

0.0055 mmol, 1.0 equiv) in 0.2 mL of acetonitrile were added 1H-

tetrazole solution (0.45 M in acetonitrile, 0.195 mL, 0.088 mmol, 16.0

equiv) followed by i-Pr₂NP(OFm)₂solution (57.5 mg in 0.2 mL of

dichloromethane, 0.110 mmol, 20.0 equiv) at room temperature in an

argon atmosphere. The resulting mixture was stirred for 50 min at the

same temperature before it was cooled to 0 °C. 0.2 mL of H₂O₂

solution (50% in water) was added to the reaction mixture at 0 °C,

allowing the resulting mixture to be stirred at the same temperature for

30 min. The resulting mixture was quenched by saturated aqueous

NaHCO₃(3.0 mL) at room temperature. The resulting mixture was

diluted by ethyl acetate (5 mL). The organic layer was separated, and

the aqueous phase was extracted with ethyl acetate (3 mL) twice. The

combined organic layers were washed with brine (5 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting mixture was

puriﬁed by column chromatography (SiO₂, ethyl acetate:hexanes,

40:60, 50:50, 60:40) to furnish the phosphorus ester together with

inseparable phosphate impurity as a colorless oil. The mixture was

moved to the next step without further puriﬁcation. To a solution of

this phosphoric ester [made from 0.0055 mmol of alcohol (+)-51] in

CH₂Cl₂/pH 7 aqueous buﬀer solution (4.4 mL, 10:1) was added DDQ

(8.0 mg) in one portion at room temperature. The resulting mixture

was stirred for 30 min at the same temperature before it was diluted

with diethyl ether (10 mL). The organic layer was separated, and the

aqueous phase was extracted with diethyl ether (2 mL) twice. The

combined organic layers were washed with brine (1 mL), dried over

MgSO₄, ﬁltered and concentrated, and the resulting mixture was

puriﬁed by column chromatography (SiO₂, ethyl acetate:hexanes,

50:50, 60:40, 80:20) to furnish alcohol (−)-53 (3.2 mg, 0.00334

mmol, 61.0% over two steps) as a colorless oil. [α]²_D⁰= −4.00 (c 0.6,

CHCl₃); IR (ﬁlm) 2925, 2853, 1729, 1555, 1451, 1381, 1252, 1076,

113.2, 108.9, 78.81, 78.75, 75.1, 75.0, 74.6, 69.55, 69.48, 69.43, 69.21,

69.17, 64.9, 56.7, 48.23, 48.21, 48.18, 48.14, 42.0, 41.5, 41.4, 39.0, 38.4,

38.2, 35.2, 33.8, 33.7, 33.1, 20.9, 19.4, 17.9, 17.8, 14.3; ³¹P NMR (202

MHz, CDCl₃) δ = −1.53; high-resolution mass (ESI) m/z 956.4521

[(M + H)⁺calcd for C₅₇H₆₇NO₁₀P, 956.4503].

Dipotassium Phosphate Form of Enigmazole A (−)-54. To a

solution of phosphoric ester (−)-53 (1 mg, 0.001 mmol, 1.0 equiv) in

0.33 mL of MeOH/H₂O (10:1) was added 2.9 mg of K₂CO₃at room

temperature. The resulting mixture was stirred for 6 h at the same

temperature, at which time C18 TLC indicated the completion of the

reaction. The mixture was diluted with H₂O (0.7 mL) before it was

extracted with pentane (0.5 mL) three times. The resulting mixture

was puriﬁed by C18 silica column chromatography (0.4 g of 40−75

μm, 70 Å, C18 silica gel, purchased from Sorbent Technology, was

packed into a Fisherbrand 9-in. Pasteur pipet, 100% H₂O, then 2:3

H₂O/MeOH) to give 0.3 mg of enigmazole A (−)-54 (dipotassium

phosphate form). [α]²_D⁰= −0.8 (c 0.03, MeOH). Dipotassium

1

phosphate (−)-54 displayed the same H NMR spectrum as did the

disodium phosphate (−)-55 [see the NMR data for (−)-55].

Free Acid Form of Enigmazole A (−)-1. To a solution of

phosphorus ester (−)-53 (2.0 mg, 0.0021 mmol, 1.0 equiv) in 0.4 mL

of MeOH/H₂O (2:1) was added 6 mg of Na₂CO₃at room

temperature. The resulting mixture was stirred for 24 h at the same

temperature before the addition of CD₃COOD (15 mg). The resulting

mixture was then stirred at the same temperature for 10 min before it

was extracted with pentane (0.5 mL) for three times. The solvent and

CD₃COOD were removed under high vacuum from the mixture to

furnish enigmazole A (−)-1 together with CD₃COONa. Further

puriﬁcation was achieved by RP HPLC (Vydac 5 μm C18, 250 × 10

mm, 5% MeCN/95% H₂O with 0.1% TFA to 40% MeCN/60% H₂O

with 0.1% TFA linear gradient over 15 min, then 40% MeCN/60%

H₂O with 0.1% TFA for 15 min, 10 mL/min, λ = 261 nm) to give

enigmazole A free acid form (−)-1 (1.4 mg, 0.0020 mmol, 95.0%) as a

colorless oil. [α]²_D⁰= −1.7 (c 0.2, MeOH); UV (MeCN/H₂O, 0.5%

1

TFA) λ_max261 nm; H NMR (500 MHz, CD₃OD) δ = 7.70 (s, 1H),

6.21 (s, 1H), 5.97 (dd, J = 12.8, 2.2 Hz, 1H), 5.24 (q, J = 6.5 Hz, 1H),

4.72 (s, 2H), 4.58 (m, 1H), 3.58 (td, J = 10.1 Hz, 3.0 Hz, 1H), 3.20 (s,

3H), 3.14 (m, 1H), 2.87 (m, 1H), 2.51 (td, J = 13.7 Hz, 3.8 Hz, 1H),

2.20−2.13 (m, 2H), 2.01−1.94 (m, 3H), 1.89 (d, J = 1.2 Hz, 3H),

1.86−1.83 (m, 1H), 1.78−1.70 (m, 4H), 1.69−1.60 (m, 2H), 1.48 (q, J

= 12.4 Hz, 1H), 1.44−1.37 (m, 1H), 1.37−1.30 (m, 1H), 1.26 (d, J =

6.6 Hz, 3H), 1.11 (d, J = 6.7 Hz, 3H), 1.05−1.01 (m, 1H), 0.98 (d, J =

5.9 Hz, 3H). Note: H11 was overlapped by CD₃OD. ¹³C NMR (125

MHz, CD₃OD) δ = 176.2, 161.9, 152.8, 146.2, 142.2, 136.0, 114.0,

109.0, 77.8 (d, J = 5.8 Hz), 76.9, 76.2, 75.9, 69.8, 65.9, 56.8, 43.0, 42.6,

42.4, 40.1, 39.6, 39.2, 36,1, 34.6 (d, J = 5.2 Hz), 33.6, 21.9, 19.5, 18.1,

17.7, 15.6.

Monosodium Phosphate Form of Enigmazole A (−)-56. To the

neat phosphoric acid (−)-1 (1.4 mg) in a 3 mm glass NMR tube was

added 0.2 mL of saturated NaHCO₃/CD₃OD solution to furnish

monophosphate (−)-56 in CD₃OD solution. [α]²_D⁰= −2.1 (c 0.2,

MeOH); IR (ﬁlm) 3411 (br) 2934, 2851, 1681, 1538, 1438, 1382,

1

1208, 1139, 1080, 967, 909, 726, 653 cm⁻¹; H NMR (500 MHz,

CD₃OD) δ = 7.68 (s, 1H), 6.21 (s, 1H), 5.95 (dd, J = 12.8, 2.5 Hz,

1H), 5.24 (q, J = 6.5 Hz, 1H), 4.70 (d, J = 1.5 Hz, 1H), 4.69 (d, J = 1.5

Hz, 1H), 4.42 (m, 1H), 3.62 (td, J = 10.1 Hz, 2.9 Hz, 1H), 3.20 (s,

3H), 3.12 (dd, J = 10.2 Hz, 8.9 Hz, 1H), 2.98 (m, 1H), 2.50 (td, J =

13.4 Hz, 3.9 Hz, 1H), 2.21 (d, J = 12.8 Hz, 1H), 2.13 (d, J = 12.8 Hz,

1H), 2.10 (m, 1H), 1.97 (t, J = 12.2, 1H), 1.89 (s, 3H), 1.88−1.83 (m,

3H), 1.80−1.72 (m, 3H), 1.66−1.60 (m, 2H), 1.54 (q, J = 12.4 Hz,

1H), 1.39 (t, J = 11.3 Hz, 1H), 1.37 (t, J = 11.1 Hz, 1H), 1.26 (d, J =

6.4 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.02 (td, J = 12.0 Hz, 2.6 Hz,

1H), 0.97 (d, J = 6.6 Hz, 3H). Note: H11 was overlapped by CD₃OD.

¹³C NMR (125 MHz, CD₃OD) δ = 176.5, 161.9, 152.7, 146.6, 142.4,

136.0, 113.9, 108.6, 77.6, 76.2, 75.7, 75.2 (d, J = 6.4 Hz), 69.8, 65.7,

56.8, 43.0, 42.6, 42.5, 40.1, 39.6, 39.3, 36,2, 34.7 (d, J = 6.6 Hz), 33.6,

21.8, 19.4, 18.3, 17.7, 15.0; ³¹P (202 MHz, CD₃OD) δ = 1.45; high-

resolution mass (ESI) m/z 598.2759 [(M − H)⁻calcd for

C₂₉H₄₅NO₁₀P, 598.2781].

1

1012, 741 cm⁻¹; H NMR (500 MHz, CDCl₃) δ = 7.76−7.68 (m,

4H), 7.56−7.49 (m, 3H), 7.46 (d, J = 7.5 Hz, 1H), 7.41−7.31 (m,

4H), 7.39 (s, 1H), 7.30−7.20 (m, 4H), 6.16 (s, 1H), 5.98 (dd, J = 11.8,

3.1 Hz, 1H), 5.18 (q, J = 6.5 Hz, 1H), 4.72 (d, J = 3.1 Hz, 2H), 4.60

(m, 1H), 4.30−4.23 (m, 2H), 4.23−4.15 (m, 2H), 4.15−4.10 (m, 2H),

3.63 (brt, J = 9.2 Hz, 1H), 3.30 (t, J = 10.7 Hz, 1H), 3.22 (s, 1H), 3.07

(t, J = 9.1 Hz, 1H), 2.71 (m, 1H), 2.49 (m, 1H), 2.10 (d, J = 13.5 Hz,

1H), 2.03 (d, J = 13.5 Hz, 1H), 1.94−1.82 (m, 2H), 1.89 (s, 3H), 1.75

(dd, J = 13.5, 4.4 Hz, 2H), 1.72−1.60 (m, 4H), 1.86−1.76 (m, 3H),

1.47−1.39 (m, 2H), 1.39−1.30 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.09

(m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ = 174.4, 160.7, 151.6, 144.6, 143.38, 143.35,

143.32, 143.29, 141.5, 141.2, 133.9, 128.13, 128.11, 128.09, 127.38,

127.36, 127.31, 125.4, 125.3, 125.24, 125.22, 120.32, 120.27, 120.25,

O

DOI: 10.1021/acs.joc.8b00899

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The Journal of Organic Chemistry

Article

Disodium Phosphate Form of Enigmazole A (−)-55. To a solution

of enigmazole A (monophosphate form) (−)-56 (1.4 mg) in 0.2 mL of

saturated NaHCO₃CD₃OD solution in a 3 mm glass NMR tube was

added 0.02 mL of 1 M NaOH CD₃OD solution to furnish enigmazole

(4) For the ﬁrst example, see: Smith, A. B., III; Verhoest, P. R.;

Minbiole, K. P.; Schelhaas, M. Total Synthesis of (+)-Phorboxazole A

Exploiting the Petasis−Ferrier Rearrangement. J. Am. Chem. Soc. 2001,

123, 10942−10953.

(5) Smith, A. B.; Fox, R. J.; Razler, T. M. Evolution of the Petasis-

Ferrier Union/rearrangement Tactic: Construction of Architecturally

Complex Natural Products Possessing the Ubiquitous cis-2,6-

Substituted Tetrahydropyran Structural Element. Acc. Chem. Res.

2008, 41, 675−687.

A (disodium phosphate form) (−)-55 in CD₃OD solution. [α]_D²⁰

=

−1.8 (c 0.2, MeOH); ¹H NMR (500 MHz, CD₃OD) δ = 7.68 (s, 1H),

6.21 (s, 1H), 5.93 (dd, J = 13.1, 2.9 Hz, 1H), 5.23 (q, J = 6.5 Hz, 1H),

4.67 (s, 2H), 4.31 (m, 1H), 3.64 (td, J = 10.8 Hz, 2.8 Hz, 1H), 3.20 (s,

3H), 3.14 (m, 1H), 3.09 (m, 1H), 2.50 (td, J = 12.3 Hz, 3.1 Hz, 1H),

2.25 (m, 1H), 2.14−2.09 (m, 1H), 2.06−1.95 (m, 2H), 1.88 (d, J = 1.2

Hz, 3H), 1.87−1.78 (m, 2H), 1.78−1.70 (m, 2H), 1.78−1.67 (m, 2H),

1.63−1.51 (m, 2H), 1.48 (q, J = 12.4 Hz, 1H), 1.40−1.47 (m, 2H),

1.26 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.06−0.99 (m, 1H),

0.97 (d, J = 6.7 Hz, 3H). Note: H11 was overlapped by CD₃OD. ¹³C

NMR (125 MHz, CD₃OD) δ = 177.4, 161.9, 152.6, 147.0, 142.5,

135.9, 114.0, 108.3, 78.0, 76.3, 75.7, 73.6, 69.8, 65.7, 56.8, 43.2, 42.7,

42.6, 40.3, 39.8, 39.5, 36,3, 34.9 (d, J = 6.8 Hz), 33.7, 21.8, 19.5, 18.6,

17.7, 15.4. Note: Na₂CO₃peak is shown in 161.5.

(6) (a) Smith, A. B., III; Boldi, A. M. Multicomponent Linchpin

Couplings of Silyl Dithianes via Solvent-Controlled Brook Rearrange-

ment. J. Am. Chem. Soc. 1997, 119, 6925−6926. (b) Smith, A. B., III;

Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.; Moser, W.

H. Multicomponent Linchpin Couplings. Reaction of Dithiane Anions

with Terminal Epoxides, Epichlorohydrin, and Vinyl Epoxides:

Efficient, Rapid, and Stereocontrolled Assembly of Advanced Frag-

ments for Complex Molecule Synthesis. J. Am. Chem. Soc. 2003, 125,

14435−14445. (c) Smith, A. B., III; Xian, M. Anion Relay Chemistry:

An Effective Tactic for Diversity Oriented Synthesis. J. Am. Chem. Soc.

2006, 128, 66−67. (d) Nguyen, M. H.; Imanishi, M.; Kurogi, T.;

Smith, A. B., III Total Synthesis of (−)-Mandelalide A Exploiting

Anion Relay Chemistry (ARC): Identification of a Type II ARC/

CuCN Cross-Coupling Protocol. J. Am. Chem. Soc. 2016, 138, 3675−

3678.

(7) (a) Oku, N.; Gustafson, K. R.; Fuller, R. W.; Wilson, J. A. Book of

abstracts of “Symposium on the chemistry of natural products, Kyoto,

Japan, September 15th, 2006; p 73. (b) Oku, N.; Takada, K.; Fuller, R.

W.; Wilson, J. A.; Peach, M. L.; Pannell, L. K.; McMahon, J. B.;

Gustafson, K. R. Isolation, Structural Elucidation, and Absolute

Stereochemistry of Enigmazole A, a Cytotoxic Phosphomacrolide

from the Papua New Guinea Marine Sponge Cinachyrella enigmatica.

J. Am. Chem. Soc. 2010, 132, 10278−10285. (c) Orbin, A. M. Studies

Directed toward the Total Synthesis of (−)-Enigmazole B. Ph.D.

Dissertation, University of Pennsylvania, 2012.

ASSOCIATED CONTENT

* Supporting Information

■

S

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.8b00899.

Spectroscopic and analytical data for all new compounds

(PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: smithab@sas.upenn.edu.

■

ORCID

William A. Maio: 0000-0001-8561-2273

Amos B. Smith III: 0000-0002-1712-8567

Notes

(8) (a) Oku, N.; Takada, K.; Fuller, R. W.; Wilson, J. A.; Peach, M.

L.; Pannell, L. K.; McMahon, J. B.; Gustafson, K. R. Isolation,

Structural Elucidation, and Absolute Stereochemistry of Enigmazole A,

a Cytotoxic Phosphomacrolide from the Papua New Guinea Marine

Sponge Cinachyrella enigmatica. J. Am. Chem. Soc. 2010, 132, 10278−

10285. (b) Skepper, C. K.; Quach, T.; Molinski, T. F. Total Synthesis

of Enigmazole A from Cinachyrella enigmatica. Bidirectional Bond

Constructions with an Ambident 2,4-Disubstituted Oxazole Synthon.

J. Am. Chem. Soc. 2010, 132, 10286−10292.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Financial support was provided by the National Institutes of

Health (National Cancer Institute) through CA-19033. We also

thank the late Dr. George Furst and Drs. Jun Gu and Rakesh

Kohli at the University of Pennsylvania for assistance in

obtaining high-resolution NMR and mass spectral data,

respectively.

(9) Ai, Y.; Kozytska, M. V.; Zou, Y.; Khartulyari, A. S.; Smith, A. B.,

III Total Synthesis of (−)-Enigmazole A. J. Am. Chem. Soc. 2015, 137,

15426−15429.

(10) Ahlers, A.; de Haro, T.; Gabor, B.; Furstner, A. Angew. Chem.,

̈

Int. Ed. 2016, 55, 1406−1411.

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Q

DOI: 10.1021/acs.joc.8b00899

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Total Synthesis of the Marine Phosphomacrolide, (-)-Enigmazole A, Exploiting Multicomponent Type i Anion Relay Chemistry (ARC) in Conjunction with a Late-Stage Petasis-Ferrier Union/Rearrangement

DOI: 10.1021/acs.joc.8b00899

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